Naoki Hiki

Safety and feasibility of laparoscopy-assisted distal gastrectomy with suprapancreatic nodal dissection for clinical stage I gastric cancer: a multicenter phase II trial (JCOG 0703)

BackgroundAlthough the number of patients undergoing laparoscopy-assisted distal gastrectomy (LADG) has been increasing, a prospective study with a sample size sufficient to investigate the benefit of LADG has never been reported. We conducted a multi-institutional phase II trial to evaluate the safety of LADG with nodal dissection for clinical stage I gastric cancer patients.MethodsThe subjects comprised patients with clinical stage I gastric cancer who were able to undergo a distal gastrectomy. LADG with D1 plus suprapancreatic node dissection was performed. The primary endpoint was the proportion of patients who developed either anastomotic leakage or a pancreatic fistula. The secondary endpoints included surgical morbidity and short-term clinical outcome.ResultsBetween November 2007 and September 2008, 176 eligible patients were enrolled. The proportion of patients who developed anastomotic leakage or a pancreatic fistula was 1.7%. The overall proportion of in-hospital grade 3 or 4 adverse events was 5.1%. The short-term clinical outcomes were as follows: 43.2% of the patients requested an analgesic on postoperative days 5–10; the median time from surgery until the first episode of flatus was 2 days; and 88 patients (50.0%) had a body temperature of 38 °C or higher during their hospital stay.ConclusionsThis trial confirmed the safety of LADG performed by credentialed surgeons in terms of the incidence of anastomotic leakage or pancreatic fistula formation. A phase III trial (JCOG 0912) to confirm the noninferiority of LADG to an open gastrectomy in terms of overall survival is ongoing.

Manipulation of the small intestine as a cause of the increased inflammatory response after open compared with laparoscopic surgery

Laparoscopic surgery of the gastrointestinal tract involves a reduced immune response compared with open surgery. The aim of this study was to assess manual handling of the gut in open procedures as the principal cause of the enhanced immune response.

Quantitative detection of micrometastases in the lymph nodes of gastric cancer patients with real-time RT-PCR: A comparative study with immunohistochemistry

Histologic examination lacks the sensitivity to detect micrometastases in gastric cancer lymph nodes. In the present study, we applied a real‐time RT‐PCR approach to the quantitative detection of micrometastases in gastric cancer lymph nodes and compared diagnostic power with routine histology and immunohistochemistry. We studied 392 lymph nodes from 21 gastric cancer patients who underwent curative surgery. Real‐time quantitative RT‐PCR was performed on a LightCycler instrument using a hybridization probe for carcinoembryonic antigen (CEA) and cytokeratin‐20 (CK20) as marker genes. Immunohistochemistry with antibodies to wide‐keratin was also performed in the lymph nodes to compare the sensitivity and specificity. Median (average) values of CEA mRNA in lymph nodes in patients with histology+, immunohistochemistry+/histology−, immunohistochemistry−/histology− and negative control results were 4,600 (16,000), 200 (400), 0 (9.8) and 0 (0.6), respectively. There were some false‐negative results with simple CEA and CK20 real‐time RT‐PCR due to the presence of low gene‐expressing gastric cancers as revealed by CEA and CK20 immunohistochemistry. CEA in combination with CK20 (duplex) real‐time RT‐PCR partially covered this weakness. Consequently, all 71 histology+ lymph nodes were positive for duplex real‐time RT‐PCR as well as wide‐keratin immunohistochemistry. Positivity rates by histology, wide‐keratin immunohistochemistry and duplex real‐time RT‐PCR were 18.0% (71/392), 20.9% (82/392) and 25.8% (101/392), respectively. In 2 of 8 patients with pT1N0, positive lymph nodes were observed by real‐time RT‐PCR but not by immunohistochemistry. These results indicate that duplex quantitative real‐time RT‐PCR is the most sensitive method for detecting micrometastases and useful for evaluating the prognostic significance of lymph node micrometastasis in gastric cancer patients.

Successful application of laparoscopic and endoscopic cooperative surgery (LECS) for a lateral-spreading mucosal gastric cancer

In the current era of endoscopic submucosal dissection (ESD) for early gastric cancer, which carries a negligible risk of lymph node metastasis, local resection of the stomach remains an option for these lesions. This is particularly so for a large intramucosal lesion or a lesion with a strong ulcer scar, for which ESD becomes a difficult option. Here, we describe a case of lateral-spreading intramucosal gastric cancer of 6-cm diameter located at the fornix of the stomach, which was successfully treated by laparoscopic and endoscopic cooperative surgery (LECS) because of the expected risk of complications during ESD. In the LECS procedure, the resection margin was appropriately determined by the endoscopic evaluation in detail and by the ESD technique. If early gastric cancer fits the criteria for endoscopic resection but would present difficulty if performing ESD, this is a good indication for the LECS procedure.

Effect of individual fat areas on early surgical outcomes after open gastrectomy for gastric cancer

Obesity is generally considered a risk factor for postoperative morbidity following open gastrectomy. Body mass index (BMI) is widely accepted as an indicator of obesity, but does not necessarily reflect the distribution of fat. It is unclear how different types of fat may affect the operative procedure and outcome.

Three-Step Esophagojejunal Anastomosis with Atraumatic Anvil Insertion Technique After Laparoscopic Total Gastrectomy

BackgroundEsophagojejunostomy during laparoscopic total gastrectomy (LATG) using a circular stapler is a difficult procedure for which there remains no widely accepted standard technique. Based upon our experience with esophagogastrostomy during laparoscopic proximal gastrectomy, we have applied a modified lift-up method to LATG.Material and methodsEsophagojejunostomy using a modified lift-up method was performed during LATG in 41 patients with early gastric cancer, from July 2005 to June 2010. The lift-up technique comprises three steps, which together reduce the difficulty of anvil insertion by lifting up the nasogastric tube connected to the anvil head.ResultsDuring the early stages of the present study, some patients who underwent LATG with the modified lift-up method developed anastomotic leakage, with stenosis occurring in two cases (4.9%) and three cases (7.3%), respectively. All patients who developed complications showed improvement following conservative treatment with no surgical procedure. The anastomotic leaks occurred during the later periods of the study. There was no mortality in the present study.ConclusionsOur modified lift-up technique facilitates circular-stapled esophagojejunostomy in LATG and could provide a more feasible and safe option for an established procedure, especially for preventing anastomotic leak.

THERAPEUTIC OUTCOMES OF ENDOSCOPIC SUBMUCOSAL DISSECTION OF UNDIFFERENTIATED-TYPE INTRAMUCOSAL GASTRIC CANCER WITHOUT ULCERATION AND PREOPERATIVELY DIAGNOSED AS 20 MILLIMETRES OR LESS IN DIAMETER

Aim:  The aim of the present study was to examine therapeutic outcomes of endoscopic submucosal dissection (ESD) of undifferentiated‐type intramucosal gastric cancer and the problems of diagnosis.

SIMULTANEOUS ONSET OF ACUTE INFLAMMATORY RESPONSE, SEPSIS-LIKE SYMPTOMS AND INTESTINAL MUCOSAL INJURY AFTER CANCER CHEMOTHERAPY

Chemotherapy is 1 method for the treatment of cancer, but serious side effects can sometimes limit the dosage given. Mild fever and diarrhea are common side effects of cancer chemotherapy. Gastrointestinal injury induced by chemotherapeutic agents may result in bacterial/endotoxin translocation from the gut into the systemic circulation. An experimental study was therefore conducted to clarify the effect of systemic chemotherapeutic agents on gastrointestinal barrier function. Male Wistar rats were divided into a 5‐fluorouracil (5‐FU) group (100 mg/kg/day for 4 days; n = 27) and a control group (n = 5). All rats were fasted and central venous catheterization was performed for total parenteral nutrition and blood sampling. Intestinal tissue was also sampled for pathological examination. Plasma levels of interleukin‐6 (IL‐6) and tumor necrosis factor α (TNFα) were determined by ELISA, bacterial translocation was quantified by lymph node culture and plasma endotoxin content of portal blood was measured by the Limulus‐amebocyte‐lysate test. In the 5‐FU group on day 4, a proportion of rats exhibited severe watery diarrhea (73.9%) and occasional vomiting (86.2%). The levels of plasma TNFα and IL‐6 were seen to increase, peaking at day 6 (IL‐6, 350.0 ± 67.8 pg/ml; TNFα, 26.1 ± 3.2 pg/ml). The pathological findings also changed on day 4. On day 6, 90% of the rats in the 5‐FU group showed dramatic sepsis‐like manifestations, whereas the control group did not. Within the 5‐FU group, only at day 6 was bacterial translocation in the rat mesenteric lymph nodes or significantly elevated levels of endotoxin evident. These results suggest that bacterial/endotoxin translocation might cause sepsis‐like manifestations after systemic chemotherapy.

Prolonged Toll-like receptor stimulation leads to down-regulation of IRAK-4 protein

Interleukin‐1 receptor‐associated kinase (IRAK)‐4 is a key mediator in the Toll‐like receptor (TLR) signaling. We found that stimulation of TLR2, TLR4, or TLR9, but not TLR3, caused a decrease in IRAK‐4 protein without affecting its mRNA level in a mouse macrophage cell line, RAW 264. The decrease in IRAK‐4 was accompanied by the appearance of a smaller molecular weight protein (32 kD), which was recognized by an anti‐IRAK‐4 antibody raised against the C‐terminal region. The decrease in IRAK‐4 and the appearance of the 32‐kD protein occurred with slower kinetics than the activation of IRAK‐1 and were suppressed by inhibitors of the proteasome, inducible inhibitor of κBα phosphorylation or protein synthesis, but not by caspase inhibitors. These results indicate that prolonged stimulation of TLR2, TLR4, or TLR9 causes a down‐regulation of IRAK‐4 protein, which may be mediated through cleavage of IRAK‐4 by a protease induced by the activation of nuclear factor‐κB.

Function-Preserving Gastrectomy for Early Gastric Cancer

The number of early gastric cancer (EGC) cases has been increasing because of improved diagnostic procedures. Applications of function-preserving gastric cancer surgery may therefore also be increasing because of its low incidence of lymph node metastasis, excellent survival rates, and the possibility of less-invasive procedures such as laparoscopic gastrectomy being used in combination. Pylorus-preserving gastrectomy (PPG) with radical lymph node dissection is one such function-preserving procedure that has been applied for EGC, with the indications, limitations, and survival benefits of PPG already reported in several retrospective studies. Laparoscopy-assisted proximal gastrectomy has also been applied for EGC of the upper third of the stomach, although this procedure can be associated with the 2 major problems of reflux esophagitis and carcinoma arising in the gastric stump. In the patient with EGC in the upper third of the stomach, laparoscopy-assisted subtotal gastrectomy with a preserved very small stomach may provide a better quality of life for the patients and fewer postoperative complications. Finally, the laparoscopy endoscopy cooperative surgery procedure combines endoscopic submucosal dissection with laparoscopic gastric wall resection, which prevents excessive resection and deformation of the stomach after surgery and was recently applied for EGC cases without possibility of lymph node metastasis. Function-preserving laparoscopic gastrectomy is recommended for the treatment of EGC if the indication followed by accurate diagnosis is strictly confirmed. Preservation of remnant stomach sometimes causes severe postoperative dysfunctions such as delayed gastric retention in PPG, esophageal reflux in PG, and gastric stump carcinoma in the remnant stomach. Moreover, these techniques present technical difficulties to the surgeon. Although many retrospective studies showed the functional benefit or oncological safety of function-preserving gastrectomy, further prospective studies using large case series are necessary.