The lung immuno-oncology prognostic score (LIPS-3): a prognostic classification of patients receiving first-line pembrolizumab for PD-L1 ≥ 50% advanced non-small-cell lung cancer.

BACKGROUND: To stratify the prognosis of patients with programmed cell death-ligand 1 (PD-L1) ≥ 50% advanced non-small-cell lung cancer (aNSCLC) treated with first-line immunotherapy. METHODS: Baseline clinical prognostic factors, the neutrophil-to-lymphocyte ratio (NLR), PD-L1 tumour cell expression level, lactate dehydrogenase (LDH) and their combination were investigated by a retrospective analysis of 784 patients divided between statistically powered training (n = 201) and validation (n = 583) cohorts. Cut-offs were explored by receiver operating characteristic (ROC) curves and a risk model built with validated independent factors by multivariate analysis. RESULTS: NLR < 4 was a significant prognostic factor in both cohorts (P < 0.001). It represented 53% of patients in the validation cohort, with 1-year overall survival (OS) of 76.6% versus 44.8% with NLR > 4, in the validation series. The addition of PD-L1 ≥ 80% (21% of patients) or LDH < 252 U/l (25%) to NLR < 4 did not result in better 1-year OS (of 72.6% and 74.1%, respectively, in the validation cohort). Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2 [P < 0.001, hazard ratio (HR) 2.04], pretreatment steroids (P < 0.001, HR 1.67) and NLR < 4 (P < 0.001, HR 2.29) resulted in independent prognostic factors. A risk model with these three factors, namely, the lung immuno-oncology prognostic score (LIPS)-3, accurately stratified three OS risk-validated categories of patients: favourable (0 risk factors, 40%, 1-year OS of 78.2% in the whole series), intermediate (1 or 2 risk factors, 54%, 1-year OS 53.8%) and poor (>2 risk factors, 5%, 1-year OS 10.7%) prognosis. CONCLUSIONS: We advocate the use of LIPS-3 as an easy-to-assess and inexpensive adjuvant prognostic tool for patients with PD-L1 ≥ 50% aNSCLC.

Osimertinib beyond disease progression in T790M EGFR-positive NSCLC patients: a multicenter study of clinicians' attitudes.

BACKGROUND: In most cases, T790M EGFR-positive NSCLC patients receiving osimertinib developed "non-drugable" progression, as the patients with common EGFR-sensitizing mutations were treated with first-line osimertinib. In both settings, chemotherapy represents the standard treatment and local ablative treatments (LATs) are potential useful options in the case of oligo-progression. METHODS: We conducted a study on "post-progression" (pp) outcomes of T790M EGFR-positive NSCLC patients treated with osimertinib, according to the therapeutic strategy applied: osimertinib beyond progression (± LATs), "switched therapies" or best supportive care only (BSC). RESULTS: 144 consecutive patients were evaluated: 53 (36.8%) did not received post-progression treatments (BSC), while 91 (63.2%) patients received at least 1 subsequent treatment; 50 patients (54.9%) received osimertinib beyond disease progression [19 (20.9%) of them with adjunctive LATs] and 41 (45.1%) a switched therapy. Median ppPFS (progression-free survival) and median ppOS (overall survival) of patients who received osimertinib beyond progression vs. switched therapies were 6.4 months vs. 4.7 months, respectively [HR 0.57 (95% CI 0.35-0.92), p = 0.0239] and 11.3 months vs 7.8 months, respectively [HR 0.57 (95% CI 0.33-0.98), p = 0.0446]. Among patients who received osimertinib beyond progression with and without LATs median ppPFS was 6.4 months and 5.7 months, respectively [HR 0.90 (95% CI 0.68-1.18), p = 0.4560], while median ppOS was 20.2 months and 9.9 months, respectively [HR 0.73 (95% CI 0.52-1.03), p = 0.0748]. At the univariate analysis, the only factor significantly related to the ppPFS was the therapeutic strategy in favor of osimertinib beyond progression (± LATs). Moreover, the only variable which was significantly related to ppOS at the multivariate analysis was osimertinib beyond progression (± LATs). CONCLUSION: Our study confirmed that in clinical practice, in case of "non-druggable" disease progression, maintaining osimertinib beyond progression (with adjunctive LATs) is an effective option.

Complex patterns of collective escape in starling flocks under predation.

ABSTRACT: Collective behaviour of animals has been a main focus of recent research, yet few empirical studies deal with this issue in the context of predation, a major driver of social complexity in many animal species. When starling (Sturnus vulgaris) flocks are under attack by a raptor, such as a peregrine falcon (Falco peregrinus), they show a great diversity of patterns of collective escape. The corresponding structural complexity concerns rapid variation in density and shape of the flock over time. Here, we present a first step towards unravelling this complexity. We apply a time series analysis to video footage of 182 sequences of hunting by falcons on flocks of thousands of starlings close to two urban roosts during winter. We distinguish several types of collective escape by determining the position and movement of individuals relative to each other (which determines darkness and shape of the flock over time) as well as relative to the predator, namely 'flash expansion', 'blackening', 'wave event', 'vacuole', 'cordon' and 'split'. We show that the specific type of collective escape depends on the collective pattern that precedes it and on the level of threat posed by the raptor. A wave event was most likely to occur when the predator attacked at medium speed. Flash expansion occurred more frequently when the predator approached the flock at faster rather than slower speed and attacked from above rather than from the side or below. Flash expansion was often followed by split, but in many cases, the flock showed resilience by remaining intact. During a hunting sequence, the frequencies of different patterns of collective escape increased when the frequency of attack by the raptor was higher. Despite their complexity, we show that patterns of collective escape depend on the predatory threat, which resembles findings in fish. SIGNIFICANCE STATEMENT: Patterns of collective escape in flocks of starlings have always intrigued laymen and scientists. A detailed analysis of their complex dynamics has been lacking so far, and is the focus of our present study: we analysed video footage of hunting by falcons on flocks of thousands of starlings and show how patterns of collective escape (namely flash expansion, blackening, wave event, vacuole, cordon and split) depend on the preceding pattern and on details of attack. A higher frequency of attack during a hunting sequence resulted in a higher frequency of collective escape events. Flash expansion happened most often when the predator attacks at greater speed. A wave event was most likely when the raptor attacks at medium (rather than high or low) speed. These results provide a first quantitative approach to social complexity in collective avoidance of a predator.

Social modulation of risky decision-making in rats (Rattus norvegicus) and tufted capuchin monkeys (Sapajus spp.).

Both human and non-human animals frequently deal with risky decisions in a social environment. Nevertheless, the influence of the social context on decision-making has been scarcely investigated. Here, we evaluated for the first time whether the presence of a conspecific influences risk preferences in rats and in tufted capuchin monkeys. Subjects received a series of choices between a constant, safe option and a variable, risky option, both alone (Alone condition) and when paired with a conspecific (Paired condition). The average payoff of the risky option was always lower than that of the safe option. Overall, the two species differed in their attitude towards risk: whereas rats were indifferent between options, capuchins exhibited a preference for the safe option. In both species, risk preferences changed in the Paired condition compared to the Alone condition, although in an opposite way. Whereas rats increased their risk preferences over time when paired with a conspecific, capuchins chose the risky option less in the Paired condition than in the Alone condition. Moreover, whereas anxiety-like behaviours decreased across sessions in rats, these behaviours where more represented in the Paired condition than in the Alone condition in capuchins. Thus, our findings extends to two distantly-related non-human species the evidence, so far available for human beings, that a decrease in anxiety corresponds to an increase in risk preferences, and vice versa. This suggests that the modulation of risk preferences by social influences observed in rats and capuchin monkeys may rely on a common, evolutionarily ancient, mechanism.

LP-211, a selective 5-HT7 receptor agonist, increases novelty-preference and promotes risk-prone behavior in rats.

Gambling disorder is associated to an increased impulsivity, a high level of novelty-seeking and a dysregulation of the forebrain neurotransmission systems. However, the neurobiological mechanisms of this addictive disorder are not fully understood and no valid pharmacological approach has yet been approved. The present study aimed to investigate the effect of 5-HT7 receptor (5-HT7 R) stimulation with a brain penetrant and selective agonist, LP-211 (0.25 and 0.50 mg kg-1 i.p.) during post-experience consolidation, (i) acutely in a novelty-preference test (Exp. 1) or (ii) sub-chronically in the Probabilistic-Delivery Task (rPDT, commonly used to measure individual differences in risk proneness of rats; Exp. 2). Results of Exp. 1 showed that 5-HT7 R activation improves consolidation of chamber-shape memory in the novelty-preference test, leading to significant novelty-induced hyperactivity and recognition, in conditions where controls displayed a null-preference. These results suggest that 5-HT7 Rs may be involved in the consolidation of information inherent to spatial environments, facilitating the recognition of novelty. Furthermore, in the operant rPDT (Exp. 2), 5-HT7 R activation shifts the choice towards a larger yet unlikely reward and turns the propensity of rats towards risk-prone behavior. Thus, 5-HT7 Rs stimulation apparently strengthens the consideration of future, bigger rewards, also enhancing the seeking of it by operant pokes. These effects may well be explained by LP-211 actions on hippocampal versus prefrontal cortex-mediated regulations, leading to improved (though suboptimal) strategy formation. However, further experiments are necessary to determine more in depth the serotonergic pathways involved.

Enhanced limbic/impaired cortical-loop connection onto the hippocampus of NHE rats: Application of resting-state functional connectivity in a preclinical ADHD model.

Due to a hyperfunctioning mesocorticolimbic system, Naples-High-Excitability (NHE) rats have been proposed to model for the meso-cortical variant of attention deficit/hyperactivity disorder (ADHD). Compared to Naples Random-Bred (NRB) controls, NHE rats show hyperactivity, impaired non-selective attention (Aspide et al., 1998), and impaired selective spatial attention (Ruocco et al., 2009a, 2014). Alteration in limbic functions has been proposed; however, resulting unbalance among forebrain areas has not been assessed yet. By resting-state functional Magnetic-Resonance Imaging (fMRI) in vivo, we investigated the connectivity of neuronal networks belonging to limbic vs. cortical loops in NHE and NRB rats (n=10 each). Notably, resting-state fMRI was applied using a multi-slice sagittal, gradient-echo sequence. Voxel-wise connectivity maps at rest, based on temporal correlation among fMRI time-series, were computed by seeding the hippocampus (Hip), nucleus accumbens (NAcc), dorsal striatum (dStr), amygdala (Amy) and dorsal/medial prefrontal cortex (PFC), both hemispheres. To summarize patterns of altered connection, clearly directional connectivity was evident within the cortical loop: bilaterally and specularly, from orbital and dorsal PFCs through dStr and hence towards Hip. Such network communication was reduced in NHE rats (also, with less mesencephalic/pontine innervation). Conversely, enhanced network activity emerged within the limbic loop of NHE rats: from left PFC, both through the NAcc and directly, to the Hip (all of which received greater ventral tegmental innervation, likely dopamine). Together with tuned-down cortical loop, this potentiated limbic loop may serve a major role in controlling ADHD-like behavioral symptoms in NHE rats.

Glycolysis gene expression analysis and selective metabolic advantage in the clinical progression of colorectal cancer.

Production of lactate even in the presence of sufficient levels of oxygen (aerobic glycolysis) seems the prevalent energy metabolism pathway in cancer cells. The analysis of altered expression of effectors causing redirection of glucose metabolism would help to characterize this phenomenon with possible therapeutic implications. We analyzed mRNA expression of the key enzymes involved in aerobic glycolysis in normal mucosa (NM), primary tumor (PT) and liver metastasis (LM) of colorectal cancer (CRC) patients (pts) who underwent primary tumor surgery and liver metastasectomy. Tissues of 48 CRC pts were analyzed by RT-qPCR for mRNA expression of the following genes: hexokinase-1 (HK-1) and 2 (HK-2), embryonic pyruvate kinase (PKM-2), lactate dehydrogenase-A (LDH-A), glucose transporter-1 (GLUT-1), voltage-dependent anion-selective channel protein-1 (VDAC-1). Differences in the expression of the candidate genes between tissues and associations with clinical/pathologic features were studied. GLUT-1, LDH-A, HK-1, PKM-2 and VDAC-1 mRNA expression levels were significantly higher in PT/LM tissues compared with NM. There was a trend for higher expression of these genes in LM compared with PT tissues, but differences were statistically significant for LDH-A expression only. RAS mutation-positive disease was associated with high GLUT-1 mRNA expression levels only. Right-sided colon tumors showed significantly higher GLUT-1, PKM-2 and LDH-A mRNA expression levels. High glycolytic profile was significantly associated with poor prognosis in 20 metastatic, RAS-mutated pts treated with first-line chemotherapy plus Bevacizumab. Altered expression of effectors associated with upregulated glucose uptake and aerobic glycolysis occurs in CRC tissues. Additional analyses are warranted for addressing the role of these changes in anti-angiogenic resistance and for developing novel therapeutics.

Internet Addiction in adolescence: Neurobiological, psychosocial and clinical issues.

Despite it has not been formally included in DSM-5 as a disorder, 'Internet addiction (IA)' has become a worldwide issue. It can be broadly defined as a non-chemical, behavioral addiction, which involves human-machine interaction. We pinpoint it as an "instrumental" form of social interaction (i.e. mediated by machines), a notion that appears useful for the sake of possible preclinical modeling. The features of Internet use reveals as addictive when this comes at the expense of genuine real-life sociability, with an overlap towards the hikikomori phenomenon (i.e., extreme retreat to one's own room). Due to the specific neuro-developmental plasticity in adolescence, IA poses risks to youths' mental health, and may likely produce negative consequences in everyday life. The thwarted development of adolescents' identity, self-image and adaptive social relationships is discussed: the IA adolescents often suffer loss of control, feelings of anger, symptoms of distress, social withdrawal, and familial conflicts. Further, more severe clinical conditions are also associated to IA, such as dysthymic, bipolar, affective, social-anxiety disorders, as well as major depression. This paper overviews the literature on IA, from neuro-biological, psycho-social and clinical standpoints, taking into account recent debates on diagnostic criteria, nosographic label and assessment tools. Neuroimaging data and neurochemical regulations are illustrated with links to pathogenetic hypotheses, which are amenable to validation through innovative preclinical modeling.

MR imaging-detectable metabolic alterations in attention deficit/hyperactivity disorder: from preclinical to clinical studies.

MR spectroscopy represents one of the most suitable in vivo tool to assess neurochemical dysfunction in several brain disorders, including attention deficit/hyperactivity disorder. This is the most common neuropsychiatric disorder in childhood and adolescence, which persists into adulthood (in approximately 30%-50% of cases). In past years, many studies have applied different MR spectroscopy techniques to investigate the pathogenesis and effect of conventional treatments. In this article, we review the most recent clinical and preclinical MR spectroscopy results on subjects with attention deficit/hyperactivity disorder and animal models, from childhood to adulthood. We found that the most investigated brain regions were the (pre)frontal lobes and striatum, both involved in the frontostriatal circuits and networks that are known to be impaired in this pathology. Neurometabolite alterations were detected in several regions: the NAA, choline, and glutamatergic compounds. The creatine pool was also altered when an absolute quantitative protocol was adopted. In particular, glutamate was increased in children with attention deficit/hyperactivity disorder, and this can apparently be reversed by methylphenidate treatment. The main difficulties in reviewing MR spectroscopy studies were in the nonhomogeneity of the analyzed subjects, the variety of the investigated brain regions, and also the use of different MR spectroscopy techniques. As for possible improvements in future studies, we recommend the use of standardized protocols and the analysis of other brain regions of particular interest for attention deficit hyperactivity disorder, like the hippocampus, limbic structures, thalamus, and cerebellum.

Compromised decision-making and increased gambling proneness following dietary serotonin depletion in rats.

Psycho-genetic studies have revealed a role for the brain serotonin system in gambling proneness and poor decision-making. We assessed whether manipulation of brain serotonin levels in rats affected performance in operant-based tasks for decision-making and gambling proneness. Male Wistar rats were exposed to an l-tryptophan (TRP) deficient diet (0.0 g/kg; T- group) or to a control, l-tryptophan containing diet (2.8 g/kg; T+ group). The same rats were tested for decision-making performance in the rodent Iowa Gambling Task (rIGT) using home-cage operant panels, and subsequently for gambling proneness in a Probabilistic Delivery Task (rPDT) using classic Skinnerboxes. At sacrifice, monoamines and metabolites were evaluated with HPLC analysis, confirming a drastically reduced serotonin synthesis, as well as altered dopamine turnover in the prefrontal cortex of T- rats. As expected, control rats (T+) progressively chose the option with the best long-term payoff in the rIGT, and also shifted from "Large & Luck-Linked" (LLL) to "Small & Sure" (SS) reinforcers in the rPDT. In contrast, depleted animals (T-) exhibited a weaker improvement of performance in the rIGT and maintained a sub-optimal attraction for LLL reinforcer in the rPDT. Comparing individual performances in both tests, we found a significant correlation between the two tasks in control (T+) but not in depleted (T-) rats. The present study revealed that (1) brain 5-HT depletion leads to poor decision-making and to gambling proneness; (2) the relationship between these two traits, shown in the control group, was disrupted in 5-HT depleted rats. The data are discussed in terms of changes within forebrain loops involved in cognitive and motivational/affective processes.