Kouichi Nonaka

Usefulness of training using animal models for colorectal endoscopic submucosal dissection: is experience performing gastric ESD really needed?

Background and study aims: Despite the clinical advantages of colorectal endoscopic submucosal dissection (ESD), an effective training system, especially for Western endoscopists, has been challenging to establish. Herein, we propose a novel training program using ex vivo animal models and evaluate the learning curve of colorectal ESD trainees without gastric ESD experience. Patients and methods: A total of 80 colorectal lesions were prospectively collected and removed by two novice operators. Before human ESD procedures, they received ESD training using an ex vivo porcine “proximal colon” model, which simulates a lumen with many folds and flexions. To assess the validity of our training system, the self-completion and en bloc R0 resection rates, the operation time, and prevalence of complications were compared between the first and latter period. Moreover the factors associated with prolonged operation time were evaluated. Results: The overall rates of self-completion and en bloc R0 resection were 98u200a% (78/80) and 100u200a% (80/80), respectively. The operation time during the first period was significantly longer than that during the latter period (86u200a±u200a50 minutes vs. 60u200a±u200a36 minutes, Pu200a=u200a0.01). Regarding complications, only two cases of perforations and delayed hemorrhage were observed during the first period; however, all of the complications were successfully managed endoscopically. The presence of fibrosis was identified as a significant independent predictor of a prolonged operation time during the first period (coefficient, 5.90; 95u200a%CI, 2.36u200a–u200a9.44, Pu200a=u200a0.002). Conclusions: Our trainees achieved high rates of self-completion and R0 resection without severe complications even during the first 20 cases, suggesting that our training programs using ex vivo animal models are useful for trainees without gastric ESD experience. Study registration: UMIN000013566

Is narrow-band imaging useful for histological evaluation of gastric mucosa-associated lymphoid tissue lymphoma after treatment?

Endoscopic diagnosis of stomach mucosa‐associated lymphoid tissue (MALT) lymphoma is often difficult because few specific findings are indicated. Even when MALT lymphoma is suspected by endoscopy, it is still difficult to make a definitive diagnosis by biopsy because lymphoma cells sometimes distribute unevenly. We previously reported that a tree‐like appearance (TLA) is a characteristic finding of MALT lymphoma by narrow‐band imaging (NBI) magnifying endoscopy and it is valuable in the selection of an optimal biopsy site in MALT lymphoma. Here, we study the frequency of TLA and evaluate the relationship between the response to eradication therapy and TLA in MALT lymphoma.

Usefulness of confocal laser endomicroscopy for the diagnosis of ileocecal lymphoma

It is often difficult to diagnose malignant lymphoma in the gastrointestinal tract using endoscopy. We report the case of ileocecal lymphoma diagnosed by probebased confocal laser endomicroscopy (pCLE) (ColoFlex UHD, Cellvizio; Mauna Kea Technologies, Paris, France). The patient was a 52-year-old man who had a positive fecal occult blood test. He underwent colonoscopy and a tumor was found on the ileocecal valve (● Fig.1). A malignant tumor was suspected and a biopsy was taken. The lesion revealed high lymphocyte infiltration, but malignant lymphoma could not be diagnosed. Further multiple biopsies were taken, but a diagnosis could still not be reached. Subsequently, fluorescein-dripping pCLE [1] was performed. Within the lesion, pCLE identified numerous small cells with destruction of normal mucosal structure, which was similar to the image of malignant lymphoma that we have observed previously (● Fig.2, ● Video 1) [2]. Polypectomy was performed, and histopathological assessment showed hyperplasia of moderate-to-large sized atypical lymphocytes (● Fig.3). The cells were immunohistochemically positive for CD20, CD79a, bcl-2, and bcl-6, and negative for CD3, CD5, CD10, and cyclinD1, which resulted in the pathological diagnosis of diffuse large cell lymphoma. The patient was diagnosed as stage I diffuse large cell lymphoma. The patient subsequently received chemotherapy. As the tumor cell size in the histopathological assessment was close to that of the small cells in the CLE image, we believe that what we observed using pCLE were the lymphoma cells.

Probe-based confocal laser endomicroscopy of the duodenal mucosa with fluorescein dispersion

Probe-based confocal laser endomicroscopy (pCLE) is a new imaging modality that enables in vivo histological evaluation of gastrointestinal mucosa during ongoing endoscopy. As confocal imaging is possible with fluorescein staining of the tissue, fluorescein contrast is necessary for pCLE. Fluorescein is given i.v. Side-effects of fluorescein include yellowcolored urine, nausea, and exanthema. However, these side-effects resolve over time. Other severe adverse effects are extremely rare. However, some studies have indicated that giving fluorescein i.v. causes shock or arterial ischemia. To promote the widespread application of pCLE, an alternative method in which pCLE can be more safely carried out should be developed. In the present study, we successfully obtained image quality similar to that of fluorescein given i.v. by dispersing fluorescein in the duodenal mucosa, and report it as a world first. The subject was a healthy 37-year-old man. Before examination, written informed consent regarding gastrointestinal dispersion of fluorescein was obtained. With respect to examination using pCLE and giving fluorescein, approval was obtained from the ethics review board of NTT Medical Center Tokyo. In the duodenal bulb, several drops of 10% fluorescein (Novartis Pharmaceutical Corporation, Bangkok, Thailand) were dripped using a tube for dispersion (Fig. 1). After 20–30 s, the duodenal mucosa was examined using pCLE (GastroFlex UHD, Cellvizio; Mauna Kea Technologies, Paris, France). pCLE revealed the villiform architecture. The epithelium was bright and uniform (Fig. 2A). Goblet cells were black (arrow). Subsequently, 2.5 mL of 10% fluorescein was i.v. injected into the same individual. After a few minutes, we obtained images of the duodenal mucosa distant from the site of 10% fluorescein dispersion. Figure 2B shows a pCLE image after the i.v. injection of 10% fluorescein. It is similar to that in Figure 2A.

Development of a new classification for in vivo diagnosis of duodenal epithelial tumors with confocal laser endomicroscopy: A pilot study

Confocal laser endomicroscopy (CLE) has been established for inu2009vivo diagnosis of various gastrointestinal diseases. However, validated criteria for confocal diagnosis of duodenal tumors do not exist. Therefore, the aim of the present pilot study was to develop a novel classification for inu2009vivo optical diagnosis of duodenal tumors using CLE.

Gastroenterology: Simultaneous practice of narrow band imaging and confocal laser endomicroscopy for a case of early duodenal cancer.

We report an experience of simultaneously performing narrow band imaging (NBI)-magnifying endoscopy and fluoresceinspraying confocal laser endomicroscopy (CLE) for a patient with early duodenal cancer, which has never been reported yet. The patient was a 59-year-old man scheduled for surgery for undifferentiated early gastric carcinoma. Preoperative upper gastrointestinal endoscopy showed a 12-mm, flat, elevated, centrally depressed lesion distal to the papilla of Vater (Fig. 1a). NBImagnifying endoscopy revealed a white opaque substance (WOS) (reportedly comprising fat droplets) at the border and small glandular structures and grossly abnormal microvessels in the central depression (Fig. 1b). Subsequently, fluorescein-spraying CLE was performed using a probe-based CLE (pCLE) (GastroFlex UHD, Cellvizio; Mauna Kea Technologies, Paris, France). Figure 2a shows a pCLE image of the normal mucosa adjacent to the lesion, revealing a villiform architecture composed of regularly arranged bright high-columnar epithelial cells with scattered dark round goblet cells (arrows). In contrast, as shown in Figure 2b, the mucosa of the lesion was composed of irregularly arranged epithelial cells forming closely packed small and large glands. The cells were generally heterogeneous, that is, variable in size and shape, and showing a mixture of bright and dark areas. A biopsy was obtained from the lesion, histologically revealing a proliferation of variable-sized atypical glands with a focal back-to-back appearance (Fig. 2c). The atypical glands were composed of pleomorphic columnar or cuboidal cells with irregularly oriented and pseudostratified oval nuclei, leading to the pathological diagnosis of tubular adenocarcinoma. In the pCLE image and the histology, size of the glands and height of the columnar epithelia were roughly the same, the former being 50 to several hundred micrometer, and the latter being 20 to 30 μm. Overall, the pCLE image seemed to well reflect the findings of biopsy histology, validating the in vivo microscopic diagnosis on the fluorescein-spraying CLE image.

In vivo imaging of duodenal follicular lymphoma with confocal laser endomicroscopy

with confocal laser endomicroscopy Follicular lymphoma arising in the duodenum is a distinct, relatively rare disease [1,2]. Here, we report our experience with confocal laser endomicroscopy (CLE) for follicular lymphoma of the duodenum with the corresponding histopathologic images, which, to our knowledge, is the first description of this. The patient was a 70-year-old woman in whom multiple small whitish polyps were noted in the descending part of the duodenum on upper gastrointestinal endoscopic screening (● Fig.1). When the polypoid lesion was observed using narrow-band imaging, the villi were fused and enlarged compared to the surrounding normal villi (● Fig.2). Curled vascular loops were present in the enlarged villi. Subsequently, fluorescein-dripping CLE [3] was performed using probe-based confocal laser endomicroscopy (pCLE) (GastroFlex UHD, Cellvizio; Mauna Kea Technologies, Paris, France). First, pCLE images of normal mucosa near the lesion were observed as a control, and revealed the villiform architecture with uniformly bright tall-columnar epithelium and dark goblet cells (● Fig.3a, arrows). Then the lesion was observed using pCLE. The width of each villus had increased compared to that of the normal villus structure, and numerous bright small cells were present (● Fig.3b). Biopsy specimens of the lesion site revealed a subepithelial nodular proliferation of smallto medium-sized atypical lymphoid cells (● Fig.4), which were immunohistochemically positive for CD20, CD79a, CD10, and BCL-2, and negative for CD3, CD5, and cyclin D1, resulting in the pathological diagnosis of follicular lymphoma. The tumor cell size in the histological section was consistent with the size of the bright cells in the pCLE image. On positron emission tomography-computed tomography (PET-CT), no accumulation was noted in any regions of the body including the duodenum, and no involvement of the bone marrow was revealed by biopsy of the bone marrow. Based on these findings, the patient was diagnosed as stage I follicular lymphoma. With sufficient informed consent from the patient, a treatment strategy of “watchful waiting”was adopted.

Confocal laser endomicroscopic and magnifying narrow-band imaging findings of gastric mucosa-associated lymphoid tissue lymphoma

The endoscopic findings of gastric mucosa-associated lymphoid tissue (MALT) lymphoma are variable, making its diagnosis very difficult. We previously reported the usefulness of magnifying narrowband imaging (NBI) for the diagnosis of gastric MALT lymphoma [1–3]. Here, we report our experience with the confocal laser endomicroscopic (CLE) imaging of gastric MALT lymphoma and the corresponding histopathological imaging. To our knowledge, this is the first such report in the world. The patient was a 71-year-old woman. Screening upper gastrointestinal endoscopy performed at our hospital revealed a shallow, brownish, depressed lesion approximately 10mm in diameter in the lesser curvature of the middle part of the gastric body (● Fig.1a). When thedepressed lesion was observed with magnifying endoscopy and NBI, it tended to lack glandular structures compared with the surrounding mucosa, and abnormal blood vessels branching in a treelike pattern, whichwe have previously reported [1–3], were observed at the same site (● Fig.1b). Subsequently, fluorescein-aided probebased confocal laser endoscopy (pCLE) was performed with the GastroFlex UHD miniprobe (Cellvizio; Mauna Kea Technologies, Paris, France) [4]. First, pCLE images of the normal mucosa around the lesion were obtained to serve as a control; these showed regular round or oval crypts with homogeneous epithelial cells (● Fig.2a). Then, pCLE was used to observe the lesion; this showed an absence of glandular structures and small, dark cells in a dense arrangement (● Fig.2b). Biopsy specimens of the lesion site exhibited a subepithelial nodular proliferation of small to medium-size centrocyte-like cells (● Fig.3a), which were immunohistochemically positive for CD20 and Bcl-2 and negative for CD3, CD10, cyclin D1, and Bcl-6 (● Fig.3b). Lymphoepithelial lesions were also observed (● Fig.3a), resulting in a pathological diagnosis of gastric MALT lymphoma. The size of the tumor cells on the histological sections was consistent with the size of the dark cells on pCLE imaging. Based on the results of positron emission tomography and computed tomography (PET-CT) and bonemarrow findings, stage II gastric MALT lymphomawas diagnosed.

Endoscopic submucosal dissection for laterally spreading tumors involving the appendiceal orifice

BackgroundSince the endoscopic resection of laterally spreading tumors (LSTs) involving the appendiceal orifice remains technically difficult, such lesions are usually treated by surgical resection. However, with recent advances in endoscopic devices, endoscopic submucosal dissection (ESD) has become feasible and may be safely performed even for lesions involving the appendiceal orifice. Therefore, in order to assess the validity of endoscopic treatment for such lesions, we retrospectively evaluated the safety and efficacy of ESD.MethodsA total of 30 patients with LSTs extending to within 10xa0mm of the appendiceal orifice (Group AO) and 122 patients with cecal LSTs located away from the appendiceal orifice (Group C) who were treated between December 2011 and September 2015 were retrospectively enrolled in the present study. The indications for ESD were determined by the preoperative endoscopic diagnosis made on the basis of Kudo’s pit pattern classification. Based on these preoperative endoscopic diagnoses, 8 of the 30 enrolled patients underwent surgical resection as the initial treatment, because the tumor showed deep invasion beyond the orifice and/or a VN pit pattern was visible. The treatment outcomes (en bloc R0 resection rates, tumor size, procedure time, and complication rates) were compared between the two groups.ResultsThe sensitivity and specificity for the cancer diagnosis were 81.8 and 94.7%, respectively. There was no significant difference in the en bloc R0 resection rate between Group AO and Group C (90.9 vs. 95.9%, Pxa0=xa00.23). Furthermore, there were also no differences in the mean tumor size (30.0xa0±xa020.8 vs. 34.9xa0±xa014.5xa0mm, Pxa0=xa00.17) or mean OR time (55.0xa0±xa039.2 vs. 58.9xa0±xa048.2xa0min Pxa0=xa00.72) between the two groups. One case from Group AO (4.5%) was complicated by a perforation, which was successfully managed endoscopically.ConclusionsAlthough proficiency in endoscopic techniques is required, our results indicate that LSTs involving the appendiceal orifice can be successfully treated by ESD.

Novel technique of endoscopic full-thickness resection for superficial nonampullary duodenal neoplasms to avoid intraperitoneal tumor dissemination

Background and study aims: Recently, laparoscopic and/or endoscopic full-thickness resection (FTR) has been reported to be a useful technique for the treatment of superficial duodenal neoplasms (SDNs). In the current study, we evaluated clinical outcomes in 5 consecutive patients who underwent resection of nonampullary SDNs using laparoscopy-assisted endoscopic full-thickness resection with ligation Device (LAEFTR-L), which is an alternative FTR method developed to avoid peritoneal dissemination. Using a snare technique with a ligation band, the duodenal lesions were easily resected. The provisional and additional sutures for the resected site prevented delayed perforation and bleeding and they also protected the abdominal cavity from direct exposure to malignant cells. Complete resection could be achieved and FTR was histologically confirmed in all cases. The mean operation time was 173 minutes (range 138u200a–u200a217 minutes). Mean diameter of the resected specimen was 24u200amm (range 18u200a–u200a32u200amm). No adverse events (AEs) were observed. LAEFTR-L, which can achieve complete resection of nonampullary SDNs without severe AEs and peritoneal dissemination, could be a useful technique for the treatment of such lesions.