Reliability of myocardial salvage assessment by cardiac magnetic resonance imaging in acute reperfused myocardial infarction

Myocardial salvage assessed by cardiac magnetic resonance imaging (CMRI) holds promise as a surrogate endpoint in studies comparing different treatment strategies for ST-elevation myocardial infarction (STEMI). The aim of this study was to evaluate the reliability of salvaged myocardium measurements by CMRI. Twenty patients underwent CMRI on 2 consecutive days early after reperfused STEMI to assess the area at risk (AAR) on T2-weighted and final infarct size (IS) on delayed enhancement images. Myocardial salvage index (MSI) was calculated (AAR minus IS). Agreement between scans 1 and 2 for the AAR, IS and MSI were analyzed using Bland?CAltman analyses. Inter- and intraobserver reliability were assessed. Paired t testing revealed a trend for a significant difference for MSI between scans 1 and 2 (scan 1: 43.8?±?22.5; scan 2: 45.5?±?22.0; P?=?0.052). The average difference for AAR and IS between scan 1 and scan 2 was ?0.5 (upper limit of agreement 5.4% of left ventricular [LV] volume; lower limit of agreement ?6.4%LV) and 0.1%LV (upper limit of agreement 2.3%LV; lower limit of agreement ?2.1%LV). The corresponding calculated MSI measurements showed a mean bias of ?1.7 (upper limit of agreement 5.5; lower limit of agreement ?8.9). Coefficients of repeatability for interobserver variability were 3.6%LV for AAR, 2.4%LV for IS and 5.4 for MSI. Likewise, for intraobserver variability, coefficients of repeatability were 5.0%LV (AAR), 2.4%LV (IS) and 4.8 (MSI). Assessment of myocardial salvage by CMRI shows acceptable reliability. Further validation studies and trials showing the prognostic value of myocardial salvage by CMRI are needed before routine implementation as a surrogate endpoint in STEMI trials.     

A missing piece? Neuropsychiatric functioning in untreated patients with tumors within the cerebellopontine angle

Introduction

Pseudoprogression (PsP) is a diagnostic dilemma in glioblastoma (GBM) after chemoradiotherapy (CRT). Magnetic resonance imaging (MRI) features may fail to distinguish PsP from early true progression (eTP), however clinical findings may aid in their distinction.

Methods

Sixty-seven patients received CRT for GBM between 2003 and 2016, and had pre- and post-treatment imaging suitable for retrospective evaluation using RANO criteria. Patients with signs of progression within the first 12-weeks post-radiation (P-12) were selected. Lesions that improved or stabilized were defined as PsP, and lesions that progressed were defined as eTP.

Results

The median follow up for all patients was 17.6 months. Signs of progression developed in 35/67 (52.2%) patients within P-12. Of these, 20/35 (57.1%) were subsequently defined as eTP and 15/35 (42.9%) as PsP. MRI demonstrated increased contrast enhancement in 84.2% of eTP and 100% of PsP, and elevated CBV in 73.7% for eTP and 93.3% for PsP. A decrease in FLAIR was not seen in eTP patients, but was seen in 26.7% PsP patients. Patients with eTP were significantly more likely to require increased steroid doses or suffer clinical decline than PsP patients (OR 4.89, 95% CI 1.003–19.27; p?=?0.046). KPS declined in 25% with eTP and none of the PsP patients.

Conclusions

MRI imaging did not differentiate eTP from PsP, however, KPS decline or need for increased steroids was significantly more common in eTP versus PsP. Investigation and standardization of clinical assessments in response criteria may help address the diagnostic dilemma of pseudoprogression after frontline treatment for GBM.

     

ENDOTHELIAL CELL PROLIFERATION ACTIVITY IN BENIGN PROSTATIC HYPERPLASIA AND PROSTATE CANCER: AN IN VITRO MODEL FOR ASSESSMENT

Purpose

Urinary excretion of several pro-angiogenic and antiangiogenic substances has been correlated with malignant tumor growth. The aim of this study was to assay angiogenic activity in urine from patients with cancer of the prostate and benign prostatic hyperplasia (BPH).

Materials and Methods

Urine specimens from 22 healthy male volunteers (control), 33 patients with BPH and 29 with organ confined prostate cancer were analyzed for angiogenic activity in a bovine capillary endothelial cell proliferation assay. In parallel the concentration of basic fibroblast growth factor and vascular endothelial growth factor was determined by enzyme immunoassay in the corresponding urine specimens.

Results

Urine samples from patients with BPH and prostate cancer increased bovine capillary endothelial cell proliferation by 13.1% and 15.1%, respectively, whereas urine from the control group showed a significantly lower angiogenic activity, increasing endothelial cell proliferation by only 0.7% (p = 0.001). Urinary basic fibroblast growth factor and vascular endothelial growth factor were highest in patients with BPH and lowest in the group with prostate cancer (p = 0.0001).

Conclusions

Urine from patients with BPH and prostate cancer stimulates endothelial cell proliferation activity. The degree of endothelial cell stimulation does not correlate with the concentration of basic fibroblast growth factor or vascular endothelial growth factor. Whether the observed pro-angiogenic activity is due to an increased production or release of (an) other angiogenic factor(s) and/or loss of (an) angiogenesis inhibitor(s), deserves further investigation.     

Dendritic cell subsets and toll-like receptors

Toll-like receptors exist as highly conserved pathogen sensors throughout the animal kingdom and they represent a key family of molecules bridging the ancient innate and adaptive immune systems. The first molecules of adaptive immunity appeared in the cartilaginous fishes and, with these, major histocompatibility proteins and cells expressing these molecules, and thus, by definition, the advent of antigen-presenting cells and the "professional" antigen-presenting cells, the dendritic cells. Dendritic cells themselves are highly specialized subsets of cells with the major roles of antigen presentation and stimulation of lymphocytes. The dendritic cell functions of inducing immunity are regulated by their own activation status, which is governed by their encounter with pathogen-associated molecular patterns that signal through pattern recognition receptors, including Toll-like receptors, expressed at the surface and within the cytoplasm and endosomal membranes of dendritic cells. Thus although dendritic cells play a crucial role in the induction of adaptive immunity, the adaptive response is itself initiated at the level of ancient receptors of the innate immune system. A further degree in the complexity of dendritic cell activation is established by the fact that not all dendritic cells are equal. Dendritic cells exist as multiple subsets that vary in location, function, and phenotype. Distinct dendritic cell subsets display great variation in the type of Toll-like receptors expressed and consequently variation in the type of pathogens sensed and the subsequent type of immune responses initiated.     

Effects of a 5-day treatment with vinclozolin on the hypothalamo-pituitary-gonadal axis in male rats

Vinclozolin (VZ), a potent antiandrogenic fungicide, is known to interfere with male reproductive function. Little data are currently available regarding possible impacts of VZ on brain function, particularly neuroendocrine activity and regulation of the hypothalamo-pituitary-gonadal (HPG) axis. Therefore, we examined the effects of VZ on gene expression in the brain (MBH/ME, MPOA/AH, striatum, hippocampus), pituitary, prostate, seminal vesicles, and epididymis of 4-month-old male rats treated daily by gavage for 5 days with VZ (150 mg/kg body weight/day). Alterations in levels of serum hormones and gene expression were determined by RIA and qRT-PCR, respectively. Our results revealed that (i) VZ decreases epididymis weights, increases serum levels of LH and T, and decreases serum TSH and total T(4) levels; (ii) VZ affects the hypothalamic expression of both estrogen receptor (ERs) subtypes, ERalpha and ERbeta; (iii) in the extrahypothalamic brain areas, VZ alters expression of ERs and androgen receptor (AR); (iv) in the pituitary, VZ up-regulates expression of the GnRH receptor, LHbeta, alpha-subunit, and TERP-1/-2; (v) in the ventral prostate, VZ increases and decreases levels of AR and ERbeta mRNA, respectively; (vi) in the seminal vesicles, VZ increases levels of AR and ERalpha mRNA expressions; (vii) in the epididymis, VZ up-regulates AR and ERbeta mRNA expression. These results indicate that in vivo VZ is not a 'pure' antiandrogen, since it exerts mixed AR antagonistic/ERs agonistic actions observed at the levels of mRNA expression of selected androgen- and estrogen-regulated genes in the CNS, pituitary, and male accessory sex organs.     

Pharmacokinetics and metabolism of benzophenone 2 in the rat

Twelve derivatives of benzophenone (BP1-BP12) are widely used as UV-screens to protect industrial products from light induced damage. There is growing public concern about industrially produced chemicals that might interfere with hormonal signalling pathways, thus having potential adverse effects on human health. The derivative 2,2',4,4'-tetrahydroxybenzophenone (BP2) which is used in cosmetic products and in packaging materials, was previously shown to be an estrogenic endocrine active chemical (EAC). While the metabolisation of BP3 has been analyzed in vivo, according to our knowledge little is known about the pharmacokinetics of BP2. Therefore we performed a dose-response experiment with 5 dosages of BP2 which was applied per gavage to adult ovariectomised (ovx) rats for 5 days. Serum samples were analyzed via HPLC. Metabolites were further identified by Helix pomatia glucuronidase treatment and subsequent ion-trap-mass spectrometry. Additionally we analyzed the time dependent metabolisation and excretion of BP2 in a kinetic study. The parent compound BP2 is metabolised to glucuronide - and sulfate-conjugates. In the serum maximum levels of BP2, BP2-glucuronide and BP2-sulfate were observed already 30 min after BP2 application while highest concentrations of BP2 and its metabolites in urine were measured 120 min after treatment. It is suggested that this biotransformation occurs via a first-pass effect in the gut wall or the liver. Despite this rapid metabolisation and excretion, the amount of unconjugated BP2 was sufficient to induce a dose dependent estrogenic effect in the uterotrophic assay.