Shigeaki Yoshida

Endoscopic mucosal resection for treatment of early gastric cancer.

BACKGROUND In Japan, endoscopic mucosal resection (EMR) is accepted as a treatment option for cases of early gastric cancer (EGC) where the probability of lymph node metastasis is low. The results of EMR for EGC at the National Cancer Center Hospital, Tokyo, over a 11 year period are presented. METHODS EMR was applied to patients with early cancers up to 30 mm in diameter that were of a well or moderately histologically differentiated type, and were superficially elevated and/or depressed (types I, IIa, and IIc) but without ulceration or definite signs of submucosal invasion. The resected specimens were carefully examined by serial sections at 2 mm intervals, and if histopathology revealed submucosal invasion and/or vessel involvement or if the resection margin was not clear, surgery was recommended. RESULTS Four hundred and seventy nine cancers in 445 patients were treated by EMR from 1987 to 1998 but submucosal invasion was found on subsequent pathological examination in 74 tumours. Sixty nine percent of intramucosal cancers (278/405) were resected with a clear margin. Of 127 cancers without “complete resection”, 14 underwent an additional operation and nine were treated endoscopically; the remainder had intensive follow up. Local recurrence in the stomach occurred in 17 lesions followed conservatively, in one lesion treated endoscopically, and in five lesions with complete resection. All tumours were diagnosed by follow up endoscopy and subsequently treated by surgery. There were no gastric cancer related deaths during a median follow up period of 38 months (3–120 months). Bleeding and perforation (5%) were two major complications of EMR but there were no treatment related deaths. CONCLUSION In our experience, EMR allows us to perform less invasive treatment without sacrificing the possibility of cure.

Appearance of enhanced tissue features in narrow-band endoscopic imaging

This study was performed to examine the usefulness of medical endoscopic imaging utilizing narrow-band illumination. The contrast between the vascular pattern and the adjacent mucosa of the underside of the human tongue was measured using five narrow-band illuminations and three broadband illuminations. The results demonstrate that the pathological features of a vascular pattern are dependent on the center wavelength and the bandwidth of illumination. By utilizing narrow-band illumination of 415+/-30 nm, the contrast of the capillary pattern in the superficial layer was markedly improved. This is an important benefit that is difficult to obtain with ordinary broadband illumination. The appearances of capillary patterns on color images were evaluated for three sets of filters. The narrow, band imaging (NBI) filter set (415+/-30 nm, 445+/-30 nm, 500+/-30 nm) was selected to achieve the preferred appearance of the vascular patterns for clinical tests. The results of clinical tests in colonoscopy and esophagoscopy indicated that NBI will be useful as a supporting method for observation of the endoscopic findings of early cancer.

Randomized phase III trial of fluorouracil alone versus fluorouracil plus cisplatin versus uracil and tegafur plus mitomycin in patients with unresectable, advanced gastric cancer : The Japan Clinical Oncology Group Study (JCOG9205)

PURPOSE To compare fluorouracil (FU) alone with FU plus cisplatin (FP) and with uracil and tegafur plus mitomycin (UFTM) for patients with advanced gastric cancer in a prospective, randomized, controlled trial. PATIENTS AND METHODS A total of 280 patients with advanced gastric cancer were randomly allocated and analyzed for survival, response, and toxicity. The survival curves were compared between groups by log-rank test on an intent-to-treat basis. RESULTS At the interim analysis, the UFTM arm showed a significantly inferior survival with higher incidences of hematologic toxic effects than did control arm FU alone, and the registration to UFTM was terminated. Both investigational regimens, FP and UFTM, had a significantly higher incidence of hematologic toxic effects than FU alone, although the effects were manageable. The overall response rates of the FU-alone, FP, and UFTM arms were 11%, 34%, and 9%, respectively. The median progression-free survival was 1.9 months with FU alone, 3.9 months with FP, and 2.4 months with UFTM, respectively. Although FP demonstrated a higher response rate (P <.001) and longer progression-free survival than did FU alone (P <.001), no differences in overall survival were observed between the arms. The median survival times and 1-year survival rates were 7.1 months and 28% with FU, 7.3 months and 29% with FP, and 6.0 months and 16% with UFTM, respectively. CONCLUSION Neither investigational regimen, FP nor UFTM, showed a survival advantage as compared with FU alone. FU alone will remain a reference arm in our future trial for advanced gastric cancer.

A prospective, multicenter study of 1111 colorectal endoscopic submucosal dissections (with video)

BACKGROUND Endoscopic submucosal dissection (ESD) is accepted as a minimally invasive treatment for early gastric cancer, although it is not widely used in the colorectum because of technical difficulty. OBJECTIVE To examine the current status of colorectal ESDs at specialized endoscopic treatment centers. DESIGN AND SETTING Multicenter cohort study using a prospectively completed database at 10 specialized institutions. PATIENTS AND INTERVENTIONS From June 1998 to February 2008, 1111 colorectal tumors in 1090 patients were treated by ESD. MAIN OUTCOME MEASUREMENTS Tumor size, macroscopic type, histology, procedure time, en bloc and curative resection rates and complications. RESULTS Included in the 1111 tumors were 356 tubular adenomas, 519 intramucosal cancers, 112 superficial submucosal (SM) cancers, 101 SM deep cancers, 18 carcinoid tumors, 1 mucosa-associated lymphoid tissue lymphoma, and 4 serrated lesions. Macroscopic types included 956 laterally spreading tumors, 30 depressed, 62 protruded, 44 recurrent, and 19 SM tumors. The en bloc and curative resection rates were 88% and 89%, respectively. The mean procedure time ± standard deviation was 116 ± 88 minutes with a mean tumor size of 35 ± 18 mm. Perforations occurred in 54 cases (4.9%) with 4 cases of delayed perforation (0.4%) and 17 cases of postoperative bleeding (1.5%). Two immediate perforations with ineffective endoscopic clipping and 3 delayed perforations required emergency surgery. Tumor size of 50 mm or larger was an independent risk factor for complications, whereas a large number of ESDs performed at an institution decreased the risk of complications. LIMITATIONS No long-term outcome data. CONCLUSIONS ESD performed by experienced endoscopists is an effective alternative treatment to surgery, providing high en bloc and curative resection rates for large superficial colorectal tumors.

A multicenter retrospective study of endoscopic resection for early gastric cancer.

BackgroundThe reported outcomes of endoscopic resection (ER) for early gastric cancer (EGC) remain limited to several single-institution studies.MethodsA multicenter retrospective study was conducted at 11 Japanese institutions concerning their results for ER, including conventional endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD).ResultsA total of 714 EGCs (EMR, 411; ESD, 303) in 655 consecutive patients were treated from January to December 2001. Technically, 511 of the 714 (71.6%) lesions were resected in one piece. The rate of one-piece resection with ESD (92.7%; 281/303) was significantly higher compared with that for EMR (56.0%; 230/411). Histologically, curative resection was found in 474 (66.3%) lesions. The rate of curative resection with ESD (73.6%; 223/303) was significantly higher compared with that for EMR (61.1%; 251/411). Blood transfusion because of bleeding was required in only 1 patient (0.1%) with EMR of 714 lesions. Perforation was found in 16 (2.2%). The incidence of perforation with ESD (3.6%; 11/303) was significantly higher than that with EMR (1.2%; 5/411). All complications were managed endoscopically, and there was no procedure-related mortality. The median follow-up period was 3.2 years (range, 0.5–5.0 years). In total, the 3-year cumulative residual-free/recurrence-free rate and the 3-year overall survival rate were 94.4% and 99.2%, respectively. The 3-year cumulative residual-free/recurrence-free rate in the ESD group (97.6%) was significantly higher than that in the EMR group (92.5%).ConclusionER leads to an excellent 3-year survival in clinical practice and could be a possible standard treatment for EGC. ESD has the advantage of achieving one-piece resection and reducing local residual or recurrent tumor.

Definitive chemoradiotherapy for T4 and/or M1 lymph node squamous cell carcinoma of the esophagus.

PURPOSE To investigate the efficacy and feasibility of concurrent chemoradiotherapy for locally advanced carcinoma of the esophagus. PATIENTS AND METHODS Fifty-four patients with clinically T4 and/or M1 lymph node (LYM) squamous cell carcinoma of the esophagus were enrolled. Patients received protracted infusion of fluorouracil 400 mg/m(2)/24 hours on days 1 to 5 and 8 to 12, 2-hour infusion of cisplatin 40 mg/m(2) on days 1 and 8, and concurrent radiation therapy at a dose of 30 Gy in 15 fractions over 3 weeks. Filgrastim was prophylactically administered to 35 patients. This schedule was repeated twice every 5 weeks, for a total radiation dose of 60 Gy, followed by two courses of fluorouracil (800 mg/m(2)/24 hours for 5 days) and cisplatin (80 mg/m(2) on day 1). RESULTS There were 21 patients with T4M0 disease, one with T2M1 LYM, 17 with T3M1 LYM, and 15 withT4M1 LYM. Forty-nine patients (91%) completed at least the chemoradiotherapy segment. The 18 patients (33%) who achieved a complete response included nine (25%) of the 36 with T4 disease and nine (50%) of the 18 with non-T4 disease. Major toxicities were leukocytopenia and esophagitis; there were four (7%) treatment-related deaths. Prophylactic filgrastim reduced the incidence of grade 3 or worse leukopenia without improving dose-intensity or response. With a median follow-up duration of 43 months, median survival time was 9 months. The 3-year survival rate was 23%. CONCLUSION Despite its significant toxicity, this combined modality seemed to have curative potential even in cases of locally advanced carcinoma of the esophagus.

Long-Term Toxicity After Definitive Chemoradiotherapy for Squamous Cell Carcinoma of the Thoracic Esophagus

PURPOSE To assess the long-term toxicity after definitive chemoradiotherapy (CRT) for squamous cell carcinoma (SCC) of the esophagus. PATIENTS AND METHODS Patients newly diagnosed with SCC of the esophagus and treated with definitive CRT between 1992 and 1999 in our institution were recruited from our database on the basis of the following criteria: age </= 75 years, performance status (PS; based on the Eastern Cooperative Oncology Group scale) 0 to 2, and clinical tumor-node-metastasis system stage I to IVA. The CRT consisted of two cycles of cisplatin 40 mg/m2 on days 1 and 8, and continuous infusion of fluorouracil 400 mg/m2/d on days 1 to 5 and 8 to 12, repeated every 5 weeks with concurrent radiotherapy of 60 Gy in 30 fractions. For the assessment of toxicity, the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer late radiation morbidity scoring scheme was adopted. RESULTS A total of 139 patients were recruited, and their characteristics were as follows: median age, 62 years (range, 38 to 75 years); 121 males and 18 females; 96 patients PS 0, 42 patients PS 1, and one patient PS 2; 15 patients T1, 11 patients T2, 60 patients T3, and 53 patients T4; and 101 patients M0, 38 patients M1a. With a median follow-up of 53 months, the median survival time and 5-year survival rate were 21 months and 29%, respectively. Of 78 patients with complete remission, two patients died as a result of acute myocardial infarction. Grade 2, 3, and 4 late toxicities occurred with the following incidences: pericarditis in eight patients, seven patients, and one patient, respectively; heart failure in zero, zero, and two patients; pleural effusion in seven, eight, and zero patients; and radiation pneumonitis in one patient, three patients, and zero patients, respectively. CONCLUSION Definitive CRT for SCC of the esophagus is effective with substantial toxicities. Additional investigation to minimize the normal tissue toxicities is warranted.

Nonrandomized comparison between definitive chemoradiotherapy and radical surgery in patients with T2–3Nany M0 squamous cell carcinoma of the esophagus

PURPOSE To compare the treatment results between radical surgery and definitive chemoradiotherapy for resectable squamous cell carcinoma of the esophagus and to identify useful clinicopathologic and biologic markers to select better treatment. METHODS AND MATERIALS Between August 1992 and April 1999, 98 consecutive patients were selected for this study; 53 were treated with chemoradiotherapy and 45 with surgery. The patients in the chemoradiotherapy group received 5-fluorouracil combined with cisplatin plus 60 Gy of radiation, and those in the surgery group received an esophagectomy with radical node dissection. Biologic markers were investigated immunohistochemically using pretreatment biopsy specimens. RESULTS The baseline clinical TNM stage was more advanced in the chemoradiotherapy group than in the surgery group. With a median follow-up period of 43 months, the 5-year survival rate was 46% in the chemoradiotherapy and 51% in the surgery group, without statistical significance (p = 0.47, log-rank test). Cox regression analysis for prognosis revealed that epidermal growth factor receptor positivity, high microvessel density, and cyclin D1 positivity yielded a low value for relative risk (0.66, 0.54, and 0.62, respectively), which favored chemoradiotherapy over surgery, without statistical significance. CONCLUSION This nonrandomized study showed a trend for the chemoradiotherapy in the treatment of esophageal carcinoma, but the results need to be confirmed by additional study.

Induction of vascular endothelial growth factor by nitric oxide in human glioblastoma and hepatocellular carcinoma cells

We evaluated the effect of nitric oxide (NO) on vascular endothelial growth factor (VEGF) gene expression in human A-172 glioblastoma cells and human HepG2 hepatocellular carcinoma cells. The mRNA level of VEGF increased in response to S-Nitroso-N-acetly-D,L-penicillamine (SNAP) in both cell lines, and increased in mRNA level well coincided with VEGF protein production in A-172 cells. SNAP at 0.5 mM induced maximal stimulation of 4.4 and 3.7 kb VEGF mRNA expression after 6 h about 11 and 8 fold increase, respectively above control level. Similar VEGF mRNA accumulation was observed also with NOR3, another chemical NO generator. To evaluate the effect of SNAP on VEGF mRNA stability, half-lives of VEGF mRNA were measured in A-172 cells cultured with or without 0.5 mM SNAP and treated with actinomycin D (25 μg/ml). Half-life for VEGF mRNA was found to be prolonged about 2.4 fold by SNAP. VEGF expression induced by SNAP was inhibited by guanylate cyclase inhibitors, methylene blue (10 μM) and LY-83583 (1 μM), and by the protein synthesis inhibitor, cycloheximide (25 μg/ml). These results suggest that induction of VEGF gene expression by NO is mediated through guanylate cyclase activity and requires on-going protein synthesis.

High frequency of K-ras mutations in human colorectal hyperplastic polyps.

BACKGROUND: Hyperplastic polyps are common benign colorectal polyps, and are thought to have little association with malignant tumours in the colorectum. However, several reports suggest that some hyperplastic polyps may develop into colorectal neoplasms. AIM: To clarify genetic alterations in colorectal hyperplastic polyps. METHODS: Twenty eight colorectal polyps having serrated components were resected from patients endoscopically. The K-ras gene mutations in codons 12 and 13 were analysed by PCR-RFLP. Intranuclear p53 protein was immunostained by the avidin-biotin complex method. RESULTS: A mutation of the K-ras gene was detected in nine (47%) of 19 hyperplastic polyps, and five (56%) of nine adenomas. p53 protein nuclear accumulation was detected immunohistochemically in two (22%) of nine adenomas, but not in any of the hyperplastic polyps. CONCLUSION: Some hyperplastic polyps may be true neoplastic lesions, and could be precursors of malignant neoplasia.