Optimal Therapeutic Response Research Articles

P095 COMPARING ORAL CORTICOSTEROIDS ≥30MG/DAY AMONG ADULT AND PEDIATRIC PATIENTS WITH NEWLY DIAGNOSED ULCERATIVE COLITIS

Ulcerative Colitis (UC) has a relapsing–remitting disease course. Sparing use of oral corticosteroids (CS) ≥30 mg/day, as mono or combination therapy, are generally reserved for rapid relief of symptoms and induction of remission to achieve optimal therapeutic response. This analysis aimed to compare patient profiles of adult and pediatric patients newly diagnosed with UC who use ≥30 mg/day CS in a real world setting. The Truven Marketscan commercial administrative claims database was used to explore the real-world utilization of ≥30mg/day CS among pediatric (children 2- 11 years old and adolescents 12-17 years old) and adult (≥18 years old) UC patients. Patients were identified based on first diagnosis of UC during 01/01/2013 -12/31/2015 and were included in the analysis if they had an additional UC diagnosis during the 1-year post-index period. Patients with pre-specified, common inflammatory comorbid conditions associated with high doses of oral CS were excluded. The final sample was subsequently stratified based on number of days (d) [0, 1-7, 8-30, 31-90, 91-180, 181-365] on ≥30mg/day oral CS during follow-up (1-year post diagnosis). Pre-index and post-index patient characteristics (demographics, medications, and health care resource use (HCRU)) are described. A total of 10,443 UC patients were included in this analysis consisting of 91 children (2-11 years old), 290 adolescents (12-17 years old), and 10,062 adults (18+ years old). Demographic information such as age, gender, and geographic location for each subgroup is displayed in Table 1. Approximately, 40.66% of children and 46.90% of adolescents received corticosteroids during the 1-year post-index period, compared to only 14.62% of adults. In addition, 25.27% of children, 34.48% of adolescents, and 6.68% of adults received corticosteroids for more than 30 days during the post-index period. Among all subgroups, patients with ≥30d of ≥30mg/day CS use were more likely to be prescribed biologics. HCRU (including gastroenterologist visits, ER visits, and inpatient visits) was higher for patients receiving ≥30mg/day of CS at least 1 day during the post-index period when compared to those not receiving ≥30mg/day of CS. HCRU was higher among the pediatric subgroups (children and adolescents) when compared to adults (Table 1). During a 1-year follow-up period, UC patients with a longer duration of ≥30mg/day CS use were more likely to be on a biologic and had increased HCRU. This analysis of real-world data suggests that there is a subset of newly diagnosed pediatric and adult patients with UC who may require longer use of higher doses of oral CS to achieve optimal therapeutic response. This analysis also suggests that pediatric UC patients are more likely to be treated with corticosteroids and have higher HCRU when compared to the adult UC population.

IL-15 enhanced antibody-dependent cellular cytotoxicity mediated by NK cells and macrophages

The goal of cancer immunotherapy is to stimulate the host immune system to attack malignant cells. Antibody-dependent cellular cytotoxicity (ADCC) is a pivotal mechanism of antitumor action of clinically employed antitumor antibodies. IL-15 administered to patients with metastatic malignancy by continuous i.v. infusion at 2 μg/kg/d for 10 days was associated with a 38-fold increase in the number and activation status of circulating natural killer (NK) cells and activation of macrophages which together are ADCC effectors. We investigated combination therapy of IL-15 with rituximab in a syngeneic mouse model of lymphoma transfected with human CD20 and with alemtuzumab (Campath-1H) in a xenograft model of human adult T cell leukemia (ATL). IL-15 greatly enhanced the therapeutic efficacy of both rituximab and alemtuzumab in tumor models. The additivity/synergy was shown to be associated with augmented ADCC. Both NK cells and macrophages were critical elements in the chain of interacting effectors involved in optimal therapeutic responses mediated by rituximab with IL-15. We provide evidence supporting the hypothesis that NK cells interact with macrophages to augment the NK-cell activation and expression of FcγRIV and the capacity of these cells to become effectors of ADCC. The present study supports clinical trials of IL-15 combined with tumor-directed monoclonal antibodies.

TLR4-dependent fibroblast activation drives persistent organ fibrosis in skin and lung.

Persistent fibrosis in multiple organs is the hallmark of systemic sclerosis (SSc). Recent genetic and genomic studies implicate TLRs and their damage-associated molecular pattern (DAMP) endogenous ligands in fibrosis. To test the hypothesis that TLR4 and its coreceptor myeloid differentiation 2 (MD2) drive fibrosis persistence, we measured MD2/TLR4 signaling in tissues from patients with fibrotic SSc, and we examined the impact of MD2 targeting using a potentially novel small molecule. Levels of MD2 and TLR4, and a TLR4-responsive gene signature, were enhanced in SSc skin biopsies. We developed a small molecule that selectively blocks MD2, which is uniquely required for TLR4 signaling. Targeting MD2/TLR4 abrogated inducible and constitutive myofibroblast transformation and matrix remodeling in fibroblast monolayers, as well as in 3-D scleroderma skin equivalents and human skin explants. Moreover, the selective TLR4 inhibitor prevented organ fibrosis in several preclinical disease models and mouse strains, and it reversed preexisting fibrosis. Fibroblast-specific deletion of TLR4 in mice afforded substantial protection from skin and lung fibrosis. By comparing experimentally generated fibroblast TLR4 gene signatures with SSc skin biopsy gene expression datasets, we identified a subset of SSc patients displaying an activated TLR4 signature. Together, results from these human and mouse studies implicate MD2/TLR4-dependent fibroblast activation as a key driver of persistent organ fibrosis. The results suggest that SSc patients with high TLR4 activity might show optimal therapeutic response to selective inhibitors of MD2/TLR4 complex formation.

The Role of Chromosomal Instability in Cancer and Therapeutic Responses.

Cancer is one of the leading causes of death, and despite increased research in recent years, control of advanced-stage disease and optimal therapeutic responses remain elusive. Recent technological improvements have increased our understanding of human cancer as a heterogeneous disease. For instance, four hallmarks of cancer have recently been included, which in addition to being involved in cancer development, could be involved in therapeutic responses and resistance. One of these hallmarks is chromosome instability (CIN), a source of genetic variation in either altered chromosome number or structure. CIN has become a hot topic in recent years, not only for its implications in cancer diagnostics and prognostics, but also for its role in therapeutic responses. Chromosomal alterations are mainly used to determine genetic heterogeneity in tumors, but CIN could also reveal treatment efficacy, as many therapies are based on increasing CIN, which causes aberrant cells to undergo apoptosis. However, it should be noted that contradictory findings on the implications of CIN for the therapeutic response have been reported, with some studies associating high CIN with a better therapeutic response and others associating it with therapeutic resistance. Considering these observations, it is necessary to increase our understanding of the role CIN plays not only in tumor development, but also in therapeutic responses. This review focuses on recent studies that suggest possible mechanisms and consequences of CIN in different disease types, with a primary focus on cancer outcomes and therapeutic responses.

From Resistance to Sensitivity: Insights and Implications of Biphasic Modulation of Autophagy by Sunitinib.

Sunitinib, a multityrosine kinase inhibitor, is currently the standard first-line therapy in metastatic renal cell carcinoma (mRCC) and is also used in treating patients with pancreatic neuroendocrine and imatinib-resistant gastrointestinal stromal tumors (GIST). Nevertheless, most patients eventually relapse secondary to intrinsic or acquired sunitinib resistance. Autophagy has been reported to contribute to both chemo-sensitivity and -resistance. However, over the last few years, controversial regulatory effects of sunitinib on autophagy have been reported. Since gaining insights into the underlying molecular insights and clinical implications is indispensible for achieving optimum therapeutic response, this minireview article sheds light on the role of a network of prosurvival signaling pathways recently identified as key mediators of sunitinib resistance with established and emerging functions as autophagy regulators. Furthermore, we underscore putative prognostic biomarkers of sunitinib responsiveness that could guide clinicians toward patient stratification and more individualized therapy. Importantly, innovative therapeutic strategies/approaches to overcome sunitinib resistance both evaluated in preclinical studies and perspective clinical trials are discussed which could ultimately be translated to better clinical outcome.

Melatonin Effects in REM Sleep Behavior Disorder Associated with Obstructive Sleep Apnea Syndrome: A Case Series.

REM sleep behavior disorder (RBD), with its main clinical symptoms of nightmares with dream-enacting behavior, is considered as a possible precursor of neurodegenerative disease. Obstructive Sleep Apnea Syndrome (OSAS) is known to be capable of provoking RBD-like symptoms by apneic event related arousals. The two sleep related pathologies must coincide in a relevant number of individuals because of overlapping prevalence in similar age groups. Until now RBD symptoms coexisting with OSAS are rarely described in scientific literature and in fact considered as OSAS mimicking RBD. We report four cases with a severe clinical RBD syndrome which were polysomnographically also diagnosed with concomitant OSAS (AHI range: 10.1 -53.2/h). Treatment with 2 mg prolonged release melatonin led to a relevant clinical improvement of RBD symptoms in all patients, so far untreated for the sleep related breathing disorder. Measure of REM sleep without atonia (RSWA) in polysomnography showed values ranging from 5.1 to 20.4% determined with the Montplaisir method. Surprisingly, RSWA values in PSG with melatonin were high, probably because of the still untreated OSAS. We presume that in patients with RBD and OSAS both pathologies contribute in varying degrees to the emergence of RBD symptoms by a destabilization of REM sleep. We suggest by consequence to consider a therapeutic strategy including the treatment of both disorders for an optimal therapeutic response.

Evaluation of Quetiapine Fumarate and its Solid Lipid Nanoparticles as antipsychotic drug in rat model of schizophrenia

Background: The present study compares the efficacy of quetiapine fumarate (QF) and QF-loaded solid lipid nanoparticles (QFSLN) as antipsychotic drugs for schizophrenia. Methods: To induce schizophrenia-like symptoms, a group of rats was injected intraperitoneally (i.p.) with ketamine (25mg/kg b.w.) for 1 week to establish a rat model of schizophrenia. The incidence of schizophrenic symptoms was estimated to be equivalent to the control group. To estimate the pronounced antipsychotic effect of QF, a low dose (LD) of 10 mg/kg b.w. and a high dose (HD) of 30 mg /kg b.w. were orally administrated to two groups of rats (designated L.QF and H.QF) for 3 weeks (2 weeks without ketamine injection; the last week with ketamine). To achieve the optimal therapeutic response of QF drug, 2 other groups of rats were administered orally the equivalent low and high doses of QF in its solid lipid nanoparticle form (L.QFSLN) and (H.QFSLN) for 3 weeks in the same manner. The treatments were given after 1 h of ketamine injection. To assess the effect of different doses of treatment on hyperlocomotion and cognitive impairment induced by ketamine, an open field test and passive avoidance test were conducted. In addition, excitatory and inhibitory amino acids, as well as catecholamines, were estimated in brain regions (cortex and hippocampus). The study was extended to estimate the side effects of different treatments on hepatorenal functions and lipid profile. Additionally, samples were subjected to immunohistochemical analysis. Results: QFSLN treatment showed enhanced effect over QF in a dose-dependent manner with minimal side effects in schizophrenic rats. In addition, immunohistochemical examinations of brain tissues confirmed the biochemical data.

Analyses of Treatment Outcome According to Age in Patients With Chronic Myeloid Leukemia Receiving Front-line Imatinib Therapy.

Previous studies have indicated that the effect of age at the diagnosis of chronic myeloid leukemia (CML) is minimized in patients treated with imatinib. The treatment response and survival rates were similar for younger and elderly patients. The aim of the present study was to evaluate the effect of age on the treatment outcomes in patients with CML receiving front-line imatinib therapy. Using age, 101 patients were divided into 3 groups: young (age, 18-44 years; YP), middle-age (age, 45-64 years; MP), and elderly (age,≥ 65 years; EP). The patients' clinical features, treatment responses, survival, and adverse events were evaluated. The complete cytogenetic response rates were similar in all 3 groups (81.8% in YP, 86.8% in MP, and 76.7% in EP; P= .328). However, the major molecular response rate was greatest in the MP group (84.2% vs. 63.6% in the YP and 60.0% in the EP group; P< .001). Most of the nonhematologic adverse events (all grades) were in the EP group (40.0% vs. 27.3% in the YP and 21.1% in the MP group; P= .005). The estimated 6-year event-free survival in the MP group (75.5%) was significantly greater than that in the YP group (58.6%) or EP group (43.4%). Also, the estimated 6-year overall survival rate in the EP group (73.5%) was significantly lower than that in the YP group (90.8%) and MP group (86.4%) (P< .001 for all). Our results have shown that middle-age patients have the best clinical outcomes, with the greatest rates of an optimal therapeutic response, longer event-free survival, and longer overall survival.

Predictive biomarkers for optimal therapeutic response to fingolimod treatment in MS patients (P5.353)

Predictive biomarkers for optimal therapeutic response to fingolimod treatment in MS patients (P5.353)

Grid Block Design Based on Monte Carlo Simulated Dosimetry, the Linear Quadratic and Hug-Kellerer Radiobiological Models.

Purpose:The clinical efficacy of Grid therapy has been examined by several investigators. In this project, the hole diameter and hole spacing in Grid blocks were examined to determine the optimum parameters that give a therapeutic advantage.Methods:The evaluations were performed using Monte Carlo (MC) simulation and commonly used radiobiological models. The Geant4 MC code was used to simulate the dose distributions for 25 different Grid blocks with different hole diameters and center-to-center spacing. The therapeutic parameters of these blocks, namely, the therapeutic ratio (TR) and geometrical sparing factor (GSF) were calculated using two different radiobiological models, including the linear quadratic and Hug–Kellerer models. In addition, the ratio of the open to blocked area (ROTBA) is also used as a geometrical parameter for each block design. Comparisons of the TR, GSF, and ROTBA for all of the blocks were used to derive the parameters for an optimum Grid block with the maximum TR, minimum GSF, and optimal ROTBA. A sample of the optimum Grid block was fabricated at our institution. Dosimetric characteristics of this Grid block were measured using an ionization chamber in water phantom, Gafchromic film, and thermoluminescent dosimeters in Solid Water™ phantom materials.Results:The results of these investigations indicated that Grid blocks with hole diameters between 1.00 and 1.25 cm and spacing of 1.7 or 1.8 cm have optimal therapeutic parameters (TR > 1.3 and GSF~0.90). The measured dosimetric characteristics of the optimum Grid blocks including dose profiles, percentage depth dose, dose output factor (cGy/MU), and valley-to-peak ratio were in good agreement (±5%) with the simulated data.Conclusion:In summary, using MC-based dosimetry, two radiobiological models, and previously published clinical data, we have introduced a method to design a Grid block with optimum therapeutic response. The simulated data were reproduced by experimental data.

The significance of angiogenesis for predicting optimal therapeutic response in chronic myeloid leukaemia patients.

In this study the correlation and the prognostic value of the morphometric parameters of angiogenesis for optimal therapeutic response to tyrosine kinase inhibitor (TKI) therapy in patients with chronic myeloid leukaemia (CML), i.e. complete cytogenetic response (CCgR) and major molecular response (MMoR), were investigated. Microvascular density (MVD) and a number of different size- and shape-related morphometric parameters of microvessels of bone marrow biopsy from 40 CML patients and 20 controls were examined. Microvessels of bone marrow were examined by using immunohistochemical staining for CD34 and quantified in the region of the most intense vascularisation by using image analysis. CML patients had significantly higher angiogenesis parameters when compared with controls. A statistically significant correlation was found between some parameters of angiogenesis and evaluated CCgR and MMoR. For achievement of CCgR, lower values of MVD, minor axis, area, circularity, and roundness and higher value of aspect ratio, while for achievement of MMoR only lower values of MVD have been identified as positive prognostic factors. Besides confirming increased angiogenesis in CML patients, this study also demonstrated prognostic significance of the degree of angiogenesis for the clinical outcome and identified angiogenic predictive factors for achieving optimal response on TKIs therapy.

Co-inhibition of CD73 and A2AR Adenosine Signaling Improves Anti-tumor Immune Responses

Preclinical studies targeting the adenosinergic pathway have gained much attention for their clinical potential in overcoming tumor-induced immunosuppression. Here, we have identified that co-blockade of the ectonucleotidase that generates adenosine CD73 and the A2A adenosine receptor (A2AR) that mediates adenosine signaling in leuokocytes, by using compound gene-targeted mice or therapeutics that target these molecules, limits tumor initiation, growth, and metastasis. This tumor control requires effector lymphocytes and interferon-γ, while antibodies targeting CD73 promote an optimal therapeutic response invivo when engaging activating Fc receptors. In a two-way mixed leukocyte reaction using a fully human anti-CD73, we demonstrated that Fc receptor binding augmented the production of proinflammatory cytokines.

The relationship between pharmacokinetic parameters of carbamazepine and therapeutic response in epileptic patients.

IntroductionThe prescribed dose and carbamazepine plasma concentration to achieve the optimal therapeutic efficacy are highly variable from one patient to the other. Our study aimed to determine whether biological parameters may be used as plasma markers that can individually adjust the carbamazepine dose necessary to optimize therapeutic efficacy.Material and methodsNinety-four epileptic patients under carbamazepine monotherapy and who have never used combination therapy were recruited from the consecutive admissions at the Department of Neurology “CHU Sahloul” of Sousse Central Hospital in Tunisia from February 2010 to April 2011. The patients were monitored for epilepsy for three years on average. Carbamazepine and 10,11-epoxide-carbamazepine concentrations were analyzed through high-performance liquid chromatography. Simultaneously, therapeutic efficacy was assessed through the annual number of seizures in each patient.ResultsOur results showed the absence of any significant correlations between specific dose (mg/kg/day), carbamazepine plasma concentrations and therapeutic efficacy (r = 0.0025, p = 0.30; r = 0.1584, p = 0.38 respectively), whereas both plasma 10,11-epoxide-carbamazepine concentration and 10,11-epoxide-carbamazepine to plasma carbamazepine ratio were closely correlated with therapeutic efficacy (r = 0.34, p = 0.03; r = 0.45, p = 0.008 respectively). The optimum therapeutic response was observed among patients who simultaneously had a plasma concentration of 0.8 μg/ml of metabolite and 5.5 μg/ml of carbamazepine.ConclusionsThe results suggest that plasma levels of both carbamazepine and of 10,11-epoxide-carbamazepine must be set to achieve an optimum therapeutic response.

Indicators for Remission of Suicidal Ideation Following Magnetic Seizure Therapy in Patients With Treatment-Resistant Depression.

Magnetic seizure therapy (MST) is a novel therapeutic option for treatment-resistant depression (TRD). Suicidal ideation is often associated with TRD and contributes to the increased mortality and morbidity of the disorder. To identify a biomarker that may serve as an indicator of remission of suicidal ideation following a course of MST by using cortical inhibition measures from interleaved transcranial magnetic stimulation and electroencephalography (TMS-EEG). Thirty-three patients with TRD were part of an open-label clinical trial of MST treatment. Data from 27 patients (82%) were available for analysis in this study. Baseline TMS-EEG measures were assessed within 1 week before the initiation of MST treatment using the TMS-EEG measures of cortical inhibition (ie, N100 and long-interval cortical inhibition [LICI]) from the left dorsolateral prefrontal cortex and the left motor cortex, with the latter acting as a control site. The MST treatments were administered under general anesthesia, and a stimulator coil consisting of 2 individual cone-shaped coils was used. Suicidal ideation was evaluated before initiation and after completion of MST using the Scale for Suicide Ideation (SSI). Measures of cortical inhibition (ie, N100 and LICI) from the left dorsolateral prefrontal cortex were selected. N100 was quantified as the amplitude of the negative peak around 100 milliseconds in the TMS-evoked potential (TEP) after a single TMS pulse. LICI was quantified as the amount of suppression in the double-pulse TEP relative to the single-pulse TEP. Of the 27 patients included in the analyses, 15 (56%) were women; mean (SD) age of the sample was 46.0 (15.3) years. At baseline, patients had a mean SSI score of 9.0 (6.8), with 8 of 27 patients (30%) having a score of 0. After completion of MST, patients had a mean SSI score of 4.2 (6.3) (pre-post treatment mean difference, 4.8 [6.7]; paired t26 = 3.72; P = .001), and 18 of 27 individuals (67%) had a score of 0 for a remission rate of 53%. The N100 and LICI in the frontal cortex-but not in the motor cortex-were indicators of remission of suicidal ideation with 89% accuracy, 90% sensitivity, and 89% specificity (area under the curve, 0.90; P = .003). These results suggest that cortical inhibition may be used to identify patients with TRD who are most likely to experience remission of suicidal ideation following a course of MST. Stronger inhibitory neurotransmission at baseline may reflect the integrity of transsynaptic networks that are targeted by MST for optimal therapeutic response.

B Cells, Antibodies, and More.

B cells play a central role in the immunopathogenesis of glomerulonephritides and transplant rejection. B cells secrete antibodies that contribute to tissue injury via multiple mechanisms. In addition, B cells contribute to disease pathogenesis in autoimmunity and alloimmunity by presenting antigens as well as providing costimulation and cytokines to T cells. B cells also play an immunomodulatory role in regulating the immune response by secreting cytokines that inhibit disease onset and/or progression. B cell-targeted approaches for treating immune diseases of the kidney and other organs have gained significant momentum. However, much remains to be understood about B-cell biology in order to determine the timing, duration, and context of optimal therapeutic response to B cell-targeted approaches. In this review, we discuss the multifaceted roles of B cells as enhancers and regulators of immunity with relevance to kidney disease and transplantation.

Suboptimal Antiplatelet Therapy Suggested By Platelet Aggregation Studies Does Not Correlate with a Change in Clinical Management

Introduction: With the expanding repertoire of antiplatelet drug targets and therapies, quantifiable parameters to assess their efficacy can prove to be useful in clinical decision-making. In this retrospective analysis we examined patients who had platelet aggregation testing done at our center between August 2008 and August 2013, focusing on those who were on some form of antiplatelet therapy during testing. Our goal was to define the impact of platelet aggregation testing on decision-making regarding continuation or change in antiplatelet therapy.Methods: Light transmission aggregometry (LTA) was used to assess efficacy of treatment with antiplatelet agents. Inhibition of platelet aggregation in response to ADP and arachidonic acid are reflective of the therapeutic effect of aspirin, while inhibition of platelet aggregation in response to ADP reflects the effect of P2Y12 receptor antagonists. As per parameters developed at our center, the combination of arachidonic acid aggregation <20 percent and ADP aggregation (at concentration of 5 uM) <70 percent is indicative of optimal therapeutic response to aspirin. Though not fully standardized, ADP aggregation < 40% is considered to be indicative of therapeutic response to clopidogrel. Descriptive statistics for frequency were used. Pearson coefficient was used to assess correlation.Results: We studied results of platelet aggregometry in 117 patients who were on some form of antiplatelet therapy - 81 on a single agent (72 on aspirin alone, 9 receiving P2Y12 antagonist alone), 34 on dual therapy (33 on aspirin + P2Y12 antagonist, 1 on aspirin + cilostazol), and 2 patients on triple therapy (1 on aspirin + P2Y12 antagonist + cilostazol, 1 on aspirin + dipyridamole + cilostazol). None of our patients were on Gp IIb/IIIa inhibitors. In total, 108 patients were on aspirin therapy and 43 patients were on P2Y12 inhibitors. In 65 out of these 117 patients, the primary indication for platelet aggregation testing was to monitor the efficacy of antiplatelet therapy, while in the remaining 52, testing was done for other indications. Fifty-nine of these 65 patients were tested in the setting of a recent thrombotic event in the cerebral, coronary, peripheral, or other vascular bed. While 68 (58%) patients had optimal therapeutic response, 49 (42%) patients - 38 of the 108 (35%) patients on aspirin, and 14 of the 43 (32%) patients on a P2Y12 inhibitor - had evidence of suboptimal response to the respective agent. However, antiplatelet therapy was changed or adjusted in only 8 of these 49 patients following these sub-optimal test results, and only 3 had repeat testing following the change (all three of whom were shown to have complete response). Among the 108 patients on aspirin therapy, the total daily dose did not correlate either with the PFA-100 closure times (Collagen/ADP or Collagen/epinephrine) or with the degree of platelet aggregation in response to any of the agonists (ADP, arachidonic acid, collagen, epinephrine or ristocetin).Conclusions: Most of the patients who underwent platelet aggregation testing to monitor the efficacy of antiplatelet therapy had a recent thrombotic event that prompted the test. Though 42% of patients on antiplatelet agent(s) had in vitro evidence of sub-optimal platelet inhibition, antiplatelet therapy was changed or adjusted in only 16% of these individuals, and only 6% had repeat testing following the change. This suggests that, though platelet aggregation testing was potentially useful in monitoring efficacy of platelet inhibition, clinical changes in antiplatelet therapy were guided more by other factors, casting uncertainty upon the cost effectiveness of platelet function testing in this population. No significant increment was found in the in vitro antiplatelet effect of aspirin with increasing daily doses, suggesting lack of a dose-response beyond 81 mg per day. DisclosuresMcCrae:Syntimmune: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees; Halozyme: Membership on an entity's Board of Directors or advisory committees; Momenta: Consultancy.

Surrogate Endpoints for Optimal Therapeutic Response to UDCA in Primary Biliary Cholangitis

Background: Ursodeoxycholic acid (UDCA) is the standard treatment for primary biliary cholangitis (PBC), as it can delay histological progression, improve long-term outcome and is extremely safe and well tolerated. However, UDCA is not always sufficient and the prognosis of patients inadequately responding to treatment is worse compared with the general population. Reliable identification of so-called non-responders is of key importance, not only for selecting patients who could benefit from additional, second-line therapy, but also for identifying those individuals who are at low risk of developing end-stage disease and in whom UDCA mono-therapy can be safely continued. Several laboratory surrogate endpoints for the long-term response to UDCA have been proposed, including the Barcelona, Paris, Toronto and Rotterdam criteria. All these criteria have limitations and the superiority of one over the other has not been firmly established. Key Messages: Recently the Global PBC Study Group developed a new prognostic tool by studying a large, representative and multinational cohort of 4,119 UDCA-treated patients. In a random sample of 2,488 cases, a risk score - the GLOBE score - was developed, predictive of transplantation-free survival. This risk score comprises age, and bilirubin, albumin, alkaline phosphatase and platelet count obtained after 1 year therapy, and has a performance (C statistic 0.81, 95% CI 0.79-0.83) that is markedly better than that of previously proposed response criteria. Comparable performance was found in an independent validation cohort of 1,631 cases (C statistic 0.82, 95% CI 0.79-0.84). A web app will allow the easy use of the score in clinical practice.

Severe eosinophilic fasciitis: comparison of treatment with d-penicillamine plus corticosteroids vs. corticosteroids alone

Objectives: To compare the therapeutic effectiveness of corticosteroids (CS) alone vs. CS plus d-penicillamine (d-Pen) in severe eosinophilic fasciitis.Method: A long-term prospective non-randomized trial of d-Pen plus CS vs. CS alone in patients with severe eosinophilic fasciitis, defined as clinically apparent cutaneous fibrotic involvement affecting more than 15% body surface area (BSA) or more than 10% BSA with joint flexion contractures.Results: Sixteen patients with severe eosinophilic fasciitis entered the study. Ten patients received d-Pen plus CS and six received CS alone. Affected BSA decreased from an average of 29% to 8.9% in the d-Pen plus CS group compared to a decrease in affected BSA from 28% to 22.83% in the CS-alone group. The reduction in affected BSA in the d-Pen plus CS group was significantly greater than in the CS-alone group (p = 0.038). Clinical improvement occurred in all d-Pen plus CS patients compared to only 33.3% of CS-alone patients (p = 0.008). There was no difference in overall frequency of adverse events between the groups (p = 0.60). The most common adverse event in the d-Pen plus CS group was proteinuria (33.3%). However, proteinuria also occurred in 16.6% in the CS-alone group.Conclusions: Treatment with CS alone failed to induce clinical improvement in the majority of the severe eosinophilic fasciitis patients. By contrast, d-Pen plus CS resulted in significantly greater clinical improvement. These results suggest that initial treatment of severe eosinophilic fasciitis with CS alone is not sufficient for optimal therapeutic response and that addition of an antifibrotic agent results in an improved outcome.

Genetic factors modifying response to glucocorticoid treatment in chronic pediatric inflammatory bowel diseases

The article concerns genetic factors that determine efficiency of steroid treatment for chronic inflammatory bowel diseases (IBD) in children, focused, mostly, on Crohn disease and nonspecific ulcerative colitis. Their incidence comprises 5 to 15 per 100 000 children and adolescents. In acute phase, therapy of these diseases is based on salicylates and glucocorticoids which regulate cytokine network and immune cell functions. Application of high-dose glucocorticoids (GCs) exerts а sufficient immunosuppressive action. These effects are performed via specific GC receptors in the target cell populations. Hence, numbers and functionality of GC receptors are important for clinical response to GC treatment. The aim of this review is discern major genetic effects upon functioning of glucocorticoid receptors. Here we discuss effects of N363S, ER22/23EK, and NR3C1 variants, the most known GC functional gene polymorphisms. These gene variants are often associated with altered GC gene expression in individual cases of IBD. Moreover, some other gene variants are able to modulate the GC receptor expression, thus making it difficult to assess genetic predisposition to altered clinical response to glucocorticoids. Hence, the regulatory effects of single gene variants upon GC receptors may not show direct correlations with clinical effects of the drug. Therefore, we propose an immediate way to assess the gene activity, i. e., quantitative analysis of the gene transcription (mRNA detection) in the patients’ cells before and during glucocorticoid therapy, presuming further application of this parameter as a predictive marker for evaluation of optimal therapeutic response in the individual IBD patients.

RhoB upregulation leads to either apoptosis or cytostasis through differential target selection.

Anaplastic thyroid carcinoma is a highly aggressive undifferentiated carcinoma with a mortality rate near 100% due to an assortment of genomic abnormalities which impede the success of therapeutic options. Our laboratory has previously identified that RhoB upregulation serves as a novel molecular therapeutic target and agents upregulating RhoB combined with paclitaxel lead to antitumor synergy. Knowing that histone deacetylase 1 (HDAC1) transcriptionally suppresses RhoB, we sought to extend our findings to other HDACs and to identify the HDAC inhibitor (HDACi) that optimally synergize with paclitaxel. Here we identify HDAC6 as a newly discovered RhoB repressor. By using isoform selective HDAC inhibitors (HDACi) and shRNAs, we show that RhoB has divergent downstream signaling partners, which are dependent on the HDAC isoform that is inhibited. When RhoB upregulates only p21 (cyclin kinase inhibitor) using a class I HDACi (romidepsin), cells undergo cytostasis. When RhoB upregulates BIMEL using class II/(I) HDACi (belinostat or vorinostat), apoptosis occurs. Combinatorial synergy with paclitaxel is dependent upon RhoB and BIMEL while upregulation of RhoB and only p21 blocks synergy. This bifurcated regulation of the cell cycle by RhoB is novel and silencing either p21 or BIMEL turns the previously silenced pathway on, leading to phenotypic reversal. This study intimates that the combination of belinostat/vorinostat with paclitaxel may prove to be an effective therapeutic strategy via the novel observation that class II/(I) HDACi antagonize HDAC6-mediated suppression of RhoB and subsequent BIMEL, thereby promoting antitumor synergy. These overall observations may provide a mechanistic understanding of optimal therapeutic response.