Relationship between emergency presentation, systemic inflammatory response, and cancer-specific survival in patients undergoing potentially curative surgery for colon cancer

Background Emergency presentation is recognized to be associated with poorer cancer-specific survival following curative resection for colorectal cancer. The present study examined the hypothesis that an enhanced systemic inflammatory response, prior to surgery, might explain the impact of emergency presentation on survival. Methods In all, 188 patients undergoing potentially curative resection for colorectal cancer were studied. Of these, 55 (29%) presented as emergencies. The systemic inflammatory response was assessed using the Glasgow Prognostic Score (mGPS), which is the combination of an elevated C-reactive protein (>10 mg/L) and hypoalbuminemia (<35 g/L). Results In the emergency group, tumor stage was greater (P < 0.01), more patients received adjuvant therapy (P < 0.01) more patients had an elevated mGPS (P < 0.01), and more patients died of their disease (P < 0.05). The minimum follow-up was 12 months; the median follow-up of the survivors was 48 months. Emergency presentation was associated with poorer 3-year cancer-specific survival in those patients aged 65 to 74 years (P < 0.01), in both males and females (P < 0.05), in the deprived (P < 0.01), in patients with tumor-node-metastasis (TNM) stage II disease (P < 0.01), in those who received no adjuvant therapy (P < 0.01), and in the mGPS 0 and 1 groups (P < 0.05) groups. On multivariate survival analysis of patients undergoing potentially curative surgery for TNM stage II colon cancer, emergency presentation (P < 0.05) and mGPS (P < 0.05) were independently associated with cancer-specific survival. Conclusions These results suggest that emergency presentation and the presence of systemic inflammatory response prior to surgery are linked and account for poorer cancer-specific survival in patients undergoing potentially curative surgery for colon cancer. Both emergency presentation and an elevated mGPS should be taken into account when assessing the likely outcome of these patients

Synthesis and biological evaluation of N-cyanoalkyl-, Naminoalkyl-, and N-guanidinoalkyl-substituted 4-aminoquinoline derivatives as potent, selective, brain permeable antitrypanosomal agents

YesCurrent drugs against human African trypanosomiasis (HAT) suffer from several serious drawbacks. The search for novel, effective, brain permeable, safe, and inexpensive antitrypanosomal compounds is therefore an urgent need. We have recently reported that the 4-aminoquinoline derivative huprine Y, developed in our group as an anticholinesterasic agent, exhibits a submicromolar potency against Trypanosoma brucei and that its homo- and hetero-dimerization can result in to up to three-fold increased potency and selectivity. As an alternative strategy towards more potent smaller molecule anti-HAT agents, we have explored the introduction of ω-cyanoalkyl, ω-aminoalkyl, or ω-guanidinoalkyl chains at the primary amino group of huprine or the simplified 4-aminoquinoline analogue tacrine. Here, we describe the evaluation of a small in-house library and a second generation of newly synthesized derivatives, which has led to the identification of 13 side chain modified 4-aminoquinoline derivatives with submicromolar potencies against T. brucei. Among these compounds, the guanidinononyltacrine analogue 15e exhibits a 5-fold increased antitrypanosomal potency, 10-fold increased selectivity, and 100-fold decreased anticholinesterasic activity relative to the parent huprine Y. Its biological profile, lower molecular weight relative to dimeric compounds, reduced lipophilicity, and ease of synthesis, make it an interesting anti-HAT lead, amenable to further optimization to eliminate its remaining anticholinesterasic activity.Wellcome Trus

Synthesis and biological evaluation of N -cyanoalkyl-, N -aminoalkyl-, and N -guanidinoalkyl-substituted 4-aminoquinoline derivatives as potent, selective, brain permeable antitrypanosomal agents

Altres ajuts: J.M.K. acknowledges funding support from the Wellcome Trust (Grant number WT092573MA). Fellowships from GC to I.S., F.J.P.-A., and E.V. are gratefully acknowledged.Current drugs against human African trypanosomiasis (HAT) suffer from several serious drawbacks. The search for novel, effective, brain permeable, safe, and inexpensive antitrypanosomal compounds is therefore an urgent need. We have recently reported that the 4-aminoquinoline derivative huprine Y, developed in our group as an anticholinesterasic agent, exhibits a submicromolar potency against Trypanosoma brucei and that its homo- and hetero-dimerization can result in to up to three-fold increased potency and selectivity. As an alternative strategy towards more potent smaller molecule anti-HAT agents, we have explored the introduction of ω-cyanoalkyl, ω-aminoalkyl, or ω-guanidinoalkyl chains at the primary amino group of huprine or the simplified 4-aminoquinoline analogue tacrine. Here, we describe the evaluation of a small in-house library and a second generation of newly synthesized derivatives, which has led to the identification of 13 side chain modified 4-aminoquinoline derivatives with submicromolar potencies against T. brucei. Among these compounds, the guanidinononyltacrine analogue 15e exhibits a 5-fold increased antitrypanosomal potency, 10-fold increased selectivity, and 100-fold decreased anticholinesterasic activity relative to the parent huprine Y. Its biological profile, lower molecular weight relative to dimeric compounds, reduced lipophilicity, and ease of synthesis, make it an interesting anti-HAT lead, amenable to further optimization to eliminate its remaining anticholinesterasic activity