Akiyoshi Mizumoto

Safety and Efficacy of Bidirectional Chemotherapy for Treatment of Patients With Peritoneal Dissemination From Gastric Cancer: Selection for Cytoreductive Surgery

There is no standard treatment for peritoneal carcinomatosis (PC) from gastric cancer. New bidirectional chemotherapy (neoadjuvant intraperitoneal‐systemic chemotherapy protocol (NIPS)) was developed. The aim of the present study was to assess the safety and efficacy of NIPS and to show the selection for cytoreductive surgery on PC from gastric cancer. Seventy‐nine patients with PC from gastric cancer were treated with NIPS. A peritoneal port system was introduced into the abdominal cavity. The peritoneal wash cytological examination through a port was done before and after NIPS. The patients were treated with oral TS‐1 twice a daily for 21 days, followed by a 1‐week rest. On day 1, 8, and 15 from the start of oral TS‐1 administration, 30 mg/m2 of Docetaxel and 30 mg/m2 of cisplatinum with 500 ml of saline were introduced into the peritoneal cavity through the port. A median course of oral TS‐1 was 2.1 course and a median time of IP chemoterapy was 5.8. Peritoneal free cancer cells (PFCCs) had been detected in 65 (82.2%) patients before NIPS, and the positive cytology changed to be negative in 41 (63.0%) patients after NIPS. After NIPS, 41 patients underwent laparotomy, and complete cytoreduction was done in 32 (78%) patients. Complete cytoreduction was done in 27 (51.9%) of 52 patients with negative cytology but in only 4 (14.8%) of 27 patients with positive cytology (P < 0.001). Patients with negative cytology after NIPS survived significantly longer than those with positive cytology. The adverse effects after NIPS were mild and there was no treatment‐related deaths. The grade 3/4 hematological adverse effects were found in 2 (2.6%) patients. Grade 3 renal toxicity and port site infection was found in three patients, respectively. NIPS using a port system is a safe and effective treatment for PC. Peritoneal wash cytology through a port system is a good indicator to select the patients to perform cytoreductive surgery. J. Surg. Oncol. 2009;100:311–316.

Involvement of 5-hydroxytryptamine 3 receptors in regulation of interdigestive gastric contractions by motilin in the dog

The effects of IV injection of 5-hydroxytryptamine 3 receptor antagonists (BRL 43694 and GR38032F) on gastrointestinal contractile activity were studied in dogs with vagally denervated fundic pouch in the conscious state by means of chronically implanted force transducers in the gastrointestinal tract and the pouch. In the interdigestive state, 5-hydroxytryptamine 3 receptor antagonists (0.01-0.1 mg/kg), if given during phase III contractions, instantly and dose-dependently inhibited the spontaneous and motilin-induced phase III contractions in the intact stomach and altered the duodenal phase III contractions to a pattern of continuous contractions, the contractile force which was 65% of the spontaneous phase III contractions in the duodenum and caused immediate caudad migration of phase III contractions along the small intestine. However, the spontaneous and motilin-induced phase III-like contractions in the denervated pouch were not affected at all by 5-hydroxytryptamine 3 receptor antagonists. When 5-hydroxytryptamine 3 receptor antagonists (0.1-3.0 mg/kg) were given during the phase I period, they did not directly stimulate gastrointestinal contractions. The cyclic fluctuation of the plasma motilin concentration with phase III activity in the stomach was also not influenced by 5-hydroxytryptamine 3 receptor antagonists, but the next phase III contractions in the stomach were inhibited. During the digestive state, however, 5-hydroxytryptamine 3 receptor antagonists (0.1-3.0 mg/kg) did not influence contractile activity in the gastrointestinal tract and in the vagally denervated fundic pouch. On the basis of recent pharmacological studies showing that the distribution of 5-hydroxytryptamine 3 receptors is recognized in the area postrema, peripheral neurons of vagal afferents, and the enteric nervous system, the results of the current study provide a basis for a hypothesis that 5-hydroxytryptamine 3 receptor antagonists are most likely to block motilin-induced signals at 5-hydroxytryptamine 3 receptors on the vagal afferents. In conclusion, the present findings suggest the possible involvement of 5-hydroxytryptamine 3 receptors on vagal afferents especially in terms of endogenous release of acetylcholine in the control of interdigestive phase III activity in the stomach by motilin.

Multidisciplinary therapy for treatment of patients with peritoneal carcinomatosis from gastric cancer

There is no standard treatment for peritoneal carcinomatosis (PC) from gastric cancer. A novel multidisciplinary treatment combining bidirectional chemotherapy [neoadjuvant intraperitoneal-systemic chemotherapy protocol (NIPS)], peritonectomy, hyperthermic intraperitoneal chemoperfusion (HIPEC) and early postoperative intraperitoneal chemotherapy has been developed. In this article, we assess the indications, safety and efficacy of this treatment, review the relevant studies and introduce our experiences. The aims of NIPS are stage reduction, the eradication of peritoneal free cancer cells, and an increased incidence of complete cytoreduction (CC-0) for PC. A complete response after NIPS was obtained in 15 (50%) out of 30 patients with PC. Thus, a significantly high incidence of CC-0 can be obtained in patients with a peritoneal cancer index (PCI) ≤ 6. Using a multivariate analysis to examine the survival benefit, CC-0 and NIPS are identified as significant indicators of a good outcome. However, the high morbidity and mortality rates associated with peritonectomy and perioperative chemotherapy make stringent patient selection important. The best indications for multidisciplinary therapy are localized PC (PCI ≤ 6) from resectable gastric cancer that can be completely removed during a peritonectomy. NIPS and complete cytoreduction are essential treatment modalities for improving the survival of patients with PC from gastric cancer.

Effects of Neoadjuvant Intraperitoneal/Systemic Chemotherapy (Bidirectional Chemotherapy) for the Treatment of Patients with Peritoneal Metastasis from Gastric Cancer

Novel multidisciplinary treatment combined with neoadjuvant intraperitoneal-systemic chemotherapy protocol (NIPS) and peritonectomy was developed. Ninety-six patients were enrolled. Peritoneal wash cytology was performed before and after NIPS through a port system. Patients were treated with 60 mg/m2 of oral S-1 for 21 days, followed by a 1-week rest. On days 1, 8, and 15, 30 mg/m2 of Taxotere and 30 mg/m2 of cisplatin with 500 mL of saline were introduced through the port. NIPS is done 2 cycles before surgery. Three weeks after NIPS, 82 patients were eligible to intend cytoreductive surgery (CRS) by gastrectomy + D2 dissection + periotnectomy to achieve complete cytoreduction. Sixty-eight patients showed positice cytology before NIPS, and the positive cytology results became negative in 47 (69%) patients after NIPS. Complete pathologic response on PC after NIPS was experienced in 30 (36.8%) patients. Stage migration was experienced in 12 patients (14.6%). Complete cytoreduction was achieved in 58 patients (70.7%). By the multivariate analysis, complete cytoreduction and pathologic response became a significantly good survival. However the high morbidity and mortality, stringent patient selection is important. The best indications of the therapy are patients with good pathologic response and PCI ≤ 6, which are supposed to be removed completely by peritonectomy.

Mechanism of motilin-induced contractions in isolated perfused canine stomach

BACKGROUND Motilin is known to induce gastric phase III contractions via neural pathways in vivo, but the local mechanism of action is not clearly determined. METHODS An isolated perfused canine stomach was used to demonstrate the mechanism of motilin. Synthetic canine motilin at doses of 0.1, 0.3, 1.0, and 3.0 micrograms/h was infused intra-arterially, and effects of several receptor antagonists on motilin-induced contractions were examined. RESULTS The immunoreactive motilin concentration of venous effluent showed that motilin at doses of 0.1 and 0.3 microgram/h was within the physiological range. Each dose of motilin induced phasic contractions in the isolated stomach, and a dose-related increase in frequency was observed, but not their mean amplitude. Atropine, hexamethonium, ICS205-930, BRL43694, phentolamine, yohimbine, and propranolol significantly inhibited motilin-induced contractions. Naloxone, methysergide, and timolol did not affect the response of motilin. Prazosin significantly increased the mean amplitude of motilin-induced contractions. CONCLUSIONS Physiological dose of motilin can initiate phasic contractions in the stomach independently of the presence of the extrinsic nerves. The results suggest that cholinergic pathway, 5-hydroxytryptamine (HT)3 receptors, and alpha receptors are involved in the motilin-induced contractions.

Morbidity and Mortality Outcomes of Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy at a Single Institution in Japan

Background. Even though cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are associated with a high morbidity and mortality rates, it has been reported that CRS and HIPEC improved survival of selected patients with peritoneal carcinomatosis. We aimed to report morbidity and mortality results of CRS and HIPEC from a single institution in Japan. Methods and Results. Total of 284 procedures of CRS were performed on patients with pseudomyxoma peritonei, peritoneal carcinomatosis (PC) from colon cancer and gastric cancer between 2007 and 2011 in our institution. The morbidity rate was 49% of all procedure, and grades I/II and grades III/IV complications were 28% and 17%, respectively. Most frequent complication was surgical site infections including intraabdominal abscess. The mortality rate was 3.5%, and reoperation was needed in 11% of all procedures. Univariate and multivariate analysis showed peritoneal carcinomatosis index (PCI) greater than 20 was the only significant factor for occurrence of postoperative complications (P < 0.01). In contrast, HIPEC significantly reduced postoperative complications (P < 0.05). Conclusions. The morbidity and mortality rates of our institution are comparable with previous reports that are in acceptable rates. Optimal patient selection such as patients with PCI less than 20 seems to be of paramount importance to CRS and HIPEC.

Mechanism of gastroprokinetic effect of EM523, an erythromycin derivative, in dogs

BACKGROUND The pharmacological properties of EM523, a nonpeptide motilin agonist, have not been well characterized. METHODS The prokinetic effect of EM523 on motor-stimulating activity in the stomach, duodenum, and jejunum in seventeen conscious dogs was studied using force transducers implanted long term. EM523 (0.3-10.0 micrograms/kg) and receptor antagonists were injected intravenously during the interdigestive state. RESULTS EM523 induced phase III-like contractions in a dose-dependent manner, and the contractions were inhibited dose dependently by pretreatment with cholinergic and 5-HT3 receptor antagonists and dopamine but not by adrenoceptor and opiate antagonists or methysergide. The plasma immunoreactive motilin level was increased after EM523 to 60% of the mean maximum value during the spontaneous phase III contractions. Pretreatment with anti-canine motilin serum inhibited EM523-induced contractions by 19.2% in the motor index, but the contractile pattern was not affected. CONCLUSIONS EM-523-induced phase III-like contractions are brought about through the cholinergic neural pathway and 5-HT3 receptors, and endogenous motilin release is partially involved.

Exogenous motilin stimulates endogenous release of motilin through cholinergic muscarinic pathways in the dog.

BACKGROUND & AIMS Exogenous motilin is believed to stimulate endogenous release of motilin, but this has not been studied in detail. The aim of this study was to investigate whether and by what mechanism exogenous motilin stimulates endogenous release of motilin in the dog. METHODS Gastric and duodenal contractile activity in conscious dogs was monitored by chronically implanted force transducers. Plasma canine motilin (c-motilin) concentrations in response to exogenous porcine motilin (p-motilin) were determined by specific radioimmunoassay for c-motilin. The release of motilin from motilin cells obtained from canine duodenal mucosa was studied in vitro using a perifusion system. RESULTS In vitro, c-motilin release was stimulated by carbachol but not by p-motilin, and the carbachol-induced c-motilin release was inhibited by atropine. In vivo, exogenous p-motilin stimulated endogenous c-motilin release and gastric and duodenal phase III-like contractions; this motilin-induced motilin release was inhibited by atropine, hexamethonium, and a 5-hydroxy-tryptamine 3 receptor antagonist. CONCLUSIONS In the dog, exogenous motilin stimulates endogenous motilin release through muscarinic receptors on motilin-producing cells via preganglionic pathways involving 5-hydroxytryptamine 3 receptors.

Stimulatory mechanism of EM523-induced contractions in postprandial stomach of conscious dogs☆☆☆

BACKGROUND & AIMS EM523, a motilin agonist, is intended to be used as a gastroprokinetic during the postprandial period, but the mechanism(s) by which EM523 stimulates postprandial contractions in the stomach has not been studied before. The aim of this study was to examine the mechanism of contraction-stimulating activity by EM523 in fed dogs. METHODS Contractile activity in the gastric antrum of 5 dogs was monitored using a long-term implanted force transducer and measured by integrating the area under the curve. Test materials were continuously infused or injected intravenously. RESULTS EM523 (1-30 micrograms/kg) induced a dose-dependent increase in fed-type contractions. EM523-induced contractile activity was partially inhibited by atropine, hexamethonium, dopamine, 5-hydroxytryptamine 3 (5-HT3) receptor antagonist, and substance P antagonist. Atropine-resistant and EM523-induced contractions were further inhibited by 5-HT3 receptor antagonist and substance P antagonist, and the combined use of the two antagonists completely eliminated the atropine-resistant and EM523-induced contractions. CONCLUSIONS EM523-induced contractions in the fed stomach are quite different from phase III contractions in the fasted state and are mediated partially through the cholinergic pathway. The noncholinergic pathway involves 5-HT3 and neurokinin 1 receptors.

Motilin controls cyclic release of insulin through vagal cholinergic muscarinic pathways in fasted dogs

The effect of motilin on insulin release has not been studied in the interdigestive state. Adult mongrel dogs were chronically implanted with force transducers in the stomach and duodenum to monitor contractile activity, and the plasma motilin and insulin concentrations were measured by a specific radioimmunoassay and enzyme immunoassay, respectively. The concentration of insulin in plasma was found to fluctuate in close association with that of motilin and phase III of the interdigestive migrating contractions in the stomach. This spontaneous release of insulin was mimicked by intravenous infusion of motilin at a dose of 0.3 μg ⋅ kg-1 ⋅ h-1. Exogenous motilin (0.01-0.3 μg/kg) dose dependently stimulated insulin release, which was abolished by atropine, hexamethonium, ondansetron, and truncal vagotomy. Phentolamine significantly enhanced, whereas propranolol inhibited, motilin-induced insulin release. In a perifusion system using islet cells from the canine pancreas, motilin did not affect insulin release. In conclusion, motilin stimulates insulin release through vagal cholinergic, muscarinic receptors on pancreatic β-cells, and the effect appears to be modulated by adrenergic nerves.The effect of motilin on insulin release has not been studied in the interdigestive state. Adult mongrel dogs were chronically implanted with force transducers in the stomach and duodenum to monitor contractile activity, and the plasma motilin and insulin concentrations were measured by a specific radioimmunoassay and enzyme immunoassay, respectively. The concentration of insulin in plasma was found to fluctuate in close association with that of motilin and phase III of the interdigestive migrating contractions in the stomach. This spontaneous release of insulin was mimicked by intravenous infusion of motilin at a dose of 0.3 microgram.kg-1.h-1. Exogenous motilin (0.01-0.3 microgram/kg) dose dependently stimulated insulin release, which was abolished by atropine, hexamethonium, ondansetron, and truncal vagotomy. Phentolamine significantly enhanced, whereas propranolol inhibited, motilin-induced insulin release. In a perifusion system using islet cells from the canine pancreas, motilin did not affect insulin release. In conclusion, motilin stimulates insulin release through vagal cholinergic, muscarinic receptors on pancreatic beta-cells, and the effect appears to be modulated by adrenergic nerves.