Differences In Clinical Response Research Articles

Novel biomarkers for prediction of poor treatment response in heart failure to guide therapy

BackgroundHeart failure is a complex clinical syndrome that occurs at the end stage of heart disease. It is a major health problem in western countries with an overall population prevalence of 2–3% which rises sharply to 10–20% at 75 years of age. Despite advances in therapy for heart failure, improvment of clinical outcomes remains a challenge for physicians: half of patients die within 4 years of diagnosis and 40% of patients, who have been admitted to hospital are dead or re-admitted to hospital within 1 year. The aim of this study was to find plasma proteins that predict differences in clinical response from standard therapy in patients with heart failure. MethodsPatients with heart failure who met inclusion and exclusion criteria were recruited. Uptitration of angiotensin-converting-enzyme-inhibitors and β blockers was done over 6 months. Patients were followed up for clinical events such as death and admission to hospital for heart failure within the next 24 months. We compared plasma proteins in 50 patients who responded to standard treatment (responders) with 50 patients who died or were re-admitted to hospital (non-responders). Plasma samples were pooled and depleted of 14 high abundance proteins and then reduced and alkylated, before digestion with trypsin to peptides. Peptides were analysed on two-dimensional liquid chromatography coupled to a tandem mass spectrometry in high definition mode which used a high pH reverse phase liquid chromatography in the first step before separation with conventional low pH reverse phase columns in the second step. Findings434 proteins were identified in the plasma of patients with heart failure. 137 proteins in both responders and non-responders were significantly overexpressed or underexpressed (p<0·05), with 97 upregulated and 40 downregulated. Several of these proteins have the potential to become novel biomarkers for prediction of treatment response. They can be classified according to five pathobiological processes in heart failure: (1) neurohormones—hepatocyte growth factor like protein and insulin like growth factor II; (2) vascular system—intercellular adhesion molecule 2, sex hormone binding globulin, and prostaglandin H2 D isomerase; (3) inflammation—C-reactive protein, and mannose binding protein C; (4) matrix and cellular remodelling—retinol binding protein 4; and (5) cardiorenal system—cystatin C. InterpretationThe discovery of novel biomarkers in this study will not only help to understand the pathophysiology of heart failure better, but also lead to the development of a more personalised approach in predicting treatment response to guide medical therapy. For example, in patients with heart failure who have abnormally increased concentrations of retinol-binding protein 4, a marker for matrix and cellular remodelling, a drug for reducing collagen deposition could be useful. In this way, unnecessary treatment in non-responders could be avoided (with implications for cost and adverse effects) and novel therapeutic targets could be identified for design of therapies to improve outcomes. FundingEuropean Union FP7 Project.

Novel agents and new therapeutic approaches for treatment of multiple myeloma.

This review summarizes the therapeutic strategies and the drugs actually in development for the management of myeloma patients. Multiple myeloma is caused by the expansion of monoclonal plasma cells and secretion of M-protein (immunoglobulins, Bence Jones protein and free light chains). Multiple myeloma still remains an incurable disease with a high incidence rate in the elderly, despite the introduction of several new therapeutic agents (bortezomib, lenalidomide and thalidomide) which have changed its natural history. The high heterogeneity of this disease leads to large differences in clinical responses to treatments. Thus, the choice of the best treatment is a difficult issue. However, the introduction of new drugs has made it possible to achieve high response rates and good quality responses with long-term disease control. Interactions between tumor cells and their bone marrow microenvironment play a pivotal role in the development, maintenance, and progression of myeloma, inducing also drug resistance. These knowledges have improved treatment options, leading to the approval of new drugs which not only target the malignant cell itself, but also its microenvironment. These agents are in preclinical/early clinical evaluation and they appear to further improve disease control, but their use is still not approved outside of clinical trials.

Role of pharmacogenomics for understanding large inter-individual differences in clinical responses and pharmacokinetics of medicines

Role of pharmacogenomics for understanding large inter-individual differences in clinical responses and pharmacokinetics of medicines

Atypical antipsychotics for psychosis in adolescents

Atypical antipsychotics for psychosis in adolescents

Equivalent beneficial effects of unilateral and bilateral prefrontal cortex transcranial magnetic stimulation in a large randomized trial in treatment-resistant major depression

Repetitive transcranial magnetic stimulation treatment (rTMS) is an effective treatment for depression but the optimal methods of administration have yet to be determined. Recent studies have produced conflicting results as to whether unilateral rTMS is more or less effective than sequentially applied bilateral rTMS. To address this we conducted a trial comparing sequential bilateral rTMS to right-sided unilateral rTMS using a priming protocol. Patients with treatment-resistant depression (n = 179) were enrolled in a two-arm randomized controlled trial across a 4-wk time period. The primary outcome assessment was the Hamilton Depression Rating Scale. Overall, there was a substantial response rate of >50% (and a 40% remission rate); however, there were no significant differences in clinical response between the two treatment groups. rTMS was well tolerated with a very low discontinuation rate. There was no relationship between response in the current trial and previous response, or non-response, to electroconvulsive therapy. We found no significant differences in clinical response between sequential bilateral rTMS and right-sided unilateral rTMS applied with a priming protocol. The results of this study do not support superior efficacy of bilateral rTMS and instead suggest that other approaches should be explored to increase treatment efficacy.

AZD3480, a Novel Nicotinic Receptor Agonist, for the Treatment of Attention-Deficit/Hyperactivity Disorder in Adults

Laboratory studies have found that acute stimulation of nicotinic acetylcholine receptors improves cognition in adult attention-deficit/hyperactivity disorder (ADHD). Clinical trials of nicotinic agonists have been mixed, underscoring the need to understand the mechanisms for individual differences in clinical response. Using cognitive models within a clinical trial framework may provide insight into these differences. This was a within-subjects, randomized, placebo-controlled double-blind trial of the nicotinic agonist AZD3480 (also termed TC-1734) at doses of 5 mg and 50 mg and placebo in adults with ADHD. The order of the 2-week treatment periods was randomized, and a 3-week wash out separated each drug treatment period. Response inhibition (Stop Signal Task [SST]) and clinical efficacy (Investigator Rated Conners Adult ADHD Rating Scale [CAARS-INV]) were the a priori primary outcome measures of cognitive and clinical effects. We hypothesized that AZD3480 treatment would improve SST performance and clinical symptoms (CAARS-INV Total ADHD Symptoms Score). Thirty subjects were randomized, with 24 included in the intent-to-treat analyses. SST performance and total ADHD symptoms were significantly improved with 50 mg of AZD3480. CAARS-INV ratings of inattention, memory problems, and emotional lability/impulsivity were significantly improved with 50 mg of AZD3480. These results support previous work suggesting that nicotinic agonists are viable as treatments for adult ADHD. Measuring cognitive endophenotypes related to both the disorder and mechanism of treatment may help further rational drug development for dimensional features that cross-cut psychiatric disorders.

FRI0088 Effect of body mass index on clinical response to anti-tnf therapy in rheumatoid arthritis

BackgroundRheumatoid Arthritis is the commonest inflammatory arthritis. Improved understanding of its pathogenesis has led to targeted therapies like TNF inhibitors. With more emphasis on personalised treatment of RA, a better...

Tu1518 Smoking Adversely Affects Colon Cancer Survival and Relapse Rates

Objective: To test the hypothesis that ever smokers would suffer more recurrences and worse overall and disease-free survival than never smokers following colon cancer resection. Summary Background Data: Smoking is associated with an increased risk of developing colon polyps, specifically aggressive polyps, as well as an increased risk of colon cancer. Large database studies have shown an increased risk of colon cancer mortality among smokers, but it is not clear whether this risk is related to differences in the biology/ aggressiveness of the disease or differences in clinical response to treatment. Methods: The medical records of 2540 patients with resected stage I-III colon cancers treated at a single institution were reviewed. Demographics, tumor and surgical variables, and follow-up information were recorded. Univariate and multivariate analyses were performed to examine predictors of overall and disease-free survival as well as time to recurrence of colon cancer. Results: Tumor variables and chemotherapy administration were similar among smokers and nonsmokers. Overall survival was significantly higher for never smokers compared to ever smokers (5 year OS 79.8% nonsmokers versus 72.3% ever smokers, p ,0.0001; HR 1.51, 95% CI 1.30 -1.74). Disease free survival was significantly higher for nonsmokers compared to smokers. Time to cancer recurrence was also significantly influenced by smoking status. Smoking status remained a poor prognostic factor in multivariate models for overall and disease-free survival as well as time to recurrence. Conclusions: This study confirms that ever smokers have worse colon cancer outcomes than never smokers. Surgeons should refer all smokers with colon polyps or cancers for smoking cessation programs. Multivariate Predictors of Disease-Free and Overall Survival

Tu1519 High Definition Colonoscopy Increases Adenoma Detection Rate

Objective: To test the hypothesis that ever smokers would suffer more recurrences and worse overall and disease-free survival than never smokers following colon cancer resection. Summary Background Data: Smoking is associated with an increased risk of developing colon polyps, specifically aggressive polyps, as well as an increased risk of colon cancer. Large database studies have shown an increased risk of colon cancer mortality among smokers, but it is not clear whether this risk is related to differences in the biology/ aggressiveness of the disease or differences in clinical response to treatment. Methods: The medical records of 2540 patients with resected stage I-III colon cancers treated at a single institution were reviewed. Demographics, tumor and surgical variables, and follow-up information were recorded. Univariate and multivariate analyses were performed to examine predictors of overall and disease-free survival as well as time to recurrence of colon cancer. Results: Tumor variables and chemotherapy administration were similar among smokers and nonsmokers. Overall survival was significantly higher for never smokers compared to ever smokers (5 year OS 79.8% nonsmokers versus 72.3% ever smokers, p ,0.0001; HR 1.51, 95% CI 1.30 -1.74). Disease free survival was significantly higher for nonsmokers compared to smokers. Time to cancer recurrence was also significantly influenced by smoking status. Smoking status remained a poor prognostic factor in multivariate models for overall and disease-free survival as well as time to recurrence. Conclusions: This study confirms that ever smokers have worse colon cancer outcomes than never smokers. Surgeons should refer all smokers with colon polyps or cancers for smoking cessation programs. Multivariate Predictors of Disease-Free and Overall Survival

Adalimumab combined with ciprofloxacin is superior to adalimumab monotherapy in perianal fistula closure in Crohn's disease: a randomised, double-blind, placebo controlled trial (ADAFI)

ObjectiveTo assess whether a combination of adalimumab and ciprofloxacin is superior to adalimumab alone in the treatment of perianal fistulising Crohn's disease (CD).DesignRandomised, double-blind, placebo controlled trial in eight Dutch...

Dietary methyl content regulates opioid responses in mice

BackgroundLarge interindividual differences in clinical responses to opioids and the variable susceptibility to abuse of this class of drugs make their use problematic. We lack a full understanding of the factors responsible for these differences. Dietary factors including methyl donor content have been noted to alter multiple physiological and behavioral characteristics of laboratory animals. The purpose of this research was to determine the effects of dietary methyl donor content on opioid responses in mice.MethodsGroups of male C57BL/6J mice were treated with high and low methyl donor diets either in the perinatal period or after weaning. Analgesic responses to morphine, as well as tolerance, opioid-induced hyperalgesia, and physical dependence were assessed.ResultsMice fed high and low methyl donor diets showed equal weight gain over the course of the experiments. Exposure to a high methyl donor diet in the perinatal period enhanced physical dependence. Dietary methyl donor content also altered analgesic responses to low doses of morphine when the dietary treatments were given to the mice after weaning. Opioid-induced hyperalgesia was unaltered by dietary methyl donor content.ConclusionHigh and low methyl donor diet treatment has selective effects on opioid responses depending on the timing of exposure. These findings suggest that examination of DNA methylation patterns in specific brain regions linked to opioid analgesia and dependence may provide specific explanations for dietary effects on opioid responses.

Genotype–phenotype correlation of cytochrome P450 2C9 polymorphism in Indian National Capital Region

Identification of polymorphism of cytochrome P450 2C9 (CYP2C9) enzymes in different ethnic populations is important to understand the differences in clinical responses to drugs. This study determines the CYP2C9 genetic polymorphism in Indian National Capital Region and correlates the phenotype-genotype. Losartan (25 mg) was administered to 107 volunteers to assess CYP2C9 activity, and, on the basis of results, volunteers were categorized as rapid and poor metabolizers. Molecular typing of CYP2C9*1 (wild type), CYP2C9*2, and CYP2C9*3 (the most common variant) was carried out by single-base primer extension technology for 37 subjects, of which 9 were poor metabolizers, and 28 were rapid metabolizers. 14.28 % of the studied population was identified as poor metabolizer for the category of drugs metabolized by CYP2C9. Significant difference was observed between the mean ratio (drug/metabolite) of poor (11.38 ± 5.88) and rapid (1.18 ± 1.11) drug metabolizers. The study suggests that phenotyping of CYP2C9 is desirable before enrollment of subjects for clinical trials or for deciding drug dose regimen as 14.28 % of study population was found to be poor metabolizer for the category of drugs metabolized by CYP2C9. This study establishes phenotype-genotype correlation, and proposes to use genotyping or phenotyping to evaluate the status of drug metabolizing capacity of CYP2C9 as a primary screening procedure before enrolling subjects in clinical trials or in clinical practice.

Strategic Biomarkers for Drug Development in Treating Rare Diseases and Diseases in Neonates and Infants

There are similar challenges in developing a product designed to treat patients with a rare disease and drugs to treat critically ill neonates and infants. Part of the challenge in developing such products as well as identifying the optimal dosing regimen for the treatment of young children arises from the complex interrelationship between developmental changes and changes in biomarkers responsive to drug therapy. These difficulties are further compounded by our lack of understanding of the key physiological factors that cause the differences in clinical responses between adults and neonates and infants. Regulatory efforts have succeeded in overcoming these challenges in many areas of pediatric and orphan drug development. Strategic applications of biomarkers and surrogate endpoints for the development and approval of a product used to treat an orphan disease will be highlighted with examples of approved products. Continued efforts are still needed to fill in our knowledge gap and to strategically link biomarkers and surrogate endpoints to clinical responses for rare diseases and diseases affecting neonates and infants.

Treatment of Chronic Paronychia: A Double Blind Comparative Clinical Trial Using Singly Vaseline, Nystatin and Fucidic Acid Ointment

Background: Chronic paronychia is a chronic inflammatory reaction of the proximal and lateral nail folds of multifactorial in etiology like irritant, bacterial and monilial causes. But housewife work is a major cause of chronic paronychia. Objective: To assess the efficacy and prophylactic effects of Vaseline by occlusion of nail folds in comparison with nystatin ointment and fucidic acid in treatment of housewife chronic paronychia. Patients and Methods: This double, blinded, comparative therapeutic, clinical trial is conducted at the Department of Dermatology-Baghdad Teaching Hospital from May 2010 to May 2011. Eighty female housewife patients with chronic paronychia were included in this trial. They were divided into three groups according to the following therapeutic model: Group A treated by Vaseline consisted of 40 patients; Group B and Group C treated by nystatin ointment, fucidic acid ointment respectively and each group consisted of 20 patients. All demographic points related to the disease were recorded from all patients. Invented score system was applied to assess the severity of disease and the response to therapy. Patients had used therapy twice daily on the proximal and lateral nail folds. Treatment duration was 12 weeks. Results: Group A (Vaseline): The recovery rate after 12 weeks of treatment was 26 (65%) patients, while there was no recovery in 14 (35%) patients. Group B (Nystatin ointment): The recovery rate after 12 weeks was 13 (65%) cases and there was no recovery in 7 (35%) patients. Group C (Fucidic acid ointment): The recovery rate 12 weeks of treatment was 12 (60%) patients and there was no recovery in 8 (40%) patients. The earliest signs of recovery in all groups were decreased in nail fold tenderness, redness, swelling followed by improvement in the nail shape, then decreased in the separation of proximal nail fold from nail bed followed by re-growth of cuticle. There was significant difference in clinical response before and after therapy in all groups (P ≤ 0.0001) while there was no statistical significant difference when the three groups were compared with each other (P = 0.784). Conclusions: Vaseline occlusion therapy of the nail folds in patient with chronic paronychia was enough to induce recovery from the disease and there was no statistical significant difference when compared with nystatin or fucidic acid treatment of chronic paronychia.

Tissue Biomarkers in Melanoma Patients Treated with TIL

While treating stage III melanoma patients with autologous therapeutic TIL in an adjuvant setting, we previously reported a significant benefit of treatment on both progression-free survival and overall survival in patients with only one invaded lymph node (early stage III) compared to patients with more than one invaded lymph nodes (advanced stage III). In this context, in order to understand the difference of activity of TIL therapy according to the progression of the illness at stage III, the first objective of the present study was to determine potential differences in the characteristics of TIL populations obtained from an early stage III and a more advanced stage III when tumor burden is more important. The second objective was to determine possible differences in tissue expression level of several molecules involved in interactions between tumor cells and T cells between early and advanced stage III considering that the tumor microenvironment of invaded lymph nodes could become more tolerant with the progression of the disease. A total of 47 samples of melanoma invaded LN from stage IIIb (AJCC 2007) melanoma patients treated with TIL plus IL-2 were included in this study. We confirmed that both PFS and OS were significantly associated to the presence of tumor-reactive T-cells among TIL injected to the patients and that these tumor reactive T cells were more frequently observed at the early stage III. Moreover, while analyzing the expression of 17 markers on 34/47 tumor specimens using immunohistochemistry, we identified that 3 tissue markers involved in interactions between melanoma cells and T cells have a significant difference of expression between early and advanced stage III: MHC class I, adhesion molecule ICAM-1 and the co-stimulation molecule LFA-3 had a significantly weaker expression in melanoma tissue specimens from advanced stage III. In addition, the expression of the alpha chain of the IL-2 receptor (CD25) and the nuclear transcription factor Foxp3 was significantly increased in the melanoma tissue specimens from advanced stage III. Our results suggest differences in the immunological status of the tumor microenvironment between early and advanced stage III, which could explain the difference in clinical response to TIL infusion in an adjuvant setting between early and advanced stage III.

Prevalence of poor and rapid metabolizers of drugs metabolized by CYP2B6 in North Indian population residing in Indian national capital territory

Identification of poor and rapid metabolizers for the category of drugs metabolized by cytochrome P450 2B6 (CYP2B6) is important for understanding the differences in clinical responses of drugs metabolized by this enzyme. This study reports the prevalence of poor and rapid metabolizers in North Indian population residing in the National Capital Territory.The prevalence of poor and rapid metabolizers was determined in the target population for the category of drugs metabolized by CYP2B6 by measuring plasma bupropion, a drug metabolized by CYP2B6, and its metabolite. Bupropion (75 mg) was administered to 107 volunteers, and the drug (bupropion) and its metabolite (hydroxybupropion) were determined simultaneously by LCMS/MS in the plasma. CYP2B6 activity was measured as hydroxybupropion/bupropion ratio, and volunteers were categorized as rapid or poor metabolizers on the basis of cutoff value of log (hydroxybupropion/bupropion). Significant differences were observed between the mean metabolite/drug ratio of rapid metabolizers (Mean = 0.59) and poor metabolizers (Mean = 0.26) with p<0.0001. Results indicate that 20.56% individuals in the target population were poor metabolizers for the category of drugs metabolized by CYP2B6. Cutoff value defined in this study can be used as a tool for evaluating the status of CYP2B6 using bupropion as a probe drug. The baseline information would be clinically useful before administering the drugs metabolized by this isoform.

Impact of Clinical Response on Different Approved Doses in Japan and the United States.

The pharmaceutical industry has increasingly aimed to achieve efficient strategies for simultaneous international and worldwide development of medicines, and there has been a growing need to understand ethnic differences in drug evaluation. Japan is one of the unique countries in which substantial domestic clinical data are required for dose selection as well as for marketing authorization. However, it appears challenging to accumulate a large amount of data in a single country in the recent shift to international drug development. To gain a better understanding of the influence of ethnic factors, the dosages of the products approved in Japan during 2003-2010 were reviewed, and differences in clinical responses between Japan and the United States were evaluated using a modeling approach. Of new medicines (new molecular entities) approved in Japan, 39 products (28.1%) have been approved at a different dose level compared with the United States, of which 13 products have considerable difference, twice or greater. Of those 13 products, only 2 were suggested to have a different clinical response, although limited data availability should be taken into careful consideration. Further investigation is recommended to establish new approaches for appropriate dose selection and thereby increase the efficiency of international drug development.

Effects of tricuspid valve regurgitation on clinical and echocardiographic outcome in patients with cardiac resynchronization therapy

The severity of tricuspid regurgitation (TR) is a predictor of outcome among heart failure patients. The interaction between cardiac resynchronization therapy (CRT) and TR has not been described. In this study, we examined the effect of pre-implant TR, and worsened TR post-implant, on response to CRT and overall survival. We included all patients with successfully implanted CRT systems between 2007 and 2010. Patients were divided into two groups pre-implant: (Gp 1) no-or-mild TR; and (Gp 2) moderate-or-severe TR. Post-implant, patients were divided into two groups: (Gp A) improved or stable TR; and (Gp B) worsened TR. The clinical and echocardiographic outcome of all patients was assessed. The study included 193 patients. Thirty-five subjects (18%) had moderate or severe TR pre-implant (Gp 2). Baseline echo parameters and 6 min walk distance were worse in Gp 2 compared with Gp 1 (mild or no TR). There was no significant difference in clinical response to CRT between the two groups. However, Gp 2 had a significantly lower echocardiographic response (35 vs. 60%, P = 0.01) and higher mortality over 3 years (OR = 6.70, 95% CI = 1.8-24.5, P = 0.004). Post-implant, 25 patients (13%) developed worsened TR (Gp B), not associated with deterioration in right ventricle function or elevation in pulmonary artery pressure. Worsened TR predicted a reduced clinical response to CRT (42 vs. 70%, P = 0.006), when compared with Gp A. The presence of baseline moderate or severe TR is associated with increased mortality but does not predict clinical or echocardiographic response to CRT. Patients with worsened TR following CRT are less likely to clinically respond to CRT. Pacing leads passing through the tricuspid valve may worsen TR. It is conceivable that avoidance of lead-induced TR by alternative implantation techniques could improve the response rate to CRT.

Pattern of esophageal eosinophilic infiltration in patients with achalasia and response to Heller myotomy and Dor fundoplication

Eosinophilic esophagitis (EoE) is now recognized as a common cause of dysphagia. Eosinophilic infiltration of the esophagus has also been associated with other conditions, such as gastroesophageal reflux disease (GERD); however, the incidence, pattern, and clinical significance of eosinophilic infiltration in achalasia are poorly documented. We sought to characterize this histological finding in patients undergoing Heller myotomy (HM) for achalasia. Ninety-six patients undergoing laparoscopic HM for primary achalasia between 1999 and 2008 were identified from a prospective database. Serial mid and distal per-endoscopic esophageal biopsies taken from patients before and after surgery were assessed for the presence of elevated intraepithelial eosinophils (EIEs). Slides from patients with reports suggestive of EIE were reviewed independently by two pathologists, and the highest eosinophil count/high-power field (eos/hpf) was recorded. Dysphagia scores (0 = none to 5 = severe dysphagia), GERD health-related quality of life scores (0 = best to 45 = worst), and 24-hour pH results were compared before and 3 months after surgery. We related the highest eos to the symptoms and response to HM. Data are presented as median (range). Paired t-test and Wilcoxon signed-rank test determined significance, *P < 0.05. Of 96 patients with achalasia, 50 had undergone pre-HM biopsies revealing EIE in 17/50 (34%), with a median of 3 eos/hpf (1-21). Two patients were found to have superimposed esophageal candidiasis. One patient met the pathologic criteria for EoE. Twenty-five of 50 (50%) postoperative biopsies demonstrated a median of 5 eos/hpf (1-62) for a total of 28/50 patients (56%) with EIE in either the preoperative or postoperative period. Four patients (8%) met the pathologic criteria for EoE, and two demonstrated persistent esophageal candidiasis. A decrease in eosinophils was found in 6/28 patients (21%) from 3/hpf (1-21) to 0.5/hpf (0-4). Increase in eosinophils was found in 22/28 patients (79%) from 0.5/hpf (0-8) to 5/hpf (1-62). Preoperative and postoperative dysphagia scores were available in 23 patients. Dysphagia scores improved in 22/23 patients. (3 [0-5] to 0 [0-2])*. Preoperative and postoperative GERD scores were available in 21 patients. GERD scores improved in 20/21 patients (10 [3-38] to 2 [2-14])*. Four of 13 patients (30.7%) demonstrated significant reflux in the postoperative period. No difference in clinical response to HM was detected between patients with preoperative EIE compared with patients with no EIE. No correlation between postoperative esophageal pH and eos was observed. A significant number of patients with achalasia demonstrate esophageal eosinophilic infiltration even at numbers demonstrable in patients with EoE (8% 4/50). While the interaction between achalasia and esophageal eosinophilic infiltration needs further investigation, this does not represent a distinct clinical entity. Thus, the presence of esophageal eosinophils in patients presenting with dysphagia should not preclude further work-up for other etiologies, including achalasia.

Classification of individuals based on ex-vivo glatiramer acetate-induced interferon-γ and interleukin-4 response

Background: Glatiramer acetate (GA) in multiple sclerosis acts through the induction of GA-specific T-helper 2 cells. Nevertheless, the phenomenon is not universal in patients, explaining individual differences in clinical response. Objective: The objective of this article was to categorize GA-treated patients. Method: An enhanced quantitative PCR assay was used for measuring ex-vivo GA-induced IFNγ and IL4 mRNA responses in mononuclear cells from 23 healthy donors, 27 untreated patients, 33 short-term (≤6 months) and 77 long-term (>6 months) GA-treated patients. Thresholds for IFNγ and IL4 transcriptional response were calculated by ROC analysis and long-term treated patients were compared in terms of prognostic stratification. Results: Thresholds for IFNγ and IL4 transcriptional response were calculated at 5.36 and 1.41 relative expression (RE). Finally, 67% of long-term treated patients scored above both response thresholds. These patients had a higher proportion of relapse-free subjects (74% vs 40% when compare to patients who scored below both thresholds) and a significantly better relapse-free survival rate (p=0.006; CI 0.29–0.75). The negative predictive value to predict adverse clinical outcome was 79% (CI 0.63–0.90), meaning that by a positive response, there is a 79% chance that the patient will not experience a negative outcome at 3 years. Conclusions: Our enhanced quantitative PCR assay produced clinically significant results for GA-treated patients. As such, if patients have a positive response, it means they have less chance of a relapse, while patients with a negative response have a greater probability of a worse outcome.