Une Liaison Dangereuse: Spontaneous Pyeloduodenal Fistula.

We describe the case of a 76-year-old woman with a spontaneous nephroduodenal fistula. The patient was initially evaluated for gastrointestinal and urinary symptoms associated with fever and anemia, after which she was admitted with the diagnosis of right chronic pyelonephritis, hydronephrosis, and renal lithiasis. The fistula was diagnosed incidentally by percutaneous pyelography during a right nephrostomy and was later confirmed with an abdominal CT scan. A multidisciplinary decision was made to surgically treat the fistula (right nephrectomy plus duodenal repair); the surgery had a short-term positive outcome. We report a systematic review of the literature related to spontaneous pyeloduodenal fistulæ and their treatments.

Novel Modality of Endoluminal Anastomotic Integrity Assessment with Fluoroangiography After Left-sided Colorectal Resections.

BACKGROUND: Several methods have been described for the intraoperative evaluation of colorectal anastomotic integrity. Technological evolution has allowed to progress from basic mechanical methods to the use of more sophisticated techniques. This study describes a novel endoluminal modality of colorectal anastomotic assessment through the use of a Disposable Rigid Scope Introducer (DRSI) also allowing for intraoperative endoluminal perfusion evaluation by indocyanine green (ICG) fluoroangiography in patients undergoing left-sided colorectal resection. METHODS: The DRSI consists of an endoluminal introducer device made up of an insertion tube and port connected to an insufflation bulb to manually insufflate the sigmoid and rectum and is compatible with any laparoscopic camera, also allowing for ICG fluoroangiography for perfusion purposes. RESULTS: The DRSI was successfully used to assess anastomotic integrity after left-sided colorectal resections performed in 16 consecutive patients. The DRSI allowed to visualize by fluoroangiography the quality of tissue perfusion at the anastomotic site in all cases, contributing to the decision of avoiding loop ileostomies in low rectal resections. In 2 cases, the DRSI showed the presence of significant anastomotic bleeding which was successfully controlled by laparoscopic suture placement. No adverse event resulted from the use of this device. CONCLUSIONS: The DRSI combines direct endoluminal visualization of the anastomosis together with real-time evaluation of its blood flow. This device holds great potential for prompt intraoperative detection of anastomotic alterations, possibly reducing the risk of postoperative anastomotic bleeding or leaks related to mechanical construction/perfusion issues. Potential advantages of this device warrant larger cohort studies and prospective randomized trials.

Neuropeptide Y Promotes Human M2 Macrophage Polarization and Enhances p62/SQSTM1-Dependent Autophagy and NRF2 Activation.

Neuropeptide Y (NPY) is an abundantly expressed peptide capable of modulating innate and adaptive immune responses and regulating chemotaxis and cytokine secretion by macrophages. Abnormal regulation of NPY is involved in the development of atherosclerosis. The inflammatory infiltrate within atherosclerotic plaque is characterized by accumulation of macrophages, which are subject to reprogram their phenotypes in response to environmental signals. Macrophage number and phenotype influence plaque fate. Here, we investigated the effect of NPY on the changes in phenotype and functions of human macrophages, from the pro-inflammatory phenotype M1 to the reparative M2, indicative of atherosclerosis regression or stabilization. Human monocytes were differentiated in vitro into macrophages with M-CSF (M0) and polarized towards an M1 phenotype with IFN-γ plus LPS M(IFN-γ/LPS) or M2 with IL-10 (M IL-10) and further challenged with NPY (10-7-10-9 M) for 8-36 h. Cell phenotype and functions were analyzed by immunofluorescence and immunochemical analyses. NPY affected macrophage surface markers and secretome profile expression, thus shifting macrophages toward an M2-like phenotype. NPY also prevented the impairment of endocytosis triggered by the oxysterol 7-keto-cholesterol (7KC) and prevented 7KC-induced foam cell formation by reducing the lipid droplet accumulation in M0 macrophages. NPY-treated M0 macrophages enhanced the autophagosome formation by upregulating the cell content of the autophagy markers LC3-II and p62-SQSTM1, increased activation of the anti-oxidative transcription factor NRF2 (NF-E2-related factor 2), and subsequently induced its target gene HMOX1 that encodes heme oxygenase-1. Our findings indicate that NPY has a cytoprotective effect with respect to the progression of the inflammatory pathway, both enhancing p62/SQSTM1-dependent autophagy and the NRF2-antioxidant signaling pathway in macrophages. NPY signaling may have a crucial role in tissue homeostasis in host inflammatory responses through the regulation of macrophage balance and functions within atherosclerosis.

Original approach for thrombolytic therapy in patients with Ilio-femoral deep vein thrombosis : 2 years follow-up.

OBJECTIVE: The aim of the study was to discuss the results of catheter-directed thrombolysis and complementary procedures to treat acute iliofemoral deep vein thrombosis (DVT) evaluating the safety and effectivness of an easy access such as the Great Saphenous Vein. METHODS AND MATERIALS: A total of 22 consecutive patients with iliofemoral thrombosis and two patients with femoro-popliteal thrombosis on recent onset diagnosed with Ultrasound Doppler and contrast venography underwent intrathrombus drip infusion of urokinase while intravenous heparin was continued using saphenical access. Residual venous stenosis were treated in six patients by percutaneous balloon Angioplasty and stenting. All patients underwent routine venous duplex imaging at 30 days, 3 months, 6 months and every 6 months thereafter. RESULTS: Complete patency of thrombosed veins was restored in 22 patients (91 %) with prompt symptomatic relief. There were no major complications in the immediate outcomes. At follow-up, two patients reported a persistant slim iliac vein stenosis, two patients had post-thrombotic syndrome, and two patients showed Deep Vein Reflux. CONCLUSION: Local thrombolysis using saphenical access was a safe and effective approach for the treatment of acute iliofemoral deep vein thrombosis. It seems to be a valid, easy and safe alternative, reducing the risks of haematoma and venous lesions, which can be observed when using femoral, popliteal, and trans-jugular access.

Actin is a target of T-cell reactivity in patients with advanced carotid atherosclerotic plaques.

Atherosclerosis is a chronic inflammatory disease of the arterial wall associated with autoimmune reactions. In a previous study, we observed the presence of actin-specific antibodies in sera from patients with carotid atherosclerosis. To extend our previous results we evaluated the possible role of actin as antigenic target of cell-mediated immune reactions in carotid atherosclerosis. Peripheral blood mononuclear cells (PBMC) from 17 patients and 16 healthy subjects were tested by cell proliferation assay and by ELISA for cytokine production. Actin induced a proliferative response in 47% of patients' PBMC samples, with SI ranging from 2.6 to 21.1, and in none of the healthy subjects' samples (patients versus healthy subjects, P = 0.02). The presence of diabetes in patients was significantly associated with proliferative response to actin (P = 0.04). IFN- γ and TNF- α concentrations were higher in PBMC from patients than in those from healthy subjects and in PBMC proliferating to actin than in nonproliferating ones. Our data demonstrate for the first time a role of actin as a target autoantigen of cellular immune reactions in patients with carotid atherosclerosis. The preferential proinflammatory Th1 activation suggests that actin could contribute to endothelial dysfunction, tissue damage, and systemic inflammation in carotid atherosclerosis.

Increased circulating levels of MIP-1α and CD14 are associated with the presence of severe stenosis and hypoechoic plaques in patients with carotid atherosclerosis.

OBJECTIVE: Carotid atherosclerosis, a major cause of ischemic cerebrovascular events, is characterized by a pro-inflammatory and pro-oxidant vascular microenvironment. The current risk score models based on traditional risk factors for cardiovascular risk assessment have some limitations. The identification of novel blood biomarkers could be useful to improve patient management. The aim of the study was to evaluate the association of selected inflammation- and oxidative stress-related markers with the presence of severe stenosis and/or vulnerable plaques. METHODS: Circulating levels of soluble CD40 ligand, interleukin-10, macrophage inflammatory protein (MIP)-1α, endoglin, CD163, CD14, E-selectin, tumor necrosis factor-α, monocyte chemoattractant protein-1, C-Reactive protein, CD40 L + T lymphocytes, total antioxidant capacity, glutathione reductase activity, and protein carbonyl content were determined in patients with carotid atherosclerosis. RESULTS: Multiparametric analysis showed significantly higher levels of MIP-1α in patients with stenosis ≥70% than in patients with stenosis <70%, and significantly higher levels of CD14 in patients with hypoechoic (vulnerable) lesions compared to those with hyperechoic (stable) ones. The area under the curve obtained by the receiver operating characteristic curve analysis was 0.7253 for MIP-1α and 0.6908 for CD14. CONCLUSIONS: Our data suggest that circulating MIP-1α and CD14 levels are associated with the presence of advanced stenosis and of vulnerable carotid plaques.

Cerebral oximetry monitoring by means of INVOS-4100 as a predictor of ischemic events during carotid endarterectomy.

Background: Several methods have been proposed to monitor cerebral perfusion during carotid endarterectomy (CEA), with the purpose of minimizing the risk of perioperative stroke. The INVOS-4100 is able to detect cerebral oxygen saturation providing an intraoperative real-time monitoring system of cerebral oximetry. The aim of this study was to evaluate the performance of the INVOS-4100 in predicting cerebral ischemia during CEA. Methods: Between January 2020 and May 2022, 68 consecutive patients were scheduled for CEA either under general anesthesia or regional anesthesia with deep and superficial cervical block. Vascular oxygen saturation was recorded continually through INVOS before and during clamping of the ICA. Awake testing was performed in the group of patients undergoing CEA under regional anesthesia. Results: Sixty-eight patients were included; 43 were males (63.2%). Severe stenosis of the artery was present in 92%. Forty-one (60.3%) patients were monitored by INVOS, while 22 (39.7%) underwent awake testing. Mean clamping time was 20 ± 6.6 min. Patients undergoing awake testing had a lower hospital stay and ICU stay during admission (p = 0.011 and p = 0.007 respectively). Comorbidities correlated with a higher ICU stay (p < 0.05). The INVOS monitoring was able to predict ischemic events with a sensitivity of 98% (AUC = 0.976). Conclusions: The present study demonstrates that cerebral oximetry monitoring was a strong predictor of cerebral ischemia, although it was not possible to determine the non-inferiority of cerebral oximetry compared to awake testing. Nonetheless, the use of cerebral oximetry evaluates only perfusion in the superficial brain tissue and an absolute rSO2 value corresponding to significant cerebral ischemia has not been established. Therefore, larger prospective studies that correlate cerebral oximetry with neurologic outcomes are needed.

T lymphocyte autoreactivity in inflammatory mechanisms regulating atherosclerosis.

Atherosclerosis has been clearly demonstrated to be a chronic inflammatory disease of the arterial wall. Both cells of the innate and the acquired immune system, particularly monocytes and T lymphocytes, are implicated in the atherogenic process, producing different cytokines with pro- and anti-inflammatory effects. The majority of pathogenic T cells involved in atherosclerosis are of the Th1 profile, that has been correlated positively with coronary artery disease. Many studies conducted to evaluate the molecular factors responsible for the activation of T cells have demonstrated that the main antigenic targets in atherosclerosis are modified endogenous structures. These self-molecules activate autoimmune reactions mainly characterized by the production of Th1 cytokines, thus sustaining the inflammatory mechanisms involved in endothelial dysfunction and plaque development. In this paper we will summarize the different T-cell subsets involved in atherosclerosis and the best characterized autoantigens involved in cardiovascular inflammation.

Intracholecystic versus Intravenous Indocyanine Green (ICG) Injection for Biliary Anatomy Evaluation by Fluorescent Cholangiography during Laparoscopic Cholecystectomy: A Case-Control Study.

(1) Background: Fluorescence cholangiography has been proposed as a method for improving the visualization and identification of extrahepatic biliary anatomy in order to possibly reduce injuries and related complications. The most common method of indocyanine green (ICG) administration is the intravenous route, whereas evidence on direct ICG injection into the gallbladder is still quite limited. We aimed to compare the two different methods of ICG administration in terms of the visualization of extrahepatic biliary anatomy during laparoscopic cholecystectomy (LC), analyzing differences in the time of visualization, as well as the efficacy, advantages, and disadvantages of both modalities. (2) Methods: A total of 35 consecutive adult patients affected by acute or chronic gallbladder disease were enrolled in this prospective case−control study. Seventeen patients underwent LC with direct gallbladder ICG injection (IC-ICG) and eighteen subjects received intravenous ICG administration (IV-ICG). (3) Results: The groups were comparable with regard to their demographic and perioperative characteristics. The IV-ICG group had a significantly shorter overall operative time compared to the IC-ICG group (p = 0.017). IV-ICG was better at delineating the duodenum and the common hepatic duct compared to the IC-ICG method (p = 0.009 and p = 0.041, respectively). The cystic duct could be delineated pre-dissection in 76.5% and 66.7% of cases in the IC-ICG and IV-ICG group, respectively, and this increased to 88.2% and 83.3% after dissection. The common bile duct could be highlighted in 76.5% and 77.8% of cases in the IC-ICG and IV-ICG group, respectively. Liver fluorescence was present in one case in the IC-ICG group and in all cases after IV-ICG administration (5.8% versus 100%; p < 0.0001). (4) Conclusions: The present study demonstrates how ICG-fluorescence cholangiography can be helpful in identifying the extrahepatic biliary anatomy during dissection of Calot's triangle in both administration methods. In comparison with intravenous ICG injection, the intracholecystic ICG route could provide a better signal-to-background ratio by avoiding hepatic fluorescence, thus increasing the bile duct-to-liver contrast.

Autoantibodies to the C-terminal subunit of RLIP76 induce oxidative stress and endothelial cell apoptosis in immune-mediated vascular diseases and atherosclerosis.

Although detection of autoantibodies in the peripheral blood from patients with immune-mediated endothelial dysfunctions has so far failed to provide tools of diagnostic or pathogenetic value, putative bioindicators include anti-endothelial cell antibodies, a heterogeneous family of antibodies that react with autoantigens expressed by endothelial cells. In this study, to identify endothelial autoantigens involved in the autoimmune processes causing endothelial damage, we screened a human microvascular endothelial cell cDNA library with sera from patients with Behçet's disease. We identified antibodies to the C-terminus of Ral binding protein1 (RLIP76), a protein that catalyzes the ATP-dependent transport of glutathione (GSH) conjugates including GSH-4-hydroxy-t-2,3-nonenal, in the serum of a significant percentage of patients with various diseases characterized by immune-mediated endothelial dysfunction, including Behçet disease, systemic sclerosis, systemic lupus erythematosus and carotid atherosclerosis. These autoantibodies increased intracellular levels of 4-hydroxy-t-2,3-nonenal, decreased levels of GSH and activated C-Jun NH2 Kinase signaling (JNK), thus inducing oxidative stress-mediated endothelial cell apoptosis. The dietary antioxidant alpha-tocopherol counteracted endothelial cell demise. These findings suggest that autoantibodies to RLIP76 play a pathogenetic role in immune-mediated vascular diseases and represent a valuable peripheral blood bioindicator of atherosclerosis and immune-mediated vascular diseases.

Platelet Lysate-Derived Neuropeptide y Influences Migration and Angiogenesis of Human Adipose Tissue-Derived Stromal Cells.

Neuropeptide Y (NPY), a powerful neurotransmitter of the central nervous system, is a key regulator of angiogenesis and biology of adipose depots. Intriguingly, its peripheral vascular and angiogenic powerful activity is strictly associated to platelets, which are source of clinical hemoderivates, such as platelet lysate (PL), routinely employed in several clinical applications as wound healing, and to preserve ex vivo the progenitor properties of the adipose stromal cells pool. So far, the presence of NPY in PL and its biological effects on the adipose stromal cell fraction (ASCs) have never been investigated. Here, we aimed to identify endogenous sources of NPY such as PL-based preparations and to investigate which biological properties PL-derived NPY is able to exert on ASCs. The results show that PL contains a high amount of NPY, which is in part also excreted by ASCs when stimulated with PL. The protein levels of the three main NPY subtype receptors (Y1, Y2, Y5) are unaltered by stimulation of ASCs with PL, but their inhibition through selective pharmacological antagonists, considerably enhances migration, and a parallel reduction of angiogenic features of ASCs including decrease in VEGF mRNA and intracellular calcium levels, both downstream targets of NPY. The expression of VEGF and NPY is enhanced within the sites of neovascularisation of difficult wounds in patients after treatment with leuco-platelet concentrates. Our data highlight the presence of NPY in PL preparations and its peripheral effects on adipose progenitors.

Intracellular expression of cytokines in peripheral blood from patients with atherosclerosis before and after carotid endarterectomy.

OBJECTIVE: We investigated the possible association of intracellular cytokine profiles in peripheral mononuclear cells in whole blood from patients with carotid atherosclerosis in whom follow-up after carotid endarterectomy (CEA) showed the onset or progression of contralateral disease. METHODS AND RESULTS: Intracellular expression of tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, interleukin (IL)-1beta, IL-6, IL-8, IL-4 and IL-10 was determined in 43 patients with carotid atherosclerosis, at baseline and at 1, 3, 6 and 12 months after CEA, and in 16 healthy subjects. When follow-up ended patients were divided into two groups, those with cured or stable disease (no onset of disease or unchanged stenosis in the contralateral vessel) and those with progressive disease (onset of disease or increased stenosis in the contralateral vessel). In patients with cured or stable disease, cytokine-positive cells significantly decreased or remained unchanged (IL-8 and IL-10) during follow-up, whereas in patients with progressive disease they increased or remained unchanged (TNF-alpha). Multivariate ANOVA confirmed that the trend of cytokine expression between baseline and 12 months differed significantly in the two groups. CONCLUSIONS: Intracellular expression of TNF-alpha, IFN-gamma, IL-1beta, IL-6, IL-8, IL-4 and IL-10 in peripheral mononuclear cells is associated with the outcome of contralateral disease after CEA.

Free hemoglobin: a dangerous signal for the immune system in patients with carotid atherosclerosis?

Atherosclerosis is a chronic inflammatory multifactorial disease in which immune responses are key pathogenetic factors. T cell-mediated immunity contributes to the initiation and progression of atherosclerotic disease, but the nature of antigens responsible for immune cell activation is still not completely elucidated. Convincing evidence supports a determinant role of autoimmune responses to self-structures in shaping the progression of the disease. Autoimmune responses may be directed against altered self-structures, such as oxidized low-density lipoproteins (LDL). Oxidative stress, increasingly reported in patients with atherosclerosis, is the major event causing protein structural modification, thus inducing the appearance of neo/cryptic epitopes on the molecule. Intraplaque hemorrhage, a common event in advanced lesions, causes the deposition of large amounts of hemoglobin (Hb). The pro-oxidative intraplaque microenvironment may induce structural changes in extra-erythrocytic free Hb, thus generating novel/cryptic autoantigenic epitopes. We demonstrated that an oxidized Hb preparation enriched in hemichromes expands IFN-gamma-secreting T lymphocytes in patients with advanced carotid atherosclerosis and enhances the phenotypical and functional maturation of human monocyte-derived dendritic cells induced by lipopolysaccharide (LPS). Overall, our findings suggest that oxidized forms of Hb could act as a dangerous signal for the immune system, thus contributing to the inflammatory process that takes place within the atherosclerotic plaque.

Heat shock proteins and autoimmunity in patients with carotid atherosclerosis.

Studies aimed at elucidating the pathogenetic mechanisms underlying the initiation and progression of human atherosclerosis have emphasized the central role of inflammatory and immune cells. Atherosclerotic plaques are infiltrated by activated macrophages, T and B lymphocytes, plasma cells, and mast cells, releasing inflammatory molecules, which amplify the severity of the disease. Endothelial cells subjected to various stress conditions express increased amounts of heat shock proteins (HSPs), some of the most successfully conserved proteins throughout evolution. Many experimental observations reviewed in this article draw attention to several HSPs targeted by a specific cellular and humoral immune response in patients with atherosclerotic disease. The review also reports preliminary data obtained by our group on the possible role of HSP90 as a candidate autoantigen in carotid atherosclerosis. Our study deals with the presence of specific antibodies and T cells directed against HSP90 in patients with carotid atherosclerotic plaques. In 60% of these subjects' sera but in none of the sera from healthy controls immunoblotting (IB) detected the presence of specific antibodies. Moreover, 20% of peripheral blood mononuclear cells (PBMC) samples from patients but none from healthy subjects proliferated in response to human purified HSP90. In vitro experiments showed an upregulation of HSP90 expression in endothelial cells exposed to oxidative stress by treatment with H(2)O(2) and greater release of soluble HSP90 in culture supernatants from H(2)O(2)-treated cells than from untreated cells.

Wounds Difficult to Heal: An Effective Treatment Strategy.

OBJECTIVE: Treatment of wounds difficult to heal concerns 50% of the elderly population in Italy and is therefore a relevant social burden. The present study shows how the treatment with autologous leuco-platelets reduces the healing time of wounds improving the functional recovery. PATIENTS AND METHODS: Patients (n=100) with ulcers of the legs were divided in two groups: 1) 50 patients treated with conventional therapies; 2) 50 patients treated with autologous leuco-platelet concentrate (LPC) and hyaluronic acid (HIAFF, Hyalofill-F® ) as a scaffold. RESULTS: After 2 months, a 49% reduction in wound area was observed in the second group and in about 65% wound reduction was achieved in 15 days (4 LPC dressings). In contrast, patients treated by conventional therapies, showed a longer healing time and a greater percentage of failures. Morphometric analysis of biopsy samples obtained from the edge as well as from the bottom of the lesions obtained from the LPC group, detected an abundant presence of neoformed capillaries, characterized by a cubic, "reactive endothelium", close to the site of LPC infiltration. CONCLUSION: These results suggest that healing was promoted not only by limiting bacterial infections but also by the release of chemotactic and proangiogenic factors from leukocytes and platelets, improving the neoformation of capillaries.

Multidisciplinary approaches to stimulate wound healing.

New civil wars and waves of terrorism are causing crucial social changes, with consequences in all fields, including health care. In particular, skin injuries are evolving as an epidemic issue. From a physiological standpoint, although wound repair takes place more rapidly in the skin than in other tissues, it is still a complex organ to reconstruct. Genetic and clinical variables, such as diabetes, smoking, and inflammatory/immunological pathologies, are also important risk factors limiting the regenerative potential of many therapeutic applications. Therefore, optimization of current clinical strategies is critical. Here, we summarize the current state of the field by focusing on stem cell therapy applications in wound healing, with an emphasis on current clinical approaches being developed. These involve protocols for the ex vivo expansion of adipose tissue-derived mesenchymal stem cells by means of a patented Good Manufacturing Practice-compliant platelet lysate. Combinations of multiple strategies, including genetic modifications and stem cells, biomimetic scaffolds, and novel vehicles, such as nanoparticles, are also discussed as future approaches.

Surgical treatment of spontaneous common carotid dissection: a case report.

BACKGROUND: Cervical carotid dissection is more common in extracranical vessel: internal carotid artery dissection (ICAD) is typical, vertebral artery dissection is uncommon, common carotid artery dissection (CCAD) is rare and even a more rare cause of ischemic stroke. Cervical artery dissections account up to 20-25% of ischemic strokes in young patients. Isolated and spontaneous common carotid artery dissection without aortic damage is unique. Indeed in the Literature 8 cases were identified. MRI and CTA were the most commonly used for diagnosis and follow-up. CASE REPORT: A 67-year-old came to our observation reporting burning pain in the right latero-cervical region in supine position, irradiated in the temporal region and recurrent episodes of migraine with aura (scintillating scotoma), in the last 3 months. The last Doppler Ultrasound control, performed after the onset of symptoms, showed an highlighted dissection wall with double lumen at the origin of the bulb and the internal carotid artery on the right. Aortic arch arteriography confirmed the diagnosis. The patient underwent surgery (longitudinal arteriotomy, removing four miointimal flaps, fastening the distal common carotid artery with 3 Kunlin's points). RESULTS: Any neurological or vascular problems after surgery were noticed. DISCUSSION AND COMMENTS: The pathogenesis can be related to a combination of an intrinsic weakness in the arterial wall and an external trigger. The diagnosis of CAD is made with MRI (78.0%), conventional angiography (31.1%), CTA (14.7%), and ultrasound (11.3%). CONCLUSION: No evidence-based guidelines exists for treatment of CCAD. In our patient surgical CEA treatment was the optimal solution.

A large well-differentiated spindle cell liposarcoma (atypical spindle cell lipomatous tumor): clinicopathologic and immunohistochemical analysis. Diagnostic and therapeutic features.

Liposarcoma is one of the more common types of soft tissue sarcomas, presenting with a wide spectrum of clinical behaviour. It is subdivided into five distinct histologic subtypes: well-differentiated, mixoid, pleomorphic, dedifferentiated and mixed-type. Well-differentiated liposarcoma accounts for about 40% to 45% of all liposarcomas therefore representing the larger subgroup of adipocytic malignancies. Well-differentiated spindle cell liposarcoma is an extremely rare subtype of well-differentiated liposarcoma/atypical lipomatous tumor which is different from the other subtypes clinicopathologically, genetically and prognostically. The most common frequent locations of lipomatous tumours are: limbs, groin, scrotum, abdominal wall and retroperitoneal area. MRI examination is a highly reliable method in the diagnosis of these neoplasms. Surgical management includes wide resection of the tumour with or without additional postoperative radiotherapy and/or chemotherapy. We describe a case of 68-year old patient with large well-differentiated spindle cell liposarcoma of the left thigh. We are discussing the clinical findings, diagnosis and therapeutic approach. In these cases, a preoperative disease classification discriminating the tumour nature is closely linked to the correct surgical management of patients.

Oxidized haemoglobin-driven endothelial dysfunction and immune cell activation: novel therapeutic targets for atherosclerosis.

Atherosclerosis is a chronic inflammatory disease of the arterial wall characterized by endothelial dysfunction, and in which innate and adaptive immune responses have a crucial role. Autoimmune reactions against several self molecules and modified self molecules have been identified in patients with atherosclerotic disease. Oxidative stress, increasingly reported in these patients is the major event causing protein structural modifications, thus inducing the appearance of neo/cryptic epitopes. Following intraplaque haemorrhage large amounts of cell-free haemoglobin (Hb) accumulate within atheroma, due to its impaired clearance by the haptoglobin-CD163 scavenging system. The pro-oxidative intraplaque microenvironment may induce Hb structural changes, thus generating neo/cryptic autoantigenic epitopes and rendering the oxidized self molecule as a dangerous signal for both immune and endothelial cells. In this review, we will present the most relevant information on Hb as a candidate self antigen involved in the pathogenesis of atherosclerotic disease and on its ability to trigger signals that drive endothelial dysfunction and immune cell activation. On these grounds, we will also discuss how these new paradigms may lead to novel therapeutic targets for cardiovascular diseases.

Cellular and molecular players in the atherosclerotic plaque progression.

Atherosclerosis initiation and progression is controlled by inflammatory molecular and cellular mediators. Cells of innate immunity, stimulated by various endogenous molecules that have undergone a transformation following an oxidative stress or nonenzymatic glycation processes, activate cells of the adaptive immunity, found at the borders of atheromas. In this way, an immune response against endogenous modified antigens takes place and gives rise to chronic low-level inflammation leading to the slow development of complex atherosclerotic plaques. These lesions will occasionally ulcerate, thus ending with fatal clinical events. Plaque macrophages represent the majority of leukocytes in the atherosclerotic lesions, and their secretory activity, including proinflammatory cytokines and matrix-degrading proteases, may be related to the fragilization of the fibrous cap and then to the rupture of the plaque. A considerable amount of work is currently focused on the identification of locally released proinflammatory factors that influence the evolution of the plaque to an unstable phenotype. A better understanding of these molecular processes may contribute to new treatment strategies. Mediators released by the immune system and associated with the development of carotid atherosclerosis are discussed.