Fondazione Humanitas per la Ricerca

BACKGROUND: No effective systemic therapy exists for patients with advanced hepatocellular carcinoma. A preliminary study suggested that sorafenib, an oral multikinase inhibitor of the vascular endothelial growth factor receptor, the platelet-derived growth factor receptor, and Raf may be effective in hepatocellular carcinoma. METHODS: In this multicenter, phase 3, double-blind, placebo-controlled trial, we randomly assigned 602 patients with advanced hepatocellular carcinoma who had not received previous systemic treatment to receive either sorafenib (at a dose of 400 mg twice daily) or placebo. Primary outcomes were overall survival and the time to symptomatic progression. Secondary outcomes included the time to radiologic progression and safety. RESULTS: At the second planned interim analysis, 321 deaths had occurred, and the study was stopped. Median overall survival was 10.7 months in the sorafenib group and 7.9 months in the placebo group (hazard ratio in the sorafenib group, 0.69; 95% confidence interval, 0.55 to 0.87; P<0.001). There was no significant difference between the two groups in the median time to symptomatic progression (4.1 months vs. 4.9 months, respectively, P=0.77). The median time to radiologic progression was 5.5 months in the sorafenib group and 2.8 months in the placebo group (P<0.001). Seven patients in the sorafenib group (2%) and two patients in the placebo group (1%) had a partial response; no patients had a complete response. Diarrhea, weight loss, hand-foot skin reaction, and hypophosphatemia were more frequent in the sorafenib group. CONCLUSIONS: In patients with advanced hepatocellular carcinoma, median survival and the time to radiologic progression were nearly 3 months longer for patients treated with sorafenib than for those given placebo. (ClinicalTrials.gov number, NCT00105443.)

Diversity and plasticity are hallmarks of cells of the monocyte-macrophage lineage. In response to IFNs, Toll-like receptor engagement, or IL-4/IL-13 signaling, macrophages undergo M1 (classical) or M2 (alternative) activation, which represent extremes of a continuum in a universe of activation states. Progress has now been made in defining the signaling pathways, transcriptional networks, and epigenetic mechanisms underlying M1-M2 or M2-like polarized activation. Functional skewing of mononuclear phagocytes occurs in vivo under physiological conditions (e.g., ontogenesis and pregnancy) and in pathology (allergic and chronic inflammation, tissue repair, infection, and cancer). However, in selected preclinical and clinical conditions, coexistence of cells in different activation states and unique or mixed phenotypes have been observed, a reflection of dynamic changes and complex tissue-derived signals. The identification of mechanisms and molecules associated with macrophage plasticity and polarized activation provides a basis for macrophage-centered diagnostic and therapeutic strategies.

BACKGROUND: The epidermal growth factor receptor (EGFR), which participates in signaling pathways that are deregulated in cancer cells, commonly appears on colorectal-cancer cells. Cetuximab is a monoclonal antibody that specifically blocks the EGFR. We compared the efficacy of cetuximab in combination with irinotecan with that of cetuximab alone in metastatic colorectal cancer that was refractory to treatment with irinotecan. METHODS: We randomly assigned 329 patients whose disease had progressed during or within three months after treatment with an irinotecan-based regimen to receive either cetuximab and irinotecan (at the same dose and schedule as in a prestudy regimen [218 patients]) or cetuximab monotherapy (111 patients). In cases of disease progression, the addition of irinotecan to cetuximab monotherapy was permitted. The patients were evaluated radiologically for tumor response and were also evaluated for the time to tumor progression, survival, and side effects of treatment. RESULTS: The rate of response in the combination-therapy group was significantly higher than that in the monotherapy group (22.9 percent [95 percent confidence interval, 17.5 to 29.1 percent] vs. 10.8 percent [95 percent confidence interval, 5.7 to 18.1 percent], P=0.007). The median time to progression was significantly greater in the combination-therapy group (4.1 vs. 1.5 months, P<0.001 by the log-rank test). The median survival time was 8.6 months in the combination-therapy group and 6.9 months in the monotherapy group (P=0.48). Toxic effects were more frequent in the combination-therapy group, but their severity and incidence were similar to those that would be expected with irinotecan alone. CONCLUSIONS: Cetuximab has clinically significant activity when given alone or in combination with irinotecan in patients with irinotecan-refractory colorectal cancer.

The epidermal growth factor receptor (EGFR) kinase inhibitors gefitinib and erlotinib are effective treatments for lung cancers with EGFR activating mutations, but these tumors invariably develop drug resistance. Here, we describe a gefitinib-sensitive lung cancer cell line that developed resistance to gefitinib as a result of focal amplification of the MET proto-oncogene. inhibition of MET signaling in these cells restored their sensitivity to gefitinib. MET amplification was detected in 4 of 18 (22%) lung cancer specimens that had developed resistance to gefitinib or erlotinib. We find that amplification of MET causes gefitinib resistance by driving ERBB3 (HER3)-dependent activation of PI3K, a pathway thought to be specific to EGFR/ERBB family receptors. Thus, we propose that MET amplification may promote drug resistance in other ERBB-driven cancers as well.

In 57 normal subjects (age 20-60 years), we analyzed the spontaneous beat-to-beat oscillation in R-R interval during control recumbent position, 90 degrees upright tilt, controlled respiration (n = 16) and acute (n = 10) and chronic (n = 12) beta-adrenergic receptor blockade. Automatic computer analysis provided the autoregressive power spectral density, as well as the number and relative power of the individual components. The power spectral density of R-R interval variability contained two major components in power, a high frequency at approximately 0.25 Hz and a low frequency at approximately 0.1 Hz, with a normalized low frequency:high frequency ratio of 3.6 +/- 0.7. With tilt, the low-frequency component became largely predominant (90 +/- 1%) with a low frequency:high frequency ratio of 21 +/- 4. Acute beta-adrenergic receptor blockade (0.2 mg/kg IV propranolol) increased variance at rest and markedly blunted the increase in low frequency and low frequency:high frequency ratio induced by tilt. Chronic beta-adrenergic receptor blockade (0.6 mg/kg p.o. propranolol, t.i.d.), in addition, reduced low frequency and increased high frequency at rest, while limiting the low frequency:high frequency ratio increase produced by tilt. Controlled respiration produced at rest a marked increase in the high-frequency component, with a reduction of the low-frequency component and of the low frequency:high frequency ratio (0.7 +/- 0.1); during tilt, the increase in the low frequency:high frequency ratio (8.3 +/- 1.6) was significantly smaller. In seven additional subjects in whom direct high-fidelity arterial pressure was recorded, simultaneous R-R interval and arterial pressure variabilities were examined at rest and during tilt. Also, the power spectral density of arterial pressure variability contained two major components, with a relative low frequency:high frequency ratio at rest of 2.8 +/- 0.7, which became 17 +/- 5 with tilt. These power spectral density components were numerically similar to those observed in R-R variability. Thus, invasive and noninvasive studies provided similar results. More direct information on the role of cardiac sympathetic nerves on R-R and arterial pressure variabilities was derived from a group of experiments in conscious dogs before and after bilateral stellectomy. Under control conditions, high frequency was predominant and low frequency was very small or absent, owing to a predominant vagal tone. During a 9% decrease in arterial pressure obtained with IV nitroglycerin, there was a marked increase in low frequency, as a result of reflex sympathetic activation.(ABSTRACT TRUNCATED AT 400 WORDS)

Macrophages are widely distributed immune system cells that play an indispensable role in homeostasis and defense. They can be phenotypically polarized by the microenvironment to mount specific functional programs. Polarized macrophages can be broadly classified in two main groups: classically activated macrophages (or M1), whose prototypical activating stimuli are IFNgamma and LPS, and alternatively activated macrophages (or M2), further subdivided in M2a (after exposure to IL-4 or IL-13), M2b (immune complexes in combination with IL-1beta or LPS) and M2c (IL-10, TGFbeta or glucocorticoids). M1 exhibit potent microbicidal properties and promote strong IL-12-mediated Th1 responses, whilst M2 support Th2-associated effector functions. Beyond infection M2 polarized macrophages play a role in resolution of inflammation through high endocytic clearance capacities and trophic factor synthesis, accompanied by reduced pro-inflammatory cytokine secretion. Similar functions are also exerted by tumor-associated macrophages (TAM), which also display an alternative-like activation phenotype and play a detrimental pro-tumoral role. Here we review the main functions of polarized macrophages and discuss the perspectives of this field.

Comprehensive analysis of the gene expression profiles associated with human monocyte-to-macrophage differentiation and polarization toward M1 or M2 phenotypes led to the following main results: 1) M-CSF-driven monocyte-to-macrophage differentiation is associated with activation of cell cycle genes, substantiating the underestimated proliferation potential of monocytes. 2) M-CSF leads to expression of a substantial part of the M2 transcriptome, suggesting that under homeostatic conditions a default shift toward M2 occurs. 3) Modulation of genes involved in metabolic activities is a prominent feature of macrophage differentiation and polarization. 4) Lipid metabolism is a main category of modulated transcripts, with expected up-regulation of cyclo-oxygenase 2 in M1 cells and unexpected cyclo-oxygenase 1 up-regulation in M2 cells. 5) Each step is characterized by a different repertoire of G protein-coupled receptors, with five nucleotide receptors as novel M2-associated genes. 6) The chemokinome of polarized macrophages is profoundly diverse and new differentially expressed chemokines are reported. Thus, transcriptome profiling reveals novel molecules and signatures associated with human monocyte-to-macrophage differentiation and polarized activation which may represent candidate targets in pathophysiology.

This paper is the second in a series of three publications relating to the European evidence-based consensus on the diagnosis and management of Crohn's disease and concerns the management of active disease, maintenance of medically induced remission and surgery. The aims and methods of the ECCO Consensus, as well as sections on diagnosis and classification are covered in the first paper [van Assche et al. JCC 2009a]. The final paper covers post-operative recurrence, fistulating disease, the management of paediatric and adolescent IBD, pregnancy, psychosomatics, extraintestinal manifestations and complementary or alternative therapy for Crohn's disease [Van Assche et al JCC 2009b]. #### Principal changes with respect to the 2006 ECCO guidelines The early use of azathioprine/mercaptopurine or methotrexate in combination with steroids is an appropriate option in moderately active localised ileocaecal CD. Anti-TNF therapy should be considered as an alternative for patients with objective evidence of active disease who have previously been steroid-refractory, steroid-dependent, or steroid-intolerant (based on Statement 5B). For those patients with severely active localised ileocaecal Crohn's disease and objective evidence of active disease who have relapsed, anti-TNF therapy with or without an immunomodulator is an appropriate option [EL1a, RG B for infliximab]. For some patients who have infrequently relapsing disease, restarting steroids with an immunomodulator may be appropriate (based on Statement 5C). All currently available anti-TNF therapies appear to have generally similar efficacy and adverse-event profiles for inflammatory (‘luminal’) Crohn's disease, so the choice depends on availability, route of delivery, patient preference, cost and national guidelines \[EL5, RG D\] (Statement 5I). Patients receiving azathioprine or mercaptopurine who relapse should be evaluated for adherence to therapy and have their dose optimised. Changing their maintenance therapy to methotrexate [EL1b RG B] or anti-TNF therapy [EL1a RGB] should be considered. Surgery should always be considered as an option in localised disease [EL4, …

Importance: Catheter ablation is effective in restoring sinus rhythm in atrial fibrillation (AF), but its effects on long-term mortality and stroke risk are uncertain. Objective: To determine whether catheter ablation is more effective than conventional medical therapy for improving outcomes in AF. Design, Setting, and Participants: The Catheter Ablation vs Antiarrhythmic Drug Therapy for Atrial Fibrillation trial is an investigator-initiated, open-label, multicenter, randomized trial involving 126 centers in 10 countries. A total of 2204 symptomatic patients with AF aged 65 years and older or younger than 65 years with 1 or more risk factors for stroke were enrolled from November 2009 to April 2016, with follow-up through December 31, 2017. Interventions: The catheter ablation group (n = 1108) underwent pulmonary vein isolation, with additional ablative procedures at the discretion of site investigators. The drug therapy group (n = 1096) received standard rhythm and/or rate control drugs guided by contemporaneous guidelines. Main Outcomes and Measures: The primary end point was a composite of death, disabling stroke, serious bleeding, or cardiac arrest. Among 13 prespecified secondary end points, 3 are included in this report: all-cause mortality; total mortality or cardiovascular hospitalization; and AF recurrence. Results: Of the 2204 patients randomized (median age, 68 years; 37.2% female; 42.9% had paroxysmal AF and 57.1% had persistent AF), 89.3% completed the trial. Of the patients assigned to catheter ablation, 1006 (90.8%) underwent the procedure. Of the patients assigned to drug therapy, 301 (27.5%) ultimately received catheter ablation. In the intention-to-treat analysis, over a median follow-up of 48.5 months, the primary end point occurred in 8.0% (n = 89) of patients in the ablation group vs 9.2% (n = 101) of patients in the drug therapy group (hazard ratio [HR], 0.86 [95% CI, 0.65-1.15]; P = .30). Among the secondary end points, outcomes in the ablation group vs the drug therapy group, respectively, were 5.2% vs 6.1% for all-cause mortality (HR, 0.85 [95% CI, 0.60-1.21]; P = .38), 51.7% vs 58.1% for death or cardiovascular hospitalization (HR, 0.83 [95% CI, 0.74-0.93]; P = .001), and 49.9% vs 69.5% for AF recurrence (HR, 0.52 [95% CI, 0.45-0.60]; P < .001). Conclusions and Relevance: Among patients with AF, the strategy of catheter ablation, compared with medical therapy, did not significantly reduce the primary composite end point of death, disabling stroke, serious bleeding, or cardiac arrest. However, the estimated treatment effect of catheter ablation was affected by lower-than-expected event rates and treatment crossovers, which should be considered in interpreting the results of the trial. Trial Registration: ClinicalTrials.gov Identifier: NCT00911508.

The aim of this guideline is to provide a minimum standard for the acquisition and interpretation of PET and PET/CT scans with [18F]-fluorodeoxyglucose (FDG). This guideline will therefore address general information about[18F]-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET/CT) and is provided to help the physician and physicist to assist to carrying out,interpret, and document quantitative FDG PET/CT examinations,but will concentrate on the optimisation of diagnostic quality and quantitative information.

UNLABELLED: This Guideline is an official statement of the European Society of Gastrointestinal Endoscopy (ESGE). The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system 1 2 was adopted to define the strength of recommendations and the quality of evidence. MAIN RECOMMENDATIONS: 1 ESGE recommends endoscopic en bloc resection for superficial esophageal squamous cell cancers (SCCs), excluding those with obvious submucosal involvement (strong recommendation, moderate quality evidence). Endoscopic mucosal resection (EMR) may be considered in such lesions when they are smaller than 10 mm if en bloc resection can be assured. However, ESGE recommends endoscopic submucosal dissection (ESD) as the first option, mainly to provide an en bloc resection with accurate pathology staging and to avoid missing important histological features (strong recommendation, moderate quality evidence). 2 ESGE recommends endoscopic resection with a curative intent for visible lesions in Barrett's esophagus (strong recommendation, moderate quality evidence). ESD has not been shown to be superior to EMR for excision of mucosal cancer, and for that reason EMR should be preferred. ESD may be considered in selected cases, such as lesions larger than 15 mm, poorly lifting tumors, and lesions at risk for submucosal invasion (strong recommendation, moderate quality evidence). 3 ESGE recommends endoscopic resection for the treatment of gastric superficial neoplastic lesions that possess a very low risk of lymph node metastasis (strong recommendation, high quality evidence). EMR is an acceptable option for lesions smaller than 10 - 15 mm with a very low probability of advanced histology (Paris 0-IIa). However, ESGE recommends ESD as treatment of choice for most gastric superficial neoplastic lesions (strong recommendation, moderate quality evidence). 4 ESGE states that the majority of colonic and rectal superficial lesions can be effectively removed in a curative way by standard polypectomy and/or by EMR (strong recommendation, moderate quality evidence). ESD can be considered for removal of colonic and rectal lesions with high suspicion of limited submucosal invasion that is based on two main criteria of depressed morphology and irregular or nongranular surface pattern, particularly if the lesions are larger than 20 mm; or ESD can be considered for colorectal lesions that otherwise cannot be optimally and radically removed by snare-based techniques (strong recommendation, moderate quality evidence).

PURPOSE: To compare the effectiveness of radio-frequency (RF) ablation with that of percutaneous ethanol injection in the treatment of small hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Eighty-six patients with 112 small (< or = 3-cm-diameter) HCCs underwent RF ablation (42 patients with 52 tumors) or percutaneous ethanol injection (44 patients with 60 tumors). Therapeutic efficacy was evaluated with dual-phase spiral computed tomography performed at least 4 months after treatment. RESULTS: Complete necrosis was achieved in 47 of 52 tumors with RF ablation (90%) and in 48 of 60 tumors with percutaneous ethanol injection (80%). These results were obtained with an average of 1.2 sessions per tumor with RF ablation and 4.8 sessions per tumor with percutaneous ethanol injection. One major complication (hemothorax that required drainage) and four minor complications (intraperitoneal bleeding, hemobilia, pleural effusion, cholecystitis) occurred in patients treated with RF ablation; no complications occurred in patients treated with percutaneous ethanol injection. CONCLUSION: RF ablation results in a higher rate of complete necrosis and requires fewer treatment sessions than percutaneous ethanol injection. However, the complication rate is higher with RF ablation than with percutaneous ethanol injection. RF ablation is the treatment of choice for most patients with HCC.

BACKGROUND: Mutations in the cardiac ryanodine receptor gene (RyR2) underlie catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited arrhythmogenic disease occurring in the structurally intact heart. The proportion of patients with CPVT carrying RyR2 mutations is unknown, and the clinical features of RyR2-CPVT as compared with nongenotyped CPVT are undefined. METHODS AND RESULTS: Patients with documented polymorphic ventricular arrhythmias occurring during physical or emotional stress with a normal heart entered the study. The clinical phenotype of the 30 probands and of 118 family members was evaluated, and mutation screening on the RyR2 gene was performed. Arrhythmias documented in probands were: 14 of 30 bidirectional ventricular tachycardia, 12 of 30 polymorphic ventricular tachycardia, and 4 of 30 catecholaminergic idiopathic ventricular fibrillation; RyR2 mutations were identified in 14 of 30 probands (36% bidirectional ventricular tachycardia, 58% polymorphic ventricular tachycardia, 50% catecholaminergic idiopathic ventricular fibrillation) and in 9 family members (4 silent gene carriers). Genotype-phenotype analysis showed that patients with RyR2 CPVT have events at a younger age than do patients with nongenotyped CPVT and that male sex is a risk factor for syncope in RyR2-CPVT (relative risk=4.2). CONCLUSIONS: CPVT is a clinically and genetically heterogeneous disease manifesting beyond pediatric age with a spectrum of polymorphic arrhythmias. beta-Blockers reduce arrhythmias, but in 30% of patients an implantable defibrillator may be required. Genetic analysis identifies two groups of patients: Patients with nongenotyped CPVT are predominantly women and become symptomatic later in life; patients with RyR2 CPVT become symptomatic earlier, and men are at higher risk of cardiac events. These data provide a rationale for prompt evaluation and treatment of young men with RyR2 mutations.

Ulcerative colitis is the most common form of inflammatory bowel disease. Its course is often mild, with few complications, and it can be cured by colectomy. Our current understanding of its pathophysiology, diagnosis, and treatment is reviewed.

PURPOSE: To study local therapeutic efficacy, side effects, and complications of radio-frequency (RF) ablation in the treatment of medium and large hepatocellular carcinoma (HCC) lesions in patients with cirrhosis or chronic hepatitis. MATERIALS AND METHODS: One-hundred fourteen patients who were under conscious sedation or general anesthesia had 126 HCCs greater than 3.0 cm in diameter treated with RF by using an internally cooled electrode. Eighty tumors were medium (3.1-5.0 cm), and 46 were large (5.1-9.5 cm). The mean diameter for all tumors was 5.4 cm. At imaging, 75 tumors were considered noninfiltrating, and 51 were considered infiltrating. RESULTS: Complete necrosis was attained in 60 lesions (47.6%), nearly complete (90%-99%) necrosis in 40 lesions (31.7%), and partial (50%-89%) necrosis in the remaining 26 lesions (20.6%). Medium and/or noninfiltrating tumors were treated successfully significantly more often than large and/or infiltrating tumors. Two major complications (death, hemorrhage requiring laparotomy) and five minor complications (self-limited hemorrhage, persistent pain) were observed. The single death was due to a break in sterile technique rather than to the RF procedure itself. CONCLUSION: RF ablation appears to be an effective, safe, and relatively simple procedure for the treatment of medium and large HCCs.

BACKGROUND: We investigated the long-term outcome of gene therapy for severe combined immunodeficiency (SCID) due to the lack of adenosine deaminase (ADA), a fatal disorder of purine metabolism and immunodeficiency. METHODS: We infused autologous CD34+ bone marrow cells transduced with a retroviral vector containing the ADA gene into 10 children with SCID due to ADA deficiency who lacked an HLA-identical sibling donor, after nonmyeloablative conditioning with busulfan. Enzyme-replacement therapy was not given after infusion of the cells. RESULTS: All patients are alive after a median follow-up of 4.0 years (range, 1.8 to 8.0). Transduced hematopoietic stem cells have stably engrafted and differentiated into myeloid cells containing ADA (mean range at 1 year in bone marrow lineages, 3.5 to 8.9%) and lymphoid cells (mean range in peripheral blood, 52.4 to 88.0%). Eight patients do not require enzyme-replacement therapy, their blood cells continue to express ADA, and they have no signs of defective detoxification of purine metabolites. Nine patients had immune reconstitution with increases in T-cell counts (median count at 3 years, 1.07x10(9) per liter) and normalization of T-cell function. In the five patients in whom intravenous immune globulin replacement was discontinued, antigen-specific antibody responses were elicited after exposure to vaccines or viral antigens. Effective protection against infections and improvement in physical development made a normal lifestyle possible. Serious adverse events included prolonged neutropenia (in two patients), hypertension (in one), central-venous-catheter-related infections (in two), Epstein-Barr virus reactivation (in one), and autoimmune hepatitis (in one). CONCLUSIONS: Gene therapy, combined with reduced-intensity conditioning, is a safe and effective treatment for SCID in patients with ADA deficiency. (ClinicalTrials.gov numbers, NCT00598481 and NCT00599781.)

BACKGROUND & AIMS: Inflammatory bowel disease (IBD) is characterised by chronic intestinal inflammation, resulting from dysregulation of the mucosal immune system and compromised intestinal epithelial barrier function. The bile salt, nuclear farnesoid X receptor (FXR), was recently implicated in intestinal antibacterial defence and barrier function. The aim of this study was to investigate the therapeutic potential of FXR agonists in the treatment of intestinal inflammation in complementary in vivo and in vitro models. METHODS: Colitis was induced in wild-type (WT) and Fxr-null mice using dextran sodium sulfate, and in WT mice using trinitrobenzenesulfonic acid. Mice were treated with vehicle or the FXR agonist INT-747, and colitis symptoms were assessed daily. Epithelial permeability assays and cytokine expression analysis were conducted in mouse colon and enterocyte-like cells (Caco-2/HT29) treated with medium or INT-747. Inflammatory cytokine secretion was determined by ELISA in various human immune cell types. RESULTS: INT-747-treated WT mice are protected from DSS- and TNBS-induced colitis, as shown by significant reduction of body weight loss, epithelial permeability, rectal bleeding, colonic shortening, ulceration, inflammatory cell infiltration and goblet cell loss. Furthermore, Fxr activation in intestines of WT mice and differentiated enterocyte-like cells downregulates expression of key proinflammatory cytokines and preserves epithelial barrier function. INT-747 significantly decreases tumour necrosis factor α secretion in activated human peripheral blood mononuclear cells, purified CD14 monocytes and dendritic cells, as well as in lamina propria mononuclear cells from patients with IBD. CONCLUSIONS: FXR activation prevents chemically induced intestinal inflammation, with improvement of colitis symptoms, inhibition of epithelial permeability, and reduced goblet cell loss. Furthermore, FXR activation inhibits proinflammatory cytokine production in vivo in the mouse colonic mucosa, and ex vivo in different immune cell populations. The findings provide a rationale to explore FXR agonists as a novel therapeutic strategy for IBD.

OBJECTIVE: integrin for the treatment of ulcerative colitis (UC) and Crohn's disease (CD). We report an integrated summary of the safety of vedolizumab. DESIGN: Safety data (May 2009-June 2013) from six trials of vedolizumab were integrated. Adverse events were evaluated in patients who received ≥1 dose of vedolizumab or placebo and were reported as exposure-adjusted incidence rates as the number of patients experiencing the event per 100 person-years (PYs) of exposure. Predictors of serious infection were assessed using a Cox proportional hazards model. RESULTS: In total, 2830 patients had 4811 PYs of vedolizumab exposure (median exposure range, 1-1977 days). No increased risk of any infection or serious infection was associated with vedolizumab exposure. Serious clostridial infections, sepsis and tuberculosis were reported infrequently (≤0.6% of patients). No cases of progressive multifocal leucoencephalopathy were observed. Independent risk factors for serious infection in UC were prior failure of a tumour necrosis factor α antagonist (HR, 1.99; 95% CIs 1.16 to 3.42; p=0.0122) and narcotic analgesic use (HR, 2.68; 95% CI 1.57 to 4.58; p=0.0003), and in CD were younger age (HR, 0.97; 95% CI 0.95 to 0.98; p<0.0001), corticosteroid (HR, 1.88; 95% CI 1.35 to 2.63; p=0.0002) or narcotic analgesic use (HR, 2.72; 95% CI 1.90 to 3.89; p<0.0001). Investigator-defined infusion-related reactions were reported for ≤5% of patients in each study. Eighteen vedolizumab-exposed patients (<1%) were diagnosed with a malignancy. CONCLUSIONS: Vedolizumab has a favourable safety profile with low incidence rates of serious infections, infusion-related reactions and malignancies over an extended treatment period. TRIAL REGISTRATION NUMBER: NCT01177228, NCT00619489, NCT00783718, NCT00783692, NCT01224171, NCT00790933.

Platelet adhesion is an essential function in response to vascular injury and is generally viewed as the first step during which single platelets bind through specific membrane receptors to cellular and extracellular matrix constituents of the vessel wall and tissues. This response initiates thrombus formation that arrests hemorrhage and permits wound healing. Pathological conditions that cause vascular alterations and blood flow disturbances may turn this beneficial process into a disease mechanism that results in arterial occlusion, most frequently in atherosclerotic vessels of the heart and brain. Besides their relevant role in hemostasis and thrombosis, platelet adhesive properties are central to a variety of pathophysiological processes that extend from inflammation to immune-mediated host defense and pathogenic mechanisms as well as cancer metastasis. All of these activities depend on the ability of platelets to circulate in blood as sentinels of vascular integrity, adhere where alterations are detected, and signal the abnormality to other platelets and blood cells. In this respect, therefore, platelet adhesion to vascular wall structures, to one another (aggregation), or to other blood cells, represent different aspects of the same fundamental biological process. Detailed studies by many investigators over the past several years have been aimed to dissect the complexity of these functions, and the results obtained now permit an attempt to integrate all the available information into a picture that highlights the balanced diversity and synergy of distinct platelet adhesive interactions.

Tumor ablation by using radio-frequency energy has begun to receive increased attention as an effective minimally invasive approach for the treatment of patients with a variety of primary and secondary malignant neoplasms. To date, these techniques have been used to treat tumors located in the brain, musculoskeletal system, thyroid and parathyroid glands, pancreas, kidney, lung, and breast; however, liver tumor ablation has received the greatest attention and has been the subject of a large number of published reports. In this article, the authors review the technical developments and early laboratory results obtained with radio-frequency ablation techniques, describe some of the early clinical applications of these techniques, and conclude with a discussion of challenges and opportunities for the future.