Positron Emission Tomography-Based Response to Target and Immunotherapies in Oncology.

2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) is a promising tool to support the evaluation of response to either target therapies or immunotherapy with immune checkpoint inhibitors both in clinical trials and, in selected patients, at the single patient's level. The present review aims to discuss available evidence related to the use of [18F]FDG PET (Positron Emission Tomography) to evaluate the response to target therapies and immune checkpoint inhibitors. Criteria proposed for the standardization of the definition of the PET-based response and complementary value with respect to morphological imaging are commented on. The use of PET-based assessment of the response through metabolic pathways other than glucose metabolism is also relevant in the framework of personalized cancer treatment. A brief discussion of the preliminary evidence for the use of non-FDG PET tracers in the evaluation of the response to new therapies is also provided.

Mechanisms underlying the predictive power of high skeletal muscle uptake of FDG in amyotrophic lateral sclerosis.

BACKGROUND: We recently reported that enhanced [18F]-fluorodeoxyglucose (FDG) uptake in skeletal muscles predicts disease aggressiveness in patients with amyotrophic lateral sclerosis (ALS). The present experimental study aimed to assess whether this predictive potential reflects the link between FDG uptake and redox stress that has been previously reported in different tissues and disease models. METHODS: The study included 15 SOD1G93A mice (as experimental ALS model) and 15 wildtype mice (around 120 days old). Mice were submitted to micro-PET imaging. Enzymatic pathways and response to oxidative stress were evaluated in harvested quadriceps and hearts by biochemical, immunohistochemical, and immunofluorescence analysis. Colocalization between the endoplasmic reticulum (ER) and the fluorescent FDG analog 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxyglucose (2-NBDG) was performed in fresh skeletal muscle sections. Finally, mitochondrial ultrastructure and bioenergetics were evaluated in harvested quadriceps and hearts. RESULTS: FDG retention was significantly higher in hindlimb skeletal muscles of symptomatic SOD1G93A mice with respect to control ones. This difference was not explained by any acceleration in glucose degradation through glycolysis or cytosolic pentose phosphate pathway (PPP). Similarly, it was independent of inflammatory infiltration. Rather, the high FDG retention in SOD1G93A skeletal muscle was associated with an accelerated generation of reactive oxygen species. This redox stress selectively involved the ER and the local PPP triggered by hexose-6P-dehydrogenase. ER involvement was confirmed by the colocalization of the 2-NBDG with a vital ER tracker. The oxidative damage in transgenic skeletal muscle was associated with a severe impairment in the crosstalk between ER and mitochondria combined with alterations in mitochondrial ultrastructure and fusion/fission balance. The expected respiratory damage was confirmed by a deceleration in ATP synthesis and oxygen consumption rate. These same abnormalities were represented to a markedly lower degree in the myocardium, as a sample of non-voluntary striated muscle. CONCLUSION: Skeletal muscle of SOD1G93A mice reproduces the increased FDG uptake observed in ALS patients. This finding reflects the selective activation of the ER-PPP in response to significant redox stress associated with alterations of mitochondrial ultrastructure, networking, and connection with the ER itself. This scenario is less severe in cardiomyocytes suggesting a relevant role for either communication with synaptic plaque or contraction dynamics.

Spinal cord hypermetabolism extends to skeletal muscle in amyotrophic lateral sclerosis: a computational approach to [18F]-fluorodeoxyglucose PET/CT images.

PURPOSE: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease leading to neuromuscular palsy and death. We propose a computational approach to [18F]-fluorodeoxyglucose (FDG) PET/CT images to analyze the structure and metabolic pattern of skeletal muscle in ALS and its relationship with disease aggressiveness. MATERIALS AND METHODS: A computational 3D method was used to extract whole psoas muscle's volumes and average attenuation coefficient (AAC) from CT images obtained by FDG PET/CT performed in 62 ALS patients and healthy controls. Psoas average standardized uptake value (normalized on the liver, N-SUV) and its distribution heterogeneity (defined as N-SUV variation coefficient, VC-SUV) were also extracted. Spinal cord and brain motor cortex FDG uptake were also estimated. RESULTS: As previously described, FDG uptake was significantly higher in the spinal cord and lower in the brain motor cortex, in ALS compared to controls. While psoas AAC was similar in patients and controls, in ALS a significant reduction in psoas volume (3.6 ± 1.02 vs 4.12 ± 1.33 mL/kg; p < 0.01) and increase in psoas N-SUV (0.45 ± 0.19 vs 0.29 ± 0.09; p < 0.001) were observed. Higher heterogeneity of psoas FDG uptake was also documented in ALS (VC-SUV 8 ± 4%, vs 5 ± 2%, respectively, p < 0.001) and significantly predicted overall survival at Kaplan-Meier analysis. VC-SUV prognostic power was confirmed by univariate analysis, while the multivariate Cox regression model identified the spinal cord metabolic activation as the only independent prognostic biomarker. CONCLUSION: The present data suggest the existence of a common mechanism contributing to disease progression through the metabolic impairment of both second motor neuron and its effector.

The pharmacotherapeutic management of obstructive sleep apnea.

Introduction: Obstructive sleep apneas are a frequent clinical condition in which there are momentary interruptions or reductions in breathing activity. To date, the gold standard therapy is the use of Continous Positive Airway Pressure (CPAP). But, due to the relatevely high frequency of poor compliant patients, there is the need to research possible pharmacological treatments for obstructive apnea (OSA). Areas covered: A recent study divided OSA into four major phenotypes. With this characterization in hand, the authors have reviewed the pharmacological treatments present to date according to the different phenotypes in which they could be used. Afterwards, they analyzed the efficacy of different medicaments for the therapy of the residual (despite CPAP treatment) excessive day-time sleepiness (EDS) that often afflicts OSA' patients. Expert opinion: Different drug classes have been evaluated, with some positive results. However, there is still the need to better define treatment strategies for every single phenotype. This underlines the importance to avoid considering the pathology like a single entity without any differences between each single form. The authors are concerned about the risk that, treating only EDS, patients could reduce their compliance to CPAP, thus not reducing the cardiovascular risk associated with OSA.

Loggerhead sea turtles (Caretta caretta): A target species for monitoring litter ingested by marine organisms in the Mediterranean Sea.

Marine litter is any persistent, manufactured or processed solid material discarded, disposed of or abandoned in the marine and coastal environment. Ingestion of marine litter can have lethal and sub-lethal effects on wildlife that accidentally ingests it, and sea turtles are particularly susceptible to this threat. The European Commission drafted the 2008/56/EC Marine Strategy Framework Directive with the aim to achieve a Good Environmental Status (GES), and the loggerhead sea turtle (Caretta caretta, Linnaeus 1758) was selected for monitoring the amount and composition of litter ingested by marine animals. An analogous decision has been made under the UNEP/MAP Barcelona Convention for the protection of the Mediterranean Sea, following the Ecosystem Approach. This work provides for the first time, two possible scenarios for the Marine Strategy Framework Directive GES, both related to "Trends in the amount and composition of litter ingested by marine animals" in the Mediterranean Sea. The study validates the use of the loggerhead turtle as target indicator for monitoring the impact of litter on marine biota and calls for immediate use of this protocol throughout the Mediterranean basin and European Region. Both GES scenarios are relevant worldwide, where sea turtles and marine litter are present, for measuring the impact of ingested plastics and developing policy strategies to reduce it. In the period between 2011 and 2014, 150 loggerhead sea turtles, found dead, were collected from the Italian Coast, West Mediterranean Sea Sub-Region. The presence of marine litter was investigated using a standardized protocol for necropsies and lab analysis. The collected items were subdivided into 4 main categories, namely, IND-Industrial plastic, USE-User plastic, RUB-Non plastic rubbish, POL-Pollutants and 14 sub-categories, to detect local diversity. Eighty-five percent of the individuals considered (n = 120) were found to have ingested an average of 1.3 ± 0.2 g of litter (dry mass) or 16 ± 3 items.

Recovery Trends of Commercial Fish: The Case of an Underperforming Mediterranean Marine Protected Area.

Temporal trends in the recovery of exploited species in marine protected areas (MPAs) are useful for a proper assessment of the efficacy of protection measures. The effects of protection on the fish assemblages of the sublittoral rocky reefs in the "Penisola del Sinis-Isola di Mal di Ventre" MPA (W. Sardinia, Italy) were evaluated using a multi-year series of data. Four surveys, conducted 7, 10, 13 and 15 years after the area was designated as an MPA and carried out in the period spanning June and July, were used to estimate the abundance and biomass of commercial species. The surveys were carried out in zones with decreasing levels of fishing restrictions within the MPA (zones A, B, C) and in unprotected zones (OUT1 and OUT2), and underwater video visual census techniques were used. Protected zones only occasionally showed higher levels of abundance or biomass, and the trajectories of those metrics were not consistent across the years. In addition, the zone with the highest level of protection (zone A) never presented levels of abundance and biomass higher than those in zones B and C. This study shows that even 15 years after designation, protection has had no appreciable effect in the MPA studied. It is argued that this is emblematic of several shortcomings in the planning, regulation and enforcement frameworks of the MPA.

Interaction between loggerhead sea turtles (Caretta caretta) and marine litter in Sardinia (Western Mediterranean Sea).

Anthropogenic debris in the environment affects many species that accidentally ingest it. The aim of this study is to evaluate the quantity and composition of marine litter ingested by loggerheads in Sardinia, thus supplying for the lack of data in the existing literature for this area. Seventeen of the 121 (14.04%) monitored turtles presented debris in their digestive tracts. Litter in faecal pellet of alive individuals (n = 91) and in gastro-intestinal contents of dead ones (n = 30) was categorized, counted and weighed. User plastic was the main category of ingested debris with a frequency of occurrence of 13.22% of the total sample, while sheet (12.39%) and fragments (9.09%) were the most relevant sub-categories. This study highlights for the first time the incidence of litter in alive turtles in Sardinia. This contribution improves the knowledge about marine litter interaction on Caretta caretta as bio-indicator. Results will be useful for the Marine Strategy implementation.

Amount and distribution of neustonic micro-plastic off the western Sardinian coast (Central-Western Mediterranean Sea).

A plethora of different sampling methodologies has been used to document the presence of micro-plastic fragments in sea water. European Marine Strategy suggests to improve standard techniques to make future data comparable. We use Manta Trawl sampling technique to quantify abundance and distribution of micro-plastic fragments in Sardinian Sea (Western Mediterranean), and their relation with phthalates and organoclorine in the neustonic habitat. Our results highlight a quite high average plastic abundance value (0.15 items/m(3)), comparable to the levels detected in other areas of the Mediterranean. "Site" is the only factor that significantly explains the differences observed in micro-plastic densities. Contaminant levels show high spatial and temporal variation. In every station, HCB is the contaminant with the lowest concentration while PCBs shows the highest levels. This work, in line with Marine Strategy directives, represents a preliminary study for the analysis of plastic impact on marine environment of Sardinia.