[Show abstract][Hide abstract] ABSTRACT: The prognosis of early gastric cancer (EGC) is good if there is no concomitant lymph node metastasis. Therefore, the early detection of EGC is important to improve the prognosis of patients with gastric cancer. In Japan, 40% to 50% of all gastric cancers are EGC, and endoscopic submucosal dissection (ESD) is widely accepted as a local treatment for these lesions, particularly for large lesions that at one time were an indication for gastrectomy because of the difficulty of en-bloc resection. Consequently, this procedure can preserve the entire stomach and the patient's postoperative quality of life. ESD has become a general technique with improved procedures and devices, and has become the preferred treatment for EGC rather than gastrectomy. Therefore, ESD may demonstrate many advantages in patients who have several comorbidities, particularly elderly population, patients taking antithrombotic agents, or patients with chronic kidney disease, or liver cirrhosis. However, it is not yet clear whether patients with both EGC and comorbidities are feasible candidates for ESD and whether they would consequently be able to achieve a survival benefit after ESD. In this review, we discuss the clinical problems of ESD in patients with EGC and those comorbid conditions.
[Show abstract][Hide abstract] ABSTRACT: A 55-year-old man was annually followed up for a large hepatic cyst. In 2006, a 20-mm nodule was detected in contact with the cyst that gradually grew thereafter. By 2013, the mass had expanded to 90 mm, and a percutaneous biopsy revealed a solitary fibrous tumor (SFT). Surgical resection was subsequently performed, and the patient has since been doing well for 11 months, without recurrence. SFT of the liver is a rare neoplasm; only 44 cases have been reported to date. This is the first report to describe the long-term progression of hepatic SFT from the time of its development.
Full-text · Article · Apr 2015 · Internal Medicine
[Show abstract][Hide abstract] ABSTRACT: Recent studies have demonstrated that cancer stem cells (CSCs) can initiate and sustain tumor growth and exhibit resistance to clinical cytotoxic therapies. Therefore, CSCs represent the main target of anticancer therapy. Interleukin-6 (IL-6) promotes cellular proliferation and drug resistance in colorectal cancer, and its serum levels correlate with patient survival. Therefore, IL-6 and its downstream signaling molecule the signal transducer and activator of transcription-3 (STAT3) represent potential molecular targets. In the present study, we investigated the effects of IL-6 and its downstream signaling components on stem cell biology, particularly the chemoresistance of CSCs, to explore potential molecular targets for cancer therapy. The colon cancer cell line WiDr was cultured in serum-free, non-adherent, and three-dimensional spheroid-forming conditions to enrich the stem cell-like population. Spheroid-forming cells slowly proliferated and expressed high levels of Oct-4, Klf4, Bmi-1, Lgr5, IL-6, and Notch 3 compared with adherent cells. Treatment with an anti-human IL-6 receptor monoclonal antibody reduced spheroid formation, stem cell-related gene expression, and 5-fluorouracil (5-FU) resistance. In addition, IL-6 treatment enhanced the levels of p-STAT3 (Tyr705), the expression of Oct-4, Klf4, Lgr5, and Notch 3, and chemoresistance to 5-FU. siRNA targeting Notch 3 suppressed spheroid formation, Oct-4 and Lgr5 expression, and 5-FU chemoresistance, whereas STAT3 inhibition enhanced Oct-4, Klf4, Lgr5, and Notch 3 expression and 5-FU chemoresistance along with reduced spheroid growth. Taken together, these results indicate that IL-6 functions in dichotomous pathways involving Notch 3 induction and STAT3 activation. The former pathway is involved in cancer stem-like cell biology and enhanced chemoresistance, and the latter pathway leads to accelerated proliferation and reduced chemoresistance. Thus, an anti-human IL-6 receptor monoclonal antibody or Notch 3 inhibition may be superior to STAT3 inhibition for CSC-targeting therapies concomitant with anticancer drugs.
Full-text · Article · Jan 2015 · International Journal of Oncology
[Show abstract][Hide abstract] ABSTRACT: The emergence of chemoresistance is a major limitation of current cancer therapies, and checkpoint kinase (Chk1) 1 positively correlates with resistance to chemo‑ or radio‑therapy. Cancer cells lacking p53 pathways are completely dependent on the S and G2/M checkpoints via Chk1; therefore, Chk1 inhibition enhances the cytotoxicity of DNA‑damaging agents only in p53‑deficient cells. However, little is known about the synergistic effect of Chk1 inhibition with 5‑FU, the most frequently used antimetabolite, in chemoresistant colorectal cells. In this study, we found that 5‑FU induced S‑phase arrest only in p53‑deficient colorectal cancer cells. 5‑FU treatment induced DNA damage and activation of ataxia telangiectasia mutated (ATM) and Chk1, leading to S‑phase arrest, and Chk1 inhibition using SB218078 reduced S‑phase arrest and increased apoptosis in the presence of 5‑FU. In contrast, in p53‑deficient, 5‑FU‑resistant (5FUR) colon cancer cells that we developed, 5‑FU enhanced DNA damage but did not induce Chk1/ATM activation or cell cycle arrest. SB218078 in combination with 5‑FU did not induce apoptosis. These results indicate that 5‑FU‑resistance abrogated the anticancer effect amplified by Chk1 inhibition, even in p53‑deficient cancer cells.
No preview · Article · Oct 2014 · International Journal of Oncology
[Show abstract][Hide abstract] ABSTRACT: Basaloid squamous carcinoma (BSC) is a rare variant of esophageal cancer. There are very few reports of "early" BSC. Here we report a case of early BSC with unusual findings by narrowband imaging magnified endoscopy (NBI-ME). A 70-year-old man with a middle thoracic esophageal tumor was referred to our hospital. White-light endoscopy revealed a reddish depressed lesion 5 mm in diameter having a subepithelial tumor-like prominence with a gentle rising slope. NBI-ME revealed irregular loop-shaped microvessels coexistent with thick irregularly branched non-looped vessels. Iodine staining revealed a pale brown lesion. We performed endoscopic submucosal dissection for diagnostic treatment. Histologic examination showed the proliferation of basal cell-like hyperchromatic tumor cells in the lamina propria and with slight invasion into the submucosa at a depth of 320 μm. The tumor cells formed solid nests and microcystic structures, containing an Alcian blue-positive mucoid matrix. The surface was covered with squamous epithelium without cellular atypia. Thin vessels were observed in the intra-epithelial papilla and thick vessels were observed around the solid nests beneath the epithelium. Based on these findings together, we diagnosed the lesion as BSC. In this case, the NBI-ME findings differed from those of typical squamous cell carcinoma in that both non-invasive cancer-like irregular loop-shaped microvessels coexisted with massively invasive cancer-like thick non-looped vessels. We speculate that the looped and non-looped vessels observed by NBI-ME histologically corresponded to thin vessels in the intra-epithelial papilla and thick vessels around the tumor nests, respectively. These NBI-ME findings might be a feature of early esophageal BSC.
Full-text · Article · Sep 2014 · World Journal of Gastroenterology
[Show abstract][Hide abstract] ABSTRACT: White opaque substance (WOS) is observed in the gastric neoplasia of 0-IIa type using a magnifying endoscopy with narrow band imaging (NBI-ME). Colonic and duodenal neoplasms with WOS have also been reported. Immunohistochemical examination with adipophilin reveals WOS in gastric neoplasms represents lipid droplets and WOS is specific for the neoplasm with intestinal or gastrointestinal phenotype. We herein report a case of adenocarcinoma of esophagogastric junction with WOS. A male patient in his sixties was found to have an esophageal elevated lesion by an esophagogastroduodenoscopy (EGD). NBI-ME showed whitish deposits which looked similar to WOS observed in gastric neoplasms. He underwent endoscopic submucosal dissection (ESD) and the lesion was resected in a single piece. This tumor had diffuse positivity for adipophilin and gastrointestinal phenotype.
No preview · Article · Jul 2014 · Digestive Endoscopy
[Show abstract][Hide abstract] ABSTRACT: Early detection of early gastric cancer (EGC) is important to improve the prognosis of patients with gastric cancer. Recent advances in endoscopic modalities and treatment devices, such as image-enhanced endoscopy and high-frequency generators, may make endoscopic treatment, such as endoscopic submucosal dissection, a therapeutic option for gastric intraepithelial neoplasia. Consequently, short-term outcomes of endoscopic resection (ER) for EGC have improved. Therefore, surveillance with endoscopy after ER for EGC is becoming more important, but how to perform endoscopic surveillance after ER has not been established, even though the follow-up strategy for more advanced gastric cancer has been outlined. Therefore, a surveillance strategy for patients with EGC after ER is needed.
[Show abstract][Hide abstract] ABSTRACT: INTRODUCTION: With development of endoscopic intervention for early gastric cancer (EGC), pre-therapeutic diagnosis of the invasion depth (T-staging) has become increasingly important. Recently some studies reported conventional endoscopy (CE) is comparable to endoscopic ultrasonography (EUS) for T-staging of EGC. However, for certain group of EGC, EUS would have additional diagnostic value because it directly provide tomographic image.
AIMS&METHODS: The aim of this study is to establish a diagnostic system for T-staging of EGC by combinating CE and EUS. A total of 233 consecutive EGC patients from April 2007 to March 2012 were included in this study. All patients underwent both CE and EUS for T-staging before treatment at Osaka University Hospital. Using CE, the criteria of massive submucosal invasion was defined as meeting at least one of following findings: 1) irregular surface, 2) submucosal tumor-like marginal prominence, 3) fusion of convergent folds in case of a lesion with fold convergence. Using EUS, massive submucosal invasion was defined as obvious irregular narrowing or budding into the sonographic layer 3. Three experienced endoscopists retrospectively reviewed the endoscopic imaging and made a diagnosis based on the criteria mentioned above. Diagnostic accuracy and inter-observer agreement was compared between CE and EUS.
RESULTS: According to pathological findings, 197 (85%) were mucosal and 36 (15%) were massively invading cancers. Overall accuracy ranged 71 to 79% in CE and 72 to 82% in EUS, respectively. There was no significant difference of diagnostic yield between CE and EUS. CE revealed fair inter-observer agreement (� ¼ 0.56 - 0.61). Kappa value of CE was higher than EUS (� ¼ 0.47 - 0.53). When diagnosed as mucosal cancer by CE, about 90% was predicted invasion depth accurately. On the other hand, when diagnosed as submucosal cancer by CE, 70% of pathological mucosal cancer was over-estimated invasion depth. EUS salvaged about 60% of these over-diagnosed cancers. Defining mucosal cancer as being diagnosed as mucosal cancer by either CE or EUS, diagnostic accuracy of combination of both modalities was more than 80% and significantly higher than CE alone (p5 0.0001, McNemar’s test).
CONCLUSION: Using our simple diagnostic criteria, CE accurately picked up mucosal cancer with fair inter-observer agreements. However, CE over-estimates invasion depth of more than half of mucosal cancer, and EUS is useful in salvaging these lesions.
[Show abstract][Hide abstract] ABSTRACT: Background
Heparin is given to patients undergoing colonoscopic polypectomy at high risk for thromboembolism. Little is known, however, about how heparin bridge therapy (HB) affects post-polypectomy bleeding (PPB). The present study aimed to identify the clinical features of PPB associated with HB. Patients and Methods
Data of consecutive inpatients who underwent colonoscopic polypectomy with antithrombotic therapy at Osaka University Hospital were retrospectively collected and categorized into a HB group or a non-HB group. The incidence and characteristics of PPB were analyzed. ResultsA total of 117 patients with 279 lesions were identified, and the HB group included 45 patients. Nine of 10 patients with PPB were in the HB group, and the incidence of PPB was significantly higher in the HB group than in the non-HB group (20.0% vs 1.4%, respectively). PPB onset was later in the HB group than inthe non-HB group (median postoperative day: 4 vs 1, respectively). Five of the nine patients with PPB (55.6%) in the HB group experienced recurrent bleeding. One patient in the HB group required a blood transfusion as a result of massive PPB. All bleeding was eventually controlled endoscopically. Hospitalization was significantly longer in the HB group than in the non-HB group (median hospitalization: 14 vs 4 days, respectively). The univariate analysis showed that the predictors of PPB were warfarin use, HB and pedunculated polyps. ConclusionsPPB associated with HB is characterized by high incidence, late onset and recurrent bleeding, resulting in long hospitalization.
No preview · Article · Jun 2013 · Digestive Endoscopy
[Show abstract][Hide abstract] ABSTRACT: We evaluated whether endoscopic ultrasonography (EUS) image quality affects the accuracy of diagnosing the vertical invasion depth of early gastric cancer (EGC). A total of 75 lesions in 75 patients suspected of having EGC were enrolled. All patients underwent EUS examination. Findings of EUS were compared with histopathologic results. We evaluated the effect of the following clinicopathologic factors: location, diameter, surface pattern, concomitant ulceration, histology type, and EUS image quality score. EUS image quality was scored based on detection repeatability, appropriate probe placement, and clarity of the five gastric wall layers including the lesion. Sixty-three lesions (84%) were pathologically mucosal and 12 lesions (16%) were submucosal cancer. Overall accuracy was 82.7%. Significantly more lesions in the upper and middle portions of the stomach were incorrectly diagnosed than in the lower portion (P = 0.0019). Lesion diameter was significantly larger among incorrectly diagnosed lesions (P = 0.0257). Low-quality images were significantly more often associated with incorrectly diagnosed lesions than with correctly diagnosed lesions (P = 0.0001). Multivariate analysis revealed that EUS image quality was associated with EUS staging accuracy (odds ratio, 21.8; 95% confidence interval, 4.5-137.6). Low-quality EUS images led to an incorrect diagnosis of invasion depth of EGC, independent of tumor location or size.
Full-text · Article · Sep 2012 · Gastroenterology Research and Practice
[Show abstract][Hide abstract] ABSTRACT: Objective MicroRNAs (miRNAs) act as tumour suppressor genes or oncogenes in the regulation of multiple carcinogenic processes. Aberrant miRNA expression is reported in Helicobacter pylori (H pylori)-related gastritis and gastric cancer. The cytotoxin-associated gene A (CagA) of H pylori has a pathophysiologically important role in gastric carcinogenesis. A study was undertaken to evaluate the effect of CagA on miRNA expression and its regulatory mechanism.
Methods The effect of CagA on miRNA expression was assessed by comprehensive miRNA microarray. The mechanisms of the in vitro and in vivo effects of CagA on histone modification and DNA methylation and the involvement of CagA-dysregulated signal transduction on let-7, an important representative miRNA in gastric carcinogenesis, were investigated.
Results In in vitro experiments, CagA significantly attenuated let-7 expression leading to Ras pathway activation. CagA enhanced c-myc, DNA methyltransferase 3B (DNMT3B) and Enhancer of Zeste homologue 2 (EZH2) expression and attenuated miR-26a and miR-101 expression, which resulted in the attenuation of let-7 expression by histone and DNA methylation. Experiments performed in CagA transgenic mice revealed that c-myc, EZH2 and DNMT3B expression were enhanced and let-7 expression was attenuated to induce Ras oncoprotein expression in the stomach, with no associated inflammation.
Conclusions H pylori CagA induces aberrant epigenetic silencing of let-7 expression, leading to Ras upregulation.