Circulating galectin-1 delineates response to bevacizumab in melanoma patients and reprograms endothelial cell biology

Blockade of vascular endothelial growth factor (VEGF) signaling with bevacizumab, a humanized anti-VEGF monoclonal antibody (mAb), or with receptor tyrosine kinase inhibitors, has improved progression-free survival and, in some indications, overall survival across several types of cancers by interrupting tumor angiogenesis. However, the clinical benefit conferred by these therapies is variable, and tumors from treated patients eventually reinitiate growth. Previously we demonstrated, in mouse tumor models, that galectin-1 (Gal1), an endogenous glycan-binding protein, preserves angiogenesis in anti-VEGF–resistant tumors by co-opting the VEGF receptor (VEGFR)2 signaling pathway in the absence of VEGF. However, the relevance of these findings in clinical settings is uncertain. Here, we explored, in a cohort of melanoma patients from AVAST-M, a multicenter, open-label, randomized controlled phase 3 trial of adjuvant bevacizumab versus standard surveillance, the role of circulating plasma Gal1 as part of a compensatory mechanism that orchestrates endothelial cell programs in bevacizumab-treated melanoma patients. We found that increasing Gal1 levels over time in patients in the bevacizumab arm, but not in the observation arm, significantly increased their risks of recurrence and death. Remarkably, plasma Gal1 was functionally active as it was able to reprogram endothelial cell biology, promoting migration, tubulogenesis, and VEGFR2 phosphorylation. These effects were prevented by blockade of Gal1 using a newly developed fully human anti-Gal1 neutralizing mAb. Thus, using samples from a large-scale clinical trial from stage II and III melanoma patients, we validated the clinical relevance of Gal1 as a potential mechanism of resistance to bevacizumab treatment

Effectiveness of hypericum perforatum L. Phytosorbent as a part of complex therapy for acute non-specific bronchopneumonia

Respiratory pathology in calves, in particular acute non-specific bronchopneumonia, is extremely common, ranks second after gastrointestinal diseases and leads to significant economic losses. The effectiveness of antimicrobial agents of various pharmacological groups (tetracyclines, aminoglycosides, penicillins) has recently significantly decreased, which is associated with the formation of antibiotic-resistant strains of conditionally pathogenic bacteria. The problem of antibiotic resistance microorganisms that induce the development of an inflammatory process in the respiratory tract of calves forces the search for new therapi es, increasing the effectiveness of standard antibiotic therapy with the help of additional prescribing of various medicinal substances. The aim of the study was to study the effectiveness of the phytosorbent Hypericum Perforatum L. in the complex therapy of calves with acute non-specific bronchopneumonia. The therapeutic effect of Hypericum Perforatum L. phytosorbent was tested in the complex therapy of 97 calves with acute non-specific bronchopneumonia was studied. Calves aged 1.8±0.3 months and weighing 53.5±1.4 kg were selected for the experiment. For comparative study of therapeutic schemes, experimental animals were divided into two groups using the principle of paired analogues. Calves with bronchopneumonia-group I (n=42) were treated with the drug Florox at a dose of 1 ml per 15 kg of body weight, which corresponded to 20 mg/kg of Florfenicol, intramuscularly, twice with an interval of 48 hours. Calves with acute non-specific bronchopneumonia-group II (n=55) were also treated with the drug Florox at a dose of 1 ml per 15 kg of body weight intramuscularly, twice at 48-hour intervals with an additional prescription of phytosorbent Hypericum Perforatum L. at a dose of 5.0 g orally 1 time per day for 7 days. The effectiveness of therapy was evaluated by clinical and laboratory blood parameters. It was found that combined therapy of calves with acute non-specific bronchopneumonia with the use of Florfenicol and Hypericum Perforatum L. phytosorbent leads to a complete recovery 16.1 % more often than in animals treated with Florfenicol in a single mode. Combination of Florfenicol with Hypericum Perforatum L. statistically significant decreasing phenomena leukocytosis, increased phagocytic activity of neutrophils, reduced serum concentrations of C-reactive protein, α-globulin, β-globulin, the increase in the concentration of albumin, γ-globulin and IgG in the treatment of sick calves. In the blood of sick animals treated with a combination of Florfenicol with Hypericum Perforatum L. phytosorbent, compared with calves treated with Florfenicol in a single mode, the number of leukocytes in the peripheral blood significantly decreased and the phagocytic activity of neutrophilic leukocytes increased. These changes indicate a significant anti-inflammatory and immunomodulatory effect of Hypericum Perforatum L. in acute non-specific bronchopneumonia in calves. © 2020, Advanced Scientific Research. All rights reserved

Evaluation of a quality improvement intervention to reduce anastomotic leak following right colectomy (EAGLE): pragmatic, batched stepped-wedge, cluster-randomized trial in 64 countries

Background: Anastomotic leak affects 8 per cent of patients after right colectomy with a 10-fold increased risk of postoperative death. The EAGLE study aimed to develop and test whether an international, standardized quality improvement intervention could reduce anastomotic leaks. Methods: The internationally intended protocol, iteratively co-developed by a multistage Delphi process, comprised an online educational module introducing risk stratification, an intraoperative checklist, and harmonized surgical techniques. Clusters (hospital teams) were randomized to one of three arms with varied sequences of intervention/data collection by a derived stepped-wedge batch design (at least 18 hospital teams per batch). Patients were blinded to the study allocation. Low- and middle-income country enrolment was encouraged. The primary outcome (assessed by intention to treat) was anastomotic leak rate, and subgroup analyses by module completion (at least 80 per cent of surgeons, high engagement; less than 50 per cent, low engagement) were preplanned. Results: A total 355 hospital teams registered, with 332 from 64 countries (39.2 per cent low and middle income) included in the final analysis. The online modules were completed by half of the surgeons (2143 of 4411). The primary analysis included 3039 of the 3268 patients recruited (206 patients had no anastomosis and 23 were lost to follow-up), with anastomotic leaks arising before and after the intervention in 10.1 and 9.6 per cent respectively (adjusted OR 0.87, 95 per cent c.i. 0.59 to 1.30; P = 0.498). The proportion of surgeons completing the educational modules was an influence: the leak rate decreased from 12.2 per cent (61 of 500) before intervention to 5.1 per cent (24 of 473) after intervention in high-engagement centres (adjusted OR 0.36, 0.20 to 0.64; P < 0.001), but this was not observed in low-engagement hospitals (8.3 per cent (59 of 714) and 13.8 per cent (61 of 443) respectively; adjusted OR 2.09, 1.31 to 3.31). Conclusion: Completion of globally available digital training by engaged teams can alter anastomotic leak rates. Registration number: NCT04270721 (http://www.clinicaltrials.gov)

Evaluation of a quality improvement intervention to reduce anastomotic leak following right colectomy (EAGLE): pragmatic, batched stepped-wedge, cluster-randomized trial in 64 countries

Background Anastomotic leak affects 8 per cent of patients after right colectomy with a 10-fold increased risk of postoperative death. The EAGLE study aimed to develop and test whether an international, standardized quality improvement intervention could reduce anastomotic leaks. Methods The internationally intended protocol, iteratively co-developed by a multistage Delphi process, comprised an online educational module introducing risk stratification, an intraoperative checklist, and harmonized surgical techniques. Clusters (hospital teams) were randomized to one of three arms with varied sequences of intervention/data collection by a derived stepped-wedge batch design (at least 18 hospital teams per batch). Patients were blinded to the study allocation. Low- and middle-income country enrolment was encouraged. The primary outcome (assessed by intention to treat) was anastomotic leak rate, and subgroup analyses by module completion (at least 80 per cent of surgeons, high engagement; less than 50 per cent, low engagement) were preplanned. Results A total 355 hospital teams registered, with 332 from 64 countries (39.2 per cent low and middle income) included in the final analysis. The online modules were completed by half of the surgeons (2143 of 4411). The primary analysis included 3039 of the 3268 patients recruited (206 patients had no anastomosis and 23 were lost to follow-up), with anastomotic leaks arising before and after the intervention in 10.1 and 9.6 per cent respectively (adjusted OR 0.87, 95 per cent c.i. 0.59 to 1.30; P = 0.498). The proportion of surgeons completing the educational modules was an influence: the leak rate decreased from 12.2 per cent (61 of 500) before intervention to 5.1 per cent (24 of 473) after intervention in high-engagement centres (adjusted OR 0.36, 0.20 to 0.64; P &lt; 0.001), but this was not observed in low-engagement hospitals (8.3 per cent (59 of 714) and 13.8 per cent (61 of 443) respectively; adjusted OR 2.09, 1.31 to 3.31). Conclusion Completion of globally available digital training by engaged teams can alter anastomotic leak rates. Registration number: NCT04270721 (http://www.clinicaltrials.gov)