Early and long-term outcomes of endoscopic submucosal dissection for early gastric cancer in a large patient series.

Endoscopic submucosal dissection (ESD) enables the curative resection of early gastric cancer (EGC); however, little information is available on the long-term outcomes of ESD. This study was conducted to clarify the clinical outcomes of a large number of patients with EGC who underwent ESD. The early outcomes were assessed in 1,209 patients and the long-term outcomes were assessed in 300 patients at a follow-up >5 years after the ESD procedure. The overall survival rates were compared between indication and expanded-indication groups, and between the patients who did or did not undergo additional surgery in an out-of-indication group. Overall survival rates were also compared among different age groups. In total, 617 lesions were classed as the indication group, 507 as the expanded-indication group and 208 as the out-of-indication group. Curative resection rates were 96.6% and 91.5% in the indication and expanded-indication groups, respectively. In terms of the long-term outcomes, 20 of the 146 patients in the indication group, 15 of the 105 patients in the expanded-indication group and one of the 23 patients who underwent additional surgery in the out-of-indication group succumbed due to causes other than gastric cancer. Among the 26 patients who did not undergo additional surgery in the out-of-indication group, 10 mortalities occurred, including one due to gastric cancer. The five-year survival rates were not significantly different between the indication and expanded-indication groups. In the out-of-indication group, the five-year survival rate for the patients who did not undergo additional surgery (65.0%) was significantly lower than that for those who did undergo additional surgery (100%) (P<0.01). The five-year survival rate of patients aged >80 years (67.1%) was significantly lower than that of the younger patients (<60 years, 91.6%; sixties, 93.0%; seventies, 84.5%) (P<0.0001). In conclusion, although expanded-indication of ESD for EGC is appropriate, comorbidities require consideration in elderly patients.

Magnifying chromoendoscopic findings of early gastric cancer and gastric adenoma.

PURPOSE: In the field of colorectal cancer and adenoma, Kudo's classification of pit pattern with magnifying chromocolonoscopy using crystal violet (CV) staining is now accepted. Magnifying endoscopy using narrow band imaging has been used for the diagnosis of gastric carcinoma; the characteristic findings of microvascular patterns have been demonstrated. However, there was limited information on magnified endoscopic findings with CV staining for gastric neoplasms in terms of their pit patterns. METHODS: Magnifying chromoendoscopy with CV was performed in 175 patients with early gastric cancer and 18 with gastric adenoma, prior to treatment. Surface patterns of gastric tumors were classified into five types: (1) long tubular pit pattern, (2) irregular size pit pattern, (3) small round pit pattern, (4) destroyed pit pattern, and (5) non-structural pattern. RESULTS: Long tubular pit pattern was most common in gastric adenoma. Well differentiated adenocarcinoma and papillary adenocarcinoma tended to show different size of pit pattern or destroyed pit pattern. Small round pit pattern was most commonly seen in moderately differentiated adenocarcinoma. Non-structural pattern was most frequently observed in poorly differentiated adenocarcinoma and signet ring cell carcinoma (P < 0.0001). CONCLUSION: For gastric neoplasms, magnifying endoscopy may help predict histopathological type.

Endoscopic submucosal dissection for laterally spreading tumours of the colorectum in 200 consecutive cases.

BACKGROUND: Colorectal laterally spreading tumours (LSTs) are classified into granular (LST-G) and non-granular (LST-NG) type; each type was sub-grouped into LST-G-H (homogenous) and LST-G-M (nodular mixed) type or LST-NG-F (flat elevated) and LST-NG-FD (pseudodepressed) type, respectively. We assessed the clinicopathological factors associated with clinical outcomes of endoscopic submucosal dissection (ESD) for colorectal LSTs, and conducted follow-up after ESD. METHODS: ESD was performed in 196 patients with 204 LSTs that fulfilled the inclusion criteria for colorectal neoplasms. Clinical outcomes including resectability and curability of ESD and perforation were investigated, and factors related to the outcomes were analysed using logistic regression. One hundred thirty-eight patients received endoscopic follow-up for more than 12 months and metastatic surveys in 79 cases of cancerous LSTs. RESULTS: The incidence of submucosal cancer was lower in LST-G type. There were no significant differences in outcomes regarding LST macroscopic types. Overall en bloc, complete and curative resection, and perforation rates were 86.8%, 77.5%, 82.8% and 9.8%, respectively. Logistic regression analysis showed higher risk of non-curative resection in LST-G-M than in LST-G-H type. No other factors were associated with outcomes. During median follow-up of 35.5 months, no locally recurrent or metastatic tumours were observed, and overall survival was still 100%. CONCLUSIONS: ESD provides acceptable resectability for colorectal LSTs by facilitating en bloc resection, irrespective of macroscopic types. The relatively long-term outcomes may be excellent, but further evaluation is needed for appropriate treatment strategy for each type of LST.

Endoscopic submucosal dissection for colorectal epithelial neoplasms.

PURPOSE: Endoscopic submucosal dissection permits removal of colorectal epithelial neoplasms en bloc, but long-term clinical outcomes remain unknown. METHODS: Endoscopic submucosal dissection was performed in 282 patients having 296 colorectal tumors that fulfilled the inclusion criteria, which included lesions greater than 20 mm in size for which en bloc resection would be difficult with endoscopic mucosal resection, lesions with fibrotic scar due to previous endoscopic treatment or biopsies, locally residual lesions after endoscopic resection, or invasive carcinoma with slight submucosal penetration. En bloc or piecemeal resection, complete (en bloc with tumor-free lateral/basal margins) or incomplete resection, and complications were assessed, and factors related to each were analyzed using logistic regression. Patients with early colon cancer received endoscopic follow-up and metastatic surveys for a median of 34 months. RESULTS: En bloc resection was achieved in 89.2% (264/296) and 234 lesions (79.1%) were deemed to have undergone complete resection. A right-side colonic location was the significant contributor to incomplete resection. Perforation was seen in 24 cases (8.1%) in association with tumor size and the presence of fibrosis. There was 1 case of locally recurrent tumor with incomplete resection, whereas neither recurrence nor residual disease was observed in the complete resection group. Neither cancer-related nor cancer-unrelated death was observed. CONCLUSIONS: Precise assessment of curability with successful en bloc resection may reduce tumor recurrence after endoscopic submucosal dissection. The prognosis of early colorectal cancer in patients treated by endoscopic submucosal dissection is likely to be excellent, although further longer follow-up studies are warranted.

Clinical outcomes of endoscopic submucosal dissection in elderly patients with early gastric cancer.

OBJECTIVES: Endoscopic submucosal dissection (ESD) has advantages over conventional endoscopic mucosa resection. The number of elderly patients (more than 75 years old) with early gastric cancer (EGC) has been steadily increasing. We sought to assess clinical outcomes of ESD for EGC in elderly. METHODS: ESD was performed for patients with EGC, who fulfilled the criteria for ESD: mucosal cancer without ulcer findings irrespective of tumor size; mucosal cancer with ulcer findings 3 cm or less in diameter; and minute submucosal invasive cancer 3 cm or less in size. Two hundred and sixty elderly patients (> or =75 years old) with 279 lesions, and 401 non-elderly patients with 434 lesions were enrolled to this study. The patients underwent ESD and then received periodic endoscopic follow-up and metastatic surveys for 6-89 months (median: 30 months). Resectability (en-bloc or piecemeal resection), curability (curative or noncurative resection), completeness (complete or incomplete resection), complications, and survival rates were assessed. RESULTS: The one-piece resection rate was significantly lower in elderly patients (93.9%) than in non-elderly patients (97.9%). The complete resection rate was significantly lower in elderly patients (87.4%) than in non-elderly patients (96.6%). Pneumonia, but not bleeding or perforation, developed in association with ESD more frequently in the elderly patients by 2.2%. Local tumor recurrence was quite rare, and the overall and disease-free survival rates were acceptable irrespective of age. CONCLUSION: En-bloc and complete resections were achieved less frequently in elderly patients, but the long-term outcomes in elderly EGC patients may be excellent, and ESD is a feasible treatment in the elderly.

Endoscopic submucosal dissection for rectal carcinoid tumors.

BACKGROUND: Endoscopic submucosal dissection (ESD) has an advantage over endoscopic mucosa resection (EMR) by enabling removal of gastrointestinal neoplasms en bloc. The ESD procedure is the treatment of choice for rectal carcinoids that have classic histologic architecture with minimal cellular pleomorphism and sparse mitoses, but it has not been applied for such tumors. METHODS: The ESD procedure was performed for patients with colorectal tumors that fulfilled the inclusion criteria specifying tumor with a diameter of 10 mm or less, no muscular layer invasion, and no metastases to the lymph nodes or distal organs. The ESD procedure was performed for patients with rectal carcinoids but no node or distal metastasis. RESULTS: This study enrolled 20 rectal carcinoid tumors from 20 consecutive patients. The mean tumor size was 7.6 mm (range, 3-16 mm). En bloc removal was achieved for all the tumors, and the complete resection (en bloc with tumor-free lateral/basal margins) rate was 90% (18/20). The two cases in which the margins were not evaluable due to burn effects still are free of recurrence and metastasis at this writing. Perforation was seen in one case, which was managed nonsurgically. CONCLUSIONS: Precise histolopathogic assessment of the specimens resected en bloc by ESD may reduce tumor recurrence and metastasis after ESD. As the treatment of choice for small rectal carcinoids, ESD is associated with nominal risks of metastatic disease.

A new thin endoscopic method of transanal drainage tube insertion for acute colonic obstruction due to colorectal cancer.

AIM: Insertion of a transanal drainage tube is effective in the management of obstructing colorectal cancer. We devised a new method of inserting the transanal drainage tube safely and quickly using a thin endoscope. METHODS: Sixteen patients (seven men and nine women) with obstructive left-sided colorectal cancer were treated by inserting a transanal drainage tube using a thin endoscope. We inserted a transanal drainage tube for 32 patients (21 men and 11 women) with left-sided colorectal cancer using the conventional method. RESULTS: Drainage tube placement by the conventional method was successful in 29 (90.6%) of 32 patients, while via the new method, it was successful in all 16 patients without major complications. Moreover, median insertion time was significantly shortened (34 minutes for the new method compared with 42 minutes for the conventional method). CONCLUSION: Management of acute colorectal obstruction by transanal drainage tube insertion using the thin endoscope was effective and safe.

Clinical outcomes of endoscopic submucosal dissection for early gastric cancer by indication criteria.

BACKGROUND AND STUDY AIMS: Endoscopic submucosal dissection (ESD) can remove early gastric cancer (EGC) en bloc. We sought to assess the feasibility and efficacy of ESD and the clinical outcomes based on the indication criteria. PATIENTS AND METHODS: 551 patients with 589 EGC lesions were divided into the guideline criteria group (elevated lesion < or =20 mm in diameter and depressed lesion < or =10 mm without ulceration) and the expanded criteria group (mucosal cancer without ulcer findings irrespective of tumor size; mucosal cancer with ulcer findings < or =3 cm in diameter; and minute submucosal invasive cancer < or =3 cm in size). RESULTS: En bloc, complete and curative resection were achieved in 98.6 and 93.0, 95.1 and 88.5, and 97.1 and 91.1%, for the guideline and expanded criteria lesions, respectively; the differences between the 2 groups were significant for each. The expanded criteria lesions were at significantly higher risk of ESD-associated bleeding and perforation. Overall survival was adequate irrespective of the indications, and the disease-specific survival rates were 100% in both. CONCLUSION: ESD for EGCs that met the expanded criteria was acceptable, though the resection rates and safety were decreased compared to those for the guideline criteria lesions.

Factors related to the curability of early gastric cancer with endoscopic submucosal dissection.

BACKGROUND: Endoscopic submucosal dissection (ESD) yields substantially high rates for curative resection of early gastric cancer (EGC). It is suggested that larger, ulcerative, or upper EGCs may prevent successful ESD. A detailed analysis of factors associated with the curability of ESD was performed. METHODS: Endoscopic submucosal dissection was performed for patients with EGC that fulfilled the expanded criteria, which specified mucosal cancer without ulcer findings irrespective of tumor size, mucosal cancer with ulcers 3 cm in diameter or smaller, and minute submucosal invasive cancer 3 cm or smaller. Resectability (en bloc or by piecemeal resection), curability (curative or non-curative), and complications were assessed, and logistic regression analysis was used to analyze the related factors. RESULTS: Ulcerative EGCs showed a significantly higher risk associated with ESD on multivariate analysis. When the risk factors (tumor size, location, and ulcer findings) were combined, the larger EGCs (>30 mm) located in the upper third or ulcerative tumors located in the upper and middle portion of the stomach were at significantly higher risk of non-curative resection. Such lesions also were associated with increased risk of procedure-related perforation. CONCLUSIONS: When risk factors including positive ulcer findings and larger size and upper location of tumors are combined, ESD should be performed more carefully.

Development of ulcerative colitis during the course of rheumatoid arthritis: Association with selective IgA deficiency.

A 56-year-old woman with a 29-year history of rheumatoid arthritis (RA) was admitted to the hospital, complaining of high fever, abdominal pain and severe bloody diarrhea. Colonoscopy revealed friable and edematous mucosa with spontaneous bleeding, diffuse erosions and ulcers extending from the rectum to the distal transverse colon. Histopathological findings of rectal biopsies were compatible with ulcerative colitis (UC). Being diagnosed as having severe active left-side UC, she was successfully treated with intravenous methylprednisolone followed by prednisolone and leukocytapheresis. Laboratory tests revealed low serum and saliva IgA levels, which might play a role in the development of UC. To our knowledge, this is the first case of UC occurring during the course of RA, accompanied by selective IgA deficiency.

Sucralfate protects intestinal epithelial cells from radiation-induced apoptosis in rats.

Radiotherapy for malignant pelvic disease is often followed by acute radiation colitis (ARC). It has been reported that sucralfate treatment has a protective effect against ARC, though the mechanisms of action are unknown. The effects of sucralfate on X-ray radiation-induced apoptosis was studied at 4 Gy in the colonic crypt cells of rats. Sucralfate enemas given prior to radiation resulted in the following: (1) reduction in number of apoptotic colonic crypt cells; (2) reduction in number of caspase-3 positive cells; (3) decreases in p53 accumulation and p21 expression; (4) decreases of Bax/Bcl-2 ratio. The protective effects of sucralfate against ARC may be partially due to the suppression of radiation-induced apoptosis by way of p53 in the colon and the protection of the colonic epithelial stem cell region.

Small cell carcinoma of the endometrium: report of a case with analysis of Wnt/beta-catenin pathway.

Small cell carcinoma of the endometrium (SCCE) is extremely rare. Previous reports indicate that SCCE frequently shows systemic spread and has a poor prognosis. Beta-catenin has been shown to be a key downstream effector of the Wnt signaling pathway, which regulates cell growth and survival. Decreased membranous expression of beta-catenin in cancers correlates with poor prognosis and is associated with dissemination of tumor cells and the formation of metastases. Recently, some different investigators demonstrated aberrant beta-catenin accumulation in neuroendocrine tumors arising in different organs, suggesting a role for the Wnt/beta-catenin signaling pathway during neuroendocrine tumorigenesis. Here, we report a new case of SCCE associated with peritoneal spreading and aggressive course; the patient died one month after surgery. This study also aimed at assessing the involvement of the Wnt signaling pathway in this rare neuroendocrine tumor. Interestingly, both intense nuclear beta-catenin accumulation and cyclin D1 immunoreactivity were restricted to carcinoma cells invading lymphatic vessels. However, mutation analysis failed to demonstrate any mutation in exon 3 of the beta-catenin gene or exon 15 of the APC gene in the present case. Although the mechanism of nuclear accumulation of beta-catenin is still unknown, the heterotopic nuclear localization of beta-catenin may play a role in the tumor invasion process and, subsequently, may be associated with the aggressive behavior of SCCE.

The protective effect of fermented milk kefir on radiation-induced apoptosis in colonic crypt cells of rats.

To evaluate the effect of fermented milk kefir on X-ray-induced apoptosis in the colon of rats, we examined the apoptotic index, the mean number of apoptotic cells detected by H&E staining per crypt in the colon, in control rats and kefir-pretreated rats drinking kefir for 12 days before irradiation. Apoptotic cells were confirmed by TUNEL staining, and active caspase-3 expression was studied by immunohistochemistry. The cell position of apoptotic cells and active caspase-3 positive cells were examined. The apoptotic index of kefir-treated rats was significantly (p < 0.05) decreased 2 h after 1 Gy irradiation in comparison with control rats at crypt cell positions 1-3, 5-7, 13, and 15. Active caspase-3 expression in the kefir-treated rats was also significantly (p < 0.05) reduced in comparison with control rats 2 h after 1 Gy irradiation at crypt cell positions 1-4, 13, and 15. This study indicated that kefir protects colonic crypt cells against radiation-induced apoptosis, which was most pronounced in the stem cell region of the crypt. The antiapoptotic effect of fermented milk kefir was due to the inhibition of caspase-3 activation.

Mechanism of the antiulcerogenic effect of IL-11 on acetic acid-induced gastric ulcer in rats.

The purpose of this study was to evaluate the healing effect of interleukin-11 (IL-11) on acetic acid-induced gastric ulcer in rats. Gastric ulcers were induced in male Wistar rats by applying acetic acid to the fundus of the stomach. Recombinant human interleukin-11 (rhIL-11 100 microg/kg/twice daily, subcutaneously) was administered starting on the 2nd day before ulcer induction up through the 7th day after ulcer induction. Control rats were injected with bovine serum albumin. At 12 hours and 7 days after ulcer induction, the animals were sacrificed, and the ulcer index, proliferating cell nuclear antigen (PCNA) expression, and IL-11alpha receptor expression in the gastric tissues were studied. The ulcer index of the rhIL-11-treated rats was significantly lower than that of the control rats at the 7th day. The expression of PCNA as evaluated by Western blotting and immunohistochemistry, was enhanced in both the mucosal proliferative zone and proper muscle layer of the rhIL-11-treated rats in comparison with that in the control rats. IL-11alpha receptor expression was observed in the mucosal neck cells of the rhIL-11-treated rats and control rats. These findings suggest that IL-11 accelerates ulcer healing by inducing the proliferation of mucosal and muscular cells.

Distinctive gene expression of receptor-type tyrosine kinase families during rat hepatocarcinogenesis.

Growth factor receptor tyrosine kinase signaling plays key roles in regulating growth of normal hepatocytes, however, which receptor-type tyrosine kinase (RTK) is involved in hepatocarcinogenesis remains undetermined. The aim of this study was to characterize the expression of these receptors in different stages of rat liver carcinogenesis. We compared the expression profile of RTK genes in rat normal liver and diethylnitrosamine-induced hepatoma tissues using a homology cloning method with degenerated primers. In situ hybridization, immunohistochemical staining, and RT-PCR were performed to analyze the cell type-specific expression of target RTKs during the chemically-induced hepatocarcinogenesis. Sequence analysis of 459 clones identified 23 different RTK genes. The Tie-2, c-Met, and Flk-1 genes were the most abundant RTK genes cloned in rat hepatoma compared to normal liver. In situ hybridization and immunohistochemical studies showed overexpression of c-Met and Flk-1 in GST-P positive preneoplastic lesions as well as neoplastic lesions. Tie-2 was expressed not only in endothelial cells but also in so-called oval cells, which are thought to be liver stem cells. Tie-2 ligand, angiopointin-1, mRNA was detected in both normal livers and hepatoma cells/tissues. In contrast, angiopoietin-2 mRNA was detected only in hepatoma tissues. These results indicate that c-Met, Tie-2 and Flk-1 signals play important roles in different stages of chemically-induced hepatocarcinogenesis. Distinctive gene expression of RTK may contribute to epigenic implication of hepatoma formation.

Altered expression of beta-catenin during radiation-induced colonic carcinogenesis.

Radiotherapy for malignant pelvic disease is commonly accompanied by treatment-induced proctitis, and rarely by colorectal cancer. Translocation of the beta-catenin protein, which is a key downstream effector of the Wnt signal transduction pathway, is frequently found in colorectal cancer. Nuclear beta-catenin enhances transcriptional activity of the cyclin D1 gene in cancer cells. Here, we evaluate the involvement of the Wnt pathway in radiation-induced colon carcinogenesis with rats (n = 36). Beta-catenin, APC, and cyclin D1 expression profiles were analyzed by immunohistochemistry in radiation-induced chronic colon injury including cancers and ulcerative lesions in rats (n = 12 in treated group, n = 12 in control group). In total, 3 cases of invasive adenocarcinomas were developed in the irradiated portion 50 weeks after a single dose of 36 Gy irradiation. Nuclear translocation of beta-catenin was observed in all radiation-induced colon cancers, whereas this protein was also found in the cytoplasm and/or nucleus of 9 cases of non-neoplastic irradiated colonocytes. Nuclear translocation of beta-catenin correlated with loss of APC and gain of cyclin D1 expression, suggesting activation of the Wnt pathway during radiation-induced colorectal carcinogenesis. A single dose of 10 Gy was also given for acute injury (n = 12: 3 each in days 0, 3, 5, and 7, respectively). Beta-catenin expression was distributed in the cytoplasm of degenerating glands at day 3 and 5, and was observed in the cell membrane of those glands with histological normalization at day 7 after irradiation. Because translocation of beta-catenin was found in irradiated-colonic mucosa as well as colon cancer, disruption of beta-catenin expression might be one of the early events in radiation-induced colonic carcinogenesis.