Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo

Deep vein thrombosis (DVT) is a major cause of cardiovascular death. The sequence of events that promote DVT remains obscure, largely as a result of the lack of an appropriate rodent model. We describe a novel mouse model of DVT which reproduces a frequent trigger and resembles the time course, histological features, and clinical presentation of DVT in humans. We demonstrate by intravital two-photon and epifluorescence microscopy that blood monocytes and neutrophils crawling along and adhering to the venous endothelium provide the initiating stimulus for DVT development. Using conditional mutants and bone marrow chimeras, we show that intravascular activation of the extrinsic pathway of coagulation via tissue factor (TF) derived from myeloid leukocytes causes the extensive intraluminal fibrin formation characteristic of DVT. We demonstrate that thrombus-resident neutrophils are indispensable for subsequent DVT propagation by binding factor XII (FXII) and by supporting its activation through the release of neutrophil extracellular traps (NETs). Correspondingly, neutropenia, genetic ablation of FXII, or disintegration of NETs each confers protection against DVT amplification. Platelets associate with innate immune cells via glycoprotein Ibα and contribute to DVT progression by promoting leukocyte recruitment and stimulating neutrophil-dependent coagulation. Hence, we identified a cross talk between monocytes, neutrophils, and platelets responsible for the initiation and amplification of DVT and for inducing its unique clinical features

Adjuvant therapy following oesophagectomy for adenocarcinoma in patients with a positive resection margin.

BACKGROUND: The role of adjuvant therapy in patients with oesophagogastric adenocarcinoma treated by neoadjuvant chemotherapy is contentious. In UK practice, surgical resection margin status is often used to classify patients for receiving adjuvant treatment. The aim of this study was to assess the survival benefit of adjuvant therapy in patients with positive (R1) resection margins. METHODS: Two prospectively collected UK institutional databases were combined to identify eligible patients. Adjusted Cox regression analyses were used to compare overall and recurrence-free survival according to adjuvant treatment. Recurrence patterns were assessed as a secondary outcome. Propensity score-matched analysis was also performed. RESULTS: Of 616 patients included in the combined database, 242 patients who had an R1 resection were included in the study. Of these, 112 patients (46·3 per cent) received adjuvant chemoradiotherapy, 46 (19·0 per cent) were treated with adjuvant chemotherapy and 84 (34·7 per cent) had no adjuvant treatment. In adjusted analysis, adjuvant chemoradiotherapy improved recurrence-free survival (hazard ratio (HR) 0·59, 95 per cent c.i. 0·38 to 0·94; P = 0·026), with a benefit in terms of both local (HR 0·48, 0·24 to 0·99; P = 0·047) and systemic (HR 0·56, 0·33 to 0·94; P = 0·027) recurrence. In analyses stratified by tumour response to neoadjuvant chemotherapy, non-responders (Mandard tumour regression grade 4-5) treated with adjuvant chemoradiotherapy had an overall survival benefit (HR 0·61, 0·38 to 0·97; P = 0·037). In propensity score-matched analysis, an overall survival benefit (HR 0·62, 0·39 to 0·98; P = 0·042) and recurrence-free survival benefit (HR 0·51, 0·30 to 0·87; P = 0·004) were observed for adjuvant chemoradiotherapy versus no adjuvant treatment. CONCLUSION: Adjuvant therapy may improve overall survival and recurrence-free survival after margin-positive resection. This pattern seems most pronounced with adjuvant chemoradiotherapy in non-responders to neoadjuvant chemotherapy