Adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with colon cancer at high risk of peritoneal carcinomatosis; the COLOPEC randomized multicentre trial

Background: The peritoneum is the second most common site of recurrence in colorectal cancer. Early detection of peritoneal carcinomatosis (PC) by imaging is difficult. Patients eventually presenting with clinically apparent PC have a poor prognosis. Median survival is only about five months if untreated and the benefit of palliative systemic chemotherapy is limited. Only a quarter of patients are eligible for curative treatment, consisting of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CR/HIPEC). However, the effectiveness depends highly on the extent of disease and the treatment is associated with a considerable complication rate. These clinical problems underline the need for effective adjuvant therapy in high-risk patients to minimize the risk of outgrowth of peritoneal micro metastases. Adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) seems to be suitable for this purpose. Without the need for cytoreductive surgery, adjuvant HIPEC can be performed with a low complication rate and short hospital stay. Methods/Design: The aim of this study is to determine the effectiveness of adjuvant HIPEC in preventing the development of PC in patients with colon cancer at high risk of peritoneal recurrence. This study will be performed in the nine Dutch HIPEC centres, starting in April 2015. Eligible for inclusion are patients who underwent curative resection for T4 or intra-abdominally perforated cM0 stage colon cancer. After resection of the primary tumour, 176 patients will be randomized to adjuvant HIPEC followed by routine adjuvant systemic chemotherapy in the experimental arm, or to systemic chemotherapy only in the control arm. Adjuvant HIPEC will be performed simultaneously or shortly after the primary resection. Oxaliplatin will be used as chemotherapeutic agent, for 30 min at 42-43 degrees C. Just before HIPEC, 5-fluorouracil and leucovorin will be administered intravenously. Primary endpoint is peritoneal disease-free survival at 18 months. Diagnostic laparoscopy will be performed routinely after 18 months postoperatively in both arms of the study in patients without evidence of disease based on routine follow-up using CT imaging and CEA. Discussion: Adjuvant HIPEC is assumed to reduce the expected 25 % absolute risk of PC in patients with T4 or perforated colon cancer to a risk of 10 %. This reduction is likely to translate into a prolonged overall survival

Cancer recurrence times from a branching process model

As cancer advances, cells often spread from the primary tumor to other parts of the body and form metastases. This is the main cause of cancer related mortality. Here we investigate a conceptually simple model of metastasis formation where metastatic lesions are initiated at a rate which depends on the size of the primary tumor. The evolution of each metastasis is described as an independent branching process. We assume that the primary tumor is resected at a given size and study the earliest time at which any metastasis reaches a minimal detectable size. The parameters of our model are estimated independently for breast, colorectal, headneck, lung and prostate cancers. We use these estimates to compare predictions from our model with values reported in clinical literature. For some cancer types, we find a remarkably wide range of resection sizes such that metastases are very likely to be present, but none of them are detectable. Our model predicts that only very early resections can prevent recurrence, and that small delays in the time of surgery can significantly increase the recurrence probability.Comment: 26 pages, 9 figures, 4 table

Magnitude of effect of lithium in short-term efficacy studies of moderate to severe manic episode

OBJECTIVES: To provide an accurate estimation of the magnitude of effect of lithium in short-term efficacy studies conducted in patients with moderate to severe manic episode. METHODS: All placebo-controlled randomized studies submitted to the Medicines Evaluation Board (MEB) in which lithium was used as the third study arm were selected for the meta-analysis. The studies were part of registration files submitted to the MEB between the years 1997 and 2005. In addition, Medline and EMbase searches were conducted with the key words 'manic' ('mania' for the EMbase search) and 'placebo' in order to identify additional placebo-controlled studies of lithium. This search was updated until March 1, 2006. Two effect size indicators were used based on the primary outcome measure of each study: Cohen's standardized effect size based on the difference in mean change from baseline, and numbers needed to treat (NNT) based on the difference in treatment response defined as >or=50% improvement from baseline on day 21. RESULTS: Six studies were identified. They involved a combined total of 470 patients in the lithium groups and 562 in the placebo groups. The overall standardized effect size was 0.40 [95% confidence interval (CI): 0.28, 0.53] and the overall NNT for response was 6 (95% CI: 4, 13). In the placebo groups response rates varied from 21% to 47%. CONCLUSIONS: The results indicate that lithium is an effective drug in the treatment of moderate to severe manic episode. The variability in placebo response indicates that a placebo control arm in efficacy studies among patients with moderate to severe manic episode is necessar

European regulatory use and impact of subgroup evaluation in marketing authorisation applications

Marketing authorisation application dossiers relating to medicinal products containing new active substances and evaluated by the European Medicines Agency (EMA) over the period 2012-2015 were examined. Major objections and other concerns relating to efficacy and safety of the day 80 assessment reports were reviewed. Overall, approved products have more subgroup concerns than nonapproved products, which seems to be a consistent pattern. Subgroup analyses are mainly assessed to have the insurance that subgroups of patients that might lack a positive benefit: risk ratio will not be wrongly included in the approved treatment indication

European regulatory use and impact of subgroup evaluation in marketing authorisation applications

Marketing authorisation application dossiers relating to medicinal products containing new active substances and evaluated by the European Medicines Agency (EMA) over the period 2012-2015 were examined. Major objections and other concerns relating to efficacy and safety of the day 80 assessment reports were reviewed. Overall, approved products have more subgroup concerns than nonapproved products, which seems to be a consistent pattern. Subgroup analyses are mainly assessed to have the insurance that subgroups of patients that might lack a positive benefit: risk ratio will not be wrongly included in the approved treatment indication

Modular synthesis and immunological evaluation of suspected allergenic galactooligosaccharides

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Administration of adjuvant chemotherapy in older patients with Stage III colon cancer: an observational study

Pathophysiology, epidemiology and therapy of agein

An ocean of surprises - trends in human use, unexpected dynamics and governance challenges in areas beyond national jurisdiction

The expanse of ocean which makes up all marine areas beyond national jurisdiction has been characterized as the last frontier of exploitation on the planet, a figurative final "Wild West". Existing users of areas beyond national jurisdiction, with the exception of fisheries, currently have a limited footprint there as a consequence, in part, of substantial hurdles in technological development that need to be overcome before many resources can be extracted at a commercially viable scale. However, we argue surprise shifts perpetuated by both established and emerging users could lead to an expansion in actors taking opportunities to chase lucrative resources that they are currently constrained from exploiting. Rapid development could also lead to a "crowded ocean" due to the multiplication of users which could present a problem given the current lack of a unified institutional framework for governance connecting the different user groups. Here, we have collated trends in human use of areas beyond national jurisdiction and offer a framework for, and examples of, unexpected dynamics relevant to living and non-living marine resources. Such an approach is necessary in order to begin to mobilize an adequate governance response to changing conditions and uses of areas beyond national jurisdiction. This governance response must be able to govern established or potential users, be flexible and adaptive in response to unexpected and unpredictable dynamics and be able to transform in the face of unpredictable future uses of this vast area. Here we present a set of institutional design principles as a first tentative step in this direction. © 2014 Elsevier Ltd