Current Therapeutic Management Research Articles

LONG NON-CODING RNAs AND AUTOPHAGY IN OSTEOSARCOMA

Osteosarcoma (OSA) is an aggressive bone tumor that occurs primarily in children and adolescents worldwide, with a high metastatic and recurrence ability. OSA is characterized by the transformation of mesenchymal cells and the formation of osteoid tissue. Although recent advancements have improved the current therapeutic management of OSA, the clinical outcomes of the disease still remain unsatisfactory. Therefore, it is important to determine the novel diagnostic markers and/or therapeutic targets for OSA. Autophagy is a highly conserved self-degradative process that plays a crucial role in various physiological mechanisms such as survival, homeostasis, development and differentiation. Dysfunction of autophagy is the relationship with the onset and development of several types of cancer, including OSA. Long non-coding ribonucleic acids (lncRNAs), a group of non-coding RNAs, regulate various pathophysiological mechanisms such as inflammation, autophagy and apoptosis. Recent studies investigating the role of lncRNAs in the pathogenesis of OSA have shown that these molecules might have diagnostic and therapeutic importance for the prevention of OSA. Here, we focus on lncRNAs that modulate autophagy in OSA and discuss the potential clinical values of lncRNAs for OSA. The current study contributes to a better understanding of OSA pathogenesis and to the development of novel therapeutic approaches for the prevention of OSA.

Recommendations for the therapeutic management of systemic juvenile idiopathic arthritis. Opinion of the Section of Developmental Age Rheumatology of the Polish Society of Rheumatology

Advances in paediatric rheumatology determine the need to update management rules and implement the latest treatment standards for patients under our care. The following case provides the current therapeutic management of patients with systemic juvenile idiopathic arthritis (SJIA), taking into consideration the Treat to Target (T2T) concept, i.e. therapy aimed at achieving remission or, when this is not possible, an alternative goal is low disease activity. Simultaneously, the authors refer to the possibility of implementing these recommendations in Polish conditions, taking into consideration the B.33 drug programme, and they highlight that therapeutic options in SJIA should include both the individual course of the disease and available treatment options in the current legal and organisational system in Poland. In the early stages of the disease, nonsteroidal anti-inflammatory drugs (NSAIDs) and glucocorticosteroids (GCs) are used for managing systemic symptoms of the disease. Advances in knowledge regarding the pathogenesis of SJIA have meant that current therapeutic strategies for the treatment of SJIA are based on targeted approaches using anti-cytokine therapy that inhibits the activity of pro-inflammatory cytokines, primarily IL-1 and IL-6, and thus it is necessary to include IL-1 or IL-6 inhibitors in treatment when NSAIDs and GCs are not effective. It is considered necessary to include IL-1 inhibitors in the B.33 programme, primarily because of its causal effect. IL-1 is a mediator of the innate immune system and is a potent inducer of fever and inflammation. IL-1 inhibitors (iIL-1) enable GC-sparing effects with a reduction in their side effects. The overall response rate to IL-1 blockers (anakinra and canakinumab) is high, up to 90%, especially in patients with treatment-resistant forms of SJIA.

Systemic juvenile idiopathic arthritis — current diagnostic and therapeutic management

Juvenile idiopathic arthritis (JIA) is a heterogeneous group of arthritis that has seven subtypes under the currently applicable ILAR classification. It is the most common arthropathy diagnosed in children, a chronic disease affecting children and adolescents. The systemic form of juvenile idiopathic arthritis (SJIA) is the most frequent subtype of the disease with a different aetiopathogenesis, broad clinical picture, various courses, burdened with numerous complications and requiring a therapeutic approach that is different than in other subtypes of JIA. In the case of SJIA, it is essential to establish the correct diagnosis as soon as possible and to initiate effective treatment and, if there is no effect after standard steroid therapy, use targeted anti-cytokine therapy. This review discusses current data on the aetiopathogenesis of the disease, clinical presentation and principles of diagnostic and therapeutic management.

The perspective of antibiotic therapeutic challenges of brucellosis in the Middle East and North African countries: Current situation and therapeutic management.

Brucellosis is among the most prevalent zoonotic infections in Middle Eastern and North African (MENA) countries, critically impacting human and animal health. A comprehensive review of studies on antibiotic susceptibility and therapeutic regimes for brucellosis in ruminants and humans in the MENA region was conducted to evaluate the current therapeutic management in this region. Different scientific databases were searched for peer-reviewed original English articles published from January 1989 to February 2021. Reports from research organizations and health authorities have been taken into consideration. Brucella melitensis and Brucella abortus have been reported from the majority of MENA countries, suggesting a massive prevalence particularly of B. melitensis across these countries. Several sporadic cases of brucellosis relapse, therapeutic failure, and antibiotic resistance of animal and human isolates have been reported from the MENA region. However, several studies proved that brucellae are still in-vitro susceptible to the majority of antibiotic compounds and combinations in current recommended World Health Organization (WHO) treatment regimens, for example, levofloxacin, tetracyclines, doxycycline, streptomycin, ciprofloxacin, chloramphenicol, gentamicin, tigecycline, and trimethoprim/sulfamethoxazole. The current review presents an overview on resistance development of brucellae and highlights the current knowledge on effective antibiotics regimens for treating human brucellosis.

Ductal Carcinoma In Situ of Breast: From Molecular Etiology to Therapeutic Management.

Ductal carcinoma in situ (DCIS) makes up a majority of noninvasive breast cancer cases. DCIS is a neoplastic proliferation of epithelial cells within the ductal structure of the breast. Currently, there is little known about the progression of DCIS to invasive ductal carcinoma (IDC), or the molecular etiology behind each DCIS lesion or grade. The DCIS lesions can be heterogeneous in morphology, genetics, cellular biology, and clinical behavior, posing challenges to our understanding of the molecular mechanisms by which approximately half of all DCIS lesions progress to an invasive status. New strategies that pinpoint molecular mechanisms are necessary to overcome this gap in understanding, which is a barrier to more targeted therapy. In this review, we will discuss the etiological factors associated with DCIS, as well as the complexity of each nuclear grade lesion. Moreover, we will discuss the possible molecular features that lead to progression of DCIS to IDC. We will highlight current therapeutic management and areas for improvement.

Diet Therapy in Eosinophilic Esophagitis. Focus on a Personalized Approach.

Eosinophilic esophagitis (EoE) is a chronic allergic disease defined by a marked eosinophilic inflammation and symptoms of esophageal dysfunction. EoE is a heterogeneous disease and severely impacts the quality of life of affected patients. The current therapeutic management of EoE is based on two cornerstones: medication and diet therapy, both effective but limited by several critical issues. The choice of one or the other therapy might depend on the different disease phenotypes (allergic vs. non-allergic, inflammatory vs. fibro-stenotic), patient's age (adult vs. childhood-onset), food habits, patient/family preference, and familiar financial resource. Diet therapy is a successful treatment but limited by low patient adherence, the need for several endoscopies, food restrictions, psychosocial impact, and potential nutritional deficiencies. All these limitations could be effectively overcome with multidisciplinary and personalized management. This review summarizes the most recent evidence on the dietary elimination approaches and will provide a practical guide to clinicians in managing and implementing dietary therapy for patients with EoE.

A modified-delphi study establishing consensus in the therapeutic management of posttrauamtic elbow stiffness

Study Design: Web-based modified Delphi study. Background: Therapy is widely considered the first choice of treatment for posttraumatic stiffness of the elbow since loss of motion is a common sequela following traumatic elbow injuries. There is high variability in practice patterns for the management of the posttraumtic elbow. Purpose: The aim of this study is to identify the current therapeutic management of posttraumatic elbow stiffness using expert consensus. Methods: This study surveyed experts using a web-based 3 round modified Delphi method. Quantitative data and comments were collected during the first round. Questions with Likert scaling were used to identify consensus (defined as 75% agreement) with each statement and comment boxes enabled open-ended responses to gather expert opinion. Lack of consensus and data from comments guided the second-round of the survey. This process was repeated after Round 2 to develop the Round 3 survey. Consensus was achieved at Round 3 and no further rounds were needed. Results: Round 1 included 34 experts (response rate 20%), not all experts were able to continue through all rounds. Round 2 included 18 experts and Round 3 included 15 experts. Survey items were categorized as follows: examination procedures, therapeutic interventions, orthotic intervention considerations, contributing patient factors, and clinical decisions and rehabilitation challenges. Twenty-five percent of items achieved consensus after Round 1, 30% after Round 2 and 52% after Round 3. Although most participants agreed that orthotic intervention is critical to patient outcomes, there were conflicting thoughts about the orthotic design and wearing schedule. Conclusions: The findings of this web-based modified Delphi study helped to establish a current body of knowledge using expert consensus to guide practice and identify specific questions that can be studied in future clinical studies on posttraumatic elbow stiffness.

Complicating Acute Myocardial Infarction. Current Status and Unresolved Targets for Subsequent Research.

Mechanical reperfusion with primary angioplasty, as the treatment of choice in acute myocardial infarction (MI), is associated not only with a high percentage of full epicardial and tissue reperfusion but also with a very good immediate and long-term clinical outcome. However, the Achilles heel of MI treatment is its ensemble of complications, such as cardiogenic shock due to severe systolic and/or diastolic dysfunction or MI mechanical complications, including perforation of the left ventricular free wall, papillary muscle rupture with acute mitral regurgitation and ventricular septal rupture. They are associated with an increased or, sometimes, with an extremely high mortality rate, determining the overall mortality in an MI patient population. In this review we summarize the mechanisms of MI complications, current therapeutic management and alternative directions for overcoming their devastating consequences. Moreover, we have sought to indicate gaps in the evidence on current treatments as the potential targets for further clinical research. From the perspective of mortality trends that are not improving, the forthcoming therapeutic management of complicated MI will require an individualized and novel approach based on their thorough pathobiology.

MPN-028: Heart Failure: A Cause of Polypharmacy, Drug-Drug, and Food-Drug Interactions in Essential Thrombocythemia

Introduction: Essential thrombocythemia (ET) is a rare BCR-ABL1-negative myeloproliferative neoplasm characterized by excessive production of platelets. Cardiovascular comorbidities, including chronic heart failure (HF), pose significant challenges in the management of ET. Polypharmacy, defined as the prescription of 5 or more drugs daily, and the risk of drug-drug (DDI) and food-drug (FDI) interactions have not been assessed so far in ET patients diagnosed with HF. Objective: To investigate the risk of polypharmacy, DDI, and FDI in ET patients with or without HF. Methods: The electronic medical records of the Internal Medicine Clinic of an emergency university hospital in Romania were searched from inception to February 2021. Electronic medical records were available since August 2014. We included all ET patients who had signed the written informed consent for participation in medical research and for whom information regarding the prescribed medications was available. The study was approved by the ethics council of the hospital. DDI and FDI were evaluated using an online drug interaction checker. Results: The study group included 15 ET patients of whom 4 suffered from HF (26.67%). Patients with ET+HF were older (77.75±7.93 versus 58.64±11.50 years, P=0.009) and were prescribed more drugs (9.25±3.40 versus 5.73±2.37 drugs/day, P=0.040) versus ET patients without HF. Patients diagnosed with ET and HF were also exposed to more potential DDI (10.25±9.50 versus 2.27±2.28, P=0.016) and FDI (3.50±3.00 versus 1.27±0.90, P=0.037). ET patients diagnosed with HF had a significantly higher number of potential major (3.25±2.63 versus 0.64±0.92, P=0.010) and moderate (5.75±5.68 versus 1.18±1.40, P=0.021) DDI, but the potential minor DDI were similar between the two groups. ET+HF patients were more likely to be at risk for major FDI (1.00±0.82 versus 0.18±0.40, P=0.020), but the risk of moderate and minor FDI was similar between ET patients with and without HF. Conclusions: HF can be considered a significant cause of polypharmacy, as well as potential DDI and FDI, in patients with ET. Further research is needed to clarify the impact of these findings on the current therapeutic management of ET, especially in patients with HF and other cardiovascular comorbidities.

ViBiBa: Virtual BioBanking for the DETECT multicenter trial program - decentralized storage and processing

BackgroundLiquid Biopsy (LB) in the form of e.g., circulating tumor cells (CTCs) is a promising non-invasive approach to support current therapeutic cancer management. However, the proof of clinical utility of CTCs in informing therapeutic decision-making for e.g., breast cancer in clinical trials and associated translational research projects is facing the issues of low CTC positivity rates and low CTC numbers – even in the metastasized situation. To compensate for this dilemma, clinical CTC trials are designed as large multicenter endeavors with decentralized sample collection, processing and storage of products, making data management highly important to enable high-quality translational CTC research. AimIn the DETECT clinical CTC trials we aimed at developing a custom-made, browser-based virtual database to harmonize and organize both decentralized processing and storage of LB specimens and to enable the collection of clinically meaningful LB sample. MethodsViBiBa processes data from various sources, harmonizes the data and creates an easily searchable multilayered database. ResultsAn open-source virtual bio-banking web-application termed ViBiBa was created, which automatically processes data from multiple non-standardized sources. These data are automatically checked and merged into one centralized databank and are providing the opportunity to extract clinically relevant patient cohorts and CTC sample collections. SummaryViBiBa, which is a highly flexible tool that allows for decentralized sample storage of liquid biopsy specimens, facilitates a solution which promotes collaboration in a user-friendly, federalist and highly structured way. The source code is available under the MIT license from https://vibiba.com or https://github.com/asperciesl/ViBiBa

Hermansky-Pudlak Syndrome and Lung Disease: Pathogenesis and Therapeutics.

Hermansky-Pudlak Syndrome (HPS) is a rare, genetic, multisystem disorder characterized by oculocutaneous albinism (OCA), bleeding diathesis, immunodeficiency, granulomatous colitis, and pulmonary fibrosis. HPS pulmonary fibrosis (HPS-PF) occurs in 100% of patients with subtype HPS-1 and has a similar presentation to idiopathic pulmonary fibrosis. Upon onset, individuals with HPS-PF have approximately 3 years before experiencing signs of respiratory failure and eventual death. This review aims to summarize current research on HPS along with its associated pulmonary fibrosis and its implications for the development of novel treatments. We will discuss the genetic basis of the disease, its epidemiology, and current therapeutic and clinical management strategies. We continue to review the cellular processes leading to the development of HPS-PF in alveolar epithelial cells, lymphocytes, mast cells, and fibrocytes, along with the molecular mechanisms that contribute to its pathogenesis and may be targeted in the treatment of HPS-PF. Finally, we will discuss emerging new cellular and molecular approaches for studying HPS, including lentiviral-mediated gene transfer, induced pluripotent stem cells (iPSCs), organoid and 3D-modelling, and CRISPR/Cas9-based gene editing approaches.

PATIENT-REPORTED OUTCOMES FOR USE OF SILVERSPLINTS IN OSTEOARTHRITIS OF THE HAND.

Pain, stiffness and joint deformity can result in significantly reduced hand function in people with osteoarthritis. Characteristic finger deformities in osteoarthritis are swan neck deformity and boutonnière deformity. Several studies have reported that an orthosis decreases pain and increases function during daily activities for patients with arthritis. The aim of this study was to review patient-reported outcomes of current conservative therapeutic management with silver ring splints (silversplints) for patients with osteoarthritis of the hand. There was a 76% improvement in overall daily functioning and a 74% reduction in pain. Several questions concerned daily activities with different types of hand function and with different types of grip and use of fingers. The results show a major improvement in both the more open grip of the hand and activities requiring fine motor skills. The ability to use force with the hand, even when wearing an orthosis, is an important result. Patients who experienced “no problems or minor problems” had significantly increased functioning in several activities of daily living, but the largest improvement in functioning was seen in “household chores” (243%), “opening jars” (150%) and “lifting groceries” (143%). Overall, silversplints appear to serve as a suitable support for the joints in osteoarthritis of the hand, providing pain relief by preventing the joint from moving through its full range of motion. Use of silversplints to treat patients with osteoarthritis of the hand should be considered as a useful, non-surgical method.LAY ABSTRACTThis study of patient-reported outcome measures regarding the use of silversplints for osteoarthritis of the hand provides insight into the additional care and quality of life provided by the use of an orthopaedic medical aid. The aims of this study are to measure the effectiveness of silversplints in daily life and to validate the efficacy of using orthopaedic medical aids. Between October 2018 and June 2020, a total of 2,231 patients with osteoarthritis were provided with silversplints and were asked about the effectiveness of the splints 3 weeks after they first started wearing them. This large-scale study found that the use of silversplints contributed to overall daily functioning, reduced pain, and increased the possibility of performing daily activities. Silversplints appear to serve as a suitable support for joints, providing pain relief and freedom of movement, but preventing the joint from moving through its full range of motion.

Prevalence of Gynecological Disorders of Goat and Pattern of Drug used at Chuadanga, Bangladesh

Background: Gynecological disorders are the major challenge for Goat production profitability in Chuadanga, a goat dominating district of Bangladesh. To control the gynecological cases of goats in Chuadanga district, it is of utmost importance to estimate the prevalence of them along with their current therapeutic management. Methods: A cross sectional study was conducted from May, 2018 to April, 2019 on a total of 89 gynecological cases of goat to estimate the prevalence of different gynecological disorders along with drug prescribing patterns at Chuadanga Sadar Upazilla, Chuadanga, Bangladesh. Relevant data on different gynecological cases of goat were collected from the registered sheets of Upazilla Veterinary Hospital (UVH) and used for this study. Result: The highest prevalence of gynecological case was of anoestrous (20.2%) followed by abortion (18.0%), retained placenta (16.9%), pyometra (10.1%), dystocia (9.0%), repeat breeding (6.7%) and prolapse of the vagina (5.6%). The prevalence of metritis was 4.5% followed by milk fever (4.5%), prolapse of the rectum (3.4%) and postpartum bleeding (1.1%). Prostaglandin (25.0%) followed by a combination of oxytocin and calcium (18.8%) and combination of oxytetracycline and metronidazole (18.8%) were commonly prescribed drugs for treating abortion cases. Vitamin AD3E (33.3%) was prescribed the highest for treating anoestrous. A combination of oxytocin and oxytetracycline (33.3%), followed by oxytocin (26.6%) were predominantly prescribed for treating retained placenta. This study reveals the overall burden of reproductive disorders of goat along with drug prescribing patterns at the Chuadanga, Bangladesh. This outcome will be supportive to know the better treatment strategy against reproductive disorders in goat.

Multiple sclerosis in Algeria, a multidisciplinary management at Bejaia University Hospital Center.

The aim of our study is to establish the clinical, para-clinical, therapeutic and progressive profile of Multiple sclerosis (MS) in the Algerian region of Bejaia. We performed a retrospective descriptive study for a period of 4 years, going from January 2015 to December 2018. Diagnosis of MS was retained according to the 2010 McDonald criteria. Epidemiological characteristics were studied, such as first clinical presentation, clinical form, biological and neuroradiological data, current therapeutic management as well as evolutionary profile by evaluation of the Expanded Disability Status Scale (EDSS). We collected 109 Patient with MS, including 71 (65%) women and 38 (35%) men with a Sex Ratio F / M of 1.86. Average age of patients was 38.7 years with extremes between 17 and 65 years. Average age of onset was 31 years (ranging from 11 to 53 years). MS diagnostic delay was 2.9 years. The most frequent MS form was the relapsing remitting (80%), then the secondary progressive (12%) and finally the primary progressive form in 8% of cases. Patients received relapses corticosteroid treatment in 73% of cases. Disease modifying therapies (DMT) was prescribed based on interferon beta in 83 patients, Natalizumab in 2 patients and cyclophosphamide in 22 patients. We observed that EDSS increased from less than 5 in all patients at onset to more than 5 in 11% of patients after an average period of 6.7 years. Despite the small sample of our population, the severe aspect of North African MS could be clearly seen in our study.

The Osteosarcoma Microenvironment: A Complex But Targetable Ecosystem.

Osteosarcomas are the most frequent primary bone sarcomas, affecting mainly children, adolescents, and young adults, and with a second peak of incidence in elderly individuals. The current therapeutic management, a combined regimen of poly-chemotherapy and surgery, still remains largely insufficient, as patient survival has not improved in recent decades. Osteosarcomas are very heterogeneous tumors, both at the intra- and inter-tumor level, with no identified driver mutation. Consequently, efforts to improve treatments using targeted therapies have faced this lack of specific osteosarcoma targets. Nevertheless, these tumors are inextricably linked to their local microenvironment, composed of bone, stromal, vascular and immune cells and the osteosarcoma microenvironment is now considered to be essential and supportive for growth and dissemination. This review describes the different actors of the osteosarcoma microenvironment and gives an overview of the past, current, and future strategies of therapy targeting this complex ecosystem, with a focus on the role of extracellular vesicles and on the emergence of multi-kinase inhibitors.

Malignant melanoma of the breast: controversies in the diagnosis and therapeutic management of a rare nosologic entity.

Melanoma of the breast is an infrequent entity, presenting as either primary or metastatic from extramammary solid neoplasms. Depending on the involvement of the skin, primary malignant melanoma of the breast (PMMB) can be classified as cutaneous or noncutaneous. Cutaneous PMMB accounts for <5% of all melanomas and only 0.5% of all breast cancers. Furthermore, despite the rarity of metastatic breast neoplasms, melanoma comprises a frequent source of metastases. Metastatic potential of melanoma is associated with poor prognosis, and the majority of patients present more than one metastatic foci at the time of diagnosis. Diagnostic approach for both primary and metastatic melanomas of the breast is substantiated by fine needle aspiration (FNA) cytology along with immunohistochemistry. Nevertheless, verification of a metastatic mammary melanoma requires the discovery of a primary lesion. The mainstay of treatment for primary tumors is surgery, with radical local excision and axillary lymph node dissection or, on occasion, axillary sentinel node resection, while for metastatic tumors it depends on the specificities of the melanoma. Adjuvant therapy is always implemented. The aim of this survey is to meticulously review the literature of primary and metastatic malignant melanomas of the breast and report epidemiologic and clinicopathologic data for this rare entity. Clinical features, histogenesis, morphological, and immunochemical findings are discussed, while the role of current diagnostic and therapeutic management of this uncommon entity is emphasized.

Expert Opinions on the Current Therapeutic Management of Inflammatory Bowel Disease During the COVID-19 Pandemic: JAPAN IBD COVID-19 TASKFORCE, Intractable Diseases, the Health and Labor Sciences Research

Expert Opinions on the Current Therapeutic Management of Inflammatory Bowel Disease During the COVID-19 Pandemic: JAPAN IBD COVID-19 TASKFORCE, Intractable Diseases, the Health and Labor Sciences Research

Iron Chelation and Ferritin below 500 Mcg/L in Transfusion Dependent Thalassemia: Beyond the Limits of Clinical Trials

Introduction The current therapeutic management of transfusion dependent thalassemia (TDT) is based on regular blood transfusion and iron chelation therapy. Transfusion iron overload remains one of the major causes of morbidity and mortality in these patients because of the accumulation in heart, liver and endocrine glands. Three iron chelators are available in clinical practice: deferoxamine (DFO), deferiprone(DFP) and deferasirox (DFX). Guidelines clearly recommend when to start iron chelation, while discontinuation criteria are not well defined. Authorised product information state that we should consider interrupting DFX if serum ferritin (SF) falls consistently below 500mcg/L. This cut off was arbitrarily determined and there are no studies evaluating the effects of chelators in presence of SF below 500 mcg/L. In our clinical practice at Rare Diseases center of Fondazione IRCCS Ca' Granda Policlinico in Milan we do not completely interrupt iron chelation in TDT patients for SF levels below 500 mcg/L. Aims and methods Aim of our study was to evaluate the appearance of adverse events due to the assumption of iron chelation therapy in those TDT patients who had SF below 500 mcg/L. In this study we retrospectively evaluated renal and liver function from 2008 throughout December 2018 in TDT patients on DFX who presented SF below 500 mcg/L for 24 consecutive months. DFX dose are all expressed with the new tablets formulation dose. We evaluated SF, iron intake, LIC and MIC, renal and hepatic function. .A total of 5076 observations were collected, with 99.5 average per patient. We evaluated the relationships among variables with correlation models with random intercept Results One hundred ninety-two TDT patients are regularly followed at our center. They receive regular transfusion treatment and iron chelation therapy to prevent secondary iron overload. 51 out of 192 patients (32 F, 19 M, aged 44 ± 7 years) treated with DFX presented mean SF below 500 mcg/L for at least 24 consecutive months. Hematological and iron status parameters are described in Table 1. We found a strong correlation between SF and LIC (p&amp;lt;0.001) and for SF&amp;lt;500 mcg/L no hepatic iron overload was observed. Conversely we did not found a correlation between SF and MIC. For SF values below 500 mcg/L there was a minimal increase in creatinine levels, however the mean creatinine values remained within the normal range.Moreover, creatinine variation between two consecutive evaluation was below 0.3 mg/dl, cut off for acute kidney injury. Similar results were observed for liver function. Although a minimal increase of mean ALT value was observed for SF below 500 mcg/L, it remained within the normal range. None of our patient showed ALT level indicative of liver damage (ALT&amp;gt; 10 x upper limit of normal) We evaluated the relation between SF and DFX dose. Mean DFX dose decreases according to SF reduction. However, for SF value &amp;lt; 240 mcg/L, DFX dose remained stable at an average of 14 mg/kg per day. Conclusion According to our preliminary data, administration of DFX in TDT patients in presence of SF below 500 mcg/L is safe. Creatinine and ALT fluctuations, that usually remain within the range of normality, are mild, and transient and do not require specific treatment. Consistently with previously published data by Cohen et al, we show that a mean dosage of DFX of 14 mg/Kg die of film-coated tablet (20 mg/Kg of dispersable formulation) are necessary to balance an iron intake of 0.3 mg/kg die in absence of iron overload. Based on these results we suggest that in TDT patients with a continuous iron intake, iron chelation should be continued even when ferritin is below 500mcg/L. Monitoring of liver and kidney function tests are recommended in patient's follow up, as well as tailoring iron chelation. Disclosures Cappellini: Vifor Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; CRISPR Therapeutics: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Honoraria; Novartis: Membership on an entity's Board of Directors or advisory committees; Genzyme/Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Motta:Sanofi-Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Unmet Medical Needs in the Management of Ulcerative Colitis: Results of an Italian Delphi Consensus.

Background The lifelong and remitting nature of ulcerative colitis results in considerable disability and a substantial negative impact on quality of life. The major goal of the therapy of ulcerative colitis is considered to be the modification of the course of the disease, so that the patient's quality of life can be improved while minimising disease-related disability. Although considerable progress in understanding the molecular pathways involved in ulcerative colitis has led to improved treatment options, there is currently no definitive cure for ulcerative colitis, there remain considerable unmet needs in terms of long-term efficacy and safety, and there are many patients who continue to be burdened by physical and psychological symptoms. Defining unmet needs can help to increase the awareness of the shortcomings of current therapeutic management and highlight the need to achieve not only a control of clinical symptoms but also control of mucosal healing, in order to attain the best possible long-term outcomes. Methods With the aim of providing a better understanding of the unmet needs of patients towards improving overall care, a Delphi process was used to obtain consensus among a group of Italian ulcerative colitis experts. The consensus group met with a major focus of delineating the unmet needs of current treatment strategies and overall management of ulcerative colitis, while also focusing on quality of life and patient care. Results Three main areas were identified: (i) treatment, (ii) monitoring and risk management, and (iii) patient-related issues. A high level of consensus was reached on all but one of the statements identified. Conclusions The findings arising from the Delphi process provide valuable insights into the unmet needs in the management of moderate-to-severe ulcerative colitis from the clinician's perspective, while emphasising the benefits of therapeutic individualization and suggesting areas that need additional study with the aim of optimising the treatment of patients with ulcerative colitis.

Drug transporter and oxidative stress gene expression in human macrophages infected with benznidazole-sensitive and naturally benznidazole-resistant Trypanosoma cruzi parasites treated with benznidazole

BackgroundChagas disease is a potentially life-threatening disease caused by the protozoan parasite Trypanosoma cruzi. Current therapeutic management is limited to treatment with nitroheterocyclic drugs, such as nifurtimox (NFX) and benznidazole (BZ). Thus, the identification of affordable and readily available drugs to treat resistant parasites is urgently required worldwide. To analyse the effects of BZ on human macrophage gene expression, a quantitative PCR (qPCR) array analysis was performed using drug transporter and oxidative stress pathway genes to compare the gene expression profiles of human differentiated THP-1 macrophage (THP-1 MΦ) cells infected or not with benznidazole-sensitive (CL Brener) and naturally benznidazole-resistant (Colombiana) T. cruzi parasites followed by treatment with BZ.ResultsThe gene expression analysis indicated that the expression levels of 62 genes were either up- or downregulated at least 3-fold in the host upon infection with CL Brener and BZ treatment, of which 46 were upregulated and 16 were downregulated. Moreover, the expression level of 32 genes was altered in THP-1 MФ cells infected with Colombiana and treated with BZ, of which 29 were upregulated and 3 were downregulated. Our results revealed that depending on the specific condition, human THP-1 MΦ cells infected with T. cruzi strains with sensitive or resistant phenotypes and treated with BZ expressed high mRNA levels of AQP1, AQP9 and ABCB1 (MDR1) compared to those of the control cells.ConclusionsOur findings suggest that the proteins encoded by AQP1, AQP9 and ABCB1 may be implicated in benznidazole detoxification. Therefore, studies on gene expression are required to better understand the host response to pathogens and drug treatment integrated with functional and metabolic data to identify potentially novel targets for the treatment of this important and neglected tropical disease.