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Blood vessels form vast networks in all vertebrate organs to sustain tissue growth, repair and homeostatic metabolism, but they also contribute to a range of diseases with neovascularisation. It is, therefore, important to define the molecular mechanisms that underpin blood vessel growth. The receptor tyrosine kinase KIT is required for the normal expansion of hematopoietic progenitors that arise during embryogenesis from hemogenic endothelium in the yolk sac and dorsal aorta. Additionally, KIT has been reported to be expressed in endothelial cells during embryonic brain vascularisation and has been implicated in pathological angiogenesis. However, it is neither known whether KIT expression is widespread in normal organ endothelium nor whether it promotes blood vessel growth in developing organs. Here, we have used single-cell analyses to show that KIT is expressed in endothelial cell subsets of several organs, both in the adult and in the developing embryo. Knockout mouse analyses revealed that KIT is dispensable for vascularisation of growing organs in the midgestation embryo, including the lung, liver and brain. By contrast, vascular changes emerged during late-stage embryogenesis in these organs from KIT-deficient embryos, concurrent with severe erythrocyte deficiency and growth retardation. These findings suggest that KIT is not required for developmental tissue vascularisation in physiological conditions, but that KIT deficiency causes foetal anaemia at late gestation and thereby pathological vascular remodelling.

Background. Major trauma describes serious injuries requiring lifesaving interventions or resulting in long-term disability; it represents about 8% of all deaths worldwide. Specific guidelines can help reduce deaths and disabilities, provided they adhere to high quality and trustworthiness standards. This article aims at introducing the development process of the Istituto Superiore di Sanità, ISS (Italian National Institute of Health) guideline for major trauma integrated management. Methods. We applied the ISS methodological standards including the GRADE-ADOLOPMENT approach for adoption, adaptation, and de novo development of trustworthy guidelines. Results. The scope was formulated by the multidisciplinary panel with stakeholders’ involvement; two guidelines were identified as appropriate sources for adolopment. Forty questions from the two source guidelines were prioritised and five new ones formulated. New systematic reviews or updates were conducted for each clinical question, Evidence to Decision frameworks developed or re-assessed and the recommendations formulated after public consultations and external review. The policy on conflicts of interest was applied throughout the process. Conclusions. Through a broad expertise representation, the early and wide stakeholders’ participation, a continual process for disclosure and management of conflict of interests and the transparency of the process, ISS standards are proving to be an efficient model for developing trustworthy clinical guidance.

Background: We conducted a systematic review to evaluate and compare the accuracy of pre-hospital triage tools for major trauma in the context of the development of the Italian National Institute of Health guidelines on major trauma integrated management. Methods: PubMed, Embase, and CENTRAL were searched up to November 2019 for studies investigating pre-hospital triage tools. The ROC (receiver operating characteristics) curve and net clinical benefit for all selected triage tools were performed. Quality assessment was performed using the Quality Assessment of Diagnostic Accuracy Studies–2. Certainty of the evidence was judged with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Results: We found 15 observational studies of 13 triage tools for adults and 11 for children. In adults, according to the ROC curve and the net clinical benefit, the most reliable tool was the Northern French Alps Trauma System (TRENAU), adopting injury severity score (ISS) > 15 as reference (sensitivity (Sn), 0.92; specificity (Sp), 0.41; 1 study; sample size, 2572; high certainty of the evidence). When mortality as reference was considered, the pre-hospital triage tool with the best net clinical benefit trajectory was the New Trauma Score (NTS) < 18 (Sn, 0.82; Sp, 0.86; 1 study; sample size, 1001; moderate certainty of the evidence). In children, high variability among all triage tools for sensitivity and specificity was found. Conclusion: Sensitivity and specificity varied across all available pre-hospital trauma triage tools. TRENAU and NTS are the best accurate triage tools for adults, whereas in the pediatric area a large variability prevents any firm conclusion.

Background: Multiple studies regarding the use of Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) in patients with non-compressible torso injuries and uncontrolled haemorrhagic shock were recently published. To date, the clinical evidence of the efficacy of REBOA is still debated. We aimed to conduct a systematic review assessing the clinical efficacy and safety of REBOA in patients with major trauma and uncontrolled haemorrhagic shock. Methods: We systematically searched MEDLINE (PubMed), EMBASE and CENTRAL up to June 2020. All randomized controlled trials and observational studies that investigated the use of REBOA compared to resuscitative thoracotomy (RT) with/without REBOA or no-REBOA were eligible. We followed the PRISMA and MOOSE guidelines. Two authors independently extracted data and appraised the risk of bias of included studies. Effect sizes were pooled in a meta-analysis using random-effects models. The quality of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation methodology. Primary outcomes were mortality, volume of infused blood components, health-related quality of life, time to haemorrhage control and any adverse effects. Secondary outcomes were improvement in haemodynamic status and failure/success of REBOA technique. Results: We included 11 studies (5866 participants) ranging from fair to good quality. REBOA was associated with lower mortality when compared to RT (aOR 0.38; 95% CI 0.20–0.74), whereas no difference was observed when REBOA was compared to no-REBOA (aOR 1.40; 95% CI 0.79–2.46). No significant difference in health-related quality of life between REBOA and RT (p = 0.766). The most commonly reported complications were amputation, haematoma and pseudoaneurysm. Sparse data and heterogeneity of reporting for all other outcomes prevented any estimate. Conclusions: Our findings on overall mortality suggest a positive effect of REBOA among non-compressible torso injuries when c

Colorectal cancer is a major cause of cancer-related death in Western countries and is associated with increased numbers of lymphatic vessels (LV) and tumor-associated macrophages (TAM). The VEGFC/VEGFR3 pathway is regarded as the principal inducer of lymphangiogenesis and it contributes to metastases; however, no data are available regarding its role during primary colorectal cancer development. We found that both VEGFC and VEGFR3 were upregulated in human non-metastatic colorectal cancer, with VEGFR3 expressed on both LVs and TAMs. With the use of three different preclinical models of colorectal cancer, we also discovered that the VEGFC/VEGFR3 axis can shape both lymphatic endothelial cells and TAMs to synergistically inhibit antitumor immunity and promote primary colorectal cancer growth. Therefore, VEGFR3-directed therapy could be envisioned for the treatment of nonmetastatic colorectal cancer.Significance: The prolymphangiogenic factor VEGFC is abundant in colorectal cancer and activates VEGFR3 present on cancer-associated macrophages and lymphatic vessels; activation of VEGFR3 signaling fosters cancer immune escape, resulting in enhanced tumor growth.