Comparison of site-specific gene expression levels in primary tumors and synchronous lymph node metastases in advanced gastric cancer.

BACKGROUND: Many malignant tumors consist of heterogeneous subpopulations of cells. This heterogeneity is associated with genetic characteristics. However, it remains unclear whether gene expression levels differ among specific sites of tumors in gastric cancer. METHODS: We studied differences in gene expression levels among specific sites of primary tumors and synchronous lymph node metastases, using formalin-fixed, paraffin-embedded specimens resected surgically from 48 patients with previously untreated advanced gastric cancer. Specimens were obtained by laser-captured microdissection from five regions: (1) nonneoplastic mucosa, (2) surface layer (mucosa) of the primary tumor (surface sections), (3) middle layer (submucosa) of the primary tumor (middle sections), (4) the deepest layer of the primary tumor (muscularis propria or deeper) at the site of deepest invasion (deep sections), and (5) level 1 synchronous lymph node metastasis (lymph node metastases). Expression levels of the following target genes were determined by quantitative real-time polymerase chain reaction: thymidylate synthase (TS), thymidine phosphorylase (TP), dihydropyrimidine dehydrogenase (DPD), epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and hypoxia-inducible factor-1α (HIF1α). RESULTS: TP, DPD, EGFR, and HIF1α gene expression levels were significantly higher in deep sections than in surface sections. TP, EGFR, VEGF, and HIF1α gene expression levels were significantly higher in lymph node metastases than in surface sections. TP, DPD, EGFR, VEGF, and HIF1α gene expression levels were positively correlated with the specific samples harvested from the tumors. CONCLUSIONS: Our results show that the expression levels of some genes in tumor cells can change in specific sites of tumors and can become higher in association with tumor progression.

Long-term outcomes of endoscopic submucosal dissection for early gastric cancer: a retrospective comparison with conventional endoscopic resection in a single center.

BACKGROUND: Few studies have compared the outcomes of endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) in patients with early gastric cancer. METHODS: We studied 780 lesions for which endoscopic treatment was indicated according to the Japanese Gastric Cancer Association (JGCA) criteria or the extended National Cancer Center (NCC) criteria from April 1995 to December 2007. A total of 359 lesions were treated by endoscopic aspiration mucosectomy (EAM) between April 1995 and March 2003 (EAM group), and 421 lesions were treated by ESD between April 2003 and December 2007 (ESD group). Long-term outcomes (local recurrence rate, overall survival) were compared between the groups. RESULTS: The median follow-up was 73 months in the EAM group and 65 months in the ESD group. Overall, the local recurrence rate was significantly lower in the ESD group (0.2 %, 1/421) than in the EAM group (4.2 %, 15/359) (p < 0.05). For lesions meeting the JGCA criteria, the local recurrence rate was 2.9 % in the EAM group and 0 % in the ESD group (p < 0.05). For lesions meeting the NCC criteria, the local recurrence rate was 12.5 % in the EAM group and 0.6 % in the ESD group (p < 0.05). There was no significant difference between the groups in overall survival. CONCLUSIONS: On long-term follow-up, ESD was associated with a lower rate of local recurrence than EAM for lesions that met the JGCA or the NCC criteria. From the point of view of radical curability, ESD can be recommended for the management of lesions that meet either set of criteria.

A phase II study of endoscopic submucosal dissection for superficial esophageal neoplasms (KDOG 0901).

BACKGROUND: Most previous studies of endoscopic submucosal dissection (ESD) for superficial esophageal neoplasms were retrospective; prospective studies are scant. OBJECTIVE: To prospectively assess the efficacy and safety of ESD for superficial esophageal neoplasms. DESIGN: Phase II study. SETTING: University hospital. PATIENTS: Fifty-two patients (median age 68 years; 48 men) who had a histologic diagnosis of superficial esophageal cancer without metastasis on CT or high-grade intraepithelial neoplasia (HGIN) were enrolled from April 2009 through November 2011. INTERVENTION: ESD was used to treat 56 lesions. All procedures were done by 4 endoscopists who each had previously performed ESD in more than 100 patients with gastric tumors. MAIN OUTCOME MEASUREMENTS: The primary endpoint was the R0 resection rate, and secondary endpoints were the safety and the rate of accurately diagnosing tumor depth on endoscopic examination. RESULTS: The median treatment time was 69 minutes (24-168 minutes). The histopathologic diagnosis was squamous cell carcinoma in 49 lesions, HGIN in 5, and tubular adenocarcinoma in 2. The en bloc resection rate and R0 resection rate were 100% and 94.6%, respectively. The rates of adverse events during ESD and after ESD were 22.2% and 53.8%, respectively, but most events were mild. One patient (1.9%) had mediastinal emphysema without perforation. The rate of accurately diagnosing tumor depth on endoscopic examination was 76.8%. LIMITATIONS: Single-center, nonrandomized study. CONCLUSION: Our study showed that ESD was an effective and relatively safe treatment for superficial esophageal neoplasms. ESD may be a useful treatment option for superficial esophageal neoplasms in hospitals with endoscopists who are experts in performing ESD for gastric tumors. ( CLINICAL TRIAL REGISTRATION NUMBER: UMIN000002047.).

Double-endoscope endoscopic submucosal dissection for the treatment of early gastric cancer accompanied by an ulcer scar (with video).

BACKGROUND: Endoscopic submucosal dissection (ESD) for early gastric cancer accompanied by an ulcer scar remains challenging. Several counter-traction techniques have been attempted to facilitate ESD, but a standard procedure remains to be established. OBJECTIVE: To evaluate the efficacy and safety of double-endoscope ESD by using a single light source in patients with early gastric cancer accompanied by an ulcer scar. DESIGN: Single center, retrospective study. SETTING: Kitasato University East Hospital. PATIENTS: A total of 30 early gastric cancers with ulcer scars were treated by double-endoscope ESD in 30 patients from October 2008 through May 2012. INTERVENTION: Double-endoscope ESD. MAIN OUTCOME MEASUREMENTS: En bloc resection rate, complete resection rate, treatment time, and adverse events. RESULTS: The use of two endoscopes for ESD provided a good field of vision and allowed counter-traction to be applied to the lesion, clearly facilitating submucosal dissection. Because only a single light source was used, the working space of the endoscope room was not compromised. Moreover, it was unnecessary to prepare another light source or to coordinate image filing. The en bloc resection rate and complete resection rate were 100% and 90%, respectively, and the median treatment time was 80 minutes. As compared with historical control data obtained before the introduction of double-endoscope ESD, the rate of cutting into the specimen was significantly lower (7% vs 35%; P = .01). No serious adverse events occurred during the procedure. Postoperatively, however, 3 patients (10%) had delayed hemorrhage, and 1 (3.3%) had a delayed perforation. LIMITATIONS: Single-center, nonrandomized study. CONCLUSION: Our experience indicates that our procedure for double-endoscope ESD is useful and feasible in patients with early gastric cancer accompanied by an ulcer scar.

DOG1 is useful for diagnosis of KIT-negative gastrointestinal stromal tumor of stomach.

Approximately 80%-95% of gastrointestinal stromal tumors (GISTs) show positive staining for KIT, while the other 5%-20% show negative staining. If the tumor is negative for KIT, but is positive for CD34, a histological diagnosis is possible. However, if the tumor is negative for KIT, CD34, S-100, and SMA, a definitive diagnosis is often challenging. Recently, Discovered on GIST-1 (DOG1) has received considerable attention as a useful molecule for the diagnosis of GIST. DOG1, a membrane channel protein, is known to be overexpressed in GIST. Because the sensitivity and specificity of DOG1 are higher than those of KIT, positive staining for DOG1 has been reported, even in KIT-negative GISTs. KIT-negative GISTs most commonly arise in the stomach and are mainly characterized by epithelioid features histologically. We describe our experience with a rare case of a KIT-negative GIST of the stomach that was diagnosed by positive immunohistochemical staining for DOG1 in a patient who presented with severe anemia. Our findings suggest that immunohistochemical staining for DOG1, in addition to gene analysis, is useful for the diagnosis of KIT-negative tumors that are suspected to be GISTs.

Argon plasma coagulation for superficial esophageal squamous-cell carcinoma in high-risk patients.

AIM: To evaluate the usefulness and safety of argon plasma coagulation (APC) for superficial esophageal squamous-cell carcinoma (SESC) in high-risk patients. METHODS: We studied 17 patients (15 men and 2 women, 21 lesions) with SESC in whom endoscopic mucosal resection (EMR), endoscopic submucosal dissection (ESD), and open surgery were contraindicated from March 1999 through February 2009. None of the patients could tolerate prolonged EMR/ESD or open surgery because of severe concomitant disease (e.g., liver cirrhosis, cerebral infarction, or ischemic heart disease) or scar formation after EMR/ESD and chemoradiotherapy. After conventional endoscopy, an iodine stain was sprayed on the esophageal mucosa to determine the lesion margins. The lesion was then ablated by APC. We retrospectively studied the treatment time, number of APC sessions per site, complications, presence or absence of recurrence, and time to recurrence. RESULTS: The median duration of follow-up was 36 mo (range: 6-120 mo). All of the tumors were macroscopically classified as superficial and slightly depressed type (0-IIc). The preoperative depth of invasion was clinical T1a (mucosal cancer) for 19 lesions and clinical T1b (submucosal cancer) for 2. The median treatment time was 15 min (range: 10-36 min). The median number of treatment sessions per site was 2 (range: 1-4). The median hospital stay was 14 d (range: 5-68 d). Among the 17 patients (21 lesions), 2 (9.5%) had recurrence and underwent additional APC with no subsequent evidence of recurrence. There were no treatment-related complications, such as bleeding or perforation. CONCLUSION: APC is considered to be safe and effective for the management of SESC that cannot be resected endoscopically because of underlying disease, as well as for the control of recurrence after EMR and local recurrence after chemoradiotherapy.

A multicenter phase II study of combined chemotherapy with docetaxel, cisplatin, and S-1 in patients with unresectable or recurrent gastric cancer (KDOG 0601).

PURPOSE: We conducted a phase II study to evaluate the efficacy and safety of a triplet regimen of docetaxel, cisplatin, and S-1 in patients with unresectable or recurrent gastric cancer. METHODS: Docetaxel (40 mg/m(2)) and cisplatin (70 or 60 mg/m(2)) were given on day 1 of a 28-day cycle. S-1 (40 mg/m(2)) was given twice daily on days 1-14. Treatment with this regimen was continued for a maximum of 6 cycles. Subsequently, patients with no disease progression received a combination of docetaxel and S-1. RESULTS: Fifty-nine patients were enrolled. The median number of administered cycles was 8 (range, 1-25). Because some patients had serious myelosuppression and renal dysfunction with 70 mg/m(2) of cisplatin, dose of cisplatin was reduced to 60 mg/m(2) after 19 patients had been treated. Common severe toxic effects of grade 3 or 4 were leukocytopenia (44%), neutropenia (72%), anemia (15%), and febrile neutropenia (14%). The overall response rate of this group was 81% (95% confidence interval (CI), 71-91%). The median overall survival and progression-free survival were 18.5 (95% CI, 15.6-21.5) and 8.7 (95% CI, 6.7-10.7) months, respectively. CONCLUSIONS: Triplet of docetaxel, cisplatin, and S-1 is a well-tolerated and highly active regimen for advanced or recurrent gastric cancer. A 60 mg/m(2) of cisplatin is as effective as 70 mg/m(2) of cisplatin.

[Treatment of ileus and carcinomatous peritonitis].

In patients with carcinomatous peritonitis caused by the invasion and peritoneal dissemination of gastrointestinal cancer, disease progression can trigger complications such as ileus, ascites, and hydronephrosis.Anorexia, impaired oral intake, nausea, vomiting, abdominal pain, abdominal bloating, anuria, and other symptoms can develop, negatively affecting patients' general condition and quality of life.The treatment of carcinomatous peritonitis is an important determinant of outcomes, but the guidelines for its diagnosis, the evaluation of its response to chemotherapy, and the question of which standard therapy to apply remain unestablished.In recent years, however, clinical trials have attempted to evaluate the benefits of systemic chemotherapy and the intraperitoneal administration of drugs such as cisplatin and paclitaxel in patients with advanced or recurrent gastric cancer who have peritoneal dissemination.In the field of palliative therapy, octreotide has been approved in Japan for the amelioration of symptoms associated with gastrointestinal obstruction.Such treatment is expected to contribute substantially to improving patients' quality of life.

Clinicopathological evaluation of duodenal well-differentiated endocrine tumors.

AIM: To assess the clinicopathological characteristics of duodenal well-differentiated endocrine tumors. METHODS: We examined clinicopathological characteristics in 11 consecutive patients with duodenal well-differentiated endocrine tumors treated by endoscopic therapy or surgery in our hospital from 1992 through 2007. Patients with well-differentiated endocrine tumors of the papilla of Vater or with gastrinoma were excluded. RESULTS: Three patients received endoscopic treatment, and 8 underwent surgery. In patients who received endoscopic treatment, the tumor diameter was less than 1.0 cm, with no histopathological evidence of lymphovascular invasion or invasion of the muscularis. There were no complications such as late bleeding or perforation after treatment. Among 8 patients with tumors less than 1.0 cm in diameter, 3 underwent partial resection, and 2 underwent radical surgery. Three patients had lymphovascular invasion, 1 had invasion of the muscularis, and 1 had proximal lymph node metastasis. Among 3 patients with tumors 1.0 cm or more in diameter, 1 underwent partial resection, and 2 underwent radical surgery. One patient had lymphovascular invasion, with no lymph node metastasis. After treatment, all patients are alive and have remained free of metastasis and recurrence. CONCLUSION: Duodenal well-differentiated endocrine tumors less than 1.0 cm in diameter have a risk of lymphovascular invasion, invasion of the muscularis, and lymph node metastasis, irrespective of procedural problems.

Current management of esophageal squamous-cell carcinoma in Japan and other countries.

The incidence of adenocarcinoma of the distal esophagus or esophagogastric junction has increased considerably in Western countries during the past 3 decades, whereas the incidence of squamous-cell carcinoma has decreased slightly. In Japan, most esophageal cancers are squamous-cell carcinomas. Endoscopic examinations are more frequently performed in Japan for routine screening and diagnosis and treatment than in other countries, thereby increasing the detection rate of superficial esophageal carcinomas. In Europe and North America, many clinical trials have been conducted to assess the effectiveness of neoadjuvant chemoradiotherapy followed by surgery in patients with resectable, advanced esophageal cancer. In Japan, surgical resection had been the mainstay of treatment for esophageal cancer. Since the results of the Japan Clinical Oncology Group (JCOG) 9907 study were reported, neoadjuvant chemotherapy with cisplatin plus 5-fluorouracil followed by surgery has emerged as a new standard treatment. As for definitive chemoradiotherapy, cisplatin, 5-fluorouracil, and concurrent radiotherapy dosed to 50.4 Gy are used as standard treatment in a randomized clinical trial performed in North America. In patients who have T4 tumors and/or M1 lymph-node metastasis, chemoradiotherapy with cisplatin and 5-fluorouracil is considered standard treatment, but docetaxel, cisplatin, and 5-fluorouracil plus concurrent radiotherapy is also being studied. Controlled studies have not shown that palliative chemotherapy is superior to best supportive care, but cisplatin plus 5-fluorouracil is still considered standard therapy. Clinical trials of targeted agents are in progress. It is hoped that targeted agents will be effective for esophageal cancer.

Narrow band imaging for detecting superficial oral squamous cell carcinoma: a report of two cases.

We present two cases of superficial squamous cell carcinoma of the floor of the mouth, which were coincidentally detected by narrow band imaging (NBI) combined with magnifying gastrointestinal endoscopy (GIE) during gastrointestinal evaluation. We successfully removed the lesions using laser assisted with NBI combined with magnifying GIE. Because NBI combined with magnifying GIE shows a well-demarcated brownish area and scattered foci of microvascular proliferation, it may play an important role in the management of superficial squamous cell carcinoma in the oral cavity.

[Clinical development of S-1 (TS-1) for advanced gastric cancer].

The 5-FU plus cisplatin containing regimen like FP, ECF and DCF, is considered to be the most effective treatment for advanced gastric cancer in the United States, Europe, and Korea. In Japan, oral fluoropyrimidine S-1 (TS-1) is currently considered to be the first candidate as the standard drug for advanced gastric cancer. S-1 based combination therapies with other promising drugs like cisplatin, irinotecan and taxanes, are expected to yield good results. Above all, S-1+CDDP therapy showed a high efficacy and expected to be a standard therapy for advanced gastric cancer. Two large phase III studies, JCOG 9912 5-FU vs S-1 vs CPT-11 +CDDP and S-1 vs S-1+CDDP, are now on going to establish an acceptable frontline standard for patients with AGC. We therefore need to develop new agents and combination chemotherapy regimens to achieve a greater survival benefit in AGC.