Nuclear heat shock protein 110 expression is associated with poor prognosis and hyperthermo-chemotherapy resistance in gastric cancer patients with peritoneal metastasis.

AIM: To investigate the significance of heat shock protein 110 (HSP110) in gastric cancer (GC) patients with peritoneal metastasis undergoing hyperthermo-chemotherapy. METHODS: Primary GC patients (n = 14) with peritoneal metastasis or positive peritoneal lavage cytology who underwent distal or total gastrectomy between April 2000 and December 2011 were enrolled in this study. The patients underwent postoperative intraperitoneal hyperthermo-chemotherapy using a Thermotron RF-8 heating device two weeks after surgery. We analyzed nuclear HSP110 expression in surgically resected tumors using immunohistochemistry. Additionally, the effect of HSP110 suppression on hyptherthermo-chemosensitivity was assessed in vitro in the MKN45 GC cell line using the HSP inhibitor KNK437. RESULTS: HSP110 immnohistochemical staining in 14 GC patients showed that five (35.7%) samples belonged to the low expression group, and nine (64.3%) samples belonged to the high expression group. Progression-free survival was significantly shorter in the HSP110 high-expression group than in the low-expression group (P = 0.0313). However, no significant relationships were identified between HSP110 expression and the clinicopathological characteristics of patients. Furthermore, high HSP110 expression was not an independent prognostic factor in GC patients with peritoneal metastasis (P = 0.0625). HSP110 expression in MKN45 cells was suppressed by KNK437 at the hyperthermic temperature of 43 °C in vitro. Comparison of MKN45 cell proliferation in the presence and absence of KNK437 at 43 °C, revealed that proliferation was significantly decreased when HSP110 was inhibited by KNK437. Additionally, HSP110 suppression via HSP inhibitor treatment increased cellular sensitivity to hyperthermo-chemotherapy in vitro. CONCLUSION: The expression of nuclear HSP110 in GC patients might be a new marker of chemosensitivity and a therapeutic target for patients who are tolerant to existing hyperthermo-chemotherapies.

Comparison of the risk of surgical site infection and feasibility of surgery between sennoside versus polyethylene glycol as a mechanical bowel preparation of elective colon cancer surgery: a randomized controlled trial.

PURPOSE: To validate the usefulness of sennoside as a substitute for polyethylene glycol (PEG) as a mechanical bowel preparation (MBP) for elective colon cancer surgery. METHODS: We performed a prospective randomized non-inferiority trial comparing the use of sennoside and PEG in MBP for elective colon cancer surgery, in terms of the risk of surgical site infection (SSI) and the feasibility of surgery. RESULTS: The overall incidence of SSIs was 2.9 % in the sennoside group (n = 68) and 6.3 % in the PEG group (n = 63) with a difference of 3.4 % (95 % confidence interval 6.9-10.6 %). The intraoperative spillage of the stool materials in the sennoside and PEG groups was 4.4 and 3.1 %, respectively, and was not significantly different (p = 0.71), even the upstream stool consistency, was more frequently observed to be non-stool in the PEG group (65.1 vs. 30.9 %, p < 0.01). CONCLUSION: MBP with sennoside could be a substitution for PEG in elective colon cancer surgery.

Nuclear PRMT1 expression is associated with poor prognosis and chemosensitivity in gastric cancer patients.

BACKGROUND: Metastatic and refractory gastric cancer (GC) are associated with a poor prognosis; therefore, the identification of prognostic factors and chemosensitivity markers is extremely important. Protein arginine methyltransferase 1 (PRMT1) may play a role in chemosensitivity/apoptosis induction via activation of the tumor suppressor forkhead box O1 (FOXO1). The purpose of this study was to clarify the expression of and relationship between PRMT1 and FOXO1 to evaluate the applicability of PRMT1 as a prognostic marker and a therapeutic tool in GC. METHODS: We investigated the clinical and functional significance of PRMT1 and FOXO1 in 195 clinical GC samples using immunohistochemistry. We performed suppression analysis of PRMT1 using small interfering RNA to determine the biological roles of PRMT1 in chemosensitivity. RESULTS: PRMT1 and FOXO1 in GC samples were predominantly expressed in the nucleus. Patients with lower PRMT1 expression (n = 131) had suppressed nuclear accumulation of FOXO1, higher recurrence after adjuvant chemotherapy, and poorer prognosis than those with higher PRMT1 expression (n = 64). PRMT1 downregulation in GC cells by RNA interference inhibited cisplatin and 5-fluorouracil sensitivity. The expression of phosphorylated FOXO1 and phosphorylated BCL-2 antagonist of cell death was upregulated in PRMT1 small interfering RNA groups. CONCLUSION: Our data suggest that the evaluation of PRMT1 expression in GC is a useful predictor of poor prognosis and recurrence after adjuvant chemotherapy. Moreover, these data suggest that PRMT1 is a promising therapeutic tool for overcoming refractory GC.

Effect of Daikenchuto, a Traditional Japanese Herbal Medicine, after Total Gastrectomy for Gastric Cancer: A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase II Trial.

BACKGROUND: Daikenchuto (DKT) has widely been used to improve abdominal symptoms by being expected to accelerate bowel motility. The purpose of this study is to examine the efficacy and safety of DKT for prevention of ileus and associated gastrointestinal symptoms after total gastrectomy. STUDY DESIGN: Two hundred and forty-five gastric cancer patients who underwent total gastrectomy were enrolled. Patients received either DKT (15.0 g/d) or matching placebo from postoperative days 1 to 12. Primary end points were time to first flatus, time to first bowel movement (BM), and frequency of BM. Secondary end points included quality of life, C-reactive protein level, symptoms indicative of a severe gastrointestinal disorder, and incidence of postoperative ileus. RESULTS: A total of 195 patients (DKT, n = 96; placebo, n = 99) were included in the per-protocol set analysis. There were no significant differences between the groups in terms of patient background characteristics. Median time to first BM was shorter in the DKT group than in the placebo group (94.7 hours vs 113.9 hours; p = 0.051). In patients with high medication adherence, median time to first BM was significantly shorter in the DKT group than in the placebo group (93.8 hours vs 115.1 hours; p = 0.014). Significantly fewer patients in the DKT group had ≥2 symptoms of gastrointestinal dysfunction than those in the placebo group on postoperative day 12 (p = 0.026). CONCLUSIONS: Administration of DKT during the immediate postoperative period after total gastrectomy appears to promote early recovery of postoperative bowel function.

[Effects of rikkunshito on postoperative anorexia].

Rikkunshito is a traditional Japanese medicine used to treat a variety of gastrointestinal symptoms. In several previous studies, it was demonstrated that rikkunshito stimulates gastrointestinal movement, accelerates gastric emptying, and promotes gastric adaptive relaxation. Clinically, it is known that rikkunshito attenuates dyspeptic symptoms, appetite loss, and gastroesophageal reflux after gastrointestinal surgery and in chemotherapy-induced nausea and anorexia. A recent study has demonstrated that rikkunshito affects the appetite-enhancing hormone ghrelin. Rikkunshito was also reported to increase plasma ghrelin levels and to enhance the action of ghrelin. Rikkunshito may alleviate dyspeptic symptoms after gastrointestinal surgery through its prokinetic effects and ghrelin.

Intragastric administration of rikkunshito stimulates upper gastrointestinal motility and gastric emptying in conscious dogs.

BACKGROUND: Traditional Japanese medicine, known as Kampo medicine, consists of mixtures of several medicinal herbs widely used to treat upper gastrointestinal disorders in Japan. Rikkunshito, one of these medicines, has not been evaluated with respect to its influence on gastrointestinal motor activity. We investigated the effect of rikkunshito on upper gastrointestinal motility and plasma ghrelin concentrations in conscious dogs. METHODS: Contractile response to intragastric administration of rikkunshito was studied via surgically implanted force transducers. A powdered extract of rikkunshito (1.3, 2.7, and 4.0 g) dissolved in water was administered into the stomachs of normal and vagotomized dogs before feeding and gastric emptying was evaluated. Several inhibitors of gastrointestinal motility (atropine, hexamethonium, and ondansetron) were injected intravenously before intragastric administration of rikkunshito. Plasma acylated ghrelin levels after intragastric administration of rikkunshito were measured. RESULTS: In a fasting state, intragastric administration of rikkunshito induced phasic contractions in the duodenum and jejunum in normal dogs. Rikkunshito-induced contractions were inhibited by atropine, hexamethonium and ondansetron. In vagotomized dogs, rikkunshito induced phasic contractions, similar to normal dogs. Gastric emptying was accelerated by intragastric administration of rikkunshito in a dose-dependent manner. The plasma acylated ghrelin level 150 min after intragastric administration of 4.0 g of rikkunshito was significantly higher than the control value. CONCLUSIONS: Intragastric administration of rikkunshito stimulates gastrointestinal contractions in the interdigestive state through cholinergic neurons and 5-HT type 3 receptors. Moreover, rikkunshito increases plasma acylated ghrelin levels. Rikkunshito may alleviate gastrointestinal disorders through its prokinetic effects.

Rikkunshito, a traditional Japanese medicine, suppresses cisplatin-induced anorexia in humans.

BACKGROUND: The aim of this study was to investigate the effects of Rikkunshito on ghrelin secretion and on cisplatin-induced anorexia in humans. METHODS: The study was performed as a crossover design, and ten unresectable or relapsed gastric cancer patients were randomly divided into two groups. Group A (n = 5) was started on Rikkunshito (2.5 g three times daily, orally) from the first course of chemotherapy and followed by a second course without Rikkunshito. A treatment with reversed order was performed for Group B (n = 5). All patients received combined chemotherapy with S-1 plus cisplatin. The primary endpoint was the amount of oral intake, and the categories of scales of anorexia, nausea, and vomiting; secondary endpoints included the plasma concentration of acylated ghrelin. RESULTS: In the Rikkunshito-on period, no decrease of the plasma concentration of acylated ghrelin induced by cisplatin was observed. The average oral intake in the Rikkunshito-on period was significantly larger than that in the Rikkunshito-off period, and the grade of anorexia was significantly lower in the Rikkunshito-on period than in the Rikkunshito-off period. CONCLUSION: Rikkunshito appeared to prevent anorexia induced by cisplatin, resulting in effective prophylactic administration of chemotherapy with cisplatin, and patients could continue their treatments on schedule.

The effect of traditional Japanese medicine (Kampo) on gastrointestinal function.

Traditional Japanese medicine (Kampo) is used to treat various disorders of the gastrointestinal tract in Japan, where it is fully integrated into the modern healthcare system. Recently, scientific research on herbal medicine in Japan has been reported in English journals. The objective of the current review is to introduce two traditional Japanese medicines and to provide evidenced-based information regarding their use. Daikenchuto, which consists of three different herbs, is the most frequently prescribed traditional Japanese medicine in Japan. Daikenchuto stimulates gastrointestinal motility though a neural reflex involving presynaptic cholinergic and 5-HT3 receptors. Daikenchuto improves postoperative bowel motility and postoperative ileus. Furthermore, it is reported to cause an increase in gastrointestinal hormones (motilin, vasoactive intestinal peptide, and calcitonin gene-related peptide) and intestinal blood flow. Rikkunshito, a traditional Japanese medicine consisting of eight herbs, is thought to stimulate gastrointestinal motility and ghrelin secretion. Rikkunshito is effective for improving the symptoms of functional dyspepsia, gastroesophageal reflux disease, and cisplatin-induced anorexia and vomiting. Traditional Japanese medicine has the potential to be used successfully in the treatment of gastrointestinal disorders. Details regarding the physiological and clinical effects of traditional Japanese medicine must be further examined in order to become more widely accepted in other countries.

Glutamine decreases the duration of postoperative ileus after abdominal surgery: an experimental study of conscious dogs.

Postoperative ileus (POI) is a transient bowel dysmotility that occurs following many types of operations and is one of the most common complications of gastrointestinal surgery. We hypothesized that enteral supplementation of glutamine after abdominal surgery would restore fuel to the small intestine, suppress oxidative stress, and lead to improvement in POI. Twelve dogs underwent distal gastrectomy and were each randomly assigned to one of two groups based on postoperative treatment: the water injection (control) group and the glutamine injection group. Water (40 ml) or L(+)-glutamine (1 g/40 ml water) was injected into the residual stomach through the gastric tube every 12 h after surgery for 7 days. Changes in the plasma and intestinal intracellular concentration of glutamine and in gastrointestinal motility were measured. The plasma and intracellular glutamine levels decreased after the operation in both groups, although the decreased intracellular glutamine levels were not significantly different than preoperative levels. The glutamine group showed a significantly smaller decrease of the plasma glutamine level compared with the control group (P < 0.05). All the dogs showed gastrointestinal dysmotility after the operation. The mean length of time between the operation and the appearance of interdigestive migrating contractions in the glutamine group was significantly shorter than in the control group (22.4 +/- 3.1 h versus 37.8 +/- 4.0 h, respectively; P < 0.05). In conclusion, glutamine could act as a motility-recovery agent after abdominal surgery and thereby decrease the duration of POI.

Feasibility study of postoperative intraperitoneal hyperthermochemotherapy by radiofrequency capacitive heating system for advanced gastric cancer with peritoneal seeding.

BACKGROUND: Gastric carcinoma patients with peritoneal dissemination have an extremely poor prognosis. Attempting to improve regional control and decrease the risk of complications related to hyperthermic chemotherapy, we applied a new treatment modality using a combination of gastrectomy with postoperative intraperitoneal hyperthermo-chemotherapy (PIHC) using Thermotron RF-8. The purpose of this study was to evaluate the feasibility of PIHC in advanced gastric carcinoma patients with peritoneal seeding. PATIENTS AND METHODS: Between March 2002 and April 2006, 20 gastric carcinoma patients with peritoneal dissemination were allocated to two groups in the patient's selection. The PIHC group (10 patients) received a 60-min PIHC with a cisplatin dose of 80 mg/m2 two weeks after surgery, and the control group (10 patients) received surgery alone. Thermotron RF-8 is a heating device that can raise temperatures in both superficial and deep-seated tumours using 8 MHz radiofrequency electromagnetic waves as a source of heat. RESULTS: No patients in either group had life-threatening complications. The most frequent nonhaematologic toxicity (grade 3) was nausea. The one-, two-, and three-year cumulative survival rates for the PIHC group were 60%, 48%, and 36%, respectively, whereas those for the control group were 40%, 10%, and 0%, respectively. The survival rates for the PIHC group were significantly higher than those for the control group. CONCLUSION: Although this study was conducted non-randomly with a small number of patients, the PIHC group had a higher survival rate and better prognosis compared with the control group.

A phase I radioimmunolocalization trial of humanized monoclonal antibody huA33 in patients with gastric carcinoma.

In order to determine the in vivo characteristics of huA33, an open label dose escalation biopsy-based phase I clinical trial and radioimmunolocalization study were conducted with a complement determinant region-grafted humanized monoclonal antibody against the A33 antigen in patients with gastric carcinoma. Thirteen patients were entered onto one of four dose levels (1.0, 2.0, 5.0 or 10.0 mg/m(2)). Patients with locally advanced (UICC-TNM [International Union Against Cancer-tumor, node, metastasis] stage over 2 but resectable at clinical diagnosis) gastric carcinoma received a single infusion of (131)I-huA33 1 week prior to surgery. Adverse events were monitored, and imaging studies with gamma camera plus ex vivo scintigraphy of the resected specimen, biodistribution study by dosimetry analysis of the biopsied and resected tissues, and immunohistochemical analysis were carried out and evaluated. No dose-limiting toxicity was observed during the trial. Therefore, the maximum tolerated dose was not reached. Although cancer tissues with + intensity and <25% extent by immunostaining in biopsied frozen sections did not show positive imaging or postoperative dosimetry findings, cancers with ++ or +++ intensity or wide (>25%) extent by frozen and paraffin sections in the biopsied specimen showed positive ex vivo tumor images and positive antigen expression in resected gastric cancer specimens, and the biodistribution analysis showed tumor uptake of (131)I-huA33. In conclusion, humanized monoclonal antibody huA33 demonstrated selective localization to gastric cancer that expressed A33 antigen strongly. These excellent targeting characteristics of huA33 indicate potential for targeted therapy of advanced gastric cancer that is refractory to cytotoxic therapy, and could also be exploitable for curatively resected early gastric cancer in an adjuvant setting.

Liver metastases of a minute rectal carcinoid less than 5mm in diameter: a case report.

We report a case of liver metastases of a minute rectal carcinoid less than 5mm in diameter, which was found during the postoperative follow-up course of a stomach cancer patient. For the early stomach cancer, laparoscope-assisted distal gastrectomy with lymph node dissection was performed on August 26, 1998. Later, abdominal CT revealed space-occupying lesions in the liver (S2). Metastatic tumors of the stomach cancer were suspected, but further examination revealed that the lesions were metastatic tumors due to a rectal carcinoid tumor. Ten months later, metastatic carcinoid tumors were found in the liver (S1, S5, S6, S7, S8). Subsegmentectomy of the liver (S7) and microwave coagulation therapy (S1, S5, S6, S8) were performed. Carcinoid tumors metastatic to the lymph nodes, liver, and other areas have been reported, but all were larger than 20mm in diameter. In this case, the primary tumor was less than 5mm in diameter, which is extremely rare. This patient was successfully treated with lateral segmentectomy, subsegmentectomy (S7), microwave coagulation therapy of the liver, and transanal extirpation. She is presently in a good condition and has had no recurrence of the carcinoid tumor from ten months after the last hepatectomy.