Explore the vast range of titles available.

Survivin has multiple functions including cytoprotection, inhibition of cell death, and cell‐cycle regulation, especially at the mitotic process stage, all of which favor cancer survival. Many studies on clinical specimens have shown that survivin expression is invariably up‐regulated in human cancers and is associated with resistance to chemotherapy or radiation therapy, and linked to poor prognosis, suggesting that cancer cells survive with survivin. It is also reported that survivin inhibition, alone or in combination with the other therapies, induces or enhances apoptosis and mitotic catastrophe in tumor cells. Moreover, certain antitumor agents can reduce survivin expression. These findings suggest that survivin may be a promising molecular target against human malignancies. (Cancer Sci 2008; 99: 1709–1714)

This article discusses current obstacles to the rapid development of safe and effective treatments for rare cancers, and considers measures required to overcome these challenges. In order to develop novel clinical options for rare cancers, which tend to remain left out of novel therapeutic development because of their paucity, efficient recruitment of eligible patients, who tend to be widely dispersed across the country and treated at different centers, is necessary. For this purpose, it is important to establish rare cancer registries that are linked with clinical studies, to organize a central pathological diagnosis system and biobanks for rare cancers, and to consolidate patients with rare cancers to facilities that can conduct clinical studies meeting international standards. Establishing an all‐Japan cooperative network is essential. Clinical studies of rare cancers have considerable limitations in study design and sample size as a result of paucity of eligible patients and, as a result, the level of confirmation of the efficacy and safety shown by the studies is relatively low. Therefore, measures to alleviate these weaknesses inherent to external conditions need to be explored. It is also important to reform the current research environment in order to develop world‐leading treatment for rare cancers, including promotion of basic research, collaboration between industry and academia, and improvement of the infrastructure for clinical studies. Collaboration among a wide range of stakeholders is required to promote the clinical development of treatment for rare cancers under a nationwide consensus. This article discusses current obstacles to the rapid development of safe and effective treatments for rare cancers, and considers measures required to overcome these challenges.

Background There are currently no accurate serum markers for detecting early risk of colorectal cancer (CRC). We therefore developed a non-targeted metabolomics technology to analyse the serum of pre-treatment CRC patients in order to discover putative metabolic markers associated with CRC. Using tandem-mass spectrometry (MS/MS) high throughput MS technology we evaluated the utility of selected markers and this technology for discriminating between CRC and healthy subjects. Methods Biomarker discovery was performed using Fourier transform ion cyclotron resonance mass spectrometry (FTICR-MS). Comprehensive metabolic profiles of CRC patients and controls from three independent populations from different continents (USA and Japan; total n = 222) were obtained and the best inter-study biomarkers determined. The structural characterization of these and related markers was performed using liquid chromatography (LC) MS/MS and nuclear magnetic resonance technologies. Clinical utility evaluations were performed using a targeted high-throughput triple-quadrupole multiple reaction monitoring (TQ-MRM) method for three biomarkers in two further independent populations from the USA and Japan (total n = 220). Results Comprehensive metabolomic analyses revealed significantly reduced levels of 28-36 carbon-containing hydroxylated polyunsaturated ultra long-chain fatty-acids in all three independent cohorts of CRC patient samples relative to controls. Structure elucidation studies on the C28 molecules revealed two families harbouring specifically two or three hydroxyl substitutions and varying degrees of unsaturation. The TQ-MRM method successfully validated the FTICR-MS results in two further independent studies. In total, biomarkers in five independent populations across two continental regions were evaluated (three populations by FTICR-MS and two by TQ-MRM). The resultant receiver-operator characteristic curve AUCs ranged from 0.85 to 0.98 (average = 0.91 ± 0.04). Conclusions A novel comprehensive metabolomics technology was used to identify a systemic metabolic dysregulation comprising previously unknown hydroxylated polyunsaturated ultra-long chain fatty acid metabolites in CRC patients. These metabolites are easily measurable in serum and a decrease in their concentration appears to be highly sensitive and specific for the presence of CRC, regardless of ethnic or geographic background. The measurement of these metabolites may represent an additional tool for the early detection and screening of CRC.

Background The prognosis of pancreatic cancer (PC) is one of the poorest among all cancers, due largely to the lack of methods for screening and early detection. New biomarkers for identifying high-risk or early-stage subjects could significantly impact PC mortality. The goal of this study was to find metabolic biomarkers associated with PC by using a comprehensive metabolomics technology to compare serum profiles of PC patients to healthy control subjects. Methods A non-targeted metabolomics approach based on high-resolution, flow-injection Fourier transform ion cyclotron resonance mass spectrometry (FI-FTICR-MS) was used to generate comprehensive metabolomic profiles containing 2478 accurate mass measurements from the serum of Japanese PC patients ( n =40) and disease-free subjects ( n =50). Targeted flow-injection tandem mass spectrometry (FI-MS/MS) assays for specific metabolic systems were developed and used to validate the FI-FTICR-MS results. A FI-MS/MS assay for the most discriminating metabolite discovered by FI-FTICR-MS (PC-594) was further validated in two USA Caucasian populations; one comprised 14 PCs, six intraductal papillary mucinous neoplasims (IPMN) and 40 controls, and a second comprised 1000 reference subjects aged 30 to 80, which was used to create a distribution of PC-594 levels among the general population. Results FI-FTICR-MS metabolomic analysis showed significant reductions in the serum levels of metabolites belonging to five systems in PC patients compared to controls (all p <0.000025). The metabolic systems included 36-carbon ultra long-chain fatty acids, multiple choline-related systems including phosphatidylcholines, lysophosphatidylcholines and sphingomyelins, as well as vinyl ether-containing plasmalogen ethanolamines. ROC-AUCs based on FI-MS/MS of selected markers from each system ranged between 0.93 ±0.03 and 0.97 ±0.02. No significant correlations between any of the systems and disease-stage, gender, or treatment were observed. Biomarker PC-594 (an ultra long-chain fatty acid), was further validated using an independently-collected US Caucasian population (blinded analysis, n =60, p =9.9E-14, AUC=0.97 ±0.02). PC-594 levels across 1000 reference subjects showed an inverse correlation with age, resulting in a drop in the AUC from 0.99 ±0.01 to 0.90 ±0.02 for subjects aged 30 to 80, respectively. A PC-594 test positivity rate of 5.0% in low-risk reference subjects resulted in a PC sensitivity of 87% and a significant improvement in net clinical benefit based on decision curve analysis. Conclusions The serum metabolome of PC patients is significantly altered. The utility of serum metabolite biomarkers, particularly PC-594, for identifying subjects with elevated risk of PC should be further investigated.

Hepatocellular carcinoma (HCC) is a common cancer in the world due to high prevalence of hepatitis B or C virus infection. Research in recent years has uncovered important molecular pathways involved in development and progression of HCC. Several genetic aberrations and molecular mechanisms responsible for initiation of hepatocarcinogenesis have been identified. Novel biomarkers for HCC are being developed for better detection and prognostication. Alpha-fetoprotein, the conventional marker of HCC, has limited sensitivity and specificity. Serum levels of isoforms of AFP based on differential lectin binding of the glycan moiety appear to be more sensitive and specific than total AFP level in early detection of HCC. The clinical usefulness of other HCC biomarkers such as des-γ-carboxy prothrombin and glypican-3 are under investigation. HCC is an aggressive tumor with early vascular invasion and metastasis. Studies over the past two decades have elucidated the clinical predictors of outcome, leading to several staging systems for HCC based on clinical parameters. However, the predictive accuracy of clinical staging systems is limited. Recent studies suggested that biological factors may provide additional prognostic information. In particular, gene expression profiling appears to be a promising approach. Study of tumor angiogenesis in HCC reveals that the expression of angiogenic factors such as vascular endothelial growth factor and angiopoietins may also predict prognosis. The elucidation of tumor biology of HCC is of particular importance in the current era of rapid development of anti-cancer molecular targeting agents, which provide hope for an effective systemic therapy for HCC.

Deaths of living liver donors have been reported in western countries, whereas the morbidity and mortality of such donors in Japan, one of the leading countries for living liver transplantation, have not been reported in detail. We aimed to review the operative morbidity and mortality of such donors in Japan. 1853 donors of 1852 living liver transplants done in 46 liver transplant centres, and registered in the database of the Japanese Liver Transplantation Society, were assessed for eight donor-related factors of morbidity and mortality. Data for 1841 donors were analysed. No perioperative mortality was recorded since inception of the liver transplantation programme in Japan from Nov 13, 1989, to April 11, 2002. 244 postoperative complications were reported in 228 (12%) donors. The frequency of complications was significantly higher in donors of the right liver lobe than in those involving the lateral segment, and left lobe graft (p<0·0001, and p<0·0001, respectively). Postoperative hospital stay was significantly longer in donors of the right lobe (mean 19·7 [SD 13·0]) than in those of the lateral segment (14·2 [7·6]), left lobe (14·0 [6·5]), and left lobe and caudate lobe (16·3 [12·1]). Re-operation related to donor hepatectomy was done in 23 donors. By contrast with western countries, no perioperative mortality was recorded in living liver donors in Japan. However, a proportion of these donors developed serious complications. This morbidity should be reduced to maintain zero mortality in living liver donors.

The platinum‐based chemotherapeutic agent oxaliplatin displays a wide range of antitumor activities. However, the underlying molecular responses to oxaliplatin in esophageal cancer remain largely unknown. In the present study, we investigated the effect of oxaliplatin on two esophageal cancer cell lines, squamous cell carcinoma (TE3) and adenocarcinoma (TE7). Following cell‐cycle arrest at G2 phase after oxaliplatin treatment, TE3 cells died via apoptosis and TE7 cells died via mitotic catastrophe. Survivin was inhibited more in TE7 cells compared with TE3 cells, but inhibition of survivin using small interfering RNA induced mitotic catastrophe in both cell lines. Further investigations indicated that survivin promoter activity was also inhibited by oxaliplatin. Among mitotic catastrophe‐associated proteins, 14–3‐3σ was decreased in TE7 cells; no evident changes were observed for aurora kinases. Oxaliplatin‐induced apoptosis in the TE3 cells was caspase dependent. However, downregulation of Bad, Bid, Puma, and Noxa, lack of cytochrome c release, and limited loss of mitochondrial membrane potential in early phase indicated possible initiation by pathways other than the mitochondrial pathway. Mechanistic studies showed that downregulation of survivin by oxaliplatin in TE7 cells was partially due to the proteasome‐mediated protein degradation pathway and partially due to the downregulation of Sp1 transcription factor. Similar results were obtained for another gastric adenocarcinoma cell line, MKN45, in which survivin was previously shown to be inhibited by oxaliplatin. These data indicate that survivin may be a key target for oxaliplatin. The ability of oxaliplatin to induce different modes of cell death may contribute to its efficacy in esophageal cancer. (Cancer Sci 2008; 99: 129–139)

Background Peritoneal relapse is the most common pattern of tumor progression in advanced gastric cancer. Clinicopathological findings are sometimes inadequate for predicting peritoneal relapse. The aim of this study was to identify patients at high risk of peritoneal relapse in a prospective study based on molecular prediction. Methods RNA samples from 141 primary gastric cancer tissues after curative surgery were profiled using oligonucleotide microarrays covering 30,000 human probes. Firstly, we constructed a molecular prediction system and validated its robustness and prognostic validity by 500 times multiple validation by repeated random sampling in a retrospective set of 56 (38 relapse-free and 18 peritoneal-relapse) patients. Secondly, we applied this prediction to 85 patients of the prospective set to assess predictive accuracy and prognostic validity. Results In the retrospective phase, repeated random validation yielded ~68% predictive accuracy and a 22-gene expression profile associated with peritoneal relapse was identified. The prediction system identified patients with poor prognosis. In the prospective phase, the molecular prediction yielded 76.9% overall accuracy. Kaplan–Meier analysis of peritoneal-relapse-free survival showed a significant difference between the “good signature group” and “poor signature group” (log-rank p  = 0.0017). Multivariate analysis by Cox regression hazards model identified the molecular prediction as the only independent prognostic factor for peritoneal relapse. Conclusions Gene expression profile inherent to primary gastric cancer tissues can be useful in prospective prediction of peritoneal relapse after curative surgery, potentially allowing individualized postoperative management to improve the prognosis of patients with advanced gastric cancer.

Expression of the Wilms' tumor gene WT1 was examined in 59 cases of colorectal adenocarcinoma to examine the involvement of WT1 in tumorigenesis. Quantitative real‐time reverse transcription‐polymerase chain reaction (RT‐PCR) showed that WT1 mRNA was expressed in the range from 7.2x10−5 to 4.9x10−1 levels (WT1 expression level in K562 leukemic cells was defined as 1.0) in all (100%) of the 28 cases of colorectal adenocarcinoma examined, and that the WT1 mRNA expression levels were higher in 20 (71%) of the 28 cases compared to those of normal‐appearing mucosal tissues examined. Immunohistochemical analysis using an anti‐WT1 antibody was performed on 46 cases of colorectal adenocarcinoma (15 of the 28 cases with WT1 mRNA expression and 31 newly collected cases), and the expression of WT1 protein was detected in 41 (89%) of the 46 cases. The direct sequencing analysis of the WT1 genomic DNA showed no mutations in any of the 10 exons of the WT1 gene in any of 5 different colorectal ade‐nocarcinomas. These results may indicate an important role of the wild‐type WT1 gene in tumorigenesis of colorectal adenocarcinoma.

Portal or splenic vein thrombosis (PSVT) is a common disorder after laparoscopic splenectomy (LS). Splenomegaly is a well-known risk factor for PSVT. However, no treatment strategy for PSVT has been established. Thirty-three consecutive patients who had undergone LS and postoperative imaging surveillance were examined. PSVT was classified according to the site of thrombosis. We evaluated patient background, operative factors, and clinical symptoms. Spleen weight of patients with PSVT (n = 17, median 218 g) was greater than that of patients without PSVT (n = 16, median 101 g). Seven patients developed thrombosis involving the entire splenic vein (total splenic vein thrombosis), and 4 of them had clinical symptoms (fever >38°C and/or abdominal pain). The incidence of clinical symptoms was significantly more frequent in patients with than without total SVT. Operation time, blood loss, and spleen weight were also significantly greater in patients with total SVT. Multiple logistic regression analysis demonstrated spleen weight was the strongest predictor of PSVT and total SVT. Patients with total SVT have greater risk factors for PSVT and frequently have clinical symptoms. They are candidates for anticoagulation therapy.