Intestinal epithelial culture under an air-liquid interface: a tool for studying human and mouse esophagi.

This study investigated whether an intestinal epithelial culture method can be applied to mouse and human esophageal cultures. The esophagi harvested from 1-day-old mice and adult humans were maintained in collagen gels. A commercially available culture medium for human embryonic stem cells was used for the human esophageal culture. We discovered that the intestinal epithelial culture method can be successfully applied to both mouse and human esophageal cultures. The long-term cultured esophageal organoids were rod-like luminal structures lined with myofibroblasts. We discovered that regeneration of the esophageal mucosal surface can be almost completely achieved in vitro, and the advantage of this method is that organoid cultures may be generated using host-derived fibroblasts as a niche. This method is a promising tool for mouse and human research in intestinal biology, carcinogenesis, and regenerative medicine.

Circulating tumour cell-derived plastin3 is a novel marker for predicting long-term prognosis in patients with breast cancer.

BACKGROUND: Identification of promising biomarkers that predict the prognosis of patients with breast cancer is needed. In this study, we hypothesised that the expression of the epithelial-mesenchymal transition-related biomarker plastin3 (PLS3) in peripheral blood could be a prognostic factor in breast cancer. METHODS: We examined PLS3 expression in breast cancer cell lines with epithelial and mesenchymal traits and in circulating tumour cells (CTCs) obtained from the peripheral blood of breast cancer patients. We investigated PLS3 expression in the peripheral blood of 594 patients with breast cancer to evaluate the clinical significance of PLS3 expression. RESULTS: Robust PLS3 expression was observed in different breast cancer cell lines (Hs578t, MCF-7, MDA-MB-468, and MDA-MB-231) as well as in a bone marrow derived cancer cell line (BC-M1). In both the training (n=298) and validation (n=296) sets, PLS3 expression was observed in CTCs of patients with breast cancer. PLS3-positive patients showed significantly poorer overall and disease-free survival than PLS3-negative patients (P=0.0001 and 0.003, respectively). Subset analysis revealed that this prognostic biomarker was relevant in patients with stage I-III cancer, particularly in patients with luminal-type and triple-negative-type tumours. CONCLUSIONS: These data demonstrated that PLS3 was expressed in CTCs undergoing the epithelial-mesenchymal transition in patients with breast cancer. Furthermore, PLS3 may be an excellent biomarker for identifying groups at risk of recurrence or with a poor prognosis.

Biological significance of fluorine-18-α-methyltyrosine (FAMT) uptake on PET in patients with oesophageal cancer.

PURPOSE: (18)F-FAMT as an amino-acid tracer for positron emission tomography (PET) is useful for detecting human neoplasms. (18)F-FAMT is accumulated in tumour cells solely via L-type amino-acid transporter 1 (LAT1). This study was conducted to investigate the biological significance of (18)F-FAMT uptake in patients with oesophageal cancer. METHODS: From April 2008 to December 2011, 42 patients with oesophageal cancer underwent both (18)F-FAMT PET/CT and (18)F-FDG PET/CT before surgical treatment. The immunohistochemical analysis of LAT1, CD98, Ki-67, CD34, p53, p-Akt and p-mTOR was performed on the primary lesions. In vitro experiments were performed to examine the mechanism of (18)F-FAMT uptake. RESULTS: High uptake of (18)F-FAMT was significantly associated with advanced stage, lymph node metastasis and the expression of LAT1, CD98, Ki-67 and CD34. LAT1 expression yielded a statistically significant correlation with CD98 expression, cell proliferation, angiogenesis and glucose metabolism. In vitro experiments revealed that (18)F-FAMT was specifically transported by LAT1. CONCLUSIONS: The uptake of (18)F-FAMT within tumour cells is determined by the LAT1 expression and correlated with cell proliferation and angiogenesis in oesophageal cancer. The present experiments also confirmed the presence of LAT1 as an underlying mechanism of (18)F-FAMT accumulation.

Comparison of endoscopic submucosal dissection with laparoscopic-assisted colorectal surgery for early-stage colorectal cancer: a retrospective analysis.

BACKGROUND AND STUDY AIMS: Endoscopic submucosal dissection (ESD) is increasingly being used to resect early colorectal carcinoma, despite the technical difficulties associated with the procedure. Laparoscopic-assisted colorectal surgery (LAC) is an alternative to open surgery for colorectal cancers, and ESD was recently introduced as another alternative. In this study, we compared ESD with LAC as minimally invasive treatments for early colorectal cancer. PATIENTS AND METHODS: The study included 589 patients (297 patients with colorectal intramucosal or slightly submucosal invasive cancers undergoing ESD; 292 patients with T1 colorectal cancers undergoing LAC) who were treated at National Cancer Center Hospital in Tokyo, Japan, between January 1998 and September 2008. The clinical outcomes of ESD and LAC were evaluated retrospectively and compared on the basis of data that were originally collected prospectively. RESULTS: In the ESD group, mean tumor size was 37 mm, mean procedure time was 106 minutes, and the en bloc and curative resection rates were 87 % and 80 %, respectively. There were 14 perforations (4.7%) and 5 cases of postprocedure bleeding (1.7%); all complications were successfully managed endoscopically except for one of the perforations, which required emergency surgery. In the LAC group, mean tumor size was 20 mm, mean operation time was 206 minutes, and complications included 31 wound infections, 2 pelvic abscesses, 3 anastomotic leakages, and 1 anastomotic bleed. Stomas were necessary in 93 % of the patients who underwent LAC for rectal cancers located below the peritoneal reflection. CONCLUSIONS: ESD was associated with a lower complication rate than LAC, with favorable en bloc and curative resection rates. The safety profile and possibility of curative treatment with colorectal ESD provide advantages for the treatment of early colorectal cancers with nul risk of lymph node metastasis.

[Perioperative management of esophageal cancer patients with endocrine or metabolic disease].

Many esophageal cancer patients have endocrine or metabolic diseases, and surgeons should therefore learn to manage these conditions in the perioperative period. Mortality and morbidity rates are higher in patients with diabetes mellitus( DM) than patients without DM, because DM is a risk factor for conditions such as ischemic heart disease, chronic renal failure, and cerebrovascular disease. Uncontrolled hyperglycemia also increases susceptibility to infection and delays wound healing. Preoperative assessment of blood glucose control and comorbidities is important in patients with DM. Rapid-acting insulin is useful for controlling blood glucose levels in the perioperative period. In patients with thyroid disease, surgery is safest at a time when thyroid hormone levels are normalized. Patients with adrenocortical insufficiency need appropriate perioperative steroid therapy. Surgery for esophageal cancer should be undertaken when endocrine and metabolic diseases are well controlled. Strict perioperative management is required to prevent complications.

Phase II multi-institutional prospective randomised trial comparing S-1+paclitaxel with S-1+cisplatin in patients with unresectable and/or recurrent advanced gastric cancer.

BACKGROUND: A combination of S-1 and cisplatin has been shown to be effective with acceptable safety for the first-line treatment of far-advanced gastric cancer in Japan. This is the first randomised phase II trial to compare S-1+paclitaxel with S-1+cisplatin in this setting. METHODS: Patients with unresectable and/or recurrent advanced gastric cancer were randomly assigned to receive one of the two regimens: S-1 (40 mg m(-2) twice daily) on days 1-14 plus paclitaxel (60 mg m(-2)) on days 1, 8, and 15 of a 4-week cycle (S-1+paclitaxel) or S-1 (40 mg m(-2) twice daily) on days 1-21 plus cisplatin (60 mg m(-2)) on day 8 of a 5-week cycle (S-1+cisplatin). The primary end point was the response rate (RR). Secondary end points included progression-free survival (PFS), overall survival (OS), and safety. RESULTS: A total of 83 patients were eligible for safety and efficacy analyses. In the S-1+paclitaxel and S-1+cisplatin groups, RRs (52.3% vs 48.7%; P=0.74) and median PFS (9 vs 6 months; P=0.50) were similar. The median OS was similar in the S-1+paclitaxel and S-1+cisplatin groups (16 vs 17 months; P=0.84). The incidence of grade 3 or higher haematological toxicity was 19.0% with S-1+paclitaxel and 19.5% with S-1+cisplatin. The incidence of grade 3 or higher non-haematological toxicity was 14.2% with S-1+paclitaxel and 17.1% with S-1+cisplatin. CONCLUSION: S-1+paclitaxel was suggested to be a feasible and effective non-platinum-based regimen for chemotherapy in patients with advanced gastric cancer. Our results should be confirmed in multicenter, phase III-controlled clinical trials.

Effects of denervation at ileocecal junction and ileocecal resection in dogs.

BACKGROUND: To investigate neural regulation at the ileocecal junction (ICJ) and motility changes after ileocecal resection (ICR). Previous studies showed normal basal motility at the ICJ directly by force transducers in dogs, but these observations were limited to normal contractile activity. METHODS: Continuous strain gauge recordings of stomach, terminal ileum, ileocecal sphincter (ICS), and colon were performed in dogs. The dogs were divided into four groups, namely control (CONT), extrinsic denervation at ICJ (ED), intrinsic denervation at ICJ (ID), and ICR groups. Colonic activity was recorded 2 h before a meal, in the early postprandial period (first 2 h), and in the late postprandial period (4-6 h after a meal). The meal lasted 5 min. KEY RESULTS: Motility index was significantly increased at the ICS (P = 0.0056) and proximal colon (P = 0.0059) after feeding. However, such changes were not observed in the ED and ID groups. The amplitude of contractions at proximal colon in the interdigestive state was significantly decreased by ED. In the ID and ICR groups, the numbers of nonmigrating contractions were significantly decreased (P < 0.05), and colonic migrating motor complex (CMMC) ratio was significantly higher than that of the CONT group (P < 0.001). The dogs in these two groups had diarrhea. CONCLUSIONS & INFERENCES: Gastrocolonic response at the ICJ may require both intrinsic and extrinsic innervation. When ID was performed, CMMC ratio increased. As a result, intraluminal water absorption may have decreased. ID may be one of the causes of diarrhea after ICR.

E/N-cadherin switch mediates cancer progression via TGF-ß-induced epithelial-to-mesenchymal transition in extrahepatic cholangiocarcinoma.

BACKGROUND: Epithelial-to-mesenchymal transition (EMT) is a fundamental process governing not only morphogenesis in multicellular organisms, but also cancer progression. During EMT, epithelial cadherin (E-cadherin) is downregulated while neural cadherin (N-cadherin) is upregulated, referred to as 'cadherin switch'. This study aimed to investigate whether cadherin switch promotes cancer progression in cholangiocarcinoma (CC). METHODS: CC cell lines were examined for migration, invasion, and morphological changes with typical EMT-induced model using recombinant TGF-ß1. The changes in E-cadherin and N-cadherin expression were investigated during EMT. We also examined E-cadherin and N-cadherin expression in resected specimens from extrahepatic CC patients (n=38), and the associations with clinicopathological factors and survival rates. RESULTS: TGF-ß1 treatment activated cell migration, invasion, and fibroblastic morphological changes, especially in extrahepatic CC HuCCT-1 cells. These changes occurred with E-cadherin downregulation and N-cadherin upregulation, that is, cadherin switch. Patients with low E-cadherin expression had a significantly lower survival rate than patients with high E-cadherin expression (P=0.0059). Patients with decreasing E-cadherin and increasing N-cadherin expression had a significantly lower survival rate than patients with increasing E-cadherin and decreasing N-cadherin expression (P=0.017). CONCLUSION: Cadherin switch promotes cancer progression via TGF-ß-induced EMT in extrahepatic CC, suggesting a target for elucidating the mechanisms of invasion and metastasis in extrahepatic CC.

A case of exfoliative esophagitis with pemphigus vulgaris.

Autoimmune blistering skin diseases, including pemphigus vulgaris, rarely involve the esophagus. We report a case of exfoliative esophagitis with pemphigus vulgaris. A sloughing esophageal cast observed by endoscopy was dissected esophageal squamous epithelium in all layers. Our case is the fifth case of pemphigus vulgaris associated with esophageal cast formation recorded in the medical literature. Prednisolone was administered, and both the pemphigus vulgaris and exfoliative esophagitis improved. Upon findings of exfoliative esophagitis by endoscopic examination, we should consider the coexistence of blistering skin diseases, including pemphigus vulgaris.

Results of a national survey on laparoscopic bariatric surgery in Japan, 2000-2009.

INTRODUCTION: In Japan, laparoscopic bariatric surgery has not been popular until recently because morbidly obese patients were infrequently encountered previous and Japanese health insurance does not cover this type of surgery. In 2010, the Japan Research Society for Endoscopic and Laparoscopic Treatments of Obesity undertook the first nationwide survey on laparoscopic bariatric surgery to evaluate its current status and outcomes. METHODS: A mail survey was sent to the society's 64 member institutions, which included almost all institutions in Japan actively performing laparoscopic gastrointestinal surgery. RESULTS: From 2000 to 2009, 340 laparoscopic bariatric procedures, in total, were performed in nine of the 64 institutions (14%). The most popular procedure was laparoscopic Roux-en-Y gastric bypass (LRYGB, n=147), second was laparoscopic sleeve gastrectomy (LSG, n=102), and third was laparoscopic adjustable gastric banding (LAGB, n=55). However, the number of LRYGB procedures has decreased while the number of LSG procedures has rapidly increased. Total morbidity rates were 12.2% for LRYGB, 10.9% for LAGB, and 7.8% for LSG. Percent excess weight loss was 78% at 5 years after LRYGB, 52% at 4 years after LAGB, and 68% at 2 years after LSG. Although the bariatric procedures frequently resolved or improved obesity-related comorbidities, LRYGB appears to be superior to LAGB, as was previously reported. CONCLUSION: The first nationwide survey of laparoscopic bariatric surgery in Japan clearly showed the current status and outcomes of this group of procedures. The Japanese results appear to be comparable to similarly undertaken surveys in Europe and the USA.

Esophagectomy for cancer: clinical concerns support centralizing operations within the larger hospitals.

Esophagectomy needs experienced surgical techniques and a well-trained perioperative care team. There are now many reports that the mortality rate after esophagectomy is higher in those hospitals with a low volume of esophagectomy and/or low surgeon's volume. The purpose of this study is to decide the respective numbers of esophagectomy operations per year to define low-volume and high-volume hospitals in Japan. If medical policy aims to further reduce mortality and morbidity associated with esophagectomy, then esophagectomy operations should be further centralized, away from low-volume hospitals, into high-volume hospitals. The Japanese Association for Thoracic Surgery has accumulated the surgical outcomes from 31 380 esophagectomy operations, registered from 709 institutes during the period from 2001 to 2006. These institutes are here classified into six groups according to the number of esophagectomy operations per year as 4 or less, 5-9, 10-19, 20-39, 40-79, and 80 or more. Using a statistical model-selection procedure by information criteria, these six groups are then classified into three categories as low-volume, medium-volume, and as high-volume hospitals. Among the 31 380 patients registered, overall, 390 patients (1.2%) died within 30 days, and 1187 patients (3.8%) died during the primary hospital stay. The odds ratio of the greatest volume group to the minimum volume group was 0.307 for the 30-day mortality rate, and 0.288 for the in-hospital mortality rate. For both the 30-day mortality rate and the in-hospital mortality rate, a hospital with less than five esophagectomy operations per year was classified as a low-volume hospital. A hospital with 40 or more esophagectomy operations per year was classified as a high-volume hospital. Concerning the number of esophagectomy operations performed per year in Japan, low-volume hospitals are defined as those where esophagectomy is performed less than five times per year, and high-volume hospitals are defined as those where esophagectomy is performed 40 or more times per year. If medical policy in Japan aims to further decrease the mortality after esophagectomy, then esophagectomy operations should be limited in these identified low-volume hospitals.

Prognostic significance of the expression of MUC1 and collagen type IV in advanced gastric carcinoma.

BACKGROUND: Scirrhous gastric carcinoma is characterized by excessive deposition of collagen in the stroma. However, the clinical significance of this fibrosis of the stomach has not been clarified. The aim of this study was to examine the fibrotic mechanism in several histological types of gastric carcinoma, and the combination of MUC1 and collagen type IV as a possible predictor of patient survival. METHODS: One hundred and two paraffin-embedded specimens of gastric carcinoma were examined by immunohistochemical staining using monoclonal antibodies against collagen type IV and MUC1. RESULTS: Collagen type IV-positive expression was significantly associated with depth of wall penetration (P = 0.025) and stage (P = 0.023). There was a significant relationship between MUC1-positive expression and interstitial collagen type IV-positive expression (P = 0.035). Survival was shorter for patients with the combination of MUC1-positive expression and interstitial collagen type IV-negative expression than for those with other expression patterns. CONCLUSION: In patients with differentiated-type advanced gastric carcinoma, the combination of MUC1-positive and interstitial collagen type IV-negative expression may be a marker of unfavourable prognosis.

Acute gastroduodenal injury after ingestion of diluted herbicide pendimethalin.

The herbicide, pendimethalin, is used worldwide, but its acute toxicity is not yet widely known. There have been some reported acute pendimethalin poisoning cases in humans and most of them intentionally ingested the concentrated formulation. We describe a 73-year-old man who developed corrosive gastroduodenal injury after accidental ingestion of the diluted (300 times with water) pendimethalin formulation. He had a history of reflux oesophagitis and had been taking omeprazol (10 mg/day) for a year. He consumed alcohol two hours after the accidental ingestion and then had nausea and epigastric pain. Endoscopy performed three days post-exposure revealed gastroduodenal injury. As he had consumed alcohol every day for years and had no history of gastroduodenal ulcer, the accidental ingestion may be associated with this injury. He was successfully treated by increasing his dosage of omeprazol (20 mg/day) for two weeks. This case indicates that ingestion of a small quantity of pendimethalin can provoke gastroduodenal injury.

Expression of carbonic anhydrase 9, a potential intrinsic marker of hypoxia, is associated with poor prognosis in oesophageal squamous cell carcinoma.

Carbonic anhydrase 9 (CA9) is a protein to be upregulated under exposure to hypoxic conditions. Hypoxic conditions are known to be associated with resistance to chemotherapy and radiotherapy, and with poor cancer prognosis. We examined CA9 expression in surgical specimens from oesophageal squamous cell carcinoma (ESCC) patients (n=127) using immunohistochemistry and real-time RT-PCR. We also examined CA9 expression and cell proliferation in ESCC cell lines (TE-2, TE-8 and TE-15) and an immortalised human oesophageal cell line (CHEK-1) using real-time RT-PCR, Western blotting, ELISA and MTT assay. Immunohistochemistry, high expression of CA9 was found in 63 of the 127 primary tumour specimens and was correlated with poor outcome (P=0.0003) and more aggressive/less favourable clinicopathological parameters (tumour size (P=0.0235), tumour depth (P<0.0001), regional lymph node metastasis (P=0.0031), distant lymph node metastasis (P=0.0077), stage (P<0.0001) and blood vessel invasion (P=0.006)). In vitro, CA9 expression in cultured cells and culture medium was also induced by hypoxia (P<0.01). CA9 is correlated with poor prognosis and malignant phenotype in patients with ESCC, and was upregulated by hypoxia. It is suggested that control of CA9 expression might improve the effectiveness of chemotherapy and radiotherapy in ESCC.

Correlation between colonic motility and defecatory disorders after anterior resection of the rectum in canine models.

The objective of this study was to describe the correlation between changes in colonic motility and defecatory disorders in four experimental canine models, with an emphasis on denervation. Therefore, we constructed a model by dividing 20 healthy mongrel dogs into four groups, i.e. control, denervation, transection and anterior resection of the rectum (AR) (denervation plus transection), and focused on the correlation between colonic motility and defecatory disorders by counting the colonic migrating motor complexes (CMMCs) and colonic non-migrating motor complexes (CNMCs). Gastrointestinal and colonic contractile activities were continuously recorded on a computer with strain gauge force transducers. The dogs' feces were checked daily, and their consistency was recorded as normal, semisolid, or watery. Compared with the control group, the transection group showed elongation of the propagation time (P < 0.05), and the mean motility index of colonic contractile activity at C4 and C5 in the denervation group was greater than that in the control group (P < 0.05). The AR group showed three features of colonic motility: (i) elongation of the mean CMMC cycle (P < 0.05); (ii) shortening of the propagation time (P < 0.05); and (iii) increment of the number of CNMCs. Concerning fecal consistency, the AR group only showed watery diarrhoea. In conclusion, we revealed the existence of a correlation between defecatory disorders and changes in colonic motility. Increased knowledge among colorectal surgeons of the changes in colonic motility that occur following colorectal surgery is very important and could lead to the curtailment of defecatory disorders among patients.

Experimental results and early clinical experience with an easy method for intracorporeal knot tying using a novel laparoscopic needleholder.

BACKGROUND: Intracorporeal suturing and knot tying are among the most difficult procedures in laparoscopic operations. An easy and inexpensive method for intracorporeal instrumental ligation with a modified laparoscopic needle driver is presented. METHODS: The needle driver developed in this study has a novel mechanism that can fix the suturing thread in a hook at the distal site of the holder's jaw hinge. This hook projects out from the rod only when the jaw of the holder is open. After the needle is removed from the tissue using the grasper, the needle driver is placed under the grasper, which the surgeon manipulates by the left hand. Then the thread is hooked on the needle driver by withdrawal of the driver with the jaw opening. The tip of the needle driver is moved over the shaft of the grasper by keeping the thread on the hook. The thread is entwined during a series of crossing movements of the rods of the forceps. The short tail of the suture material is gripped and tied up as a first throw of ligation. The side edge of the jaw, used for thread cutting, is sharpened by grinding. RESULTS: When the angle of the forceps is set at 90 degrees in the box trainer, no difference in terms of ligation time and degree of error is observed between the hook and conventional C-loop methods. In the case of the 30 degree forceps angle, the novel method is superior to the conventional method. CONCLUSION: The novel needle driver provides an easy and inexpensive method for performing an intracorporeal ligation, particularly in a case involving a sharp axis angle of the forceps. More clinical experience is necessary for evaluation of this method, but it has potential advantages in laparoscopic operations.

Anticancer effects of gallic acid isolated from Indonesian herbal medicine, Phaleria macrocarpa (Scheff.) Boerl, on human cancer cell lines.

The natural antioxidant gallic acid (GA) was isolated from fruits of a medicinal Indonesian plant, Phaleria macrocarpa (Scheff.) Boerl. The structure was identified on the basis of spectroscopic analysis and comparison with authentic compound. GA demonstrated a significant inhibition of cell proliferation in a series of cancer cell lines and induced apoptosis in esophageal cancer cells (TE-2) but not in non-cancerous cells (CHEK-1). Observation of the molecular mechanism of apoptosis showed that GA up-regulated the pro-apoptosis protein, Bax, and induced caspase-cascade activity in cancer cells. On the other hand, GA down-regulated anti-apoptosis proteins such as Bcl-2 and Xiap. In addition, GA also induced down-regulation of the survival Akt/mTOR pathway. In non-cancerous cells, we observed delayed expression of pro-apoptosis related proteins. Our results suggest that GA might be a potential anticancer compound. However, in depth in vivo studies are needed to elucidate the exact mechanism.

The peptide hormone xenin induces gallbladder contractions in conscious dogs.

Xenin is a 25-amino acid peptide isolated from human gastric mucosa. The biological activities of xenin include modulating intestinal motility and affecting exocrine pancreatic secretion and gastric acid secretion. The physiological effect of xenin on the gastrointestinal tract, however, is incomplete. The objective of this study is to investigate the effects of xenin on the gastrointestinal tract motility of conscious dogs. Gastrointestinal tract and gallbladder contractions were monitored by chronically implanted force transducers. Synthetic xenin was injected intravenously during the interdigestive state with or without pretreatment with cholinergic blockers. The effects of xenin following cholecystectomy and truncal vagotomy were also investigated. Xenin induced gallbladder and jejunal contractions, although a dose-dependent response was shown only with gallbladder contractions. These effects were inhibited by pretreatment with cholinergic blockers, but were not enhanced by truncal vagotomy. The jejunal contractions were completely inhibited by cholecystectomy. The only direct effect of xenin in terms of gastrointestinal motility was to induce gallbladder contractions in conscious dogs. The neural pathway mediating xenin's action was cholinergic, but not the vagal. This novel finding indicates a new role of xenin.

Phase I/II study of S-1 combined with paclitaxel in patients with unresectable and/or recurrent advanced gastric cancer.

Both paclitaxel and S-1 are effective against gastric cancer, but the optimal regimen for combined chemotherapy with these drugs remains unclear. This phase I/II study was designed to determine the maximum tolerated dose (MTD), recommended dose (RD), dose-limiting toxicity (DLT), and objective response rate of paclitaxel in combination with S-1. S-1 was administered orally at a fixed dose of 80 mg m-2 day-1 from days 1 to 14 of a 28-day cycle. Paclitaxel was given intravenously on days 1, 8, and 15, starting with a dose of 40 mg m-2 day-1. The dose was increased in a stepwise manner to 70 mg m-2. Treatment was repeated every 4 weeks unless disease progression was confirmed. In the phase I portion, 17 patients were enrolled. The MTD of paclitaxel was estimated to be 70 mg m-2 because 40% of the patients given this dose level (two of five) had DLT. The RD was determined to be 60 mg m-2. In the phase II portion, 24 patients, including five with assessable disease who received the RD in the phase I portion, were evaluated. The median number of treatment courses was six (range: 1-17). The incidence of the worst-grade toxicity in patients given the RD was 28 and 8%, respectively. All toxic effects were manageable. The response rate was 54.1%, and the median survival time was 15.5 months. Our phase I/II trial showed that S-1 combined with paclitaxel is effective and well tolerated in patients with advanced gastric cancer.

Impaired blood rheology in critically ill patients in an intensive care unit.

Critically ill patients are at increased risk of thromboembolic complications. Japanese patients admitted to the intensive care unit of Gunma University Hospital were divided into critically ill (high score) and moderately ill (low score) groups according to mean Acute Physiology and Chronic Health Evaluation (APACHE) II score. White blood cell count, potassium, creatinine, immunoglobulin G and blood passage time, measured using the microchannel method, were significantly higher and the platelet aggregation score and platelet count were significantly lower in the high-score group than in the low-score group, but other haemorheological parameters did not differ significantly between the two groups. White blood cell count, potassium, creatinine, APACHE II score and levels of immunoglobulins G, A and M were positively correlated with blood passage time in all patients. Critically ill patients had impaired blood rheology, which could result from increased white blood cell count, potassium, creatinine and immunoglobulins and may be associated with the pathophysiology of the thromboembolic process.