Mitsuru Iwama

Gene amplification of EGFR, HER2, FGFR2 and MET in esophageal squamous cell carcinoma

Molecular targeted therapy is expected to be a promising therapeutic approach for the treatment of esophageal squamous cell carcinoma (ESCC); however, the gene amplification status of molecular targeted genes in ESCC remains largely unclear. The gene amplification of EGFR, HER2, FGFR2 and MET was examined using a real-time PCR-based copy number assay of 245 ESCC surgical specimens of formalin-fixed, paraffin-embedded samples. Fluorescence in situ hybridization (FISH) and comparative genomic hybridization analyses verified the results of the copy number assay. EGFR mutation was detected using the Scorpions-ARMS method. The EGFR status and drug sensitivity to an EGFR tyrosine kinase inhibitor was then evaluated in vitro. Gene amplification of EGFR and HER2 was observed in 7% (16/244) and 11% (27/245) of the ESCC specimens. A multivariate analysis revealed that HER2 amplification was a significant predictor of a poor prognosis in patients with stage III post-operative ESCC. The L861Q type of EGFR mutation with hypersensitivity to EGFR tyrosine kinase inhibitor was found in one of the eight ESCC cell lines and one del745 type of EGFR mutation was identified in 107 clinical samples. In addition, we demonstrated for the first time that FGFR2 amplification was observed in 4% (8/196) of the ESCC specimens. MET amplification was observed in 1% (2/196). In conclusion, the frequent gene amplification of EGFR, HER2 and FGFR2 and the presence of active EGFR mutations were observed in ESCC specimens. Our results strongly encourage the development of molecular targeted therapy for ESCC.

A newly modified esophagogastrostomy with a reliable angle of His by placing a gastric tube in the lower mediastinum in laparoscopy-assisted proximal gastrectomy

BackgroundAn optimal reconstruction method for proximal gastrectomy (PG) remains elusive. Esophagogastrostomy (EG) is technically simple but suffers from the disadvantage of gastroesophageal reflux. Jejunal interposition (JI) has a low rate of gastroesophageal reflux, but the procedure is more complicated, and delayed gastric emptying is a problem.MethodsWe created a modified EG and have used the modified technique for PG since 2006. The procedure involves shaping the remnant stomach into a gastric conduit. The EG is performed high on the anterior wall, and the conduit is kept straight by applying a circular stapler inserted from the anterior wall of the antrum. The tip of the gastric conduit is then inserted into the lower mediastinum, creating a sharp angle of His. In this retrospective cohort study, the clinical and physiological outcomes were compared between 25 patients who underwent this procedure and 21 patients who underwent JI from 2001 to 2005.ResultsLaparoscopic procedures were performed more frequently, and residual food and bile reflux were less common in the EG group than in the JI group. No significant differences in remnant gastritis or reflux esophagitis were observed between the two groups. However, the late complication of intestinal obstruction occurred only in the JI group.ConclusionsThe modified EG technique has advantages over the JI technique because of its simplicity and low incidence of residual food and bile reflux. The next step would be to explore this technique further by a prospective multi-institutional study to confirm the reproducibility of its benefits. Miniabstract: The modified EG technique has advantages over the JI technique because of its simplicity, high rate of laparoscopy use, and low incidence of gastroesophageal reflux.

Novel esophageal reconstruction technique via transmediastinal route from posterior to anterior mediastinum after esophagectomy

Background The incidence of metachronous esophageal squamous cell cancer (ESCC) after head and neck cancer (HNC) and in elderly patients has increased. Both elderly ESCC patients and ESCC patients after HNC surgery are at potential risk for dysphagia, and for the latter, surgery in the neck is difficult. An intrathoracic anastomosis that bypasses the cervical procedure is preferable to preserve swallowing function and reduce surgical risk. In gastrectomized patients, because the stomach cannot be used as a substitute, securing graft blood supply is critical, but microvascular anastomosis cannot be easily added in procedures for intrathoracic posterior mediastinal reconstruction. Thus, we have developed a novel technique for esophageal reconstruction in gastrectomized patients who are elderly or who had undergone HNC surgery, enabling concomitant intrathoracic anastomosis and microvascular anastomosis. The purpose of this study was to evaluate the usefulness and safety of this technique. Methods The jejunal or ileocolic graft is first pulled up through the anterior mediastinum and is then passed into the right thoracic cavity via a small hole made in the anterior mediastinal pleura. The graft is finally anastomosed with the remnant esophagus in the upper posterior mediastinum. Thereafter, microvascular anastomosis is performed in the retrosternal space. Results Four patients underwent this new reconstruction procedure with no significant postoperative complications, good swallowing function postoperatively, and no retention of food in the graft. Conclusions This novel transmediastinal reconstruction technique is a possible option for highly selected patients to enable intrathoracic anastomosis and the addition of microvascular anastomosis.

Intraperitoneal Administration of Paclitaxel Followed by Paclitaxel, Cisplatin, and S-1 Chemotherapy for Cytology-positive Gastric Cancer: A Feasibility Study

Background/Aim: A preliminary study evaluating the feasibility of single intraperitoneal (IP) administration of paclitaxel followed by paclitaxel and cisplatin with S-1 (PCS) systemic chemotherapy for cytology-positive (CY1) gastric cancer. Patients and Methods: Staging laparoscopy was performed to confirm CY1 and P0 status. Initially, patients received IP paclitaxel. Beginning 7 days later PCS was given every 3 weeks followed by second-look laparoscopy. Results: Nine patients were enrolled. The toxic effects of IP and systemic chemotherapy were acceptable. After chemotherapy, 8 patients converted from CY1P0 to CY0P0 and 1 patient from CY1P0 to CY1P1. Gastrectomy was performed on 8 patients except for the CY1P1 patient. Four patients were alive without recurrence. The 2-year overall and progression-free survival rates were 76% and 65%, respectively. Conclusion: Combination chemotherapy with IP paclitaxel and sequential PCS is safe and may be effective for CY1 gastric cancer.

Intraperitoneal and Systemic Chemotherapy for Patients with Gastric Cancer with Peritoneal Metastasis: A Phase II Trial

Aim: To conduct a phase II study of single intraperitoneal (i.p.) administration of paclitaxel followed by paclitaxel, cisplatin, and S-1 (PCS) chemotherapy for patients with gastric cancer with peritoneal metastasis (PM). Patients and Methods: Staging laparotomy was performed to confirm PM. Initially, patients received i.p. paclitaxel. Beginning 7 days later, PCS was given every 3 weeks followed by second-look laparoscopy. Primary and secondary endpoints were the overall survival (OS) rate, and response rate and patient safety, respectively. Results: Seventeen patients were enrolled. The overall response rate was 70.5% (12/17). Grade 3/4 toxic effects included neutropenia and leukopenia. After chemotherapy, PM disappearance was confirmed in 11 patients. Gastrectomy was eventually performed in 11 patients. The 1-year OS rate was 82.4% and the median survival time was 23.9 months considering the overall cohort. Conclusion: Combination chemotherapy with i.p. paclitaxel and PCS is well tolerated and effective in patients with gastric cancer with PM.