Roy Soetikno

Endoscopic submucosal dissection of early gastric cancer

The purpose of this review was to examine a remarkable technical advance regarding the indications for and the technique of endoscopic resection of early gastric cancer. Endoscopic mucosal resection (EMR) of early gastric cancer with no risk of lymph node metastasis has been a standard technique in Japan, probably owing to the high incidence of gastric cancer in Japan and the fact that more than half of Japanese gastric cancer cases are diagnosed at an early stage. Very recently, several EMR techniques have become increasingly accepted and regularly used in Western countries. Although these minimally invasive techniques are safe, convenient, and efficacious, they are unsuitable for large lesions in particular. Difficulty in correctly assessing the depth of tumor invasion and an increase in local recurrence when standard EMR procedures are used have been reported in cases of large lesions, because such lesions are often resected piecemeal owing to the technical limitations of standard EMR. A new development in therapeutic endoscopy, called endoscopic submucosal dissection (ESD), allows the direct dissection of the submucosa, and large lesions can be resected en bloc. ESD is not limited by resection size and is expected to replace surgical resection. However, it is still associated with a higher incidence of complications than standard EMR procedures and requires a high level of endoscopic skill. The endoscopic indications, techniques, and management of complications of ESD for early gastric cancer for properly carrying out established therapeutic endoscopy are described.

Endoscopic Mucosal Resection for Early Cancers of the Upper Gastrointestinal Tract

The purpose of this literature review is to examine recent advances in technique and technology of endoscopic mucosal resection of superficial early cancers of the upper gastrointestinal tract. Endoscopic mucosal resection (EMR) of superficial early cancers of the upper gastrointestinal tract is standard technique in Japan and is increasingly used in Western countries. Newer techniques of EMR allow removal of larger lesions en-bloc. These minimally invasive techniques, when applied correctly, allow safe and efficacious treatment in situations that would otherwise require major surgery. Through the establishment of long-term outcomes data, standardization of endoscopic and pathologic reporting, and newer EMR technology and techniques, the future treatment of early cancers in the upper gastrointestinal tract may be achieved primarily through the endoscope.

Detection of colonic dysplasia in vivo using a targeted heptapeptide and confocal microendoscopy

A combination of targeted probes and new imaging technologies provides a powerful set of tools with the potential to improve the early detection of cancer. To develop a probe for detecting colon cancer, we screened phage display peptide libraries against fresh human colonic adenomas for high-affinity ligands with preferential binding to premalignant tissue. We identified a specific heptapeptide sequence, VRPMPLQ, which we synthesized, conjugated with fluorescein and tested in patients undergoing colonoscopy. We imaged topically administered peptide using a fluorescence confocal microendoscope delivered through the instrument channel of a standard colonoscope. In vivo images were acquired at 12 frames per second with 50-μm working distance and 2.5-μm (transverse) and 20-μm (axial) resolution. The fluorescein-conjugated peptide bound more strongly to dysplastic colonocytes than to adjacent normal cells with 81% sensitivity and 82% specificity. This methodology represents a promising diagnostic imaging approach for the early detection of colorectal cancer and potentially of other epithelial malignancies.A combination of targeted probes and new imaging technologies provides a powerful set of tools with the potential to improve the early detection of cancer. To develop a probe for detecting colon cancer, we screened phage display peptide libraries against fresh human colonic adenomas for high-affinity ligands with preferential binding to premalignant tissue. We identified a specific heptapeptide sequence, VRPMPLQ, which we synthesized, conjugated with fluorescein and tested in patients undergoing colonoscopy. We imaged topically administered peptide using a fluorescence confocal microendoscope delivered through the instrument channel of a standard colonoscope. In vivo images were acquired at 12 frames per second with 50-microm working distance and 2.5-microm (transverse) and 20-microm (axial) resolution. The fluorescein-conjugated peptide bound more strongly to dysplastic colonocytes than to adjacent normal cells with 81% sensitivity and 82% specificity. This methodology represents a promising diagnostic imaging approach for the early detection of colorectal cancer and potentially of other epithelial malignancies.

Long-term outcomes of autoimmune pancreatitis: a multicentre, international analysis

Objective Autoimmune pancreatitis (AIP) is a treatable form of chronic pancreatitis that has been increasingly recognised over the last decade. We set out to better understand the current burden of AIP at several academic institutions diagnosed using the International Consensus Diagnostic Criteria, and to describe long-term outcomes, including organs involved, treatments, relapse frequency and long-term sequelae. Design 23 institutions from 10 different countries participated in this multinational analysis. A total of 1064 patients meeting the International Consensus Diagnostic Criteria for type 1 (n=978) or type 2 (n=86) AIP were included. Data regarding treatments, relapses and sequelae were obtained. Results The majority of patients with type 1 (99%) and type 2 (92%) AIP who were treated with steroids went into clinical remission. Most patients with jaundice required biliary stent placement (71% of type 1 and 77% of type 2 AIP). Relapses were more common in patients with type 1 (31%) versus type 2 AIP (9%, p<0.001), especially those with IgG4-related sclerosing cholangitis (56% vs 26%, p<0.001). Relapses typically occurred in the pancreas or biliary tree. Retreatment with steroids remained effective at inducing remission with or without alternative treatment, such as azathioprine. Pancreatic duct stones and cancer were uncommon sequelae in type 1 AIP and did not occur in type 2 AIP during the study period. Conclusions AIP is a global disease which uniformly displays a high response to steroid treatment and tendency to relapse in the pancreas and biliary tree. Potential long-term sequelae include pancreatic duct stones and malignancy, however they were uncommon during the study period and require additional follow-up. Additional studies investigating prevention and treatment of disease relapses are needed.

Validation of a Simple Classification System for Endoscopic Diagnosis of Small Colorectal Polyps Using Narrow-Band Imaging

BACKGROUND & AIMS Almost all colorectal polyps ≤ 5 mm are benign, yet current practice requires costly pathologic analysis. We aimed to develop and evaluate the validity of a simple narrow-band imaging (NBI)-based classification system for differentiating hyperplastic from adenomatous polyps. METHODS The study was conducted in 4 phases: (1) evaluation of accuracy and reliability of histologic prediction by NBI-experienced colonoscopists; (2) development of a classification based on color, vessels, and surface pattern criteria, using a modified Delphi method; (3) validation of the component criteria by people not experienced in endoscopy or NBI analysis (25 medical students, 19 gastroenterology fellows) using 118 high-definition colorectal polyp images of known histology; and (4) validation of the classification system by NBI-trained gastroenterology fellows, using still images. We performed a pilot evaluation during real-time colonoscopy. RESULTS We developed a classification system for the endoscopic diagnosis of colorectal polyp histology and established its predictive validity. When all 3 criteria were used, the specificity ranged from 94.9% to 100% and the combined sensitivity ranged from 8.5% to 61.0%. The specificities of the individual criteria were lower although the sensitivities were higher. During real-time colonoscopy, endoscopists made diagnoses with high confidence for 75% of consecutive small colorectal polyps, with 89% accuracy, 98% sensitivity, and 95% negative predictive values. CONCLUSIONS We developed and established the validity of an NBI classification system that can be used to diagnose colorectal polyps. In preliminary real-time evaluation, the system allowed endoscopic diagnoses of colorectal polyp histology.

SCENIC International Consensus Statement on Surveillance and Management of Dysplasia in Inflammatory Bowel Disease

Patients with ulcerative colitis or Crohn’s colitis have an increased risk of colorectal cancer (CRC). Most cases are believed to arise from dysplasia, and surveillance colonoscopy therefore is recommended to detect dysplasia. Detection of dysplasia traditionally has relied on both examination of the mucosa with targeted biopsies of visible lesions and extensive random biopsies to identify invisible dysplasia. Current U.S. guidelines recommend obtaining at least 32 random biopsy specimens from all segments of the colon as the foundation of endoscopic surveillance. However, much of the evidence that provides a basis for these recommendations is from older literature, when most dysplasia was diagnosed on random biopsies of colon mucosa. With the advent of video endoscopy and newer endoscopic technologies, investigators now report that most dysplasia discovered in patients with inflammatory bowel disease (IBD) is visible. Such a paradigm shift may have important implications for the surveillance and management of dysplasia. The evolving evidence regarding newer endoscopic methods to detect dysplasia has resulted in variation among guideline recommendations from organizations around the world. We therefore sought to develop unifying consensus recommendations addressing 2 issues: (1) How should surveillance colonoscopy for detection of dysplasia be performed? (2) How should dysplasia identified at colonoscopy be managed?

Endoscopic prediction of deep submucosal invasive carcinoma: validation of the Narrow-Band Imaging International Colorectal Endoscopic (NICE) classification

BACKGROUND A simple endoscopic classification to accurately predict deep submucosal invasive (SM-d) carcinoma would be clinically useful. OBJECTIVE To develop and assess the validity of the NBI international colorectal endoscopic (NICE) classification for the characterization of SM-d carcinoma. DESIGN The study was conducted in 4 phases: (1) evaluation of endoscopic differentiation by NBI-experienced colonoscopists; (2) extension of the NICE classification to incorporate SM-d (type 3) by using a modified Delphi method; (3) prospective validation of the individual criteria by inexperienced participants, by using high-definition still images without magnification of known histology; and (4) prospective validation of the individual criteria and overall classification by inexperienced participants after training. SETTING Japanese academic unit. MAIN OUTCOME MEASUREMENTS Performance characteristics of the NICE criteria (phase 3) and overall classification (phase 4) for SM-d carcinoma; sensitivity, specificity, predictive values, and accuracy. RESULTS We expanded the NICE classification for the endoscopic diagnosis of SM-d carcinoma (type 3) and established the predictive validity of its individual components. The negative predictive values of the individual criteria for diagnosis of SM-d carcinoma were 76.2% (color), 88.5% (vessels), and 79.1% (surface pattern). When any 1 of the 3 SM-d criteria was present, the sensitivity was 94.9%, and the negative predictive value was 95.9%. The overall sensitivity and negative predictive value of a global, high-confidence prediction of SM-d carcinoma was 92%. Interobserver agreement for an overall SM-d carcinoma prediction was substantial (kappa 0.70). LIMITATIONS Single Japanese center, use of still images without prospective clinical evaluation. CONCLUSION The NICE classification is a valid tool for predicting SM-d carcinomas in colorectal tumors.

A randomised tandem colonoscopy trial of narrow band imaging versus white light examination to compare neoplasia miss rates

Objective: Colonoscopy, the “gold standard” screening test for colorectal cancer (CRC), has known diagnostic limitations. Advances in endoscope technology have focused on improving mucosal visualisation. In addition to increased angle of view and resolution features, recent colonoscopes have non-white-light optics, such as narrow band imaging (NBI), to enhance image contrast. We aimed to study the neoplasia diagnostic characteristics of NBI, by comparing the neoplasm miss rate when the colonoscopy was performed under NBI versus white light (WL). Design: Randomised controlled trial. Setting: US Veterans hospital. Patients: Elective colonoscopy adults. Intervention: We randomly assigned patients to undergo a colonoscopic examination using NBI or WL. All patients underwent a second examination using WL, as the reference standard. Main outcome measures: The primary end point was the difference in the neoplasm miss rate, and secondary outcome was the neoplasm detection rate. Results: In 276 tandem colonoscopy patients, there was no significant difference of miss or detection rates between NBI or WL colonoscopy techniques. Of the 135 patients in the NBI group, 17 patients (12.6%; 95% confidence interval (CI) 7.5 to 19.4%) had a missed neoplasm, as compared with 17 of the 141 patients (12.1%; 95% CI 7.2 to 18.6%) in the WL group, with a miss rate risk difference of 0.5% (95% CI −7.2 to 8.3). 130 patients (47%) had at least one neoplasm. Missed lesions with NBI showed similar characteristics to those missed with WL. All missed neoplasms were tubular adenomas, the majority (78%) was ⩽5 mm and none were larger than 1 cm (one-sided 95% CI up to 1%). Nonpolypoid lesions represented 35% (13/37) of missed neoplasms. Interpretation: NBI did not improve the colorectal neoplasm miss rate compared to WL; the miss rate for advanced adenomas was less than 1% and for all adenomas was 12%. The neoplasm detection rates were similar high using NBI or WL; almost a half the study patients had at least one adenoma. Clinicaltrials.gov identifier: NCT00628147

Susceptibility to hepatotoxicity in transgenic mice that express a dominant-negative human keratin 18 mutant.

Keratins 8 and 18 (K8/18) are intermediate filament phosphoglycoproteins that are expressed preferentially in simple-type epithelia. We recently described transgenic mice that express point-mutant human K18 (Ku, N.-O., S. Michie, R.G. Oshima, and M.B. Omary. 1995. J. Cell Biol. 131:1303-1314) and develop chronic hepatitis and hepatocyte fragility in association with hepatocyte keratin filament disruption. Here we show that mutant K18 expressing transgenic mice are highly susceptible to hepatotoxicity after acute administration of acetaminophen (400 mg/Kg) or chronic ingestion of griseofulvin (1.25% wt/wt of diet). The predisposition to hepatotoxicity results directly from the keratin mutation since nontransgenic or transgenic mice that express normal human K18 are more resistant. Hepatotoxicity was manifested by a significant difference in lethality, liver histopathology, and biochemical serum testing. Keratin glycosylation decreased in all griseofulvin-fed mice, whereas keratin phosphorylation increased dramatically preferentially in mice expressing normal K18. The phosphorylation increase in normal K18 after griseofulvin feeding appears to involve sites that are different to those that increase after partial hepatectomy. Our results indicate that hepatocyte intermediate filament disruption renders mice highly susceptible to hepatotoxicity, and raises the possibility that K18 mutations may predispose to drug hepatotoxicity. The dramatic phosphorylation increase in nonmutant keratins could provide survival advantage to hepatocytes.

Automated computer interviews to elicit utilities: potential applications in the treatment of deep venous thrombosis.

OBJECTIVE To assess the practicality of an automated computer interview as a method to assess preferences for use in decision making. To assess preferences for outcomes of deep vein thrombosis (DVT) and its treatment. STUDY DESIGN A multimedia program was developed to train subjects in the use of different preference assessment methods, presented descriptions of mild post-thrombotic syndrome (PTS), severe PTS and stroke and elicited subject preferences for these health states. This instrument was used to measure preferences in 30 community volunteers and 30 internal medicine physicians. We then assessed the validity of subject responses and calculated the number of quality-adjusted life years (QALYs) for each individual for each alternative. RESULTS All subjects completed the computerized survey instrument without assistance. Subjects generally responded positively to the program, with volunteers and physicians reporting similar preferences. Approximately 26.5% of volunteers and physicians had preferences that would be consistent with the use of thrombolysis. Individualization of therapy would lead to the most QALYs. CONCLUSIONS Utilization of computerized survey instruments to elicit patient preferences appears to be a practical and valid approach to individualize therapy. Application of this method suggests that there may be many patients with DVT for whom treatment with a thrombolytic drug would be optimal.