Proton pump inhibitor after endoscopic resection for esophageal squamous cell cancer: multicenter prospective randomized controlled trial.

BACKGROUND: Whether proton pump inhibitors (PPIs) relieve heartburn or precordial pain after endoscopic resection (ER) for esophageal squamous cell carcinoma (ESCC) remains unclear. The aim of this study was to investigate the efficacy of PPI therapy for these symptoms after ER for ESCC. METHODS: We conducted a multicenter prospective randomized controlled trial among 15 hospitals in Japan. In total, 229 patients with cT1a ESCC were randomly assigned to receive PPI therapy for 5 weeks after ER (the PPI group, n = 115) or follow-up without PPI therapy (the non-PPI group, n = 114). The primary end point was the incidence of gastroesophageal reflux disease (GERD)-like symptoms after ER from a self-reported questionnaire (Frequency Scale for Symptoms of GERD). Secondary end points were ulcer healing rate at 5 weeks, incidence of pain, improvement rate of symptoms in those who started PPI therapy because of GERD-like symptoms in the non-PPI group, and adverse events. RESULTS: No significant difference was observed in the incidence of GERD-like symptoms after ER between the non-PPI and PPI groups (30 % vs 34 %, respectively). No significant differences were observed in the ulcer healing rate at 5 weeks (84 % vs 85 %) and incidence of pain within 1 week (36 % vs 45 %). In nine of ten patients (90 %) who started PPI therapy because of GERD-like symptoms in the non-PPI group, PPI administration relieved GERD-like symptoms. No adverse events related to PPI administration were observed. CONCLUSION: PPI therapy is not efficacious in reducing symptoms and did not promote healing of ulcers in patients undergoing ER for ESCC.

Activating GNAS and KRAS mutations in gastric foveolar metaplasia, gastric heterotopia, and adenocarcinoma of the duodenum.

BACKGROUND: Heterotopic gastric-type epithelium, including gastric foveolar metaplasia (GFM) and gastric heterotopia (GH), is a common finding in duodenal biopsy specimens; however, there is still controversy regarding their histogenetic backgrounds. METHODS: We analysed a total of 177 duodenal lesions, including 66 GFM lesions, 81 GH lesions, and 30 adenocarcinomas, for the presence of GNAS, KRAS, and BRAF mutations. RESULTS: Activating GNAS mutations were identified in 27 GFM lesions (41%) and 23 GH lesions (28%). The KRAS mutations were found in 17 GFM lesions (26%) and 2 GH lesions (2%). A BRAF mutation was found in only one GFM lesion (2%). These mutations were absent in all 32 normal duodenal mucosa specimens that were examined, suggesting a somatic nature. Among the GFM lesions, GNAS mutations were more common in lesions without active inflammation. Analyses of adenocarcinomas identified GNAS and KRAS mutations in 5 (17%) and 11 lesions (37%), respectively. Immunohistochemically, all the GNAS-mutated adenocarcinomas diffusely expressed MUC5AC, indicating gastric epithelial differentiation. CONCLUSIONS: A significant proportion of GFM and GH harbours GNAS and/or KRAS mutations. The common presence of these mutations in duodenal adenoma and adenocarcinoma with a gastric epithelial phenotype implies that GFM and GH might be precursors of these tumours.

Development and external validation of a nomogram for overall survival after curative resection in serosa-negative, locally advanced gastric cancer.

BACKGROUND: Few nomograms can predict overall survival (OS) after curative resection of advanced gastric cancer (AGC), and these nomograms were developed using data from only a few large centers over a long time period. The aim of this study was to develop and externally validate an elaborative nomogram that predicts 5-year OS after curative resection for serosa-negative, locally AGC using a large amount of data from multiple centers in Japan over a short time period (2001-2003). PATIENTS AND METHODS: Of 39 859 patients who underwent surgery for gastric cancer between 2001 and 2003 at multiple centers in Japan, we retrospectively analyzed 5196 patients with serosa-negative AGC who underwent Resection A according to the 13th Japanese Classification of Gastric Carcinoma. The data of 3085 patients who underwent surgery from 2001 to 2002 were used as a training set for the construction of a nomogram and Web software. The data of 2111 patients who underwent surgery in 2003 were used as an external validation set. RESULTS: Age at operation, gender, tumor size and location, macroscopic type, histological type, depth of invasion, number of positive and examined lymph nodes, and lymphovascular invasion, but not the extent of lymphadenectomy, were associated with OS. Discrimination of the developed nomogram was superior to that of the TNM classification (concordance indices of 0.68 versus 0.61; P < 0.001). Moreover, calibration was accurate. CONCLUSIONS: We have developed and externally validated an elaborative nomogram that predicts the 5-year OS of postoperative serosa-negative AGC. This nomogram would be helpful in the assessment of individual risks and in the consideration of additional therapy in clinical practice, and we have created freely available Web software to more easily and quickly predict OS and to draw a survival curve for these purposes.

Feasibility of endoscopic mucosal resection as salvage treatment for patients with local failure after definitive chemoradiotherapy for stage IB, II, and III esophageal squamous cell cancer.

Local failure after definitive chemoradiotherapy (CRT) for stage IB, II, and III esophageal cancer is one of the causes of poor outcome. Endoscopic mucosal resection (EMR) is an effective treatment for superficial esophageal cancer. However, its feasibility as a salvage treatment for local recurrent or residual tumors after definitive CRT for stage IB, II, and III esophageal cancer remains unclear. Between January 2000 and February 2008, 274 patients with stage IB, II, and III esophageal squamous cell cancer excluding T4 received definitive CRT at the National Cancer Center Hospital, Japan. Of these patients, nine patients with local recurrence after achieving complete response and two patients with residual tumor underwent salvage EMR. The technique of salvage EMR involved a strip biopsy method. We retrospectively reviewed the 11 patients (13 lesions). Characteristics of all 11 patients were as follows: median age of 69 (range: 45-78); male/female: 10/1; baseline clinical stage (Union for International Cancer Control 7th) IB/IIA/IIB/III: 1/3/7/0. The depth of resected tumor was limited to the mucosal layer in seven lesions and submucosal in six lesions. En bloc resection was performed on six lesions (46%). The vertical margin was free of cancer cells in 11 lesions (84.6%). No major complications, such as hemorrhage requiring blood transfusion and perforation, were experienced. At a median follow-up period of 38.9 months (range: 5.3-94 months) after salvage EMR, no recurrence was detected in six patients (54%). Local recurrence was detected in five patients (27%). Of these patients, two had lung metastasis simultaneously, and one was also detected lung metastasis 2 months after the detection of local recurrence. The 5-year survival rate after salvage EMR was 41.6%. Salvage EMR is a feasible treatment option for local recurrent or residual lesions after definitive chemotherapy and/or radiotherapy for stage IB, II, and III esophageal squamous cell cancer.

Is endoscopic submucosal dissection an effective treatment for operable patients with clinical submucosal invasive early gastric cancer?

BACKGROUND AND STUDY AIMS: Gastrectomy with lymph node dissection is the gold standard curative treatment for clinical submucosal invasive early gastric cancer (cSM EGC), but a relatively small number of operable patients with cSM EGC have undergone endoscopic submucosal dissection (ESD) instead because they refused surgery. The aim of this study was to determine the effectiveness of ESD in these operable patients. METHODS: The therapeutic outcomes of ESD were retrospectively assessed for 38 patients with 38 operable cSM EGC lesions who initially refused surgery at the National Cancer Center Hospital, Tokyo, from January 1999 to December 2008. RESULTS: The en bloc resection rate was 84.2% (32 lesions) and the complete (R0) resection rate was 63.2% (24 lesions). A total of 33 lesions (86.8%) involved submucosal invasion on pathology. Resection was non-curative in 34 patients (89.5%), 22 of whom (64.7%) underwent subsequent gastrectomy after the need for such surgery was carefully explained to them again. The median follow-up period was 73.2 months (range 3-115 months). Local recurrence was detected in one patient, distant metastasis in two patients, and both local recurrence and distant metastasis were detected in one patient. None of these four patients with recurrence (10.5%) had undergone surgery when their recurrent disease was detected and all of them died from gastric cancer. The 5-year cause-specific survival rate for all patients was 91.8%. CONCLUSION: The 5-year cause-specific survival rate for all patients was lower than the previously reported rate of 96.7% for pathologically submucosal invasive EGC patients after gastrectomy; therefore, ESD appears to have been an ineffective treatment for operable patients with cSM EGC.

FGFR2 gene amplification and clinicopathological features in gastric cancer.

BACKGROUND: Frequency of FGFR2 amplification, its clinicopathological features, and the results of high-throughput screening assays in a large cohort of gastric clinical samples remain largely unclear. METHODS: Drug sensitivity to a fibroblast growth factor receptor (FGFR) inhibitor was evaluated in vitro. The gene amplification of the FGFRs in formalin-fixed, paraffin-embedded (FFPE) gastric cancer tissues was determined by a real-time PCR-based copy number assay and fluorescence in situ hybridisation (FISH). RESULTS: FGFR2 amplification confers hypersensitivity to FGFR inhibitor in gastric cancer cell lines. The copy number assay revealed that 4.1% (11 out of 267) of the gastric cancers harboured FGFR2 amplification. No amplification of the three other family members (FGFR1, 3 and 4) was detected. A FISH analysis was performed on 7 cases among 11 FGFR2-amplified cases and showed that 6 of these 7 cases were highly amplified, while the remaining 1 had a relatively low grade of amplification. Although the difference was not significant, patients with FGFR2 amplification tended to exhibit a shorter overall survival period. CONCLUSION: FGFR2 amplification was observed in 4.1% of gastric cancers and our established PCR-based copy number assay could be a powerful tool for detecting FGFR2 amplification using FFPE samples. Our results strongly encourage the development of FGFR-targeted therapy for gastric cancers with FGFR2 amplification.

Endoscopic resection of early gastric cancer treated by guideline and expanded National Cancer Centre criteria.

BACKGROUND: Criteria for endoscopic resection in patients with early gastric cancer (EGC) have been expanded recently by the National Cancer Centre (NCC). This study compared long-term outcomes in patients with EGC who underwent endoscopic treatment according to guideline criteria with those treated according to expanded criteria. METHODS: Baseline and outcome data from patients undergoing curative endoscopic resection for EGC between January 1999 and December 2005 were collected from electronic medical records. Survival time hazard ratios and 95 per cent confidence intervals were calculated using the Cox proportional hazards model. RESULTS: Of 1485 patients who had a curative resection, 635 (42.8 per cent) underwent resection according to traditional criteria and 625 (42.1 per cent) according to expanded criteria. There was no significant difference in overall survival between the groups. CONCLUSION: Patients who have treatment following the expanded criteria have similar long-term survival and outcomes to those treated according to guideline criteria.

Use of Gascon and Pronase either as a pre-endoscopic drink or as targeted endoscopic flushes to improve visibility during gastroscopy: a prospective, randomized, controlled, blinded trial.

OBJECTIVE: To assess whether endoscopic flushes of the bubble-bursting agent Gascon and the mucolytic agent Pronase are as effective in terms of improving endoscopic mucosal visibility as a pre-endoscopic drink of the same agents. MATERIAL AND METHODS: A total of 112 patients attending a Japanese tertiary referral centre for upper gastrointestinal endoscopy were randomized to receive either the standard Japanese procedure of a pre-endoscopic drink of water containing Gascon and Pronase with endoscopic flushes of 20-ml aliquots of water, or no pre-endoscopic therapy but endoscopic flushes of 20-ml aliquots of water containing Gascon, with or without Pronase as necessary. RESULTS: Visibility scores were significantly better in the pre-endoscopic drink group than in either of the endoscopic flush groups. The group receiving a pre-endoscopic drink required fewer flushes during the procedure and there was no difference in the endoscopic time between the three groups. CONCLUSIONS: Our results suggest that endoscopic spraying of these bubble-bursting and mucolytic agents is not able to offer equivalent improvements in endoscopic mucosal visibility when compared with the standard Japanese therapy of a pre-endoscopic drink of these agents. The addition of Pronase to the spray solution had no measurable benefit over Gascon alone. We therefore cannot recommend endoscopic spraying of mucous clearing agents over their use as a pre-endoscopic drink.

Feasibility of endoscopic mucosal resection for superficial pharyngeal cancer: a minimally invasive treatment.

BACKGROUND AND STUDY AIMS: New diagnostic techniques have recently been developed so detection of superficial pharyngeal cancer is dramatically increasing and endoscopic mucosal resection (EMR) can now be performed on an experimental basis. The aim of this study was to clarify the effectiveness of EMR for superficial pharyngeal cancer. PATIENTS AND METHODS: Between 2004 and 2007, 31 patients with 37 pharyngeal lesions underwent EMR at our hospital. EMR using a cap-fitted endoscope (EMR-C) was used on 34 lesions and strip biopsies on the remaining three. We retrospectively assessed the effectiveness of those procedures in treating superficial pharyngeal cancer. RESULTS: Median procedure time was 45 minutes (range 20 - 180 minutes) and median hospital stay was 7 days (range 4 - 12 days). Regarding complications, one patient experienced laryngeal edema, one suffered aspiration pneumonia, and two sustained dermatitis around the mouth caused by Lugol staining. Histologically, 18 lesions were confirmed as carcinoma in situ and the other 19 lesions demonstrated microinvasion of the subepithelial tissue with lymphatic invasion in one case. During the median follow-up period of 40 months (range 21 - 62 months), two patients received radiotherapy and two patients underwent an additional EMR because of recurrent tumors. Five other patients developed metachronous superficial pharyngeal cancers, but all those lesions were resected primarily by EMR while two of the study's 31 patients died from esophageal cancer. None of the remaining 20 patients experienced any recurrent or metachronous tumors during their follow-up periods. CONCLUSIONS: Our results indicated that EMR was a safe, effective, and minimally invasive treatment for superficial pharyngeal cancer.

The indolent course and high incidence of t(14;18) in primary duodenal follicular lymphoma.

BACKGROUND: Information on the clinical behavior of the recently proposed primary duodenal follicular lymphoma (DFL) is limited. PATIENTS AND METHODS: Demographic data, signs, symptoms, disease stage, and treatment of the patients diagnosed in National Cancer Center Hospital from 1999 to 2007 were collected and analyzed. RESULTS: Twenty-seven patients were studied. Nineteen patients were asymptomatic at the time of diagnosis. Twenty patients had stage I disease. The histological grade was 1 or 2 in 26 patients. IgH/BCL2 fusion was shown in 20 of the examined 24 cases (83%). Fourteen patients received therapy upon diagnosis (local radiotherapy in 2 patients and chemotherapy in 12 including rituximab therapy), their response rate was 85%, and the estimated progression-free survival (PFS) rate at 3 years was 70%. One patient developed histological transformation. The other 13 patients were followed up; their estimated PFS rate at 3 years was 74%. Five among six cases responded to treatment even after progressive disease. All 27 patients have survived with a median follow-up time of 47.9 months. CONCLUSIONS: The majority of primary DFL patients have a localized tumor of low-grade histology and are positive for t(14;18). Watchful waiting might be an alternative approach for its indolent course; however, further studies are warranted.

Risk factors for cardiac and pyloric stenosis after endoscopic submucosal dissection, and efficacy of endoscopic balloon dilation treatment.

BACKGROUND AND STUDY AIMS: Bleeding and perforation are major complications of endoscopic submucosal dissection (ESD) for early gastric cancer (EGC), but post-ESD stenosis represents a severe delayed complication that can result in clinical symptoms such as dysphagia and nausea. The aims of this study were to determine the risk factors and evaluate the clinical treatment for post-ESD stenosis. METHODS: A total of 2011 EGCs resected by ESD at our institution between 2000 and 2005 were reviewed retrospectively. Resection was defined as cardiac when any mucosal defect was located in the squamocolumnar junction, and as pyloric when any mucosal defect was located < 1 cm from the pylorus ring. Post-ESD stenosis was defined when a standard endoscope could not be passed through the stenosis. We examined the incidence of post-ESD stenosis, its relationship with relevant factors, and the clinical course of post-ESD stenosis patients. RESULTS: Post-ESD stenosis occurred with seven of 41 cardiac resections (17 %) and eight of 115 pyloric resections (7 %). Circumferential extent of the mucosal defect of > 3/4 and longitudinal extent > 5 cm were each significantly related to occurrence of post-ESD stenosis with both cardiac and pyloric resections. All 15 affected patients were successfully treated by endoscopic balloon dilation. CONCLUSIONS: A circumferential extent of the mucosal defect of > 3/4 or longitudinal extent of > 5 cm in length were both demonstrated to be risk factors for post-ESD stenosis, in both cardiac and pyloric resections, and endoscopic balloon dilation was shown to be effective in treating post-ESD stenosis.

Treatment strategy after non-curative endoscopic resection of early gastric cancer.

BACKGROUND: Endoscopic resection (ER) is indicated for patients with early gastric cancer who have a negligible risk of lymph node metastasis (LNM). Histological examination of the resected specimen may indicate a possible risk of LNM or a positive resection margin. These patients are considered to have undergone non-curative ER. The aim of this study was to determine the appropriate treatment strategy for such patients. METHODS: A total of 298 patients who had non-curative ER were classified into those with a positive lateral margin only (group 1; 72 patients) and those with a possible risk of LNM (group 2; 226 patients). RESULTS: Surgery was performed within 6 months of non-curative ER in 19 patients in group 1 and 144 in group 2. In group 1, nine patients were found to have local residual tumours, all limited to the mucosal layer without LNM. In Group 2, 13 patients had residual disease, including four local tumours without LNM, two local tumours with LNM and seven cases of LNM alone. The rate of LNM after surgery was 6.3 per cent in group 2. CONCLUSION: Surgery remains the standard treatment after non-curative ER in patients with a possible risk of LNM.

Routine coagulation of visible vessels may prevent delayed bleeding after endoscopic submucosal dissection--an analysis of risk factors.

BACKGROUND AND STUDY AIM: Endoscopic submucosal dissection (ESD) has been reported to be associated with a higher complication rate than standard endoscopic mucosal resection. We aimed to clarify the risk factors for delayed bleeding after ESD for early gastric cancer (EGC). METHODS: 1083 EGCs in 968 consecutive patients undergoing ESD during a 4-year period were reviewed. Post-ESD coagulation (PEC) preventive therapy of visible vessels in the resection area, using a coagulation forceps, was introduced and mostly performed during the later 2 years. Various factors related to patients, tumors, and treatment including PEC were investigated using univariate and multivariate analysis with regard to delayed post-ESD bleeding, evidenced by hematemesis or melena, that required endoscopic treatment. RESULTS: Delayed bleeding occurred after ESD of 63 lesions (5.8 % of all lesions and 6.5 % of patients), controlled in all cases by endoscopic hemostasis; blood transfusion was required in only one case. Tumor location in the upper third of the stomach and PEC were independent factors indicating a lower rate of delayed bleeding according to both univariate and multivariate analysis. CONCLUSIONS: This retrospective study suggested that preventive coagulation of visible vessels in the resection area after ESD may lead to a lower bleeding rate.

Clinical outcome after endoscopic mucosal resection for esophageal squamous cell carcinoma invading the muscularis mucosae--a multicenter retrospective cohort study.

BACKGROUND AND STUDY AIMS: Endoscopic mucosal resection (EMR) is now commonly indicated for esophageal squamous cell carcinoma (ESCC) within the lamina propria mucosa. However, EMR for ESCC that has invaded the muscularis mucosa is controversial because the risk of lymph node metastasis is not negligible. We conducted a multicenter retrospective cohort study to investigate the incidence of lymph node metastasis and survival after EMR for ESCC invading the muscularis mucosa. PATIENTS AND METHODS: A total of 104 patients with 111 lesions invading the muscularis mucosa, were retrospectively studied at eight institutes. No patients exhibited evidence of metastasis of lymph nodes or distant organs prior to EMR. Overall and cause-specific survival rates were calculated from the date of EMR to the date of death or the most recent follow-up visit. Survival curves were plotted according to the Kaplan-Meier method. RESULTS: In total, 86 patients (82.7%) who did not receive further treatment such as chemotherapy, irradiation therapy, chemoradiotherapy, or esophagectomy after EMR were followed up. Only two patients (1.9%) developed lymph node metastasis after EMR. With a median follow-up period of 43 months (range, 8-134 months), overall and cause-specific survival rates at 5 years after EMR were 79.5% and 95.0%, respectively. CONCLUSIONS: EMR for ESCC that invades the muscularis mucosa has curative potential as a minimally invasive treatment option.

Gastric perforation during endoscopic resection for gastric carcinoma and the risk of peritoneal dissemination.

BACKGROUND: The potential risk of peritoneal seeding following perforation caused by endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) is unknown. METHODS: Between January 1991 and December 2003, 90 patients suffered gastric perforation during EMR or ESD at the National Cancer Centre Hospital, Tokyo. The clinical and pathological evidence for peritoneal dissemination in these patients was assessed retrospectively. RESULTS: Eighty-four patients were followed up at this hospital for a median of 53.6 (range 7.0-136.6) months; the remaining six patients were followed up at other institutions. In 83 patients the perforation was repaired by endoscopic clip application and seven patients underwent emergency surgery. Gastrectomy was carried out in 33 patients who had non-curative endoscopic surgery. Among these, peritoneal fluid was sampled during operation in nine patients and was cytologically negative for malignancy. The other 24 patients who had a gastrectomy did not have ascites so cytology was not performed. No peritoneal dissemination was noted during follow-up. CONCLUSION: This study suggests that perforation associated with EMR and ESD does not lead to peritoneal dissemination even in the long term.

Variation of temporal characteristics in human cerebral hemodynamic responses to electric median nerve stimulation: a near-infrared spectroscopic study.

Using near-infrared spectroscopy, we studied cerebral hemodynamic responses to electric median nerve stimulation in ten subjects. The recordings were conducted by optical fibers placed over the left scalp. Electric stimuli were delivered to contra- and ipsilateral median nerves, respectively. Hemodynamic responses in the secondary somatosensory cortex were observed following each median nerve stimulation, except for three drowsy subjects. The contralateral stimulation tended to induce a larger response. The degree of change in oxygenated hemoglobin was hardly related to stimulus intensities, and was augmented by attention. Four subjects showed long-lasting responses throughout the stimulus periods, while three other subjects revealed transient responses. Thus, taking account of the temporal activation patterns is necessary for proper interpretation of the hemodynamic response following electric nerve stimulation.

Cortical mapping of gait in humans: a near-infrared spectroscopic topography study.

While we have a fair understanding of how and where forelimb-hand manipulative movements are controlled by the neocortex, due to functional imaging studies, we know little about the control of bipedal movements such as walking because of technical difficulties. We succeeded in visualizing cortical activation patterns of human gait by measuring relative changes in local hemoglobin oxygenation using a recently developed near-infrared spectroscopic (NIRS) topography technique. Walking activities were bilaterally associated with increased levels of oxygenated and total hemoglobin in the medial primary sensorimotor cortices and the supplementary motor areas. Alternating foot movements activated similar but less broad regions. Gait imagery increased activities caudally located in the supplementary motor areas. These findings provide new insight into cortical control of human locomotion. NIRS topography might be also useful for evaluating cerebral activation patterns during pathological gait and rehabilitative intervention.

Hremx, the ascidian homologue of ems/emx, is expressed in the anterior and posterior-lateral epidermis but not in the central nervous system during embryogenesis.

Recent comparative studies on expression patterns of homeobox genes in the development between ascidians and vertebrates have come to suggest a possibility that a common basic mechanism may exist in the patterning of the central nervous system (CNS). The ems/emx genes have been demonstrated to be involved in the formation and patterning of the anterior CNS in Drosophila and vertebrate embryos. In the present study, we have isolated and analyzed expression of Hremx, the ascidian homologue of ems/emx with particular attention to whether it is expressed in the larval ascidian CNS. Expression of Hremx was detected in the anterior trunk and lateral tail epidermis but not in the anterior CNS. The two expression domains of the epidermis responded in different ways upon treatment with retinoic acid: the anterior expression domain was unaltered, while the posterior expression domain extended to the anterior. The present result suggests that Hremx may have a function in anterior patterning but not in the patterning of the CNS in the ascidian embryo. We suggest the possibility that the function of ems/emx genes in the patterning of the anterior CNS in Drosophila and vertebrate embryos might have been acquired independently in the lineages to Drosophila and vertebrates.