Concomitant intraperitoneal and systemic chemotherapy for extensive peritoneal metastases of colorectal origin: protocol of the multicentre, open-label, phase I, dose-escalation INTERACT trial

INTRODUCTION: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) has become standard of care for patients with peritoneal metastases of colorectal origin with a low/moderate abdominal disease load. In case of a peritoneal cancer index (PCI) score >20, CRS-HIPEC is not considered to be beneficial. Patients with a PCI >20 are currently offered palliative systemic chemotherapy. Previous studies have shown that systemic chemotherapy is less effective against peritoneal metastases than it is against haematogenous spread of colorectal cancer. It is suggested that patients with peritoneal metastases may benefit from the addition of intraperitoneal chemotherapy to systemic chemotherapy. Aim of this study is to establish the maximum tolerated dose of intraperitoneal irinotecan, added to standard of care systemic therapy for colorectal cancer. Secondary endpoints are to determine the safety and feasibility of this treatment and to establish the pharmacokinetic profile of intraperitoneally administered irinotecan. METHODS AND ANALYSIS: This phase I, '3+3' dose-escalation, study is performed in two Dutch tertiary referral centres. The study population consists of adult pa

The shared socio-economic pathway (SSP) greenhouse gas concentrations and their extensions to 2500

Anthropogenic increases in atmospheric greenhouse gas concentrations are the main driver of current and future climate change. The integrated assessment community has quantified anthropogenic emissions for the shared socio-economic pathway (SSP) scenarios, each of which represents a different future socio-economic projection and political environment. Here, we provide the greenhouse gas concentrations for these SSP scenarios – using the reduced-complexity climate–carbon-cycle model MAGICC7.0. We extend historical, observationally based concentration data with SSP concentration projections from 2015 to 2500 for 43 greenhouse gases with monthly and latitudinal resolution. CO2 concentrations by 2100 range from 393 to 1135 ppm for the lowest (SSP1-1.9) and highest (SSP5-8.5) emission scenarios, respectively. We also provide the concentration extensions beyond 2100 based on assumptions regarding the trajectories of fossil fuels and land use change emissions, net negative emissions, and the fraction of non-CO2 emissions. By 2150, CO2 concentrations in the lowest emission scenario are approximately 350 ppm and approximately plateau at that level until 2500, whereas the highest fossil-fuel-driven scenario projects CO2 concentrations of 1737 ppm and reaches concentrations beyond 2000 ppm by 2250. We estimate that the share of CO2 in the total radiative forcing contribution of all considered 43 long-lived greenhouse gases increases from 66 % for the present day to roughly 68 % to 85 % by the time of maximum forcing in the 21st century. For this estimation, we updated simple radiative forcing parameterizations that reflect the Oslo Line-By-Line model results. In comparison to the representative concentration pathways (RCPs), the five main SSPs (SSP1-1.9, SSP1-2.6, SSP2-4.5, SSP3-7.0, and SSP5-8.5) are more evenly spaced and extend to lower 2100 radiative forcing and temperatures. Performing two pairs of six-member historical ensembles with CESM1.2.2, we estimate the effect on surface air temperatures of applying latitudinally and seasonally resolved GHG concentrations. We find that the ensemble differences in the March–April–May (MAM) season provide a regional warming in higher northern latitudes of up to 0.4 K over the historical period, latitudinally averaged of about 0.1 K, which we estimate to be comparable to the upper bound (∼5 % level) of natural variability. In comparison to the comparatively straight line of the last 2000 years, the greenhouse gas concentrations since the onset of the industrial period and this studies' projections over the next 100 to 500 years unequivocally depict a “hockey-stick” upwards shape. The SSP concentration time series derived in this study provide a harmonized set of input assumptions for long-term climate science analysis; they also provide an indication of the wide set of futures that societal developments and policy implementations can lead to – ranging from multiple degrees of future warming on the one side to approximately 1.5 ∘C warming on the other

State-to-state inelastic scattering of stark-decelerated oh radicals with ar atoms

Contains fulltext : 99101.pdf (publisher's version ) (Open Access

Hemodynamic effects of amlodipine, bisoprolol, and lisinopril in hypertensive patients after liver transplantation 1.

Background: Hypertension is common after liver transplantation. There are few published data on optimum treatment. Augmentation index (AIx) is a measure of arterial wave reflection determined by pulse wave analysis.Methods: Amlodipine was administered to 24 hypertensive liver transplant recipients. Thirteen patients intolerant of or unresponsive to amlodipine were randomized to a crossover study comparing bisoprolol with lisinopril.Results: With amlodipine, systolic blood pressure (SBP) fell from 154+/-2 mm Hg to 130+/-2 mm Hg, and AIx also fell. With bisoprolol, SBP fell from 154+/-2 mm Hg to 142+/-4 mm Hg, but AIx increased. With lisinopril, SBP fell from 154+/-2 mm Hg to 130+/-5 mm Hg, and AIx also fell (P <0.001 throughout).Conclusions: Amlodipine is an effective treatment for hypertension. The increased AIx with bisoprolol indicates increased wave reflection such that central aortic pressure is reduced less than peripheral SBP. Lisinopril reduces AIx and reduces SBP more than bisoprolol and is the preferred drug

Dose dependant increase in plasma interleukin 6 after recombinant tumour necrosis factor infusion in humans

Several studies have shown that the cytokine interleukin-6 (IL-6) is produced in response to tumour necrosis factor (TNF) in vitro. This study examines the in vivo relation between these two cytokines with assays of plasma IL-6 and TNF levels in subjects with chronic hepatitis B undergoing immunomodulatory therapy with recombinant TNF (rTNF). Plasma IL-6 was detected from 20 min after rTNF infusion with levels peaking after 2-3 h and levels correlated with the dose of rTNF administered (r = 0.67, P = 0.004). Peak levels of IL-6 (mean 295, range 266-297 ng/l) were lower than those seen in certain disease states despite the very high peak levels of rTNF (mean 11,750, range 5623-18,620 ng/l). These findings suggest that the very high levels of IL-6 found in certain disease states are not purely the result of circulating TNF. Other factors such as endotoxin or other cytokines may also play a role in determining levels of plasma IL-6

Elevated plasma interleukin-6 and increased severity and mortality in alcoholic hepatitis

Recent studies in alcoholic hepatitis have proposed a role for the cytokine tumour necrosis factor-alpha (TNF-alpha) a mediator of endotoxic shock in sepsis. In this study plasma levels of the closely related cytokine interleukin-6 (IL-6) were assayed in 96 samples from 58 patients with severe alcoholic hepatitis, and 69 patients in control groups (21 normal, 10 alcoholic without liver disease, 10 inactive alcoholic cirrhosis, 18 chronic liver disease, 10 chronic renal failure). Plasma IL-6 levels were markedly elevated in patients with alcoholic hepatitis when compared with all control groups (P less than 0.001). IL-6 levels were higher in patients who died (P = 0.04) and correlated with the features of severe disease including: increased grade of encephalopathy, increased neutrophil count, increased prothrombin ratio, hypotension, increased serum creatinine and increased serum bilirubin. Surprisingly, no correlation was found between levels of plasma IL-6 and plasma TNF-alpha or endotoxin, or the presence of infection; an inverse correlation was found between plasma IL-6 and serum globulins. These findings provide further evidence that the IL-6/TNF cytokine system is activated in severe alcoholic hepatitis and may mediate hepatic or extra-hepatic tissue damage

Leukotriene and prostaglandin production following infusion of tumour necrosis factor in man

Tumor necrosis factor-alpha is believed to be an important mediator of endotoxaemia and septic shock, the effects of which are thought to be mediated through the generation of cysteinyl-leukotrienes, thromboxane A2 and other prostanoids. We have investigated the production of these eicosanoids and also that of prostacyclin in vivo after infusion of tumor necrosis factor-alpha into 4 subjects with a chronic hepatitis B virus infection. This resulted in plasma TNF levels considerably greater than those observed in septic shock. Urinary excretion rate of leukotriene E4 increased by 2 to 3-fold in all subjects by 8 h following TNF infusion. Urinary excretion of thromboxane B2 and 6-oxo-prostaglandin F1 alpha, however, increased in the first 4 h in 3/4 subjects by 2 to 40-fold and returned towards baseline by 8 h. Excretion of the hepatic metabolite, 2,3-dinor 6-oxo-prostaglandin F1 alpha, increased in all subjects (2 to 4-fold at 4h). We conclude that there is increased production of cysteinyl leukotrienes, thromboxane A2 and prostacyclin after infusion of tumour necrosis factor into man