Impact of liver tumour burden, alkaline phosphatase elevation, and target lesion size on treatment outcomes with 177Lu-Dotatate: an analysis of the NETTER-1 study

Purpose: To assess the impact of baseline liver tumour burden, alkaline phosphatase (ALP) elevation, and target lesion size on treatment outcomes with 177Lu-Dotatate. Methods: In the phase 3 NETTER-1 trial, patients with advanced, progressive midgut neuroendocrine tumours (NET) were randomised to 177Lu-Dotatate (every 8 weeks, four cycles) plus octreotide long-acting release (LAR) or to octreotide LAR 60 mg. Primary endpoint was progression-free survival (PFS). Analyses of PFS by baseline factors, including liver tumour burden, ALP elevation, and target lesion size, were performed using Kaplan-Meier estimates; hazard ratios (HRs) with corresponding 95% CIs were estimated using Cox regression. Results: Significantly prolonged median PFS occurred with 177Lu-Dotatate versus octreotide LAR 60 mg in patients with low ( 50%) liver tumour burden (HR 0.187, 0.216, 0.145), and normal or elevated ALP (HR 0.153, 0.177), and in the presence or absence of a large target lesion (diameter > 30 mm; HR, 0.213, 0.063). Within the 177Lu-Dotatate arm, no significant difference in PFS was observed amongst patients with low/moderate/high liver tumour burden (P = 0.7225) or with normal/elevated baseline ALP (P = 0.3532), but absence of a large target lesion was associated with improved PFS (P = 0.0222). Grade 3 and 4 liver function abnormalities were rare and did not appear to be associated with high baseline liver tumour burden. Conclusions: 177Lu-Dotatate demonstrated significant prolongation in PFS versus high-dose octreotide LAR in patients with advanced, progressive midgut NET, regardless of baseline liver tumour burden, elevated ALP, or the presence of a large target lesion. Clinicaltrials.gov : NCT01578239, EudraCT: 2011-005049-11

Impact of liver tumour burden, alkaline phosphatase elevation, and target lesion size on treatment outcomes with 177Lu-Dotatate: an analysis of the NETTER-1 study

Purpose: To assess the impact of baseline liver tumour burden, alkaline phosphatase (ALP) elevation, and target lesion size on treatment outcomes with 177Lu-Dotatate. Methods: In the phase 3 NETTER-1 trial, patients with advanced, progressive midgut neuroendocrine tumours (NET) were randomised to 177Lu-Dotatate (every 8 weeks, four cycles) plus octreotide long-acting release (LAR) or to octreotide LAR 60 mg. Primary endpoint was progression-free survival (PFS). Analyses of PFS by baseline factors, including liver tumour burden, ALP elevation, and target lesion size, were performed using Kaplan-Meier estimates; hazard ratios (HRs) with corresponding 95% CIs were estimated using Cox regression. Results: Significantly prolonged median PFS occurred with 177Lu-Dotatate versus octreotide LAR 60 mg in patients with low ( 50%) liver tumour burden (HR 0.187, 0.216, 0.145), and normal or elevated ALP (HR 0.153, 0.177), and in the presence or absence of a large target lesion (diameter > 30 mm; HR, 0.213, 0.063). Within the 177Lu-Dotatate arm, no significant difference in PFS was observed amongst patients with low/moderate/high liver tumour burden (P = 0.7225) or with normal/elevated baseline ALP (P = 0.3532), but absence of a large target lesion was associated with improved PFS (P = 0.0222). Grade 3 and 4 liver function abnormalities were rare and did not appear to be associated with high baseline liver tumour burden. Conclusions: 177Lu-Dotatate demonstrated significant prolongation in PFS versus high-dose octreotide LAR in patients with advanced, progressive midgut NET, regardless of baseline liver tumour burden, elevated ALP, or the presence of a large target lesion. Clinicaltrials.gov: NCT01578239, EudraCT: 2011-005049-11

Caractérisation d'un biomarqueur pour l'étude en tomographie par émission de positons des récepteurs muscariniques de type M2 pour le diagnostic précoce de la maladie d'Alzheimer

Alzheimer’s disease (AD) has an increasingly critical impact on society from the socio-economic point of view in addition to being very burdensome for the patients themselves, their relatives and friends. Diagnosis of certitude is only at post mortem and no single biomarker has yet been found to be accurate for early in vivo diagnosis. The current available treatments are only symptomatic. The few treatments under research trials have failed to demonstrate a disease modification for either lack of actual treatment efficacy or for lack of population homogeneity and for lack of reliable in vivo biomarkers able to detect a modification. In this context, it is both urgent and necessary to identify an in vivo biomarker that enables i) the differential diagnosis of AD among other dementias and ii) the assessment of treatment efficacy as a follow up in AD patients, is clearly very noticeable. This work aims to characterize the 3-(3-(3-fluoropropylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine [FP-TZTP], by use of in vitro, ex–vivo and in vivo methods in rodents, to assess whether it is a suitable biomarker for Alzheimer’s disease. An impairment of the M2 subtype of the muscarinic receptors was noticed in AD patients and clear evidences of M2 selectivity in knock out mice previously injected with the fluorinated radiotracer FP-TZTP was observed. To further characterize such M2 selectivity, we performed in vitro cell culture and ex-vivo tissue dipping studies (Results #1). Encouraged by the ex-vivo results, we went on to the in vivo world. We elected the non-invasive nuclear medicine imaging technique Positron Emission Tomography (PET) to assess the biodistribution of the [18F]FP-TZTP in rats by use of the Advanced Technology Laboratory Animal Scanner (ATLAS) developed at the National Institutes of Health, Bethesda, MD, USA (Results #4). We had first assessed the ATLAS as a legitimate tool by use of a commonly used and well known radiotracer, the [18F]fluorodeoxyglucose ([18F]FDG) (Results #2 and #3). Our studies suggest that [18F]FP-TZTP may be a biomarker for AD as it is a suitable tracer for in vivo quantification of the M2 receptors.La maladie d'Alzheimer (MA) a un impact socio-économique majeur. Le diagnostic n’est certain qu’à l'autopsie. Il n’existe pas de biomarqueur assurant un diagnostic précoce in vivo. Les quatre traitements actuellement disponibles sont symptomatiques. Les autres traitements qui ont fait l’objet d’essais de recherche clinique, n’ont pas démontré de modification de l’évolution de la maladie. Les hypothèses sous-jacentes à cet échec sont soit l’inefficacité du traitement, soit un manque d'homogénéité de la population étudiée (diagnostic différentiel parfois très compliqué), soit l’absence de biomarqueurs fiables in vivo en mesure de détecter une modification. Dans ce contexte, il est essentiel d'identifier un biomarqueur in vivo qui permette d’établir le diagnostic différentiel entre la MA et les autres démences et d’évaluer l'efficacité des traitements. Ce travail vise à caractériser in vitro, ex vivo et in vivo le 3 - (3 - (3-fluoropropylthio) -1,2,5-thiadiazole-4-yl) -1,2,5,6-tétrahydro-1-méthylpyridine [FP-TZTP], chez les rongeurs pour évaluer son intérêt en tant que biomarqueur potentiel pour la maladie d'Alzheimer. Après avoir établi que l’expression du sous type M2 des récepteurs muscariniques était modifiée précocement dans la MA, nous avons mis en évidence une distribution du radiotraceur fluoré FP-TZTP spécifique de M2 chez la souris génétiquement modifiée ‘knock out’. Afin de mieux caractériser ce radiotraceur, nous avons effectué des études de culture cellulaire in vitro ainsi que des études ex-vivo sur du tissu cérébral pour comprendre la spécificité du [18F]FP-TZTP (Résultats #1). Les résultats ex-vivo nous ont encouragés à réaliser les études in vivo. Nous avons choisi la tomographie par émission de positons (TEP) qui permet l’étude in vivo et non invasive de la biodistribution du [18F]FP-TZTP chez le rat, en utilisant le scanner pour animaux de petite taille (ATLAS) développé par « The National Institutes of Health , Bethesda, MD, USA» (Résultats #4). Pour cela, nous avons dans un premier temps testé l'ATLAS au moyen de deux études métaboliques chez le rat, avec un traceur couramment utilisé, le [18F]fluorodéoxyglucose ([18F]FDG) (Résultats #2; Résultats #3). Nos études suggèrent que le [18F]FP-TZTP est un traceur approprié pour la quantification en TEP des récepteurs muscariniques de type M2, utile pour le diagnostic précoce de la MA

Characterization of a potential in vivo biomarker for Alzheimer's Disease

La maladie d'Alzheimer (MA) a un impact socio-économique majeur. Le diagnostic n’est certain qu’à l'autopsie. Il n’existe pas de biomarqueur assurant un diagnostic précoce in vivo. Les quatre traitements actuellement disponibles sont symptomatiques. Les autres traitements qui ont fait l’objet d’essais de recherche clinique, n’ont pas démontré de modification de l’évolution de la maladie. Les hypothèses sous-jacentes à cet échec sont soit l’inefficacité du traitement, soit un manque d'homogénéité de la population étudiée (diagnostic différentiel parfois très compliqué), soit l’absence de biomarqueurs fiables in vivo en mesure de détecter une modification. Dans ce contexte, il est essentiel d'identifier un biomarqueur in vivo qui permette d’établir le diagnostic différentiel entre la MA et les autres démences et d’évaluer l'efficacité des traitements. Ce travail vise à caractériser in vitro, ex vivo et in vivo le 3 - (3 - (3-fluoropropylthio) -1,2,5-thiadiazole-4-yl) -1,2,5,6-tétrahydro-1-méthylpyridine [FP-TZTP], chez les rongeurs pour évaluer son intérêt en tant que biomarqueur potentiel pour la maladie d'Alzheimer. Après avoir établi que l’expression du sous type M2 des récepteurs muscariniques était modifiée précocement dans la MA, nous avons mis en évidence une distribution du radiotraceur fluoré FP-TZTP spécifique de M2 chez la souris génétiquement modifiée ‘knock out’. Afin de mieux caractériser ce radiotraceur, nous avons effectué des études de culture cellulaire in vitro ainsi que des études ex-vivo sur du tissu cérébral pour comprendre la spécificité du [18F]FP-TZTP (Résultats #1). Les résultats ex-vivo nous ont encouragés à réaliser les études in vivo. Nous avons choisi la tomographie par émission de positons (TEP) qui permet l’étude in vivo et non invasive de la biodistribution du [18F]FP-TZTP chez le rat, en utilisant le scanner pour animaux de petite taille (ATLAS) développé par « The National Institutes of Health , Bethesda, MD, USA» (Résultats #4). Pour cela, nous avons dans un premier temps testé l'ATLAS au moyen de deux études métaboliques chez le rat, avec un traceur couramment utilisé, le [18F]fluorodéoxyglucose ([18F]FDG) (Résultats #2; Résultats #3). Nos études suggèrent que le [18F]FP-TZTP est un traceur approprié pour la quantification en TEP des récepteurs muscariniques de type M2, utile pour le diagnostic précoce de la MA.Alzheimer’s disease (AD) has an increasingly critical impact on society from the socio-economic point of view in addition to being very burdensome for the patients themselves, their relatives and friends. Diagnosis of certitude is only at post mortem and no single biomarker has yet been found to be accurate for early in vivo diagnosis. The current available treatments are only symptomatic. The few treatments under research trials have failed to demonstrate a disease modification for either lack of actual treatment efficacy or for lack of population homogeneity and for lack of reliable in vivo biomarkers able to detect a modification. In this context, it is both urgent and necessary to identify an in vivo biomarker that enables i) the differential diagnosis of AD among other dementias and ii) the assessment of treatment efficacy as a follow up in AD patients, is clearly very noticeable. This work aims to characterize the 3-(3-(3-fluoropropylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine [FP-TZTP], by use of in vitro, ex–vivo and in vivo methods in rodents, to assess whether it is a suitable biomarker for Alzheimer’s disease. An impairment of the M2 subtype of the muscarinic receptors was noticed in AD patients and clear evidences of M2 selectivity in knock out mice previously injected with the fluorinated radiotracer FP-TZTP was observed. To further characterize such M2 selectivity, we performed in vitro cell culture and ex-vivo tissue dipping studies (Results #1). Encouraged by the ex-vivo results, we went on to the in vivo world. We elected the non-invasive nuclear medicine imaging technique Positron Emission Tomography (PET) to assess the biodistribution of the [18F]FP-TZTP in rats by use of the Advanced Technology Laboratory Animal Scanner (ATLAS) developed at the National Institutes of Health, Bethesda, MD, USA (Results #4). We had first assessed the ATLAS as a legitimate tool by use of a commonly used and well known radiotracer, the [18F]fluorodeoxyglucose ([18F]FDG) (Results #2 and #3). Our studies suggest that [18F]FP-TZTP may be a biomarker for AD as it is a suitable tracer for in vivo quantification of the M2 receptors

Sex change in Clownfish: molecular insights from transcriptome analysis

19 páginas, 6 figuras, 3 tablas.-- This work is licensed under a Creative Commons Attribution 4.0 International LicenseSequential hermaphroditism is a unique reproductive strategy among teleosts that is displayed mainly in fish species living in the coral reef environment. The reproductive biology of hermaphrodites has long been intriguing; however, very little is known about the molecular pathways underlying their sex change. Here, we provide the first de novo transcriptome analyses of a hermaphrodite teleost´s undergoing sex change in its natural environment. Our study has examined relative gene expression across multiple groups—rather than just two contrasting conditions— and has allowed us to explore the differential expression patterns throughout the whole process. Our analysis has highlighted the rapid and complex genomic response of the brain associated with sex change, which is subsequently transmitted to the gonads, identifying a large number of candidate genes, some well-known and some novel, involved in the process. The present study provides strong evidence of the importance of the sex steroidogenic machinery during sex change in clownfish, with the aromatase gene playing a central role, both in the brain and the gonad. This work constitutes the first genome-wide study in a social sex-changing species and provides insights into the genetic mechanism governing social sex change and gonadal restructuring in protandrous hermaphroditesPeer reviewe

Cytotoxic effects of nickel nanowires in human fibroblasts

AbstractThe increasing interest in the use of magnetic nanostructures for biomedical applications necessitates rigorous studies to be carried out in order to determine their potential toxicity. This work attempts to elucidate the cytotoxic effects of nickel nanowires (NWs) in human fibroblasts WI-38 by a colorimetric assay (MTT) under two different parameters: NW concentration and exposure time. This was complemented with TEM and confocal images to assess the NWs internalization and to identify any changes in the cell morphology. Ni NWs were fabricated by electrodeposition using porous alumina templates. Energy dispersive X-ray analysis, scanning electron microscopy and transmission electron microscopy imaging were used for NW characterization. The results showed decreased cell metabolic activity for incubation times longer than 24h and no negative effects for exposure times shorter than that. The cytotoxicity effects for human fibroblasts were then compared with those reported for HCT 116 cells, and the findings point out that it is relevant to consider the cellular size. In addition, the present study compares the toxic effects of equivalent amounts of nickel in the form of its salt to those of NWs and shows that the NWs are more toxic than the salts. Internalized NWs were found in vesicles inside of the cells where their presence induced inflammation of the endoplasmic reticulum

[18F]FDG positron emission tomography/computed tomography and multidetector computed tomography roles in thymic lesion treatment planning

Rationale: Thymic masses may represent an unsolved diagnostic problem which often require surgical procedures for an accurate staging. A non-invasive way to determine the nature of thymic lesions would help identify the patients which are true candidates for surgery. Our retrospective study aims to assess multidetector computed tomography and 2-[18F]fluoro-2-deoxyglucose positron emission tomography/computed tomography ([18F]FDG-PET/CT) capacity to distinguish benign from malignant thymic lesions. Methods: Helical multidetector CT (MDCT) and [18F]FDG-PET/CT of twenty consecutive patients presenting with a thymic mass at our Institute were retrospectively analyzed. MDCT scans were focused on morphologic features and invasiveness characteristics. Qualitative and semi-quantitative analyses by maximum standardized uptake value corrected for body weight (SUVbw max) were performed on [18F]FDG-PET/CT. In all cases, readers were blinded to pathology findings. Both imaging techniques were correlated to final pathology. Student's t-test was performed on SUVbw max stratified for thymic epithelial tumors. Results: In the group of benign lesions MDCT correctly identified well-defined margins of masses in 8 out of 8 patients whereas [18F]FDG-PET/CT was negative in 7 out of 8 patients. Among malignant lesions MDCT revealed mediastinum fat or infiltration of adjacent organs in 10/12 patients. On the other hand [18F]FDG-PET/CT showed increased radiotracer uptake in 12/12 patients. Conclusions: MDCT and [18F]FDG-PET/CT alone are not able to differentiate the nature of thymic lesions. However, they are two non-invasive complementary techniques which can be used to differentiate benign from high-risk malignant thymic lesions. These findings should be taken into account before surgery is performed as a diagnostic procedure. © 2008 Elsevier Ireland Ltd. All rights reserved

Circulating levels of VCAM and MMP-2 may help identify patients with more aggressive prostate cancer

Background: Prostate adenocarcinoma is generally characterized by slow progression although some phenotypes have a more aggressive behavior with tendency to local invasion and distant metastases, mainly to bones. Better specific care could be provided to the aggressive phenotype-group of patients if pre-surgical identification were available. Material and Methods: Correlations between pre-surgical levels of 6 blood molecules and pathological tumour staging, post-surgical Gleason score and disease-free survival have been observed. Plasma and sera from 162 men affected by prostate adenocarcinoma were analysed with ELISA to assess levels of neovascularization-related molecule (VEGF), endothelial cell adhesion molecule (VCAM), extracellular matrix destruction-related molecules (MMP-2, MMP-9), and tissue inhibitors of metalloproteinase (TIMP-1 and TIMP-2). Results: The median values of serum determinations were for VEGF 279 pg/ml, VCAM 633 ng/ml, MMP-2 206 ng/ml and MMP-9 614 ng/ml. Plasma medians (ng/ml) were 94 for TIMP-1 and 90 for TIMP-2. Patients with VCAM values > 633 ng/ml had a worse disease-free survival than patients with values <633 ng/ml with an adjusted Hazard Ratio of 2.1, significant (95% confidence interval 0.8-5.6). Patients with levels of MMP-2 < 206 ng/ml showed an increased risk of progression (adjusted HR 1.7; 95% C.I. 0.6-4.8). Conclusions: Levels of VCAM and MMP-2 should be checked in patients with prostate adenocarcinoma, because distant spread is more likely to occur in patients with high levels of VCAM and low levels of MMP-2. The scientific community should further investigate impact on prognosis of VCAM and MMP-2. © 2008 Bentham Science Publishers Ltd

Role of [18F]FDG-PET/CT after radiofrequency ablation of liver metastases: Preliminary results

Purpose: Focal metastasis may be treated with radiofrequency ablation (RFA), a low invasive method yet limited by the lack of direct evidence of radicality of treatment. We, hereby, aimed at assessing the role of positron emission tomography-computed tomography (PET/CT) with fluoride radiolabeled deoxy-glucose ([18F]FDG) in RFA treatment success evaluation and early diagnosis of local relapse of liver metastasis after RFA procedure. Methods: RFA was performed in nine patients on 12 liver metastasis, serially imaged through [18F]FDG-PET/CT and multidetector CT (MDCT) at 1, 3, 6, and 9 months after treatment. Eight lesions were also scanned with [ 18F]FDG-PET/CT at 1 week after treatment. Imaging analyses were performed on 47 [18F]FDG-PET/CT and 51 MDCT. Imaging reading outcomes were compared to each other and to biopsy tissue results when available. Results: In one case, [18F]FDG-PET/CT revealed radiotracer uptake at RFA site a week after procedure. Negative concordant outcome was obtained on eight lesions at 1 month after RFA, on eight cases at 3 months, on four at 6 months, and on two cases at 9 months. Extra-liver (peritoneal) disease was detected in one case by both [18F]FDG-PET/CT and MDCT. In seven cases, [18F]FDG-PET/CT revealed the presence of local recurrence earlier than MDCT. In no cases did MDCT detect local relapse earlier than [ 18F]FDG-PET/CT. Conclusion: [18F]FDG-PET/CT may detect RFA treatment failure as well as local relapse after RFA earlier than MDCT. © 2008 Springer-Verlag