Review article: Asia-Pacific consensus recommendations on endoscopic tissue acquisition for biliary strictures.

BACKGROUND: Pre-operative tissue diagnosis for suspected malignant biliary strictures remains challenging. AIM: To develop evidence-based consensus statements on endoscopic tissue acquisition for biliary strictures. METHODS: The initial draft of statements was prepared following a systematic literature review. A committee of 20 experts from Asia-Pacific region then reviewed, discussed, and modified the statements. Two rounds of independent voting were conducted to reach a final version. Consensus was considered to be achieved when 80% or more of voting members voted "agree completely" or "agree with some reservation." RESULTS: Eleven statements achieved consensus. The choice of tissue sampling modalities for biliary strictures depends on the clinical setting, the location of lesion, and availability of expertise. Detailed radiological and endoscopic evaluation is useful to guide the selection of appropriate tissue acquisition technique. Standard intraductal biliary brushing and/or forceps biopsy is the first option when endoscopic biliary drainage is required with an overall (range) sensitivity and specificity of 45% (26%-72%) and 99% (98%-100%), and 48% (15%-100%) and 99% (97%-100%), respectively, in diagnosing malignant biliary strictures. Probe-based confocal laser endomicroscopy and fluorescence in situ hybridisation using 4 fluorescent-labelled probes targeting chromosomes 3, 7, 17 and 9p21 locus may be added to improve the diagnostic yield. Cholangioscopy-guided biopsy and EUS-guided tissue acquisition can be considered after prior negative conventional tissue sampling with an overall (range) sensitivity and specificity of 60% (38%-88%) and 98% (83%-100%), and 80% (46%-100%) and 97% (92%-100%), respectively, in diagnosing malignant biliary strictures. CONCLUSION: These consensus statements provide evidence-based recommendations for endoscopic tissue acquisition of biliary strictures.

The effects of administration of the Lactobacillus gasseri strain CP2305 on quality of life, clinical symptoms and changes in gene expression in patients with irritable bowel syndrome.

AIMS: To clarify the effects of Lactobacillus gasseri CP2305 (CP2305) on quality of life and clinical symptoms and its functional mechanisms in patients with irritable bowel syndrome (IBS). METHODS AND RESULTS: After the patients were administered CP2305 daily for 4 weeks, the IBS-severity index score was significantly improved compared with that of the placebo group, and this improvement was accompanied by a reduction in health-related worry and changes in intestinal microbiota. The gene expression profiling of the peripheral blood leucocytes showed that CP2305 treatment significantly up-regulated genes related to eukaryotic initiation factor 2 (EIF2) signalling. Eighty-two genes were down-regulated in IBS patients compared with healthy controls. The expression of 23 of these genes exhibited a CP2305-dependent increase associated with an improvement in IBS severity. The majority of the restored genes were related to EIF2 signalling. CONCLUSIONS: CP2305 administration is a potential candidate therapeutic option for patients with IBS. SIGNIFICANCE AND IMPACT OF THE STUDY: Although probiotics have been proposed to benefit IBS patients, objective clinical evidence and elucidation of the functional mechanism remain insufficient. Our study demonstrated that CP2305 administration beneficially influences IBS patients in both subjective and objective evaluations, and gene expression profiling provided insights into the functional mechanism.

Endoscopic treatment for early stage colorectal tumors: the comparison between EMR with small incision, simplified ESD, and ESD using the standard flush knife and the ball tipped flush knife.

BACKGROUND: Early stage colorectal tumors can be removed by endoscopic mucosal resection but larger such tumors (20 mm) may require piecemeal resection. Endoscopic submucosal dissection (ESD) using newly developed endo-knives has enabled en-block resection of lesions regardless of size and shape. However ESD for colorectal tumor is technically difficult. Therefore, we performed EMR with small incision (EMR with SI) for more reliable EMR, ESD with snaring (simplified ESD) and ESD using the standard Flush knife and the novel ball tipped Flush knife (Flush knife BT) for easier and safer colorectal ESD. AIMS: The aims of our study were (1) to compare the treatment results of the following 3 methods (EMR with SI/si-mplified ESD/ESD) for early stage colorectal tumors, and (2) to assess the performance of Flush knife BT in colorectal ESD. METHODS: We treated 24/44/468 colorectal tumors and examined the clinicopathological features and treatment results such as tumor size, resected specimen size, procedure time, en-bloc resection rate, complication rate. We also treated 58 colorectal tumors (LST-NG:20, LST-G:36, other:2) using standard Flush knife and 80 colorectal tumors (LST-NG:32, LSTG:44, other:2) using Flush knife BT, and examined the clinicopathological features and treatment results mentioned above and also the procedure speed. RESULT: The median tumor size (mm) (EMR with SI/ simplified EMR/ESD) was 20/17/30 (EMR with SI vs. simplified ESD: p = n.s, simplified ESD vs. ESD: p < 0.0001). The median resected specimen size (mm) was 22.5/26/41 (EMR with SI vs. simplified ESD: p = 0.0018, simplified ESD vs. ESD: p < 0.0001). The procedure time (min.) was 19/27/60 (EMR with SI vs. simplified ESD: p = n.s, simplified ESD vs. ESD: p < 0.0001) The en-block resection rate (%) was 83.3/90.9 /98.9. The complication rate (post-operative bleeding rate/perforation p=n.s). In the treatment results of ESD for LSTs by knives, there was no difference between standard Flush knife and Flush knife BT for clinicopathological features and treatment results (procedure time, complication rate and en bloc R0 resection rate). However, procedure speed (cm2/min.) of LST-G was significantly faster in the Flush knife BT than in standard Flush knife. (standard Flush knife: 0.21 vs. Flush knife BT: 0.27, p = 0.034). CONCLUSION: EMR with small incision (EMR with SI) and ESD with snaring (simplified ESD) are good option to fill the gap between EMR and ESD in the colorectum, and also considered to become the nice training for the introduction of ESD. Flush knife BT appears to improve procedure speed compared with standard Flush knife, especially for LST-G in colo-rectal ESD.

Retrospective study of technical aspects and complications of endoscopic submucosal dissection for laterally spreading tumors of the colorectum.

BACKGROUND AND STUDY AIMS: Laterally spreading tumors - non granular type (LST-NG) are more often considered candidates for endoscopic submucosal dissection (ESD) than laterally spreading tumors - granular type (LST-G), because of their higher potential for submucosal invasion. However, ESD for LST-NG can be technically difficult. The aim of our study was to compare our ESD results for LST-NG and for LST-G. PATIENTS AND METHODS: Ninety-nine LST-NG and 169 LST-G measuring 20 mm in size or more were removed by ESD. We retrospectively evaluated the clinicopathological features of the tumors and treatment results (en bloc resection rate, procedure time and speed, rate of use of ancillary devices, and complication and recurrence rates). RESULTS: Histopathology revealed that there were more submucosally invasive lesions in the LST-NG than in the LST-G group (28 % vs. 9 %; P < 0.0001). The en bloc resection rate, en bloc R0 resection rate, and en bloc curative resection rate of LST-NG were similar to those of LST-G (LST-NG: 99 %, 98 %, and 88 %; LST-G: 99 %, 98 %, and 91 %). In LST-NG, the median procedure time tended to be longer (LST-NG: 69 min; LST-G: 60 min) and the median procedure speed was slower (LST-NG: 0.15 cm (2)/min; LST-G: 0.25 cm (2)/min; P < 0.0001). Use of ancillary devices was higher for LST-NG (38 % vs. 15 % for LST-G; P < 0.0001), as was the perforation rate (5.1 % vs. 0.6 % for LST-G; P = 0.027). No recurrence was seen in either group. CONCLUSIONS: ESD was an effective treatment method for both LST-NG and LST-G. However, the degree of technical difficulty appears higher for LST-NG than for LST-G lesions, as shown by the lower dissection speed and higher perforation rate. ESD for LST-NG should probably be performed by those with significant experience of colorectal ESD.

The performance of a novel ball-tipped Flush knife for endoscopic submucosal dissection: a case-control study.

BACKGROUND: Endoscopic submucosal dissection (ESD) using short needle knives is safe and effective, but bleeding is a problem due to low haemostatic capability. AIM: To assess the performance of a novel ball-tipped needle knife (Flush knife-BT) for ESD with particular emphasis on haemostasis. METHODS: A case-control study to compare the performance for ESD of 30 pairs of consecutive early gastrointestinal lesions (oesophagus: 12, stomach: 32, colorectum: 16) with standard Flush knife (F) vs. Flush knife-BT (BT). Primary outcome was efficacy of intraprocedure haemostasis. Secondary outcomes included procedure time, procedure speed (dividing procedure time into the area of resected specimen), en bloc resection rate and recurrence rate. RESULTS: Median intraoperative bleeding points and bleeding points requiring haemostatic forceps were smaller in the BT group than in the F group (4 vs. 8, P < 0.0001, 0 vs. 3, P < 0.0001). There was no difference between groups for procedure time; however, procedure speed was shorter in the BT group (P = 0.0078). En bloc and en bloc R0 resection rates were 100%, with no perforation or post-operative bleeding. No recurrence was observed in either group at follow-up 1 year postprocedure. CONCLUSIONS: Ball-tipped Flush knife (Flush knife-BT) appears to improve haemostatic efficacy and dissection speed compared with standard Flush knife.

Vitamin K3 attenuates lipopolysaccharide-induced acute lung injury through inhibition of nuclear factor-kappaB activation.

Vitamin K is a family of fat-soluble compounds including phylloquinone (vitamin K1), menaquinone (vitamin K2) and menadione (vitamin K3). Recently, it was reported that vitamin K, especially vitamins K1 and K2, exerts a variety of biological effects, and these compounds are expected to be candidates for therapeutic agents against various diseases. In this study, we investigated the anti-inflammatory effects of vitamin K3 in in vitro cultured cell experiments and in vivo animal experiments. In human embryonic kidney (HEK)293 cells, vitamin K3 inhibited the tumour necrosis factor (TNF)-alpha-evoked translocation of nuclear factor (NF)-kappaB into the nucleus, although vitamins K1 and K2 did not. Vitamin K3 also suppressed the lipopolysaccharide (LPS)-induced nuclear translocation of NF-kappaB and production of TNF-alpha in mouse macrophage RAW264.7 cells. Moreover, the addition of vitamin K3 before and after LPS administration attenuated the severity of lung injury in an animal model of acute lung injury/acute respiratory distress syndrome (ARDS), which occurs in the setting of acute severe illness complicated by systemic inflammation. In the ARDS model, vitamin K3 also suppressed the LPS-induced increase in the serum TNF-alpha level and inhibited the LPS-evoked nuclear translocation of NF-kappaB in lung tissue. Despite marked efforts, little therapeutic progress has been made, and the mortality rate of ARDS remains high. Vitamin K3 may be an effective therapeutic strategy against acute lung injury including ARDS.

The results and limitations of endoscopic submucosal dissection for colorectal tumors.

In the colorectal tumor, the lesions suitable for the endoscopic treatment are those with no lymph node metastasis such as adenomas, intramucosal cancers, and minimally invasive submucosal cancer (invasion depth 1000 m, well and moderately differentiated type, no lymphovascular invasion). The new endOscopic technique, endoscopic submucosal dissection (ESD) enables en-bloc resection of the lesions regardless of their size and location. In order to perform ESD more easily, safely, and efficiently, we invented water jet short needle knives (Flush knife). Emitting a jet of water from the tip of a sheath enables submucosal local injection with a knife itself without replacement of operative instruments, which leads to efficient treatment. Especially, Flush knife is very effective for the lesions located at lower rectum and anal canal where there are many vessels. We treated a total of 361 colorectal lesions by ESD between June 2002 and July 2007, and en-block complete resection rate was 98.3 %. In 12 cases, "muscle retracting sign" was recognized. This sign is an index of the discontinuation of ESD, but it is impossible to diagnose preoperatively. The postoperative bleeding occurred in 0.8 % (3 cases: no blood transfusion is needed). The intraoperative perforation occurred in 1.9 % (6 cases: 5 cases were treated conservatively, 1 case was treated surgically) and the postoperative perforation occurred in 1 case (0.3%) treated surgically. ESD is the extremely effective treatment for the colorectal tumors and also is possible to be performed safely with the appropriate choice of the devices and strategy for dissection.

Effect of different proton pump inhibitors, differences in CYP2C19 genotype and antibiotic resistance on the eradication rate of Helicobacter pylori infection by a 1-week regimen of proton pump inhibitor, amoxicillin and clarithromycin.

AIM: To investigate the effect of different proton pump inhibitors, S-mephenytoin 4'-hydroxylase (CYP2C19) genotype and antibiotic susceptibility on the eradication rate of Helicobacter pylori. METHODS: One hundred and eighty-seven H. pylori-infected peptic ulcer patients were randomly treated with either rabeprazole (10 mg b.d.) or lansoprazole (30 mg b.d.) plus amoxicillin (750 mg b.d.) and clarithromycin (400 mg b.d.) for 1 week. The antibiotic susceptibility and CYP2C19 genotype (extensive or poor metabolizer) were investigated. RESULTS: The eradication rates in the rabeprazole-amoxicillin-clarithromycin (RAC) and lansoprazole-amoxicillin-clarithromycin (LAC) groups were 75% and 69%, respectively, on an intention-to-treat basis, and 80% and 75%, respectively, on a per protocol basis. The eradication rate for clarithromycin-resistant strains was significantly lower than that for clarithromycin-sensitive strains (24% vs. 86%, P < 0.05). For clarithromycin-sensitive strains in the LAC group, there was a tendency for a lower eradication rate in extensive than poor metabolizers. The eradication rate in extensive metabolizers in the RAC group tended to be higher than that in extensive metabolizers in the LAC group (89% vs. 78%, P = 0.079726). CONCLUSIONS: The success of the 1-week proton pump inhibitor-amoxicillin-clarithromycin regimen depends on the susceptibility of H. pylori to clarithromycin. Moreover, differences in CYP2C19 genotype influence the eradication rates of lansoprazole-based therapy, and the rabeprazole-based regimen has an advantage especially in extensive metabolizers.

Regulation of growth and apoptosis of cultured guinea pig gastric mucosal cells by mitogenic oxidase 1.

We previously reported that primary cultures of guinea pig gastric pit cells expressed all of the phagocyte NADPH oxidase components (gp91-, p22-, p67-, p47-, and p40-phox) and could spontaneously release superoxide anion (O(2)(-)). We demonstrate here that pit cells express a nonphagocyte-specific gp91-phox homolog (Mox1) but not gp91-phox. Inclusion of catalase significantly inhibited [(3)H]thymidine uptake during the initial 2 days of culture. Pit cells, matured on day 2, slowly underwent spontaneous apoptosis. Scavenging O(2)(-) and related oxidants by superoxide dismutase plus catalase or N-acetyl cysteine (NAC) and inhibiting Mox1 oxidase by diphenylene iodonium activated caspase 3-like proteases and markedly enhanced chromatin condensation and DNA fragmentation. This accelerated apoptosis was completely blocked by a caspase inhibitor, z-Val-Ala-Asp-CH(2)F. Mox1-derived reactive oxygen intermediates constitutively activated nuclear factor-kappaB, and inhibition of this activity by nuclear factor-kappaB decoy oligodeoxynucleotide accelerated their spontaneous apoptosis. These results suggest that O(2)(-) produced by the pit cell Mox1 oxidase may play a crucial role in the regulation of their spontaneous apoptosis as well as cell proliferation.

[Epidemiology of alveolar hydatid disease (AHD) and estimation of infected period of AHD in Rebun Island, Hokkaido].

An epidemiological study was performed of endemic alveolar hydatid disease (AHD, multilocular echinococcosis), Rebun Island, Hokkaido and the period of AHD infection of patients was estimated. Death certificates of the residents of the island were analyzed, and 74 deaths (43 males and 31 females) by AHD were found out of the 3,126 deaths that occurred during the period from 1948 to 1990. The red fox population of the island was estimated on the basis of past researchs. The deaths due to AHD distributed around a major peak (n = 67) between 1948-1975 and there were 7 sporadic cases between 1976-90. The red fox population on the island had been estimated to be largest in 1935. The mean infection period from initial AHD infection to death was estimated to be 26 +/- 7 years (x +/- SD) on the basis of the period between the year in which the peak red fox population was observed (1935) and the major peak of patient death (1962). The mean symptomatic period was 5 +/- 5 years, and the mean latent period from infection to the onset of AHD was 21 +/- 7 years. Sex ratio (M/F = 28/13 = 2.15) was higher (P < 0.05) at the age groups below 10 and 26-45 years than the other age groups (15/18 = 0.83), and playing outdoors during childhood and working outdoors in the prime of life were assumed to be the causes of infection.

Is a proton pump inhibitor necessary for the treatment of lower-grade reflux esophagitis?

The efficacy of histamine H2 receptor antagonist (H2RA) and proton pump inhibitor (PPI) therapies in healing reflux esophagitis was compared in a prospective randomized case-control comparative study. A total of 71 patients with grade A to D esophagitis (Los Angeles classification) were given either famotidine 20 mg twice a day (Fam; n = 35) or omeprazole 20 mg once daily (Ome; n = 36) for 8 weeks. Endoscopy was performed to assess healing in 57 patients. Healed patients were followed-up without H2RA or PPI therapy for 3 months. At the end of follow-up, endoscopy was able to be performed in 33 patients. Healing rates for patients in the Fam and Ome groups were 58.6% (17/OFF and 97.4% (27/28), respectively (P < 0.001), and when limited to grade A to B, healing rates were 60.9% (14/23) and 100% (25/25), respectively (P < 0.001). Concerning Helicobacter pylori infection, healing rates for the Fam and Ome groups in H. pylori (+) patients were 90.0% (9/10) and 90.9% (10/11), respectively (P = 1.00). Remission rates in the Fam and Ome groups were 45.0% (91/2)) and 33.3% (6/18), respectively (P > 0.4). In regard to alcohol drinking, remission rates of daily and social drinkers were 7.7% and 42.4%, respectively (P < 0.03). Thus, PPI should be the drug of choice even for healing lower-grade reflux esophagitis, especially in H. pylori (-) patients. Treatment with H2RA may be an alternative choice in H. pylori (+) patients. After healing, most patients cannot sustain remission without maintenance therapy.

A patient with rectal cancer associated with ulcerative colitis in whom endoscopic ultrasonography was useful for diagnosis.

Endoscopic ultrasonography (EUS) was helpful for the diagnosis of rectal cancer associated with ulcerative colitis. The patient was a 38-year-old Japanese man with a 19-year history of relapsing-remitting type ulcerative colitis involving the entire colon. Routine colonoscopy revealed multiple polypoid prominences in the upper portion of the rectum. EUS revealed a hypoechoic mass in the submucosa beneath and around the polypoid lesion on the most oral side. Signet ring cells were found in a biopsy specimen from this lesion. Subtotal colectomy was performed. A depressed lesion was observed around the prominence on the most oral side; histologically, this lesion was poorly differentiated mucinous and signet ring cell carcinoma extending into the subserosa. The polypoid lesion on the most anal side was well differentiated adenocarcinoma, which was limited to the mucosa. Our findings suggest that EUS is helpful for detecting invasive cancer associated with ulcerative colitis.

Diagnostic endoscopic retrograde cholangiopancreatography.

Endoscopic retrograde cholangiopancreatography (ERCP) is still a gold standard in the diagnostic work-up of the pancreaticobiliary system. However, the problem of post-ERCP pancreatitis has not yet been solved. Since the appearance of magnetic resonance cholangiopancreatography (MRCP), there has been a trend for it to replace ERCP as an imaging tool. At present, MRCP equipment is not available at every institution. In addition, MRCP images are not satisfactorily comparable to those provided by ERCP, although technological advances will fill this gap in the near future. If this is achieved, diagnostic ERCP may be reduced to the specific tasks of obtaining histological and cytological materials, and for functional studies.

Morphological changes of larval Echinococcus multilocularis in mice treated with albendazole or mebendazole.

Using DBA/2J mice, tissue homogenates of larval Echinococcus multilocularis were injected into the mesenteric veins to generate the liver infection. Mice were treated with either albendazole or mebendazole for prolonged periods to examine the morphological changes of the metacestode. Albendazole induced disorganization of both laminated and germinal layers and suppressed the maturation of vesicles. Amorphous but loosely laminated PAS-positive material was observed inside the damaged vesicles, although new vesicles slightly developed inside or outside of the damaged ones. Active proliferation of vesicles occurred after treatment with albendazole was terminated. Hydatid cysts were more severely damaged in mice treated with mebendazole and new vesicles did not develop around the damaged ones. Also, hydatid cysts reappeared after treatment with mebendazole was terminated. These results indicate that these drugs do not eliminate larval E. multilocularis in the long-term, but mebendazole has a higher suppressive effect on multivesiculation than albendazole.

[Risk factors for gastrointestinal bleeding].

Gastrointestinal bleeding sometimes causes life-threatening state. It is important to understand the underlining risk factors for prevention and treatment of this condition. In 1997, 81 patients with massive gastrointestinal bleeding were admitted to the life-saving center in Kyoto First Red Cross Hospital. In these patients, 14 subjects (17%) had been receiving hemodialysis. Eight patients (10%) were taking anti-coagulant or antiplatelet drugs. Eight patients (10%) had hypertension and were given calcium antagonists. Seven subjects (9%) had liver cirrhosis and/or hepatocellular carcinoma. Because these patients often fall into life-threating state, we must pay special attention to the prevention and cure for gastrointestinal bleeding. For example, it may be necessary to change to heparin free hemodialysis for patients having active bleeding. In anticoagulated patients, it may be required that sufficient hemostatic therapy without risking thromboembolic sequelae. In addition to careful managements, we have better to consider the eradication therapy for all of these high risk groups with Helicobacter pylori infection.

A successfully treated case of multiple liver abscesses accompanied by portal venous gas.

A case with multiple liver abscess accompanied by massive portal venous gas is reported. A 61-yr-old male was admitted because of left lower abdominal pain, fever, and diarrhea. Abdominal x-ray examination demonstrated multiple branching lucencies in the liver. Computed tomography revealed multiple liver abscesses and massive gas in the portal system as well as a thickened wall of the sigmoid colon. Enema study using contrast medium revealed a perforation of the sigmoid colon with diverticulitis. The outcome was favorable after sigmoid colectomy in addition to intensive treatment with antibiotics. Bacteroides fragilis, which produces gas (H2 and NH3) by fermentation, was isolated not only from the resected specimen but also from blood samples. Although the presence of portal venous gas is a sign of poor prognosis in patients with intestinal infectious diseases, the sensitive detection of hepatic portal venous gas by computed tomography and the appropriate treatment may improve the patient's prognosis.