Effects of the selective kainate receptor antagonist ACET on altered sensorimotor gating in a genetic model of reduced NMDA receptor function

The pathophysiology of schizophrenia may involve reduced NMDA receptor function. Accordingly, experimental models of NMDA receptor hypofunction may be useful for testing potential new antipsychotic agents and for characterizing neurobiological abnormalities relevant to schizophrenia. We demonstrated previously that mice under-expressing the NR1 subunit of the NMDA receptor show supersensitive behavioral responses to kainic acid and that a kainate receptor antagonist normalized altered behaviors in the mutant mice (NR1neo/neo). The present work examined effects of another selective kainate receptor antagonist, (S)-1-(2-Amino-2-carboxyethyl)-3-(2-carboxy-5-phenylthiophene-3-yl-methylpyrimidine-2,4-dione (ACET), on altered behavioral phenotypes in the genetic model of NMDA receptor hypofunction. ACET, at a dose of 15 mg/kg, partially reversed the deficits in prepulse inhibition produced by the mutation. The 15 mg/kg dose of ACET was also effective in reversing behavioral effects of the selective kainate agonist ATPA. However, ACET did not significantly reduce the increased locomotor activity and rearing behavior observed in the NR1neo/neo mice. These findings show that a highly selective kainate receptor antagonist can affect the deficits in sensorimotor gating in the NR1neo/neo mice. The results also provide further support for the idea that selective kainate receptor antagonists could be novel therapeutic candidates for schizophrenia

Neratinib + capecitabine sustains health-related quality of life in patients with HER2-positive metastatic breast cancer and ≥ 2 prior HER2-directed regimens

Health-related quality of life; Metastatic breast cancer; NeratinibCalidad de vida relacionada con la salud; Cáncer de mama metastásico; NeratinibQualitat de vida relacionada amb la salut; Càncer de mama metastàtic; NeratinibPurpose To characterize health-related quality of life (HRQoL) in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) from the NALA phase 3 study. Methods In NALA (NCT01808573), patients were randomized 1:1 to neratinib + capecitabine (N + C) or lapatinib + capecitabine (L + C). HRQoL was assessed using seven prespecified scores from the European Organisation for Research and Treatment of Cancer Quality Of Life Questionnaire core module (QLQ-C30) and breast cancer-specific questionnaire (QLQ-BR23) at baseline and every 6 weeks. Descriptive statistics summarized scores over time, mixed models evaluated differences between treatment arms, and Kaplan–Meier methods were used to assess time to deterioration in HRQoL scores of ≥ 10 points. Results Of the 621 patients randomized in NALA, patients were included in the HRQoL analysis if they completed baseline and at least one follow-up questionnaire. The summary, global health status, physical functioning, fatigue, constipation, and systemic therapy side effects scores were stable over time with no persistent differences between treatment groups. There were no differences in time to deterioration (TTD) for the QLQ-C30 summary score between treatment arms; the hazard ratio (HR) for N + C vs. L + C was 0.94 (95% CI 0.63–1.40). Only the diarrhea score worsened significantly more in the N + C arm as compared to the L + C arm, and this remained over time (HR for TTD for N + C vs. L + C was 1.71 [95% CI 1.32–2.23]). Conclusion In NALA, patients treated with N + C maintained their global HRQoL over time, despite a worsening of the diarrhea-related scores. These results may help guide optimal treatment selection for HER2-positive MBC.This work was supported by Puma Biotechnology Inc., Los Angeles, CA, USA [no grant number is applicable]. Puma Biotechnology Inc. funded the provision of editorial support provided by CMD Consulting and Miller Medical Communications

Efficacy of Neratinib Plus Capecitabine in the Subgroup of Patients with Central Nervous System Involvement from the NALA Trial

Capecitabina; Neoplàsies del sistema nerviós central; Neratinibcapecitabina; Neoplasias del sistema nervioso central; NeratinibCapecitabine; Central nervous system neoplasms; NeratinibBackground Neratinib has efficacy in central nervous system (CNS) metastases from HER2-positive metastatic breast cancer (MBC). We report outcomes among patients with CNS metastases at baseline from the phase III NALA trial of neratinib plus capecitabine (N + C) versus lapatinib plus capecitabine (L + C). Materials and Methods NALA was a randomized, active-controlled trial in patients who received two or more previous HER2-directed regimens for HER2-positive MBC. Patients with asymptomatic/stable brain metastases (treated or untreated) were eligible. Patients were assigned to N + C (neratinib 240 mg per day, capecitabine 750 mg/m2 twice daily) or L + C (lapatinib 1,250 mg per day, capecitabine 1,000 mg/m2 twice daily) orally. Independently adjudicated progression-free survival (PFS), overall survival (OS), and CNS endpoints were considered. Results Of 621 patients enrolled, 101 (16.3%) had known CNS metastases at baseline (N + C, n = 51; L + C, n = 50); 81 had received prior CNS-directed radiotherapy and/or surgery. In the CNS subgroup, mean PFS through 24 months was 7.8 months with N + C versus 5.5 months with L + C (hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.41–1.05), and mean OS through 48 months was 16.4 versus 15.4 months (HR, 0.90; 95% CI, 0.59–1.38). At 12 months, cumulative incidence of interventions for CNS disease was 25.5% for N + C versus 36.0% for L + C, and cumulative incidence of progressive CNS disease was 26.2% versus 41.6%, respectively. In patients with target CNS lesions at baseline (n = 32), confirmed intracranial objective response rates were 26.3% and 15.4%, respectively. No new safety signals were observed. Conclusion These analyses suggest improved PFS and CNS outcomes with N + C versus L + C in patients with CNS metastases from HER2-positive MBC.Funded by Puma Biotechnology, Inc. Medical writing support was also funded by Puma Biotechnology Inc. and provided by Miller Medical Communications

Increased sensitivity to kainic acid in a genetic model of reduced NMDA receptor function

The pathophysiology of schizophrenia may involve reduced NMDA receptor function and experimental models of NMDA receptor hypofunction have proven useful for characterizing neurobiological abnormalities potentially relevant to schizophrenia. The present study assessed behavioral responses and induction of Fos after administration of kainic acid to wild type mice (NR1+/+) and mice with genetically reduced NMDA receptor expression (NR1neo/neo). At a dose of 20 mg/kg kainic acid induced lethal seizures in 100% of the NR1neo/neo mice tested but produced no lethal seizures in the wild type mice. The NR1neo/neo mice also exhibited enhanced behavioral responses to kainic acid at a dose of 15 mg/kg but no lethal seizures were produced by this dose. A greater induction of Fos was observed in neocortical and limbic cortical regions of the NR1neo/neo compared to NR1+/+ mice after administration of 15 mg/kg kainic acid. In contrast, there were no differences between the genotypes in kainic acid induced of Fos in the amygdala, hippocampus, lateral septum, and nucleus accumbens. In order to determine if altered behavioral phenotypes of the NR1neo/neo mice could be related to increased sensitivity of kainate receptors to endogenous glutamate, effects of the highly selective kainate antagonist LY382884 were examined. The kainate antagonist reduced the exaggerated acoustic startle responses, deficits in prepulse inhibition of acoustic startle, and motor hyperactivity in the NR1neo/neo mice. These findings suggest that selective kainate receptor antagonists could be novel therapeutic candidates for schizophrenia

Are Patients Making High-Quality Decisions about Breast Reconstruction after Mastectomy? [Outcomes Article]

Variation in rates of breast reconstruction after mastectomy has raised concerns about the quality of decisions about reconstruction. We sought to evaluate patient decision making about reconstruction, using a validated measure of knowledge and preferences related to reconstruction

Neural activation deficits in a mouse genetic model of NMDA receptor hypofunction in tests of social aggression and swim stress

Mice with reduced expression of the NR1 subunit of the NMDA receptor (NR1 hypomorphic mice) display altered behavioral phenotypes that may relate to behavioral characteristics of schizophrenia. Altered phenotypes in the NR1 hypomorphs include marked deficits in species-typical behavioral interactions in tests of social aggression and social affiliation. To gain insight into neuroanatomical circuits disrupted by reduced NMDA receptor function, the present work compared regional brain activation in NR1 hypomorphic mice and their wild type controls after a resident-intruder test. Induction of Fos protein was used as an index of neuronal activation. Wild type mice exhibited robust induction of Fos in select brain regions, including specific nuclei of the hypothalamus and amygdala, lateral septum, and widespread regions of the cerebral cortex. Although the behavioral patterns were different for male and female mice, neuroanatomical patterns of Fos induction were remarkably similar for the two sexes. To determine socially specific components of Fos induction by the resident-intruder test, responses were compared for mice assessed in a test of general arousal and stress involving forced swim. Some common brain regions were activated by both tests but regionally specific differences were also found. The NR1 hypomorphic mice tested in the resident-intruder procedure displayed distinctly different behavioral interactions compared to the wild type mice and exhibited a significantly blunted Fos response in almost all brain regions. The mutant mice also exhibited reduced Fos in response to swim stress in specific brain regions. These data suggest that the NR1 hypomorphic mice have functional activation deficits in response to social challenge and swim stress

Preweaning Sensorimotor Deficits and Adolescent Hypersociability in Grin1 Knockdown Mice

Mice with knockdown of the N-methyl-D-aspartate (NMDA) receptor NR1 subunit, encoded by the gene Grin1, have been investigated as a model for the intrinsic NMDA hypofunction hypothesized for schizophrenia. Previous work has shown that adult Grin1 mutant mice have overt deficits in habituation and sensorimotor gating, exaggerated reactivity to environmental stimuli, reduced social approach, and other alterations that reflect behavioral manifestations of schizophrenia. In humans, the emergence of overt symptoms of the disorder typically occurs in adolescence or early adulthood, suggesting a role for aberrant maturation of NMDA receptor signaling in symptom onset. The following study evaluated Grin1 mutant mice for abnormal behavioral phenotypes during the preweaning, adolescent, and adult periods. Measures included open field activity, prepulse inhibition of acoustic startle responses, and social preference in a three-chamber choice task. Mice from the C57BL/6J inbred strain, one of the parental strains for the Grin1 line, were also tested. The results showed that developmental reduction of NMDA receptor function led to significant alterations in behavior during the second and third weeks of life, including exaggerated startle responses and sensorimotor gating deficits on postnatal day 13, and pronounced hypersociability in adolescence. Male Grin1 mutant mice were more susceptible than female mice to the detrimental effects of decreased NMDA signaling. Overall, these findings provide evidence that reduced Grin1 function leads to abnormal phenotypes in the preweaning period, and that deficient NMDA signaling can lead to both overt hypersociability or marked asociality, dependent upon sex and age

Reversal of social deficits by subchronic oxytocin in two autism mouse models

Social deficits are a hallmark feature of autism spectrum disorder (ASD) and related developmental syndromes. Although there is no standard treatment for social dysfunction, clinical studies have identified oxytocin as a potential therapeutic with prosocial efficacy. We have previously reported that peripheral oxytocin treatment can increase sociability and ameliorate repetitive stereotypy in adolescent mice from the C58/J model of ASD-like behavior. In the present study, we determined that prosocial oxytocin effects were not limited to the adolescent period, since C58/J mice, tested in adulthood, demonstrated significant social preference up to 2 weeks following subchronic oxytocin treatment. Oxytocin was also evaluated in adult mice with underexpression of the N-methyl-D-aspartate receptor NR1 subunit (encoded by Grin1), a genetic model of autism- and schizophrenia- like behavior. Subchronic oxytocin had striking prosocial efficacy in male Grin1 knockdown mice; in contrast, chronic regimens with clozapine (66 mg/kg/day) or risperidone (2 mg/kg/day) failed to reverse deficits in sociability. Neither the subchronic oxytocin regimen, nor chronic treatment with clozapine or risperidone, reversed impaired prepulse inhibition in the Grin1 knockdown mice. Overall, these studies demonstrate oxytocin can enhance sociability in mouse models with divergent genotypes and behavioral profiles, adding to the evidence that this neurohormone could have therapeutic prosocial efficacy across a spectrum of developmental disorders

Measuring decision quality: psychometric evaluation of a new instrument for breast cancer chemotherapy

Abstract Background Women diagnosed with early stage (I or II) breast cancer face a highly challenging decision – whether or not to undergo adjuvant chemotherapy. We developed a decision quality instrument for chemotherapy for early stage breast cancer and sought to evaluate its performance. Methods Cross-sectional, mailed survey of recent breast cancer survivors, providers, and healthy controls and a retest survey of survivors. The decision quality instrument includes questions on knowledge and personal goals. It results in a knowledge score and concordance score, which reflects the percentage of patients who received treatments that match their goals. Hypotheses related to acceptability, feasibility, validity, and reliability of the survey instrument were examined. Results Responses were received from 352 patients, 89 providers and 35 healthy controls. The decision quality instrument was feasible to implement with few missing data. The knowledge scores had good retest reliability (intraclass correlation coefficient (ICC) =0.75). Knowledge scores discriminated between providers and patients (mean difference 31.1%, 95% CI 26.9, 35.3) and between patients and healthy controls (mean difference 11.2, 95% CI 5.4, 17.1). Most providers reported that the knowledge items covered essential content. Two of the five goal items had a ceiling effect, and one goal had low content validity. The goal items had moderate retest reliability (ICC’s 0.57 to 0.78). In the multivariable model of treatment, none of the patient goals was associated with receipt of chemotherapy. Age and hormone receptor status were the only variables independently associated with chemotherapy. Most patients (77.6%) had treatment concordant with that predicted by the model. Patients who had concordant treatment had similar levels of confidence and regret as those who did not. Conclusions The Decision Quality Instrument is a reliable and valid measure of patient knowledge about chemotherapy, but its ability to measure concordance with patient goals is limited. In this sample, patient goals were not associated with treatment, and most patients reported they were not asked their preference, suggesting that goals were not adequately considered in decision making

Decision Making about Surgery for Early-Stage Breast Cancer

Practice variation in breast cancer surgery has raised concerns about the quality of treatment decisions. We sought to evaluate the quality of decisions about surgery for early stage breast cancer by measuring patient knowledge, concordance between goals and treatments, and involvement in decisions