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Hemochromatosis is a hereditary disease that causes an inappropriate intestinal absorption of Fe resulting in its accumulation in multiple organs, such as liver, heart and skin. Fe metabolism indicators in the circulation do not provide reliable indication of organ overload as they can be influenced by other clinical conditions. Assessing metabolism organs such as liver requires invasive procedures which is not adequate to patient’s serial observations. Our aim was establishing cross sectional and longitudinal information on the amount of Fe that deposited in skin and liver during a life period, how iron is cleared out by therapy intervention and study the relationship of these changes between the two organs using non-invasive methods. Results on skin Fe deposition were evaluated by nuclear microscopy techniques and liver Fe concentrations determined by quantitative magnetic resonance imaging. Skin and liver Fe concentrations were correlated. Though Fe deposits in the two organs were differently associated with blood Fe metabolism conventional markers. Fe serial variations in skin and liver highlighted the value of assessing Fe organ deposits for estimating hemochromatosis evolution and therapy efficacy.

Acute allograft rejection remains a major complication after liver transplantation. We report a semiquantitative imaging method of detecting acute allograft rejection with 18F-FDG PET. Methods: Syngeneic and allogeneic transplanted rats, with or without immunosuppressive treatment, were subjected to serial PET. Autoradiography of the liver was conducted in both the syngeneic and the allogeneic rats. Results: A significant increment of 18F-FDG accumulation in liver allografts was observed by PET on day 2. The 18F-FDG signal was concentrated in the area where inflammatory cells around the vessels were detected by autoradiography. Allotransplanted rats treated with an immunosuppressive agent displayed a marked decrease in hepatic 18F-FDG uptake, compared with allotransplanted rats that were not treated. Conclusion:18F-FDG PET may be a valid method for facilitating the development of protocols to diagnose graft rejection and to monitor the efficacy of immunosuppressive therapy.

Aim. To compare different strategies of start antihypertensive therapy in out-patients. Material and methods. 120 out-patients with arterial hypertension (HT) 1-2 stages were included in the study and randomized in 3 groups. Patients of group «A» received start treatment in compliance with age, clinical features and mechanisms of hypertension. Patients of group «B» received step-by-step start antihypertensive therapy based on doses titration and addition of the second (third) drug if necessary. Patients of group «C» received fixed drug combination with addition of other antihypertensive medicines if necessary. Decrease of BP level and number of visits were used as criteria of therapy efficacy. Pharmacoeconomic analysis of antihypertensive therapy was done in all groups. Results. Strategy of HT start therapy in group «C» had advantages in speed of blood pressure normalization, number of necessary visits and in pharmacoeconomic efficacy in comparison with the strategies in group «A» and «B». Conclusion . HT start therapy with implementation of fixed low dose combination leads to the best result in comparison with other strategy based on step-by-step drug replacement (as well as their combining) or monotherapy dose titration.

INTRODUCTION Continuous mobile cardiac outpatient telemetry (MCOT) may have several advantages over traditional ambulatory monitoring systems in the diagnostic evaluation of symptoms such as palpitations, dizziness, and syncope. However, only limited published data are available showing its advantages. METHODS AND RESULTS We reviewed the records of 122 consecutive patients evaluated using MCOT for palpitations, presyncope/syncope, or to monitor the efficacy of a specific antiarrhythmic therapy. Ten of 17 patients (59%) studied for presyncope/syncope had a diagnosis made with MCOT. Eight of these 17 patients had a previous negative evaluation for presyncope/syncope and five had an event correlated with the heart rhythm during the monitoring period. Nineteen patients monitored for palpitations or presyncope/syncope were asymptomatic during monitoring but had a prespecified arrhythmia detected. When MCOT was used as the first ambulatory monitoring system to evaluate palpitations (n = 18), 73% of patients correlated their symptoms with the underlying cardiac rhythm. Seven of 21 patients monitored for medication titration had dosage adjustments during outpatient monitoring. CONCLUSIONS MCOT can detect asymptomatic clinically significant arrhythmias, and was especially useful to identify the cause of presyncope/syncope, even in patients with a previous negative workup. This outpatient monitoring system allows patients to undergo daily medication dose titration in the outpatient setting, thus avoiding hospitalization.

Background— Ventricular restraint is a nontransplantation surgical treatment for heart failure. The effect of varying restraint level on left ventricular (LV) mechanics and remodeling is not known. We hypothesized that restraint level may affect therapy efficacy. Methods and Results— We studied the immediate effect of varying restraint levels in an ovine heart failure model. We then studied the long-term effect of restraint applied over a 2-month period. Restraint level was quantified by use of fluid-filled epicardial balloons placed around the ventricles and measurement of balloon luminal pressure at end diastole. At 4 different restraint levels (0, 3, 5, and 8 mm Hg), transmural myocardial pressure (P tm ) and indices of myocardial oxygen consumption (MV̇ o 2 ) were determined in control (n=5) and ovine heart failure (n=5). Ventricular restraint therapy decreased P tm and MV̇ o 2 , and improved mechanical efficiency. An optimal physiological restraint level of 3 mm Hg was identified to maximize improvement without an adverse affect on systemic hemodynamics. At this optimal level, end-diastolic P tm and MV̇ o 2 indices decreased by 27% and 20%, respectively. The serial longitudinal effects of optimized ventricular restraint were then evaluated in ovine heart failure with (n=3) and without (n=3) restraint over 2 months. Optimized ventricular restraint prevented and reversed pathological LV dilatation (130±22 mL to 91±18 mL) and improved LV ejection fraction (27±3% to 43±5%). Measured restraint level decreased over time as the LV became smaller, and reverse remodeling slowed. Conclusions— Ventricular restraint level affects the degree of decrease in P tm , the degree of decrease in MV̇ o 2 , and the rate of LV reverse remodeling. Periodic physiological adjustments of restraint level may be required for optimal restraint therapy efficacy.

In the past there has been reliance on heartburn and acid regurgitation as the cardinal symptoms of gastro-esophageal reflux. Now it is recognized that diverse additional symptoms including extraesophageal manifestations are essential components of gastroesophageal reflux disease (GERD). Furthermore, previous reliance in mucosal damage at endoscopy as evidence of therapeutic success in the management of GERD has proven of only limited value in the diverse world of GERD symptoms. Indeed is now apparent that the relationship between symptoms and lesions is modest at best. Most patients with GERD have no overt erosions or ulceration at endoscopy and they frequently suffer from a wide array of complaints other than heartburn that contribute to their diminished perception of life's quality. To address these problems, multidimensional questionnaires designed to encompass the diverse symptomatology of GERD have been investigated, principally, to provide a reproducible metric of change in the subjective response to pharmacologic therapy during trials for patients with nonerosive reflux disease. The most promising of these instruments is The ReQuest questionnaire, because it has been extensively validated in multiple patient groups and cultures, appears highly promising in this regard and for erosive disease too and may ultimately prove to be of value for the initial evaluation of patients with GERD. We propose that accurate symptom delineation complemented with endoscopy performed in selected groups of patients will become the mainstay in diagnosis of GERD and the assessment of therapy efficacy.

Anti-tumor necrosis factor (TNF) alpha therapy has changed the course of psoriatic arthritis (PsA), but clinical experience about lengthening of time intervals between drug administrations is still limited. The aims of the study were to evaluate: (1) the long-term efficacy (over a 4-year period) of etanercept/adalimumab in a subset of PsA patients who did not require switches; and (2) the progressive lengthening of time intervals between treatments in patients who achieved minimal disease activity (MDA). PsA outpatients attending the Rheumatology Clinic-University of Padova who took a single anti-TNF agent (etanercept/adalimumab) for a 4-year period were studied. Therapy efficacy was assessed using clinical, biochemical, and disease activity (DA) indexes. The intervals between treatments were empirically and progressively lengthened after MDA was reached and maintained. One hundred and forty-one patients (mean age, 51.22 ± 12.34 years; mean disease duration, 12.1 ± 8.42 years) treated with etanercept/adalimumab (47.5% and 52.5%, respectively) were studied. DA indexes showed a marked, persistent improvement in all the patients throughout 4 years. The interval between injections could be extended in 46.1% of the patients (35% for adalimumab, 58% for etanercept) without provoking relapses. The mean therapy interval at the end of the study period was 3.12 weeks for adalimumab 40 mg (with respect to 2 weeks) and 2.75 weeks for etanercept 25 mg (with respect to 0.5 weeks). The new therapy timetable also led to cost savings. In conclusion, lengthening the time intervals between injections of anti-TNF agents in PsA patients who reach MDA is safe, effective, cost-effective, and facilitates patient compliance.

Stem cell therapy may in the future become a routine treatment for aspects of aniridia. In this chapter we will discuss how one such corneal stem cell therapy approach is already in use in the clinic as an unlicensed experimental medicine, the results achieved so far and the likely direction of future research to improve therapy efficacy.

The distribution of Fe in skin was assessed to monitor body Fe status in human hereditary hemochromatosis. The paper reports on data from nine patients with hemochromatosis that were studied along the therapeutic programme. Systemic evaluation of Fe metabolism was carried out by measuring with PIXE technique the Fe concentration in plasma and blood cells, and by determining with biochemical methods the indicators of Fe transport in serum (ferritin and transferrin). The Fe distribution and concentration in skin was assessed by nuclear microscopy and Fe deposits in liver estimated through nuclear magnetic resonance. Elevated Fe concentrations in skin were related to increased plasma Fe (p < 0.004), serum ferritin content (p < 0.01) and Fe deposits in liver (p < 0.004). The relationship of Fe deposits in organs and metabolism markers may help to better understand Fe pools mobilisation and to establish the quality of skin as a marker for the disease progression and therapy efficacy.

Objective: This work describes the medicinal plants and/or herbal medicines usage by the population assisted by Brazilian Public Health System (SUS), and their prescription by health professionals in the Brazilian Northeast. Methods: Questionnaires were applied for public health system users; pharmacists who work at compounding pharmacies; physicians and nurses. Data were submitted to descriptive statistical analysis. Results: The sociodemographic profile was individuals between 40 and 59 yearsold, majority of females, low family income, and low schooling levels. A great number of individuals (89.3%) used plant products, without prescription and based on traditional knowledge. There was a common trend regarding a lack of knowledge of plant toxicity potential. Regarding health professionals, 90% stated having knowledge about medicinal plants and/or herbal medicines, and 80% believe that its effect is important. Conclusion: The study reveals the major usage of herbal medicines and/or medicinal plants by familiar low income and low schooling level without prescription from a physician. These factors may cause a risk/benefit imbalance where could have a reduction in therapy efficacy and high toxicity potential of the drugs. This reinforces the need of pharmacosurveillance toward usage of medicinal plants and herbal medicines in the public health system.

Automatic atrial antitachycardia pacing (ATP) can terminate atrial tachyarrhythmias (ATs) in patients with an implanted device. We investigated if the programmable delay between AT onset and ATP influences therapy efficacy.Patients with intermittent ATs and an implanted DDDRP pacemaker were randomized to receive ATP either immediately or 30min after AT detection. After four months stored data were interrogated, AT-related symptoms were assessed, and patients crossed over to the alternative treatment arm for another four months. Stored atrial electrograms were analyzed for degree of AT organization and ATP success.In 22 patients (64% male; 72+/-7 years), ATP success rates were higher during immediate than during delayed ATP (device classification: 59+/-7% vs. 22+/-5%, P0.01; manual analysis: 36+/-6% vs. 12+/-5%, P0.01). Higher efficacy of immediate ATP was associated with a larger proportion of organized (Type I) AT prior to therapy (71% vs. 44% during delayed ATP). No difference was found in total AT numbers and duration, AT burden or related symptoms.The programmable delay between arrhythmia onset and therapy delivery significantly influences the success-rate of ATP. However, a higher efficacy of immediate compared with delayed ATP does not translate into a reduction of AT burden or related symptoms.

Saliva is a secretion of the salivary and mucous glands and is of major importance in the maintainance of oral health. Over the last few decades, saliva has been evaluated as a diagnostic fluid in medicine for determining systemic disease markers as well as for monitoring numerous drugs, narcotics, and hormones. The biochemical analysis of saliva is particularly important in dentistry. The estimation of the risk of appearance and diagnosis of disease, monitoring of disease progression, evaluation of therapy efficacy for caries, periodontitis, premalignant and malignant oral lesions, as well as infectious diseases of the oral cavity, can be assessed by analyzing different constituent: of saliva, individuals at risk of caries can be identified using test: that determine saliva flow rate, saliva buffer capacity, and colonization of the oral cavity by cariogenic bacteria. Today, these rapid and simple diagnostic tests are used routinely in caries risk determination. The study and use of saliva-based diagnostics have increased over the last few decades. Clinical testing of saliva shows much promise. However, there is a need for much additional research in this area, before the true clinical value of saliva as a diagnostic fluid in dentistry can be determined.

The aim of this review is to summarise the clinical role of nuclear medicine in rheumatology taking into consideration the most specific diagnostic applications and other worthwhile therapeutic contributions. Traditional bone scintigraphy and recent inflammation-targeting radiopharmaceuticals, such as radiolabelled leucocytes and immunoscintigraphy, now allow us to obtain highly sensitive total-body and tomographical imaging information that can be used for the diagnosis of osteoarticular disease. The most common extra-articular manifestations of rheumatic diseases due to digestive, central nervous, respiratory and cardiovascular system involvement can be diagnosed by specific scintigraphic methods. Radiosynovectomy plays an important role in providing effective treatment for some joint diseases that are resistant to pharmacological therapy. Diagnostic and therapeutic applications of nuclear medicine show the highest efficacy in the early phase of rheumatic diseases. In more advanced stages, scintigraphical techniques play a complementary role to radiographical investigations in the assessment of prognosis and therapy efficacy.

Atherosclerosis imaging has taken on increasing importance in the understanding of the natural history of coronary artery disease and the processes leading to luminal narrowing, as well as the assessment of disease burden and therapy efficacy. Intravascular ultrasound (IVUS) has emerged as the new gold standard for atherosclerosis imaging because it provides cross-sectional images of both the arterial wall and lumen with excellent resolution, reveals the diffuse nature of atherosclerosis and the involvement of reference segments, and takes into account vessel wall remodeling. In addition to its clinical indications, IVUS is now widely used as the primary efficacy assessment measure of several antiatherosclerotic approaches in randomized clinical trials. Advantages of IVUS include its ability to reveal antiatherosclerotic effects within a relatively short period of time and with a reasonable sample size, which is in contrast to trials assessing angiographic changes or clinical events. IVUS can also help to determine dose-response relationships in the development of novel pharmacologic agents. IVUS is currently the ideal imaging modality for clinical trials of atherosclerosis progression/regression.

New developments in dual chamber implantable cardioverter defibrillators (ICD) have increased the specificity of therapy delivery. This study was performed to examine the performance of an algorithm, focusing on its ability to distinguish slow ventricular tachycardia (VT) from sinus rhythm or supraventricular tachyarrhythmias. The patient population included 77 men and 13 women, 63 ± 11 years old, treated with ICDs after episodes of spontaneous or inducible ventricular tachyarrhythmias. They were randomized to programming of the ICD to a lower limit of VT detection at 128 beats/min (group I, n = 44), versus 153 beats/min II (group II, n = 46). The primary endpoint of the study consisted of comparing the specificity and sensitivity of the algorithm between the two groups of patients. Over a 10.1 ± 3.5 months follow-up, 325 episodes were detected in the Tachy zone in group I, versus 106 in group II. The sensitivity and specificity of the algorithm in group I were 98.8% and 94.4%, respectively, versus 100% and 89% in group II (NS). A single episode of VT at a rate of 132 beats/min was diagnosed as SVT in group I. The sensitivity and specificity of the algorithm for tachycardias

Interphase fluorescence in situ hybridization (I-FISH) using labeled nucleic acid probes detects chromosomal and genetic aberrations at a cellular level. I-FISH is a relatively fast and sensitive technique for evaluating a large number of cells and revealing more specific information than other techniques. It has been proven to be an invaluable molecular test in cytologic analyses for the detection of subtle genetic alterations that correlate with disease progression. In this postgenomic era, with the draft of the human genome available and expansion of the knowledge of tumor-specific genetic changes, the application of I-FISH probes in cytologic analysis should be of great value in the early detection, risk assessment, and monitoring of therapy efficacy in cancer. Here, we outline the principle of the I-FISH procedure, present suggestions to efficiently analyze cytologic materials, provide examples of practical applications, and discuss new aspects of the technique.

9516 Background: Immune checkpoint inhibitor therapy, ICT, achieves durable remissions in 30-50% of patients (pts) with metastatic melanoma (Larkin et al. NEJM 2015). It is still unclear what host factors modulate response to ICT. Preclinical mouse studies with B16 melanoma demonstrated that ICT response was dependent on the presence of specific commensal gut bacteria (Vetizou et al. Science 2015; Sivan et al. Science2015). These specific gut bacteria induced the maturation of dendritic cells (DCs) and T-cells needed for effective ICT. We sought to determine whether specific gut microbiota are associated with improved response to ICT in melanoma patients. Methods: 37 melanoma pts treated with ICT (nivolumab plus ipilimumab or pembrolizumab alone) at UTSW Medical Center were enrolled. Fecal samples were collected prior to ICT. Genomic DNA was extracted, and metagenomic shotgun sequencing (MSS) performed on an Illumina HiSeq 2500 PE-100. Taxonomic (MetaPhlAn) and functional (HUMAnN) analysis was performed on MSS data. Disease status was assessed by CT scans and physical exams every two months. Results: Among the 23 evaluable pts, 8 were classified as RECIST responders, 5 with stable disease and 10 with progression. RECIST responder microbiomes were significantly enriched with Methanobrevibacter smithii(p = 0.03; LDA coupled with effect size measurements, LEfSe; Kruskal-Wallis test) , Bacteroides thetaiotamicron(p = 0.03) , Lactobacillus plantarum(p = 0.04), and Eubacterium limosum(p = 0.01) compared to those with progressive disease. Conclusions: MSS identified 4 specific gut microbiota associated with improved response to ICT therapy in melanoma pts. All of these bacteria have been shown to modulate host immune response (Bang PLoS One 2014; Hickey Cell Host Microbe 2016; Rigaux Allergy 2009; Kaunachi World J Gastroentertol 2006). To gain mechanistic insight and confirm causality, shotgun metabolomics on the same fecal specimens used for MSS, in vitroimmune cell assays using the gut microbiota identified, and preclinical modeling in a mouse melanoma model with ICT are underway. These studies may lay the foundation for optimizing the host response to ICT.

Methods for correction of magnetic field distribution within the optical radiation coverage zone of magnetic laser therapy apparatuses were developed. These methods in medical apparatuses provide a 3.5–4.0-fold decrease in the magnetic induction in the therapeutic zone of ring magnets. Magnetic field strength was optimized using magnetic tips made of soft magnetic materials. Engineering solution of magnetotherapeutic apparatuses provides optimal value of magnetic induction in the zone of an optical beam. The magnetic field induction can be varied within range |B| = 27–75 mTl using magnetic core position. This regulation allows magnetic therapy efficacy to be adapted to the patient’s pathology, age, and individual physiology.

Osteoporosis is becoming an increasingly important public health issue and the measurement of BMD is important for diagnosing osteoporosis as well as predicting fracture risk and evaluating therapy efficacy. DXA is currently the best established method for osteoporosis diagnosis, and, however, QCT is more sensitive to the change of BMD with the ability of measuring the volumetric BMD. With the disadvantage of the relatively higher radiation dose over DXA, the clinical application of QCT in the management of osteoporosis warrants further development.

Robotic-assisted walking training has spread in recent years with positive results regarding its efficacy. However there are few information regarding the target people for a more effective robotic rehabilitation. The present study is aimed to investigate if possible demographic factors can influence robotic-assisted walking training. The study was performed in a neurorehabilitation setting. A total of 74 patients were randomized in robotic-assisted gait training abbreviated conventional therapy (RAGT) and floor-assisted gait training abbreviated conventional therapy intervention (FAGT). Outcome measure was the walking ability measured by Functional Ambulation Classifications (FAC). Results show that in RAGT group walking recovery was more effective for female than males (p=0.0048) and for patients over 65 years (≥65 yrs, p=0.040). This combined gender/age effect was not observed in FAGT group. Among demographic factors gender and age are critical for selecting stroke patients with higher chance of gait robotic gait therapy efficacy.

Nasopharyngeal carcinoma(NPC) is one of common head and neck cancers which mainly threaten people in Southeast Asia. PET/CT play an important roles in radiotherapy for NPC. This article reviews the PET/CT in the diagnosis, staging, guiding treatment, monitoring of therapy efficacy, focal residual and recurrence, prognosis and progress of NPC.

We have coevaluated a combination of test processes for diagnosing von Willebrand disease (vWD) and monitoring deamino-delta-D-arginine vasopressin (DDAVP) therapy. Using normal controls (n = 23), closure time (CT) ranges measured by PFA-100(R) were (mean +/- 2SD): (i) collagen/ADP cartridge (C/ADP): 67-127 s (ii) collagen/epinephrine (C/Epi): 94-162 s. From a panel of 125 patients undergoing evaluation for clinical haemostatic defects, 29/30 samples from patients with vWD [17/18 type 1, 1/1 type 3, 3/3 type 2A, 7/7 type 2B and 1/1 pseudo-vWD] gave prolonged CTs using C/Epi. The C/ADP was less sensitive, being normal in 7/18 of the type 1 vWD individuals, with higher sensitivity to more severe vWD. Individuals with haemophilia (six factor VIII-deficient, one factor XI-deficient) gave normal CTs, while those with clinical thrombocytopenia (n=13) gave normal or prolonged CTs, somewhat dependent on platelet count. The PFA-100 was also evaluated as a part of the laboratory monitoring procedure in patients with either vWD or haemophilia undergoing a DDAVP trial as a therapeutic management process. For vWD, correction of an initially prolonged CT by DDAVP, accompanied by normalization of von Willebrand factor (vWF) measurable by von Willebrand factor antigen, vWF collagen binding activity and vWF ristocetin cofactor assays (vWF:Ag, vWF:CBA and vWF:RCof), was achieved in type 1 vWD (n=5). In an individual with type 2A vWD, DDAVP normalized vWF:Ag and vWF:RCof, but had no apparent effect on the baseline maximally prolonged CT. In an individual with type 2B vWD, factor VIII/vWF concentrate also normalized vWF:Ag and vWF:RCof, but similarly had no apparent effect on the baseline maximally prolonged CT. vWF:CBA did not normalize for either of these individuals, potentially suggesting that normalization of vWF:CBA might be required for normalization of CT. This concept is supported by correlation analysis undertaken between CT and various vWF parameters. Among these, vWF:CBA held the strongest relationship in our data set, which showed an inverse progressive rise in CT for falling vWF:CBA. Based on these results, we would conclude that the PFA-100 is highly sensitive to the presence of vWD, and may thus provide a valuable screening test for vWD. Furthermore, the combined utility of the PFA-100 and vWF:CBA as markers of DDAVP responsiveness may prove to be simple, quick but powerful, predictors for its clinical efficacy.

To our knowledge comparative data on the effectiveness of and patient preference for intracavernous injection therapy and sildenafil are still not available. We evaluated the efficacy of sildenafil as well as patient preference in a group of impotent men on intracavernous injection for more than a year.Patients on intracavernous injection therapy for more than a year without neurological disease and/or a contraindication to sildenafil treatment were recruited for study. In phase 1 we determined the efficacy of 50 and 100 mg. sildenafil citrate at home. In phase 2 responders to sildenafil were asked to use the preferred dose orally for a month and choose intracavernous injection or sildenafil. In phase 3 patients were asked to continue either treatment for 3 more months. Patient preferences were reported at the end of phases 2 and 3.Of the 180 men recruited 155 with a mean age of 56.4 +/- 12.6 years on intracavernous injection for a mean of 26 +/- 9 months accepted and were included in our series. Overall 116 men (74.8%) responded to sildenafil during study phase 1. After 1 month of treatment 71 responders (61.2%) preferred to continue with the oral drug, 31 (26.7%) returned to intracavernous injection and 14 (12.1%) used each drug alternately. Three months later 74 of the 116 responders (63.8%) preferred oral treatment and 38 (32.8%) chose intracavernous injection, while 4 (3. 4%) continued to use each treatment alternately.Sildenafil is highly effective in intracavernous injection responders, although a certain group prefer to continue intracavernous injection. While sildenafil should be considered first line treatment, men with erectile dysfunction should be aware of all treatment options available because nonresponders to sildenafil may respond to intracavernous injection.

The proportion of studies that use one-tailed statistical significance tests (pi) in a population of studies targeted by a meta-analysis can affect the bias of the sample effect sizes (sample ESs, or ds) that are accessible to the meta-analyst. H. C. Kraemer, C. Gardner, J. O. Brooks, and J. A. Yesavage (1998) found that, assuming pi = 1.0, for small studies (small Ns) the overestimation bias was large for small population ESs (delta < or = 0.2) and reached a maximum for the smallest population ES (viz., delta = 0). The present article shows (with a minor modification of H. C. Kraemer et al.'s model) that when pi = 0, the small-N bias of accessible sample ESs is relatively small for delta < or = 0.2, and a minimum (in fact, nonexistent) for delta = 0. Implications are discussed for interpretations of meta-analyses of (a) therapy efficacy and therapy effectiveness studies, (b) comparative outcome studies, and (c) studies targeting small but important population ESs.

Trabajo presentado en el 50th International Liver Congress, celebrado en Viena, Austria, del 22 al 26 de abril de 2015

Recently, the 1997 revised guidelines were published for the treatment of HIV-infected patients. These guidelines, while having a dramatic effect on the morbidity and mortality associated with HIV infection, will require the implementation of a coordinate interdisciplinary “Care Path” for each patient. This review presents updated information on the HIV life cycle and the latest approach to antiretroviral therapy. The new approach to therapy is to utilize combination antiretroviral therapy including two retroviral inhibitors with a protease inhibitor. Further, the importance of viral load has become a primary indicator of prognosis and therapy efficacy. The CD4 cell count is important, but it is of secondary significance in treatment effectiveness measurement and indication of disease progress. The complexity of the new guidelines increases the need for a well-planned interdisciplinary “Critical Path” which is then utilized for development of a patient-specific “Care Path.”

Lymphomas are heterogeneous but potentially curable group of neoplasms. Treatment of lymphomas has rapidly evolved overtime with significant improvement in the cure rate and reductions in treatment-related toxicities. Despite excellent results, treatment programs are continued to be developed to achieve better curative and safety profiles. In these patients individualized therapy schemes can be devised based on a well-defined risk categorization. The therapy efficacy can be increased early during therapy in non-responding patients with escalated therapy protocols or with the addition of radiation therapy, particularly, in advanced-stage or unfavorable risk patients. The increasing availability of positron emission tomography using 18F-fluorodeoxyglucose, particularly fused with computed tomography (FDG-PET/CT) has lead to the integration of this modality into the routine staging and restaging for lymphoma with convincing evidence that it is a more accurate imaging modality compared with conventional imaging techniques. FDG-PET/CT is also is a promising surrogate for tumor chemosensitivity early during therapy. This review will summarize published data on the utility of FDG-PET/CT imaging in the staging, restaging, and predicting therapy response in patients with lymphoma.

We are in the midst of an epidemic of Alzheimer’s disease (AD) in developed countries. We have postulated that ingestion of inorganic copper from drinking water and taking supplement pills and a high fat diet are major causative factors. Ingestion of inorganic copper can directly raise the blood free copper level. Blood free copper has been shown by the Squitti group to be elevated in AD, to correlate with cognition, and to predict cognition loss. Secondly, we have shown that AD patients are zinc deficient compared to age matched controls. Zinc is important in neuronal protection. We carried out a 6-month small double blind trial of a new zinc formulation on AD patients. We found that in patients 70 years and older, zinc therapy protected against cognition decline compared to placebo controls. We also found that zinc therapy significantly lowered blood free copper levels. So zinc efficacy could be due to restoring neuronal zinc levels, to lowering blood free copper levels, or to both.

Nanotechnology has been extensively explored for drug delivery. Here, we introduce the concept of a nanodrug based on synergy of photothermally-activated physical and biological effects in nanoparticle-drug conjugates. To prove this concept, we utilized tumor necrosis factor-alpha coated gold nanospheres (Au-TNF) heated by laser pulses. To enhance photothermal efficiency in near-infrared window of tissue transparency we explored slightly ellipsoidal nanoparticles, its clustering, and laser-induced nonlinear dynamic phenomena leading to amplification and spectral sharpening of photothermal and photoacoustic resonances red-shifted relatively to linear plasmonic resonances. Using a murine carcinoma model, we demonstrated higher therapy efficacy of Au-TNF conjugates compared to laser and Au-TNF alone or laser with TNF-free gold nanospheres. The photothermal activation of low toxicity Au-TNF conjugates, which are in phase II trials in humans, with a laser approved for medical applications opens new avenues in the development of clinically relevant nanodrugs with synergistic antitumor theranostic action.

Objective: To evaluate two cases of intermittent exotropia (IX(T)) treated by vision therapy the efficacy of the treatment by complementing the clinical examination with a 3-D video-oculography to register and to evidence the potential applicability of this technology for such purpose. Methods: We report the binocular alignment changes occurring after vision therapy in a woman of 36 years with an IX(T) of 25 prism diopters (Δ) at far and 18 Δ at near and a child of 10 years with 8 Δ of IX(T) in primary position associated to 6 Δ of left eye hypotropia. Both patients presented good visual acuity with correction in both eyes. Instability of ocular deviation was evident by VOG analysis, revealing also the presence of vertical and torsional components. Binocular vision therapy was prescribed and performed including different types of vergence, accommodation, and consciousness of diplopia training. Results: After therapy, excellent ranges of fusional vergence and a “to-the-nose” near point of convergence were obtained. The 3-D VOG examination (Sensoro Motoric Instruments, Teltow, Germany) confirmed the compensation of the deviation with a high level of stability of binocular alignment. Significant improvement could be observed after therapy in the vertical and torsional components that were found to become more stable. Patients were very satisfied with the outcome obtained by vision therapy. Conclusion: 3D-VOG is a useful technique for providing an objective register of the compensation of the ocular deviation and the stability of the binocular alignment achieved after vision therapy in cases of IX(T), providing a detailed analysis of vertical and torsional improvements.

Cancer presents high mortality and morbidity globally, largely due to its complex and heterogeneous nature as well as the lack of effective biomarkers. There is an urgent need to identify clinically relevant markers for better diagnosis, prognosis, monitoring treatment efficacy, and accelerating the development of novel targeted therapeutics. Proteomics study of cancer may identify and characterize functional proteins that drive the transformation of malignancy as well as discover biomarkers to detect early-stage cancer, predict prognosis, determine therapy efficacy, identify novel drug targets, and ultimately develop personalized medicine. The technology platforms for proteomics analysis have advanced considerably over the last few years. Driven by these advancements in technology, a number of potential biomarkers have been identified in the tissues, blood, and body fluids.

Arterial wall mass transport properties dictate local distribution of biomolecules or locally delivered dugs. Knowing how these properties vary between coronary artery locations could provide insight into how therapy efficacy is altered between arterial locations.We introduced an indocarbocyanine drug surrogate to the lumens of left anterior descending and right coronary (LADC; RC) arteries from pigs with or without a pressure gradient. Interstitial fluorescent intensity was measured on live samples with multiphoton microscopy. We also measured binding to porcine coronary SMCs in monoculture.Diffusive transport constants peaked in the middle sections of the LADC and RC arteries by 2.09 and 2.04 times, respectively, compared to the proximal and distal segments. There was no statistical difference between the average diffusivity value between LADC and RC arteries. The convection coefficients had an upward trend down each artery, with the RC being higher than the LADC by 3.89 times.This study demonstrates that the convective and diffusive transport of lipophilic molecules changes between the LADC and the RC arteries as well as along their length. These results may have important implications in optimizing drug delivery for the treatment of coronary artery disease.

11535Background: Initial flare-ups of cancer deposits have been observed under nivolumab and pembrolizumab therapy, making imaging evaluations uneasy. In that setting, we hypothesized that circulat...

e12521Background: Alopecia is a common and distressing side-effect endured by breast cancer patients recieving chemotherapy. Scalp-cooling methods have been reported to decrease the incidence of al...

1523Background: MSI status is predictive of anti-PD-1/L1 therapy efficacy independent of tumor histology. This study describes the development and validation of a novel computational method to assess MSI status. In addition, we sought to determine the MSI prevalence and mutation characteristics in the cohort by applying the method to 11,573 clinical solid tumor cases previously assayed with CGP. Methods: To determine MSI status, 114 intronic homopolymer repeat loci with adequate coverage on the CGP panel were analyzed for length variability and compiled into an overall MSI score via principal components analysis. Translation of the MSI score to MSI-H (microsatellite high) or MSS (microsatellite stable) was established using training data. A matched-normal sample is not required, and CGP is accurate when tumor content is at least 20%. Results: Our methodology was validated in 69 samples with MSI status (20 MSI-H, 49 MSS) previously determined by standard clinical testing (PCR or immunohistochemistry). Conc...

544 Background: Sunitinib (SU) and Pazopanib (PZ) have been compared head-to-head in the first-line phase III COMPARZ study in metastatic renal cell carcinoma (mRCC). We compared SU versus PZ, to confirm outcomes and subsequent second-line therapy efficacy in a population-based setting. Methods: We used the IMDC to assess overall survival (OS), progression-free survival (PFS), response rate (RR) and performed proportional hazard regression adjusting for IMDC prognostic groups. Second-line OS2 and PFS2 were also evaluated. Results: We obtained data from 3,606 patients with mRCC treated with either first line SU (n=3226) or PZ (n=380) with an overall median follow-up of 43.5 months (m) (CI95% 41.4 – 46.4). IMDC risk group distribution for favorable prognosis was 440 (17.3%) for SU vs 72 (25%) for PZ, intermediate prognosis 1414 (55.6%) for SU vs 153 (53%) for PZ, poor prognosis 689 (27.1%) for SU vs 62 (22%) for PZ, p= 0.0027. We found no difference between SU vs. PZ for OS (20.1 [CI95% 18.76-21.42] vs. 23.68 m [CI95% 19.54 - 28.81] p=0.19), PFS (7.22 [CI95% 6.76 - 7.78] vs. 6.83 m [CI95% 5.58 - 8.27] p=0.49). The RR was similar in both groups (Table 1). Adjusted HR for OS and PFS were 0.952 (CI95% 0.788 – 1.150 p=0.61) and 1.052 (CI95% 0.908 – 1.220 p = 0.49), respectively. We also found no difference in any second-line treatment between either post-SU vs. post-PZ groups for OS2 (12.88 [CI95% 11.89 – 14.19] vs. 12.91 m [CI95% 10.3 – 19.1] p=0.47) and PFS2 (3.67 [CI95% 3.38 – 3.87] vs. 4.53 m [CI95% 3.08 – 5.35] p=0.4). There was no statistical difference in OS2 and PFS2 if everolimus was used after SU or PZ (p = 0.33 and p = 0.41, respectively) or if axitinib was used after SU or PZ (p = 0.73 and p = 0.72, respectively). Conclusions: We confirmed in real world practice, that SU and PZ have similar efficacy in the first-line setting for mRCC and do not affect outcomes with subsequent second-line treatment. [Table: see text]

independent variable and Ni, NPi, NUV, NUP, nMVV and sleep duration (hours) as dependent variables. Strong and moderate correlations were defined as Spearman’s coefficient 0.6 and 0.2-0.6, respectively. Statistical significance was considered at p 0.05. RESULTS: Eighty eight consecutive men who presented with LUTS completed a 24-hr FVC (median age 70, interquartile range (IQR): 64.5-74.5, range: 27-88; median ANV 2, IQR: 1.5-4, range: 0-15). In 1,597 community dwelling men (95% of the responders) who completed a 3-day FVC, for whom, due to missing data regarding sleeping hours (n 375) and due to meeting exclusion criteria (n 143), the nocturnal voiding frequency and volume could be analyzed in 1082 men (median age 61, IQR: 56.1-66.4, range: 49.4-78.2; median ANV 1.5, IQR: 1.0-2.0, range: 0-4.5). Results are depicted in the Table. CONCLUSIONS: In both men with LUTS and community dwelling with and without LUTS, there exists a strong correlation between nocturia severity and the nocturia index (Ni). In both cohorts there is moderate correlation between nocturia severity and the NPi, NUV, NUP and sleep duration. Surprisingly, the nMVV did not correlate with nocturia severity. The nocturia index is the single best diary parameter predicting nocturia severity. This finding strongly suggests that therapy of nocturia is best carried out by treatments designed to more closely match nocturnal urine production with bladder capacity.

The discovery and increased understanding of tumor targets has led to the development and approval of 12 small molecule tyrosine kinase inhibitors (TKIs). Despite tremendous efforts in TKI development, treatment efficacies with these therapeutics are still too low and improvements require a personalized medicine approach. Positron emission tomography (PET) with radiolabeled TKIs (TKI-PET) is a tracking, quantification and imaging method, which provides a unique understanding of the behavior of these drugs in vivo and of the interaction with their target(s). In this article we provide an overview of tracer synthesis and development because each TKI requires a tailor made approach. Moreover, we describe current preclinical work and the first proof-of-principle clinical studies on the application of TKI-PET, illustrating the potential of this approach for improving therapy efficacy and personalized cancer treatment.

Despite the significant gains in the treatment of breast cancer over the last decade, further improvements in survival using traditional chemotherapeutic agents have begun to plateau. Bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor, has provided promise for continued gains in therapy efficacy.The authors review Phase III data concerning the safety of bevacizumab in breast cancer, summarize data on efficacy and discuss the risk:benefit ratio of the drug. The data for this review were obtained by searching in the PubMed database. This review enables the reader to overview current knowledge on the efficacy and safety of bevacizumab in breast cancer.Insight into complex risk-benefit calculations for bevacizumab is missing. In unselected patients with HER2-negative metastatic breast cancer, the risk of serious side effects of bevacizumab overshadows the benefit of the drug. However, increased response rates and progression-free survival in the majority of Phase III trials suggest that the drug is of benefit in a subgroup of patients. Although requiring close monitoring, most side effects are manageable. Reliable, validated predictive biomarkers are of utmost importance to improve the likelihood of clinical benefit.

The sensitive measurement of biomolecular interactions has use in many fields and industries such as basic biology and microbiology, environmental/agricultural/biodefense monitoring, nanobiotechnology, and more. For diagnostic applications, monitoring (detecting) the presence, absence, or abnormal expression of targeted proteomic or genomic biomarkers found in patient samples can be used to determine treatment approaches or therapy efficacy. In the research arena, information on molecular affinities and specificities are useful for fully characterizing the systems under investigation. Many of the current systems employed to determine molecular concentrations or affinities rely on the use of labels. Examples of these systems include immunoassays such as the enzyme-linked immunosorbent assay (ELISA), polymerase chain reaction (PCR) techniques, gel electrophoresis assays, and mass spectrometry (MS). Generally, these labels are fluorescent, radiological, or colorimetric in nature and are directly or indirectly attached to the molecular target of interest. Though the use of labels is widely accepted and has some benefits, there are drawbacks which are stimulating the development of new label-free methods for measuring these interactions. These drawbacks include practical facets such as increased assay cost, reagent lifespan and usability, storage and safety concerns, wasted time and effort in labelling, and variability among the different reagents due to the labelling processes or labels themselves. On a scientific research basis, the use of these labels can also introduce difficulties such as concerns with effects on protein functionality/structure due to the presence of the attached labels and the inability to directly measure the interactions in real time. Presented here is the use of a new label-free optical biosensor that is amenable to microarray studies, termed the Interferometric Reflectance Imaging Sensor (IRIS), for detecting proteins, DNA, antigenic material, whole pathogens (virions) and other biological material. The IRIS system has been demonstrated to have high sensitivity, precision, and reproducibility for different biomolecular interactions [1-3]. Benefits include multiplex imaging capacity, real time and endpoint measurement capabilities, and other high-throughput attributes such as reduced reagent consumption and a reduction in assay times. Additionally, the IRIS platform is simple to use, requires inexpensive equipment, and utilizes silicon-based solid phase assay components making it compatible with many contemporary surface chemistry approaches. Here, we present the use of the IRIS system from preparation of probe arrays to incubation and measurement of target binding to analysis of the results in an endpoint format. The model system will be the capture of target antibodies which are specific for human serum albumin (HSA) on HSA-spotted substrates.

Drug delivery systems are designed to improve therapy efficacy as well as patient compliance. This could be accomplished by specifically targeting a medication intact to its active site, therefore reducing side-effects and enabling high local drug concentrations. Silica nanoparticles have gained ground in the biomedical field for their biocompatibility and biodegradability, being themselves inert and stable, thus enabling a variety of formulation designs for application in the pharmaceutical industry. This paper is a review of the recent patents on the applications of silica nanoparticles for drug delivery and their preparation. The review will focus on the different techniques available to obtain silica nanoparticles with variable morphology and their drug targeting applications, providing an overview of silica particles synthesis described in the literature.