Atsushi Katagiri

MAGNIFYING OBSERVATION OF MICROVASCULAR ARCHITECTURE OF COLORECTAL LESIONS USING A NARROW-BAND IMAGING SYSTEM

We reviewed the magnifying observation of the microvascular architecture of colorectal lesions and discuss the utility of the detailed observation of the microvascular architecture for differential diagnosis during narrow‐band imaging (NBI) colonoscopy. Angiogenesis is critical to the transition of premalignant lesions in a hyperproliferative state to the malignant phenotype. Therefore, diagnosis based on angiogenic or vascular morphologic changes might be ideal for early detection or diagnosis of neoplasms. In this review, we propose the term ‘meshed capillary’ for the distinction between non‐neoplastic and neoplastic lesions and the capillary classification ‘capillary pattern’ for the differential diagnosis of colorectal lesions. We believe that the combined use of NBI optical chromoendoscopy and real chromoendoscopy decreases the time and cost of screening colonoscopy. To assess the feasibility and efficacy of using the NBI system, further studies are required for colorectal lesions and other lesions of the gastrointestinal tract.

Molecular differences between sporadic serrated and conventional colorectal adenomas.

Purpose: The purpose is to compare the molecular characteristics of serrated adenomas (SAs) with those of conventional adenomas (CADs) and hyperplastic polyps (HPs). Experimental Design: We evaluated the proliferative activity and molecular alterations in 47 SAs (25 pure-type and 22 mixed-type), 71 CADs, and 23 HPs. Results: The proliferative activity of SAs, as evaluated by Ki-67 expression, was intermediate between CADs and HPs. There was no significant difference in the incidence of KRAS or p53 mutations between the three histological groups. In the microsatellite instability (MSI) analysis, 21% of SAs (9 of 43) showed MSI at two or more loci (MSI-H); corresponding values were 5% of CADs (3 of 64) and 8% of HPs (1 of 13; SAs versus CADs, P = 0.0125). MSI-H was more likely to be found in pure-type SAs (36%; 8 of 22) than in mixed-type SAs (5%; 1 of 21; P = 0.0212). Loss of hMLH-1 expression was found in 8 of 9 SAs with MSI-H. The incidence of BRAF or KRAS mutations was 36 and 15% of SAs, respectively; the combined incidence of BRAF and KRAS mutations occurred in 49% of SAs. However, there was no significant difference in the incidence of BRAF or KRAS mutations between SAs with and without MSI-H. Conclusions: Genetic instability is more frequently implicated in the tumorigenesis of SAs, especially pure-type SAs, than in that of CADs. In contrast, activation of the Ras/Raf/MEK/MAP kinase cascade by BRAF or KRAS mutation, independently of the genetic instability, may be associated with the progression of about half of SAs.

Definitive chemoradiotherapy for patients with malignant stricture due to T3 or T4 squamous cell carcinoma of the oesophagus.

We retrospectively investigated the efficacy and feasibility of concurrent chemoradiotherapy for patients with severe dysphagia caused by oesophageal squamous cell carcinoma. Concurrent chemoradiotherapy was performed in 57 patients with T3 or T4 disease containing M1 lymph node (LYM) disease. Chemotherapy consisted of protracted infusion of 5-fluorouracil (5-FU) 400 mg m−2 24 h−1 on days 1–5 and 8–12, combined with 2-h infusion of cisplatin (CDDP) 40 mg m−2 on days 1 and 8. Radiation treatment at a dose of 30 Gy in 15 fractions of the mediastinum was administered concomitantly with chemotherapy. A course schedule with 3-week treatment and a 1 to 2-week break was applied twice, with a total radiation dose of 60 Gy, followed by two or more courses of 5-FU and CDDP. In all, 24 patients (42%) achieved a complete response, and the 3-year survival rate was 19%. Major toxicities were leukocytopenia and oesophagitis, and there were two (4%) treatment-related deaths. In contrast, 22 patients with T3 disease survived longer than 35 patients with T4 disease (P=0.001); however, the survival rate in 15 patients with M1 LYM disease did not differ significantly from that in 42 patients without M1 LYM disease (P=0.3545). Our results indicate that definitive chemoradiotherapy is potentially curative for locally advanced oesophageal carcinoma with malignant stricture. The efficacy and survival of patients treated with this regimen are related to the T factor.

Late toxicity in complete response cases after definitive chemoradiotherapy for esophageal squamous cell carcinoma

BackgroundWe retrospectively investigated long-term toxicity after concurrent chemoradiotherapy (CRT) for patients with esophageal squamous cell carcinoma (ESCC).MethodsConcurrent chemoradiotherapy was performed in 110 patients with T1 to T4 disease containing M1 lymph node (LYM) disease. Chemotherapy consisted of protracted infusion of 5-fluorouracil 400 mg/m2 per 24 h on days 1 to 5 and 8 to 12, combined with 2-h infusion of cisplatin 40 mg/m2 on days 1 and 8. Radiation treatment of the mediastinum at a dose of 30 Gy in 15 fractions was administered concomitantly with chemotherapy. A course schedule with a 3-week treatment and a 2-week break was applied twice, with a total radiation dose of 60 Gy. For the assessment of toxicity, the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer late radiation morbidity scoring schema was adopted.ResultsA total of 81 patients were recruited in patients with stage I to IVA. Of 34 patients with complete response, 1 patient died as a result of acute myocardial infarction. Grade 2, 3, and 4 late toxicities occurred with the following incidences: pericarditis in 3 patients, 1 patient, and 2 patients, respectively; heart failure in 0, 0, and 3 patients; pleural effusion in 2, 3, and 0 patients; and radiation pneumonitis in 0, 0, and 1 patient, respectively.ConclusionsDefinitive chemoradiotherapy for ESCC is effective with substantial toxicities. Further investigation is warranted to minimize the normal tissue toxicities.

Characterization of Colorectal Lesions Using a Computer-Aided Diagnostic System for Narrow-Band Imaging Endocytoscopy

Figure 1. Output image. (1) Computer diagnosis. (2) Input endocytoscopy with narrow band imaging. (3) Extracted vessel image, in which the green area denotes the extracted vessels. The light-green vessel has the maximum diameter. (4) Probability of computer diagnosis. 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 REndoscopy established the Preservation and Incorporation of Valuable Endoscopic Innovations for diminutive colorectal polyps. Preservation and Incorporation of Valuable Endoscopic Innovations suggests that, if an endoscopist diagnoses an agreement of >90% in determining postpolypectomy surveillance intervals and a negative predictive value of >90% with adenomatous histology, pathologic diagnosis might not be necessary. Although magnifying chromoendoscopy, narrow-band imaging (NBI), endocytoscopy (EC), and confocal laser endomicroscopy are highly accurate, interpretation of these modalities is difficult for novices. Furthermore, achieving a negative predictive value of >90% for adenoma is not easy using these modalities and requires comprehensive experiments. To achieve a breakthrough on this issue, we developed a computer-aided diagnosis (CAD) system for EC. This system automatically provides highly accurate diagnosis as expert endoscopists concurrently take EC images (Video Clip 1). Our previous system, based on glandular structural and cellular atypia, required endoscopists to use dye for staining. In contrast, the endocytoscopic vascular pattern can effectively evaluate microvessel findings using EC with NBI (EC-NBI) without using any dye. We reported that EC-NBI has a highly accurate diagnostic ability, similar to other modalities. Because dye staining complicates the procedure, our CAD system for EC-NBI represents a powerful tool for novices and experts who do not use dyes on a routine basis. Therefore, we developed a tentative CAD system model for EC-NBI image. Abbreviations used in this paper: CAD, computer-aided diagnosis; EC, endocytoscopy; EC-NBI, endocytoscopy with narrow-band imaging; NBI, narrow-band imaging; SSA/P, sessile serrated adenoma/polyp.

Management of T1 colorectal cancers after endoscopic treatment based on the risk stratification of lymph node metastasis.

Recent advances in endoscopic technology have allowed many T1 colorectal carcinomas to be resected endoscopically with negative margins. However, the criteria for curative endoscopic resection remain unclear. We aimed to identify risk factors for nodal metastasis in T1 carcinoma patients and hence establish the indication for additional surgery with lymph node dissection.

Study of p53 gene alteration as a biomarker to evaluate the malignant risk of Lugol-unstained lesion with non-dysplasia in the oesophagus

Mutations of the p53 gene are detected frequently in oesophageal dysplasia and cancer. It is unclear whether Lugol-unstained lesions (LULs) with non-dysplastic epithelium (NDE) are precursors of oesophageal squamous cell carcinoma (ESCC). To study the genetic alterations of NDE in the multistep process of oesophageal carcinogenesis, we determined the relationship between p53 mutations and LULs-NDE. Videoendoscopy with Lugol staining was performed prospectively in 542 oesophageal cancer-free subjects. Lugol-unstained lesions were detected in 103 subjects (19%). A total of 255 samples, including 152 LULs (NDE, 137; dysplasia, 15) and 103 paired samples of normal staining epithelium, were obtained from 103 subjects. After extraction of DNA and polymerase chain reaction analysis, direct sequencing method was applied to detect mutations of the p53 gene. The p53 mutation was detected in five of 137 samples with LULs-NDE (4%) and in five of 15 samples with dysplasia (33%). A hotspot mutation was found in 20% of LULs-NDE with p53 mutation and in 40% of dysplasia with p53 mutation. In contrast, no p53 mutations were found in 103 paired NDE samples with normal Lugol staining. In biopsy samples from oesophageal cancer-free individuals, the p53 missense mutations containing a hotspot mutation were found in NDE, which was identified as an LUL. These findings suggest that some LULs-NDE may represent the earliest state of oesophageal squamous cell carcinoma in Japanese individuals.

A case of autoimmune pancreatitis complicated with immune thrombocytopenia during maintenance therapy with prednisolone.

A unique form of chronic pancreatitis, primary inflammatory sclerosis of the pancreas, which may result from an autoimmune mechanism, was first reported by Sarles et al (1). Since then, several authors have reported similar cases, and Yoshida et al (2) first proposed the concept of autoimmune pancreatitis. One of the characteristics of so-called autoimmune pancreatitis is an occasional association with other autoimmune diseases such as Sj ̈ ogren’s syndrome (3), primary biliary cirrhosis (4), and primary sclerosing cholangitis (4, 5). However, autoimmune pancreatitis rarely associates with immune thrombocytopenia, and only one case has been previously reported in the Japanese literature (6). According to this report, autoimmune pancreatitis and immune thrombocytopenia occurred concomitantly. We report a case complicated with immune thrombocytopenia during maintenance therapy with prednisolone for autoimmune pancreatitis. In our case, elevation of serum level of total immunoglobulin (Ig) G was thought to be suggestive of the development of other autoimmune disease, and the determination of IgG subclass would provide a useful tool to differentiate exacerbation of autoimmune pancreatitis from the development of other autoimmune disease.

Clinicopathological and Molecular Features of Colorectal Serrated Neoplasias With Different Mucosal Crypt Patterns

OBJECTIVES:Endoscopic examination shows that serrated neoplasias (SNs), such as serrated adenomas and sessile serrated adenomas, exhibit different mucosal crypt patterns. However, it remains unclear whether advanced serrated polyps with different mucosal crypt patterns have different clinicopathological or molecular features.METHODS:We classified the mucosal crypt patterns of 86 SNs into three types (hyperplastic, adenomatous, and mixed pattern) and evaluated their clinicopathological and molecular features.RESULTS:We found significant differences in the proliferative activity status between SNs with mixed/adenomatous patterns and those with the hyperplastic patterns. SNs with the hyperplastic pattern were frequently located in the proximal colon and had a macroscopically superficial appearance, whereas SNs with the adenomatous pattern were often located in the distal colon and had a protruding appearance. Furthermore, a significant difference was observed in the frequency of the CpG island methylator phenotype (CIMP), involving the methylation of two or more CIMP-related genes (MINT1, MINT2, MINT31, p16, and MLH1), between SNs with the hyperplastic pattern and those with the mixed/adenomatous patterns (18/32 (56%) vs. 8/28 (29%) or 7/26 (27%); P=0.0309 or P=0.0249, respectively). Moreover, the prevalence of KRAS mutations was significantly higher in SNs with the adenomatous pattern than in those with the hyperplastic pattern (7/26 (27%) vs. 1/32 (3%); P=0.0173). In comparison with other patterns, the mixed pattern was detected more frequently in mixed serrated polyps (MSPs), which contain separate histological components. Some MSPs exhibited concordant molecular alterations among the different histological components.CONCLUSIONS:The clinicopathological and molecular features of SNs correlated strongly with their mucosal crypt patterns, which were observed using chromoendoscopy.

Distinct molecular features of different macroscopic subtypes of colorectal neoplasms.

BACKGROUND Colorectal adenoma develops into cancer with the accumulation of genetic and epigenetic changes. We studied the underlying molecular and clinicopathological features to better understand the heterogeneity of colorectal neoplasms (CRNs). METHODS We evaluated both genetic (mutations of KRAS, BRAF, TP53, and PIK3CA, and microsatellite instability [MSI]) and epigenetic (methylation status of nine genes or sequences, including the CpG island methylator phenotype [CIMP] markers) alterations in 158 CRNs including 56 polypoid neoplasms (PNs), 25 granular type laterally spreading tumors (LST-Gs), 48 non-granular type LSTs (LST-NGs), 19 depressed neoplasms (DNs) and 10 small flat-elevated neoplasms (S-FNs) on the basis of macroscopic appearance. RESULTS S-FNs showed few molecular changes except SFRP1 methylation. Significant differences in the frequency of KRAS mutations were observed among subtypes (68% for LST-Gs, 36% for PNs, 16% for DNs and 6% for LST-NGs) (P<0.001). By contrast, the frequency of TP53 mutation was higher in DNs than PNs or LST-Gs (32% vs. 5% or 0%, respectively) (P<0.007). We also observed significant differences in the frequency of CIMP between LST-Gs and LST-NGs or PNs (32% vs. 6% or 5%, respectively) (P<0.005). Moreover, the methylation level of LINE-1 was significantly lower in DNs or LST-Gs than in PNs (58.3% or 60.5% vs. 63.2%, P<0.05). PIK3CA mutations were detected only in LSTs. Finally, multivariate analyses showed that macroscopic morphologies were significantly associated with an increased risk of molecular changes (PN or LST-G for KRAS mutation, odds ratio [OR] 9.11; LST-NG or DN for TP53 mutation, OR 5.30; LST-G for PIK3CA mutation, OR 26.53; LST-G or DN for LINE-1 hypomethylation, OR 3.41). CONCLUSION We demonstrated that CRNs could be classified into five macroscopic subtypes according to clinicopathological and molecular differences, suggesting that different mechanisms are involved in the pathogenesis of colorectal tumorigenesis.