New functions of C3G in platelet biology: Contribution to ischemia-induced angiogenesis, tumor metastasis and TPO clearance.

C3G is a Rap1 guanine nucleotide exchange factor that controls platelet activation, aggregation, and the release of α-granule content. Transgenic expression of C3G in platelets produces a net proangiogenic secretome through the retention of thrombospondin-1. In a physiological context, C3G also promotes megakaryocyte maturation and proplatelet formation, but without affecting mature platelet production. The aim of this work is to investigate whether C3G is involved in pathological megakaryopoiesis, as well as its specific role in platelet mediated angiogenesis and tumor metastasis. Using megakaryocyte-specific C3G knockout and transgenic mouse models, we found that both C3G overexpression and deletion promoted platelet-mediated angiogenesis, induced by tumor cell implantation or hindlimb ischemia, through differential release of proangiogenic and antiangiogenic factors. However, only C3G deletion resulted in a higher recruitment of hemangiocytes from the bone marrow. In addition, C3G null expression enhanced thrombopoietin (TPO)-induced platelet production, associated with reduced TPO plasma levels. Moreover, after 5-fluorouracil-induced platelet depletion and rebound, C3G knockout mice showed a defective return to homeostatic platelet levels, indicating impaired platelet turnover. Mechanistically, C3G promotes c-Mpl ubiquitination by inducing Src-mediated c-Cbl phosphorylation and participates in c-Mpl degradation via the proteasome and lysosome systems, affecting TPO internalization. We also unveiled a positive role of platelet C3G in tumor cell-induced platelet aggregation, which facilitated metastatic cell homing and adhesion. Overall, these findings revealed that C3G plays a crucial role in platelet-mediated angiogenesis and metastasis, as well as in platelet level modulation in response to pathogenic stimuli.

Efficacy and safety of intramuscular administration of allogeneic adipose tissue derived and expanded mesenchymal stromal cells in diabetic patients with critical limb ischemia with no possibility of revascularization: study protocol for a randomized controlled double-blind phase II clinical trial (The NOMA Trial).

BACKGROUND: Chronic lower limb ischemia develops earlier and more frequently in patients with type 2 diabetes mellitus. Diabetes remains the main cause of lower-extremity non-traumatic amputations. Current medical treatment, based on antiplatelet therapy and statins, has demonstrated deficient improvement of the disease. In recent years, research has shown that it is possible to improve tissue perfusion through therapeutic angiogenesis. Both in animal models and humans, it has been shown that cell therapy can induce therapeutic angiogenesis, making mesenchymal stromal cell-based therapy one of the most promising therapeutic alternatives. The aim of this study is to evaluate the feasibility, safety, and efficacy of cell therapy based on mesenchymal stromal cells derived from adipose tissue intramuscular administration to patients with type 2 diabetes mellitus with critical limb ischemia and without possibility of revascularization. METHODS: A multicenter, randomized double-blind, placebo-controlled trial has been designed. Ninety eligible patients will be randomly assigned at a ratio 1:1:1 to one of the following: control group (n = 30), low-cell dose treatment group (n = 30), and high-cell dose treatment group (n = 30). Treatment will be administered in a single-dose way and patients will be followed for 12 months. Primary outcome (safety) will be evaluated by measuring the rate of adverse events within the study period. Secondary outcomes (efficacy) will be measured by assessing clinical, analytical, and imaging-test parameters. Tertiary outcome (quality of life) will be evaluated with SF-12 and VascuQol-6 scales. DISCUSSION: Chronic lower limb ischemia has limited therapeutic options and constitutes a public health problem in both developed and underdeveloped countries. Given that the current treatment is not established in daily clinical practice, it is essential to provide evidence-based data that allow taking a step forward in its clinical development. Also, the multidisciplinary coordination exercise needed to develop this clinical trial protocol will undoubtfully be useful to conduct academic clinical trials in the field of cell therapy in the near future. TRIAL REGISTRATION: ClinicalTrials.gov NCT04466007 . Registered on January 07, 2020. All items from the World Health Organization Trial Registration Data Set are included within the body of the protocol.

Abdominal aortic aneurysm and acute appendicitis: a case report and review of the literature.

BACKGROUND: Abdominal aortic aneurysm and acute appendicitis occur relatively frequently in elderly patients. However, the co-occurrence of the two pathologies is very rare and serious. CASE PRESENTATION: We present the case of an elderly Caucasian patient who was aware of having an abdominal aortic aneurysm but refused treatment and was subsequently admitted to the hospital's emergency department with acute abdominal symptoms. A computed tomography scan raised the possibility of complication due to the characteristics of the aneurysm. The patient then agreed to emergency surgery. Laparotomy revealed the existence of an acute perforated appendicitis with a significant abscess in the right iliac fossa and an uncomplicated aneurysm. Appendectomy was performed and the abscess drained. The postoperative period passed without complications, and the patient again refused surgery for the aneurysm, which due to its anatomical characteristics was not a candidate for standard endovascular treatment. CONCLUSIONS: In light of this experience, we review the literature about the relationship between abdominal aortic aneurysm and acute appendicitis.

Simple and complex carotid paragangliomas. Three decades of experience and literature review.

BACKGROUND: Carotid paragangliomas are rare tumors. They are usually unique, non-secreting, resectable, and benign. However, additional rare cases of complex tumors (bilateral, secretory, nonresectable, or malignant) complicate the management and final outcomes. METHODS: Records of paragangliomas from our hospital are reviewed. Criteria defining complex paragangliomas have been previously defined. These are compared with those of the simple group. RESULTS: Fifty patients, two groups: simple (n = 39) and complex (n = 11). The patients in the complex group were significantly younger (47.7 vs 63.8 years). Postoperative nerve complications (45.4% vs 6.3%) and mortality during follow-up (27.3% vs 0%) were significantly more common in the complex group. Vascular complications (0% vs 3.1%) and early mortality (0%) were similarly in both groups. CONCLUSIONS: Patients with complex carotid paragangliomas are heterogeneous. The former are younger, exhibit a high degree of diagnostic and therapeutic complexity, and have poorer morbidity and mortality. Surgical experience and interdisciplinary collaboration are essential.

Spontaneous rupture of a mechanical valve in a mitral position (On-X) with migration-embolization to aortic bifurcation from the perspective of the vascular surgeon.

We report on the case of spontaneous rupture of an On-X-pure pyrolytic carbon mechanical valve prosthesis implanted seven years earlier, in a mitral position, at our hospital. The patient was admitted with valvular dysfunction and acute pulmonary edema requiring emergency surgery (prosthesis replacement); the absence of a leaflet was confirmed intraoperatively. The patient presented severe respiratory failure, which prolonged the postoperative period. A CT scan showed that the migrated leaflet was located in the aortic bifurcation with no apparent arterial lesion. Four months later, once the patient had recovered, laparotomy and aortotomy were performed in order to retrieve the leaflet, which was found to have become included (neoendothelized) in the aortic wall without compromising the latter's integrity or obstructing the blood flow. A subsequent CT scan confirmed the persistence of the leaflet in its initial position. The literature review highlights two singular facts: 1) this is the second published case of the escape of a leaflet from an On-X prosthesis (the first patient died); 2) this is the first case in which a laparotomy was performed to retrieve the leaflet but finally a decision was made to leave it in situ. Seven months later, the patient remained asymptomatic.

Sequential intravenous allogeneic mesenchymal stromal cells as a potential treatment for thromboangiitis obliterans (Buerger's disease).

Thromboangiitis obliterans (TAO), also known as Buerger's Disease, is an occlusive vasculitis linked with high morbidity and amputation risk. To date, TAO is deemed incurable due to the lack of a definitive treatment. The immune system and inflammation are proposed to play a central role in TAO pathogenesis. Due to their immunomodulatory effects, mesenchymal stromal cells (MSCs) are the subject of intense research for the treatment of a wide range of immune-mediated diseases. Thus far, local intramuscular injections of autologous or allogeneic MSCs have shown promising results in TAO. However, sequential intravenous allogeneic MSC administration has not yet been explored, which we hypothesized could exert a systemic anti-inflammatory effect in the vasculature and modulate the immune response. Here, we report the first case of a TAO patient at amputation risk treated with four sequential intravenous infusions of bone marrow-derived allogeneic MSCs from a healthy donor. Following administration, there was significant regression of foot skin ulcers and improvements in rest pain, Walking Impairment Questionnaire scores, and quality of life. Sixteen months after the infusion, the patient had not required any further amputations. This report highlights the potential of sequential allogeneic MSC infusions as an effective treatment for TAO, warranting further studies to compare this approach with the more conventionally used intramuscular MSC administration and other cell-based therapies.

Management patterns and outcomes in symptomatic venous thromboembolism following allogeneic hematopoietic stem cell transplantation. A 15-years experience at a single center.

BACKGROUND: Experience is limited with regard to antithrombotic therapy in patients with venous thromboembolism (VTE) following allogeneic hematopoietic stem cell transplantation (HSCT). DESIGN AND METHODS: We described a cohort of patients presenting with symptomatic VTE following allogeneic HSCT, including management patterns and outcomes. RESULTS: Twenty-four patients developed a deep vein thrombosis and/or pulmonary embolism unrelated to a catheter. Median time of VTE diagnosis and duration of antithrombotic therapy were 9.5 and 6months. Eleven patients were treated with full-dose low molecular weight heparin (LMWH). Eleven patients with minor bleeding, thrombocytopenia or renal failure received prophylactic dose LMWH. In two patients an inferior vena cava filter was inserted due to thrombocytopenia and bleeding. There were 2 major and 4 life-threatening bleeding episodes, so LMWH was discontinued permanently. Two deaths were directly attributable to bleeding. Ten patients developed a catheter-associated VTE. Median time to diagnosis and duration of anticoagulation was 2.5 and 3months. Catheter was removed in all patients. LMWH was administered at therapeutic-dose in 4 patients, and was reduced by bleeding in 2 of them. LMWH was administered at prophylactic-dose in 6 patients, and was reduced by renal failure in one patient. There were three episodes of minor bleeding. Rate of clot recurrence was 29.4% (n=10). Patients at recurrence were without antithrombotic treatment (n=4), intermediate-dose LMWH (n=2), low-dose LMWH (n=2) or acenocumarol (n=2). Eight patients with recurrence VTE had extensive chronic graft versus host disease (GVHD). CONCLUSIONS: LMWH was used in most HSCT recipients but half of them may not receive full-dose LMWH. Thrombocytopenia, renal impairment and bleeding were the reasons for reducing LMWH. Also, rates of clinically relevant hemorrhage or recurrent VTE were highly significant. The development of GVHD could mainly explain these findings.

Influence of UGT2B7, CYP3A4, and OPRM1 Gene Polymorphisms on Transdermal Buprenorphine Pain Control in Patients with Critical Lower Limb Ischemia Awaiting Revascularization.

BACKGROUND: Pain control in critical limb ischemia (CLI) varies considerably between individuals. OBJECTIVE: To evaluate pharmacogenetically the response to transdermal buprenorphine (BUP-TTS) in patients with CLI who are awaiting revascularization. METHODS: One hundred and seven patients with CLI were treated with BUP-TTS. The following were analyzed: (1) pain perception (visual analog scale (VAS) before and 4 days after treatment) and (2) genetics: glucuronosyltransferase (UGT2B7), cytochrome (CYP3A4), and µ-opioid receptor (OPRM1) gene polymorphisms. RESULTS: Ninety-three patients completed the study. The VAS score by the fourth day of analgesia dropped from 6.82 to 3.38 (P < 0.05). The analgesic response to BUP-TTS was greater in men than in women (P = 0.019). Patients who were AA homozygotes for the CYP3A4 gene showed the best response to analgesic treatment (P = 0.003). The combination of the CYP3A4 gene with UGT2B7 or OPRM1 was favorable to the effect of the CYP3A4 gene (P = 0.045 and P = 0.026, respectively). The combination of UGT2B7 with OPRM1 was ineffective (P = 0.648). The 3 polymorphisms together had no effect on response to treatment (P = 0.461). CONCLUSIONS: BUP-TTS is efficacious in the control of pain in patients with CLI. The homozygous AA carriers of the CYP3A4 gene respond better to treatment with BUP-TTS.

Incidence and risk factors for life-threatening bleeding after allogeneic stem cell transplant.

Bleeding is a frequent complication after allogeneic haematopoietic stem cell transplantation (HSCT) and may affect survival. The purpose of this study was to determine the incidence and risk factors for life-threatening bleeding after HSCT by retrospective evaluation of 491 allogeneic HSCT recipients. With a median follow-up of 33 months, 126 out of 491 allogeneic HSCT recipients experienced a haemorrhagic event (25·7%) and 46 patients developed a life-threatening bleeding episode (9·4%). Pulmonary and gastrointestinal bleeding were the most common sites for life-threatening bleeding, followed by central nervous system. In multivariate analyses, the presence of severe thrombocytopenia after day +28 and the development of grade III-IV acute graft-versus-host disease (GVHD) or thrombotic microangiopathy (TMA) retained their association with life-threatening bleeding events. The overall survival at 3 years among patients without bleeding was 67·1% for only 17·1% for patients with life-threatening bleeding (P < 0·001). In conclusion, life-threatening bleeding is a common complication after allogeneic HSCT. Prolonged severe thrombocytopenia, acute grade III-IV GVHD and TMA were associated with its development.

Monitoring the practice of vascular surgery: findings from a national registry (1996-2011).

BACKGROUND: The goal of this article is to present for the first time to the international community the detailed findings and outcomes of the Spanish Vascular Registry (SVR) after 16 years of experience. METHODS: We examined the nationwide registry promoted by the Spanish Society of Angiology and Vascular Surgery (1996-2011). The changes in vascular surgical activity in Spain during the period of study were examined. We evaluated the number of services, medical specialists, consultations, admissions, and operations that occurred in Spain. We also assessed the trends in therapeutic activity and the medical and social impact of vascular pathology. RESULTS: A mean of 60 centers (range = 32-83) participated in the SVR (79.3 % of the total). In the last year of the study period, 94.3 % centers (100 % of teaching centers) participated. The mean number of activities per hospital per year was 5,298 consultations, 2,625 vascular explorations, 630 hospital admissions (61 % elective and 31 % emergency), and 742 surgical procedures. A total of 29,289 carotid stenosis procedures had been registered over 16 years. Both carotid endarterectomy (CEA) and carotid artery stenting (CAS) procedures have increased in frequency over time. In 2011, CAS constituted 19.3 % of all carotid procedures. A total of 31,703 abdominal aortic aneurysm (AAA) operations were registered during the study period. Surgery for ruptured AAA remained stable over time. Since its appearance in the year 2000, endovascular treatment (EVAR) increased steadily over time. Currently, EVAR represents about half of all AAA surgery (50.2 %). The total rate of in-hospital operative deaths was 1.1 %, but in-hospital mortality for open arterial surgery was 4 %. Mortality has decreased of late. CONCLUSIONS: The SVR has enabled us to understand the development and implementation of vascular surgery throughout Spain and to note the increased healthcare activity and the better overall results obtained as a consequence.

Analysis of incidence, risk factors and clinical outcome of thromboembolic and bleeding events in 431 allogeneic hematopoietic stem cell transplantation recipients.

Allogeneic hematopoietic stem cell transplantation recipients have an increasing risk of both hemorrhagic and thrombotic complications. However, the competing risks of two of these life-threatening complications in these complex patients have still not been well defined. We retrospectively analyzed data from 431 allogeneic transplantation recipients to identify the incidence, risk factors and mortality due to thrombosis and bleeding. Significant clinical bleeding was more frequent than symptomatic thrombosis. The cumulative incidence of a bleeding episode was 30.2% at 14 years. The cumulative incidence of a venous or arterial thrombosis at 14 years was 11.8% and 4.1%, respectively. The analysis of competing factors for venous thrombosis revealed extensive chronic graft-versus-host disease to be the only independent prognostic risk factor. By contrast, six factors were associated with an increased risk of bleeding; advanced disease, ablative conditioning regimen, umbilical cord blood transplantation, anticoagulation, acute III-IV graft-versus-host disease, and transplant-associated microangiopathy. The development of thrombosis did not significantly affect overall survival (P=0.856). However, significant clinical bleeding was associated with inferior survival (P<0.001). In allogeneic hematopoietic stem cell transplantation, significant clinical bleeding is more common than thrombotic complications and affects survival.

Open and endovascular treatment for pseudoaneurysms of the superior mesenteric artery.

BACKGROUND: Pseudoaneurysms of the superior mesenteric artery are rare, and their natural history is characterized by their tendency to rupture, thereby leading to a high mortality rate. Compared with classic surgical techniques (open), in recent years the possibility of endovascular treatment has increased. RESULTS: We report the cases of two patients with a pseudoaneurysm of the superior mesenteric artery. Each case was successfully treated in a different way: open and endovascular surgery. CONCLUSION: Despite the advantages (less risk for the patient) and good results obtained with endovascular surgery, this cannot completely replace open surgery. The choice of the most appropriate therapeutic option for pseudoaneurysms of the superior mesenteric artery depends on the state of the patient and the characteristics of the lesion. Open and endovascular surgical techniques are complementary, not mutually exclusive, techniques.

Femoral vein injury and transposition techniques: a new approach to venous reconstruction in the setting of trauma.

Femoral vein (FV) injury is infrequent but potentially serious. Venous repair is the procedure of choice and multiple technical options are performed. This article describes a novel venous reconstruction technique of transposition of the injured FV into the deep femoral vein (DFV) system. Two men, 26 years and 32 years old, were evaluated after suffering penetrating wounds to the inguinal region, resulting in proximal FV injuries. Both the patients were treated with a lateral venorraphy of the common FV and transposition of the FV to DFV (end-to-side anastomosis). Venous thrombectomy was not required; intravenous unfractionated heparin and local acting heparin were administered during surgery. Low molecular weight heparin therapy was routinely administered before intervention in combination with elastic compression stockings. Duplex ultrasound at 1 month and 6 months after the injury demonstrated patency and luminal integrity of the involved vein in both the patients. Clinical follow-up without duplex at 12 months and 18 months revealed no evidence of chronic venous insufficiency. In instances of penetrating injury to the proximal FV, transposition to the DFV represents a novel and effective alternative to establishing venous outflow from the extremity. This technique is relatively simple and presents good permeability in the medium term. However, possible and often tolerated ligation of penetrating FV injuries should be considered a last option.

[Risk of venous thromboembolic disease in general surgery]. / Riesgo de la enfermedad tromboembólica venosa en cirugía general.

Despite preventive efforts, venous thromboembolic disease (VTED) is still a major problem for surgeons due to its frequency and the morbidity, mortality and enormous resource consumption caused by this entity. However, the most important feature of VTED is that it is one of the most easily preventable complications and causes of death. To take appropriate prophylactic decisions (indication, method, initiation, duration, etc.), familiarity with the epidemiology of VTED in general surgery and some of its most significant populations (oncologic, laparoscopic, bariatric, ambulatory and short-stay) is essential. These factors must also be known to determine the distinct risk factors in these settings with a view to stratifying preoperative risk.

[Prevention of venous thromboembolic disease in general surgery]. / Prevención de la enfermedad tromboembólica venosa en cirugía general.

Postoperative venous thromboembolic disease (VTED) affects approximately one in four general surgery patients who do not receive preventive measures. In addition to the risk of pulmonary embolism, which is often fatal, patients with VTED may develop long-term complications such as post-thrombotic syndrome or chronic pulmonary hypertension. In addition, postoperative VTED is usually asymptomatic or produces clinical manifestations that are attributed to other processes and consequently this complication is often unnoticed by the surgeon who performed the procedure. Thus, the most effective strategy consists of effective prevention of VTED using the most appropriate prophylactic measures against the patient's thromboembolic risk. There is sufficient evidence that VTED can be prevented by pharmacological methods, especially heparin and its derivatives and with mechanical methods such as support tights or intermittent pneumatic compression of the lower extremities. To reduce the incidence of VTED as far as possible, strategies have been proposed that include a combination of drugs and mechanical methods, new antithrombotic drugs, or prolonging the duration of prophylaxis in patients at very high risk, such as those who have undergone surgery for cancer. Another important aspect is the optimal moment to initiate prophylaxis with anticoagulant drugs with the aim of achieving an adequate equilibrium between antithrombotic efficacy and the risk of hemorrhagic complications. The present article reviews the available evidence to attempt to optimize prevention of VTED in general surgery and in some special groups, such as laparoscopic surgery, short-stay surgery and obesity.

Surgery of vagal paragangliomas: six patients and review of literature.

BACKGROUND AND AIMS: Vagal paragangliomas (VPs) represent a rare pathology in which surgery is usually recommended, but where experience is crucial to reduce the number of post-operative complications. In this study, we present our experience and a review of the literature. METHODS: Between 1991 and 2006 we have treated 42 patients with 50 paragangliomas of the head and neck (26 carotid, 18 jugular/tympanic and 6 vagal). Examination of the literature (Medline and non-indexed Spanish source) from the last 30 years has revealed 23 series that each reported more than three cases; reaching a total of 332 VPs. RESULTS: VPs are infrequent among paragangliomas of the head and neck (6/50) presenting clinical peculiarities such as multiple tumours, and malignant evolution. Within this current series, surgery was possible in all cases. Post-operative dysfunction in cranial nerves was frequent (the cranial X nerve was systematically sacrificed). There were no bronco-aspirations or mortalities. The literature review reveals similar results. CONCLUSION: To obtain the best results, it is important that the candidates for surgery be selected by experts within multidisciplinary groups.

Emergency surgery of the abdominal aorta in a porcine model: two sequential experiments.

The aim of this study was to design an aggressive nonlethal animal model that would simulate surgical treatment of the abdominal aorta with a view to studying the systemic inflammatory response. Fourteen pigs were subjected to two sequential experiments. Experiment A was performed to determine the response to two degrees of hemorrhage: (A1) 40% bleeding; and (A2) 60% bleeding over 15 minutes followed by midline laparotomy and aortic dissection. Experiment B included two methods of aortic repair: (B1) aortic resection and replacement with a prosthesis; and (B2) aortic bypass without aortic resection. In the latter two groups, suprarenal aortic cross-clamping was placed for 30 minutes after a 40% hemorrhage. We analyzed various inflammatory markers and mortality. The 40% bleeding (vs. 60%) elicited a smaller decrease in mean arterial pressure (110 +/- 6 vs. 89 +/- 9 mmHg) but did not cause irreversible shock or mortality. After the 40% hemorrhage, the B1 aortic repair caused two cases of paraplegia. We have developed a model to study the combined effect of bleeding and aortic cross-clamping.

The comparative abilities of propofol and sevoflurane to modulate inflammation and oxidative stress in the kidney after aortic cross-clamping.

BACKGROUND: Propofol has been reported to provide protection against ischemia-reperfusion injury. Nuclear transcription factor kappa B (NFkappaB) plays a key role in oxidative stress and the inflammatory response during ischemia-reperfusion. We compared the effect of propofol with sevoflurane on kidney NFkappaB expression and systemic inflammatory responses induced by aortic clamping. METHODS: Twenty piglets were divided into four groups: sham surgery group with propofol (group SP, n = 5); sham group with sevoflurane (group SS, n = 5); and suprarenal clamping for 30 min with aorta-aortic bypass under propofol (group CP, n = 5) or sevoflurane (group CS, n = 5) anesthesia. Propofol was administered at 4 mg x kg(-1) x h(-1) i.v. and sevoflurane given at 1.5% inspiratory concentration. Peripheral blood and kidney biopsies were taken before the start of surgery, 15 min after unclamping the aorta, 24, 48, 72 h, and 7 days after surgery. Plasma creatinine, myeloperoxidase, tumor necrosis factor-alpha, interleukin 1-beta; and kidney superoxide anion and superoxidase dismutase were measured. The expression of inducible nitric oxide synthase and renal tissue NFkappaB was measured using Western blotting. RESULTS: Compared with the CS group, animals in the CP group had lower concentrations of myeloperoxidase, tumor necrosis factor-alpha, interleukin 1beta, superoxide anion, superoxidase dismutase (P < 0.05) from 24 to 72 h after surgery and diminished NFkappaB expression and inducible nitric oxide synthase activity (P < 0.05) at 48 and 72 h after surgery, respectively. CONCLUSIONS: Compared with sevoflurane, propofol administration during suprarenal aortic clamping and unclamping led to modulation of markers of inflammation and decreased NFkappaB expression.