Novel biomarkers in early diagnosis of acute myocardial infarction compared with cardiac troponin T

Aims: To evaluate the role of novel biomarkers in early detection of acute myocardial infarction (MI) in patients admitted with acute chest pain.
Methods and results: A prospective study of 664 patients presenting to two coronary care units with chest pain was conducted over 3 years from 2003. Patients were assessed on admission: clinical characteristics, ECG (electrocardiogram), renal function, cardiac troponin T (cTnT), heart fatty acid binding protein (H-FABP), glycogen phosphorylase-BB, NT-pro-brain natriuretic peptide, D-dimer, hsCRP (high sensitivity C-reactive protein), myeloperoxidase, matrix metalloproteinase-9, pregnancy associated plasma protein-A, soluble CD40 ligand. A =12 h cTnT sample was also obtained. MI was defined as cTnT = 0.03 µg/L. In patients presenting <4 h of symptom onset, sensitivity of H-FABP for MI was significantly higher than admission cTnT (73 vs. 55%; P = 0.043). Specificity of H-FABP was 71%. None of the other biomarkers challenged cTnT. Combined use of H-FABP and cTnT (either one elevated initially) significantly improved the sensitivities of H-FABP or cTnT (85%; P = 0.004). This combined approach also improved the negative predictive value, negative likelihood ratio, and the risk ratio.
Conclusion: Assessment of H-FABP within the first 4 h of symptoms is superior to cTnT for detection of MI, and is a useful additional biomarker for patients with acute chest pain.

Pre-hospital body surface potential mapping improves early diagnosis of acute coronary artery occlusion in patients with ventricular fibrillation and cardiac arrest

Aims: To determine whether 80-lead body surface potential mapping (BSPM) improves detection of acute coronary artery occlusion in patients presenting with out-of-hospital cardiac arrest (OHCA) due to ventricular fibrillation (VF) and who survived to reach hospital. Methods and results: Of 645 consecutive patients with OHCA who were attended by the mobile coronary care unit, VF was the initial rhythm in 168 patients. Eighty patients survived initial resuscitation, 59 of these having had BSPM and 12-lead ECG post-return of spontaneous circulation (ROSC) and in 35 patients (age 69±13 yrs; 60% male) coronary angiography performed within 24. h post-ROSC. Of these, 26 (74%) patients had an acutely occluded coronary artery (TIMI flow grade [TFG] 0/1) at angiography. Twelve-lead ECG criteria showed ST-segment elevation (STE) myocardial infarction (STEMI) using Minnesota 9-2 criteria - sensitivity 19%, specificity 100%; ST-segment depression (STD) =0.05. mV in =2 contiguous leads - sensitivity 23%, specificity 89%; and, combination of STEMI or STD criteria - sensitivity 46%, specificity 100%. BSPM STE occurred in 23 (66%) patients. For the diagnosis of TFG 0/1 in a main coronary artery, BSPM STE had sensitivity 88% and specificity 100% (c-statistic 0.94), with STE occurring most commonly in either the posterior, right ventricular or high right anterior territories. Conclusion: Among OHCA patients presenting with VF and who survived resuscitation to reach hospital, post-resuscitation BSPM STE identifies acute coronary occlusion with sensitivity 88% and specificity 100% (c-statistic 0.94). © 2012 Elsevier Ireland Ltd.

Early diagnosis improves survival in kidney cancer

Kidney cancers account for 2-3% of all adult malignancies in the UK. Men are predominantly affected by renal cancer with an average age at diagnosis of 64 years. Renal (or clear) cell carcinoma (RCC) accounts for 90% of kidney cancers. Early diagnosis improves survival with five-year survival rates for renal cancer of 70-94% for localised tumours in the UK. RCC should be suspected in the presence of localising symptoms such as flank pain, a loin mass or haematuria; constitutional upset including weight loss, pyrexia and/or night sweats; or with unexplained laboratory tests. Smoking, obesity and hypertension are the most important and most common risk factors. Environmental exposure to asbestos, cadmium and trichloroethylene are less common risk factors. Patients on chronic dialysis and renal transplant recipients are at increased risk of RCC in their native kidneys. If kidney cancer is suspected on history, physical examination or initial screening tests then a red flag ultrasound examination of the renal tracts should be requested. Dipstick urinalysis is of great value as asymptomatic haematuria may be the only abnormal test in the presence of non-specific symptoms such as weight loss or loin pain. Visible or non-visible haematuria, in the absence of proteinuria, suggests an underlying structural abnormality is present in the kidneys, ureters or bladder. Surgical removal of RCCs, where feasible, may result in cure in up to 40-60% of cases. Individuals too frail for major surgery may benefit from thermal ablation and cryotherapy. Agents that target the VEGF and mTOR pathways are considered first line in the treatment of metastatic RCC. Sunitinib, recommended by NICE, is administered orally and acts by inhibiting the VEGF receptor.

Investigation of the Human Brain Metabolome to Identify Potential Markers for Early Diagnosis and Therapeutic Targets of Alzheimer’s Disease

A study combining high resolution mass spectrometry (liquid chromatography-quadrupole time-of-flight-mass spectrometry, UPLC-QTof-MS) and chemometrics for the analysis of post-mortem brain tissue from subjects with Alzheimer’s disease (AD) (n = 15) and healthy age-matched controls (n = 15) was undertaken. The huge potential of this metabolomics approach for distinguishing AD cases is underlined by the correct prediction of disease status in 94–97% of cases. Predictive power was confirmed in a blind test set of 60 samples, reaching 100% diagnostic accuracy. The approach also indicated compounds significantly altered in concentration following the onset of human AD. Using orthogonal partial least-squares discriminant analysis (OPLS-DA), a multivariate model was created for both modes of acquisition explaining the maximum amount of variation between sample groups (Positive Mode-R2 = 97%; Q2 = 93%; root mean squared error of validation (RMSEV) = 13%; Negative Mode-R2 = 99%; Q2 = 92%; RMSEV = 15%). In brain extracts, 1264 and 1457 ions of interest were detected for the different modes of acquisition (positive and negative, respectively). Incorporation of gender into the model increased predictive accuracy and decreased RMSEV values. High resolution UPLC-QTof-MS has not previously been employed to biochemically profile post-mortem brain tissue, and the novel methods described and validated herein prove its potential for making new discoveries related to the etiology, pathophysiology, and treatment of degenerative brain disorders.

Prognoses and improvement for head and neck cancers diagnosed in Europe in early 2000s: The EUROCARE-5 a population-based study.

BACKGROUND: Head and neck (H&N) cancers are a heterogeneous group of malignancies, affecting various sites, with different prognoses. The aims of this study are to analyse survival for patients with H&N cancers in relation to tumour location, to assess the change in survival between European countries, and to investigate whether survival improved over time.
METHODS: We analysed about 250,000 H&N cancer cases from 86 cancer registries (CRs). Relative survival (RS) was estimated by sex, age, country and stage. We described survival time trends over 1999-2007, using the period approach. Model based survival estimates of relative excess risks (RERs) of death were also provided by country, after adjusting for sex, age and sub-site.
RESULTS: Five-year RS was the poorest for hypopharynx (25%) and the highest for larynx (59%). Outcome was significantly better in female than in male patients. In Europe, age-standardised 5-year survival remained stable from 1999-2001 to 2005-2007 for laryngeal cancer, while it increased for all the other H&N cancers. Five-year age-standardised RS was low in Eastern countries, 47% for larynx and 28% for all the other H&N cancers combined, and high in Ireland and the United Kingdom (UK), and Northern Europe (62% and 46%). Adjustment for sub-site narrowed the difference between countries. Fifty-four percent of patients was diagnosed at advanced stage (regional or metastatic). Five-year RS for localised cases ranged between 42% (hypopharynx) and 74% (larynx).
CONCLUSIONS: This study shows survival progresses during the study period. However, slightly more than half of patients were diagnosed with regional or metastatic disease at diagnosis. Early diagnosis and timely start of treatment are crucial to reduce the European gap to further improve H&N cancers outcome.

Circulating miRNAs: Potential Novel Biomarkers for Hepatopathology Progression and Diagnosis of Schistosomiasis Japonica in Two Murine Models

BACKGROUND: Schistosomiasis remains a major public health issue, with an estimated 230 million people infected worldwide. Novel tools for early diagnosis and surveillance of schistosomiasis are currently needed. Elevated levels of circulating microRNAs (miRNAs) are commonly associated with the initiation and progression of human disease pathology. Hence, serum miRNAs are emerging as promising biomarkers for the diagnosis of a variety of human diseases. This study investigated circulating host miRNAs commonly associated with liver diseases and schistosome parasite-derived miRNAs during the progression of hepatic schistosomiasis japonica in two murine models.

METHODOLOGY/PRINCIPAL FINDINGS: Two mouse strains (C57BL/6 and BALB/c) were infected with a low dosage of Schistosoma japonicum cercariae. The dynamic patterns of hepatopathology, the serum levels of liver injury-related enzymes and the serum circulating miRNAs (both host and parasite-derived) levels were then assessed in the progression of schistosomiasis japonica. For the first time, an inverse correlation between the severity of hepatocyte necrosis and the level of liver fibrosis was revealed during S. japonicum infection in BALB/c, but not in C57BL/6 mice. The inconsistent levels of the host circulating miRNAs, miR-122, miR-21 and miR-34a in serum were confirmed in the two murine models during infection, which limits their potential value as individual diagnostic biomarkers for schistosomiasis. However, their serum levels in combination may serve as a novel biomarker to mirror the hepatic immune responses induced in the mammalian host during schistosome infection and the degree of hepatopathology. Further, two circulating parasite-specific miRNAs, sja-miR-277 and sja-miR-3479-3p, were shown to have potential as diagnostic markers for schistosomiasis japonica.

CONCLUSIONS/SIGNIFICANCE: We provide the first evidence for the potential of utilizing circulating host miRNAs to indicate different immune responses and the severity of hepatopathology outcomes induced in two murine strains infected with S. japonicum. This study also establishes a basis for the early and cell-free diagnosis of schistosomiasis by targeting circulating schistosome parasite-derived miRNAs.

Contingent screening for down syndrome is an efficient alternative to non-disclosure sequential screening

Objective To present a first and second trimester Down syndrome screening strategy, whereby second-trimester marker determination is contingent on the first-trimester results. Unlike non-disclosure sequential screening (the Integrated test), which requires all women to have markers in both trimesters, this allows a large proportion of the women to complete screening in the first trimester. Methods Two first-trimester risk cut-offs defined three types of results: positive and referred for early diagnosis; negative with screening complete; and intermediate, needing second-trimester markers. Multivariate Gaussian modelling with Monte Carlo simulation was used to estimate the false-positive rate for a fixed 85% detection rate. The false-positive rate was evaluated for various early detection rates and early test completion rates. Model parameters were taken from the SURUSS trial. Results Completion of screening in the first trimester for 75% of women resulted in a 30% early detection rate and a 55% second trimester detected rate (net 85%) with a false-positive rate only 0.1% above that achievable by the Integrated test. The screen-positive rate was 0.1% in the first trimester and 4.7% for those continuing to be tested in the second trimester. If the early detection rate were to be increased to 45% or the early completion rate were to be increased to 80%, there would be a further 0.1% increase in the false-positive rate. Conclusion Contingent screening can achieve results comparable with the Integrated test but with earlier completion of screening for most women. Both strategies need to be evaluated in large-scale prospective studies particularly in relation to psychological impact and practicability.

Mutational hotspot in Exon 20 of PIK3CA in breast cancer among Singapore Chinese

The recent identification of somatic mutations in the catalytic region of PIK3 (PIK3CA) in breast cancer and demonstration of their oncogenic function has implicated PIK3CA in mammary carcinogenesis. To investigate possible ethnic differences in patterns of PIK3CA mutations in Singaporean Chinese breast cancer and to characterize these in a panel of cell lines, we sequenced exons 9 and 20 in 80 primary tumors, 19 breast cancer cell lines and 7 normal human mammary epithelial cells (HMECs). Searching for novel hotspots of mutation, we sequenced additional exons ( 1, 2, 6, 7, 14 and 18) in 20 primary tumors and 6 breast cancer cell lines. We detected 33 point mutations in 31 of 80 (39%) breast cancers, and 11 mutations in 10 of 19 (53%) breast cancer cell lines. No mutations were detected in normal breast tissue adjacent to the tumor, or in the 6 normal HMECs. The exon 20 A3140G (H1047R) substitution was identified most frequently (22/31, 71%) and showed a significant association with patient age ( p = 0.043) and stage of the disease ( p = 0.025), but not with ER/PR status or histological grade of the tumor. The incidence of point mutations in PIK3CA, the A3140G substitution in particular, in Singapore breast cancers are among the most frequent reported to date for any gene in breast cancer. The results suggest that mutation of PIK3CA might contribute to development of early stage breast cancer and could provide a potent target for early diagnosis and therapy.

The development of effective biomarkers for Alzheimer's disease:a review

OBJECTIVE: There is a widely recognised need to develop effective Alzheimer's disease (AD) biomarkers to aid the development of disease-modifying treatments, to facilitate early diagnosis and to improve clinical care. This overview aims to summarise the utility of key neuroimaging and cerebrospinal fluid (CSF) biomarkers for AD, before focusing on the latest efforts to identify informative blood biomarkers. DESIGN: A literature search was performed using PubMed up to September 2011 for reviews and primary research studies of neuroimaging (magnetic resonance imaging, magnetic resonance spectroscopy, positron emission tomography and amyloid imaging), CSF and blood-based (plasma, serum and platelet) biomarkers in AD and mild cognitive impairment. Citations within individual articles were examined to identify additional studies relevant to this review. RESULTS: Evidence of AD biomarker potential was available for imaging techniques reflecting amyloid burden and neurodegeneration. Several CSF measures are promising, including 42 amino acid ß-amyloid peptide (Aß(42) ); total tau (T-tau) protein, reflecting axonal damage; and phosphorylated tau (P-tau), reflecting neurofibrillary tangle pathology. Studies of plasma Aß have produced inferior diagnostic discrimination. Alternative plasma and platelet measures are described, which represent potential avenues for future research. CONCLUSIONS: Several imaging and CSF markers demonstrate utility in predicting AD progression and determining aetiology. These require standardisation before forming core elements of diagnostic criteria. The enormous potential available for identifying a minimally-invasive, easily-accessible blood measure as an effective AD biomarker currently remains unfulfilled. Copyright © 2012 John Wiley & Sons, Ltd.

Standardization of diagnostic biomarker concentrations in urine; the hematuria caveat

Sensitive and specific urinary biomarkers can improve patient outcomes in many diseases through informing early diagnosis. Unfortunately, to date, the accuracy and translation of diagnostic urinary biomarkers into clinical practice has been disappointing. We believe this may be due to inappropriate standardization of diagnostic urinary biomarkers. Our objective was therefore to characterize the effects of standardizing urinary levels of IL-6, IL-8, and VEGF using the commonly applied standards namely urinary creatinine, osmolarity and protein. First, we report results based on the biomarker levels measured in 120 hematuric patients, 80 with pathologically confirmed bladder cancer, 27 with confounding pathologies and 13 in whom no underlying cause for their hematuria was identified, designated “no diagnosis”. Protein levels were related to final diagnostic categories (p = 0.022, ANOVA). Osmolarity (mean = 529 mOsm; median = 528 mOsm) was normally distributed, while creatinine (mean = 10163 µmol/l, median = 9350 µmol/l) and protein (0.3297, 0.1155 mg/ml) distributions were not. When we compared AUROCs for IL-6, IL-8 and VEGF levels, we found that protein standardized levels consistently resulted in the lowest AUROCs. The latter suggests that protein standardization attenuates the “true” differences in biomarker levels across controls and bladder cancer samples. Second, in 72 hematuric patients; 48 bladder cancer and 24 controls, in whom urine samples had been collected on recruitment and at follow-up (median = 11 (1 to 20 months)), we demonstrate that protein levels were approximately 24% lower at follow-up (Bland Altman plots). There was an association between differences in individual biomarkers and differences in protein levels over time, particularly in control patients.

Mycobacterium chelonae keratitis:Resolution after debridement and presoaked collagen shields

We report a case of Mycobacterium chelonae keratitis following corneal injury by a foreign body. Diagnosis was made by Ziehl-Neelsen staining and Lowenstein-Jensen culture of corneal scrapings. On the basis of the in vitro susceptibility testing, the patient was treated with topical fortified amikacin. Given the lack of response to this therapy, we decided to carry out a debridement of the infiltrative areas to eliminate infected tissue, and to use an amikacin-soaked collagen shield supplemented every 4 h with topical fortified amikacin to promote healing of the debrided area and to potentiate the effects of the antibiotic therapy. After this treatment, clinical resolution was observed and a further acid-fast stain and culture for mycobacterium were negative. Debridement of the infiltrative areas could be used in cases of mycobacterium keratitis when early diagnosis is made and before the corneal infection has become widespread.