Secondary Treatment Failure Research Articles

Nanobody Targeting of Epidermal Growth Factor Receptor (EGFR) Ectodomain Variants Overcomes Resistance to Therapeutic EGFR Antibodies.

Epidermal growth factor receptor (EGFR) ectodomain variants mediating primary resistance or secondary treatment failure in cancer patients treated with cetuximab or panitumumab support the need for more resistance-preventive or personalized ways of targeting this essential pathway. Here, we tested the hypothesis that the EGFR nanobody 7D12 fused to an IgG1 Fc portion (7D12-hcAb) would overcome EGFR ectodomain-mediated resistance because it targets a very small binding epitope within domain III of EGFR. Indeed, we found that 7D12-hcAb bound and inhibited all tested cell lines expressing common resistance-mediating EGFR ectodomain variants. Moreover, we assessed receptor functionality and binding properties in synthetic mutants of the 7D12-hcAb epitope to model resistance to 7D12-hcAb. Because the 7D12-hcAb epitope almost completely overlaps with the EGF-binding site, only position R377 could be mutated without simultaneous loss of receptor functionality, suggesting a low risk of developing secondary resistance toward 7D12-hcAb. Our binding data indicated that if 7D12-hcAb resistance mutations occurred in position R377, which is located within the cetuximab and panitumumab epitope, cells expressing these receptor variants would retain sensitivity to these antibodies. However, 7D12-hcAb was equally ineffective as cetuximab in killing cells expressing the cetuximab/panitumumab-resistant aberrantly N-glycosylated EGFR R521K variant. Yet, this resistance could be overcome by introducing mutations into the Fc portion of 7D12-hcAb, which enhanced immune effector functions and thereby allowed killing of cells expressing this variant. Taken together, our data demonstrate a broad range of activity of 7D12-hcAb across cells expressing different EGFR variants involved in primary and secondary EGFR antibody resistance.

Ustekinumab in Real-Life Practice: Experience in 116 Patients with Moderate-To-Severe Psoriasis.

Ustekinumab is a monoclonal antibody directed against the p40 subunit common to both IL-12 and IL-23 cytokines.Although the evidence of ustekinumab efficacy and safety in clinical trials is extensively recognized, data on its use in clinical practice islimited. Our objective is to report on the real-life experience of two Portuguese dermatology departments with ustekinumab in patientswith moderate to severe psoriasis, and to identify the clinical characteristics associated with a weaker clinical response. Clinical, demographic, and therapeutic response data was retrospectively collected in 116 patients withmoderate to severe psoriasis treated with ustekinumab between November 2009 and December 2015. A PASI75 therapeutic response was observed in 67.2%, 85.3%, 89.6% and 88.7% of patients at weeks 4, 12, 24 and 52,respectively. Ustekinumab was discontinued in seven patients (three due to primary failure, three due to secondary treatment failure,and one due to adverse events). Neither cardiovascular events nor cases of reactivation of previous infections (tuberculosis, hepatitisB) were observed during follow-up. In nine patients methotrexate was used as adjuvant therapy, and fourteen patients requiredustekinumab dosage optimization. No side effects were observed in the two latter groups. The therapeutic response was higher inpatients naïve to biologic therapies as compared to non-naïve patients. A trend towards lower clinical response was observed in patients weighing between 90-100 kg, anddosage optimization in this group of patients may be of value prior to considering biologic switch.

Absence of Relationship Between Crohn's Disease Activity Index or C-Reactive Protein and Infliximab Exposure Calls for Objective Crohn's Disease Activity Measures for the Evaluation of Treatment Effects at Treatment Failure.

Circulating infliximab (IFX) concentrations correlate with clinical outcomes, forming the basis of the IFX concentration monitoring in patients with Crohn's disease. This study aims to investigate and refine the exposure-response relationship by linking the disease activity markers "Crohn's disease activity index" (CDAI) and C-reactive protein (CRP) to IFX exposure. In addition, we aim to explore the correlations between different disease markers and exposure metrics. Data from 47 Crohn's disease patients of a randomized controlled trial were analyzed post hoc. All patients had secondary treatment failure at inclusion and had received intensified IFX of 5 mg/kg every 4 weeks for up to 20 weeks. Graphical analyses were performed to explore exposure-response relationships. Metrics of exposure included area under the concentration-time curve (AUC) and trough concentrations (Cmin). Disease activity was measured by CDAI and CRP values, their change from baseline/last visit, and response/remission outcomes at week 12. Although trends toward lower Cmin and lower AUC in nonresponders were observed, neither CDAI nor CRP showed consistent trends of lower disease activity with higher IFX exposure across the 30 evaluated relationships. As can be expected, Cmin and AUC were strongly correlated with each other. Contrarily, the disease activity markers were only weakly correlated with each other. No significant relationship between disease activity, as evaluated by CDAI or CRP, and IFX exposure was identified. AUC did not add benefit compared with Cmin. These findings support the continued use of Cmin and call for stringent objective disease activity (bio-)markers (eg, endoscopy) to form the basis of personalized IFX therapy for Crohn's disease patients with IFX treatment failure.

Analytical and clinical performance evaluation of two POC tests for therapeutic drug monitoring of infliximab.

Background Infliximab (IFX) is an effective therapy in patients with inflammatory bowel disease. Serum IFX trough concentrations correlate well with clinical, biological and endoscopic outcomes. Therefore, therapeutic drug monitoring (TDM) of infliximab is useful for dose optimization and prevention of secondary treatment failure. In the present study, analytical and clinical performance of two point-of-care (POC) tests, RIDA®QUICK IFX Monitoring assay (R-biopharm) and Quantum Blue® Infliximab assay (Bühlmann), have been evaluated and compared to our established enzyme-linked immunosorbent assay (ELISA) (apDia IFX ELISA). Methods Analytical performance was assessed according to the CLSI EP5-A2 protocol using the manufacturer's kit controls and different serial dilution series. Method comparison with our established ELISA was done using a wide range of consecutive patient samples (n=180). Clinical concordance was evaluated by categorization based on well-known therapeutic cut-off points (3-7 μg/mL). Results The analytical performance of both POC tests was inferior to the established ELISA, but acceptable based on the manufacturer's quality claims. Eight-point serial dilution confirmed the analytical performance data in the low-level measuring range. Eleven-point serial dilution demonstrated linearity for both POC tests over the studied concentration range. Method comparison with the ELISA showed significant negative proportional bias for the RIDA®QUICK IFX Monitoring assay. However, good correlation and clinical concordance were shown. Quantum Blue® Infliximab assay showed a significant positive proportional and a negative systematic bias in comparison with the ELISA, resulting in overestimation of IFX levels with impact on clinical concordance data. Conclusions Both POC tests have their own specific benefits and drawbacks but are suitable for therapeutic drug monitoring of IFX. However, long-term monitoring of IFX trough levels requires measurement of IFX concentrations with the same assay.

A draft of the interdisciplinary guidelines for diagnosis, methods for assessment of the degree of inflammatory activity, therapeutic efficacy, and for the use of biological agents in patients with concomitant immunoinflammatory diseases (psoriasis, psoriatic arthritis, Crohn's disease)

Psoriasis, psoriatic arthritis (PsA) and inflammatory bowel disease (IBD) are multifactorial chronic immunoinflammatory disorders with characteristic common genetic markers that determine their common pathophysiology and similar immune abnormalities. In particular, IL12/23 signaling pathway of the immune pathogenesis of the above mentioned diseases is related to the IL23R gene polymorphism. Common pathophysiological features, in their turn, produce a high risk and prevalence of comorbidity. Clinicians' unawareness of these particulars of the immunoinflammatory disorders might lead to the absence of interdisciplinary collaboration, late diagnosis of one of these disorders and polypharmacy, because each specialist (i.e., a dermatologist, a rheumatologist, a gastroenterologist) would administer his/hers treatments independently. In this context, the issues of the multidisciplinary approach to this problem are becoming highly relevant for earlier diagnosis and adequate treatment choice that is optimal for all disorders which contribute to the pathological process, taking into account common mechanism of their development. Therefore, there is the necessity to establish an interdisciplinary working group consisting of the leading specialists of the Russian Federation in rheumatology, dermatology, and gastroenterology, with a purpose to elaborate a consensus on the immunoinflammatory comorbidities. At the discretion of the Russian Association of Rheumatologists (RAR), Russian Society of Dermatovenerologists and Cosmetologists (RSDVC), Russian IBD Study Society (RIBDS), such a group has been formed of 11 experts corresponding to their scientific expertise in the area. The main aim of the Working Group was to develop a universal interdisciplinary questionnaire for detection of the signs and symptoms of the immunoinflammatory disorders (psoriasis, PsA, IBD), as well as development of a draft project of the interdisciplinary guidelines on the early diagnosis, methods of activity assessment and indications to the use of genetically engineered biological agents in patients with comorbid immunoinflammatory comorbidities (psoriasis, PsA, IBD). Procedure of the interdisciplinary guidelines elaboration . The Working Group elaborated a draft project of the up-to-date evidence-based guidelines and proposed a multidisciplinary questionnaire. An interdisciplinary expert council of specialists in dermatology, rheumatology and gastroenterology discussed each position of the proposed guidelines and was adopted by a simple majority of votes through an open voting at the Second Russian Debates “Dermatology, Rheumatology, Gastroenterology: focus on the interdisciplinary interaction” (Moscow, December 12–13, 2017). Results : 1 . A universal interdisciplinary questionnaire to detect clinical signs of immunoinflammatory disorders (psoriasis, PsA, IBD) has been created. It contains the main questions the answers to which are needed for a specialist physician (a dermatologist, a rheumatologist or a gastroenterologist) to suspect comorbidity and to refer the patient to a corresponding specialist. The questionnaire has three parts, each of them with questions to the patient aimed at the detection of the symptoms of psoriasis, PsA, and IBD. 2 . An algorithm for interaction between dermatologists, rheumatologists and gastroenterologists has been developed aimed at optimal management of patients with comorbid immunoinflammatory disorders. 3 . Goals of treatment of immunoinflammatory disorders (psoriasis, PsA, Crohn's disease) have been formulated according to the “treat-to-target” (Т2Т) concept. 4 . Criteria for assessment of activity and severity of the immunoinflammatory disorders (psoriasis, PsA, and Crohn's disease) have been formulated. 5 . The draft describes the indications for the administration of genetically engineered biological agents (GEBA), factors influencing the choice of treatment, criteria for GEBA efficacy assessment, indications to a change of a GEBA in primary or secondary treatment failure. Conclusion : In accordance with the results of discussion with specialists from various regions of the Russian Federation and with the decision of the Expert Council, it is planned to validate the questionnaire, with subsequent inclusion of the position of the draft project into the clinical guidelines on the management of patients with psoriasis, PsA, and Crohn's disease.

Stacked classifiers for individualized prediction of glycemic control following initiation of metformin therapy in type 2 diabetes

ObjectiveMetformin is the preferred first-line medication for management of type 2 diabetes and prediabetes. However, over a third of patients experience primary or secondary therapeutic failure. We developed machine learning models to predict which patients initially prescribed metformin will achieve and maintain control of their blood glucose after one year of therapy. Materials and methodsWe performed a retrospective analysis of administrative claims data for 12,147 commercially-insured adults and Medicare Advantage beneficiaries with prediabetes or diabetes. Several machine learning models were trained using variables available at the time of metformin initiation to predict achievement and maintenance of hemoglobin A1c (HbA1c) < 7.0% after one year of therapy. ResultsAUC performances based on five-fold cross-validation ranged from 0.58 to 0.75. The most influential variables driving the predictions were baseline HbA1c, starting metformin dosage, and presence of diabetes with complications. ConclusionsMachine learning models can effectively predict primary or secondary metformin treatment failure within one year. This information can help identify effective individualized treatment strategies. Most of the implemented models outperformed traditional logistic regression, highlighting the potential for applying machine learning to problems in medicine.

Treatment of post-intubation laryngeal granulomas: systematic review and proportional meta-analysis.

IntroductionLaryngeal granulomas post intubation are benign but recurrent lesions. There is no consensus for its treatment.ObjectiveTo describe the effectiveness of different treatment modalities for primary or recurrent laryngeal granulomas resulting from endotracheal intubation.MethodsSystematic review and proportional meta-analysis. Eligibility criteria – experimental or observational studies with at least five subjects. Outcomes studied – granuloma resolution, recurrence, and time for resolution. Databases used – Pubmed, Embase, Lilacs, and Cochrane. The Stats Direct 3.0.121 program was used.ResultsSix studies were selected, with 85 patients. The treatments registered were: antireflux therapy, speech therapy, anti-inflammatory drugs, steroids, antibiotics, zinc sulfate and surgery. 85 patients from six studies had primary treatment: surgery ± associations (41 patients), resolution chance 75% (95% CI: 0.3–100%, I2 = 90%), absolute relapse risk 25% (95% CI: 0.2–71%); medical treatment (44 patients), resolution chance 86% (95% CI: 67–97%); and absolute relapse risk 14% (95% CI: 3–33%). There was no significant difference between groups. Three studies, encompassing 19 patients, analyzed secondary treatment (failure or recurrence after primary treatment); three subjects presented new recurrence. The time needed to resolve the lesions varied from immediate, after surgery, to 23 months, for inhaled steroid.ConclusionThere is no evidence of high quality that proves the efficacy of any treatment for laryngeal granulomas resulting from endotracheal intubation.

Improve ICG Based Photodynamic Properties Through Conjugation of ICG Into Nano-Graphene Oxide Against Enterococcus faecalis

Background: Nowadays, a new technique such as photodynamic therapy (PDT) is used to achieve effective root canal disinfection and eliminate Enterococcus faecalis as the most prevalent species associated with secondary endodontic infections and treatment failures. Employment of an optimized nontoxic photosensitizer (PS) such as indocyanine green (ICG) is a crucial part of this technique; the current study aimed at improving ICG photodynamic properties through conjugation of ICG into nano-graphene oxide (nGO) as a new PS, to evaluate the antimicrobial effects of nGO/ICG against E. faecalis. Methods: The nGO was synthesized based on the modified Hummer method and then, direct loading of ICG onto its surface. The nGO formation was evaluated using the scanning electron microscope (SEM). The antimicrobial effect of nGO/ICG-PDT against E. faecalis was assessed by counting colony forming units (CFUs). Results and Conclusion: The SEM analysis confirmed successful synthesis of nGO. The nGO/ICG-PDT at an incorporated concentration of 400 µg/mL ICG with irradiation at an energy density of 31.2 J/cm2 showed significant reduction in the number of E. faecalis higher than PDT based on ICG (1000 µg/mL) (P < 0.05). Since nGO-ICG-PDT showed a significant reduction in the count of E. faecalis at low concentration of ICG (400 µg/mL), it could be proposed as a new approach to treat endodontic infections, alone or in combination with conventional root canal treatment.

Drug immunogenicity in patients with inflammatory arthritis and secondary failure to tumour necrosis factor inhibitor therapies: the REASON study.

The aims were to evaluate the prevalence of anti-drug antibodies (ADA) in patients with RA or SpA experiencing secondary failure to anti-TNF therapy and to correlate ADA presence with anti-TNF concentration and clinical response. This was a cross-sectional, observational study of patients with active RA or SpA experiencing secondary failure to etanercept (ETN), infliximab (INF) or adalimumab (ADL). Concomitant non-biologic DMARDs were permitted. Serum anti-TNF and ADA levels were measured with two-site ELISA. Among 570 evaluable patients, those with RA (n = 276) were mostly female (80 vs 39%), older (56 vs 48 years), received concomitant DMARDs (83 vs 47%) and had maintained good clinical disease control for longer (202 vs 170 weeks) compared with patients with SpA (n = 294). ADA were found in 114/570 (20.0%) patients; 51/188 (27.1%) against INF and 63/217 (29.0%) against ADL; none against ETN. Of these 114 patients, 92 (81%) had no detectable serum drug concentrations. Proportionately more patients with SpA (31.3%) had anti-INF antibodies than those with RA (21.1%; P = 0.014). A significantly lower proportion of patients receiving concomitant DMARDs (16.5%) developed ADA than those on monotherapy (26.4%; P < 0.05). In patients with RA or SpA and secondary failure, the development of ADA against ADL or INF, but not ETN, appears to be one of the main reasons for secondary treatment failure, but not the only one. Further investigations are needed to determine other causes of anti-TNF failure.

Transcription factor 7-like 2 rs7903146 polymorphism and therapeutic response to sulfonylureas in patients with type 2 diabetes

Background Transcription factor 7-like 2 (TCF7L2) variations were related to a modified hypoglycemic reaction to sulfonylureas (SUs) in patients with type 2 diabetes mellitus (T2D). Aims The aim of the present work was to show the relationship between TCF7L2 rs7903146 polymorphism and the hypoglycemic reaction to SUs in T2D patients. Patients and methods We enlisted 54 already diagnosed T2D patients who were treated with SUs. Utilizing secondary SU treatment failure, defined as glycated hemoglobin more than 7%, they were divided into two groups: responders and nonresponders. We genotyped the TCF7L2 rs7903146 single-nucleotide polymorphism by utilizing TaqMan allelic discrimination assay-based real-time PCR. Result A relationship between the TCF7L2 rs7903146 genotypes TT, CC, CT and therapeutic response to SUs in T2D patients was assessed. In the nonresponders group, the most frequent genotype was the TT (P=0.038) and the most frequent allele was T (P=0.034). Binary logistic regression analysis showed predictors to failure of SUs treatment, providing that TCF7L2 rs7903146 was the significant factor. The TT genotype showed a statistically significant association with nonresponse to SUs, about 4.6 times more than the rest of the genotypes (CC or CT) [P=0.029; odds ratio (OR), 4.643; 95% confidence interval, 1.175–18.355]. The distribution of TCF7L2 rs7903146 alleles was found to be statistically significant, with the OR indicating that the nonresponder status was 2.291 times greater for T allele as opposed to C allele (P=0.034; OR, 2.29; 95% confidence interval, 1.059–4.959). The other factors as sex, age, and duration of the disease were not statistically significant (P=0.334, 0.267, and 0.242, respectively). Conclusion TCF7L2 rs7903146 variant was associated with therapeutic response to SUs and it was observed that the most frequent allele in the nonresponders group was the T allele, whereas the most frequent allele in the responders group was the C allele.

Endovascular surgery in Marfan syndrome: CON.

The frequency of endovascular stent grafting procedures to treat various conditions of the thoracic aorta has increased dramatically over the past three decades. Stent grafting has been applied on a limited basis in patients with Marfan syndrome and other connective tissue disorders, despite recommendations from current guidelines and expert consensus statements against its use in this setting. A review of publications reporting outcomes after stent grafting of the descending thoracic aorta in Marfan patients with acute or chronic aortic dissection indicates that these procedures can be accomplished with rates of early mortality, stroke and spinal cord ischemic injury that are comparable to those observed in patients who do not have Marfan syndrome. However, the rates of primary treatment failure (principally endoleak), secondary treatment failure, need for open repair and late death among the Marfan patients are substantially higher than those observed in patients without this condition. In addition, the rates of retrograde aortic dissection and development of stent-graft induced new entry (SINE), are also greater among patients with Marfan syndrome. All of these findings argue strongly against the routine use of endovascular grafts in Marfan patients with type B or residual type A dissection. Few data are available to assess the role of endografting in Marfan patients with aneurysmal disease, but the progressive aortic dilatation noted in these patients argues strongly against its use in this setting as well. At present, the available data indicate that there is no justification for elective stent grafting in Marfan patients with aortic dissection or aneurysm. The only reasonable indications for primary aortic stent grafting are in the setting of acute aortic dissection or rupture, where the intervention is considered life-saving and rarely, considering the relatively young age of these patients, where the risk of open operation is considered to be prohibitive.

Intraperitoneal Vancomycin Plus Either Oral Moxifloxacin or Intraperitoneal Ceftazidime for the Treatment of Peritoneal Dialysis−Related Peritonitis: A Randomized Controlled Pilot Study

Intraperitoneal administration of antibiotics is recommended as a first treatment for managing peritoneal dialysis (PD)-related peritonitis. However, the efficacy of oral administration of quinolones has not been well studied. Randomized controlled pilot study. 80 eligible patients with PD-related peritonitis from Peking University First Hospital (40 in each arm). Intraperitoneal vancomycin, 1g, every 5 days plus oral moxifloxacin, 400mg, every day (treatment group) versus intraperitoneal vancomycin, 1g, every 5 days plus intraperitoneal ceftazidime, 1g, every day (control group). The primary end point was complete resolution of peritonitis, and secondary end points were primary or secondary treatment failure. PD effluent white blood cell count. Baseline demographic and clinical characteristics of the 2 groups were comparable. There were 24 and 22 Gram-positive organisms, 6 and 7 Gram-negative organisms, 9 and 10 culture-negative samples, and 1 and 1 fungal sample in the treatment and control groups, respectively. Complete resolution of peritonitis was achieved in 78% and 80% of cases in the treatment and control groups, respectively (OR, 0.86; 95% CI, 0.30-2.52; P=0.8). There were 3 and 1 cases of relapse in the treatment and control groups, respectively. Primary and secondary treatment failure rates were not significantly different (33% vs 20% and 10% vs 13%, respectively). In each group, there was 1 peritonitis-related death and 6 transfers to hemodialysis therapy. During the 3-month follow-up period, 7 and 3 successive episodes of peritonitis occurred in the treatment and control groups, respectively. Only 2 adverse drug reactions (mild nausea and mild rash, respectively) were observed in the 2 groups. Sample size was relatively small and the eligibility ratio was low. Also, the number of peritonitis episodes was low, limiting the power to detect a difference between groups. This pilot study suggests that intraperitoneal vancomycin with oral moxifloxacin is a safe, well-tolerated, practical, and effective first-line treatment for PD-related peritonitis. Larger adequately powered clinical trials are warranted.

Quantification of Staphylococcus aureus adhesion forces on various dental restorative materials using atomic force microscopy

In the oral cavity dental restorative biomaterials can act as a reservoir for infection with opportunistic Staphylococcus aureus pathogen, which can lead to the occurrence of secondary caries and treatment failures. Our aim was to evaluate the adhesion forces by S. aureus on four dental restorative biomaterials and to correlate this finding to differences in specific surface characteristics. Additionally, the influence of salivary conditioning films in exerted adhesion forces was investigated. The substrate hydrophobicity was measured by goniometer and the surface free energy was calculated using the equilibrium advancing contact angle values of water, formamide, and diiodomethane on the tested surfaces. The surface roughness was determined using atomic force microscope (AFM). Additionally, cell force spectroscopy was achieved to quantify the forces that drive cell-substrate interactions. S. aureus bacterium exerted a considerable adhesion forces on various dental restorative materials, which decreased in the presence of saliva conditioning film. The influence of the surface roughness and free energy in initial adhesion appears to be more important than the effect of hydrophobicity, either in presence or absence of saliva coating. Hence, control of surface properties of dental restorative biomaterials is of crucial importance in preventing the attachment and subsequent the biofilm formation.

Retrospective Study on the Use of Infliximab and Adalimumab Drug and Antibody Levels for Clinical Decision Making in IBD Patients at a University-Based Single-Center Practice

Introduction: Anti TNF agents are now first line medications to treat moderate to severe Crohn's disease (CD) and Ulcerative colitis (UC). However, primary and secondary treatment failure still frequently occur due to immunogenicity1,2. Antibodies to infliximab (ATIs), also known as human anti-chimeric antibodies (HACAs), form immune complexes with the drug and are associated with decreased infliximab levels, shorter duration of response, and higher risk of infusion reactions3-5. Assays developed to detect anti-drug antibodies and drug levels for both infliximab and adalimumab were initially used for research but several commercially available tests are now on the market for clinical use6. Individualized therapy based on antibody and drug level testing has been found to be more cost effective than empiric dose escalation in patients with Crohns disease who lost response to infliximab7,8. However, data on utilization of testing in routine clinical practice is newly emerging. We present the outcomes of drug and antibody testing for 80 patients on anti TNF therapy at a single center gastroenterology practice within a university hospital setting. Methods: All patients that had infliximab and adalimumab drug level and antibody testing using the AnserTM assay by Prometheus laboratories between August 2012 and March 2015 were identified and their charts were retrospectively reviewed. Demographic characteristics, disease activity, current therapy, serum drug and antibody levels, and management after testing were recorded and analyzed. Results: Drug and antibody tests were obtained from 80 patients. The majority of patients had IBD for over 2 years. Sixity one percent had Crohn's disease with a mean age of 37.2. The most common reason for checking levels was loss of response (63.8%). 61.3% of patients were secondary nonresponders to anti TNF, and 35% of patients were responding. Therapeutic drug levels were found in 76.3% of patients and antibodies were detected in 20% of patients. Dose changes and anti TNF discontinuation occurred in 29% and 30% of patients, respectively while 41.3 % had no change to the anti TNF regimen. Conclusion: Serum infliximab and adalimumab drug and antibody level testing frequently aids clinical decision making in the real world setting resulting in medication changes in a majority of cases.Table 1Table 2: Testing results n =80

Su1516 Treatment Failure and Delayed Complication Due to Shedding of the Over-the Scope Clip: Experience in Three Cases

The over the scope clip (OTSC) was designed to close acute perforations, fistulas, and to provide hemostasis. Small case series suggest a high rate of treatment success but it has not previously been emphasized that delayed shedding of the clip can lead to secondary treatment failure and perforation. Our experience: Case #1 was a 73-year-old man with hematochezia. Colonoscopy showed a bleeding diverticulum in the sigmoid colon that did not respond to use of standard clips, injection with epinephrine and banding.

AB0665 Apparent Late TNFI Secondary Treatment Failure in Axial Spondyloarthritis

BackgroundSecondary failure of TNF inhibitor (TNFi) treatment in ankylosing spondylitis (AS) and axial spondyloarthritis (axSpA) is an important clinical problem. Clear guidelines for discontinuing biologic treatment exist, based on persistence...

Very early reduction in efficacy of botulinum toxin therapy for cervical dystonia in patients with subsequent secondary treatment failure: a retrospective analysis

The objective of this study was to estimate the probability of development of partial secondary treatment failure (PSTF) in patients with cervical dystonia (CD) who had been treated over up to 9 years with repetitive intramuscular injections of botulinum neurotoxin type A (BoNT/A). The temporal course of treatment response in patients in whom PSTF was detected retrospectively was compared to patients with a normal clinical response. For this purpose, charts of all CD patients treated in our outpatient clinic between 1988 and 2001 were retrospectively analyzed. Extracted data included time of all injections, dose per visit, disease severity measured by TSUI scores, and time of determination of neutralizing antibodies. Final data analysis using a special formal definition of PSTF was based on charts of 568 patients having exclusively been treated with abobotulinumtoxinA. PSTF onset was observed in our CD cohort during the entire treatment period analyzed, with no clustering at any time point. Probability to develop PSTF was 14.5 % in 9 years. Thus, mean PSTF incidence was 1.6 % per year. The mean TSUI score of patients with retrospectively defined PSTF (n = 33) became already significantly worse after the second injection when compared with the group without PSTF (n = 535). Our data indicate that clinical response in patients developing PSTF later on differs from that of patients without PSTF already very early in the course of botulinum neurotoxin type A treatment, and that PSTF remains undetected at this early stage. Reduced response may therefore be present in a number of CD patients who think they still respond normally to continuous BoNT/A treatment.

Neutralizing antibodies to botulinum neurotoxin type A in aesthetic medicine: five case reports

Botulinum neurotoxin injections are a valuable treatment modality for many therapeutic indications as well as in the aesthetic field for facial rejuvenation. As successful treatment requires repeated injections over a long period of time, secondary resistance to botulinum toxin preparations after repeated injections is an ongoing concern. We report five case studies in which neutralizing antibodies to botulinum toxin type A developed after injection for aesthetic use and resulted in secondary treatment failure. These results add to the growing number of reports in the literature for secondary treatment failure associated with high titers of neutralizing antibodies in the aesthetic field. Clinicians should be aware of this risk and implement injection protocols that minimize resistance development.

Intrinsic Biological Variability In High-Risk-Myelodysplastic Syndrome Impacts Overall Survival (OS) In Patients Experiencing Cytogenetic Evolution Treated With Azanucleosides

BackgroundMyelodysplastic syndromes (MDS) comprise a heterogeneous group of clonal myeloid disorders characterized by marrow failure and variable risk for acute leukemia transformation. The revised International prognostic scoring system (R-IPSS) biologically defines 5 risk disease categories and assists in logistic outcome prediction and treatment algorithm. For those patients (pts) with high risk MDS, treatment with hypomethylating agents (HMAs) such as azacitidine (AZA) and decitabine (DAC) is associated with prolonged survival. However primary and secondary treatment failures are common phenomenon and treatment outcomes after failure are dismal (Prebet T et al. JCO. 2011; Prebet T. Haematologica.2013). Mechanisms of loss of response to azanucleosides are largely unknown. Cytogenetic evolution (CE) defined as the acquisition of additional clones or karyotypic abnormalities in pts with preexisting normal or aberrant karyotype, during disease course or after treatment, is observed in about 30% of MDS patients, and is linked to genomic instability resulting in adverse outcomes. We investigated risk factors for CE in MDS pts treated with HMAs and its impact of OS. MethodFrom 2000-2012, 13/124 pts (16%) (Median age 59 years; range 54-80) with confirmed diagnosis of MDS treated with HMAs were identified from the Michael E. Medical Center Cancer Registry. Patients were included if at least 2 G-banding metaphases studies were available and corresponded to: (1) karyotyping at disease diagnosis; and (2) at the time of azanucleoside failure. Overall Survival (OS) was analyzed for pts who have received HMAs with and without evidence of CE. Multivariate Cox regression analysis was performed to assess the impact of multiple independent variables on clinical outcome. ResultsThe incidence of CE in patients treated with HMAs was 38%. Median R-IPSS scores at diagnosis for pts with and without CE were 7.5 (5-very high; WHO subgroups: RCMD [2] and RAEB-2 [3]) vs. 4.75 (4-high and 4-Int; WHO subgroups: RCMD [3], RCUD [1] CMML [2]; MDS/MPN [2]) P=0.003. OS for pts with and without CE treated with HMAs was 419 days (d) vs 743 d, respectively P=0.001;CI= 0.23-0.89. In patients with CE, univariate analysis identified platelets and blast count at disease initiation (P=0.03, each) as prognostic variables impacting clinical outcome; however, by multivariate analysis a non-statistically significant trend was observed only for R-IPSS, P=0.21. (Table 1).Table 1Impact of Independent Variables on Survival in Patients Receiving Azanucleosides and Experiencing CE.Univariate(P)MultivariatePlatelets (K/uL)0.030.78Hemoglobin (g/dL)0.890.45ANC (K/uL)0.060.46Blast (%)0.030.42Age (years)0.360.57R-IPSS0.090.21 [Display omitted] ConclusionIn our retrospective analysis, acquisition of CE at the time of azanucleoside failure was associated with unfavorable outcome. Exploratory logistic regression analysis suggests that high-risk disease biology at disease initiation modulates incidence of CE in MDS pts treated with azanucleosides. Larger coalesced cohort of MDS pts experiencing CE could facilitate understanding of mechanisms associated with acquisition of genomic instability during azanucleoside failure and assist in identification of novel MDS targeted therapies that could ensure sustained response. Disclosures:No relevant conflicts of interest to declare.

Moxifloxacin for Buruli ulcer/HIV coinfected patients

Buruli ulcer is a necrotizing infection of skin and soft tissue caused by Mycobacterium ulcerans that results in significant morbidity and often long-term disability. It is endemic in West and Central Africa affecting regions similarly burdened by a high prevalence of HIV. According to the Medecins Sans Frontieres programme in Akonolinga, Cameroon, the prevalence of HIV is approximately three to six times higher in Buruli ulcer-treated patients compared to the regional estimated HIV prevalence [1]. Similarly in Benin, patients with Buruli ulcer were eight times more likely to have HIV infection than those without Buruli ulcer [2]. HIV also affects the clinical presentation of Buruli ulcer disease with an increased incidence of multiple, larger, and ulcerated lesions [1,3]. Patients often present with severe immunosuppression, with 26% of patients in Akonolinga presenting with CD4þ cell counts less than 200 cells/ml, and in urgent need of antiretroviral therapy [1].