Akio Hidemura

Phase II study of weekly intravenous and intraperitoneal paclitaxel combined with S-1 for advanced gastric cancer with peritoneal metastasis

BACKGROUND A phase II study to evaluate the efficacy and tolerability of weekly i.v. and i.p. paclitaxel (PTX) combined with S-1 was carried out in gastric cancer patients with peritoneal metastasis. PATIENTS AND METHODS Gastric cancer patients with peritoneal dissemination and/or cancer cells on peritoneal cytology were enrolled. PTX was administered i.v. at 50 mg/m(2) and i.p. at 20 mg/m(2) on days 1 and 8. S-1 was administered at 80 mg/m(2)/day for 14 consecutive days, followed by 7 days rest. The primary end point was the 1-year overall survival (OS) rate. Secondary end points were the response rate, efficacy against malignant ascites and safety. RESULTS Forty patients were enrolled, including 21 with primary tumors with peritoneal dissemination, 13 with peritoneal recurrence and six with positive peritoneal cytology only. The median number of courses was 7 (range 1-23). The 1-year OS rate was 78% (95% confidence interval 65% to 90%). The overall response rate was 56% in 18 patients with target lesions. Malignant ascites disappeared or decreased in 13 of 21 (62%) patients. The frequent grade 3/4 toxic effects included neutropenia (38%), leukopenia (18%) and anemia (10%). CONCLUSION Combination chemotherapy of i.v. and i.p. PTX with S-1 is well tolerated and active in gastric cancer patients with peritoneal metastasis.

Supplemental glutamine augments phagocytosis and reactive oxygen intermediate production by neutrophils and monocytes from postoperative patients in vitro

The energy substrate for neutrophils has been believed to be glucose. However, a recent investigation has demonstrated that neutrophils use glutamine (Gln) as well as glucose. Nevertheless, little is known about the effects of Gln on neutrophil function. Thus, this study was designed to investigate the effects of Gln on phagocytosis and reactive oxygen intermediate (ROI) production by neutrophils from postoperative patients in vitro. Eleven patients who had undergone major gastrointestinal surgery were randomly selected. Peripheral blood was drawn before surgery and on postoperative days (PODs) 1, 3, and 7. The blood was washed with medium to remove plasma. Washed whole blood was incubated in RPMI 1640 medium containing neither Gln nor glucose for 24 h at 37 degrees C. The medium was supplemented with Gln at a concentration of 0, 500, 1000, or 2000 microM. Whole blood was then assessed for phagocytosis by flow cytometry using fluorescent beads. ROI production by phagocytes was measured by flow cytometry using dihydrorhodamine 123. In each assay, the neutrophil population was gated and analyzed. Serum amino acids were also measured. Postoperative serum Gln level decreased significantly until POD 7. Phagocytosis by neutrophils on PODs 3 and 7 was significantly greater at 2000 microM Gln than at other Gln concentrations. Neutrophil ROI production was significantly greater at 2000 microM Gln than at 0 microM Gln at each time point. In conclusion, supplemental Gln enhances both phagocytosis and ROI production by neutrophils from postoperative patients in vitro.

Phase I Pharmacokinetic Study of Weekly Intravenous and Intraperitoneal Paclitaxel Combined with S-1 for Advanced Gastric Cancer

Objectives: A dose-escalation study of weekly intraperitoneal paclitaxel (PTX) combined with S-1 and intravenous PTX was performed to determine the maximum-tolerated dose (MTD) and recommended dose (RD) in gastric cancer patients. Patients and Methods: Nine gastric cancer patients with peritoneal dissemination and/or cancer cells on peritoneal cytology were enrolled. PTX was administered intravenously on days 1 and 8 at a fixed dose of 50 mg/m2, and intraperitoneally with an initial dose of 20 mg/m2, stepped up to 30 or 40 mg/m2. S-1 was administered at a fixed dose of 80 mg/m2/day for 14 consecutive days, followed by 7 days of rest. A pharmacokinetic study of PTX was also performed. Results: The MTD was determined to be 30 mg/m2, as 2 of 3 patients developed dose-limiting toxicities, grade 3 febrile neutropenia and diarrhea. Therefore, the RD was determined to be 20 mg/m2. The intraperitoneal and serum PTX concentration remained effective for over 72 and 48 h, respectively. Conclusions: Combined chemotherapy of S-1 plus weekly intravenous and intraperitoneal PTX was shown to be a safe regimen that should be further explored in clinical trials.

Oral Administration of Bifidobacterium longum Culture Condensate in a Diet-Restricted Murine Peritonitis Model Enhances Polymorphonuclear Neutrophil Recruitment Into the Local Inflammatory Site

Dietary restriction impairs polymorphonuclear neutrophil (PMN) recruitment into the local inflammatory site, resulting in susceptibility to infection. Probiotics enhance host immunity via conditioning host intestinal microflora. Oral administration of Bifidobacterium longum culture condensate (BCC) in a diet-restricted murine peritonitis model may enhance PMN recruitment into the inflammatory site. Male ICR mice (n = 40) were assigned in equal numbers to control or BCC groups and subjected to 75% restricted food intake for 7 d. During dietary restriction, controls received only standard mouse chow, whereas the BCC group received standard mouse chow containing 1% BCC. Mice were killed before (0 h) or after (2 or 4 h) intraperitoneal glycogen injection. Peritoneal lavage fluid and exudative cells were recovered by peritoneal lavage. Peritoneal exudative cell number was counted. Tumor necrosis factor-alpha, interleukin-6, macrophage inflammatory protein-2, and interleukin-10 concentrations in peritoneal lavage fluid were determined by enzyme-linked immunosorbent assay. CD11b, CD18, CD31, and CD62L expressions on circulating PMNs were measured by flow cytometry. Oral BCC administration upregulated PMN recruitment into the peritoneal cavity and increased peritoneal fluid cytokine concentrations as well as CD18 and CD62L expressions on circulating PMNs during glycogen-induced peritonitis. Oral BCC administration in a diet-restricted murine peritonitis model augmented PMN recruitment into the inflammatory site by upregulating cytokine concentrations in the local inflammatory site and adhesion molecule expression on circulating PMNs. Oral BCC administration may be a favorable modality for improving dietary restriction-induced host immunosuppression.

Vagus Nerve Preservation Selectively Restores Visceral Fat Volume in Patients with Early Gastric Cancer who Underwent Gastrectomy

BACKGROUND Body weight loss is a well-known complication after gastrectomy, and is mainly due to reduced fat volume. The effect of vagotomy on the postoperative fat volume was investigated in patients with early stage gastric cancer who underwent gastrectomy. METHODS Subcutaneous fat area (SFA) and visceral fat area (VFA) were separately measured in a computed tomographic (CT) image at the level of the umbilicus using Fat Scan software. The changes in these two fat areas were determined by comparing CT images taken before and more than 6 mo after gastrectomy, and the ratio of postoperative to preoperative fat area was calculated in 77 patients. RESULTS VFA was reduced significantly greater after total gastrectomy (TG) than distal gastrectomy (DG) (P = 0.0003). In 63 patients who underwent DG, the reduction in VFA, but not in SFA, was significantly less in vagus nerve-preserved than in vagus nerve-nonpreserved cases (59.0% ± 24.2% versus 74.9% ± 28.2%, P = 0.027). If compared in each case, VFA showed a significantly greater decrease than did SFA in vagus-nonpreserving, but not in vagus-preserving, gastrectomy (68.2% ± 37.0% versus 52.7% ± 25.2%, P < 0.0001; 76.3% ± 30.0% versus 74.9% ± 28.2%, P = 0.79). CONCLUSIONS The vagus nerve has a function to locally regulate the amount of intra-abdominal fat tissue, and selective vagotomy in gastrectomy results in a preferential reduction of visceral fat in gastrectomy. Surgical denervation of vagus may be reconsidered as a reasonable treatment for excessive obesity.

Relative effects of glucose and glutamine on reactive oxygen intermediate production by neutrophils.

ABSTRACT The energy source for neutrophils (PMNs) has long been believed to be glucose. However, it has been shown recently that PMNs use glutamine as well as glucose. Nevertheless, the comparative effects of glucose and glutamine on PMN function remain to be clarified. This study investigated the relative effects of glucose and glutamine on reactive oxygen intermediate (ROI) production by PMNs. In experiment 1, PMNs (1 × 106/mL) isolated from healthy volunteers were incubated in RPMI 1640 medium containing neither glucose nor glutamine for 4, 12, 18, and 24 h at 37°C. The medium was supplemented with 0 or 200 mg/dL (0 or 11 mM, respectively) glucose and glutamine (0, 0.5, 1, or 2 mM). PMN cell death was assessed on the basis of hypodiploid DNA by flow cytometry using propidium iodide DNA staining. ROI production by PMNs was determined by flow cytometry using dihydrorhodamine 123. In experiment 2, isolated PMNs were cultured in RPMI 1640 medium containing neither glucose nor glutamine. The medium was supplemented with glucose (0 or 11 mM) and a competitive inhibitor of glycolysis, 2‐deoxy‐D‐glucose (2‐DG; 0 or 20 mM). Each medium was supplemented with glutamine (0, 0.5, 1, or 2 mM) and incubated for 12 h at 37°C. Then, ROI production by PMNs was measured. PMN cell death was not affected by glucose or glutamine in this experiment. In contrast, ROI production by PMNs was greater at 11 mM glucose than at 0 mM glucose at all incubation times studied. At 11 mM glucose, supplemental glutamine enhanced PMN ROI production after 18 and 24 h culture. In contrast, at 0 mM glucose, glutamine augmented ROI production by PMNs after 12 h as well as with 18 and 24 h incubations. PMN ROI production after 12 h culture was significantly greater at 11 mM glucose without 2‐DG than at both 11 and 0 mM glucose with addition of 2‐DG. In addition, supplemental glutamine enhanced ROI production by PMNs when 2‐DG was added at 11 and 0 mM glucose. Glucose is essential for PMN ROI production. Under conditions of glucose depletion in vitro, glutamine is of importance in ROI production by PMNs, whereas the enhancing effect of glutamine on PMN ROI production is minor compared to that of glucose.

Intra-peritoneal administration of paclitaxel with non-animal stabilized hyaluronic acid as a vehicle--a new strategy against peritoneal dissemination of gastric cancer.

BACKGROUND AND AIM Intra-peritoneal administration (i.p.) of Taxanes has recently been reported to be effective for the treatment of peritoneal dissemination, presumably because extremely high concentration of the drug is achievable onto the disseminated nodules as compared to intra-venous administration. Here, we aimed to investigate the ability of non-animal stabilized hyaluronic acid (NASHA) to retain the anti-cancer drugs in the peritoneal cavity, and, consequently, improve the efficacy of i.p. administration of paclitaxel. METHODS Mice were inoculated i.p. with MKN45P gastric cancer cells. The mice received i.p. administrations of paclitaxel, without or with NASHA, once a week for 3 consecutive weeks, and the intra-peritoneal nodules were counted after 4 weeks. The ability of NASHA to retain the i.p. administered liquid and paclitaxel in abdominal cavity was also investigated. Finally, the concentration of paclitaxel in metastatic nodule was measured with HPLC. RESULTS In the group receiving paclitaxel with NASHA, the number of disseminated nodules were significantly smaller than in those receiving paclitaxel without NASHA. The fluid volumes and concentration of paclitaxel recovered from the abdominal cavity as well as the concentrations of paclitaxel in metastatic nodule were significantly increased by the addition of NASHA. CONCLUSION Our results indicate that NASHA improves the exposure time of i.p. administrated paclitaxel to disseminated nodules by retaining the drug in the abdominal cavity. Since the material is used in cosmetic surgery with few adverse effects, NASHA can be clinically used as the vehicle for the i.p. administration of anti-cancer agents for advanced gastric cancer with peritoneal dissemination.

Complications and Management of an Implanted Intraperitoneal Access Port System for Intraperitoneal Chemotherapy for Gastric Cancer with Peritoneal Metastasis

OBJECTIVE The efficacy of intraperitoneal chemotherapy for gastric cancer with peritoneal metastasis has been verified by clinical trials. To perform intraperitoneal chemotherapy safely and effectively, the appropriate management of intraperitoneal access ports is essential. The aim of this study was to investigate the occurrence of port complications during cyclically repeated intraperitoneal chemotherapy. METHODS The medical records of 131 gastric cancer patients with peritoneal metastases who received intraperitoneal paclitaxel between 2005 and 2011 were retrospectively analyzed. RESULTS The median period of intraperitoneal chemotherapy using a port system was 12.9 months (range: 0.8-61.5 months), and a total of 27 (20.6%) patients experienced port complications. Inflow obstruction (7.6%) and infection (6.9%) were the main complications, followed by reflux (3.1%), subcutaneous masses (1.5%) and fistulae (1.5%). The median interval between port implantation and port complication was 5.4 months (range: 0.3-40.9 months). Complications were controllable and chemotherapy was not terminated by complications. Survival was not affected by the presence or absence of port complications (median survival time: 22.5 vs. 17.2 months, respectively; P=0.65). CONCLUSIONS Intraperitoneal chemotherapy for gastric cancer using a port is safe and feasible under appropriate management.

Weekly intravenous and intraperitoneal paclitaxel combined with S-1 for malignant ascites due to advanced gastric cancer.

Malignant ascites caused by gastric cancer are chemotherapy resistant and carry a poor prognosis. The efficacy of a regimen including intraperitoneal paclitaxel (PTX) was evaluated in 33 gastric cancer patients with ascetic fluid in the peritoneal cavity diagnosed with computed tomography (CT) scanning. Synchronous administration of intravenous (50 mg/m2) and intraperitoneal (20 mg/m2) PTX was performed via a subcutaneously placed intraperitoneal catheter on days 1 and 8, and S-1 was administered twice daily at 80 mg/m2/day for 14 consecutive days from day 1 to day 14, followed by 7 days of rest. The ascitic fluid volume was calculated with NIH Image J software using continuous CT images. After 2–4 treatment cycles, 23 (70%) patients showed reductions in their ascitic volumes of >50%. Ascites disappeared completely in 8 patients and were markedly reduced (to <3% of the original volume) in 4 of the 9 patients (44%) who initially had massive (>2,500 ml) ascites. Median overall survival was significantly better in patients with ascitic reduction. Weekly intravenous and intraperitoneal PTX combined with S-1 was highly effective in gastric cancer with malignant ascites. The change in ascitic fluid volumes determined by CT image measurements is a useful predictor of outcome in these patients.

Malnutrition Impairs CD11b/CD18 Expression on Circulating Polymorphonuclear Neutrophils and Subsequent Exudation into Inflammatory Sites in the Early Phase of Glycogen-Induced Murine Peritonitis

BACKGROUND The effects of malnutrition on polymorphonuclear neutrophil (PMN) exudation are not well understood. The purpose of this study was to examine the effects of short-term dietary restriction on adhesion molecule expression on circulating PMNs and PMN exudation into the inflamed site in a glycogen-induced peritonitis model. METHODS Twelve mice were randomly assigned to one of two groups. The ad libitum and diet-restricted groups received mouse chow ad libitum (estimated consumption: 132 g/kg per day) and 33 g/kg per day, respectively, for 7 days. Then, 2 mL of a 1% glycogen solution was intraperitoneally administered to all mice. After 4 hours, the animals were killed. Whole blood was drawn by cardiac puncture. Peritoneal exudative cells were harvested by lavaging the peritoneal cavity. Expressions of CD11b, CD18, and CD62L were measured by flow cytometry. RESULTS Dietary restriction did not affect the numbers of circulating leukocytes, PMNs, or monocytes. However, CD11b and CD18 expressions on circulating PMNs were significantly lower in the diet-restricted than in the ad libitum group. In contrast, CD62L expression on circulating PMNs was not affected by dietary restriction. The number of exudative PMNs was significantly lower in the diet-restricted group than in the ad libitum group. The expressions of CD11b, CD18 and CD62L on exudative PMNs were unaffected by dietary restriction. There was a significant positive correlation between exudative PMN numbers and CD18 expression on circulating PMNs. CONCLUSIONS Severe dietary restriction in our murine model decreased beta2 integrin expression on circulating PMNs and inhibited PMN exudation into inflamed sites in the early phase of inflammation. These events may increase susceptibility to bacterial infection. Nutritional replenishment may improve host defense in part by enhancing PMN adhesion molecule expression.