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Objectives: Distinguishing between intramucosal cancer and submucosal invasive cancer is vital for optimal treatment selection for patients with superficial nonampullary duodenal adenocarcinoma (SNADAC); however, standard diagnostic systems for diagnosing invasion depth are as yet undetermined., Methods: Of 205 patients with SNADAC who underwent treatment at our institution between 2006 and 2022, 188 had intramucosal cancer and 17 had submucosal invasive cancer. The clinical, endoscopic, and pathological features used in the preoperative diagnosis of invasion depth and the diagnostic performance of endoscopic ultrasonography (EUS) were retrospectively analyzed in 85 patients., Results: The oral side of the papilla tumor location, protruded or mixed macroscopic type, and moderately-to-poorly differentiated adenocarcinoma based on biopsy specimens were significantly more frequent in submucosal invasive cancer than in intramucosal cancer (88% vs. 48%; 94% vs. 42%; 47% vs. 0%, respectively). From the relationship between the endoscopic features and the submucosal invasive cancer incidence, submucosal invasion risk was stratified as: (i) low-risk (risk, 2%), all lesions located on the anal side of the papilla and superficial macroscopic type on the oral side of the papilla; and (ii) high-risk (risk, 23%), protruded or mixed macroscopic type on the oral side of the papilla. Based on the biopsy specimens, all eight patients with moderately-to-poorly differentiated adenocarcinoma had submucosal invasive cancer. Furthermore, EUS was not associated with invasion depth's diagnostic accuracy improvements., Conclusion: Optimal treatment indications for SNADAC can be selected based on the risk factors of submucosal invasion by tumor location, macroscopic type, and biopsy diagnosis., (© 2023 Japan Gastroenterological Endoscopy Society.)

Background: In Japan, the standard management of Barrett's esophageal adenocarcinoma after endoscopic submucosal dissection involves follow-up; however, multifocal synchronous/metachronous lesions are sometimes observed after endoscopic submucosal dissection. Risk stratification of multifocal cancer facilitates appropriate treatment, including eradication of Barrett's esophagus in high-risk cases; however, no effective risk stratification methods have been established. Thus, we identified the risk factors for multifocal cancer and explored risk-stratified treatment strategies for residual Barrett's esophagus., Methods: We retrospectively reviewed the data of 97 consecutive patients with superficial Barrett's esophageal adenocarcinomas who underwent curative resection with endoscopic submucosal dissection. Multifocal cancer was defined by the presence of synchronous/metachronous lesions during follow-up. We used Cox regression analysis to identify the risk factors for multifocal cancer and subsequently analyzed differences in cumulative incidences., Results: The cumulative incidences of multifocal cancer at 1, 3, and 5 years were 4.4%, 8.6%, and 10.7%, respectively. Significant risk factors for multifocal cancer were increased circumferential and maximal lengths of Barrett's esophagus. The cumulative incidences of multifocal cancer at 3 years were lower for patients with circumferential length < 4 cm and maximal length < 5 cm (2.9% and 1.2%, respectively) than for patients with circumferential length ≥ 4 cm and maximal length ≥ 5 cm (51.5% and 49.1%, respectively)., Conclusions: Risk stratification of multifocal cancer using length of Barrett's esophagus was effective. Further multicenter prospective studies are needed to substantiate our findings., (© 2024. The Author(s), under exclusive licence to The Author(s) under exclusive licence to The Japan Esophageal Society.)

Background: The incidence of Barrett's esophageal adenocarcinoma (BEA) is increasing, and endoscopic submucosal dissection (ESD) has been frequently performed for its treatment. However, the differences between the characteristics and ESD outcomes between short- and long-segment BEA (SSBEA and LSBEA, respectively) are unclear. We compared the clinicopathological characteristics and short- and long-term outcomes of ESD between both groups., Methods: We retrospectively reviewed 155 superficial BEAs (106 SSBEAs and 49 LSBEAs) treated with ESD in 139 patients and examined their clinicopathological features and ESD outcomes. SSBEA and LSBEA were classified based on whether the maximum length of the background mucosa of BEA was < 3 cm or ≥ 3 cm, respectively., Results: Compared with SSBEA, LSBEA showed significantly higher proportions of cases with the macroscopically flat type (36.7% vs. 5.7%, p < 0.001), left wall location (38.8% vs. 11.3%, p < 0.001), over half of the tumor circumference (20.4% vs. 1.9%, p < 0.001), and synchronous lesions (17.6% vs. 0%, p < 0.001). Compared with SSBEA, regarding ESD outcomes, LSBEA showed significantly longer resection duration (91.0 min vs. 60.5 min, p < 0.001); a lower proportion of submucosal invasion (14.3% vs. 29.2%, p = 0.047), horizontal margin negativity (79.6% vs. 94.3%, p = 0.0089), and R0 resection (69.4% vs. 86.8%, p = 0.024); and a higher proportion of post-procedural stenosis cases (10.9% vs. 1.9%, p = 0.027). The 5-year cumulative incidence of metachronous cancer in patients without additional treatment was significantly higher for LSBEA than for SSBEA (25.0% vs. 0%, p < 0.001)., Conclusions: The clinicopathological features of LSBEA and SSBEA and their treatment outcomes differed in many aspects. As LSBEAs are difficult to diagnose and treat and show a high risk of metachronous cancer development, careful ESD and follow-up or eradication of the remaining BE may be required., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

We herein report two cases of early esophageal adenocarcinoma derived from non-Barrett's columnar epithelium. Both patients, a 65-year-old woman and 60-year-old man, had elevated lesions on white-light imaging. Magnifying endoscopy revealed slightly irregular surface and vessel patterns, and both patients were successfully treated with endoscopic submucosal dissection. Histopathologically, both lesions comprised of well-differentiated gastric mucin phenotype adenocarcinoma. One lesion was accompanied by ectopic gastric mucosa, but the other was speculated to be ectopic gastric mucosa according to the tumor locus at the upper thoracic esophagus. Despite its rarity, endoscopists should consider the existence of adenocarcinoma derived from non-Barrett's columnar epithelium.

Objectives: Given the differences in clinical and biological characteristics between cervical adenocarcinoma and squamous cell carcinoma, this study aimed to conduct an exploratory analysis to examine the molecular characteristics of cervical adenocarcinoma in a Japanese population., Methods: This study explored the simultaneous testing of multiple mutations targeting cervical adenocarcinoma using next-generation sequencing (NGS). The following genes were analyzed: BCAR4, CD274, PDCD1LG2, KRAS, ARID1A, PTEN, ALK, EGFR, ROS1, BRAF, PIK3CA, EP300, EBXW7, SHCBP1, TGFBR2, SMAD4, ERBB2, ERBB3, and KLF5. Tumor tissue and blood samples were obtained at the time of primary treatment. The NGS-based molecular profiles obtained from Tokai University (49 specimens) were compared with the registered data in The Cancer Genome Atlas (TCGA) database (133 specimens)., Results: The study cohort had higher rates of adenocarcinoma than the TCGA cohort (44.9% vs. 18.0%; P = 0.001). The adenocarcinomas in the study cohort had more alterations in ROS1, EGFR, EP300, SHCBP1, ALK, and PIK3CA than those in the TCGA cohort. Among them, ROS1 had the highest number of gene alterations (median, 7.00 ± 2.63). In the study cohort, patients with a high number of ROS1 alterations had a significantly higher recurrence rate (5-year recurrence rate, 48.8% vs. 14.6%; hazard ratio [HR], 4.32; 95% confidence interval [CI], 1.20-15.50; P = 0.014) and lower overall survival than those with low alterations (5-year survival rate, 70.7% vs. 93.1%; HR, 7.15; 95% CI, 1.08-58.22; P = 0.032)., Conclusion: The current exploratory analysis suggests that ROS1 gene alteration may be a prognostic biomarker in cervical adenocarcinoma in Japanese patients., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Curative rates of endoscopic treatment for undifferentiated-type early gastric cancer (EGC), particularly mixed poorly differentiated adenocarcinoma (MIXED-POR), are lower than those of endoscopic treatment for the differentiated type. Magnifying endoscopy with narrow-band imaging (ME-NBI) is useful for diagnoses of the histological type. This study aimed to investigate the detection rates of MIXED-POR among undifferentiated-type EGCs using biopsy and ME-NBI in order to improve curative rates through endoscopic treatment., Methods: We analyzed 267 lesions initially subjected to endoscopic submucosal resection (ESD) and histologically diagnosed as undifferentiated-type EGCs between July 2005 and December 2016 at our hospital. We obtained written informed consent from all participants. Biopsy and ME-NBI findings were compared to distinguish pure signet ring cell carcinoma (PURE-SIG) and MIXED-POR. ME-NBI findings were divided into 2 categories depending on the presence of irregular vessels. Results of biopsy and ME-NBI (combination method) were also analyzed, and detection rates of MIXED-POR and PURE-SIG were evaluated in terms of sensitivity, specificity, and accuracy., Results: Overall, 114 lesions were analyzed. Fifty-eight lesions (50.9%) were identified as MIXED-POR. With biopsy, the detection rate of MIXED-POR was significantly lower than that of PURE-SIG (p < 0.0001). ME-NBI detected significantly more MIXED-POR with irregular vessels than PURE-SIG (p < 0.0001). The combination method could detect significantly more MIXED-POR than PURE-SIG (p < 0.0001). The sensitivity and accuracy for MIXED-POR diagnosis were significantly higher with the combination method than with biopsy alone (p < 0.0001)., Discussion/conclusion: Combining biopsy and ME-NBI improved the accuracy of pretreatment diagnosis before ESD in undifferentiated-type cancer., (© 2021 S. Karger AG, Basel.)

Background: Management strategies for primary non-ampullary duodenal adenocarcinoma (NADAC) in early stage are not well established given its low incidence. This study aimed to elucidate clinicopathological features of early NADAC, including risk for lymph nodal metastasis (LNM)., Methods: In total, 166 patients with early NADAC underwent initial treatment at our institution between 2006 and 2019, of whom 153 had intramucosal (M-) and 13 had submucosal (SM-) NADAC. These endoscopic and pathological features were retrospectively analyzed. Risk factors for LNM were evaluated in 46 early NADAC patients who underwent surgery with lymph node dissection., Results: Compared with M-NADAC, SM-NADAC was significantly more frequently located at the proximal side of the papilla, with mixed elevated and depressed macroscopic type, histologically poorly differentiated tumor and lymphovascular invasion (LVI) (85% vs. 47%, P = 0.009; 54% vs. 5%, P < 0.001; 23% vs. 0%, P < 0.001; and 46% vs. 0%, P < 0.001, respectively). The frequency of LNM was significantly higher in SM-NADAC than in M-NADAC (5/12, 42% vs. 0/34, 0%; P < 0.001). In SM-NADAC, the frequency of LNM was higher in poorly differentiated than in well to moderately differentiated tumors (3/3, 100% vs. 2/9, 22%) and higher in tumors with LVI than in those without LVI (3/5, 60% vs. 2/7, 29%). Regarding invasion depth, 2 of 4 patients with SM invasion (400 ≤ × < 500 µm) showed LNM. However, in this study, no patients developed very shallow SM invasion (0 < × < 400 µm)., Conclusions: SM-NADAC showed high LNM risk. Surgical treatment with regional lymph node dissection is recommended as a treatment strategy for SM-NADAC.

We aimed to clarify the differences in therapeutic outcomes of patients with pure undifferentiated-type and mixed undifferentiated-type cancers who underwent endoscopic submucosal dissection (ESD), and whether pre-treatment diagnosis of mixed undifferentiated-type cancer is associated with requiring additional surgery after ESD. Patients subjected to ESD as initial treatment between May 2005 and March 2017 were enrolled. There were 277 undifferentiated-type cancers (265 patients). Histologically, 258 lesions were pure-type and 19 were mixed-type. We compared therapeutic outcomes and pre-treatment factors (tumour diameter, tumour depth, ulcerative findings, tumour location, and the macroscopic, and histological type of the biopsy specimen) between pure-type and mixed-type lesions, and between cases not requiring additional surgeries and cases requiring additional surgeries. Tumour diameter >20 mm, submucosal invasion, and the presence of ulcerative findings made pre-treatment diagnosis more difficult for mixed-type than for pure-type lesions. In cases requiring additional surgery, pre-treatment diagnosis of mixed-type lesions was significantly more likely than pre-treatment diagnosis of pure-type lesions. For mixed-type lesions, pre-treatment histological diagnosis and careful consideration are necessary to determine indications for ESD to avoid additional surgery after ESD.

Background and Aim: The study aims to clarify the endoscopic features and clinicopathological differences in superficial Barret's esophageal adenocarcinoma (s-BEA) derived from short-segment Barrett's esophagus (SSBE) and long-segment Barrett's esophagus (LSBE)., Methods: We reviewed data of 130 patients (141 lesions) with pathologically confirmed s-BEA (SSBE: 95 patients and 95 lesions; LSBE: 35 patients and 46 lesions). We analyzed endoscopic and clinicopathological features of s-BEA in patients with SSBE and LSBE., Results: The distribution of lesions according to macroscopic findings were as follows (s-BEA in SSBE vs LSBE): flat type (0-IIb), 3.2% (3/95) vs 32.6% (15/46) (P < 0.001); accompanied type 0-IIb, 2.1% (2/95) vs 21.7% (10/46) (P < 0.001); and complex type (0-I + IIb, 0-IIa + IIc, etc.), 30.5% (29/95) vs 50.0% (23/46) (P = 0.025). Complex-type s-BEAs had high incidences of T1b invasions and poorly differentiated components (simple type: 22.5% [20/89] and 18.0% [16/89]; complex type: 59.6% [31/52] and 44.2% [23/52], P < 0.001 and P = 0.002, respectively). In SSBE, 72.6% (69/95) of lesions were located at the right anterior wall (P = 0.01). All flat-type or depressed-type lesions derived from SSBE were identified as reddish areas, whereas only 65.2% (15/23) from LSBE were identified as reddish areas (P < 0.001)., Conclusions: In LSBE, flat-type, accompanied-type 0-IIb, and complex-type lesions were significantly more prevalent. Furthermore, complex-type s-BEAs tended to have T1b invasions and poorly differentiated components. S-BEAs in LSBE should be more carefully evaluated on endoscopic appearance including flat-type and complex-type lesions than in SSBE., (© 2019 The Authors. Journal of Gastroenterology and Hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background: The double-tracer method has been established for sentinel node (SN) mapping in gastric cancer surgery. However, there remain several unresolved issues that prevent its widespread use in clinical practice. In this study, we aimed to demonstrate the feasibility of single-tracer SN mapping in laparoscopic surgery for gastric cancer, using indocyanine green (ICG) fluorescence imaging with a one-step nucleic acid amplification (OSNA) assay intraoperatively., Methods: Patients with clinical T1N0M0 gastric adenocarcinoma preoperatively were considered for inclusion if they had a single primary lesion 4 cm or less in maximal diameter. Immunohistochemical staining with the anti-cytokeratin 19 antibody was performed on preoperative biopsy specimens, and patients with faint positive reactions were excluded. Intraoperatively, single-tracer SN biopsy with ICG fluorescence imaging was performed, followed by laparoscopic gastrectomy with modified D1+ or D2 lymph node dissection., Results: Twenty eligible patients underwent SN biopsy and laparoscopic gastrectomy. SNs were identified in 17 cases (85%), with a median number of three SNs per patient. The median times for SN mapping and OSNA assay were 19 and 35 min, respectively. OSNA assay detected one metastatic lymph node, but all other nodes were negative. No adverse effects were observed in relation to SN mapping., Conclusions: Single-tracer SN mapping by ICG fluorescence imaging with intraoperative diagnosis by OSNA assay is feasible and safe. SNs can be identified in most patients, without producing false-negative results. Further clinical trial to demonstrate the sensitivity is ongoing.

Background and Aims: The incidence of metachronous gastric cancer (MGC) in patients whose primary gastric neoplasm is discovered after Helicobacter pylori eradication remains unclear. Here, we evaluated the long-term effect of previous H pylori eradication on development of MGC after endoscopic submucosal dissection (ESD)., Methods: We analyzed prospectively collected data of consecutive patients with successful H pylori eradication more than 1 year before (eradicated group, 180 patients) or after (control group, 602 patients) initial curative ESD. These patients were also followed by endoscopy for over 2 years. Propensity score matching and inverse probability of treatment weighting (IPTW) were used to adjust for confounding variables during data analysis. The main outcome was the incidence of MGC after initial ESD., Results: In a propensity-matched analysis of 174 pairs, the incidence of MGC was similar in the 2 cohorts (33.9 per 1000 person-years vs 40.8 per 1000 person-years in the control group, P = .454) at a median follow-up of 4.1 years (interquartile range, 3.0-5.6). Incidences were also similar in the 2 groups when data were analyzed using IPTW, even after exclusion of 123 patients with successful H pylori eradication <5 years before initial ESD. Multiple Cox regression analysis revealed age, differentiated-type histology, and initial multiplicity were predictors of MGC in patients after initial curative ESD., Conclusions: The frequency of follow-up surveillance after initial curative ESD should be kept constant, irrespective of whether H pylori eradication is performed before or after initial curative ESD., (Copyright © 2019. Published by Elsevier Inc.)

Objectives: A Japanese multicenter prospective cohort study examining endoscopic resection (ER) for early gastric cancer (EGC) has been conducted using a Web registry developed to determine the short-term and long-term outcomes based on absolute and expanded indications. We hereby present the short-term outcomes of this study., Methods: All consecutive patients with EGC or suspected EGC undergoing ER at 41 participating institutions between July 2010 and June 2012 were enrolled and prospectively registered into the Web registry. The baseline characteristics were entered before ER, and the short-term outcomes were collected at 6 months following ER., Results: Nine thousand six hundred and sixteen patients with 10 821 lesions underwent ER (endoscopic submucosal dissection [ESD]: 99.4%). The median procedure time was 76 min, and R0 resections were achieved for 91.6% of the lesions. Postoperative bleeding and intraoperative perforation occurred in 4.4% and 2.3% of the patients, respectively. Significant independent factors correlated with a longer procedure time (120 min or longer) were as follows: tumor size >20 mm, upper-third location, middle-third location, local recurrent lesion, ulcer findings, gastric tube, male gender, and submucosa. Histopathologically, 10 031 lesions were identified as common-type gastric cancers. The median tumor size was 15 mm. Noncurative resections were diagnosed for 18.3% of the lesions. Additional surgery was performed for 48.6% (824 lesions) of the 1695 noncurative ER lesions with a possible risk of lymph node (LN) metastasis. Among them, 64 (7.8%) exhibited LN metastasis., Conclusions: This multicenter prospective study showed favorable short-term outcomes for gastric ESD., (© 2018 Japan Gastroenterological Endoscopy Society.)

Background and Aims: The prognosis of esophageal cancer is relatively poor. Patients are usually diagnosed at an advanced stage when it is often too late for effective treatment. Recently, artificial intelligence (AI) using deep learning has made remarkable progress in medicine. However, there are no reports on its application for diagnosing esophageal cancer. Here, we demonstrate the diagnostic ability of AI to detect esophageal cancer including squamous cell carcinoma and adenocarcinoma., Methods: We retrospectively collected 8428 training images of esophageal cancer from 384 patients at the Cancer Institute Hospital, Japan. Using these, we developed deep learning through convolutional neural networks (CNNs). We also prepared 1118 test images for 47 patients with 49 esophageal cancers and 50 patients without esophageal cancer to evaluate the diagnostic accuracy., Results: The CNN took 27 seconds to analyze 1118 test images and correctly detected esophageal cancer cases with a sensitivity of 98%. CNN could detect all 7 small cancer lesions less than 10 mm in size. Although the positive predictive value for each image was 40%, misdiagnosing shadows and normal structures led to a negative predictive value of 95%. The CNN could distinguish superficial esophageal cancer from advanced cancer with an accuracy of 98%., Conclusions: The constructed CNN system for detecting esophageal cancer can analyze stored endoscopic images in a short time with high sensitivity. However, more training would lead to higher diagnostic accuracy. This system can facilitate early detection in practice, leading to a better prognosis in the near future., (Copyright © 2019. Published by Elsevier Inc.)

Background and Aim: Previous studies of surgical specimens have found that the presence of mixed histological components in differentiated-type early gastric cancer (EGC) is a risk factor for lymph node metastasis and indicates greater malignancy. As there have been no reports on its endoscopic treatment, we examined endoscopic curative resection in relation to differentiated-type-predominant mixed-type (MT)., Methods: This was a single-center, retrospective study. Subjects were 2585 differentiated-type EGC in 2551 patients treated with endoscopic submucosal dissection (ESD) in our hospital between March 2005 and January 2016. These lesions comprised 2231 cases of curative resection and 354 cases of non-curative resection. Histologically, 2339 lesions were pure differentiated-type (PDT) and 246 lesions were MT. Rates of curative resection were compared, according to tumor size, between different histological types., Results: When curative and non-curative cases were compared using multivariate analysis among lesions measuring ≤20 mm for factors other than those determining curative resection, significant differences were obtained for tumor diameter, ulcer, and MT. Among lesions measuring 21-30 mm, ulcer and MT were associated with significant differences. Among lesions measuring >30 mm, upper region and MT were associated with significant differences. Curative resection rates, in relation to histological type among lesions measuring ≤20 mm, were 93.4% for PDT and 63.4% for MT, whereas corresponding rates were 85.1% and 60.0%, respectively, among lesions measuring 21-30 mm, and 55.3% and 30.2%, respectively, among lesions measuring >30 mm., Conclusion: We found that MT was a risk factor for non-curative resection irrespective of lesion size., (© 2018 Japan Gastroenterological Endoscopy Society.)

Background: Comparisons between surgical cases of mixed poorly differentiated adenocarcinoma and pure signet ring cell carcinoma have revealed higher frequencies of lymph node metastasis and submucosal invasion in the former. However, this comparison has not been reported for endoscopically treated cases. Therefore, we compared cases of curative and noncurative resection in patients who underwent endoscopic submucosal dissection to determine what factors could influence the curative resection rate., Methods: We analyzed 268 undifferentiated-type early gastric cancers in 264 patients treated with endoscopic submucosal dissection in our hospital between March 2005 and March 2017, involving 229 and 39 cases of curative and noncurative resection, respectively. Treatment results were compared between 129 lesions of pure signet ring cell carcinoma and 139 lesions of mixed poorly differentiated adenocarcinoma., Results: The overall curative resection rate was 85.4% (229/268). On comparing noncurative and curative resection cases, after excluding factors that determine curative resection (e.g., tumor diameter), we found that the former was associated with older age and significantly more mixed poorly differentiated adenocarcinomas, with odds ratios of 1.052 [95% confidence interval (CI), 1.017-1.089] and 2.746 (95% CI, 1.162-6.485), respectively, on multivariate analysis. The curative resection rate was significantly higher in pure signet ring cell carcinoma than in mixed poorly differentiated adenocarcinoma (93.8% vs. 77.7%, respectively)., Conclusion: Advanced age and mixed poorly differentiated adenocarcinoma predicted endoscopic noncurative resection.

Background: In recent years, effective outcomes of endoscopic submucosal dissection (ESD) for esophagogastric junction cancer including short-segment Barrett's esophagus (SSBE) cancer have been reported. However, the efficacy of ESD for long-segment Barrett's esophagus (LSBE) cancer is unknown., Aim: To clarify the treatment outcomes of ESD for LSBE cancer versus SSBE cancer., Methods: A total of 86 patients with 91 superficial Barrett's esophageal adenocarcinomas who underwent ESD were enrolled; of these, 68 had underlying SSBE and 18 had LSBE. Procedure outcomes and prognosis were compared., Results: There was no significant difference in age and tumor diameter among patients. The only complication observed was stricture, but it was not significant (2 vs. 9%). No significant difference was observed in the negative horizontal margin rates (94.1 vs. 95.7%), R0 resection rates (83.8 vs. 82.6%), curative resection rates (72.1 vs. 73.9%), and noncurative factors. Both LSBE and SSBE cancer showed favorable 3-year overall survival rates (95.0 vs. 94.4%) in the median observation period of 28.5 months., Conclusions: ESD for LSBE cancer achieved procedure outcomes and short-term prognosis comparable to SSBE. ESD has the potential to be an effective therapeutic option for esophageal neoplasms in patients with LSBE., (© 2018 S. Karger AG, Basel.)

Objectives: Siewert type II esophagogastric junction adenocarcinoma encompasses both gastric cardia adenocarcinoma (GCA) and Barrett's esophageal adenocarcinoma (BEA) due to short-segment Barrett's esophagus. We compared these two types of Siewert type II esophagogastric junction adenocarcinoma in terms of background factors and clinical outcomes of endoscopic submucosal dissection (ESD)., Methods: We enrolled 139 patients (142 lesions) who underwent ESD from 2006 to 2014 at our institution. Background factors evaluated were age, sex, body mass index, hypertension, hyperlipidemia, hyperuricemia, diabetes mellitus, smoking, drinking, double cancer, and endoscopic findings. Clinical outcomes evaluated were procedure time, en bloc resection rate, curative resection rate, and adverse events., Results: There were 87 GCA lesions (61.2%) and 55 BEA lesions. Features of BEA [55 lesions (38.8%)] included a younger age, small diameter, and a protruding type, along with a high frequency of esophageal hiatal hernia and less mucosal atrophy. There were no significant differences in lifestyle-related background factors between the GCA and BEA groups. Curative resection rate was greater for GCA (81%) than for BEA (66%) (P = 0.01). There were no serious adverse events in either group. Among the factors for noncurative resection, lymphovascular invasion and depth of invasion were greater for BEA (33.3 vs. 7 and 20.7 vs. 8.2%, respectively (P < 0.01). Of the noncured patients, 70% underwent additional surgery and none had postoperative lymph node metastasis., Conclusions: Siewert type II adenocarcinoma encompasses two types of cancers with different etiologies: GCA and BEA. Although there are no significant differences in lifestyle-related background factors between GCA and BEA, BEA is a risk factor for noncurative resection via ESD.

A 72-year-old male with nausea and heartburn was found to have early pharyngeal squamous cell carcinoma, superficial and advanced esophageal squamous cell carcinoma and early esophageal adenocarcinoma by esophagogastroduodenoscopy. Computerized tomography demonstrated left cardiac lymph node swellings. We prioritized the treatment for esophageal squamous cell carcinoma, as this was the most advanced cancer among the triple primaries. The patient underwent neoadjuvant chemotherapy for esophageal squamous cell carcinoma followed by esophagectomy. Four months after esophagectomy, endoscopic submucosal dissection for pharyngeal squamous cell carcinoma was performed. This is a first report of pharyngeal squamous cell carcinoma, esophageal squamous cell carcinoma and esophageal adenocarcinoma occurring as triple primary cancers in a single patient. Smoking-induced tumor formation through DNA methylation is a common risk factor for patients with triple primary malignancies, being an example of epigenetic field cancerization induced by exposure to carcinogenic factors.

Background and Aim: The usefulness of magnifying endoscopy with narrow-band imaging (ME-NBI) in undifferentiated-type early gastric cancers (UD-type EGCs) is unclear. This study investigated the accuracy of ME-NBI in the diagnostic demarcation., Methods: Among UD-type EGCs that were initially surgically resected between June 2011 and August 2014 in this hospital, 74 lesions were studied that were preoperatively diagnosed with white-light imaging (WLI) or endoscopic ultrasonography as lesions for which endoscopic treatment was not indicated and found to be early gastric cancers by postoperative pathology. The demarcation line was marked on the most oral and anal sides with argon plasma coagulation using WLI and ME-NBI, and the diagnostic demarcation of cancer was defined as correct, if consistent with the results of postoperative pathology. The length of extension into the proliferative zone, distance between crypts and inflammatory cell infiltration (updated Sydney classification: USC) were compared between the correctly diagnosed and the misdiagnosed cases., Results: The diagnosis was correct in 62 cases (83.8 %). The average distance between crypts in correctly diagnosed and misdiagnosed cases was approximately 1.9 and 1.3 times, respectively, that in normal mucosa (p < 0.0001). The accuracy of diagnosis was higher when atrophy and neutrophil and monocyte infiltration were mild according to the USC (p < 0.05). The additional use of ME-NBI improved the accuracy of diagnosis by 36.5 % compared with the use of WLI alone., Conclusion: The use of ME-NBI in the preoperative diagnosis of the demarcation of cancer is useful to prevent postoperative positive surgical margins.

Background: Diagnostic endoscopy occasionally shows synchronous early gastric cancer (EGC) and esophageal cancer (EC) in the same patient. The treatment plan for these comorbid cancers is unclear because, as EGC is commonly treated surgically, information on post-chemotherapy outcomes for EGC are lacking, although chemotherapy and chemoradiotherapy are important in treating EC. Here, we evaluated whether unresected EGC could be safely observed while synchronous EC is treated with chemotherapy in patients with both cancers., Methods: We enrolled 30 patients with both EGC and EC who were treated with 5-FU plus cisplatin (FP) from January 2006 to September 2013, and who were evaluated with endoscopy before chemotherapy, and approximately every 3 months afterwards., Results: The response rate to FP for EGC was 46.8 %. Notably, five cases (16.7 %) had clinically complete responses with no progressive disease. Progression-free survival was 100 % at 6 months and 96.2 % at 1 year. In univariate analysis, FP was significantly more effective for mixed-type and undifferentiated adenocarcinoma than for differentiated adenocarcinoma., Conclusions: FP was effective for EGC. EGC was stable without progression for more than 6 months while patients underwent FP treatment for EC. We consider observing EGC with no treatment during chemotherapy for EC to be appropriate disease management.

In Japan, the criteria for cancer of the esophagogastric junction (EGJ) are that the center of the lesions are located within 2cm from the EGJ orally and anally. The main histology of these lesions are squamous cell carcinoma and adenocarcinoma. Squamous cell carcinoma of the esophagus is treated following the guidelines published by the Japan Esophageal Society. This paper focuses on EGJ adenocarcinomas, which include cardiac gastric cancer and Barrett's cancer originating from the short-segment Barrett's esophagus. EGJ cancer is resected endoscopically at the termination of the palisade vessels or upper end of the gastric fold. The various types of cancer involving the EGJ are treated following the guidelines published by each medical specialist society in Japan. The main endoscopic treatment is endoscopic submucosal dissection. The EGJ is a narrow space, and therefore lesions are approached from the oral approach or anal approach using a reverse endoscope. Bleeding, perforation, and stenosis are major complications. When two-thirds or more of the wall is resected, stenosis occurs. Endoscopic therapy for cancer originating in the EGJ has not yet been fully established.

Objectives: It is well known that a poorly differentiated endometrial adenocarcinoma shows more rapid progression and a worse response to therapy than a well-differentiated endometrial adenocarcinoma. Qualitative and quantitative changes of cell surface glycolipids occur during neoplastic transformation. Sulfatide is one of the sulfated glycolipids in the cell membrane that may have an important role in various functions such as cell adhesion. To examine the molecular background of the morphological and biological features of well-differentiated and poorly differentiated cancer, we measured the levels of lipids, especially glycolipids, in tumor tissues from patients with endometrial carcinoma., Materials and Methods: We determined the composition of lipids and glycolipids in tumor tissues, investigated glycosyltransferase messenger RNA expression by the reverse transcription-polymerase chain reaction, and assessed the localization of galactosylceramide sulfotransferase (an enzyme involved in sulfatide biosynthesis) by immunohistochemical staining., Results: No significant differences were observed between well-differentiated and poorly differentiated cancer with respect to the levels of cholesterol ester, cholesterol, phospholipids, cholesterol sulfate, ceramides, neutral glycolipids of the globo series, and GM3 ganglioside. However, the amount of sulfatides in well-differentiated tumors was significantly greater than that in poorly differentiated tumors, which was confirmed by thin-layer chromatography and immunostaining with a monoclonal antisulfatide antibody. Altered expression of sulfatide was found to be secondary to a change of galactosylceramide sulfotransferase messenger RNA expression. Immunohistochemical staining revealed that galactosylceramide sulfotransferase expression was characteristically observed in glandular areas but not in solid areas., Conclusion: These findings suggest that sulfatide contributes to the well-differentiated phenotype of endometrial adenocarcinoma and that it is being expressed in normal uterine endometrium at sites of gland formation during the luteal phase, as we have previously reported.

Background: Endoscopic ultrasonography (EUS) has become a reliable method for predicting the invasion depth of early gastric cancer (EGC). This study evaluated the accuracy of EUS in identifying lesions meeting expanded-indication criteria for endoscopic submucosal dissection (ESD) and analyzed clinicopathologic factors influencing the diagnostic accuracy of EUS in assessing tumor invasion depth., Methods: This study investigated 542 EGCs of 515 patients who underwent EUS pretreatment. The pretreatment EUS-determined diagnosis was compared with the final histopathologic evaluation of resected specimens, and the impact of various clinicopathologic parameters on diagnostic accuracy was analyzed., Results: The diagnostic accuracy of EUS in identifying lesions meeting expanded-indication criteria for ESD was 87.8% (259/295) for differentiated adenocarcinoma (D-type) 30 mm in diameter or smaller, 43.5% (10/23) for D-type tumor larger than 30 mm in diameter, and 75% (42/56) for undifferentiated adenocarcinoma (UD-type) 20 mm in diameter or smaller. Using multivariate analysis, the diagnostic accuracy of EUS in predicting tumor invasion depth was determined to be decreased significantly by ulcerous change and large tumor size (diameter, ≥30 mm)., Conclusion: For patients with EGC, D-type lesions 30 mm in diameter or smaller and UD-type lesions 20 mm in diameter or smaller can be diagnosed with high accuracy by EUS, but larger D-type lesions (diameter, >30 mm) should be considered carefully in terms of EUS-based treatment decisions. Findings of ulceration and large tumors are associated with incorrect diagnosis of tumor invasion depth by EUS.

Objectives: Although sporadic nonampullary duodenal adenoma (SNDA) is regarded as a precancerous lesion, its natural course is uncertain. The aim of this study was to evaluate the risk of development of adenocarcinoma in SNDA lesions initially diagnosed as showing low-grade dysplasia (LGD; category 3) or high-grade dysplasia (HGD; category 4.1)., Methods: We analyzed 68 SNDAs, diagnosed based on initial and subsequent biopsies, in 66 consecutive patients. Of these, 46 (43 LGD lesions, 3 HGD lesions) were followed up for ≥6 months without treatment (mean 27.7±16.9 months; range 6-72 months), including 8 lesions that were eventually resected during follow-up. Sixteen lesions (eight LGD lesions, eight HGD lesions) were resected immediately, either endoscopically or surgically, and six lesions were excluded because of a short follow-up (<6 months). The histopathological diagnoses and macroscopic changes were evaluated., Results: Among the 43 LGD lesions followed up for ≥6 months, 34 (79.1%) showed no histopathological changes during follow-up, whereas the remaining 9 (20.9%) showed progression to HGD, including 2 (4.7%) that progressed eventually to noninvasive carcinoma (category 4.2). Macroscopically, 76.7% (33 of 43) of the LGD lesions showed no notable changes in size, 16.3% (7 of 43) became undetectable, 4.7% (2 of 43) reduced in size, and 2.3% (1 of 43) became larger in size. In contrast, all the three HGD lesions that were followed up for ≥6 months remained unchanged histologically, based on biopsy, and showed no notable macroscopic changes, although one of these HGD lesions resected endoscopically revealed evidence of noninvasive carcinoma. Although we diagnosed all lesions as HGD from biopsy samples, a high percentage of cancers (54.5%, 6 of 11) were diagnosed from resected specimens. A multivariate analysis identified HGD diagnosed at first biopsy and a lesion diameter of ≥20 mm as being significantly predictive of progression to adenocarcinoma., Conclusions: LGD lesions show a low risk of progression to adenocarcinoma, but some risk of progression to HGD, which warrants careful follow-up biopsy. However, HGD lesions and large SNDAs≥20 mm in diameter show a high risk of progression to adenocarcinoma. Therefore, they should be treated immediately.

Background: Delayed bleeding is one of the major complications of endoscopic submucosal dissection (ESD). The aim of this study is to determine the incidence rate and clinical factors associated with delayed bleeding, as well as the time interval between bleeding and ESD for gastric neoplasm., Methods: We investigated 647 lesions in 582 consecutive patients undergoing ESD for gastric neoplasm., Results: Delayed bleeding after ESD was evident in all 28 lesions from 28 patients (4.33% of all specimens, 4.81% of patients), and all achieved endoscopic hemostasis. Resected specimen width (≥40 mm) was the only significant factor associated with delayed bleeding on univariate and multivariate analysis. In early delayed bleeding (bleeding occurring on or before the fourth postoperative day), wide resected specimen and tumor location in the lower third of the stomach were significant risk factors. In late delayed bleeding (bleeding occurring after the fifth operative day), wide resected specimen, tumor location in the middle third of the stomach, hypertension, and high body mass index (≥25 kg/m(2)) were significant factors. Delayed bleeding in patients with tumors in the upper and middle third of the stomach (median 8.0 days; range 1-20 days) occurred significantly later as compared with patients who had tumors in the lower third (median 2.0 days; range 1-34 days)., Conclusions: Risk factors for delayed bleeding, and the probable underlying mechanism involved, differed depending on the time elapsed between surgery and the bleeding episode.

A 58-year-old woman was found to have a 45-mm abdominal mass adjacent to the pancreas on screening ultrasonography, and subsequent esophagogastroduodenoscopy revealed a small gastric cancer (13 mm in diameter). We initially performed endoscopic submucosal dissection (ESD), and routine histological examination of the specimen sectioned at 2-mm intervals revealed a poorly differentiated adenocarcinoma and signet ring cell carcinoma confined to the mucosa without lymphatic-vascular capillary involvement or ulceration. These findings satisfied the expanded criteria for ESD we reported recently. We next performed laparoscopic excisional biopsy of the abdominal mass, and histological examination with immunohistochemical staining revealed a metastatic lymph node (LN) resulting from the gastric cancer. Distal gastrectomy with extended lymphadenectomy was then performed and histological examination indicated no residual cancer cells or any additional LN metastases. After the above-described clinical course, further analysis was conducted because of the highly unusual nature of this case; 60 additional deep-cut sections from the resected specimen were performed, with one section showing lymphatic involvement in the mucosa on hematoxylin and eosin staining. This case suggests practical limitations in determining lymphatic involvement through routine histological examination, which may not always be able to detect LN metastasis.

Aim: The aim of the present study was to examine therapeutic outcomes of endoscopic submucosal dissection (ESD) of undifferentiated-type intramucosal gastric cancer and the problems of diagnosis., Methods: We reviewed 58 patients with preoperatively diagnosed undifferentiated-type intramucosal early gastric cancer (EGC) without ulceration with a diameter of 20 mm or smaller (expanded-indication lesion) who underwent ESD at the Cancer Institute Hospital between September 2003 and August 2008., Results: The overall rates of one-piece resection and complete resection were 98% and 90% respectively, and the median operation time was 70 min. Bleeding was seen in 8.6% and perforation in 3.4%. The curative resection rate was low at 79%. Factors responsible for non-curative resection were most commonly submucosal invasions. If limited to pathologically diagnosed expanded-indication lesions, the curative resection rate was 98%. The difference in tumor size between a macroscopic diameter and a histological diameter was within +/-5 mm in 96% of expanded-indication lesions, with none of these cases having a histological diameter that exceeded the macroscopic diameter by more than 5 mm., Conclusion: ESD was technically feasible for expanded-indication lesions of undifferentiated-type EGC. We achieved a high rate of curative resection by the markings at sites 5 mm beyond the preoperatively determined lesion area. Factors responsible for non-curative resection were most commonly submucosal invasions. We should diagnose the depth of such lesions more carefully.

Background: Hypoxia-inducible factor-1 (HIF-1) is an essential transcription factor that mediates cellular and systemic homeostatic responses to reduced oxygen availability in mammals. So far, using immunohistochemistry we have analyzed the association of HIF-1alpha expression with histological type among epithelial ovarian tumors. In the present study, quantitative analyses of activated HIF-1 level in the nucleus and of accumulated HIF-1alpha level in the cytoplasm were performed to clarify whether or not the hypoxic state would be correlated to histology, malignancy, and tumor size in epithelial ovarian tumors., Method: HIF-1 level in the nucleus was analyzed using DNA binding assay, and HIF-1alpha level in the cytoplasm was measured by ELISA for a total of 36 epithelial ovarian tumors as follows: 5 serous adenocarcinomas (SEAs), 7 clear cell adenocarcinomas (CLAs), 7 endometrioid adenocarcinomas (ENAs), 4 mucinous adenocarcinomas (MUAs), 2 mucinous borderline tumors (MBTs), and 11 mucinous adenomas., Results: HIF-1 level (mg/ml) in the nucleus and HIF-1alpha level (mg/ml) in the cytoplasm were on average 0.116 and 0.178 for SEAs, 0.328 and 0.306 for CLAs, 0.171 and 0.305 for ENAs, 0.097 and 0.176 for MUAs, 0.224 and 0.180 for mucinous borderline tumors, 0.152 and 0.154 for mucinous adenomas. CLAs showed the highest levels for both of HIF-1 and HIF-1alpha, while MUAs showed the lowest levels of both. Mucinous adenomas were higher in HIF-1 than MUAs., Conclusion: Hypoxic state was considered to be closely related to histological type of epithelial ovarian tumors, suggesting that CLAs may be most hypoxic. In the comparison of mucinous tumors, malignancies would not always become most hypoxic. Tumor size may not be strongly associated with hypoxic state.

We report an unusual case of endometrial adenocarcinoma in a 80-year-old woman who underwent mastectomy for breast cancer at 68 years of age. The tumor diffusely involved the entire thickness of the myometrium. Atypical cells throughout the tumor contained abundant oxiphilic cytoplasm and were arranged in a solid or solid-tubular nests in a focal papillary manner. Components of the carcinoma were focally observed in situ. The tumor was classified according to the International Federation of Gynecology and Obstetrics (FIGO) as grade 2 and stage IIIa. Immunohistochemistry revealed that the tumor cells were positive for p53 but negative for vimentin, estrogen, and progesterone receptors, GCDFP-15, and mammaglobin. They were positive for antimitochondrial antigen and thyroid transcription factor-1. The Ki-67 labeling index was approximately 50%. Immunostaining revealed endometrial oncocytic carcinoma. Distinguishing between primary uterine neoplasm and carcinoma caused by metastasis of breast cancer appears important.

Background: Endoscopic resection (ER) has been accepted as minimally invasive treatment in patients with early gastric cancer (EGC) who have a negligible risk of lymph node metastasis. It has already been determined which lesions in differentiated-type EGC present a negligible risk of lymph node metastasis, and ER is being performed for these lesions. In contrast, no consensus has been reached on which lesions in undifferentiated-type (UD-type) EGC present a negligible risk for lymph node metastasis, nor have indications for ER for UD-type EGC been established., Methods: We investigated 3843 patients who had undergone gastrectomy with lymph node dissection for solitary UD-type EGC at the Cancer Institute Hospital, Tokyo, and the National Cancer Center Hospital, Tokyo. Seven clinicopathological factors were assessed for their possible association with lymph node metastasis., Results: Of the 3843 patients, 2163 (56.3%) had intramucosal cancers and 1680 (43.7%) had submucosal invasive cancers. Only 105 (4.9%) intramucosal cancers compared with 399 (23.8%) submucosal invasive cancers were associated with lymph node metastases. By multivariate analysis, tumor size 21 mm or more, lymphatic-vascular capillary involvement, and submucosal penetration were independent risk factors for lymph node metastasis (P < 0.001, respectively). None of the 310 intramucosal cancers 20 mm or less in size without lymphatic- vascular capillary involvement and ulcerative findings was associated with lymph node metastases (95% confidence interval, 0-0.96%)., Conclusion: UD-type intramucosal EGC 20 mm or less in size without lymphatic-vascular capillary involvement and ulcerative findings presents a negligible risk of lymph node metastasis. We propose that in this circumstance ER could be considered.

The expression of hypoxia inducible factor-1alpha (HIF-1alpha) and glucose transporter-1 (GLUT-1) was immunohistochemically analyzed in ovarian adenocarcinomas with the aim of elucidating whether hypoxic status is associated with histological type or structural character. The following ovarian adenocarcinomas were used: serous adenocarcinoma (SEA), 21 cases; mucinous adenocarcinoma (MUA), 19 cases; endometrioid adenocarcinoma (ENA), 16 cases; clear cell adenocarcinoma (CLA), 19 cases. High-level expression (3+) of HIF-1alpha was observed in 100% of SEAs, 58% of MUAs, 100% of ENAs and 89% of CLAs, and high-level expression of GLUT-1 in 76% of SEAs, 26% of MUAs, 50% of ENAs and 67% of CLAs. Heterogeneous or localized staining was relatively evident for GLUT-1. Immunohistochemical profiles were in accord with the immunoblotting and mRNA levels of both markers. ELISA for the detection of active HIF-1 demonstrated that HIF-1 is strongly activated in SEAs, ENAs and CLAs as compared to MUAs. Our results show that GLUT-1 overexpression is to some extent regulated by HIF-1alpha and is also strongly associated with histological features, i.e., papillary or stratified structure accompanied by little or no vascular stroma. In conclusion, hypoxic status differs according to the histological type of ovarian adenocarcinoma and the micro-environmental conditions of each type.

Metastasis of breast cancer to the esophagus has been reported but is rare. It is often difficult to diagnose metastases of breast cancer to the esophagus because they are often located in the submucosa and covered with normal mucosa. Although several methods have been reported in order to obtain specimens for pathological diagnosis, the adverse effects including bleeding and perforation were considerable problems. We report a case of a patient with esophageal stricture due to metastatic breast cancer to the esophagus. Pathological diagnosis was successfully obtained using endoscopic mucosal resection of the esophagus.

Background: To date, there has not been an in-depth investigation to identify differences in the effects of bleeding prevention among different routes of administration of H2 receptor antagonists to treat gastric ulcers following endoscopic mucosal resection (EMR)., Aim: To prospectively compare the frequency of bleeding following EMR between patients treated with intravenous (IV) famotidine and those with oral famotidine., Methods: Fifty-three patients with neoplastic gastric lesions (33 carcinoma and 20 adenoma) treated by EMR were included. Subjects underwent EMR with circumferential mucosal incision assisted by submucosal injection of sodium hyaluronate (EMRSH), followed by IV or oral (PO) administration of famotidine at a dosage of 40 mg/day for 2 days. Patients with odd ID numbers were assigned to IV therapy (30 cases) while even numbers were given PO therapy (23 cases). Frequencies and endoscopic findings of bleeding during the first 2 days after EMR were examined., Results: Frequency of bleeding within 2 days after EMR was 3 and 4% in IV and PO patients, respectively, showing no significant difference. No significant difference was seen in the endoscopic findings of bleeding and therapy, either, with respective IV and PO findings at 23 and 26%., Conclusions: No significant difference was observed in frequency of bleeding within 2 days after gastric EMR between IV and oral administrations of famotidine.

A total of 1,512 women participated in mass screenings for uterine body cancer (UBC) from 1998 to 2003 at Tokai University Hospital. Their rate in the examinees of uterine cervical cancer (UCC) mass screenings was 4.7%. Among the 1,512 examinees, endometrial cytological abnormalities (class III or higher) were found in 17 (1.1%) cases. As a result, UBC was detected in two patients (0.13%). One case was diagnosed as class V, adenocarcinoma, and she underwent hysterectomy. In another case, adenocarcinoma was found to be associated with atypical endometrial hyperplasia in hysterectomy specimens. For the remaining 15 cases diagnosed as class III, the cytological abnormalities disappeared after a follow-up except for 3 patients who were not followed at Tokai University Hospital. In a comparison of the examinees with or without genital bleeding, the cytological abnormalities were more frequently detected in the former group; 4.2% (6/142) vs. 0.6% (5/819) (p < 0.05). We recommend examinees aged 40 years or higher with a complaint of genital bleeding to participate in UBC mass screening for detection of endometrial adenocarcinoma at early stages.