Martin Goetz

High definition colonoscopy combined with i-Scan is superior in the detection of colorectal neoplasias compared with standard video colonoscopy: a prospective randomized controlled trial

INTRODUCTION Colonoscopy is the accepted gold standard for the detection of colorectal cancer. The aim of the current study was to prospectively compare high definition plus (HD+) colonoscopy with I-Scan functionality (electronic staining) vs. standard video colonoscopy. The primary endpoint was the detection of patients having colon cancer or at least one adenoma. METHODS A total of 220 patients due to undergo screening colonoscopy, postpolypectomy surveillance or with a positive occult blood test were randomized in a 1 : 1 ratio to undergo HD+ colonoscopy in conjunction with I-Scan surface enhancement (90i series, Pentax, Tokyo, Japan) or standard video colonoscopy (EC-3870FZK, Pentax). Detected colorectal lesions were judged according to type, location, and size. Lesions were characterized in the HD+ group by using further I-Scan functionality (p- and v-modes) to analyze pattern and vessel architecture. Histology was predicted and biopsies or resections were performed on all identified lesions. RESULTS HD+ colonoscopy with I-Scan functionality detected significantly more patients with colorectal neoplasia (38 %) compared with standard resolution endoscopy (13 %) (200 patients finally analyzed; 100 per arm). Significantly more neoplastic (adenomatous and cancerous) lesions and more flat adenomas could be detected using high definition endoscopy with surface enhancement. Final histology could be predicted with high accuracy (98.6 %) within the HD+ group. CONCLUSIONS HD+ colonoscopy with I-Scan is superior to standard video colonoscopy in detecting patients with colorectal neoplasia based on this prospective, randomized, controlled trial.

In vivo diagnosis of collagenous colitis by confocal endomicroscopy

Collagenous colitis is a form of microscopic colitis which has recently been recognised as an entity of its own, characterised by chronic watery diarrhoea of unknown aetiology. The diagnosis of collagenous colitis relies on histopathological examination of biopsy specimens from colorectal mucosa, which is usually of normal macroscopic appearance. The typical histological feature is diffuse thickening of the subepithelial collagen layer beneath the basement membrane and an unspecific chronic inflammatory infiltrate of the lamina propria.1–3 Recently, a confocal laser endomicroscope has been developed that is integrated into the distal tip of a conventional video endoscope. This confocal laser microscope (EC-3870CIFK; Pentax, Tokyo, Japan) was designed to enable subsurface imaging of living tissue during ongoing endoscopy and allows confocal microscopy in addition to standard video endoscopy. Images are generated by intravenously administered fluorescein sodium as the fluorescent contrast agent and an argon ion laser integrated into the system that generates an excitation wavelength of 488 nm.4,5 For the first time, we used …

High-definition endoscopy with i-Scan and Lugol's solution for more precise detection of mucosal breaks in patients with reflux symptoms.

BACKGROUND AND STUDY AIMS Patients with gastroesophageal reflux disease are subdivided into non-erosive (NERD) and erosive reflux disease (ERD). The newly available EPKi processor enables high-definition resolution above HDTV standard (HD+). The aim of the study was to test the efficacy of HD+ esophagogastroduodenoscopy alone and in conjunction with i-Scan (newly developed postprocessing digital filter) and chromoendoscopy (Lugols solution) for differentiation of reflux patients. METHODS The distal esophagus of patients with heartburn was inspected with three imaging modalities. HD+ was followed by i-Scan and 15-mL Lugols solution (1.5 %). The esophagus was evaluated for mucosal breaks (Los Angeles Classification [LA]). Small visible changes were also characterized, and targeted biopsies were performed. End points of the study were the presence and grade of esophagitis and the number of circumscribed changes. RESULTS A total of 50 patients were included (female 29; mean age 54.7 years). HD+ identified nine patients with mucosal breaks (LA 7A; 2C), i-Scan was able to detect 12 patients (LA 8A; 2B; 2C; 0D) ( P = n. s.) and chromoendoscopy identified 25 patients (LA 16A; 7B; 1C, 1D) ( P < 0.01). Furthermore, a higher grade of esophagitis was recognized by using i-Scan and Lugols solution in 19 patients. The number of circumscribed lesions could be increased from 21 (HD+) to 58 (i-Scan) ( P < 0.01), and up to 85 after Lugol spraying ( P < 0.01). CONCLUSIONS Lugols solution in conjunction with HD+ endoscopy significantly improves the identification of patients with esophagitis and reduces misclassification. The i-Scan filter and chromoendoscopy help to identify reflux-associated lesions.

In vivo confocal laser endomicroscopy of the human liver: a novel method for assessing liver microarchitecture in real time

BACKGROUND AND STUDY AIMS Confocal endomicroscopy is a unique novel tool for in vivo histology in humans. Due to limitations imposed by the form of the equipment and by sterilization workflows, its use has been limited to the gastrointestinal tract so far. We have developed a rigid miniaturized probe for confocal endomicroscopy of the human liver during laparoscopy. PATIENTS AND METHODS To assess the feasibility and potential clinical value of this new system (diameter 6.3 mm), 25 patients with liver disease were examined during routine minilaparoscopy under conscious sedation. RESULTS Subsurface serial images (from surface to 250 microm) were generated in real time after fluorescein injection, permitting visualization of hepatocytes, bile ducts, sinusoids, and collagen fibers in vivo. Typical appearances of liver diseases were identified. Confocal diagnosis of moderate-to-severe steatosis and pericellular fibrosis correlated well with histopathologic analysis of subsequent biopsies (83.3 % and 84.6 %, respectively). In addition, intra-abdominal structures such as gallbladder, omentum, and stomach were analyzed by endomicroscopy. CONCLUSIONS A miniaturized imaging system for confocal laparoscopy allowed in vivo microscopic analysis of healthy and diseased human liver for the first time during ongoing minilaparoscopy. Although such in vivo imaging does not yet compete with conventional histopathology, this novel confocal laparoscopy system may be of future relevance for immediate morphodynamic analysis in liver disease and the targeting of biopsies in vivo.

In vivo molecular imaging with cetuximab, an anti-EGFR antibody, for prediction of response in xenograft models of human colorectal cancer.

BACKGROUND AND STUDY AIMS Molecular imaging has mainly been studied for detection of lesions using diagnostic probes. The aim of the current trial was to evaluate in vivo confocal laser endomicroscopy (CLE) with cetuximab, an antibody targeting the epidermal growth factor receptor (EGFR), for detection and moreover early prediction of response to molecular chemotherapy in models of human colorectal cancer (CRC). METHODS Xenografts with cetuximab-sensitive (HT29) and cetuximab-resistant (SW620) human CRC cell lines were induced in 44 mice. CLE was performed 48 h after injection of a fluorescently labelled cetuximab test dose, and compared with isotype antibody or untreated controls on d0, and d30 (HT29) or d15 (SW620). Initial fluorescence intensity was examined in relation to clinical readouts (tumor growth, thriving, mortality) during cetuximab treatment vs. controls. Results were validated in vivo with wide-field molecular imaging in three HT29 mice and ex vivo using fluorescence-activated cell sorting (FACS) and immunohistochemistry. RESULTS All HT29 xenografts showed specific fluorescence in vivo after cetuximab injection on d0 and d30. Fluorescence at d0 was significantly stronger in cetuximab-treated HT29 tumors than in HT29 controls (P = 0.0017) or cetuximab-treated SW620 tumors (P = 0.0027), and accorded with significantly slower tumor progression (P = 0.0009), better overall survival (P = 0.02), and better physical condition (P < 0.0001). Cetuximab sensitivity could be predicted from fluorescence intensity at d0 with high positive predictive value. CONCLUSIONS Molecular CLE was for the first time linked to early prediction of response to targeted therapy in models of human CRC. Therapeutic antibodies can be used as molecular beacons in CLE and wide-field techniques. These results may indicate a promising principle for early patient stratification.

Acetic acid compared with i-scan imaging for detecting Barrett’s esophagus: a randomized, comparative trial

BACKGROUND Traditional surveillance in patients with Barretts esophagus (BE) has relied on random biopsies. Targeted biopsies that use advanced imaging modalities may significantly improve detection of specialized columnar epithelium (SCE). OBJECTIVE We compared the efficacy of targeted biopsies that used i-scan or acetic acid to random biopsies in the detection of SCE. DESIGN Patients with visible columnar lined epithelium or known BE were randomized at a 1:1 ratio to undergo acetic acid application or i-scan with targeted biopsies. SETTING Targeted biopsies were performed based on surface architecture according to the Guelrud classification followed by 4-quadrant biopsies. PATIENTS A total of 95 patients were randomized. INTERVENTION A total of 46 patients underwent acetic acid staining, and 49 underwent i-scan imaging. Random biopsies were performed in 86 patients. MAIN OUTCOME MEASUREMENTS The primary outcome was the yield of SCE as confirmed by histologic assessment. RESULTS The diagnostic yield for SCE was significantly higher with targeted biopsies than with random biopsies in both groups combined (63% vs 24%; P = .0001). The yield of targeted biopsies was significantly greater with both i-scan (66% vs 21%; P = .009) and acetic acid (57% vs 26%; P = .012) technologies and did not differ between these groups. The accuracy for predicting SCE was 96% (k = .92) for i-scan and 86% (k = .70) for acetic acid analysis. LIMITATIONS No dysplastic lesions were found. CONCLUSION The i-scan or acetic acid-guided biopsies have a significantly higher diagnostic yield for identifying SCE, with significantly fewer biopsies, as compared with a protocol of random biopsies. Acetic acid and i-scan showed comparable results diagnosing SCE in our study. ( CLINICAL TRIAL REGISTRATION NUMBER NCT01442506.).

High definition plus colonoscopy combined with i-scan tone enhancement vs. high definition colonoscopy for colorectal neoplasia: A randomized trial.

BACKGROUND High definition endoscopy is the accepted standard in colonoscopy. However, an important problem is missed polyps. AIMS Our objective was to assess the additional adenoma detection rate between high definition colonoscopy with tone enhancement (digital chromoendoscopy) vs. white light high definition colonoscopy. METHODS In this prospective randomized trial patients were included to undergo a tandem colonoscopy. The first exam was a white light colonoscopy with removal of all visualized polyps. The second examination was randomly assigned in a 1:1 ratio as either again white light colonoscopy (Group A) or colonoscopy with tone enhancement (Group B). Primary endpoint was the adenoma detection rate during the second withdrawal (sample size calculation - 40 per group). RESULTS 67 lesions (Group A: n=34 vs. Group B: n=33) in 80 patients (mean age 61 years, male 64%) were identified on the first colonoscopy. The second colonoscopy detected 78 additional lesions: n=60 with tone enhancement vs. n=18 with white light endoscopy (p<0.001). Tone enhancement found more additional adenomas (A n=20 vs. B n=6, p=0.006) and identified significantly more missed adenomas per subject (0.5 vs. 0.15, p=0.006). CONCLUSIONS High definition plus colonoscopy with tone enhancement detected more adenomas missed by white light colonoscopy.

MedJet – a new CO2-based disposable cleaning device allows safe and effective bowel cleansing during colonoscopy: a pilot study

BACKGROUND AND STUDY AIMS Complete bowel cleansing is mandatory for effective colon cancer screening and surveillance. The aim of the current pilot study, which was conducted in humans, was to test the safety and efficiency of a newly developed disposable cleaning device, the MedJet, for intraprocedural bowel cleansing. PATIENTS AND METHODS Patients with screening or surveillance colonoscopy after previous polypectomy were included. The colonoscope was first inserted to the cecum and the overall cleansing was assessed according to the Ottawa scale. The MedJet device was used if colon cleansing had been incomplete. The MedJet catheter was passed over the working channel of the colonoscope and the colon was cleaned during withdrawal. The MedJet device delivered controlled jets comprising compressed CO2 and minimal amounts of sterile water, which allowed disintegration and removal of residual stool. The efficiency of cleaning was assessed according to the Boston scale. RESULTS A total of 32 patients (16 female; mean age 61 years) were treated with the device. No device-related adverse or serious adverse events were noted. MedJet application during withdrawal provided effective and significant improvement in bowel cleansing (P = 0.005). Furthermore, 18 adenomas and 1 colon cancer, which were hidden behind stool remnants, could be identified in 11 patients following use of the MedJet device. However, the withdrawal times were prolonged (11.4±6.0 minutes) due to the additional cleaning procedure. All patients tolerated the procedure well. CONCLUSIONS The new MedJet device enabled highly effective and safe bowel cleansing during colonoscopy. The catheter-based system was easy to use and CO2 was applied for cleansing. The procedure was well tolerated by patients.

Successful treatment of pouchitis with Vedolizumab, but not fecal microbiota transfer (FMT), after proctocolectomy in ulcerative colitis

Dear Editor, With great interest have we read the case report by Fang et al. in this journal [1]. The authors describe a case with sustained response to treatment of chronic pouchitis with a single fecal microbiota transfer (FMT). Pouchitis occurs in 23–46% of patients following IPAA [2] and can be debilitating. Initial experience with new treatment modalities is frequently enthusiastic, and case reports on FMT in ulcerative colitis naturally report better outcomes than randomised trials [3]. Following our own encouraging results of FMT in Clostridium difficile colitis, we were similarly enthusiastic about this new treatment option as Fang et al., given the well known dysbalance of microbiota in chronic pouchitis. In our patient, a 54-year-old Caucasian male, restorative proctocolectomy with ileoanal pouch anastomosis (IPAA) had become necessary 17 years ago in severe refractory ulcerative colitis. Pouchitis was first diagnosed in March 2014, and stenosis with chronic inflammation at the outlet of the feeding limb had necessitated balloon dilatation for several times. In 2015, a severe flare of pouchitis with up to 20 liquid (including 4 nightly) stools associated with diffuse abdominal pain and bloating was refractory to metronidazole, VSL#3, budesonide, mesalamine, and hydrocortisone rectal foam. Endoscopy showed inflammation in the pouch and in the afferent ileal limb, edema, granularity, and mucous exudates. Ulcerations were present in the pouch, circular ulcerations in a stenosis of the afferent limb entry site, and in the abanal ileal mucosa. Histology confirmed acute inflammation (granulocytes, ulceration) combined with signs of regeneration. Stool samples were negative for C. difficile. In July 2015, FMT was performed. The donor (patient’s son) was screened negative for hepatitis A, B, C, E, HIV, syphilis, enteropathogenic bacteria, worms, parasites, viruses (Noro, Rota, Adeno), Clostridium difficile, and multiresistant pathogens. Chronic inflammatory diseases of the donor and prior antimicrobial therapy in the past 3 months were ruled out. A fresh sample (<6 h) of donor stool was diluted in 500 ml of 0.9% saline and filtered through gauze. Endoscopic delivery of 250 ml of the fresh suspension (<6 h) was performed proximal to and within the pouch after bowel preparation with enemas. Symptoms (bloating and pain) transiently improved for about 5 days, but stool urgency and frequency remained grossly unchanged. A second and third FMT were performed 5 and 9 weeks later, respectively, but did not result in sustained symptomatic or any endoscopic response. With approval of Vedolizumab in mid 2015, the patient was switched to anti-integrin therapy and showed sustained clinical and endoscopic response to Vedolizumab 300 mg i.v. at weeks 0, 2, 6, and every 8 weeks. After five doses, pouch and ileal ulcerations had healed completely (apart from one fourth of the circumference of the afferent limb entry), the stenosis was easily traversable, and edema and mucous exudates were no longer present. Clinically, the patient is now in excellent condition, reports about ten daily stools without any abdominal discomfort. Treating suspected dysbiosis by reestablishing homeostasis of intestinal microbiota is a successful concept in the treatment of pouchitis, given the efficacy of VSL#3 * Martin Goetz martin.goetz@med.uni-tuebingen.de

Analysis of interobserver variability for endomicroscopy of the gastrointestinal tract

BACKGROUND Endomicroscopy allows in vivo microscopic investigation of enteral mucosa during endoscopic examinations. The aim of this study was to determine interobserver variability in the evaluation of endomicroscopic pictures of several organs by groups of investigators composed of confocal experts, pathologists and students. METHODS Twenty-five selected representative endomicroscopic pictures of the colon, stomach and oesophagus (total number, 75) were evaluated based on tissue, inflammatory and neoplastic changes (secondary endpoints). The endomicroscopic presence of neoplastic features was the primary endpoint and correlated with the final histological diagnosis. RESULTS The kappa values for experts examining colon, stomach, and oesophagus pictures were 0.80, 0.91, and 0.488, respectively; for students 0.74, 0.684, and 0.527 and for pathologists 0.749, 0.633, and 0.346, respectively. Neoplasia was accurately diagnosed in 67-97% of patients with no significant differences between the 3 groups. Tissue differentiation was determined best by pathologists, whereas the degree of inflammation was better diagnosed by experts and students. In all 3 groups the diagnosis of oesophageal diseases was the most difficult. CONCLUSIONS Endomicroscopic images can be interpreted with high concordance. In our study, the diagnostic reliability was not different between students, endomicroscopic experts, and pathologists. Thus, endomicroscopy could be an additional and reliable imaging modality for diagnosing mucosal neoplasia of the gut.