MRI-derived radiomics to guide post-operative management of glioblastoma: Implication for personalized radiation treatment volume delineation.

Background: The glioblastoma's bad prognosis is primarily due to intra-tumor heterogeneity, demonstrated from several studies that collected molecular biology, cytogenetic data and more recently radiomic features for a better prognostic stratification. The GLIFA project (GLIoblastoma Feature Analysis) is a multicentric project planned to investigate the role of radiomic analysis in GB management, to verify if radiomic features in the tissue around the resection cavity may guide the radiation target volume delineation. Materials and methods: We retrospectively analyze from three centers radiomic features extracted from 90 patients with total or near total resection, who completed the standard adjuvant treatment and for whom we had post-operative images available for features extraction. The Manual segmentation was performed on post gadolinium T1w MRI sequence by 2 radiation oncologists and reviewed by a neuroradiologist, both with at least 10 years of experience. The Regions of interest (ROI) considered for the analysis were: the surgical cavity ± post-surgical residual mass (CTV_cavity); the CTV a margin of 1.5 cm added to CTV_cavity and the volume resulting from subtracting the CTV_cavity from the CTV was defined as CTV_Ring. Radiomic analysis and modeling were conducted in RStudio. Z-score normalization was applied to each radiomic feature. A radiomic model was generated using features extracted from the Ring to perform a binary classification and predict the PFS at 6 months. A 3-fold cross-validation repeated five times was implemented for internal validation of the model. Results: Two-hundred and seventy ROIs were contoured. The proposed radiomic model was given by the best fitting logistic regression model, and included the following 3 features: F_cm_merged.contrast, F_cm_merged.info.corr.2, F_rlm_merged.rlnu. A good agreement between model predicted probabilities and observed outcome probabilities was obtained (p-value of 0.49 by Hosmer and Lemeshow statistical test). The ROC curve of the model reported an AUC of 0.78 (95% CI: 0.68-0.88). Conclusion: This is the first hypothesis-generating study which applies a radiomic analysis focusing on healthy tissue ring around the surgical cavity on post-operative MRI. This study provides a preliminary model for a decision support tool for a customization of the radiation target volume in GB patients in order to achieve a margin reduction strategy.

Perception of smoke-free policies among workers in an Italian Local Health Agency: survey of opinions, knowledge and behaviours.

AIM: This study evaluated the opinions and knowledge of the Health-Care-Workers and other employees about smoking in the workplace and investigated their perceptions about the implementation and strengthening of smoke-free policies and their views of proposed smoking cessation course. METHODS: This cross-sectional study analyzed data resulting from a questionnaire administered in the Local Health Agency of Rieti (Italy). Comparisons have been made according to smoking status of participants: Ever Smokers (ES) or Never Smokers (NS). RESULTS: The study was conducted on a sample of 300 workers, the majority of whom think that the smoking ban is not observed in the workplace due to lack of respect for colleagues (59.2% of NS vs 40% of ES, p=0.022). Exposure to Secondhand smoke (SHS) is reported by 15.2% of ES and 30.3% of NS (p=0.006). About 50% of the participants think that the smoking ban has led to an improvement in the quality of interpersonal relationships. Strengthening the smoking ban through frequent inspections would be very effective according to 78% of ES and 88% of NS (p=0.043); having smoking cessation courses within the agency would be considered useful by 56% of ES and 68% of NS (p= 0.064). Relatively few respondents knew of the association between smoking and bladder cancer (35.2% of ES and 47.2% of NS, p=0.061), and asthma exacerbation (66% of ES and 77% of NS, p=0.040). Logistic regression models adjusted for age, gender, work categories and smoking status show that ES report that they are less likely to be exposed to SHS (OR= 0.42, 95% CI 0.22-0.78, p=0.006) and to think that people smoke because of lack of respect (OR= 0.46, 95% CI 0.24-0.87, p=0.018). More frequent inspections (OR= 0.50, 95% CI 0.26-0.95, p=0.037) and smoking cessation courses (OR= 0.61, 95% CI 0.37-1.00, p=0.053) are considered less effective by ES. ES are less likely to know that smoking is a cause of bladder cancer (OR= 0.54, 95% CI 0.32-0.90, p=0.019) and asthma exacerbation (OR= 0.53, 95% CI 0.31-0.92, p=0.023). Fifty-seven percent of current smokers would like to quit, but only 41% would join a cessation course in the agency. CONCLUSION: The results obtained may be used to analyze the effectiveness of tobacco control policy and programs aimed at freeing companies from smoke. Policy makers should provide the best possible protection for workers against exposure to SHS, in particular with enforcement of the smoking ban and smoking cessation courses tailored to maximize potential benefits for both workers and employers.

GABA release and GAD67 mRNA expression in rat hippocampus following entorhinal cortex activation.

This study investigate the effect of stimulation of glutamatergic afferents originating in the entorhinal cortex on possible changes of GABAergic transmission in the CA1 subregion of the hippocampus. Microdialysis was used to monitor extracellular GABA and in situ hybridization to measure levels of glutamic acid decarboxylase67 (GAD67) mRNA. A dose-dependent increase in extracellular levels of GABA in the dorsal CA1 subregion was detected following injection of 2.4 and 9.6 micrograms quisqualate into the lateral entorhinal cortex whereas 0.24 microgram had no effect. The GABA increase was attenuated by local administration of tetrodotoxin (TTX), indicating neuronal origin. A 60% decrease and a 160% increase were seen in levels of GAD67 mRNA in the CA1 following injection of 0.24 and 9.6 micrograms quisqualate, respectively. This study provides evidence of an entorhinal cortex influenced stimulatory effect on GABAergic activity in the CA1. However, no direct relationship was found between stimulated GABA release and subsequently measured GAD67 mRNA levels. The increased GABA release and the apparent adaptive increase in GAD67 mRNA levels by the strongest stimulation may be due to an endogenous inhibitory neuroprotective response to an excitotoxic influence.

[Hormone replacement therapy (HRT). The effects at 12 months on the risk factors for menopausal osteoporosis]. / Terapia ormonale sostitutiva (HRT). Effetti a dodici mesi sugli indici di rischio per l'osteoporosi menopausale.

Cessation of ovarian activity is accompanied by a more or less marked and more or less accelerated reduction in bone mass; the degree and speed of the process--which occurs in all women--depends on individual (genetic factors influencing peak bone mass, duration of child-bearing period), iatrogenic (treatment with corticosteroids or thyroid hormones) or accidental factors (post-traumatic immobilization). Whatever the factor that triggers off the process, the end result is the destruction of bone tissue. This process may be documented by hematochemical (Nordin's test) and instrumental parameters (MOC and similar techniques). Oestroprogestin (and to a lesser extent calcitonin) hormone replacement therapy has been demonstrated to be highly efficacious in countering this involutive process. The authors report data obtained following the evaluation of 35 women in menopause undergoing. Nordin's test and measurement of the plasma level of estradiol using RIA, before and after twelve months after the start of osteoprotective treatment. Of the 35 patients 9 received only progestin, 22 an oestroprogestin combination (of these 18 patients received estrogen transdermally and 4 orally), and 4 calcitonin administered parenterally. A statistically significant positive correlation with Nordin's test was only found in the group receiving oestrogen therapy. In conclusion, it may be affirmed that in the absence of contraindications oestrogens represent the elective form of treatment for menopausal osteoporosis. Acceptable results have been reported in the literature also using calcitonin, but this treatment could not be evaluated in this study owing to the reduced number of the sample treated.

[The effects of hormone replacement therapy (HRT) on lipid metabolism in the menopause]. / Effetti della terapia ormonale sostitutiva (HRT) sul metabolismo lipidico in menopausa.

INTRODUCTION AND AIMS: During menopause the number of cardiovascular attacks increases parallel to the elimination of estradiol production. The administration of the latter reverses this tendency owing to a compound mechanism (improved HDL) cholesterol/total cholesterol ratio, diminished vasal resistance). MATERIALS AND METHODS: The authors present a study performed in 34 patients in menopause receiving oestroprogestinic replacement therapy using an oral or transdermal route. Metabolic status (serum concentrations of total cholesterol (TC) and HDL cholesterol (C.HDL) was evaluated in all patients before treatment and after 12 months. RESULTS: A statistically significant positive correlation (p < 0.0001) was found between the use of oestrogen and serum levels of HDL. This correlation appeared to be more evident in patients using transdermal treatment compared to the oral form. CONCLUSIONS: The authors conclude that in the absence of contraindications, hormone replacement therapy in menopause exercises a beneficial effect on the lipid status, contributing to diminishing the risk of cardiovascular attacks. The possibility of an increased incidence of breast cancer is now being evaluated, whereas effective protection of the endometrium against the risk of hyperplasia and cancer was shown using the doses of progestin used in this study, which coincide with those currently prescribed in the literature.

Glutamate release correlates with brain-derived neurotrophic factor and trkB mRNA expression in the CA1 region of rat hippocampus.

Synthesis of the neurotrophic factor brain-derived neurotrophic factor (BDNF) and its receptor TrkB in the hippocampus have been proposed to be influenced by endogenous glutamate. To test this hypothesis we have investigated if increases in BDNF and trkB mRNAs are associated with changes in the synaptic release of glutamate in the dorsal hippocampus in the conscious rat by combining the technique of in vivo microdialysis with in situ hybridization histochemistry. A 35% and 66% increase in extracellular levels of glutamate in the dorsal CA1 region was detected following injection into the lateral entorhinal cortex of 2.4 and 9.6 microg of the non-NMDA glutamate receptor agonist quisqualate, respectively. The increase in glutamate was attenuated by local administration of tetrodotoxin (TTX) indicating neuronal origin. Levels of BDNF and trkB mRNAs were increased in the hippocampus in a dose-dependent fashion following the stimulations. The extracellular levels of glutamate in individual animals correlated to the levels of BDNF and trkB mRNAs in the dorsal CA1 region of the hippocampus. This study provides for the first time evidence of an entorhinal cortex influenced concentration-dependent relationship between the release of endogenous glutamate in vivo and neuronal expression of mRNAs for BDNF and its receptor trkB in the hippocampus.

Differential regulation by N-methyl-D-aspartate and non-N-methyl-D-aspartate receptors of acetylcholine release from the rat striatum in vivo.

The modulation of striatal cholinergic neurons by glutamatergic inputs was studied by monitoring the output of acetylcholine collected via a transversal microdialysis probe implanted into the striatum of freely moving rats. A transversal microdialysis membrane was inserted in the striatum and acetylcholine or GABA levels in the dialysate were measured. Acetylcholine levels in the dialysate were quantified by a high-performance liquid chromatography method with an electrochemical detector, while GABA levels were measured by a high-performance liquid chromatography method with a fluorescence detector. The dialysis membrane was perfused with Ringer solution containing 7 microM physostigmine sulphate and drugs, dissolved in the perfusion solution, were administered locally via the dialysis membrane. Local administration of the N-methyl-D-aspartate antagonist 3-[(RS)-2-carboxypiperazin-4-yl]-propyl-1-phosphonic acid (25-100 microM) brought about a decrease in striatal acetylcholine output which was dose-dependent, reversible and partially antagonized by 100 microM N-methyl-D-aspartate. On the other hand, local administration of the non-N-methyl-D-aspartate antagonist 2,3-dihydroxy-6-nitro-7-sulfamoil-benzo(F)quinoxaline was followed by an increase in acetylcholine output which reached a maximum of about +55% at 12.8 microM 2,3-dihydroxy-6-nitro-7-sulfamoil-benzo(F)quinoxaline and was readily reversed when the drug was withdrawn from the perfusion solution. Local administration of the non-N-methyl-D-aspartate receptor agonist (S)-alfa-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (50 and 200 microM) decreased acetylcholine output and this effect was reversed by simultaneous perfusion with the GABA antagonist bicuculline (50 microM).(ABSTRACT TRUNCATED AT 250 WORDS)

Glutamatergic regulation of acetylcholine output in different brain regions: a microdialysis study in the rat.

The glutamatergic regulation of cortical and striatal cholinergic neurons was investigated by measuring ACh output from the parietal cortex and striata of freely moving rats after administration of the competitive NMDA-receptor antagonist 3-((RS)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP). It has been shown that intracerebroventricular administration of 5 nmol of CPP brings about a long lasting 100% increase in ACh output from the parietal cortex but does not affect ACh output from the striatum. Conversely, local perfusion of the striata with 50 microM CPP results in a 45% decrease in ACh output from the striatum but has no effect on parietal ACh output. The decrease in striatal ACh output induced by CPP is antagonized by concurrent perfusion with NMDA. In conclusion, glutamate may exert both inhibitory and excitatory modulatory effects on ACh output, through NMDA receptors, according to the neuronal circuitry existing in different brain regions.