Curcumin: A new candidate for melanoma therapy?

Melanoma remains among the most lethal cancers and, in spite of great attempts that have been made to increase the life span of patients with metastatic disease, durable and complete remissions are rare. Plants and plant extracts have long been used to treat a variety of human conditions; however, in many cases, effective doses of herbal remedies are associated with serious adverse effects. Curcumin is a natural polyphenol that shows a variety of pharmacological activities including anti-cancer effects, and only minimal adverse effects have been reported for this phytochemical. The anti-cancer effects of curcumin are the result of its anti-angiogenic, pro-apoptotic and immunomodulatory properties. At the molecular and cellular level, curcumin can blunt epithelial-to-mesenchymal transition and affect many targets that are involved in melanoma initiation and progression (e.g., BCl2, MAPKS, p21 and some microRNAs). However, curcumin has a low oral bioavailability that may limit its maximal benefits. The emergence of tailored formulations of curcumin and new delivery systems such as nanoparticles, liposomes, micelles and phospholipid complexes has led to the enhancement of curcumin bioavailability. Although in vitro and in vivo studies have demonstrated that curcumin and its analogues can be used as novel therapeutic agents in melanoma, curcumin has not yet been tested against melanoma in clinical practice. In this review, we summarized reported anti-melanoma effects of curcumin as well as studies on new curcumin formulations and delivery systems that show increased bioavailability. Such tailored delivery systems could pave the way for enhancement of the anti-melanoma effects of curcumin. © 2016 UIC

A literature review on surgery for cervical vagal schwannomas

Cervical vagal schwannoma is a benign, slow-growing mass, often asymptomatic, with a very low lifetime risk of malignant transformation in general population, but diagnosis is still a challenge. Surgical resection is the treatment of choice even if its close relationship with nerve fibres, from which it arises, threats vagal nerve preservation. We present a case report and a systematic review of literature. All studies on surgical resection of cervical vagal schwannoma have been reviewed. Papers matching the inclusion criteria (topic on surgical removal of cervical vagal schwannoma, English language, full text available) were selected. Fifty-three patients with vagal neck schwannoma submitted to surgery were identified among 22 studies selected. Female/male ratio was 1.5 and median age 44 years. Median diameter was 5 cm (range 2 to 10). Most schwannoma were asymptomatic (68.2%) and received an intracapsular excision (64.9%). Postoperative symptoms were reported in 22.6% of patients. Cervical vagal schwannoma is a benign pathology requiring surgical excision, but frequently postoperative complications can affect patients lifelong, so, surgical indications should be based carefully on the balance between risks and benefits

Preface

Reproductive tract bleeding in women is a naturally occurring event during menstruation and childbirth. In women with menorrhagia, however, congenital bleeding disorders historically have been underdiagnosed. This consensus is intended to allow physicians to better recognize bleeding disorders as a cause of menorrhagia and consequently offer effective disease-specific therapies. © 2009 Mosby, Inc. All rights reserved

Fibrinogen concentrate for treatment of bleeding and surgical prophylaxis in congenital fibrinogen deficiency patients

Background: Congenital fibrinogen deficiency is an ultra-rare disorder in which patients can experience severe and/or frequent bleeding episodes (BEs). Here, we present the largest prospective study to date on the treatment of this disorder. Methods: Hemostatic efficacy of human fibrinogen concentrate (HFC; FIBRYGA\uae, Octapharma AG) for treatment of bleeding or surgical prophylaxis was assessed by investigators and adjudicated by an independent data monitoring and endpoint adjudication committee (IDMEAC) according to a four-point scale, using objective criteria. Thromboelastometry maximum clot firmness (MCF) was also determined. Results: Twenty-five afibrinogenemia patients were treated with HFC: 24 for on-demand treatment of 89 BEs, and nine as prophylaxis for 12 surgeries. For BEs, treatment success (rating of excellent or good) evaluated by investigators was 96.6% (90% confidence interval [CI], 0.92-0.99; two missing ratings, classified as failures) and by the IDMEAC was 98.9% (90% CI, 0.95-0.999). Mean \ub1 standard deviation (SD) increase in MCF was 5.8 \ub1 2.5 mm one hour after the first HFC infusion (mean \ub1 SD dose, 61.88 \ub1 11.73 mg/kg). For the 12 surgeries (median [range] HFC dose/surgery, 85.80 mg/kg [34.09-225.36]), intraoperative and postoperative treatment success were both rated 100% (90% CI, 0.82-1.00) by investigators and the IDMEAC. Three adverse events were possibly treatment related, including a moderate case of thrombosis. There were no deaths, no severe allergic or hypersensitivity reactions, and no clinical evidence of neutralizing antifibrinogen antibodies. Conclusions: Human fibrinogen concentrate was efficacious for on-demand treatment of bleeding and as surgical prophylaxis, with a favorable safety profile, in patients with congenital afibrinogenemia

Consensus on the standardization of terminology in thrombotic thrombocytopenic purpura and related thrombotic microangiopathies

Essentials An international collaboration provides a consensus for clinical definitions. This concerns thrombotic microangiopathies and thrombotic thrombocytopenic purpura (TTP). The consensus defines diagnosis, disease monitoring and response to treatment. Requirements for ADAMTS-13 are given. Summary: Background Thrombotic thrombocytopenic purpura (TTP) and hemolytic\ue2\u80\u93uremic syndrome (HUS) are two important acute conditions to diagnose. Thrombotic microangiopathy (TMA) is a broad pathophysiologic process that leads to microangiopathic hemolytic anemia and thrombocytopenia, and involves capillary and small-vessel platelet aggregates. The most common cause is disseminated intravascular coagulation, which may be differentiated by abnormal coagulation. Clinically, a number of conditions present with microangiopathic hemolytic anemia and thrombocytopenia, including cancer, infection, transplantation, drug use, autoimmune disease, and pre-eclampsia and hemolysis, elevated liver enzymes and low platelet count syndrome in pregnancy. Despite overlapping clinical presentations, TTP and HUS have distinct pathophysiologies and treatment pathways. Objectives To present a consensus document from an International Working Group on TTP and associated thrombotic microangiopathies (TMAs). Methods The International Working Group has proposed definitions and terminology based on published information and consensus-based recommendations. Conclusion The consensus aims to aid clinical decisions, but also future studies and trials, utilizing standardized definitions. It presents a classification of the causes of TMA, and criteria for clinical response, remission and relapse of congenital and immune-mediated TTP

Caplacizumab reduces the frequency of major thromboembolic events, exacerbations, and death in patients with acquired thrombotic thrombocytopenic purpura.

BACKGROUND Acquired thrombotic thrombocytopenic purpura (aTTP) is a life-threatening autoimmune thrombotic microangiopathy. In spite of treatment with plasma exchange and immunosuppression, patients remain at risk for thrombotic complications, exacerbations and death. In the Phase II TITAN study, treatment with caplacizumab, an anti-vWF Nanobody(®) , was shown to reduce the time to confirmed platelet count normalization and exacerbations during treatment. OBJECTIVE The clinical benefit of caplacizumab was further investigated in a post-hoc analysis of the incidence of major thromboembolic events and exacerbations during the study drug treatment period and TTP-related death during the study. METHODS The Standardized MedDRA Query (SMQ) for 'embolic and thrombotic events' was run to investigate the occurrence of major thromboembolic events and exacerbations in the safety population of the TITAN study, which consisted of 72 patients of whom 35 received caplacizumab and 37 received placebo. RESULTS Four events (1 pulmonary embolism and 3 aTTP exacerbations) were reported in 4 patients in the caplacizumab group, while 20 such events were reported in 14 patients in the placebo group (2 acute myocardial infarctions, 1 ischemic and 1 hemorrhagic stroke, 1 pulmonary embolism, 1 deep vein thrombosis, 1 venous thrombosis and 13 aTTP exacerbations). Two of the placebo-treated patients died from aTTP during the study. CONCLUSION In total, 11.4% of caplacizumab-treated patients versus 43.2% of placebo-treated patients experienced one or more major thromboembolic event, an exacerbation or died. This analysis shows the potential for caplacizumab to reduce the risk of major thromboembolic morbidities and mortality associated with aTTP. This article is protected by copyright. All rights reserved

p Factor V Leiden but not the factor II 20210G>A mutation is a risk factor for premature coronary artery disease: a case-control study in Iran

Background: Factor V Leiden (FVL) and factor II c.*97G>A (rs1799963) are genetic risk factors for venous thromboembolism. Their contribution to coronary artery disease (CAD) is less clear. Objectives: This study aimed to investigate the association between FVL, rs1799963, and premature CAD in Iranians.Methods: We performed a genetic case-control study of 944 cases and 1081 controls from the premature CAD Milano-Iran study, including patients aged 18-55 (female) and 18-45 years (male) who underwent coronary angiography at the Tehran Heart Centre (Iran) in 2004-2011. Cases had luminal stenosis & GE;50% in at least 1 main coronary ar-tery or branch. Controls were age-and sex-matched with no CAD history. FVL and rs1799963 were genotyped using TaqMan SNP genotyping assays. Association was tested by logistic regression adjusted for matching factors and ethnicity. Effect modi-fication by sex and cardiovascular risk factors (metabolic [obesity, hypertension, hyperlipidemia, and diabetes], and smoking) was assessed.Results: The risk of premature CAD was increased by 50% in FVL carriers (adjusted odds ratio [adjOR] 1.54 [95% CI, 0.95-2.48]) and slightly reduced in rs1799963 carriers (adjOR 0.71 [95% CI, 0.40-1.27]). These effects were more pronounced in women than men (FVL, adjOR 1.66 vs 1.25; rs1799963, adjOR 0.60 vs 1.07). The risk of premature CAD was substantially increased in carriers of FVL with at least 1 metabolic risk factor compared with noncarriers without metabolic risk factors (adjOR 25.14 [95% CI, 12.51-50.52]).Conclusion: FVL but not FII rs1799963 was associated with an increased risk of CAD in young Iranians. This risk increased considerably when combined with metabolic car-diovascular risk factors.Clinical epidemiolog

Generation of anti-idiotypic antibodies to detect anti-spacer antibody idiotopes in acute thrombotic thrombocytopenic purpura patients

In autoantibody-mediated autoimmune diseases, autoantibody profiling allows to stratify patients and link autoantibodies with disease severity and outcome. However, in immune-mediated thrombotic thrombocytopenic purpura patients, stratification according to antibody profiles and their clinical relevance has not been fully explored. We aimed at developing a new type of autoantibody profiling assay for immune-mediated thrombotic thrombocytopenic purpura based on the use of anti-idiotypic antibodies. Anti-idiotypic antibodies against 3 anti-spacer autoantibodies were generated in mice and were used to capture the respective anti-spacer idiotopes from 151 acute immune-mediated thrombotic thrombocytopenic purpura plasma samples. We next deciphered these anti-spacer idiotope profiles in immune-mediated thrombotic thrombocytopenic purpura patients and investigated if these limited idiotope profiles could be linked with disease severity. We developed 3 anti-idiotypic antibodies that recognized particular idiotopes in the anti-spacer autoantibodies II-1, TTP73 or I-9, that are involved in ADAMTS13 binding. Thirty-five, 24 and 42% of patients were positive for antibodies with the II-1, TTP73 and I-9 idiotopes, respectively. Stratifying patients according to the corresponding 8 anti-spacer idiotope profiles revealed an until now unknown insight into the anti-spacer II-1, TTP73 and I-9 idiotope profiles in these patients. Finally, these limited idiotope profiles showed no association with disease severity. We successfully developed 3 anti-idiotypic antibodies that allowed us to determine the profiles of the anti-spacer II-1, TTP73 and I-9 idiotopes in immune-mediated thrombotic thrombocytopenic purpura patients. Increasing the number of patients and/or future development of additional anti-idiotypic antibodies against other anti-ADAMTS13 autoantibodies might allow to identify idiotope profiles of clinical, prognostic value

ADAMTS13 phenotype in plasma from normal individuals and patients with thrombotic thrombocytopenic purpura

The activity of ADAMTS13, the von Willebrand factor cleaving protease, is deficient in patients with thrombotic thrombocytopenic purpura (TTP). In the present study, the phenotype of ADAMTS13 in TTP and in normal plasma was demonstrated by immunoblotting. Normal plasma (n = 20) revealed a single band at 190 kD under reducing conditions using a polyclonal antibody, and a single band at 150 kD under non-reducing conditions using a monoclonal antibody. ADAMTS13 was not detected in the plasma from patients with congenital TTP (n = 5) by either antibody, whereas patients with acquired TTP (n = 2) presented the normal phenotype. Following immunoadsorption of immunoglobulins, the ADAMTS13 band was removed from the plasma of the patients with acquired TTP, but not from that of normal individuals. This indicates that ADAMTS13 is complexed with immunoglobulin in these patients. The lack of ADAMTS13 expression in the plasma from patients with hereditary TTP may indicate defective synthesis, impaired cellular secretion, or enhanced degradation in the circulation. This study differentiated between normal and TTP plasma, as well as between congenital and acquired TTP. This method may, therefore, be used as a complement in the diagnosis of TTP