Study protocol of the SACURA trial: a randomized phase III trial of efficacy and safety of UFT as adjuvant chemotherapy for stage II colon cancer

BACKGROUND: Adjuvant chemotherapy for stage III colon cancer is internationally accepted as standard treatment with established efficacy, but the usefulness of adjuvant chemotherapy for stage II colon cancer remains controversial. The major Western guidelines recommend adjuvant chemotherapy for “high-risk stage II” cancer, but this is not clearly defined and the efficacy has not been confirmed. METHODS/DESIGN: SACURA trial is a multicenter randomized phase III study which aims to evaluate the superiority of 1-year adjuvant treatment with UFT to observation without any adjuvant treatment after surgery for stage II colon cancer in a large population, and to identify “high-risk factors of recurrence/death” in stage II colon cancer and predictors of efficacy and adverse events of the chemotherapy. Patients aged between 20 and 80 years with curatively resected stage II colon cancer are randomly assigned to a observation group or UFT adjuvant therapy group (UFT at 500–600 mg/day as tegafur in 2 divided doses after meals for 5 days, followed by 2-day rest. This 1-week treatment cycle is repeated for 1 year). The patients are followed up for 5 years until recurrence or death. Treatment delivery and adverse events are entered into a web-based case report form system every 3 months. The target sample size is 2,000 patients. The primary endpoint is disease-free survival, and the secondary endpoints are overall survival, recurrence-free survival, and incidence and severity of adverse events. In an additional translational study, the mRNA expression of 5-FU-related enzymes, microsatellite instability and chromosomal instability, and histopathological factors including tumor budding are assessed to evaluate correlation with recurrences, survivals and adverse events. DISCUSSION: A total of 2,024 patients were enrolled from October 2006 to July 2010. The results of this study will provide important information that help to improve the therapeutic strategy for stage II colon cancer. TRIAL REGISTRATION: ClinicalTrials.gov NCT00392899

A new Approach to El Nino Prediction beyond the Spring Season

The enormous societal importance of accurate El Nino forecasts has long been recognized. Nonetheless, our predictive capabilities were once more shown to be inadequate in 2014 when an El Nino event was widely predicted by international climate centers but failed to materialize. This result highlighted the problem of the opaque spring persistent barrier, which severely restricts longer-term, accurate forecasting beyond boreal spring. Here we show that the role played by tropical seasonality in the evolution of the El Nino is changing on pentadal (five-year) to decadal timescales and thus that El Nino predictions beyond boreal spring will inevitably be uncertain if this change is neglected. To address this problem, our new coupled climate simulation incorporates these long-term influences directly and generates accurate hindcasts for the 7 major historical El Ninos. The error value between predicted and observed sea surface temperature (SST) in a specific tropical region (5°N-5°S and 170°-120°W) can consequently be reduced by 0.6 Kelvin for one-year predictions. This correction is substantial since an "El Nino" is confirmed when the SST anomaly becomes greater than +0.5 Kelvin. Our 2014 forecast is in line with the observed development of the tropical climate

ADAM8 in squamous cell carcinoma of the head and neck: a retrospective study

<p>Abstract</p> <p>Background</p> <p>A disintegrin and metalloproteinase (ADAMs) have been associated with multiple malignancies. ADAMs are involved in cell fusion, cell migration, membrane protein shedding and proteolysis. ADAM8 has been found to be overexpressed in squamous cell carcinomas of the lung. A new study showed that ADAM8 is significantly overexpressed in metastasis of squamous cell carcinomas of the head and neck (HNSCC).</p> <p>Methods</p> <p>We determined ADAM8 levels in the serum of 79 HNSCC patients at the time of diagnosis, in 35 patients 3 months after treatment and in 10 patients 1 year after therapy and compared the results to the sera of 31 healthy volunteers. We also constructed tissue microarrays to detect ADAM8 immunohistochemically in 100 patients. The results were correlated with the survival data of the patients to determine the diagnostic and prognostic value.</p> <p>Results</p> <p>The data demonstrated that patients with high ADAM8 expression in the tumor have worse survival rates. We found that high ADAM8 serum levels correlated with high ADAM8 expression in tumor samples. Soluble ADAM8 levels did not show any prognostic or diagnostic properties.</p> <p>Conclusion</p> <p>In summary ADAM8 expression is a prognostic factor for survival of patients with head and neck squamous cell carcinoma.</p

Long-term cultivation of colorectal carcinoma cells with anti-cancer drugs induces drug resistance and telomere elongation: an in vitro study

BACKGROUND: The role of telomerase activation in the expression and/or maintenance of drug resistance is not clearly understood. Therefore, we investigated the relationships, among the telomerase activity, telomere length and the expression of multidrug resistance genes in colorectal cancer cell lines cultivated with anti-cancer drugs. METHODS: LoVo and DLD-1 cells were continuously grown in the presence of both CDDP and 5-FU for up to 100 days. Cell proliferation, telomerase activity, telomere length and the expression of multidrug resistance genes were serially monitored as the PDL increased. RESULTS: The expression of multidrug resistance genes tended to increase as the PDL increased. However, an abnormal aneuploid clone was not detected as far as the cells were monitored by a DNA histogram analysis. Tumor cells showing resistance to anti-cancer drugs revealed a higher cell proliferation rate. The telomere length gradually increased with a progressive PDL. The telomerase activity reached a maximum level at 15 PDL in LoVo cells and at 27 PDL in DLD-1 cells. An increase in the mRNA expression of the telomerase components, especially in hTERT and in hTR, was observed at the same PDLs. CONCLUSIONS: These results suggest that a high telomerase activity and an elongation of telomeres both appear to help maintain and/or increase drug resistance in colorectal cancer cells. Cancer cells with long telomeres and a high proliferative activity may thus be able to better survive exposure to anti-cancer drugs. This is presumably due to an increased chromosome stability and a strong expression of both mdr-1 and MRP genes

Co-activation of macrophages and T cells contribute to chronic GVHD in human IL-6 transgenic humanised mouse model.

BACKGROUND: Graft-versus host disease (GVHD) is a complication of stem cell transplantation associated with significant morbidity and mortality. Non-specific immune-suppression, the mainstay of treatment, may result in immune-surveillance dysfunction and disease recurrence. METHODS: We created humanised mice model for chronic GVHD (cGVHD) by injecting cord blood (CB)-derived human CD34 FINDINGS: In cGVHD humanised mice, we found activation of T cells in the spleen, lung, liver, and skin, activation of macrophages in lung and liver, and loss of appendages in skin, obstruction of bronchioles in lung and portal fibrosis in liver recapitulating cGVHD. Acute GVHD humanised mice showed activation of T cells with skewed TCR repertoire without significant macrophage activation. INTERPRETATION: Using humanised mouse models, we demonstrated distinct immune mechanisms contributing acute and chronic GVHD. In cGVHD model, co-activation of human HSPC-derived macrophages and T cells educated in the recipient thymus contributed to delayed onset, multi-organ disease. In acute GVHD model, mature human T cells contained in the graft resulted in rapid disease progression. These humanised mouse models may facilitate future development of new molecular medicine targeting GVHD

Simply longer is not better: reversal of theta burst after-effect with prolonged stimulation

From all rTMS protocols at present, the theta burst stimulation (TBS) is considered the most efficient in terms of number of impulses and intensity required during a given stimulation. The aim of this study was to investigate the effects of inhibitory and excitatory TBS protocols on motor cortex excitability when the duration of stimulation was doubled. Fourteen healthy volunteers were tested under four conditions: intermittent theta bust stimulation (iTBS), continuous theta burst stimulation (cTBS), prolonged intermittent theta bust stimulation (ProiTBS) and prolonged continuous theta burst stimulation (ProcTBS). The prolonged paradigms were twice as long as the conventional TBS protocols. Conventional facilitatory iTBS converted into inhibitory when it was applied for twice as long, while the normally inhibitory cTBS became facilitatory when the stimulation duration was doubled. Our results show that TBS-induced plasticity cannot be deliberately enhanced simply by prolonging TBS protocols. Instead, when stimulating too long, after-effects will be reversed. This finding supplements findings at the short end of the stimulation duration range, where it was shown that conventional cTBS is excitatory in the first half and switches to inhibition only after the full length protocol. It is relevant for clinical applications for which an ongoing need for further protocol improvement is imminent