Phase II Study of Intraperitoneal Administration of Paclitaxel Combined with S-1 and Cisplatin for Gastric Cancer with Peritoneal Metastasis.

BACKGROUND: Intraperitoneal chemotherapy is promising for gastric cancer with peritoneal metastasis. Although a phase III study failed to show a statistically significant superiority of intraperitoneal paclitaxel combined with S-1 and intravenous paclitaxel, the sensitivity analysis suggested clinical efficacy. Thus, attempts to combine intraperitoneal paclitaxel with other systemic therapies with higher efficacy have been warranted. We sought to explore the efficacy of intraperitoneal paclitaxel with S-1 and cisplatin. PATIENTS AND METHODS: Gastric cancer patients with peritoneal metastasis were enrolled in the phase II trial. In addition to the established S-1 and cisplatin regimen every 5 weeks, intraperitoneal paclitaxel was administered on days 1, 8, and 22 at a dose of 20 mg/m2. The primary endpoint was overall survival rate at 1 year after treatment initiation. Secondary endpoints were progression-free survival and toxicity. RESULTS: Fifty-three patients were enrolled and fully evaluated for efficacy and toxicity. The 1-year overall survival rate was 73.6% (95% confidence interval 59.5-83.4%), and the primary endpoint was met. The median survival time was 19.4 months (95% confidence interval, 16.1-24.6 months). The 1-year progression-free survival rate was 49.6% (95% confidence interval, 34.6-62.9%). The incidences of grade 3/4 hematological and non-hematological toxicities were 43% and 47%, respectively. The frequent grade 3/4 toxicities included neutropenia (25%), anemia (30%), diarrhea (13%), and anorexia (17%). Intraperitoneal catheter and implanted port-related complications were observed in four patients. There was one treatment-related death. CONCLUSIONS: Intraperitoneal paclitaxel combined with S-1 and cisplatin is well tolerated and active in gastric cancer patients with peritoneal metastasis.

Gallbladder hemorrhage associated with segmental arterial mediolysis: a case report.

BACKGROUND: Gallbladder hemorrhage is a rare but fatal condition. The reported causes of gallbladder hemorrhage include iatrogenesis, atherosclerotic changes in the cystic arteries, acute cholecystitis or cholelithiasis, malignancy, trauma, hemophilia, pseudoaneurysm, and the use of oral anticoagulant medications. Recently, segmental arterial mediolysis (SAM) has been reported as a possible etiology of life-threatening abdominal, retroperitoneal, and intracranial hemorrhages. However, no previous reports have described the association between gallbladder hemorrhage and SAM. CASE PRESENTATION: A 59-year-old man was transferred to our hospital complaining of upper abdominal pain and vomiting. Contrast-enhanced computed tomography revealed high-density images of the gallbladder and common bile duct. However, there were no obvious findings of gallstones, cholecystitis, tumors, or aneurysms. He was diagnosed with gallbladder hemorrhage and bile duct obstruction. We performed a laparoscopic cholecystectomy after endoscopic biliary drainage. The gross appearance of the surgically resected specimen showed 12 small (3-12 mm), slightly elevated lesions on the gallbladder mucosa. Histologically, these slightly elevated lesions consisted of dilated muscular arteries of the gallbladder wall with fibrinoid degeneration of the media and focal loss of the internal and external elastic laminae. The histopathological diagnosis was confirmed as SAM. CONCLUSIONS: To the best of our knowledge, this is the first reported case of a gallbladder hemorrhage associated with SAM. Our case report shows that SAM can cause gallbladder hemorrhage, suggesting that SAM should be considered in the differential diagnosis of gallbladder hemorrhage.

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.

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.

Primary hepatic neuroendocrine carcinoma diagnosed by needle biopsy: a case report.

BACKGROUND: Primary hepatic neuroendocrine carcinomas (NECs) are extremely rare. The rate of recurrence after resection is extremely high, and the prognosis is poor. It is debatable whether chemotherapy or surgical resection is the optimal initial treatment for primary hepatic NECs. Therefore, selecting an appropriate therapeutic approach for patients with primary hepatic NECs remains clinically challenging. We present a case of primary hepatic NEC in a patient who developed recurrence after undergoing surgical resection. CASE PRESENTATION: A 78-year-old man with bone metastases of prostate cancer was referred to our department because of a solitary 66-mm tumor in the left lateral segment of the liver, which was detected on annual follow-up by computed tomography after prostate resection. A biopsy and preoperative diagnostic workup identified the lesion as a primary hepatic neuroendocrine carcinoma; therefore, left lateral segmentectomy was performed. Immunohistochemically, the tumor was positive for chromogranin A, synaptophysin, and CD 56, and the Ki-67 index was 40%. This neuroendocrine carcinoma was classified as a large cell type. Adjuvant chemotherapy with carboplatin + etoposide was initially administered a month after surgery. However, lymph node recurrence occurred 4 months after surgery, and the patient died of systemic metastases 15 months after surgical resection. CONCLUSIONS: Due to the lack of availability of abundant quantities of relevant, high-quality data, there is no standard therapy for primary hepatic NECs. Selecting the most appropriate treatment for patients depending on several factors, such as the stage and differentiation of a tumor and a patient's performance status and clinical course, is consequently preferred. More cases need to be studied to establish the best treatment strategy for primary hepatic NEC.

Intraperitoneal Chemotherapy as Adjuvant or Perioperative Chemotherapy for Patients with Type 4 Scirrhous Gastric Cancer: PHOENIX-GC2 Trial.

The prognosis of patients with type 4 scirrhous gastric cancer remains poor due to a high risk of peritoneal metastasis. We have previously developed combined chemotherapy regimens of intraperitoneal (IP) paclitaxel (PTX) and systemic chemotherapy, and promising clinical efficacy was reported in gastric cancer with peritoneal metastasis. Herein, a randomized, phase III study is proposed to verify the efficacy of IP PTX to prevent peritoneal recurrence. Gastric cancer patients with type 4 tumors and without apparent distant metastasis, including peritoneal metastasis, will be randomized for standard systemic chemotherapy or combined IP and systemic chemotherapy based on peritoneal lavage cytology findings. Those with negative peritoneal cytology will receive radical gastrectomy and adjuvant chemotherapy of S-1 plus docetaxel (control arm), or S-1 plus intravenous and IP PTX (experimental arm). Those with positive peritoneal cytology will receive three courses of S-1 plus oxaliplatin (control arm), or S-1 plus oxaliplatin and IP PTX (experimental arm). Subsequently, they undergo gastrectomy and receive postoperative chemotherapy of S-1 plus docetaxel (control arm), or S-1 plus intravenous and IP PTX (experimental arm). The primary endpoint is disease free survival after a 3-year follow-up period. Secondary endpoints are overall survival, survival without peritoneal metastasis, safety, completion rate, curative resection rate, and histological response of preoperative chemotherapy. A total of 300 patients are to be enrolled.

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/m(2)) and intraperitoneal (20 mg/m(2)) PTX was performed via a subcutaneously placed intraperitoneal catheter on days 1 and 8, and S-1 was administered twice daily at 80 mg/m(2)/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.

Solitary splenic metastasis from early gastric cancer: report of a case.

Solitary metastasis of a malignancy to the spleen is rare. We herein describe a case of splenic metastasis from early gastric cancer. A 76-year-old man underwent an endoscopic mucosal resection (EMR) for early gastric carcinoma in the cardia. Pathologically, the tumor showed invasion into the submucosal layer, and the stump of the surgical specimen appeared to be positive for malignant cells. He thus underwent a proximal gastrectomy with nodal dissection. One year later, serum carcinoembryonic antigen was elevated, and a splenic mass was detected by computed tomography and ultrasonography. Because the tumor increased in size very gradually and no metastatic lesions were detected at the other sites, we performed a splenectomy. The lesion was pathologically diagnosed as metastasis from the previous gastric carcinoma, and the patient remains healthy to date without recurrence, more than 2 years after the splenectomy. When solitary metastasis to the spleen is suspected during the postoperative follow-up of a patient with gastric cancer, a splenectomy is a potentially effective treatment.

[A case report of anorectal malignant melanoma showing a complete response after DTIC/ACNU/VCR therapy].

We report herein the case of a 64-year-old male who presented with hematochezia. The patient was diagnosed with malignant melanoma of the anorectum using colonoscopy. Preoperative studies revealed no distant metastases, and he underwent Miles operation. Pathological exams revealed that the tumor had invaded the submucosa with lymphatic and venous invasion. Cancer cells were found in regional lymph nodes. Post-operative CT scan demonstrated multiple metastases in the liver, and he received two courses of combined chemotherapy, DAV regimen (dacarbazine: DTIC 100 mg iv days 1-5, nimustine hydrochloride: ACNU 100 mg iv day 1, vincristine sulfate: VCR 1 mg iv day 1), leading to a complete response. However, malignant melanoma cells were found in hernia contents at the operation for left inguinal hernia, which led to a diagnosis of recurrent malignant melanoma. The patient has subsequently been well without any sign of recurrence including liver metastases. To our knowledge, this is the first report of a complete response in a patient with multiple liver metastases of anorectal malignant melanoma after DAV regimen.

Differential diagnosis and laparoscopic resection of an adrenal pseudocyst: A case report.

BACKGROUND: Adrenal pseudocysts are infrequent entities and definite preoperative diagnosis is difficult. We present a case of left adrenal pseudocyst, which was intraoperatively identified as having an adrenal origin and was resected using a laparoscopic approach. PRESENTATION OF CASE: A 41-year-old female was referred to our hospital for examination and treatment of a cystic lesion in the pancreatic tail. Preoperative diagnostic imaging studies showed a cystic lesion with intramural nodular structure, measuring 39 mm in the largest diameter and located between the pancreatic tail and the left adrenal gland. However, the origin of the cystic lesion remained unclear, and a definite preoperative diagnosis was not established. The cystic lesion was intraoperatively identified as having an adrenal origin after the division of the loose connective tissue layer around the lesion under the laparoscopic magnified view. Laparoscopic left adrenalectomy was performed as radical treatment and the histopathological diagnosis confirmed the presence of an adrenal pseudocyst. DISCUSSION: We could not ascertain the origin of the cystic lesion from the left adrenal gland and establish a definite diagnosis based on the findings of the preoperative diagnostic imaging modalities. Laparoscopic surgery could be more advantageous than the conventional open approach as not only a minimally invasive treatment option but also as an intraoperative diagnostic tool for cystic lesions in the pancreatic tail. CONCLUSION: This case report suggests that laparoscopic surgery could be clinically useful as not only a minimally invasive treatment but also an intraoperative diagnostic tool for cystic lesions in the pancreatic tail region.

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/m(2), and intraperitoneally with an initial dose of 20 mg/m(2), stepped up to 30 or 40 mg/m(2). S-1 was administered at a fixed dose of 80 mg/m(2)/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/m(2), as 2 of 3 patients developed dose-limiting toxicities, grade 3 febrile neutropenia and diarrhea. Therefore, the RD was determined to be 20 mg/m(2). 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.

Metastatic esophageal tumor from cecal carcinoma.

A 55-year-old man developed progressive dysphagia 14 months after palliative colectomy and subsequent systemic chemotherapy for advanced cecal cancer with carcinomatosis peritonei. Radiologic and endoscopic examinations suggested a submucosal tumor in the lower esophagus causing a severe luminal stricture. A self-expanding metal stent was placed for palliation. The prosthesis was effective for several months, but ingrowth of the tumor caused re-stricture of the esophagus. Since his general condition was quite good without any evidence of recurrence of the cecal cancer, we performed bypass surgery for palliation. The pathological appearance of the tumor was compatible with the metastasis of cecal cancer. Our case suggests that a surgical approach can be considered as a therapeutic method for metastatic esophageal tumor, even in patients with advanced cancer, as long as the primary tumor is satisfactorily controlled.

Rectovaginal fistula after low anterior resection for rectal cancer healed by nonoperative treatment.

BACKGROUND: Rectovaginal fistula (RVF) is a serious complication after colorectal anastomosis using a double-stapling technique. RVF following this procedure has been considered to be refractory to conservative treatment. CASE PRESENTATION: A 75-year-old woman who underwent laparoscopy-assisted low anterior resection for early rectal cancer developed RVF on the 12th postoperative day. Conservative treatment was chosen and was successful. She was discharged from the hospital after 3 weeks with a normal oral diet. Colonoscopy on the 50th postoperative day showed that the RVF was closed. CONCLUSION: Conservative treatment may be effective for RVF after colorectal anastomosis using a double-stapling technique when there is no evidence of defecation through the vagina.

Analysis of tyrosine phosphorylation in resident peritoneal cells during diet restriction by laser scanning cytometry.

Tyrosine phosphorylation plays a critical role in signal transduction pathways in immune cells. Laser scanning cytometer (LSC), a newly developed microscope-based cytofluorometer, may overcome shortcomings of Western blotting and flow cytometry in the detection of intracellular signaling transduction. The aims of this study were to visualize and quantitate intracellular phosphotyrosine in the peritoneal cells harvested from diet-restricted mice by LSC. In addition, using LSC, we identified the main cell type with activated tyrosine phosphorylation in response to an inflammatory stimulus and we investigated the intracellular distribution of tyrosine phosphorylation within the peritoneal macrophages. Mice were assigned to the ad libitum and diet-restricted, i.e., 75% restricted food intake, groups. After 7 days of pair feeding, the peritoneal cells were harvested. Tyrosine phosphorylation in the harvested cells with either N-formyl-methionyl-leucyle-phenylalanine (fMLP) or lipopolysaccharide (LPS) stimulation was examined using LSC. Tyrosine phosphorylation of peritoneal cells from the diet-restricted group was significantly higher than that from the ad libitum group, regardless of stimulation. Stimulation of peritoneal cells with either fMLP or LPS significantly increased tyrosine phosphorylation in the ad libitum group, but not in the diet-restricted group. The relocation feature of LSC revealed that the cells with distinct tyrosine phosphorylation were macrophages. Topographic analysis demonstrated that phosphotyrosine was localized mainly in the cytoplasm of these cells. In summary, LSC revealed that tyrosine phosphorylation is mainly in the cytoplasm of the peritoneal macrophages and is deranged by diet restriction. LSC is a powerful tool for the study of intracellular signaling transduction.

Patients with postoperative infections have sticky neutrophils before operation.

Appropriate polymorphonuclear neutrophil (PMN) recruitment is essential for host defense against infection. We investigated the significance of the preoperative PMN adhesion-migration process, as assessed by the flow chamber method, on postoperative infectious complications. Thirty-one consecutive patients with gastrointestinal malignancies, 21 colorectal and 10 gastric, who were undergoing elective surgery were enrolled. PMNs, isolated preoperatively from each patient's venous blood, were perfused onto a tumor necrosis factor alpha-stimulated human umbilical vein endothelial cell (HUVEC) monolayer through the flow chamber. We evaluated the adherent PMN number, the migrated PMN number, and the stuck PMN number by directly inspecting PMN interactions with a HUVEC monolayer under continuous shear flow simulating postcapillary venules. The expression of adhesion molecules on circulating PMNs was also measured. Patients were grouped into an infectious and a noninfectious group according to the occurrence of postoperative infectious complications defined by the Centers for Disease Control criteria. Eleven patients developed postoperative infectious complications. Although the number of preoperative in vitro adherent PMNs in patients with postoperative infection was significantly higher than in those without postoperative infection (P = 0.01), migrated PMN number was similar in both groups. Stuck PMN number tended to be higher in the infectious group than in the noninfectious group. The migrated PMN number showed a significant positive correlation with the adherent PMN number in the noninfectious group but not in the infectious group. Preoperative CD31 expression on circulating PMNs was significantly lower in the infectious group than in the noninfectious group. Preoperative in vitro derangement of the PMN adhesion-migration process is closely associated with postoperative infectious complications.

Differences in neutrophil death among beta-lactam antibiotics after in vitro killing of bacteria.

Antibiotic therapy is an essential treatment for gram-negative bacterial infections. Antibiotic-induced endotoxin release and subsequent production of inflammatory cytokines reportedly depend on the type of antibiotic action. This study examined the effects of various beta-lactam antibiotics on cell death of human polymorphonuclear neutrophils (PMNs) cocultured with Escherichia coli (E. coli) in vitro. E. coli morphology after antibiotic treatment was determined. PMNs and E. coli were cocultured with antibiotics for 0, 4, or 12 h. Levels of endotoxin and cytokines (TNF-alpha, IL-1beta, and IL-6) in the supernatants were measured. The filtrates of antibiotic-treated E. coli supernatants were cocultured with PMNs for 0, 4, or 12 h. In all experiments, ampicillin (ABPC), cefazolin sodium (CEZ), cefoperazone sodium (CPZ), latamoxef sodium (LMOX), imipenem (IPM), and polymyxin B sulfate (PLB) were used at 30 microg/mL. PMNs were isolated from healthy volunteers. PMN cell death was assessed by flow cytometry and light microscopy. ABPC, CEZ, CPZ, and LMOX, which induce bacterial filament formation with lysis, caused PMN necrosis when cocultured with E. coli. In contrast, IPM, which induces bacterial spheroplast formation with lysis, caused PMN apoptosis. Levels of endotoxin, TNF-alpha and IL-6 in the supernatants with IPM and PLB were significantly lower than in those with other beta-lactam antibiotics. The filtrates of IPM- and PLB-treated E. coli supernatants induced PMN apoptosis, whereas those treated with other beta-lactam antibiotics increased PMN necrosis. Beta-lactam antibiotics have different impacts on the types of PMN cell death after E. coli killing. Underlying mechanisms and the clinical relevance of IPM-induced PMN apoptosis in severe gram-negative infection warrant further investigation.

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.

Diet restriction impairs extracellular signal-regulated kinase activation of peritoneal exudative cells after N-formyl-methionyl-leucyl-phenylalanine stimulation in a murine peritonitis model.

BACKGROUND: Phosphorylation of extracellular signal-regulated kinase (ERK) enhances various inflammatory responses in immune cells. It is unknown whether dysfunction of immune cells during malnutrition is attributed to derangement of ERK activation. METHODS: Male Institute of Cancer Research (ICR) mice received chow (146 g/kg per day, ad libitum or 36.5 g/kg per day, diet-restricted) for 7 days. Mice (n = 55) were given 6.5 mg/kg of an ERK inhibitor (PD98059) or vehicle intraperitoneally (IP), at 2 hours before cecal ligation and puncture (CLP). Survival was observed up to 60 hours. Detection of phosphorylated ERK (pERK) in the peritoneal exudative cells (PECs) was done as follows. In a separate study, PECs were harvested by peritoneal lavage 2 hours after an IP injection of 1% glycogen. PECs were incubated with or without 100 nmol/L N-formyl-methionyl-leucyl-phenylalanine (fMLP) for 1 minute. PEC ERK activation was detected with Western blot analysis (n = 38), by densitometric quantification, and with a laser scanning cytometer (LSC; n = 13). Subpopulations of PECs were determined by Wright-Giemsa staining. Unstimulated pERK expression was normalized to 100% for Western blot analysis. RESULTS: Diet restriction reduced survival after CLP compared with the ad libitum mice. ERK inhibition showed no effect on survival in diet-restricted mice but reduced survival in ad libitum mice. There were no differences in subpopulations of PECs 2 hours after glycogen injection between the groups. Western blot analysis revealed that fMLP stimulation significantly increased the phosphorylation of ERK1/2 in PECs from the ad libitum group (ERK1, 199 +/- 41%; ERK2, 211 +/- 49%; p < .03) but not in those from diet-restricted mice (ERK1, 98 +/- 10%; ERK2, 91 +/- 9%). Mean fluorescence intensity (MFI) of pERK in PECs obtained by LSC was significantly elevated after fMLP in the ad libitum group (from 19.4 +/- 1.5 MFI to 22.4 +/- 1.2 MFI; p < .05) but did not change in the diet-restricted group (from 19.4 +/- 1.8 MFI to 19.1 +/- 1.5 MFI). CONCLUSIONS: ERK activation is essential for survival in this murine sepsis model. Impaired ERK activation of PECs may, at least in part, impair host defense during malnutrition.

Early gastric cancer shows different associations with adipose tissue volume depending on histological type.

BACKGROUND: Visceral obesity is known to be a risk factor for diabetes and cardiovascular disease. Cancer of the gastric cardia has been shown to have a close association with obesity in Western countries. In order to examine the possible relationship between fat volume and the development of gastric cancer (GC), we quantified visceral and subcutaneous fat areas of computed tomography (CT) images of patients with early GC. METHODS: A total of 210 patients who underwent endoscopic resection or surgical gastrectomy and whose disease was pathologically diagnosed as early GC were investigated for total fat area (TFA), visceral fat area (VFA), and subcutaneous fat area (SFA) with Fat Scan software, using a CT slice at the umbilical level, and the relationships of these findings with clinical and pathological data were analyzed. The same analysis was performed in 147 patients with early colorectal cancer (CRC). RESULTS: TFA, VFA, and SFA values in GC patients were not significantly different from the values in CRC patients. These values did not differ with the location of the GC. However, patients with undifferentiated-type GC had significantly smaller VFAs and SFAs than those with differentiated-type GC. Among the patients with undifferentiated GC, TFA and SFA values in the patients with submucosal cancer were significantly smaller than those in the patients with mucosal cancer. CONCLUSION: GC has different associations with adipose tissue volume according to its histological type. As compared with differentiated GC, lower adipose tissue volume may be a preferential environment for the development and progression of undifferentiated GC.