Marker Of Disease Status Research Articles

VEGF and IL-6 As Markers of Severity and Response to Treatment in Waldenstrom Macroglobulinemia and IgM-Monoclonal Gammopathy of Undetermined Significance: A Monocentric Experience

Background: Angiogenesis plays an important role in the development and the maintenance of hematolymphoid malignancies. Serum levels of angiogenic cytokines, such as vascular endothelial growth factor (VEGF) and interleukin 6 (IL-6), are known to be increased in patients with Waldenstrom Macroglobulinemia (WM) and IgM monoclonal gammopathy of undetermined significance (MGUS). Even if the role of IL-6 and VEGF as markers of disease status and severity has been recognized, only a limited number of studies have addressed the role of cytokines in WM and there is no proof about any correlation between their serum levels in WM and IgM-MGUS patients. Nevertheless, their dosage at various stages of the disease aims to understand if they have a comparable pattern, and therefore they could be used in clinical practice for disease monitoring. Aims: This study aims to find a correlation of serum levels of VEGF and IL-6 with the burden of disease in our patients with IgM-MGUS and WM and to evaluate a possible relationship between the two angiogenic cytokines, in an attempt to identify potential markers of severity. Methods: We performed a retrospective monocentric study of 18 patients (ten with WM and eight with IgM-MGUS) with a median age of 73 years (range: 52-90), whose 66% were male. Patients with WM were at different stages of disease (four were naive, four in remission, two relapsed/refractory). A total of 18 controls with a similar age and gender distribution were also tested. Controls were selected among patients with neuropathies in the absence of any hematological condition. We used the 1:1 ratio for the selection of controls: for every male or female WM patient, one control of the same gender and of similar age was included. In order to find a relationship of VEGF and IL-6 with a laboratory parameter, IgM levels dosage for each patient have been measured at the same time-point of the measurement of the cytokines. In all patients and controls, we evaluated serum levels of VEGF and IL-6 using Immunoassay panels (i.e., anti-IL-6 and anti-VEGF ELISA kit). Results: All patients showed elevated values of angiogenic cytokines when compared with controls (P value < 0.05). Both VEGF and IL-6 serum levels (median values: 623,5 pg/mL and 4,5 pg/mL, respectively; ranges: 113,4-1981 pg/mL and 0,3-21,9 pg/mL, respectively) showed a positive correlation with IgM serum levels (median value: 2055 mg/dL, range: 300-6123 pg/mL) (Fig. 1a and 1b). Furthermore, the relationship between IL-6 and VEGF was statistically significant and could be explained by a linear model (P value = 0,007) (Fig. 1c). No statistically significant differences were observed between the different phases of WM. Conclusions: Evidence from our sample shows that serum levels of angiogenic cytokines as VEGF and IL-6 have a comparable pattern with IgM levels. Therefore, it seems reasonable to suggest that they could be used in clinical practice as markers of severity of disease and response to treatment. Moreover, since the cytokines profiles are comparable, IL-6 can be used interchangeably with VEGF, allowing the monitoring of the disease with easily availability and unexpensive techniques. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Neurocognition as a biomarker in the rare autonomic disorders of CCHS and ROHHAD.

Congenital central hypoventilation syndrome (CCHS) and rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) are rare disorders of autonomic regulation with risk for disrupted neurocognitive development. Our aim is to summarize research on neurocognitive outcomes in these conditions, advance understanding of how to best support these individuals throughout development, and facilitate future research. We conducted a narrative review of literature on neurocognitive outcomes in CCHS and ROHHAD, supplemented with previously unpublished data from patients with CCHS and ROHHAD at our Center for Autonomic Medicine in Pediatrics (CAMP). Individuals with CCHS and ROHHAD experience a wide range of neurocognitive functioning ranging from above average to below average, but are at particular risk for difficulties with working memory, processing speed, perceptual reasoning, and visuographic skills. An assessment framework emphasizing fluid cognition seems especially appropriate for these conditions. Owing to small cohorts and varied methods of data collection, it has been difficult to identify associations between disease factors (including CCHS PHOX2B genotypes) and cognitive outcomes. However, results suggest that early childhood is a period of particular vulnerability, perhaps due to the disruptive impact of recurrent intermittent hypoxic episodes on brain and cognitive development. Neurocognitive monitoring is recommended as a component of routine clinical care in CCHS and ROHHAD as a marker of disease status and to ensure that educational support and disability accommodations are provided as early as possible. Collaborative efforts will be essential to obtain samples needed to enhance our understanding of neurocognitive outcomes in CCHS and ROHHAD.

Disease severity and status in Stevens-Johnson syndrome and toxic epidermal necrolysis: Key knowledge gaps and research needs.

Stevens–Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are on a spectrum of cutaneous drug reactions characterized by pan-epidermal necrosis with SJS affecting < 10% of body surface area (BSA), TEN > 30%, and SJS/TEN overlap between 10 and 30%. Severity-of-illness score for toxic epidermal necrolysis (SCORTEN) is a validated tool to predict mortality rates based on age, heart rate, BSA, malignancy and serum urea, bicarbonate, and glucose. Despite improved understanding, SJS/TEN mortality remains constant and therapeutic interventions are not universally accepted for a number of reasons, including rarity of SJS/TEN; inconsistent definition of cases, disease severity, and endpoints in studies; low efficacy of interventions; and variations in treatment protocols. Apart from mortality, none of the other endpoints used to evaluate interventions, including duration of hospitalization, is sufficiently standardized to be reproducible across cases and treatment centers. Some of the gaps in SJS/TEN research can be narrowed through international collaboration to harmonize research endpoints. A case is made for an urgent international collaborative effort to develop consensus on definitions of endpoints such as disease status, progression, cessation, and complete re-epithelialization in interventional studies. The deficiencies of using BSA as the sole determinant of SJS/TEN severity, excluding internal organ involvement and extension of skin necrosis beyond the epidermis, are discussed and the role these factors play on time to healing and mortality beyond the acute stage is highlighted. The potential role of artificial intelligence, biomarkers, and PET/CT scan with radiolabeled glucose as markers of disease status, activity, and therapeutic response is also discussed.

Abstract OT1-05-01: Glycoprotein 88 (GP-88) serum levels as a marker of response to therapy in patients with metastatic breast cancer

Abstract The ability to detect metastatic breast cancer (MBC) &amp; readily monitor response to therapy is an important goal in the management of breast cancer (BC). Imaging is used for the assessment &amp; monitoring of disease progression. However, this is expensive &amp; represents a late marker of disease status. The disease may progress significantly on ineffective treatment &amp; the patient may have treatment related toxicities due to the lack of knowledge of the progression at earlier times. Circulating tumor associated biomarkers CA15-3 &amp; CEA can be used to track disease status of MBC, however, they are not always a reliable measure of disease progression. The monitoring of disease progression through measurement of drivers of disease may better reflect the disease status &amp; enable proactive management sooner. GP88 (granulin/epithelin precursor or progranulin) has been identified as a driver of tumorigenesis &amp; disease progression through its signaling as an autocrine growth &amp; survival factor for several cancers including BC1. We hypothesized that measurement of circulating serum GP88 levels can serve as a biomarker to monitor MBC disease status &amp; be prognostic to outcome 2. Clinical studies have demonstrated circulating levels of GP88 statistically differ in healthy volunteers, early BC patients (pts), &amp; pts with metastatic disease &amp; levels correlate with overall survival2,3. The primary aim of this prospective study is to identify whether there is a statistically significant change in serum GP88 levels associated with response to treatment &amp; time to progression of BC as measured by RECIST 1.1 criteria in MBC pts. Under an IRB approved protocol at the University of Maryland Greenbaum Comprehensive Cancer Center, a total of 103 female pts with measurable or evaluable metastatic disease who have been re-staged in within 4 weeks &amp; will continue or begin new therapy &amp; meet the additional criteria will be consented &amp; enrolled. Currently, we have enrolled 23 pts. In addition to standard of care laboratory assessment &amp; radiographic imaging/staging every 2-3 months, blood samples will be collected from each patient. The samples will be stored at -70C until tested for GP88 using a GP88 enzyme linked immunoassay. We will analyze the serial GP88 serum levels &amp; correlate with treatment response using RECIST 1.1 criteria (stable, progression, response), time to progression &amp; overall survival. We assume that pts will provide a baseline &amp; 4 follow up visits/GP-88 levels &amp; that 20% of the visits will record a disease progression &amp; time to progression. The probable &amp; clinically relevant GP-88 test performance will then have 75% sensitivity &amp; 46% false positivity with 85% power in a sample of 90 pts.

Prognostic Role of Serum Amino Acids in Head and Neck Cancer.

Introduction Serum amino acid (AA) profiles represent a valuable tool in the metabolic assessment of cancer patients; still, information on the AA pattern in head and neck cancer (HNC) patients is insufficient. The aim of the study was to assess whether serum AA levels were associated with the stage of neoplastic disease and prognosis in primary HNC patients. Methods Two hundred and two primary HNC patients were included in the study. Thirty-one AAs and derivatives were measured in serum through an ultraperformance liquid chromatography-mass spectrometry (UPLC-MS). The association between AA concentrations and the stage (advanced versus early) of HNC was estimated using a multivariable logistic regression model. A multivariable Cox regression model was used to evaluate the prognostic significance of each AA. Results At the multivariable logistic regression analysis, increased levels of alpha-aminobutyric acid, aminoadipic acid, histidine, proline, and tryptophan were associated with a reduced risk of advanced stage HNC, while high levels of beta-alanine, beta-aminobutyric acid, ethanolamine, glycine, isoleucine, 4-hydroxyproline, and phenylalanine were associated with an increased risk of advanced stage HNC. Furthermore, at multivariate analysis, increased levels of alpha-aminobutyric acid were associated with increased overall survival (OS), while high levels of arginine, ethanolamine, glycine, histidine, isoleucine, 4-hydroxyproline, leucine, lysine, 3-methylhistidine, phenylalanine, and serine were associated with decreased OS. Conclusions Our study suggests that AA levels are associated with the stage of disease and prognosis in patients with HNC. More study is necessary to evaluate if serum AA levels may be considered a hallmark of HNC and prove to be clinically useful markers of disease status and prognosis in HNC patients.

Salivary Fructosamine as a Noninvasive Glycemic Biomarker: A Systematic Review

Standard diagnostic and monitoring methods for glycemic status involve invasive sample collection through venous puncture or fingerstick. Recent attention has been focused on exploring noninvasive methods through oral biofluids. Specifically, serum fructosamine has been established as a short-term (2- to 3-wk) marker of disease status in patients with diabetes. Fructosamine measured through noninvasive means such as saliva has shown promise, but its clinical applicability is unknown. Evaluate the available evidence on using salivary fructosamine as a reliable noninvasive marker to screen and diagnose patients with diabetes mellitus in the clinical setting. A comparative analysis of the correlative accuracy of salivary fructosamine measurements with established blood glycemic biomarkers such as serum fructosamine, blood glucose, and HbA1c will be conducted. Six electronic databases (PubMed, PubMed Central, MEDLINE, EMBASE, Scopus, Cochrane Library) were searched for original research papers (clinical and animal studies) that were relevant to the objective of this systematic review. The search was initiated on May 28, 2020. The systematic review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Bias risk assessment, overall quality, and level of evidence were based on the Oxford Centre for Evidence-Based Medicine, Appraisal Tool for Cross-Sectional Studies, and Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies tool. Heterogeneity was assessed using the National Institutes of Health quality assessment tool for cross-sectional studies. A total of 174 records were identified. Full-text articles screened for eligibility (n = 21) identified only 6 original research articles relevant to the research question and were thus included in the systematic review. The types of studies identified were cross-sectional and in vivo studies. Three studies (3/6) showed positive correlation of salivary fructosamine with blood glucose levels, while 1 study (1/6) demonstrated a positive correlation with glycated hemoglobin (HbA1c). Limitations related to sample size and selection were identified along with a fair level of interstudy heterogeneity. Based on the evidence evaluated, the utility of salivary fructosamine as a noninvasive marker to screen and diagnose patients with diabetes is doubtful. The overall level of evidence was low (IIIB) and the risk of bias was determined to be high. Further evidence in the form of large-scale well-controlled studies is needed prior to recommending salivary fructosamine as a noninvasive diagnostic tool for glycemic status in patients with diabetes mellitus.

Genome-wide association study using truncated likelihood with incomplete information for stratum specific missingness

In many case–control genetic association studies, a secondary phenotype that may have common genetic factors with disease status can be identified. However, the secondary phenotype is observed only for case subjects but may be used as a surrogate marker for disease status. When information on the secondary phenotype is available only for a case group, due to cost and different data sources, fitting a linear regression model that ignores supplementary phenotype data may provide limited knowledge regarding the genetic associations. Herein, existing scientific information that the missing secondary phenotype values of control subjects lie in a certain range is incorporated, and a truncated joint likelihood function is established to estimate the effects of genotype and other covariates in the model. The performance of the proposed method is investigated through numerical studies and, for illustration, the procedure is applied to rheumatoid arthritis data provided by the Genetic Analysis Workshop 16.

Optimizing ethambutol dosing among HIV/tuberculosis co-infected patients: a population pharmacokinetic modelling and simulation study.

Reduced ethambutol serum concentrations are commonly observed among TB patients co-infected with HIV and may lead to treatment failure. To perform a population pharmacokinetic study of ethambutol in HIV/TB patients, and to evaluate an intensified ethambutol weight-based dosing strategy to support pharmacokinetic target attainment. We conducted a prospective study of ethambutol pharmacokinetics among HIV/TB patients administered first-line TB treatment in Botswana, with study visits before and after initiation of ART. Clinical and disease status markers, including HIV-associated systemic immune activation and gut dysfunction biomarkers, were evaluated as covariates of ethambutol pharmacokinetic parameters in non-linear mixed effects analysis. Monte Carlo simulations were performed to compare pharmacokinetic target attainment under standard and intensified weight-based ethambutol dosing strategies. We studied 40 HIV/TB patients prior to initiation of ART, of whom 24 returned for a second visit a median of 33 days following ART initiation. Ethambutol serum concentrations were best explained by a two-compartment model with first-order elimination, with a significant improvement in oral bioavailability following ART initiation. In Monte Carlo simulations, a supplementary ethambutol dose of 400 mg daily led to >2-fold improvements in pharmacokinetic target attainment probabilities in lung tissue, both before and after ART initiation. Low serum ethambutol concentrations were commonly observed among HIV/TB patients in Botswana, and the oral bioavailability of ethambutol increased following ART initiation. Supplementary ethambutol dosing among HIV/TB patients may provide a strategy to optimize anti-TB treatment regimens in this high-risk population.

MicroRNA Profiling Reveals Marker of Motor Neuron Disease in ALS Models.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder marked by the loss of motor neurons (MNs) in the brain and spinal cord, leading to fatally debilitating weakness. Because this disease predominantly affects MNs, we aimed to characterize the distinct expression profile of that cell type to elucidate underlying disease mechanisms and to identify novel targets that inform on MN health during ALS disease time course. microRNAs (miRNAs) are short, noncoding RNAs that can shape the expression profile of a cell and thus often exhibit cell-type-enriched expression. To determine MN-enriched miRNA expression, we used Cre recombinase-dependent miRNA tagging and affinity purification in mice. By defining the in vivo miRNA expression of MNs, all neurons, astrocytes, and microglia, we then focused on MN-enriched miRNAs via a comparative analysis and found that they may functionally distinguish MNs postnatally from other spinal neurons. Characterizing the levels of the MN-enriched miRNAs in CSF harvested from ALS models of MN disease demonstrated that one miRNA (miR-218) tracked with MN loss and was responsive to an ALS therapy in rodent models. Therefore, we have used cellular expression profiling tools to define the distinct miRNA expression of MNs, which is likely to enrich future studies of MN disease. This approach enabled the development of a novel, drug-responsive marker of MN disease in ALS rodents.SIGNIFICANCE STATEMENT Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease in which motor neurons (MNs) in the brain and spinal cord are selectively lost. To develop tools to aid in our understanding of the distinct expression profiles of MNs and, ultimately, to monitor MN disease progression, we identified small regulatory microRNAs (miRNAs) that were highly enriched or exclusive in MNs. The signal for one of these MN-enriched miRNAs is detectable in spinal tap biofluid from an ALS rat model, where its levels change as disease progresses, suggesting that it may be a clinically useful marker of disease status. Furthermore, rats treated with ALS therapy have restored expression of this MN RNA marker, making it an MN-specific and drug-responsive marker for ALS rodents.

Classification of Huntington's disease stage with support vector machines: A study on oculomotor performance.

Alterations in oculomotor performance are among the first observable physical alterations during presymptomatic stages of Huntington's disease (HD). Quantifiable measurements of oculomotor performance have been studied as possible markers of disease status and progression in presymptomaticand early symptomatic stages of HD, on the basis of traditional analysis methods. Whether oculomotor performance can be used to classify individuals according to HD disease stage has yet to be explored via the application of machine-learning methods. In the present study, we report the application of the support vector machine (SVM) algorithm to oculomotor features pooled from a four-task psychophysical experiment. We were able to automatically distinguish control participants from presymptomatic HD (pre-HD) participants with an accuracy of 73.47%, a sensitivity of 74.31%, and a specificity of 72.64%; to distinguish control participants from HD patients with an accuracy of 81.84%, a sensitivity of 76.19%, and a specificity of 87.48%; and to distinguish pre-HD participants from HD patients with an accuracy of 83.54%, a sensitivity of 92.62%, and a specificity of 74.45%. These results demonstrate that the application of supervised classification methods to oculomotor features is a valuable and promising approach to the automatic detection of disease stage in HD.

F02 Cognitive And Oculomotor Performance In Premanifest Huntington Disease: One-year Follow-up

Background Cognitive and oculomotor performance have been extensively studied in Huntington Disease (HD), but evidence for significant deficits in premanifest gene carriers is still controversial. Moreover, their role as markers of disease status and progression is not yet convincingly established. Aims This study aims to understand the evolution of neuropsychological and saccadic performance in premanifest HD (preHD) over a course of 3 years. The results of the baseline assessment and preliminary longitudinal data regarding the one-year follow-up visit of the preHD group are shown here. Methods 15 preHD participants and 22 controls completed the baseline assessment. 10 preHD participants have completed the second visit so far. A comprehensive neuropsychological test battery was used to evaluate the overall cognitive functioning of the participants. An experimental paradigm was designed to assess oculomotor function. Participants completed four different horizontal saccadic tasks with an increasing executive/memory load: prosaccade, antisaccade, 1-or-2 back memory prosaccade and antisaccade. Success rate (percentage of error free trials), latency, directional and timing errors were calculated. Results No significant differences were found between preHD and controls in any of the neuropsychological tests, suggesting a similar overt cognitive baseline at visit #1. The cognitive results of the preHD group at visits #1 and #2 showed that their performance improved in some of the tests used. Concerning saccadic parameters, the preHD group exhibited at baseline a significantly faster response time compared to controls, specifically in memory antisaccades. At visit #2, preHD participants showed a lower success rate and an increased latency, particularly in tasks involving inhibitory processes. Conclusions These data suggest that oculomotor performance of the preHD group may rely on more automatic responses when an executive/memory load is added to the task, deteriorates in time, and also that temporal saccade properties can mark the presence of early neurodegeneration in HD. Furthermore, despite an already evident decline in the saccadic performance of preHD individuals after one year, this is not paralleled by overt cognitive deficits as measured by conventional neuropsychological tests.

Advances in imaging of tuberculosis

To review the main applications, advantages and limitations of ¹⁸F-FDG PET and PET/computed tomography (CT), and some other tracers in imaging of tuberculosis (TB). In pulmonary TB, granulomas typically demonstrate increased ¹⁸F-FDG uptake, and areas of active TB can be differentiated from old or inactive disease by dual time point imaging. However, standardized uptake value measurements are high in both TB and malignant lesions, with significant overlap that limits their usefulness. In extrapulmonary TB, ¹⁸F-FDG PET detects more tuberculous lesions than CT, is of value in assessing response to tuberculostatic treatment, and helps in diagnosing spinal infection and identifying TB-related spondylitis; however, again, differentiation of malignant versus TB lymph node involvement is problematic. ¹⁸F-FDG PET can also be considered a marker of disease status in patients with HIV and TB co-infection. Overall, evaluation of treatment response is potentially the most important clinical application of ¹⁸F-FDG PET in TB, owing to its ability to distinguish active from inactive disease. ¹⁸F-FDG PET and PET/CT may assist early diagnosis and facilitate differentiation between malignancies and TB, identification of extrapulmonary TB, staging of TB, and assessment of treatment response.

Does Uncoupling Protein 2 Expression Qualify as Marker of Disease Status in LRRK2-Associated Parkinson's Disease?

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common known genetic cause of late-onset Parkinson's disease (PD). However, the penetrance of the disease is below 50% at 60 years of age. LRRK2 is associated with the mitochondrial membrane, and mutant forms impair the function of the organelle and autophagosome clearance in human cells, including induced pluripotent stem cell-derived neurons. Elevated expression of uncoupling proteins has been identified as the cause of mitochondrial depolarization in human fibroblasts with G2019S LRRK2. To identify factors that contribute to the penetrance of LRRK2 mutations, we studied respiratory chain function, markers of mitochondrial uncoupling, oxidative stress, and autophagy in fibroblasts from affected and unaffected carriers of the G2019S mutation. Independent of disease status, all mutation carriers showed reduced mitochondrial membrane potential, increased proton leakage, and more fragmented mitochondria. However, a significant increase in the expression of uncoupling protein 2 (UCP2) was only detected in affected individuals with the G2019S mutation in LRRK2. Since oxidative stress and autophagic markers were selectively increased in some of the PD patients, we hypothesize that UCP2 expression is upregulated in response to elevated reactive oxygen species generation in affected mutation carriers and that UCP2 mRNA levels might, therefore, serve as markers of disease status in LRRK2-associated PD.

Arginase Activity - A Marker of Disease Status in Patients with Visceral Leishmaniasis in Ethiopia

The underlying mechanisms resulting in the profound immune suppression characteristic of human visceral leishmaniasis (VL) are not fully understood.Here, we tested the hypothesis that arginase, an enzyme associated with immunosuppression, is higher in patients with VL and contributes to impaired T cell responses. We recruited patients with VL before and after treatment and healthy controls and measured the arginase metabolism in the blood of these individuals. Our results show that arginase activity is significantly higher in the blood of patients with active VL as compared to controls. These high levels of arginase decline considerably once the patients are successfully treated. We identified the phenotype of arginase-expressing cells among PBMCs as neutrophils and show that their frequency was increased in PBMCs of patients before treatment; this coincides with reduced levels of L-arginine in the plasma and decreased expression levels of CD3ζ in T cells.

Abstract OT2-3-07: A randomized, phase 2 study of the poly (ADP-ribose) polymerase (PARP) inhibitor veliparib (ABT-888) in combination with temozolomide (TMZ) or in combination with carboplatin (C) and paclitaxel (P) versus placebo plus C/P in subjects with BRCA1 or BRACA2 mutation and metastatic breast cancer

Abstract Background: Veliparib is a potent, oral PARP inhibitor that inhibits DNA repair, primarily through single strand break repair. BRCA1/2 mutated tumors are defective in homologous recombination, leading to more error prone mechanisms of DNA repair and increased sensitivity to PARP inhibition. Veliparib and TMZ recently demonstrated promising activity in BRCA1/2 mutation carriers, and veliparib and C/P is being evaluated in a CTEP Phase 1 study. This Phase 2 multinational study will evaluate veliparib in combination with TMZ and in combination with C/P compared to an active, placebo-controlled arm of C/P in subjects with BRCA1 or BRCA2 mutation and metastatic breast cancer. Methods: Approximately 240 subjects will be randomized in a 1:1:1 ratio to: 1) Veliparib 40 mg BID D1-7 + TMZ (150–200 mg/m2 QD D1-5) of every 28 day cycle; or 2) Veliparib 120 mg BID D1-7 + C (AUC 6, D3) and P (175 mg/m2, D3) of every 21 day cycle or 3) placebo BID D1-7 + C/P. Key eligibility includes known deleterious BRCA1/2 mutation, ≤1 prior chemotherapy for metastatic disease, and no prior platinum agent. Randomization will be stratified by hormone receptor positive versus negative, prior vs. no prior cytotoxic therapy, and ECOG 0–1 vs 2. The primary objective is progression-free survival (PFS) using RECIST 1.1. Secondary objectives include overall survival, objective response rate, duration of response and safety/tolerability. Optional paired tissue biopsies will be obtained at baseline and at progression to evaluate markers of response and resistance. Additional correlatives for response include assessment of peripheral blood, CTCs, and archived tissue for markers of disease status, gene methylation and mutational status, and tumor-specific alteration of cellular proteins/peptides and/or nucleic acids. Using the log-rank test for PFS, with 150 PFS events the study will have ≥ 80% power at 2-sided α level of 0.05 to detect a statistically significant treatment effect assuming a true hazard ratio of 0.58 favoring the 2 treatment groups containing veliparib. As of June 11, 2012, 5 subjects have been enrolled. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT2-3-07.

152 Are neurophysiological parameters an objective measure of disease status and progression in primary progressive multiple sclerosis?

BackgroundObjective monitoring of disability progression is critical for any trial of novel agents in the treatment of multiple sclerosis. Currently, Kurtzke's Expanded Disability Status Scale (EDSS) is the most widely...

Evaluation of inorganic ions and enzymes levels in saliva of patients with chronic periodontitis and healthy subjects

Chronic periodontitis is an inflammatory disease of tissues supporting the teeth. Inorganic ions and salivary enzymes have been most intensely studied as a potential marker for periodontal disease. This study aimed to detect sodium, potassium, magnesium and calcium ions level in saliva & also to assess the activity of creatin kinase (CK) and gamma glutamyle tranferase (GGT) enzymes in saliva of patients with chronic periodontitis and healthy subjects and correlate the mean salivary levels of these ions and enzymes with clinical periodontal parameters (PLI, GI, PPD and CAL). Materials and Methods: The study sample consists of (23) patients with chronic periodontitis and (12) healthy subjects of both gender with age ranged (35-45) years .Plaque index (PLI). Gingival index (GI), probing pocket depth (PPD) and clinical attachment level (CAL) are the periodontal parameters used in this study, un stimulated saliva sample were collected from all subjects and the levels of sodium, calcium, Magnesium, potassium, CK and GGT enzymes in each specimen were analyzed for each group .A statistical analysis was done to estimate the levels of these ions and enzymes in saliva and correlate the mean salivary inorganic and enzyme levels with the clinical periodontal parameters. Results: The present study showed that highly significant and significant differences in the levels of inorganic ions Na+ and Ca+2 respectively was found between chronic periodontitis and control group, while non significant differences in the level of Mg+2 and K+ ions were found between the study group and control group. Highly significant differences in the levels of salivary enzymes CK and GGT were found between the control group and chronic periodontitis group. This study showed a positive correlation between the activity CK enzyme and PLI, GI and CAL. Also there was a significant correlation found between Na+, Ca+2 and CAL. Concerning PPD, there was no correlation between those ions and enzymes with PPD in chronic periodontitis patients. Conclusion: estimation of those in organic ions and enzymes in saliva of chronic periodontitis may be used as potential diagnostic markers of disease status in periodontal tissues.

Using the Millon Behavioral Medicine Diagnostic (MBMD) to Evaluate the Need for Mental Health Services in Association with Biomarkers of Disease Status Among HIV Positive Men and Women

Psychological distress states have been related to rate of disease progression among HIV-positive individuals. However, the measures that have been used in this research as well as the treatment context of the populations studied are highly variable, making it challenging for clinicians to incorporate such measures into screening batteries. The present study examined the association of two summary scales of the Millon Behavioral Medicine Diagnostic (MBMD; Millon et al., Millon Behavioral Medicine Diagnostic. NCS Assessments, Minneapolis, 2001), with markers of HIV disease status (CD4 and CD8 cell counts, viral load) among an ethnically diverse sample of 147 HIV-positive individuals (52 men who have sex with men, 34 men who have sex with women, and 51 women) who had recently initiated Highly Active Antiretroviral Therapy (HAART). After controlling for age and months since HIV diagnosis, we found that higher scores on the overall MBMD Psych Referral Summary Scale, reflecting a need for mental health treatment, were related to greater HIV viral load but did not relate to CD4 or CD8 cell counts. Subgroup analyses revealed that Psych Referral scores were related to greater HIV viral load only for the men who have sex with men (MSM) subgroup. These results suggest that the MBMD may help in identifying psychosocial characteristics associated with some markers of disease status in persons with HIV and perhaps may also be useful in identifying individual differences in response to treatment and eventual disease outcome.

The mouth in HIV/AIDS: markers of disease status and management challenges for the dental profession

There are over 30 million people in the world with HIV infection and, whilst the rate of new infections is slowing, this number continues to grow. Although in Australia the overall prevalence of HIV infection in adults aged 15-49 is officially estimated at only 0.2%, representing less than 20,000 people living with HIV and AIDS, our geographical area contains populations with prevalences exceeding 10 times this. Oral health professionals must therefore practise safe, standard infection control at all times and be aware of the oral manifestations of HIV disease. These are predominantly opportunistic infections with fungi such as Candida albicans or with viruses of the herpes family, particularly herpes simplex, herpes zoster and Epstein-Barr virus infections. Warts or papillomas may arise due to human papilloma viruses--even in individuals on effective antiretroviral therapy. Rare types of fungal infection can occur, and severe bacterial infections, notably tuberculosis, are an ever-present risk. Susceptibility to periodontal breakdown is somewhat enhanced by the effects of HIV disease itself, and caries activity may increase because the patient neglects attention to diet and oral hygiene. Restorative and periodontal care need, therefore, to be maintained at a high level. Oral opportunistic infections cause much distress and the diagnosis and management of these is the responsibility of our profession.

Correlation of Met expression in TCC of the bladder with stage and grade.

e15110 Background: Bladder cancer has the highest cost per patient in the US compared to all other cancers, reflecting the complexity and prevalence of this disease. Current methods of bladder cancer detection and staging need improvement: cystoscopy misses small tumors and CIS; and cytology is at best 80% sensitive and 90-95% specific. Oncogenic signaling via Met, the tyrosine kinase receptor for hepatocyte growth factor (HGF), is associated with multiple neoplastic processes, including bladder cancer. The goal of this study was to investigate whether Met expression could differentiate grade and stage in well-established models of bladder TCC. Methods: Commercially available cell-lines derived from bladder TCC were grown: RT4: papillary, low grade (LG), HT1376: pT2, high grade (HG), T24: pT3, HG, TCC-SUP pT4, HG, +metastasis. Cells were serum-deprived for 24-hours prior to performing a sensitive and quantitative electrochemiluminescence immunoassay. Additionally, soluble-Met levels were assessed in patients with and without known Bladder TCC. Statistical analysis (t-test, unpaired, double-tail test) was performed in GraphPad. Results: Met expression levels correlated directly with pathologic stage (Ta vs T2/T3 vs T4, p=0.0002 and p=0.0297) and grade (low grade vs. high grade, p=0.0001) in TCC of the bladder. HGF levels and steady-state Met activation levels were undetectable in all cell-lines tested, ruling out the possibility of an autocrine loop. Met phosphorylation was readily detectable upon stimulation with exogenous HGF. In urine samples, Met levels differentiated between patients with and without bladder TCC and between different grades and stages. Conclusions: A sensitive, quantitative, high throughput method was used to determine Met protein levels in cultured cell models of bladder TCC as well as soluble-Met in urine samples. Met expression correlated directly with pathologic stage and grade, suggesting that Met expression may serve as a marker of disease status and progression in TCC of the bladder and potentially as a molecular target for pharmacological intervention. No significant financial relationships to disclose.