Norihito Wada

Laparoscopy-assisted Proximal Gastrectomy with Sentinel Node Mapping for Early Gastric Cancer

BackgroundLaparoscopy-assisted proximal gastrectomy (LAPG) remains a relatively uncommon procedure because of certain technical issues, such as curability, safety, and retention of postoperative patients’ quality of life. The aim of the present study was to evaluate the feasibility of a newly developed LAPG procedure for early-stage proximal gastric cancer.MethodsWe enrolled 37 consecutive patients who were preoperatively diagnosed with cT1N0M0 primary gastric cancer in the upper third of the stomach with the primary tumor diameter less than 4xa0cm. Laparoscopy-assisted proximal gastrectomy with sentinel node (SN) mapping and esophagogastric anastomosis with a circular stapler and transoral placement of the anvil was attempted.ResultsThe LAPG procedure was completed in 36 patients. It was converted to laparoscopy-assisted total gastrectomy in one patient because one SN detected intraoperatively was positive for metastasis by intraoperative pathological diagnosis. There were no severe postoperative complications in any patient. Only one patient (3%) complained of mild reflux symptoms immediately after operation, which were graded endoscopically as B by the Los Angeles Classification of gastroesophageal reflux disease; however, the symptoms were controlled well by a proton-pump inhibitor. Sentinel nodes were detected successfully in 37 (100%) of our patients. The mean number of dissected lymph nodes and identified SNs per case was 29.7 and 5.8, respectively. The sensitivity of prediction of nodal metastasis (including isolated tumor cells) and diagnostic accuracy based on SN status were 100% (3/3) and 100% (37/37), respectively. All patients have been free from recurrence for a median follow-up period of 26xa0months.ConclusionsThis study reveals that our novel LAPG approach is curative and represents a feasible minimally invasive surgical procedure with minimal morbidity and postoperative reflux esophagitis in patients with upper-third early-stage gastric cancer.

Adjuvant therapy with imatinib mesylate after resection of primary high-risk gastrointestinal stromal tumors in Japanese patients

BackgroundImatinib mesylate, a small-molecule tyrosine kinase inhibitor, is currently used for adjuvant therapy of patients who have undergone resection of high-risk gastrointestinal stromal tumors (GISTs). There are no data concerning the efficacy and safety of postoperative adjuvant therapy with imatinib for Japanese or East Asian patients with GIST.MethodsA single-arm, open-label, multicenter trial was conducted in 17 hospitals in Japan. The eligibility criteria included histologically proven primary high-risk GISTs with macroscopic complete resection. Patients were treated with imatinib at a dose of 400xa0mg/day for 1xa0year after surgery. The primary endpoint was recurrence-free survival as assessed by Kaplan–Meier analysis. The secondary endpoints were overall survival and safety. This study was registered with ClinicalTrials.gov, number NCT00171977.ResultsA total of 64 patients were enrolled between September 2004 and July 2006. The median age of the patients was 59.5xa0years. Forty-nine (76.6%) patients completed the 1-year treatment, whereas 15 (23.4%) patients did not complete the treatment owing to recurrence, toxicities, and consent withdrawal. At the median follow-up period of 109xa0weeks, 20 patients had recurrence. The 3-year recurrence rate was 42.7% (95% confidence interval 29.2–56.3%), which exceeded the expected recurrence rate in this trial. The recurrence-free and overall survival rates at 2xa0years were 71.1 and 93.7%, respectively. The most frequent adverse drug reaction of any grade was eyelid edema (48.4%), followed by neutropenia (40.6%), leukopenia (39.1%), nausea (39.1%), rash (37.5%), and peripheral edema (37.5%), most of which were mild and manageable.ConclusionsAdjuvant therapy with imatinib at 400xa0mg/day for 1xa0year is well tolerated by Japanese patients and possibly reduces the risk of early recurrence of high-risk GISTs.

Antitumor effect of cetuximab in combination with S-1 in EGFR-amplified gastric cancer cells

Overexpression of human epidermal growth factor receptor (EGFR) has been detected in gastric cancer (GC) and is associated with poor outcomes. Combination treatment regimens with EGFR-targeting agents and cytotoxic agents are considered to be a potential therapeutic option for EGFR-overexpressing GC. Herein, we have investigated the effects of combination treatment with the oral fluoropyrimidine S-1 and the EGFR-targeting agent cetuximab in GC cells with or without EGFR overexpression. EGFR expression was determined by FACS and quantitative PCR in GC cells. Experimental 5-fluorouracil (5FU) was used instead of S-1 for in vitro experiments. The efficacy of 5FU or cetuximab monotherapy or combination 5FU/cetuximab therapy was examined in vitro and in vivo. Clinical specimens were examined for EGFR by immunohistochemistry (IHC). EGFR expression score was defined as strong membrane and cytoplasmic staining in at least 50–75% of cells. The combination of 5FU and cetuximab synergistically inhibited cell proliferation and exhibited an enhanced proapoptotic effect in GC cells with EGFR overexpression. Cetuximab also induced down-regulation of phosphorylation of EGFR and AKT, leading to diminished signaling. The antitumor effect of the combination of S-1 and cetuximab in vivo was also greater than that of either drug alone. Our preclinical findings thus indicate that the combination of S-1 and EGFR-targeting therapy is a promising treatment option for GC with EGFR overexpression.

Role of integrin α1 subunits in gastric cancer patients with peritoneal dissemination

The interaction between gastric cancer (GC) cells and the peritoneum is a critical event in peritoneal dissemination. The molecular mechanisms of this dissemination, however, remain unclear. Integrins are heterodimeric cell adhesion molecules consisting of α and β subunits that serve as adhesion receptors for extracellular matrix proteins and cellular ligands, and may participate in GC peritoneal dissemination. In this study, we isolated fresh GC cells from a patient with peritoneal metastasis and examined them for integrin expression and investigated the role of integrin α1 subunit molecules in GC. Five clones (KGC1C2, KGC1F3, KGC1H3, KGC1E8, KGC1G10) were established from the clinical GC sample and used in an in vitro adhesion model using a single cell culture method. Each clone was transplanted into the peritoneal cavity of SCID mice, where each clone formed tumors and caused conglutination of organs in the abdominal cavity. We analyzed the expression of integrin subunits for each clone by flow cytometry and found that the expression ratio of α1 subunits paired with β1 subunits was detected at higher levels than other subunits. To verify that anti-integrin α1 subunit (CD49a) antibody inhibits cell adhesion in an in vitro adhesion assay, each clone was treated with anti-CD49a antibody, which significantly inhibited cell adhesion compared to the untreated group. Characterization of α1 subunit expression in GC may be useful in optimizing treatments for different individuals. Having high metastatic abilities, these 5 new GC clones may be beneficial for analyzing integrin function in tumor metastasis.

Intraoperative fluorescence lymphography using indocyanine green in a patient with chylothorax after esophagectomy: report of a case

We report a case of chylothorax treated successfully by a new diagnostic tool: indocyanine green (ICG) fluorescence lymphography. The patient, a 65-year-old man with adenocarcinoma of the esophagogastric junction, underwent radical esophagectomy, which was followed by the development of chylothorax. On postoperative day 10, we performed transabdominal ligation of the thoracic duct. During the re-operation, we injected ICG into the mesentery of the small bowel. We then performed mass ligation of the tissue right and dorsal of the aorta, including the thoracic duct, after which a near-infrared camera system revealed a fluorescent stripe on the caudal part of the ligation. The remnant thoracic duct appeared to be dilated as a result of lymphatic stasis. The patient was discharged 35xa0days after his initial surgery. We report this case to demonstrate the usefulness of intraoperative ICG lymphography as a tool to identify and confirm ligation of the thoracic duct transabdominally.

Clinical utility of the Revised Cardiac Risk Index in non-cardiac surgery for elderly patients: a prospective cohort study

PurposeWe investigated the association between the Revised Cardiac Risk Index (RCRI) and postoperative outcomes in patients undergoing non-cardiac surgery.MethodsThe predictive value of the RCRI for the risk of perioperative complications, length of hospital stay and hospital cost were evaluated from a prospective cohort of 119 patients aged ≥65xa0years undergoing elective major digestive, breast or vascular surgery.ResultsComparing three groups RCRI 0, 1 and ≥2, the morbidity rates were 0, 30 and 68xa0%; the median length of hospitalization was 5, 14 and 28xa0days; and the median cost was 665,000, 1,480,000 and 2,160,000 yen, respectively. The mortality rate was 0xa0% in all groups. The RCRI 0 group included only non-high-risk (breast and peripheral vascular) surgeries. In addition, comparing the two groups by excluding non-high-risk surgeries (RCRI 1 and ≥2), the median morbidity rates were 31 and 67xa0%, the median length of hospitalization was 15 and 28xa0days, and the median cost was 1,550,000 and 2,130,000 yen, respectively. The RCRI score was the only independent predictor of the perioperative complications.ConclusionsIn the case of non-cardiac surgery, the RCRI can identify patients at higher risk of perioperative complications, a prolonged hospital stay and higher hospital cost.