Biological markers and prognosis in recurrent oral cancer after salvage surgery

Objective: To analyze the prognostic effect of epidermal growth factor receptor (EGFR), matrix metalloproteinases 2 and 9, and vascular endothelial growth factor expression in patients with locally recurrent oral carcinoma after salvage surgery. Design: Retrospective cohort study. Settings: Tertiary center cancer hospital. Patients: The charts of 111 patients with local recurrence of oral carcinomas were retrospectively analyzed. The previous treatment consisted of surgery in 33 patients (30.0%), radiotherapy with or without chemotherapy in 46 patients (41.0%), and surgery with adjuvant radiotherapy in 32 patients (29.0%). The expression of EGFR, matrix metalloproteinases 2 and 9, and vascular endothelial growth factor was analyzed with a tissue microarray immunohistochemical technique. Main Outcome Measures: Overall survival and cancer-specific survival (CSS). Results: The recurrences were diagnosed in less than 1 year in 69 patients (62.2%) and in more than 1 year in 42 patients (37.8%). The prognosis was worse in the group with the disease-free interval of less than 1 year (P=.01). Patients with more advanced disease (clinical stage of recurrence, III/IV) had worse rates of CSS (P=.04). Cases that were positive for EGFR had a 3-year CSS of 27.2%, while EGFR-negative cases had a 3-year CSS of 64.3% (P=.001). The expression of matrix metalloproteinases 2 (P=.83) and 9 (P=.15) and vascular endothelial growth factor (P=.86) was not significant in this group. In multivariate analysis, only the disease-free interval and the overexpression of EGFR were associated with a higher risk of cancer death. Conclusions: Local recurrence in oral carcinomas carries a poor prognosis. A disease-free interval of more than 1 year and a EGFR-negative expression are the main prognostic factors related to better CSS in patients treated with salvage surgery.

Biological markers in noninvasive brain stimulation trials in major depressive disorder: a systematic review

Objectives: The therapeutic effects of transcranial magnetic stimulation (TMS) and transcranial direct current stimulation in patients with major depression have shown promising results; however, there is a lack of mechanistic studies using biological markers (BMs) as an outcome. Therefore, our aim was to review noninvasive brain stimulation trials in depression using BMs. Methods: The following databases were used for our systematic review: MEDLINE, Web of Science, Cochrane, and SCIELO. We examined articles published before November 2012 that used TMS and transcranial direct current stimulation as an intervention for depression and had BM as an outcome measure. The search was limited to human studies written in English. Results: Of 1234 potential articles, 52 articles were included. Only studies using TMS were found. Biological markers included immune and endocrine serum markers, neuroimaging techniques, and electrophysiological outcomes. In 12 articles (21.4%), end point BM measurements were not significantly associated with clinical outcomes. All studies reached significant results in the main clinical rating scales. Biological marker outcomes were used as predictors of response, to understand mechanisms of TMS, and as a surrogate of safety. Conclusions: Functional magnetic resonance imaging, single-photon emission computed tomography, positron emission tomography, magnetic resonance spectroscopy, cortical excitability, and brain-derived neurotrophic factor consistently showed positive results. Brain-derived neurotrophic factor was the best predictor of patients’ likeliness to respond. These initial results are promising; however, all studies investigating BMs are small, used heterogeneous samples, and did not take into account confounders such as age, sex, or family history. Based on our findings, we recommend further studies to validate BMs in noninvasive brain stimulation trials in MDD.

Ultrasound versus biological markers in the evaluation of periportal fibrosis in human Schistosoma mansoni

In this paper, the authors review the literature and share their experience of the principal biological markers of fibrosis for the evaluation of periportal fibrosis (PPF) caused by mansoni schistosomiasis. These biological markers are compared to diagnostic ultrasound (US) scans as means of grading PPF. We also review procollagen type I and III, collagen type IV, laminin, hyaluronic acid (HA), immunoglobulin G, platelets, aspartate aminotransferase to platelet ratio index (APRI) and gamma-glutamyl transpeptidase as markers of the disease. Although there are several good markers for evaluating PPF and portal hypertension, such as HA, platelets or APRI, none can yet replace US. These markers may, however, be used to identify patients at greater risk of developing advanced disease in endemic areas and determine who will need further care and US studies.

Biological markers of alcohol consumption in alcoholised drivers: Comparison of capillary electrophoresis (CZE CDT) and a direct immunoassay (N Latex CDT) with the traditional method of anion-exchange chromatography-immunoturbidimetry (%CDT TIA).

Objectives: The aim of this study was to compare specificity and sensitivity of different biological markers that can be used in a forensic field to identify potentially dangerous drivers because of their alcohol habits. Methods: We studied 280 Swiss drivers after driving while under the alcohol influence. 33 were excluded for not having CDT N results, 247 were included (218 men (88%) and 29 women (12%). Mean age was 42,4 (SD:12, min: 20 max: 76). The evaluation of the alcohol consumption concerned the month before the CDT test and was considered as such after the interview: Heavy drinkers (>3 drinks per day): 60 (32.7%), < 3 drinks per day and moderate: 127 (51.4%) 114 (46.5%), abstinent: 60 (24.3%) 51 (21%). Alcohol intake was monitored by structured interviews, self-reported drinking habits and the C-Audit questionnaire as well as information provided by their family and general practitioner. Consumption was quantified in terms of standard drinks, which contain approximately 10 grams of pure alcohol (Ref. WHO). Results: comparison between moderate (less or equal to 3 drinks per day) and excessive drinkers (more than 3 drinks) Marker ROC area 95% CI cut-off sensitivity specificity CDT TIA 0.852 0.786-0917 2.6* 0.93 LR+1.43 0.35 LR-0.192 CDT N latex 0.875 0.821-0.930 2.5* 0.66 LR+ 6.93 0.90 LR- 0.369 Asialo+disialo-tf 0.881 0.826-0.936 1.2* 0.78 LR+4.07 0.80 LR-0.268 1.7° 0.66 LR+8.9 0.93 LR-0.360 GGT 0.659 0.580-0.737 85* 0.37 LR+2.14 0.83 LR-0.764 * cut-off point suggested by the manufacturer ° cut-off point suggested by our laboratory Conclusion: With the cut-off point established by the manufacturer, CDT TIA performed poorly in term of specificity. N latex CDT and CZE CDT were better, especially if a 1.7 cut-off is used with CZE

Marqueurs biologiques des statuts vitaminiques B12 et D: aspects analytiques d'importance clinique [Biological markers for the status of vitamins B12 and D: the importance of some analytical aspects in relation to clinical interpretation of results].

Biological markers for the status of vitamins B12 and D: the importance of some analytical aspects in relation to clinical interpretation of results When vitamin B12 deficiency is expressed clinically, the diagnostic performance of total cobalamin is identical to that of holotranscobalamin II. In subclinical B12 deficiency, the two aforementioned markers perform less well. Additional analysis of a second, functional marker (methylmalonate or homocysteine) is recommended. Different analytical approaches for 25-hydroxyvitamin D quantification, the marker of vitamin D deficiency, are not yet standardized. Measurement biases of up to +/- 20% compared with the original method used to establish threshold values are still observed.

Monitoring of biological markers indicative of doping: the athlete biological passport

The athlete biological passport (ABP) was recently implemented in anti-doping work and is based on the individual and longitudinal monitoring of haematological or urine markers. These may be influenced by illicit procedures performed by some athletes with the intent to improve exercise performance. Hence the ABP is a valuable tool in the fight against doping. Actually, the passport has been defined as an individual and longitudinal observation of markers. These markers need to belong to the biological cascade influenced by the application of forbidden hormones or more generally, affected by biological manipulations which can improve the performance of the athlete. So far, the haematological and steroid profile modules of the ABP have been implemented in major sport organisations, and a further module is under development. The individual and longitudinal monitoring of some blood and urine markers are of interest, because the intraindividual variability is lower than the corresponding interindividual variability. Among the key prerequisites for the implementation of the ABP is its prospect to resist to the legal and scientific challenges. The ABP should be implemented in the most transparent way and with the necessary independence between planning, interpretation and result management of the passport. To ensure this, the Athlete Passport Management Unit (APMU) was developed and the WADA implemented different technical documents associated to the passport. This was carried out to ensure the correct implementation of a profile which can also stand the challenge of any scientific or legal criticism. This goal can be reached only by following strictly important steps in the chain of production of the results and in the management of the interpretation of the passport. Various technical documents have been then associated to the guidelines which correspond to the requirements for passport operation. The ABP has been completed very recently by the steroid profile module. As for the haematological module, individual and longitudinal monitoring have been applied and the interpretation cascade is also managed by a specific APMU in a similar way as applied in the haematological module. Thus, after exclusion of any possible pathology, specific variation from the individual norms will be then considered as a potential misuse of hormones or other modulators to enhance performance.

ECIL recommendations for the use of biological markers for the diagnosis of invasive fungal diseases in leukemic patients and hematopoietic SCT recipients.

As culture-based methods for the diagnosis of invasive fungal diseases (IFD) in leukemia and hematopoietic SCT patients have limited performance, non-culture methods are increasingly being used. The third European Conference on Infections in Leukemia (ECIL-3) meeting aimed at establishing evidence-based recommendations for the use of biological tests in adult patients, based on the grading system of the Infectious Diseases Society of America. The following biomarkers were investigated as screening tests: galactomannan (GM) for invasive aspergillosis (IA); β-glucan (BG) for invasive candidiasis (IC) and IA; Cryptococcus Ag for cryptococcosis; mannan (Mn) Ag/anti-mannan (A-Mn) Ab for IC, and PCR for IA. Testing for GM, Cryptococcus Ag and BG are included in the revised EORTC/MSG (European Organization for Research and Treatment of Cancer/Mycoses Study Group) consensus definitions for IFD. Strong evidence supports the use of GM in serum (A II), and Cryptococcus Ag in serum and cerebrospinal fluid (CSF) (A II). Evidence is moderate for BG detection in serum (B II), and the combined Mn/A-Mn testing in serum for hepatosplenic candidiasis (B III) and candidemia (C II). No recommendations were formulated for the use of PCR owing to a lack of standardization and clinical validation. Clinical utility of these markers for the early management of IFD should be further assessed in prospective randomized interventional studies.

Autolytic Mycobacterium leprae Hsp65 fragments may act as biological markers for autoimmune diseases

Investigating the proteolytic activity of the recombinant Mycobacterium leprae Heat Shock Protein of 65 kDa (rHsp65), chaperonin 2 (cpn2), we observed that it displays high instability. The fragmentation process starts at the C-terminus followed by progressive degradation of the N-terminus, which leads to a stable fragment comprising the middle region of the molecule. Urea was able to prevent autolysis, probably due to its denaturing action, while EDTA increased degradation levels indicating the need for metal ions. Peptides originated from autolysis were purified and analyzed by mass spectrometry, generating a continuous map. Since the bacteria and mammalian Hsp60 are known to be targets of the immune response and have been implicated in autoimmune diseases and chronic inflammation, the in vivo effect of rHsp65 peptides was evaluated in the spontaneous Systemic Lupus Erythematosus (SLE) model developed by the (NZB/NZW)F(1) mouse hybrids, and their individual anti-rHsp65 IgG2a/IgG1 antibody titer ratio was determined. The results showed orientation toward a T(H)1 responsiveness, and the treatment with the rHsp65 peptides diminished the environmental variance of the survival time of treated animals. These results outline the fact that environmental factors may also act through the modified stability expression of Heat Shock Proteins intervening during autoimmune processes. (C) 2011 Elsevier Ltd. All rights reserved.

Historical and recent biological markers of exposure to fluoride

Recent and historical biomarkers assess chronic or subchronic exposure to fluoride. The most studied recent biomarkers are nails and hair. Both can be non-invasively obtained, although collection of nails is more accepted by the subjects. External contamination may be a problem for both biomarkers and still needs to be better evaluated. Nails have been more extensively studied. Although the available knowledge does not allow their use as predictors of dental fluorosis by individual subjects, since reference values of fluoride have not yet been established, they have a strong potential for use in epidemiological surveys. Toenails should be preferred instead of fingernails, and variables that are known to affect nail fluoride concentrations - such as age, gender and geographical area - should be considered. The main historical biomarkers that could indicate total fluoride body burden are bone and dentin. Of these, bone is more studied, but its fluoride concentrations vary according to the type of bone and subjects' age and gender. They are also influenced by genetic background, renal function and remodeling rate, variables that complicate the establishment of a normal range of fluoride levels in bone that could indicate 'desirable' exposure to fluoride. The main issue when attempting to use bone as biomarker of fluoride exposure is the difficulty and invasiveness of sample collection. In this aspect, collection of dentin, especially from 3rd molars that are commonly extracted, is advantageous. However, mean values also span a wide range and reference concentrations have not been published yet. © 2011 S. Karger AG, Basel.

Mild cognitive impairment (part 2): Biological markers for diagnosis and prediction of dementia in Alzheimer's disease

To present a critical review of publications reporting on the rationale and clinical implications of the use of biomarkers for the early diagnosis of Alzheimer's disease (AD). Methods: We conducted a systematic search of the PubMed and Web of Science electronic databases, limited to articles published in English between 1999 and 2012, and based on the following terms: mild cognitive impairment, Alzheimer's disease OR dementia, biomarkers. We retrieved 1,130 articles, of which 175 were reviews. Overall, 955 original articles were eligible. Results: The following points were considered relevant for the present review: a) rationale for biomarkers research in AD and mild cognitive impairment (MCI); b) usefulness of distinct biomarkers for the diagnosis and prediction of AD; c) the role of multimodality biomarkers for the diagnosis and prediction of AD; d) the role of biomarkers in clinical trials of patients with AD and MCI; and e) current limitations to the widespread use of biomarkers in research and clinical settings. Conclusion: Different biomarkers are useful for the early diagnosis and prediction of AD in at-risk subjects. Nonetheless, important methodological limitations need to be overcome for widespread use of biomarkers in research and clinical settings. © 2013 Associação Brasileira de Psiquiatria.

The canonical correlation between the biological markers of performance and physical fitness in high level judo athletes

The objective of this research was to verify the relationship between biological markers of performance of elite judo athletes and performance in different physical fitness tests. Twenty-one judo athletes were involved in the present observational and correlational study. Dermatoglyphic variables and the 2D:4D digit ratio were considered as biological markers, while the physical fitness variables analyzed were body fat, maximal strength, muscular power, the aerobic and anaerobic profile, and performance in specific tests. The statistics involved canonical correlations and a multivariate technique. A high and significant canonical correlation was observed between groups of variables, the first expressed by 1=0.999 (p<0.0001) and the second by 2=0.997 (p<0.001). It appears that, beyond height and body mass, total ridge count, pattern intensity for fingers and 2D:4D had more canonical loading. The physical fitness component of the first canonical variable incorporated, with high intensity were: the sum of skinfold thickness, the bench press onerepetition maximum (1RM), upper and lower body aerobic power. In the second canonical variable, physical fitness was composed of the squat 1RM, suspension time on the bar, the SJFT-index, and mean power during the upper body Wingate test. The data of this investigation showed the interdependence between biological markers of performance and physical fitness in high level judo athletes.

Bloodstream infections in pediatric ECLS: usefulness of daily blood culture monitoring and predictive value of biological markers. The British Columbia experience

INTRODUCTION: The incidence of bloodstream infection (BSI) in extracorporeal life support (ECLS) is reported between 0.9 and 19.5%. In January 2006, the Extracorporeal Life Support Organization (ELSO) reported an overall incidence of 8.78% distributed as follows: respiratory: 6.5% (neonatal), 20.8% (pediatric); cardiac: 8.2% (neonatal) and 12.6% (pediatric). METHOD: At BC Children's Hospital (BCCH) daily surveillance blood cultures (BC) are performed and antibiotic prophylaxis is not routinely recommended. Positive BC (BC+) were reviewed, including resistance profiles, collection time of BC+, time to positivity and mortality. White blood cell count, absolute neutrophile count, immature/total ratio, platelet count, fibrinogen and lactate were analyzed 48, 24 and 0 h prior to BSI. A univariate linear regression analysis was performed. RESULTS: From 1999 to 2005, 89 patients underwent ECLS. After exclusion, 84 patients were reviewed. The attack rate was 22.6% (19 BSI) and 13.1% after exclusion of coagulase-negative staphylococci (n = 8). BSI patients were significantly longer on ECLS (157 h) compared to the no-BSI group (127 h, 95% CI: 106-148). Six BSI patients died on ECLS (35%; 4 congenital diaphragmatic hernias, 1 hypoplastic left heart syndrome and 1 after a tetralogy repair). BCCH survival on ECLS was 71 and 58% at discharge, which is comparable to previous reports. No patient died primarily because of BSI. No BSI predictor was identified, although lactate may show a decreasing trend before BSI (P = 0.102). CONCLUSION: Compared with ELSO, the studied BSI incidence was higher with a comparable mortality. We speculate that our BSI rate is explained by underreporting of "contaminants" in the literature, the use of broad-spectrum antibiotic prophylaxis and a higher yield with daily monitoring BC. We support daily surveillance blood cultures as an alternative to antibiotic prophylaxis in the management of patients on ECLS.

Direct metabolites of Ethanol as biological markers of alcohol use: Basic aspects and applications

In addition to self reports and questionnaires, biomarkers are of relevance in the diagnosis of and therapy for alcohol use disorders. Traditional biomarkers such as gamma-glutamyl transpeptidase or mean corpuscular volume are indirect biomarkers and are subject to the influence of age, gender and non-alcohol related diseases, among others. Direct metabolites of ethanol such as Ethyl glucuronide (EtG), ethyl sulphate (EtS) and phosphatidylethanol (PEth) are direct metabolites of ethanol, that are positive after intake of ethyl alcohol. They represent useful diagnostic tools for identifying alcohol use even more accurately than traditional biomarkers. Each of these drinking indicators remains positive in serum and urine for a characteristic time spectrum after the cessation of ethanol intake - EtG and EtS in urine up to 7 days, EtG in hair for months after ethanol has left the body. Applications include clinical routine use, emergency room settings, proof of abstinence in alcohol rehabilitation programmes, driving under influence offenders, workplace testing, assessment of alcohol intake in the context of liver transplantation and foetal alcohol syndrome. Due to their properties, they open up new perspectives for prevention, interdisciplinary cooperation, diagnosis of and therapy for alcohol-related problems.