Effects Of New Therapies Research Articles

Optical Coherence Tomography Imaging and Quantitative Assessment for Monitoring Dry Age-related Macular Degeneration

The purpose of this article is to show the feasibility of the ‘Advanced [retinal pigment epithelium] RPE analysis’ software tool to measure drusen area and volume as well as the area of geographic atrophy (GA) in patients with dry age-related macular degeneration (AMD). The source data from spectral domain optical coherence tomography (SD-OCT) images obtained from three patients with confirmed dry AMD using Cirrus™ HD-OCT (Carl Zeiss Meditec) were re-evaluated with the new software analysis tool Advanced RPE analysis. The area of GA as well as drusen area and volume were measured and analysis of results were presented along with calculated values in two clearly arranged screens. Changes between visits were easily detectable and could be followed over time. Results correlated well with clinical observation. The conclusion reached was that the new Advanced RPE analysis software allows the automated, objective and quantitative assessment of atrophic lesions and drusen. It thus could prove to be useful in determining disease stages as well as prognosis more precisely, and provides the opportunity to monitor the effectiveness of new therapies in clinical trials.

Amyloid imaging for Alzheimer's disease

Biomarkers for Alzheimer's disease (AD) may facilitate early and accurate diagnosis and offer a way to track the effectiveness of new therapies. Amyloid imaging offers an unrivaled ability to visualize the presence and anatomical distribution of fibrillar beta-amyloid (Aβ) pathology non-invasively in living humans. New diagnostic criteria for AD incorporate the use of such biomarkers as amyloid imaging, highlighting the importance of this technology going forward. Here, the author reviews individual amyloid tracers, including the (11)C-labeled tracer Pittsburgh compound B and the (18)F-labeled tracers nearing FDA approval. While these tracers are reliable at detecting fibrillar Aβ pathology, there is a weaker connection with true AD pathology, reflecting the complex relationship between Aβ and AD. The author discusses apolipoprotein E genotyping and spinal fluid Aβ levels in relation to amyloid imaging, and considers the possible uses of amyloid imaging as a diagnostic instrument in the clinic, or as a clinical trials tool for selecting patients or monitoring outcomes. Selected literature retrieved by Medline searches for 'amyloid imaging' and related terms from 2001 to present is discussed. Amyloid imaging accurately portrays the presence of fibrillar Aβ pathology in the brain. However, fundamental questions about the role of Aβ in AD must be answered before the full potential of amyloid imaging can be realized.

In vivo fluorescence imaging of E‐selectin: Quantitative detection of endothelial activation in a mouse model of arthritis

In vivo optical imaging can delineate at the macroscopic level processes that are occurring at the cellular and molecular levels. E-selectin, a leukocyte adhesion molecule expressed on endothelium, is induced by tumor necrosis factor α (TNFα) and other cytokines involved in the pathogenesis of rheumatoid arthritis (RA). Collagen-induced arthritis (CIA) in mice is widely used to study the disease mechanisms and identify new treatments for RA. The purpose of this study was to demonstrate E-selectin-targeted fluorescence imaging in vivo in a mouse model of paw edema generated by local injection of TNFα as well as in mice with CIA. Animals with either CIA or TNFα-induced paw edema were injected with anti-E-selectin or control antibodies labeled with a DyLight 750-nm near-infrared (NIR) probe. In vivo imaging studies were undertaken using an NIR optical imaging system, and images were coregistered with plain radiographic images. The mean fluorescence intensity measured over the time-course of TNFα-induced edema demonstrated a 1.97-fold increase (P<0.001) in signal in inflamed paws at 8 hours following injection of anti-E-selectin antibody, as compared to that in the isotype control. In the CIA model, a 2.34-fold increase in E-selectin-targeted signal was demonstrated (P<0.01). Furthermore, significant E-selectin-targeted signal was observed in the paws of animals immunized with collagen that did not display overt signs of arthritis. E-selectin-targeted fluorescence in vivo imaging is a quantifiable method of detecting endothelial activation in arthritis and can potentially be applied to the quantification of disease and the investigation of the effects of new therapies. Importantly, this approach may also be useful for the detection of subclinical disease in RA.

Evaluating Patient-Centered Outcomes in the Randomized Controlled Trial and Beyond: Informing the Future with Lessons from the Past

In the era of molecular oncology, patients still define a useful therapy as one that allows them to live longer and helps them to live better. Although patient outcomes have clearly improved as a result of randomized controlled trials (RCT), it is critical that contemporary trials retain the perspective of these fundamental patient-centered outcomes. Trends in study design, results, and interpretation of oncology RCTs from the past provide a useful framework in which to consider how the research community may approach trial design in the future. Although the RCT remains the standard for establishing efficacy, this article also considers how population-based outcome studies can provide insight into effectiveness of new therapies and explores how the results of RCTs translate into benefit in the general population.

P57 Administration of branched chain amino acids to hyperammonemic cirrhotic animals is associated with worsening of hyperammonemia and increase in brain oedema

IntroductionDespite branched chain amino acids (BCAA) being used for over 30 years, its efficacy in treating hyperammonemia remains controversial. Recent studies suggest that the use of BCAA in cirrhosis is...

Ultrahigh-resolution microstructural diffusion tensor imaging reveals perforant path degradation in aged humans in vivo

The perforant path (PP) undergoes synaptic changes in the course of aging and dementia. Previous studies attempting to assess the integrity of the PP in humans using diffusion tensor imaging (DTI) were limited by low resolution and the inability to identify PP fibers specifically. Here we present an application of DTI at ultrahigh submillimeter resolution that has allowed us to successfully identify diffusion signals unique to the PP and compare the intensity of these signals in a sample of young adults and older adults. We report direct evidence of age-related PP degradation in humans in vivo. We find no evidence of such loss in a control pathway, the alveus, suggesting that these findings are not evidence for a global decline. We also find no evidence for specific entorhinal gray matter atrophy. The extent of PP degradation correlated with performance on a word-list learning task sensitive to hippocampal deficits. We also show evidence for gray matter diffusion signals consistent with pyramidal dendrite orientation in the hippocampus and cerebral cortex. Ultrahigh-resolution microstructural DTI is a unique biomarker that can be used in combination with traditional structural and functional neuroimaging methods to enhance detection of Alzheimer disease in its earliest stages, test the effectiveness of new therapies, and monitor disease progression.

Costs of Managing Chronic Immune Thrombocytopenic Purpura (ITP) in Adults: A Retrospective Analysis.

Abstract 4462 Background and objectivesThe treatment of chronic immune thrombocytopenic purpura (ITP) requires therapies which vary considerably in type, duration, and cost. The impact of ITP on resource utilization and direct healthcare costs in France is currently unknown. Yet it is crucial to gain a better understanding of the cost of ITP, particularly in its chronic form, in order to determine the value of new therapies in this therapeutic area. We report here the annual costs in a group of patients with chronic ITP enrolled consecutively and followed for a period of one year in a single French reference center. Design and MethodsThis is a single-center, single-arm, retrospective, observational cohort study in which adult (>18 years) patients with chronic ITP (diagnosed as per ASH guidelines) were enrolled and followed for at least one year. Patients with secondary ITP were excluded. Resource utilization and costs for treatments (drugs and splenectomy) and hospitalization/visits were estimated over a one-year follow-up, from a French public hospital perspective. Costs per patient were estimated (mean), and bootstrapping methods were used to calculate 95% confidence intervals (as cost data are not normally distributed). Healthcare resource utilization was analyzed for the entire population (whole group) and in two subgroups in which patients had a more severe form of the disease. The first subgroup (subgroup 1) included patients who were admitted to the hospital during the one-year study period for ITP treatment, treatment of side effects related to ITP treatment, or bleeding symptoms. Among them, we selected a second subgroup (subgroup 2) in which the severity of the disease required at least one intravenous immunoglobulin (IVIg) infusion during the one-year study period. IVIg treatment is costly and commonly used as a rescue therapy in patients with ITP. ResultsA total of 57 consecutive patients (42F/15M) with a mean age of 48 years (SD: 19) at ITP diagnosis were studied. Mean platelet count at diagnosis was 28 ± 26×109/L. Mean length of ITP duration at the time of inclusion in the study was 3.1 years (SD: 2) and 8 patients had undergone splenectomy. Subgroup 1 included 27 patients (47%) who were admitted to the hospital during the one-year study period (full hospitalization, n=23; and/or day hospitalization, n=8). Among them, 12 patients (21%) received at least one IVIg infusion during the one-year study period and were included in subgroup 2. When severity was not considered (whole group), the total mean cost per patient for the one-year study period was €7,293 [3,369; 13,584]. In subgroup 1, of 27 patients with at least one hospitalization, costs rose substantially, with costs being roughly twice that of the whole group: €15,334 [7,876; 27,459] mean cost per patient. Finally, the most dramatic cost increase was observed in 12 patients who received IVIg (subgroup 2). Costs in this group were more than three times those in the whole group: €26,581 [12,241; 50,578] mean cost per patient. IVIg costs accounted for 50% of the whole group costs and up to 64% of costs when considering patients with the most severe disease. Interpretation and conclusionManagement of adults with chronic severe ITP is costly in France, with IVIg use being a major cost driver. From a budget payer's perspective, the availability of therapeutic agents that could reduce the need for IVIg and emergency hospitalizations could mitigate the costs of current ITP treatments. As the present study investigated only a limited group of patients from a single center, further research to better understand the likely effect of new therapies on resource utilization and costs is warranted. Disclosures:Eckert:AMGEN: Employment. Poitrinal:AMGEN: Employment. Francesconi:AMGEN: Employment. Haddad:AMGEN: Employment. Riou França:AMGEN: Employment. Launois:AMGEN: Employment. Godeau:AMGEN: Consultancy.

Computerised analysis of standardised ultrasonographic images to monitor the repair of surgically created core lesions in equine superficial digital flexor tendons following treatment with intratendinous platelet rich plasma or placebo

The effectiveness of new therapies to treat tendon injuries is difficult to determine and is often based on semi-quantitative methods, such as grey level analysis of ultrasonographic images or subjective pain scores. The alternatives are costly and long-lasting end-stage studies using experimental animals. In this study, a method of ultrasonographic tissue characterisation (UTC), using mathematical analysis of contiguous transverse ultrasonographic images, was used for intra-vital monitoring of the healing trajectory of standardised tendon lesions treated with platelet rich plasma (PRP) or placebo. Using UTC it was possible to detect significant differences between the groups in the various phases of repair. At end stage, over 80% of pixels showed correct alignment in the PRP group, compared with just over 60% in the placebo group (P<0.05). UTC also showed significant differences in the course of the healing process between PRP treated and placebo treated animals throughout the experiment. It was concluded that computerised analysis of ultrasonographic images is an excellent tool for objective longitudinal monitoring of the effects of treatments for superficial digital flexor tendon lesions in horses.

Electrical impedance tomography is able to track changes in respiratory function in endotoxin‐challenged rodents

In order to assess and optimize the effect of new therapies for acute lung injury (ALI) in rodent models, a monitoring technique that continuously assesses the functional state of the lung is mandatory. Electrical impedance tomography (EIT) has been suggested as a technique for quantifying lung inflammation in ALI. However, EIT has not been evaluated in a rodent model of ALI. EIT measurements were compared in ventilated Sprague-Dawley rats (n = 14), randomly subjected to intratracheal administration of endotoxin (LPS) or saline (control). Lung mechanics, lung weight wet/dry ratio and inflammatory markers in bronchoalveolar lavage fluid were also evaluated. LPS caused a significant decrease in lung compliance and TLC as compared with control (-42.0%, P = 0.04, and -27.9%, P = 0.02, respectively). These changes were paralleled by differences in mean impedance changes as detected by EIT (Spearman's rank correlation coefficient: rho = 0.66 and 0.73, respectively, P < 0.01). LPS increased the lung weight wet/dry ratio (6.35 +/- 0.42 vs 5.15 +/- 0.07, P = 0.003), and the bronchoalveolar lavage total WCC (8.96 +/- 1.87 vs 1.16 +/- 0.10 x 10(9)/L, P = 0.002) as compared with control. The lung weight wet/dry ratio was inversely related to the mean impedance change (rho = -0.76, P < 0.01). This study has demonstrated for the first time that eight-electrode EIT readily tracks the inflammatory response of lung tissue in a rodent model of ALI. EIT may thus provide a promising, non-invasive technique for monitoring the time-course of ALI in rodent models, and for testing novel pharmacological strategies to counter it.

Tendency towards erosive regression on magnetic resonance imaging at 12 months in rheumatoid arthritis patients treated with rituximab

Magnetic resonance imaging (MRI) may provide a more complete and accurate assessment of the effect of new therapies on joint destruction and joint inflammation in rheumatoid arthritis (RA) patients than...

Metastatic renal cell cancer treatments: an indirect comparison meta-analysis.

BackgroundTreatment for metastatic renal cell cancer (mRCC) has advanced dramatically with understanding of the pathogenesis of the disease. New treatment options may provide improved progression-free survival (PFS). We aimed to determine the relative effectiveness of new therapies in this field.MethodsWe conducted comprehensive searches of 11 electronic databases from inception to April 2008. We included randomized trials (RCTs) that evaluated bevacizumab, sorafenib, and sunitinib. Two reviewers independently extracted data, in duplicate. Our primary outcome was investigator-assessed PFS. We performed random-effects meta-analysis with a mixed treatment comparison analysis.ResultsWe included 3 bevacizumab (2 of bevacizumab plus interferon-a [IFN-a]), 2 sorafenib, 1 sunitinib, and 1 temsirolimus trials (total n = 3,957). All interventions offer advantages for PFS. Using indirect comparisons with interferon-α as the common comparator, we found that sunitinib was superior to both sorafenib (HR 0.58, 95% CI, 0.38–0.86, P = < 0.001) and bevacizumab + IFN-a (HR 0.75, 95% CI, 0.60–0.93, P = 0.001). Sorafenib was not statistically different from bevacizumab +IFN-a in this same indirect comparison analysis (HR 0.77, 95% CI, 0.52–1.13, P = 0.23). Using placebo as the similar comparator, we were unable to display a significant difference between sorafenib and bevacizumab alone (HR 0.81, 95% CI, 0.58–1.12, P = 0.23). Temsirolimus provided significant PFS in patients with poor prognosis (HR 0.69, 95% CI, 0.57–0.85).ConclusionNew interventions for mRCC offer a favourable PFS for mRCC compared to interferon-α and placebo.

A Behavioral Characterization on the Motor and Emotional Deficits of the 6-OHDA Parkinson Disease Rat Model

A Behavioral Characterization on the Motor and Emotional Deficits of the 6-OHDA Parkinson Disease Rat Model

Can a Newer MR Contrast Agent Be Used to Monitor Disease Progression in Muscular Dystrophy?

Schmidt et al (1) showed that MR imaging by using gadofluorine M, a fluorinated macrocyclic gadolinium-based contrast agent, enabled detection of disease progression in a model of muscular dystrophy in mice, whereas a macromolecular contrast agent did not. MR imaging with contrast agents such as gadofluorine M might ultimately be used in patients with muscular dystrophy to monitor disease progression and to assess the effectiveness of newer therapies currently under development.

Abstract 4386: Single-Center Experience in Large Cohort of Patients with Pulmonary Arterial Hypertension Related to Congenital Heart Disease over 15 years: Effect of New Therapies

Introduction: The aim of this study was to define the epidemiology, clinical parameters and 15-year follow-up of a large single-center cohort of patients with pulmonary arterial hypertension (PAH) related to congenital heart disease (CHD) and to evaluate the effect of emerging therapeutic strategies in this population. Methods: All patients diagnosed with PAH related to CHD between 1993 and 2008 were studied and clinical, echocardiographic, maximal and submaximal exercise as well as hemodynamic data were recorded. Results: A total of 60 pts aged 21 ± 14 (0.1–51) years at diagnosis were included in the study. Of these, 44 (73%) had unrestrictive mixing lesions and Eisenmenger syndrome and the rest non-mixing lesions, mainly repaired CHD. Of this population, 24 (40%) were &lt;18yrs and the remainder adults at diagnosis at our institution. Seven (12%) pts in WHO Class II received no therapy, 45 (75%) pts in Class II-III monotherapy (34 bosentan with 1 discontinuation after corrective surgery, 6 sildenafil, 5 sitaxsentan) with clinical and exercise improvement. Due to deterioration, 6 (10%) pts received addition of sildenafil after 3±1 years of bosentan monotherapy and 2 (3%) pts addition of epoprostenol after 1 year of the above combination therapy. Over 6±4 (1–15) years of follow-up, 49 (82%) pts remained stable on no or monotherapy, 4 pts (7%) deteriorated after 1–5 years monotherapy but stabilized on combination therapy and 7 (12%) pts died (3 from intractable right heart failure despite escalation of therapy and 4 suddenly while on therapy). The unrestrictive mixing group had 2 (4%) and the non-mixing group 5 (33%) deaths respectively. Conclusions: Long-term improvement and stabilization is possible in pts with PAH related to CHD with either monotherapy or combination therapy in case of deterioration overtime while on treatment. Death in this population may be sudden or due to intractable right heart failure, while survival is significantly better in pts with unrestrictive mixing. Larger long-term registry studies are needed to evaluate survival and clinical condition of these pts in the current treatment era and to improve medical management of this population.

In vivo characterization of plaque composition in late Cardiac Allograft Vasculopathy

Purpose: Allograft vasculopathy is the leading cause of late mortality after cardiac transplantation. Late cardiac allograft vasculopathy, as seen at necropsy, manifests as a diffuse obliterative process characterized by concentric intimal proliferation. Investigation of coronary plaque composition in vivo has become possible with the introduction of virtual histology (VH) intravascular ultrasound (IVUS). In this study we evaluated the feasibility of in vivo plaque characterization in late allograft vasculopathy using VH-IVUS. Methods and Materials: 15 patients (median age 61years; 3273years) 8 years (4-14years) after heart transplantation were included into this study. In all patients at least one coronary artery was investigated using VH-IVUS. VH-IVUS data were obtained using a continuous pullback (0.5mm/s) and a commercially available mechanical sector scanner (Eagle Eye GoldTM, Volcano Therapeutics). A region of interest (11-15mm) was selected and analyses were done offline with pcVH-review software (Volcano Therapeutics). Four histological plaque components (fibrous, fibrolipidic, necrotic and calcified) were correlated with a specific spectrum of the radiofrequency signal. Results: Median plaque length was 14mm (11-15mm), vessel segment volume 209mm3 (125-314mm3), and plaque-plus-media-volume 95mm3 (46-156mm3), resulting in a volume stenosis of 44% (34-56%). The remodeling index was 1.01 (0.88-1.21). VH demonstrated that 67% (47-77%) of plaque volumen was composed of fibrous, 10% (5-19%) of fibrolipidic, 14% (8-26%) of necrotic and 7% (2-12%) of calcified tissue. Conclusions: In vivo analysis of plaque composition in cardiac allograft vasculopathy is feasible using VH-IVUS. The high proportion of fibrous tissue identified by VH is well in line with post mortem data. It can be speculated that the addition of VH to standard IVUS will be helpful for the differentiation between early allograft vasculopathy from donor-transmitted atherosclerosis, and for investigating the effects of new therapy on disease progression.

NeuroAIDS

The neurological complications of AIDS (NeuroAIDS) include neurocognitive impairment and HIV-associated dementia (HAD; also known as AIDS dementia and HIV encephalopathy). HAD is the most significant and devastating central nervous system (CNS) complications associated with HIV infection. Despite recent advances in our knowledge of the clinical features, pathogenesis, and neurobiological aspects of HAD, it remains a formidable scientific and therapeutic challenge. An understanding of the mechanisms of HIV neuroinvasion, CNS proliferation, and HAD pathogenesis provide a basis for the interpretation of the diagnostic features of HAD and its milder form, HIV-associated minor cognitive/motor disorder (MCMD). Current diagnostic strategies are associated with significant limitations, but it is hoped that the use of biomarkers may assist researchers and clinicians in predicting the onset of the disease process and in evaluating the effects of new therapies.

Modelos experimentales de isquemia cerebral

To provide a summary of the different experimental models of cerebral ischemia designed both under in vivo and in vitro conditions. A clear and concise description of the specific types of brain lesion reproduced by each model is given together with the most frequent technical troubles associated. Experimental models of cerebral ischemia have contributed substantially to the understanding of the physiopathology of the ischemic brain injury and to test the beneficial effects of new therapies. Outcome of patients suffering from an ischemic stroke has improved considerably with the use of these models, particularly after the introduction of thrombolytic and neuroprotective drugs. Experimental models allow the study of the evolving ischemic brain injury under strict and controlled conditions. Usefulness of experimental models is limited by their reliability, simplicity and reproducibility among different researchers. Small rodents, especially rats, have been the preferred animals used to develop models of cerebral ischemic injury, due to their cerebral physiology and vascularisation which is closer to the human. The use of experimental models of cerebral ischemia constitutes the most suitable tool to investigate the physiopathology of this type of injury. However their simplicity prevents an exact reproduction of the cerebral damage observed in clinical settings. This could be the main reason for the discrepancies observed between the therapeutic effect in the experimental and clinical studies.

Role of the HLA Class II

The paper highlights the role of different HLA class II molecules in hepatic and lymphoproliferative HCV-related disorders. HLA molecules have been reviewed, according to an in silico cluster classification, based on the sequence, the biochemical structure of the pockets, and the functional characteristics of the HLA II molecules. Thus, by reducing the complexity of HLA II polymorphism, characteristics that unite different HLA molecules with specific HCV-associated pathologies may be recognized with greater case. Results show that HLA clusters associated with better dlimination of the virus are protective against HCC development, while the same clusters are associated with a higher risk of developing cryoglobulinemic syndrome and the concomitant NHL. These data added further acknowledgements on pathogenetic mechanisms associated with HCV infection. Results also highlight differences of NHL occurring in HCV-positive subjects, with or without a concomitant type II autoimmune cryoglobulinemic syndrome, suggesting that cryoglobulinemic background associated with NHL should be considered in the evaluation of the effectiveness of new therapies in the course of HCV-associated NHLs.

Prognosis and Clinical Trial Design in Traumatic Brain Injury: The IMPACT Study

Traumatic brain injury (TBI) is a major health and socio-economic problem throughout the world. Many randomized controlled trials (RCTs) have been performed to investigate the effectiveness of new therapies, but none have convincingly demonstrated benefit. Clinical trials in TBI pose complex methodological challenges and meeting these requires new approaches. The challenges are related to the heterogeneity of head injuries, to optimum analysis of outcome and to aspects of the design of trials. To address these, we have created the IMPACT database on TBI through merging individual patient data from eight RCTs and three observational surveys. This database forms a culture medium in which innovative approaches to improving trial design and analysis are being explored. We hypothesize that the statistical power of TBI trials may be increased by adjusting for heterogeneity with covariate adjustment and/or prognostic targeting, by exploiting the ordinal nature of the Glasgow Outcome Scale and by relating the outcome obtained in individual patients to their baseline prognostic risk. Extensive prognostic analysis was required as a first step towards our aim of optimizing the chance of demonstrating benefit of new therapies in future trials. The fruits of this analysis are reported in detail in the subsequent reports in this issue of the Journal of Neurotrauma. The results will lead to the development and validation of new prognostic models, which will be applied to deal with heterogeneity. The findings will be synthesized into recommendations for the design and analysis of future RCTs, with the expectation of increasing the likelihood of demonstrating the benefit of a truly effective new therapy or therapeutic agent in victims of a head injury.

The Disease Spectrum in Premature Infants and the Progress of Pharmacological Treatment

Liveborn infants delivered before 37 week of postmenstrual age or less than 2,500g of birth weight are defined as premature infants. Recently, the unprecedented progress in neonatal practice has achieved remarkable improvements in the survival of extremely premature infants. However, immature organ function and the complication of therapy still contribute to the high mortality and morbidity from a spectrum of disease especially in extremely premature, low birth weight infants; respiratory distress syndrome, chronic lung disease, necrotizing enterocolitis, intraventricular hemorrhage, nosocomial infection, and prolonged hospitalization consist of the spectrum of disease in premature infants. To achieve further progress in neonatal-perinatal practice, randomized clinical trials should be employed not just to test the effectiveness of new therapies but also to evaluate competing strategies toward evidence-based, better clinical practic