Nivolumab or Atezolizumab in the Second-Line Treatment of Advanced Non-Small Cell Lung Cancer? A Prognostic Index Based on Data from Daily Practice.

BACKGROUND: The efficacy of nivolumab and atezolizumab in advanced pre-treated NSCLC was documented in prospective trials. We aim to confirm the benefits and indicate predictive factors for immunotherapy in daily practice. METHODS: This study was a retrospective analysis. The median PFS and OS were estimated using the Kaplan-Meier method. The log-rank test was used for comparisons. Multivariate analyses were performed using the Cox regression method. RESULTS: A total of 260 patients (ECOG 0-1) with advanced NSCLC (CS III-IV) were eligible to receive nivolumab or atezolizumab as second-line treatment. Median PFS and OS were three months (95% confidence interval [CI] 2.57-3.42) and 10 months (95% CI 8.03-11.96), respectively, for the overall population. The median OS for the atezolizumab arm was eight months (95% CI 5.89-10.1), while for the nivolumab group, it was 14 months (95% CI 10.02-17.97) (p = 0.018). The sum of all measurable changes >100.5 mm (p = 0.007; HR = 1.003, 95% CI 1.001-1.005), PLT > 281.5 G/l (p < 0.001; HR = 1.003, 95% CI 1.001-1.003) and bone metastases (p < 0.004; HR = 1.58, 95% CI 1.04-2.38) were independent negative prognostic factors for OS in multivariate analysis. Based on preliminary analyses, a prognostic index was constructed to obtain three prognostic groups. Median OS in the subgroups was 16 months (95% CI 13.3-18.7), seven months (95% CI 4.83-9.17) and four months (95% CI 2.88-5.13), respectively (p < 0.001). CONCLUSIONS: Nivolumab and atezolizumab provided clinical benefit in real life. Clinical and laboratory factors may help to identify subgroups likely to benefit. The use of prognostic indices may be valuable in clinical practice.

Beta Blockers with Statins May Decrease All-Cause Mortality in Patients with Cardiovascular Diseases and Locally Advanced Unresectable Non-Small-Cell Lung Cancer after Chemoradiotherapy.

The study was conducted in the era when maintenance immunotherapy with durvalumab was not available in clinical practice after chemoradiotherapy (CRT) in unresectable non-small-cell lung cancer (NSCLC). The main aim of the study was to check whether the presence of cardiovascular diseases (CVD) and their pharmacotherapy affects the overall survival (OS) in such NSCLC patients undergoing sequential CRT. The group of 196 patients were analyzed: 101 patients with CVD (51.53%) and 95 patients with other reasons of qualification for sequential CRT (decreased performance status, older age, and other non-cardiovascular co-morbidities). Although patients with CVD were more often in older age, and they more often experienced cardiac and nephrological complications (p < 0.05 for all), there was a statistically nonsignificant trend for lower all-cause mortality in patients with CVD. The lowest all-cause mortality was observed in patients treated with beta-blockers and statins after two (HR = 0.31; 95%CI: 0.1-0.98; p = 0.047), three (HR = 0.33; 95%CI: 0.13-0.81; p = 0.015) and even four (HR = 0.45; 95%CI: 0.22-0.97; p = 0.027) years of follow-up. The benefit in OS remained significant in 101 patients with CVD treated with beta-blockers (HR = 0.65; 95%CI: 0.43-0.99; p = 0.045), and eventually statin, throughout the whole follow-up (log-rank p < 0.05). Further prospective studies are necessary to confirm the role of beta-blockers and statins in reduction of mortality in NSCLC patients undergoing radical CRT.

Performance-Status Deterioration during Sequential Chemo-Radiotherapy as a Predictive Factor in Locally Advanced Non-Small Cell Lung Cancer.

The role of sequential chemoradiotherapy in non-small cell lung cancer (NSCLC) patients who are not eligible for concurrent therapy has not been clearly defined. The aim of this study was to determine the usefulness of Karnofsky performance status (KPS) monitoring and to define the factors determining clinical deterioration during sequential chemoradiotherapy in patients treated from July 2009 to October 2014. The study included 196 patients. The clinical stage was defined as III A in 94 patients (48%) and III B in 102 patients (52%). Reduced KPS was found in 129 patients (65.8%). Baseline KPS had no significant prognostic significance. Deterioration of KPS during chemoradiotherapy was observed in 53 patients (27%) and had a negative predictive value for both worse-progression free survival (HR = 1.44; 95% CI: 1.03-1.99; p = 0.03) and overall survival (HR = 1.42; 95% CI: 1.02-1, 99; p = 0.04). The deterioration of KPS correlated with the disease control rate 6 weeks after the end of chemoradiotherapy (p = 0.0085). The risk of KPS worsening increased with each subsequent day between the end of chemotherapy and the start of radiotherapy (OR = 1.03; 95%CI: 1.01-1.05; p = 0.001), but decreased with each year of older age of patients (OR = 0.94, 95% CI: 0.9-0.98, p = 0.009). The time between the end of chemotherapy and the start of radiotherapy determined the prognosis of NSCLC after chemoradiotherapy. It should be adjusted to the age of patients.

Acute stress modulates noradrenergic signaling in the ventral tegmental area-amygdalar circuit.

Noradrenergic neurotransmission is a critical mediator of stress responses. In turn, exposure to stress induces noradrenergic system adaptations, some of which are implicated in the etiology of stress-related disorders. Adrenergic receptors (ARs) in the ventral tegmental area (VTA) have been demonstrated to regulate phasic dopamine (DA) release in the forebrain, necessary for behavioral responses to conditional cues. However, the impact of stress on noradrenergic modulation of the VTA has not been previously explored. We demonstrate that ARs in the VTA regulate dopaminergic activity in the VTA-BLA (basolateral amygdala) circuit, a key system for processing stress-related stimuli; and that such control is altered by acute stress. We utilized fast-scan cyclic voltammetry to assess the effects of intra-VTA microinfusion of α1 -AR and α2 -AR antagonists (terazosin and RX-821002, respectively), on electrically evoked phasic DA release in the BLA in stress-naïve and stressed (unavoidable electric shocks - UES) anesthetized male Sprague-Dawley rats. In addition, we used western blotting to explore UES-induced alterations in AR protein level in the VTA. Intra-VTA terazosin or RX-821002 dose-dependently attenuated DA release in the BLA. Interestingly, UES decreased the effects of intra-VTA α2 -AR blockade on DA release (24 h but not 7 days after stress), while the effects of terazosin were unchanged. Despite changes in α2 -AR physiological function in the VTA, UES did not alter α2 -AR protein levels in either intracellular or membrane fractions. These findings demonstrate that NA-ergic modulation of the VTA-BLA circuit undergoes significant alterations in response to acute stress, with α2 -AR signaling indicated as a key target.

Recruitment of inhibitory neuronal pathways regulating dopaminergic activity for the control of cocaine seeking.

Drug seeking is associated with the ventral tegmental area (VTA) dopaminergic (DA) activity. Previously, we have shown that brief optogenetic inhibition of VTA DA neurons with 1 s pulses delivered every 9 s attenuates cocaine seeking under extinction conditions in rats without producing overt signs of dysphoria or locomotor sedation. Whether recruitment of neuronal pathways inhibiting VTA neuronal activity would suppress drug seeking remains unknown. Here, we asked if optogenetic stimulation of the lateral habenula (LHb) efferents in the rostromedial tegmental nucleus (RMTg) as well as RMTg efferents in VTA would reduce drug seeking. To investigate this, we measured how recruitment of elements of this inhibitory pathway affects cocaine seeking in male rats under extinction conditions. The effectiveness of brief optogenetic manipulations was confirmed electrophysiologically at the level of electrical activity of VTA DA neurons. Real-time conditioned place aversion (RT-CPA) and open field tests were performed to control for potential dysphoric/sedating effects of brief optogenetic stimulation of LHb-RMTg-VTA circuitry. Optogenetic stimulation of either RMTg or LHb inhibited VTA DAergic neuron firing, whereas similar stimulation of RMTg efferents in VTA or LHb efferents in RMTg reduced cocaine seeking under extinction conditions. Moreover, stimulation of LHb-RMTg efferents produced an effect that was maintained 24 h later, during cocaine seeking test without stimulation. This effect was specific, as brief optogenetic stimulation did not affect locomotor activity and was not aversive. Our results indicate that defined inhibitory pathways can be recruited to inhibit cocaine seeking, providing potential new targets for non-pharmacological treatment of drug craving.

Regulation of cocaine seeking behavior by locus coeruleus noradrenergic activity in the ventral tegmental area is time- and contingency-dependent.

Substance use disorder is linked to impairments in the ventral tegmental area (VTA) dopamine (DA) reward system. Noradrenergic (NA) inputs from locus coeruleus (LC) into VTA have been shown to modulate VTA neuronal activity, and are implicated in psychostimulant effects. Phasic LC activity controls time- and context-sensitive processes: decision making, cognitive flexibility, motivation and attention. However, it is not yet known how such temporally-distinct LC activity contributes to cocaine seeking. In a previous study we demonstrated that pharmacological inhibition of NA signaling in VTA specifically attenuates cocaine-seeking. Here, we used virally-delivered opsins to target LC neurons for inhibition or excitation, delivered onto afferents in VTA of male rats seeking cocaine under extinction conditions. Optogenetic stimulation or inhibition was delivered in distinct conditions: upon active lever press, contingently with discreet cues; or non-contingently, i.e., throughout the cocaine seeking session. Non-contingent inhibition of LC noradrenergic terminals in VTA attenuated cocaine seeking under extinction conditions. In contrast, contingent inhibition increased, while contingent stimulation reduced cocaine seeking. These findings were specific for cocaine, but not natural reward (food) seeking. Our results show that NA release in VTA drives behavior depending on timing and contingency between stimuli - context, discreet conditioned cues and reinforcer availability. We show that, depending on those factors, noradrenergic signaling in VTA has opposing roles, either driving CS-induced drug seeking, or contributing to behavioral flexibility and thus extinction.

Effects of brief inhibition of the ventral tegmental area dopamine neurons on the cocaine seeking during abstinence.

Preclinical studies strongly suggest that cocaine seeking depends on the neuronal activity of the ventral tegmental area (VTA) and phasic dopaminergic (DA) signaling. Notably, VTA pharmacological inactivation or dopamine receptor blockade in the forebrain may induce behavioral inhibition in general and acute aversive states in particular, thus reducing cocaine seeking indirectly. Such artifacts hinder successful translation of these findings in clinical studies and practice. Here, we aimed to evaluate if dynamic VTA manipulations effectively reduce cocaine seeking. We used male tyrosine hydroxylase (TH) IRES-Cre+ rats along with optogenetic tools to inhibit directly and briefly VTA DA neurons during conditioned stimulus (CS)-induced cocaine seeking under extinction conditions. The behavioral effects of optogenetic inhibition were also assessed in the real-time dynamic place aversion, conditioned place aversion, and CS-induced food-seeking tests. We found that brief and nondysphoric/nonsedative pulses of VTA photo-inhibition (1 s every 9 s, ie, for 10% of time) attenuated CS-induced cocaine seeking under extinction conditions in rats expressing archaerhodopsin selectively on the TH+ neurons. Furthermore, direct inhibition of the VTA DA activity reduced CS-induced cocaine seeking 24 hours after photo-modulation. Importantly, such effect appears to be selective for cocaine seeking as similar inhibition of the VTA DA activity had no effect on CS-induced food seeking. Thus, briefly inhibiting VTA DA activity during CS-induced cocaine seeking drastically and selectively reduces seeking without behavioral artifacts such as sedation or dysphoria. Our results point to the therapeutic possibilities of coupling nonpharmacologic treatments with extinction training in reducing cocaine addiction.

Alpha1-adrenergic receptor blockade in the ventral tegmental area modulates conditional stimulus-induced cocaine seeking.

Exposure to drug-associated cues evokes drug-craving and upregulates noradrenaline (NA) and dopamine (DA) system activity. Importantly, conditional stimulus-induced drug-seeking behavior depends particularly on phasic DA signaling downstream from the ventral tegmental area (VTA), a midbrain structure key for the regulation of cocaine seeking. In particular, the activity of the alpha1-adrenergic receptor (α1-AR), which has recently been hypothesized to modulate salience encoding, is capable of bidirectional regulation of VTA dopaminergic activity. Thus, the impact of the conditional stimuli (CSs) on drug-seeking behavior might involve α1-AR signaling in the VTA. To date, the role of VTA α1-ARs in regulating CS-induced cocaine seeking has not been studied. In male Sprague-Dawley rats, we found that intra-VTA terazosin, a selective α1-AR antagonist, attenuated CS-induced cocaine seeking in a novel context and under extinction conditions, as well as CS-induced reinstatement of cocaine seeking. In contrast, terazosin microinfusion in a dose that attenuated CS-induced cocaine seeking had no effects on CS-induced food seeking or stress (2 mg/kg yohimbine)-evoked reinstatement of cocaine seeking. The potential nonspecific effects (sedative, anxiogenic) of α1-AR blockade of the VTA were also measured in the open-field test. Finally, using immunostaining, we demonstrated dopamine ß-hydroxylase (DBH)-positive afferents in the VTA of cocaine-abstinent rats, providing a neuroanatomical substrate for the α1-AR mechanism. These results demonstrated for the first time that NAergic signaling via VTA α1-ARs potently and selectively regulates CS-induced cocaine seeking. Our findings provide new neuronal mechanisms that regulate cocaine craving.

Evaluation of ultrasonic vocalizations in a neurodevelopmental model of schizophrenia during the early life stages of rats.

In an animal neurodevelopmental model of schizophrenia, we investigated ultrasonic communication and social behavior in male and female rats. Pregnant dams were treated with methylazoxymethanol acetate (MAM; 22 mg/kg) at 17 days of gestation. First, we examined the ultrasonic vocalizations (USVs) emitted by 8-day-old pups isolated from their mothers and placed in a familiar or an unfamiliar environment. Second, we assessed tickling-induced USVs, social play (SP) behavior and accompanying USVs in 30-day-old juveniles. Independent of the prenatal treatment, sex differences were noted at both ages. In the pups isolated from their mothers, compared to the females, the males produced flatter calls with a lower frequency. Compared to the females, the tickling-induced male USVs were characterized by a higher frequency, and the male SP-induced USVs showed a broader bandwidth and more modulated structure. Additionally, the numbers of both SP-induced USVs and SP episodes in the males were higher than those in the females. In contrast, the MAM exposure reduced the ultrasonic communication and social behavior independent of age almost equally in the male and female rats. The MAM-exposed isolated pups and juveniles experiencing tickling and social interaction displayed lower USV bandwidths, suggesting that the complexity of their ultrasonic communication was reduced. In addition, the MAM-exposed juveniles demonstrated a lower number of 50-kHz "happy calls" and decreased SP duration, which is suggestive of social withdrawal or negative-like symptoms. These data demonstrate that young MAM-exposed rats display an atypical repertoire of USVs and reduced play behavior suggestive of communication deficits associated with schizophrenia.

[Gefitinib in patients with advanced non-small-cell lung cancer]. / Gefitynib u chorych na niedrobnokomórkowego raka pluca w zaawansowanym stadium.

INTRODUCTION: Patients with advanced non-small cell lung cancer (NSCLC) have a very poor prognosis. Individualization of treatment and identification of therapeutic molecular targets may improve outcomes. Gefitinib was introduced recently among several other molecular-targeted drugs of activity in NSCLC. Gefitinib is indicated for patients diagnosed with advanced or disseminated NSCLC with an activating mutation in the EGFR (epidermal growth factor receptor) gene. The paper summarize experience with gefitinib in the Department of Lung and Thoracic Tumors of Maria Sklodowska-Curie Memorial Cancer Centre and Institute in Warsaw. MATERIAL AND METHODS: The group of 11 patients diagnosed with advanced NSCLC and activating mutations in the EGFR gene was analyzed. Patients were treated from April 2010 to April 2011. Tolerability, objective response rate (ORR) and progression free survival (PFS), which was calculated by the Kaplan-Meier method, were assessed. RESULTS: Median observation time from the start of gefitinib treatment was 14 months (range 4,8-19 months). The rate of one-year survival in this group of patients was 91% (10 patients) with 54% of patients (6 patients) surviving one year without progression of disease. The ORR rate of 82% and median PFS 11.4 months were reached. No treatment-related deaths were reported. Among the complications skin toxicity (82%) and diarrhea (45%) were most frequently observed, in most cases the Common Toxicity Criteria for Adverse Events (CTCAE) first grade. CONCLUSIONS: The results confirm the literature data on the efficacy and safety profile of gefitinib in the treatment of patients with the diagnosis of advanced NSCLC and activating mutation in the EGFR gene.

CTLA-4, CD28, and ICOS gene polymorphism associations with non-small-cell lung cancer.

Polymorphisms in genes encoding CD28, ICOS, and CTLA-4 were demonstrated to be associated with susceptibility to malignancies. To the best of our knowledge, no study on this association has been performed in a Caucasian population for non-small-cell lung cancer (NSCLC). In the present work, we investigated the polymorphisms CTLA-4c.49A>G (rs231775), CTLA-4g.319C>T (rs5742909), CTLA-4g.*642AT(8_33), CTLA-4g.*6230G>A (CT60) (rs3087243), CTLA-4g.*10223G>T (Jo31) (rs11571302), CD28c.17+3T>C (rs3116496), and ICOSc.1554+4GT(8_15) in 208 NSCLC patients and 326 controls. The distributions of the allele and genotype were similar in both groups for CTLA-4, CD28, and ICOS gene polymorphisms. However, we noted a tendency toward overrepresentation of individuals possessing the CTLA-4c.49A>G[A] allele in NSCLC patients compared with controls (0.84 vs 0.79, p = 0.09). The association became significant compared with controls in women for the CTLA-4c.49A>G[A] allele and CTLA-4c.49A>G[AA] genotype (0.67 vs 0.54, p = 0.01, and 0.47 vs 0.30, p = 0.02; respectively). Moreover, the constellation of alleles CTLA-4c.49A>G[A]/CT60[G]/CD28c.17+3T>C[T]/ICOSc.1554+4GT(8_15)[>10] increased the risk of NSCLC about 2-fold (p = 0.002). The same constellation of alleles combined with smoking, CTLA-4g.319C>T[T], and ICOSc.1554+4GT(8_15)[>10] was associated with a decreased overall survival rate. In conclusion, the constellation of specific alleles in CTLA-4, CD28, and ICOS genes contributes to the susceptibility and clinical course of NSCLC.