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PURPOSE The phase III ACHIEVE trial conducted in Japan was one of six prospective studies included in the International Duration Evaluation of Adjuvant Therapy collaboration, which explored whether 3 months of adjuvant fluorouracil, leucovorin, and oxaliplatin (FOLFOX) or capecitabine and oxaliplatin (CAPOX) therapy would be noninferior to 6 months of treatment in patients with curatively resected stage III colon cancer. We report the final analyses of survival and long-term safety. PATIENTS AND METHODS Eligible patients were randomly assigned (1:1) to either 3 or 6 months of adjuvant chemotherapy (modified [m]FOLFOX6 or CAPOX, as selected by the treating physician). Random assignment was stratified according to number of involved lymph nodes, center, regimen, primary site, and age. The primary end point was disease-free survival, assessed in the modified intention-to-treat population. Overall survival (OS) was a secondary end point. RESULTS The modified intention-to-treat population comprised 1,291 patients: 641 in the 6-month treatment group and 650 in the 3-month treatment group. Median follow-up for this analysis was 74.7 months. Five-year OS rates were comparable: 87.0% in the 3-month treatment group and 86.4% in the 6-month treatment group (hazard ratio, 0.91; 95% CI, 0.69 to 1.20; P = .51). Subgroup analysis of OS did not reveal a significant interaction between baseline characteristics and treatment duration. Peripheral sensory neuropathy lasting longer than 5 years was more common in the 6- compared with 3-month treatment group (16% v 8%, respectively), and in those receiving mFOLFOX6 compared with CAPOX (14% v 11%, respectively). CONCLUSION In Asian patients, shortening adjuvant therapy duration from 6 to 3 months did not compromise efficacy and reduced the rate of long-lasting peripheral sensory neuropathy. In this setting, 3 months of CAPOX therapy is an appropriate adjuvant treatment option.

BACKGROUND Mesenchymal stem cells are expected to have a therapeutic effect on progressive neurodegenerative diseases for which there is currently no fundamental treatment. AIMS OF THE STUDY The aim is to confirm that repeated infusion of autologous adipose tissue-derived stem cells (ADSCs) can be safely administered to patients with Parkinson's disease, and to investigate the effects of this as a pilot study. METHODS Three patients with Parkinson's disease received five or six repeated infusions of ADSCs at intervals of approximately one month. Observations were based on medical examinations by a neurologist and interviews with the patient and caregivers. The severity of Parkinson's disease was assessed using the Hoehn & Yahr staging scale and Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS). RESULTS No adverse events were observed during the observation period from the start of treatment to six months after the end of the last dose. MDS-UPDRS improved in all three patients. CONCLUSIONS Repeated administration of Autologous ADSCs for Parkinson's disease was safe and feasible. The results of this pilot study provide insight into the value of further research.

Regenerative medicine is a medical treatment that aims to restore lost human body functions by regenerating missing or dysfunctional organs and tissues using stem cells, etc. There are three major types of stem cells used in regenerative medicine: induced pluripotent stem cells (iPS cells), embryonic stem cells (ES cells), and mesenchymal stem cells (MSCs). MSCs are expected to be widely applied to regenerative medicine because of their ability to differentiate into various types of cells, repair cells and tissues; anti-inflammatory effects; secretion of various growth factors; and resolution of abnormally accumulated protein amyloid. MSCs can be derived from bone marrow, dental pulp, and other sources, but adipose tissue-derived stem cells (ADSCs) may be superior in that they can be harvested with the least amount of invasion, and therefore, a sufficient amount of stem cells can be cultured relatively easily. When MSCs are administered systemically by intravenous infusion, they tend to accumulate at the site of disease, a property known as "homing," which is extremely advantageous for clinical applications. In Japan, stem cell therapy can be performed only after the research or treatment plan has been reviewed and approved by the "Committee for Specific Approval of Regenerative Medicine" and submitted to the Ministry of Health, Labor and Welfare for approval in accordance with the "Act on Securing the Safety of Regenerative Medicine" and after approval by the ethics committee of the facility where the therapy is performed. In this review, the characteristics of MSCs, the actual status of their clinical application, and their future prospects are presented.

We propose the intravenous administration of autologous adipose-derived stem cells as a new treatment for Alzheimer's disease. We hypothesize that the stem cells will secrete neprilysin in the brain to break down and remove amyloid deposits in the Alzheimer's brain. We have shown a case of skin amyloid deposition that disappeared after stem cell administration and confirmed that the stem cells administered had neprilysin activity. In addition to neprilysin secretion, other mechanisms of action of stem cells include nerve regeneration, nerve repair, growth factor secretion, anti-inflammatory effects, and angiogenesis. The harvesting of adipose-derived stem cells is minimally invasive, and intravenous administration can be safely repeated. We hope that the efficacy of this new treatment will be verified and that it will bring a ray of hope to patients suffering from this incurable disease.

In the current strategy against locally advanced and recurrent rectal cancers possibly involving intrapelvic nerves, there has been a serious dilemma between extensive surgery and limited surgery. The former can attain high tumor curability by sacrificing the nerve functions while the latter prioritizes the patient quality of life by preserving the nerve functions but with a compromised curability. Here we present a new surgical strategy for locally advanced and recurrent rectal cancers, which realize both high tumor curability and good quality of life. A new artificial nerve conduit (polyglycolic acid collagen tube) developed by in site tissue engineering technology was applied to recovery the disturbed functions after removing the nerves from 11 patients undergoing extensive surgery for intrapelvic advanced or recurrent colorectal cancers. The reconstructed nerves included eight autonomic nerves which are essential for the genitourinary function and three somatic nerves which control the sensation and mobility of the legs. Out of ten cases followed up more than 2 years and evaluated fully, eight including two report cases showed a functional recovery of the disturbed autonomic and somatic nerves clinically. The nerve function started to recover from 3 to 6 months after the operation and continued to improve with times. No specific complications associated with the nerve repair have been noted. The new strategy utilizing the nerve conduit can be a breakthrough in radical operations for locally advanced and recurrent rectal cancers to resolve the problems between tumor curability and the patient quality of life.

Objective This study aimed to evaluate in situ tissue-engineered esophagus in a canine model after experimental resection and replacement of a full circumferential defect of the intrathoracic esophagus. Methods Two types of scaffolding were fabricated. In the KF(+) group (n = 6), oral keratinocytes and fibroblasts cultured on human amniotic membrane were sheeted on polyglycolic acid felt with smooth muscle tissue and were then rolled around tubes. In the KF(−) group (n = 6), the same procedure was followed, but the keratinocytes and fibroblasts were omitted. Both scaffolds were wrapped in omentum and implanted in the abdomen. In the KF(+) group, at 3 weeks after implantation, the scaffold developed into a tube with a well-differentiated lumen of stratified squamous cells surrounded by a thick smooth muscle-like tissue (in situ tissue-engineered esophagus). A part of the esophagus was resected and replaced by the graft in the same dogs. Results In the KF(−) group, strictures developed after esophageal replacement, with almost complete obstruction within 2 to 3 weeks. In contrast, in the KF(+) group, the in situ tissue-engineered esophagus showed good distensibility and the dogs remained without feeding problems through 420 days. Esophageal peristalsis transferred food to the stomach, despite the absence of peristaltic activity in the in situ tissue-engineered esophagus itself. The thickness of the squamous epithelial layer and the smooth muscle layer of the in situ tissue-engineered esophagus were similar to that of the adjacent native esophagus. Conclusion The in situ tissue-engineered esophagus can successfully replace the intrathoracic esophagus, and this procedure may offer a promising surgical approach to esophageal diseases.

In this study, we conducted a limited survey of reports of surgical randomized controlled trials, using the consolidated standards of reporting trials (CONSORT) statement and additional check items to clarify problems in the evaluation of surgical reports.A total of 13 randomized trials were selected from two latest review articles on biliary surgery. Each randomized trial was evaluated according to 28 quality measures that comprised items from the CONSORT statement plus additional items. Analysis focused on relationships between the quality of each study and the estimated effect gap ("pooled estimate in meta-analysis" -- "estimated effect of each study").No definite relationships were found between individual study quality and the estimated effect gap. The following items could have been described but were not provided in almost all the surgical RCT reports: "clearly defined outcomes"; "details of randomization"; "participant flow charts"; "intention-to-treat analysis"; "ancillary analyses"; and "financial conflicts of interest". The item, "participation of a trial methodologist in the study" was not found in any of the reports.Although the quality of reporting trials is not always related to a biased estimation of treatment effect, the items used for quality measures must be described to enable readers to evaluate the quality and applicability of the reporting. Further development of an assessment tool is needed for items specific to surgical randomized controlled trials.

YM529, a new third generation bisphosphonate, induced apoptosis of a human breast cancer cell line, MX-1. Cytotoxic activity of YM529 was more potent than that of incadronate. YM529 activated caspase-9, but not caspase-8, and induced the release of cytochrome c into cytosol. YM529 increased Bax expression and decreased Bcl-2 expression, while it did not induce caspase-8-dependent Bid truncation. Farnesyl pyrophosphate prevented YM529-mediated cytotoxicity. These results suggest that YM529 is a potent therapeutic agent for human breast cancers, activating the mitochondria-dependent apoptotic pathway through the inhibition of protein farnesylation.

Radiotherapy is an effective treatment for some esophageal cancers, but the molecular mechanisms of radiosensitivity remain unknown. RUNX3, a novel tumor suppressor of gastric cancer, functions in transforming growth factor (TGF)-beta-dependent apoptosis. We obtained paired samples from 62 patients with advanced esophageal cancers diagnosed initially as T3 or T4 with image diagnosis; one sample was obtained from a biopsy before presurgical radiotherapy, and the other was resected in surgical specimens after radiotherapy. RUNX3 was repressed in 67.7% cases of the pretreatment biopsy samples and 96.7% cases of the irradiated, resected samples. The nuclear expression of RUNX3 was associated with radiosensitivity and a better prognosis than cytoplasmic or no RUNX3 expression (P0.003); cytoplasmic RUNX3 expression was strictly associated with radioresistance. RUNX3 was downregulated and its promoter was hypermethylated in all radioresistant esophageal cancer cell lines examined. Stable transfection of esophageal cancer cells with RUNX3 slightly inhibited cell proliferation in vitro, enhanced the antiproliferative and apoptotic effects of TGF-beta and increased radiosensitivity in conjunction with Bim induction. In contrast, transfection of RUNX3-expressing cells with a RUNX3 antisense construct or a Bim-specific small interfering RNA induced radioresistance. Treatment with 5-aza-2'-deoxycytidine restored RUNX3 expression, increased radiosensitivity and induced Bim in both control and radioresistant cells. These results suggest that RUNX3 silencing promotes radioresistance in esophageal cancers. Examination of RUNX3 expression in pretreatment specimens may predict radiosensitivity, and induction of RUNX3 expression may increase tumor radiosensitivity.

ERM (ezrin/radixin/moesin) proteins are organizers of apical actin cortical layer in general. We previously reported that the knockout of radixin resulted in Rdx − / − mice with displacement/loss of the canalicular transporter Mrp2, giving rise to Dubin–Johnson syndrome-like conjugated hyperbilirubinemia in the mixed genetic background (C57BL/6-129/Sv) (Kikuchi, et al. (2002) Nature Genetics 31, 320–325). However, when these mice were kept under mixed genetic background for years (late mixed backgrounds; LMB), the conjugated hyperbilirubinemia gradually became inconspicuous, while evidence of liver injury increased. We examined the effect of genetic background by backcrossing LMB Rdx − / − mice to C57BL/6 and 129/Sv wild type mice with the result that the Rdx − / − congenic mice regained hyperbilirubinemia with reduced hepatocellular damage. As revealed by immunofluorescence and western blots, the localization/expression of apical transporters, Mrp2, CD26, P-gps, and Bsep were not influenced by backcrossing, though those of a basolateral transporter, Mrp3, were strikingly increased by backcrossing.

症例は76歳, 男性. 検診でCA19-9高値 (486.6U/ml) を指摘されて当院を受診した. 腹部造影CT検査で腹部傍大動脈領域に8×3cmの腫瘤を認め, 上・下部消化管内視鏡・MRI・FDG-PETも行ったが, 原発巣となりうる病変を同定することはできなかった. 病理組織診断のために試験開腹を行い, 診断は高度の線維化を伴う膵外発育型膵癌であった. 7病日目に突然の腹痛・39度台の発熱とともに敗血症性ショックとなり, 腹部造影CT検査を行ったところ, 腸間膜脂肪織炎, 横行結腸壁肥厚および腸間膜静脈・門脈ガス血症を認めた. 発症後8時間で緊急開腹手術を行い, 横行結腸切除術・上行結腸人工肛門造設術を行った. 術後は急速に敗血症を離脱して, 軽快退院した. 腸間膜脂肪織炎による門脈ガス血症の報告はこれまでにないが, 早期の診断と迅速な原因の除去によって軽快することを示した.

Background The purpose of this study was to regenerate a larger size of small intestinal tissue than that of our previous study and to evaluate the regeneration of the endocrine cells (ECC) and nerve system of autologous tissue-engineered small intestine. The effect of implantation of large numbers of smooth muscle cells (SMC) for the regeneration of small intestine was also investigated. Methods Two types of scaffolds with different cell densities were fabricated: low density (LD) of SMC in the scaffold and high density (HD) of SMC in the scaffold. Both scaffolds were implanted into defects of isolated ileum in a canine model. Animals were sacrificed at 8, 12, 18, and 24 weeks. Results The area of engineered small intestine in the HD group was four times larger than that in the LD group, although that was smaller in size than the original size of the defect. There were no significant changes in the thickness of regenerated smooth muscle layer (SML) in the LD and HD groups. The numbers of endocrine cells gradually increased after implantation. At 18 weeks of regeneration, the number of ECC reached levels comparable to that of normal mucosa. The nerve fibers extended to the center of the graft area and were observed in regenerated SML and regenerated villi at 24 weeks. Conclusions The ECC and nerve fibers were regenerated in autologous in situ tissue-engineered small intestine. Seeding a large number of SMC was not sufficient for the regeneration of the small intestine in a tubular configuration.

Multiple attempts have been made to replace biliary defects with a variety of materials. Recently, successful biliary reconstruction using the Gore-Tex vascular graft has been reported experimentally and clinically We designed a new artificial bile duct consisting of collagen sponge and polypropylene mesh. We presently evaluated the feasibility of using this prosthesis as a scaffold for bile duct tissue regeneration in a canine model. Our prosthesis, a sponge made from porcine dermal collagen, is reinforced with a polypropylene mesh cylinder. We used the prosthesis to reconstruct the middle portion of the common bile duct in seven beagle dogs to evaluate its efficacy. While one dog died of biliary stricture 8 months after operation, six survived without problems to scheduled time points for tissue evaluation at 1 to 12 months. All prostheses had become completely incorporated into the host. A confluent epithelial lining was observed within 3 months. In cholangiograms the prosthesis displayed long-term patency in the six dogs and provided satisfactory bile drainage for up to 12 months. Our graft thus shows promise for repair of biliary defects and should lead to development of a new treatment for biliary reconstruction.

The first randomized controlled trial in medicine was an investigation of streptomycin in 1948.1 Since then, randomized controlled trials have been widely recognized as offering the gold standard for evaluating treatment efficacy and effectiveness and are classified as providing the highest grade of evidence in the hierarchy of research designs.2 Evaluations in the 1970s and 1980s suggested that observational studies may spuriously overestimate treatment benefits, yielding misleading conclusions.3–6 In recent years, this debate has resurfaced. Some reports have suggested that for selected medical topics, both randomized and observational studies, may yield very similar results.7,8 Conversely, opposing results have been reported from a large number of diverse medical topics.9 Although these previous studies have contained some surgical topics, most have assessed topics involving pharmacotherapies. However, pharmacologic and surgical therapies differ in clinical nature, and results for pharmacologic investigations may therefore not apply to surgical fields. This issue warrants investigation with a focus on the surgical area, and no previous studies appear to have undertaken an exhaustive assessment of a single clinical field. The present study investigated digestive surgery, allowing a systematic search and evaluation. This systematic and exhaustive search of a large number of diverse articles on digestive surgery seeks to answer the following question: Do observational studies in digestive surgery tend to produce the same results as randomized controlled trials?

Postoperative chylothorax is an uncommon but well-recognized and potentially life-threatening complication of esophagectomy for esophageal cancer. Its management remains controversial. A 71-year-old man with cancer of the thoracic esophagus was admitted to our hospital. A standard curative esophagectomy with extensive lymphadenectomy was performed. Two days after operation, chest roentgenography and computed tomography showed a massive right pleural effusion. A thoracic tube was placed in the right pleural cavity. The drainage volume of pleural effusion increased (up to 1500 ml/day), and chylothorax was diagnosed. Conservative drainage was continued for 4 days, but chyle leakage persisted. Minocycline hydrochloride 200 mg diluted in 50 ml saline was infused into the right pleural cavity through the tube to seal the leak. The patient concurrently received continuous positive-pressure ventilation (CPPV). The effusion completely resolved 30 h after beginning this combined treatment. To our knowledge, the treatment of chylothorax by CPPV plus chemical pleurodesis has not been reported previously in the English-language literature. Our method is simple, rapid, and may be a treatment option for patients with persistent chylothorax after esophagectomy that does not respond to conservative management or for patients in whom surgery is contraindicated.

In this randomized multicenter Phase III study, patients with curatively resected Stage II/IIIA gastric cancer were assigned to postoperative adjuvant therapy with an oral fluoropyrimidine S-1 alone (2 weeks of treatment and 1 week of rest for 6 months, followed by 2 weeks of treatment and 2 weeks of rest for 6 months) or S-1 combined with an oral biological response modifier PSK (the same regimen of S-1 plus daily PSK for 12 months). The main objective was to evaluate the survival benefit and quality of life (QOL) of combined therapy. The primary end points were the time to relapse and the duration of survival after surgery, i.e. the rates of disease-free survival and overall survival at 3 and 5 years. The secondary end points were the relations of survival rates to drug compliance, QOL, adverse events, postoperative complications, relapse status, and the preoperative expression of immune or tumor markers. The sample size was 140 per treatment arm.

In small intestinal malignant lymphoma (SIML), the correlation between specific chromosomal abnormalities and clinicopathological features remains unclear. The aim of this study was to determine the frequency of chromosomal translocations involving the BCL1, BCL2, c-MYC, BCL6 and MALT1 genes by using fluorescence in situ hybridization directly on paraffin-embedded tissue sections (tissue-FISH).Twenty-six cases diagnosed as having SIML between 1996 and 2003 were the subjects of the clinicopathological investigation conducted in this study. Tissue-FISH was performed with specific probes on paraffin-embedded tissue sections as described previously.The primary site was frequently located at the duodenum (9 cases, 35%). In accordance with the World Health Organization classification, 14 (53%) cases were diagnosed as having diffuse large B-cell lymphoma (DLBCL) and 6 (23%) as marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT). Macroscopically, DLBCL and MALT lymphoma displayed various macroscopic features. Cytogenetically, IGH-BCL2 translocation was detected in 3 (21%) out of 14 DLBCL cases, but in none of the MALT lymphomas. BCL6 translocation was detected in 5 (35%) of 14 DLBCL cases and in 1 (17%) of 6 MALT lymphoma cases (17%). API2-MALT1 translocation was detected in 1 (7%) of 14 DLBCL cases and in 1 (17%) of 6 MALT lymphoma cases.The duodenum was preferentially involved in SIML. DLBCL and MALT lymphoma showed various macroscopic features. Tissue-FISH analysis disclosed that DLBCL is cytogenetically heterogeneous. Furthermore, our study validated tissue-FISH as an additional promising diagnostic tool for detecting specific chromosomal translocations in NHL.

症例は80歳の女性で, 平成16年5月に軽度の下痢・腹痛・右下腹部腫瘤のために近医を受診した. 腹部CT, X線検査にて右下腹部に手拳大の腹壁浸潤を疑う嚢胞性腫瘤を認めた. 腫瘤は充実性成分を持ち, CT・MRI・FDG-PET・腫瘍マーカーなどより「虫垂癌・腹膜播種」と考えた. 手術時診断も同様であったが, 病理組織学的診断は乳頭状腺癌がclear cell carcinoma成分を持つ非常にまれな原発性腹膜嚢胞性腺癌であり, 中腎傍管 (paramesonephric duct/mullerian) 由来であると考えられた. 文献的には非常に予後の悪い癌であるが, 本症例においては外科的切除に加えてCDDP+TS-1の術後化学療法にて再発腫瘍の縮小を認め, 手術後17か月で外来通院治療中である.

Background and Objectives Local disease is the most frequent recurrence pattern of rectal carcinoma, and its prognosis is not good. One reason for the poor prognosis is the difficulty of making the diagnosis at an early stage. To detect local recurrence as early as possible, we produced the monoclonal antibody, A7-gadolinium (Mab A7-Gd), conjugate as a contrast agent for magnetic resonance imaging to distinguish between carcinoma and normal tissue. Methods We examined the in vitro immunoreactivity of Mab A7 coupled to Gd by chelate, and stability of Mab A7-EDTA-Gd in human serum. Its in vivo distribution in nude mice with human colorectal carcinoma was also examined. Results Mab A7-Gd retained binding activities that were nearly identical to intact Mab A7. Mab A7-Gd was stable in human serum. More radiolabeled Mab A7-Gd accumulated in the tumor than normal mouse IgG-Gd. Both Mab A7-Gd and normal mouse IgG-Gd disappeared from blood linearly over time. Accumulation levels in normal tissues decreased linearly over time but were lower than those in tumors. Conclusions Mab A7 conjugated to gadolinium selectively accumulated in the tumor. Our results suggest that it is potentially suitable as a contrast agent for MR imaging to detect local rectal carcinoma recurrence. J. Surg. Oncol. 2006;94:144–148. © 2006 Wiley-Liss, Inc.

Background: Local recurrence, the most frequent pattern of recurrence of rectal carcinoma, is almost always fatal. The difficulty of diagnosing local recurrence contributes importantly to the poor prognosis. Methods: We coupled monoclonal antibody (Mab) A7, which reacts specifically with human colorectal carcinoma, to ferromagnetic lignosite (FML) particles to distinguish rectal carcinoma from other tissues by magnetic resonance (MR) imaging. We examined retention of immunoreactivity by the A7-FML complexes in vitro, and also their distribution in vivo according to radiolabeling and MR imaging when injected into nude mice bearing human colorectal carcinoma xenografts. Results: A7-FML retained binding activity nearly identical to that of Mab A7. Significantly more 125I-labeled A7-FML accumulated in engrafted tumors than did 125I-labeled normal mouse IgG-FML complexes (P

A series of molecular pathological investigations of the molecules that stimulate the cyclin dependent kinases (CDK1, 2, 4, and 6) have led to enormous accumulation of knowledge of the clinical significance of these molecules for cancer diagnosis. However, the molecules have yet to be applied to clinical cancer diagnosis, as there is no available technology for application of the knowledge in a clinical setting. We hypothesized that the direct measurement of CDK activities and expressions (CDK profiling) might produce clinically relevant values for the diagnosis. This study investigated the clinical relevance of CDK profiling in gastrointestinal carcinoma tissues by using originally developed expression and activity analysis methods. We have established novel methods and an apparatus for analyzing the expression and activities of the CDK molecules in lysate of tumor tissue in a clinical setting, and examined 30 surgically dissected gastrointestinal carcinomas and corresponding normal mucosal specimens. We demonstrate here that remarkably elevated CDK2 activity is evident in more than 70% of carcinoma tissues. Moreover, a G1-CDK activity profiling accurately mirrored the differences in proliferation between tumor and normal colonic tissues. Our results suggest that CDK profiling is a potent molecular–clinical approach to complement the conventional pathological diagnosis, and to further assist in the individualized medications.

Dynamic contrast-enhanced magnetic resonance imaging (CE-MRI) has emerged as a promising diagnostic modality in various breast cancer treatments. However, little is known about the correlation between the pattern of time to signal intensity curves (TIC) on the CE-MRI and clinicopathologic features. This study was designed to investigate these correlations and evaluate the predictive value of TIC on CE-MRI in order to identify high-risk patients.Between 2001 and 2003, 101 lesions were evaluated to detect malignancy on CE-MRI in 101 women who were suspected of having breast tumors based on either clinical findings or conventional imaging studies. Moreover, the clinicopathologic findings were compared with the pattern of TIC for the 69 surgically treated malignant lesions.In detecting malignancy, the sensitivity, specificity, and accuracy were 78.7%, 88.5%, and 81.2%, respectively, in the 101 breast lesions. Especially for the 69 surgically treated malignant lesions, in comparison with breast cancer tumors with the benign pattern of TIC, the breast cancer tumors with a malignant pattern were found more frequently in lymphatic invasion (P0.01) and lymph node metastasis (P0.005), although no statistical correlation regarding the histological type, tumor size, vascular invasion, extensive intraductal component, hormone receptor status, or pathological stage was noted between the two groups. According to a logistic regression model, lymph node metastasis was found to be a significant independent variable.The pattern of TIC could be used to predict lymphatic spreading associated with lymph node metastasis prior to surgery as well as to detect malignancy. Therefore, a more detailed evaluation should be made to identify the presence of lymphatic spreading in patients with a malignant pattern of TIC.

Superparamagnetic iron oxide (SPIO)-based colloid has been used clinically as a tissue-specific magnetic resonance contrast agent. We coupled monoclonal antibody A7 (Mab A7), which reacts specifically with human colorectal carcinoma, to Ferumoxides (SPIO) and examined the accumulation of this conjugate in xenografted tumours in nude mice. We examined in vitro immunoreactivity of Mab A7 coupled to Ferumoxides and its in vivo distribution in nude mice with human colorectal carcinoma. Magnetic resonance imaging of tumour-bearing nude mice was performed 72 h after injection of A7-Ferumoxides. A7-Ferumoxides retained binding activities that were nearly identical to intact Mab A7. More of the radiolabelled A7-Ferumoxides accumulated in the tumour than normal mouse IgG-Ferumoxides from 12 h onwards after injection (P

While agents targeting estrogen receptors are most effective in adjuvant therapy for human breast cancers expressing estrogen receptors after surgery, breast cancers lacking estrogen receptor are clinically serious, because they are highly malignant and exhibit resistance to the usual anti-cancer drugs, including estrogen receptor-antagonists and DNA breaking agents. Here, we found that MX-1, a human breast cancer cell line lacking estrogen receptors, exhibited higher AP-1 activity and expressed higher levels of c-Jun, c-Fos, and Fra-1 when compared with conventional estrogen receptor-positive human breast cancer cell lines. The prenylphenol antibiotic ascochlorin suppressed the AP-1 activity of MX-1 cells, and selectively killed MX-1 cells, partly due to induction of apoptosis. Our results suggest that AP-1 is an effective clinical target molecule for the treatment of estrogen receptor-negative human breast cancer.

Our previous studies suggest that a lack of RUNX3 function is causally related to the genesis and progression of human gastric cancer. This study was conducted to determine whether alteration of RUNX3 gene expression could be detected in the normal-looking gastric remnant mucosa, and to ascertain any difference in the potential of gastric carcinogenesis between the anastomotic site and other areas in the remnant stomach after distal gastrectomy for peptic ulcer (RB group) or gastric cancer (RM group), by analysing RUNX3 expression with special reference to topography. A total of 89 patients underwent distal gastrectomy for gastric cancer from the intact stomach (GCI group) and 58 patients underwent resection of the remnant stomach for gastric cancer (RB group: 34 cases, RM group: 24 cases). We detected RUNX3 and gene promoter methylation by in situ hybridisation, quantitative reverse transcriptase–polymerase chain reaction (RT–PCR), and methylation-specific PCR. The interval between the initial surgery and surgery for remnant gastric cancer (interval time) was 10.4 years in the RM group, and 27.5 years in the RB group. Cancers in the RB group were significantly more predominant in the anastomosis area (P

今回, 我々は先天性無フィブリノゲン (以下, Fbgと略記) 血症患者に対し, Fbg製剤補充下に回盲部切除術を施行し, 良好な経過を得たので報告する. 症例は36歳の男性で, 主訴は右下腹部痛. 以前より先天性無Fbg 血症と診断されていた. 急性虫垂炎による限局性腹膜炎と診断し手術を行った. 入院時の血漿Fbg値は50mg/dl (基準値200～400mg/dl) であった. 手術直前にFbg製剤10gを静注し, 執刀直前の血漿Fbg 値は198mg/dlであった. 開腹所見より憩室炎と診断し, 回盲部切除術を施行した. 術中出血傾向は認めなかった. 術後もFbg製剤を血漿Fbg値を目安に静注投与し, 血漿Fbg値は術後8日目まで100～199mg/dlで推移した. 術後は特に合併症なく経過した. 本症例においてはFbg製剤補充療法が有用と考えられた. また, 血漿Fbg値は100mg/dl以上に維持することが望ましいと考えられた.

Background and Objectives The incidence of gastric cancer, in people over 70 years of age, has increased remarkably. Aggressive lymphadenectomy with gastrectomy has been reported to improve survival in patients with gastric cancer. Because complication rates following gastrectomy increase with advancing age, we sought to determine whether this procedure was merited in elderly patients with gastric cancer. Methods We performed a retrospective analysis of 202 patients who underwent total gastrectomy with extended lymphadenectomy for gastric carcinoma. Postoperative complication rates were compared between patients over and under 70 years of age. Results The 10-year survival rates of patients under and over 70 years of age following total gastrectomy with extended lymphadenectomy were not significantly different. Although medical comorbidities in each group were similar, pulmonary dysfunction was significantly more common following total gastrectomy in patients over 70 years than in patients under 70 years. Moreover, logistic regression analysis revealed that patient's age was the only variable that independently correlated with the presence of postoperative complications. Conclusions The prognosis of the gastric cancer patients over 70 years of age was similar to that of younger patients after total gastrectomy with extensive lymphadenectomy. However, pulmonary dysfunction was significantly more common in patients over 70 years old. J. Surg. Oncol. 2005;91:232–236. © 2005 Wiley-Liss, Inc.

今回, 我々は肺癌術後に腸重積で発症した多形癌の小腸転移の1例を経験したので報告する. 症例は75歳の男性で, 2003年4月上旬に肺癌に対して胸腔鏡下左上葉切除術を受けた. 病理組織学的には新WHO分類の扁平上皮癌の関連組織型であるpleomorphic carcinoma (多形癌) の診断を得た. 術後3か月から貧血が出現し, 腹部X線検査で鏡面像を認め腸閉塞と診断した. イレウス管からの小腸造影でTreitz 靭帯から50cmの空腸に狭窄部を認め, CTで層状の腹腔内腫瘤を認めた. 以上から, 肺癌の小腸転移による腸重積を疑い, 開腹術を施行した. 開腹するとTreitz靭帯より50cmに重積を起こした空腸を認め小児手拳大の腫瘤を形成していたため, 小腸部分切除術を施行した. 病理組織学的には肺癌の小腸転移であった. 術後16か月を経過した現在, 再発は認められていない.

全内臓逆位を伴った巨大腹腔内遊離体の1例を経験したので,文献的考察を加えて報告した.症例は75歳,全内臓逆位を伴った男性で, 2002年10月に肝S5に径15mmの肝細胞癌を指摘され,ラジオ波焼灼療法 (radio-frequency ablation; RFA) 目的にて入院中,頻尿を主訴に当院泌尿器科を受診.精査にて膀胱を圧迫する後腹膜腫瘍を認めた. 2003年1月,再入院し摘出術を施行した.病理組織検査では腹腔内遊離体の診断を得た.術後経過は良好で10日目に退院,現在外来通院中である.本症例のような全内臓逆位を伴った腹腔内遊離体の本邦での報告例は,われわれが調べた限りではなかった.

Peritoneal dissemination is the most common mode of metastasis in gastric cancer. We previously reported the importance of milky spots (MS), peritoneal lymphoid tissues, as selective sites of cancer implantation in peritoneal dissemination. In the present study, we first demonstrated that intraperitoneal injection of adenovirus vector encoding the GFP gene into tumor-free nude mice resulted in GFP expression at omental and mesenteric MS; MS macrophages were target cells for adenovirus infection. We confirmed that intraperitoneal injection of adenovirus vector encoding the NK4 gene (AdNK4) resulted in NK4 production localized to the peritoneal cavity, especially the omentum. Adenovirus vector-mediated MS-selective transgene expression was markedly impaired in tumor-bearing mice whose MS had already been replaced by infiltrating cancer cells. However, prior injection of AdNK4 successfully inhibited MS-selective cancer cell implantation, resulting in suppression of peritoneal dissemination and prolongation of survival. Adenovirus vector-mediated MS-selective delivery of a therapeutic gene may prevent peritoneal dissemination of gastric cancer.

Background Postoperative survival in patients with scirrhous gastric carcinoma is poorer than that in patients with other gastric carcinomas. Methods We retrospectively examined outcome in patients with scirrhous gastric carcinoma who underwent gastrectomy to determine how to increase postoperative survival. Postoperative survival in patients with scirrhous gastric carcinoma was compared with that in patients having other gastric cancers overall and by disease stage. Prognostic factors were examined for all patients including those with stage III disease. Results By multivariate analysis, disease stage, patient age, and scirrhous carcinoma were significant prognostic factors. Five-year survival in patients with stage III scirrhous carcinoma was significantly worse than those with other stage III gastric carcinomas. Extent of lymphadenectomy was one of the variables influencing survival in patients with stage III scirrhous carcinoma. Conclusions Gastrectomy with extended lymphadenectomy should be performed to maximize survival in patients with stage III scirrhous gastric carcinoma.

It is difficult to predict recurrence in patients who undergo curative gastrectomy for gastric carcinoma. If the timing and site of recurrence can be predicted, it becomes easier to detect recurrent disease. Records of 290 patients who died of tumor recurrence after curative gastrectomy for gastric carcinoma were retrospectively analyzed to determine whether the depth of carcinoma invasion is independently correlated with the time to death due to tumor recurrence. Additionally, the relation between the pattern of recurrence and the depth of invasion of the gastric wall was examined. Postoperative survival in patients with tumors with deep invasion was shorter than that of patients with tumors with shallow invasion. Depth of invasion was a predictor of survival on multivariate analysis. When carcinoma invaded into deeper layers, the incidence of peritoneal metastasis and local recurrence rose and that of hematogenous metastasis fell. In conclusion, the timing of death and the site of recurrence after gastrectomy for gastric carcinoma might be predicted by the depth of invasion of the gastric wall.

Radiation therapy is a powerful tool for the treatment of oesophageal cancer. We established radioresistant cell lines by applying fractionated irradiation in order to identify differentially expressed genes between parent and radioresistant cells. Six oesophageal cancer cell lines (TE-2, TE-5, TE-9, TE-13, KYSE170, and KYSE180) were treated with continuous 2 Gy fractionated irradiation (total dose 60 Gy). We compared expression profiles of each parent and radioresistant lines on a cDNA microarray consisting of 21168 genes. In the fractionated irradiation trial, four radioresistant sublines (TE-2R, TE-9R, TE-13R, KYSE170R) were established successfully, and we identified 19 upregulated and 28 downregulated genes common to radioresistant sublines. Upregulated genes were associated with apoptosis and inflammatory response (BIRC2 and COX-2), DNA metabolism (CD73), and cell growth (PLAU). Downregulated genes were associated with apoptosis (CASP6), cell adhesion (CDH1 and CDH3), transcription (MLL3), and cell cycle (CDK6). Some of these genes were known to be associated with radiation response, such as COX-2, but others were novel. Reverse transcription-polymerase chain reaction confirmed that genes selected by cDNA microarray were overexpressed in clinical specimens of radioresistant cases. Global gene analysis of radioresistant sublines may provide new insight into mechanisms of radioresistance and effective radiation therapy.

En-bloc resection for cancer has been a standard procedure based on the concept that there may be a small number of "invisible" cancer cells around the primary tumor and metastatic lymph nodes. However, there are few histopathologic studies of this issue.Perinodal involvement of cancer cells, defined as existence of cancer cells in the attached fatty tissue around the dissected lymph nodes, was assessed in 123 node-positive and 15 node-negative gastric cancers by both hematoxylin-eosin staining and immunohistochemistry.Perinodal involvement was found in 79 (57%) of the 138 patients. The incidence was higher in patients with tumors invading the deeper layer, the macroscopic diffuse type, the presence of lymphatic or vascular invasion (P.05), and advanced disease (stage I, 17%; II, 62%; III, 67%; IV, 80%). Survival of patients with perinodal involvement was less than that of patients without perinodal involvement (46% vs 87%; P.005). Perinodal involvement was found, by multivariate analyses, to be a significant prognostic factor.Perinodal cancer cells are observed frequently in gastric cancers with lymph node metastases, and the involvement appears to be a reliable prognostic factor for gastric cancers.

We previously performed a global analysis of the gene expression of gastric cancer cell lines established from metastases to the peritoneal cavity with the cDNA microarray method, which made it possible to analyse the expression of approximately 21168 genes for the identification of novel markers for the detection of micrometastases in the peritoneal cavity. One of the upregulated genes is dopa decarboxylase (DDC), which is responsible for the synthesis of the key neurotransmitters dopamine and serotonine. We have examined its potential as a novel marker for the detection of peritoneal micrometastases of gastric cancer.DDC mRNA in the peritoneal wash from 112 gastric cancer patients was quantified for comparison of carcinoembryonic antigen (CEA) mRNA by means of real-time reverse transcriptase-polymerase chain reaction (RT-PCR) with a fluorescently labelled probe to predict peritoneal recurrence. The quantity of DDC and CEA correlated with wall penetration. Real-time RT-PCR could quantitate 10-10(6) DDC-expressing gastric cancer cells per 10(7) mesothelial cells. The cutoff value was set at the upper limit of the quantitative value for noncancer patients, and those above this cutoff value constituted the micrometastasis (MM+) group. Of 15 cases with peritoneal dissemination, 13 were MM+DDC (87% sensitivity), and one of 48 t1 cases was MM+ (98% specificity). DDC levels in peritoneal washes from patients with synchronous peritoneal metastases were more than 50 times higher than in those from patients without metastasis (P

症例は56歳,女性.主訴は右側腹部腫瘤.平成9年7月3日胃癌(占拠部位AM)に対し,胃全摘・脾合併切除術, D2郭清, Roux-Y再建術を施行された.病理組織所見は, signet ring cell carcinoma, m, (broad), ly0, v0, aw (-), ow (-), n0, P0, H0, M0, stage Iaであった.その後,再発なく内科外来通院中であった.平成14年8月頃より右側腹部の腫瘤を自覚するも放置していた.その後増大傾向がみられたため,平成14年9月19日に当科を受診した.摘出生検の結果,胃癌の皮膚転移と診断された.早期胃癌の中でも深達度m癌の根治術後に緩徐な経過をたどり,他臓器転移なく複数個の皮膚転移のみをきたした極めて稀な症例であると考えられた.

To treat established melanoma in mice, intratumoral transfer of bleomycin and/or an interleukin (IL)-12 expression vector was performed by means of electroporation. Although either bleomycin alone or the IL12 gene alone significantly suppressed the subcutaneous tumors, the combination therapy drastically improved the therapeutic outcome. Three of eight mice (37.5%) that received both bleomycin and the IL12 gene showed complete remission of the preestablished tumors and rejected subsequent rechallenge with the tumor cells. We also examined whether electrochemo-gene therapy for subcutaneous tumor mass induced suppression of pulmonary metastasis that had been established by intravenous inoculation of the melanoma cells. Although metastatic foci were significantly reduced in number in groups that were given IL12 gene alone or bleomycin plus IL12 gene, it was only the combination therapy that significantly prolonged the mean survival period of the tumor-bearing animals. Natural killer (NK) and cytotoxic T lymphocyte cytolytic activities were markedly enhanced in the mice that received the chemo-gene therapy, while IL12 gene therapy alone partially elevated the NK cytotoxicity. The present study suggests that the electroporation-mediated delivery of the IL12 gene and bleomycin synergistically elicits innate and adaptive anti-melanoma immune responses, resulting in marked suppression of the treated tumors as well as bystander metastatic lesions.

Background One of the reasons for the poor prognosis of pancreatic carcinoma is the difficulty of obtaining an early diagnosis of pancreatic carcinoma. One possibility is the application of radioimmunoscintigraphy using radiolabeled monoclonal antibodies (Mabs). Methods We labeled chimeric (human/mouse) Fab fragments of Mab A7 (chA7Fab) with 99mTc and examined the distribution of 99mTc-labeled chA7Fab in nude mice bearing human pancreatic carcinoma. Results The tumor accumulation of 99mTc-labeled chA7Fab was larger than that of 99mTc-labeled A7 from 2 to 6 hr after injection. 99mTc-labeled chA7Fab disappeared from blood more rapidly than 99mTc-labeled A7. For all resected normal tissues except kidney, the accumulation of 99mTc-labeled chA7Fab was low and similar to that of 99mTc-labeled A7. Conclusions Because the half-life of 99mTc is short (6 hr), chA7Fab, which accumulates rapidly in tumors, may be a better carrier of 99mTc than intact Mab A7. J. Surg. Oncol. 2003;84:160–165. © 2003 Wiley-Liss, Inc.

IL-21 supports proliferation of mature T and B cells and facilitates expansion and maturation of natural killer (NK) cells in synergy with IL-15. However, the biological implications of IL-21 in vivo have not been fully elucidated. IL-21 and IL-15 expression plasmids were intravenously injected under high pressure into the tail veins of mice, which were subsequently challenged by an intravenous injection of RLmale1 lymphoma cells. The IL15 gene transfection significantly reduced the numbers of metastatic tumor foci in the liver. In contrast, when IL21 and IL15 genes were cotransfected, complete regression was achieved in 80% of the mice. The cytokine gene therapy was also performed in mice that had been intravenously inoculated with the tumor cells. Forty percent of mice that received a single injection of a mixture of cytokine genes successfully rejected the preestablished metastatic lymphoma and showed tumor-free survival for more than 300 days. IL-21 significantly elevated the cytotoxic T lymphocyte activity in the spleens of tumor-inoculated mice, while the two cytokines augmented NK killing activity in a synergistic manner. These results strongly suggest that the codelivery of IL-21 and IL-15 elicits powerful antitumor immune responses, resulting in marked therapeutic efficacy against metastatic tumors.

A new drug delivery formulation, biodegradable glycolic acid-lactic acid copolymer (PGLA) microspheres incorporating cisplatin (CDDP-MS) has been developed for the treatment of peritoneal carcinomatosis. Scanning electron microscopy showed that CDDP-MS has a smooth surface and few cisplatin crystals in the hollow. An electron probe micro analyzer revealed that cisplatin was located mainly in the matrix in the state of a molecule. Release profile in vitro of CDDP from microspheres showed that the initial burst was 21.2% and the remaining CDDP was released slowly thenceforth over 14 days. Hydrolysis of CDDP-MS progresses very slowly during the 14 days, but there was no morphological change in the SEM views. The dimethylformamide content entrapped within CDDP-MS, determined by a gas chromatography, was 136 ppm at the evaporation temperature of 47 degrees C. The 50% lethal dose value of CDDP-MS, calculated by the Litchfield-Wilcoxon method, was reduced to 57% of the cisplatin solution. Therapeutic experiment on mice with peritoneal carcinomatosis showed that CDDP-MS did not enhance therapeutic effect as compared with the same dose dosage of a cisplatin aqueous solution but large quantities of cisplatin could be given in case of CDDP-MS owing to less toxicity.

Biodegradability of new types of polyglycolic acid (PGA)-collagen composite tubes for nerve regeneration was evaluated in the peritoneal cavity. Hollow PGA mesh tubes were coated with atelocollagen solution, dried at room temperature, and then subjected to dehydrothermal treatment (hollow composite tubes). Hollow composite tubes filled with collagen sponge were also investigated in this study (sponge tubes). Tubes were fixed at the parietal peritoneum of BALB/c mice, and excised 0.5, 1, 2 and 3 months after the insertion. The inner areas of the excised tubes were measured microscopically. The rate of remained inner areas were calculated and analyzed statistically by one-way ANOVA and Fisher's PLSD test. 1 month after the insertion, the inner areas of the sponge tubes were well maintained, though they were not maintained in the hollow composite tubes. The rate of remained inner areas of the sponge tubes was significantly larger than that of the hollow composite tubes until 2 months after insertion. These results suggest that sponge tubes are more suitable than hollow composite tubes for nerve regeneration in the peritoneal cavity.

膵頭十二指腸切除術後の膵空腸吻合縫合不全,膵液瘻は今日においても治療に難渋する合併症である.今回,われわれは膵頭十二指腸切除術後の難治性膵液瘻に対して非観血的に内瘻化し,良好な結果を得たので報告する.症例は71歳の男性.下部胆管癌の診断で膵頭十二指腸切除術を施行.膵管チューブ抜去後に,膵空腸吻合部ドレーン孔より膵液瘻を生じたが,自然治癒し退院した.退院後1週間目に膵液瘻が再燃し,再入院となった.瘻孔より膵管と対側腸管内にカニュレーションできたことより,局所麻酔下に瘻孔を通してendoprosthesisを両者間に橋渡しする形で留置し内瘻化した.難治性膵液瘻の治療として,非観血的内瘻術は低侵襲で非常に有効な治療法であると考えられた.

Background/Aims: Gain-of-function mutations in exons 9, 11 and 13 of the c-kit gene in gastrointestinal stromal tumors (GISTs) have been identified, and it has been reported that the prognosis is worse for patients with mutation-positive GISTs than for those with mutation-negative GISTs. We studied c-kit mutations in gastrointestinal mesenchymal tumors. By chance, the c-kit mutation in exon 11 was found in myogenic and neurogenic tumors as well as in GISTs. Furthermore, we studied the clinical prognostic utility of these mutations. Methods: Ten gastrointestinal mesenchymal tumors were stained with HE and immunohistochemically analyzed with α-smooth muscle actin, S-100 protein, CD34 and c-kit. In these tumors, as well as in 11 cases of leiomyomas, PCR-amplified DNA from the juxtamembrane (JM) domain of exon 11, the extracellular domain of exon 9 and the tyrosine kinase domain 1 of exon 13 showed a high frequency of c-kit mutation and was sequenced. Results: Although c-kit mutations have previously been reported only in GISTs, we found c-kit mutations in the JM domain of exon 11 in one myogenic and one neurogenic tumor as well as in two GISTs. No c-kit mutation was seen in the 11 cases of leiomyomas. In addition, all four cases with c-kit mutation in exon 11 suffered a relapse sooner than the other cases without c-kit mutations. Conclusion: Clinically, the prognosis was worse for the patients with mutation-positive gastrointestinal mesenchymal tumors than for those with mutation-negative tumors. We therefore conclude that the gain-of-function mutation in exon 11 of the c-kit gene is an important prognostic factor for gastrointestinal mesenchymal tumors, including myogenic and neurogenic tumors as well as GISTs.

A 49-year-old man was admitted to Hospital of Kyoto Prefectural University of Medicine complaining of epigastralgia and jaundice. There was a tumor (approximately 30 mm) in the pancreatic head on ultrasound, computed tomography and magnetic resonance imaging. Endoscopic retrograde cholangiopancreatography revealed a stenosis of the main pancreatic duct in the head of the pancreas. Pancreatoscopy with the peroral electronic pancreatoscope (PEPS) was performed to differentiate between pseudotumorous pancreatitis (PTP) and pancreatic carcinoma. The PEPS showed non-erosive erythematous mucosa around the stenosis and this unique finding was different from that of pancreatic carcinoma. Pylorus-preserving pancreatoduodenectomy was performed under the possible diagnosis of carcinoma. As a result, the diagnosis of PTP was confirmed histopathologically. At present, the diagnosis of PTP is difficult because of similar findings with carcinoma in various imaging procedures. However, we consider that detailed observation and accurate morphologic assessment of the main pancreatic duct with the PEPS has the possibility of differentiating PTP from pancreatic carcinoma.

Advanced gastric cancer is often accompanied by metastasis to the peritoneum, resulting in a high mortality rate. Mechanisms involved in gastric cancer metastasis have not been fully clarified because metastasis involves multiple steps and requires a combination of altered expressions of many different genes. Thus, independent analysis of any single gene would be insufficient to understand all of the aspects of gastric cancer peritoneal dissemination. In this study, we performed a global analysis of the differential gene expression of a gastric cancer cell line established from a primary main tumour (SNU-1) and of other cell lines established from the metastasis to the peritoneal cavity (SNU-5, SNU-16, SNU-620, KATO-III and GT3TKB). The application of a high-density cDNA microarray method made it possible to analyse the expression of approximately 21 168 genes. Our examinations of SNU-5, SNU-16, SNU-620, KATO-III and GT3TKB showed that 24 genes were up-regulated and 17 genes down-regulated besides expression sequence tags. The analysis revealed the following altered expression such as: (a) up-regulation of CD44 (cell adhesion), keratins 7, 8, and 14 (epitherial marker), aldehyde dehydrogenase (drug metabolism), CD9 and IP3 receptor type3 (signal transduction); (b) down-regulation of IL2 receptor γ, IL4-Stat (immune response), p27 (cell cycle) and integrin β4 (adhesion) in gastric cancer cells from malignant ascites. We then analysed eight gastric cancer cell lines with Northern blot and observed preferential up-regulation and down-regulation of these selected genes in cells prone to peritoneal dissemination. Reverse transcriptase–polymerase chain reaction confirmed that several genes selected by DNA microarray were also overexpressed in clinical samples of malignant ascites. It is therefore considered that these genes may be related to the peritoneal dissemination of gastric cancers. The results of this global gene expression analysis of gastric cancer cells with peritoneal dissemination, promise to provide a new insight into the study of human gastric cancer peritoneal dissemination. British Journal of Cancer (2002) 87, 1153–1161. doi:10.1038/sj.bjc.6600580 www.bjcancer.com © 2002 Cancer Research UK

The ezrin-radixin-moesin (ERM) family of proteins crosslink actin filaments and integral membrane proteins. Radixin (encoded by Rdx) is the dominant ERM protein in the liver of wildtype mice and is concentrated at bile canalicular membranes (BCMs). Here we show that Rdx(-/-) mice are normal at birth, but their serum concentrations of conjugated bilirubin begin to increase gradually around 4 weeks, and they show mild liver injury after 8 weeks. This phenotype is similar to human conjugated hyperbilirubinemia in Dubin-Johnson syndrome, which is caused by mutations in the multidrug resistance protein 2 (MRP2, gene symbol ABCC2), although this syndrome is not associated with overt liver injury. In wildtype mice, Mrp2 concentrates at BCMs to secrete conjugated bilirubin into bile. In the BCMs of Rdx(-/-) mice, Mrp2 is decreased compared with other BCM proteins such as dipeptidyl peptidase IV (CD26) and P-glycoproteins. In vitro binding studies show that radixin associates directly with the carboxy-terminal cytoplasmic domain of human MRP2. These findings indicate that radixin is required for secretion of conjugated bilirubin through its support of Mrp2 localization at BCMs.