Tricyclic Pyrazoles. Part 8. Synthesis, Biological Evaluation and Modelling of Tricyclic Pyrazole Carboxamides as Potential CB2 Receptor Ligands with Antagonist/Inverse Agonist Properties.

Previous studies have investigated the relevance and structure-activity relationships (SARs) of pyrazole derivatives in relation with cannabinoid receptors, and the series of tricyclic 1,4-dihydroindeno[1,2-c]pyrazoles emerged as potent CB2receptor ligands. In the present study, novel 1,4-dihydroindeno[1,2-c]pyrazole and 1H-benzo[g]indazole carboxamides containing a cyclopropyl or a cyclohexyl substituent were designed and synthesized to evaluate the influence of these structural modifications towards CB1and CB2receptor affinities. Among these derivatives, compound 15 (6-cyclopropyl-1-(2,4-dichlorophenyl)-N-(adamantan-1-yl)-1,4-dihydroindeno[1,2-c]pyrazole-3-carboxamide) showed the highest CB2receptor affinity (Ki= 4 nM) and remarkable selectivity (KiCB1/KiCB2= 2232), whereas a similar affinity, within the nM range, was seen for the fenchyl derivative (compound 10: Ki= 6 nM), for the bornyl analogue (compound 14: Ki= 38 nM) and, to a lesser extent, for the aminopiperidine derivative (compound 6: Ki= 69 nM). Compounds 10 and 14 were also highly selective for the CB2receptor (KiCB1/KiCB2> 1000), whereas compound 6 was relatively selective (KiCB1/KiCB2= 27). The four compounds were also subjected to GTPγS binding analysis showing antagonist/inverse agonist properties (IC50for compound 14 = 27 nM, for 15 = 51 nM, for 10 = 80 nM and for 6 = 294 nM), and this activity was confirmed for the three more active compounds in a CB2receptor-specific in vitro bioassay consisting in the quantification of prostaglandin E2 release by LPS-stimulated BV2 cells, in the presence and absence of WIN55,212-2 and/or the investigated compounds. Modelling studies were also conducted with the four compounds, which conformed with the structural requirements stated for the binding of antagonist compounds to the human CB2receptor

Evaluating the incidence of pathological complete response in current international rectal cancer practice

The mainstay of management for locally advanced rectal cancer is chemoradiotherapy followed by surgical resection. Following chemoradiotherapy, a complete response may be detected clinically and radiologically (cCR) prior to surgery or pathologically after surgery (pCR). We aim to report the overall complete pathological response (pCR) rate and the reliability of detecting a cCR by conventional pre-operative imaging.A pre-planned analysis of the European Society of Coloproctology (ESCP) 2017 audit was performed. Patients treated by elective rectal resection were included. A pCR was defined as a ypT0 N0 EMVI negative primary tumour; a partial response represented any regression from baseline staging following chemoradiotherapy. The primary endpoint was the pCR rate. The secondary endpoint was agreement between post-treatment MRI restaging (yMRI) and final pathological staging.Of 2572 patients undergoing rectal cancer surgery in 277 participating centres across 44 countries, 673 (26.2%) underwent chemoradiotherapy and surgery. The pCR rate was 10.3% (67/649), with a partial response in 35.9% (233/649) patients. Comparison of AJCC stage determined by post-treatment yMRI with final pathology showed understaging in 13% (55/429) and overstaging in 34% (148/429). Agreement between yMRI and final pathology for T-stage, N-stage, or AJCC status were each graded as 'fair' only (n = 429, Kappa 0.25, 0.26 and 0.35 respectively).The reported pCR rate of 10% highlights the potential for non-operative management in selected cases. The limited strength of agreement between basic conventional post-chemoradiotherapy imaging assessment techniques and pathology suggest alternative markers of response should be considered, in the context of controlled clinical trials

Anastomotic leak after manual circular stapled left-sided bowel surgery: analysis of technology-, disease-, and patient-related factors /

Anastomotic leak rates after colorectal surgery remain high. In most left-sided colon and rectal resection surgeries, a circular stapler is utilized to create the primary bowel anastomosis. However, it remains unclear whether a relationship between circular stapler technology and anastomotic leak in left-sided colorectal surgery exists