Τετάρτη 17 Οκτωβρίου 2018
Survival analysis of carboplatin added to an anthracycline/taxane-based neoadjuvant chemotherapy and HRD score as predictor of response – final results from GeparSixto
Abstract
Background
In the neoadjuvant GeparSixto study, adding carboplatin to taxane- and anthracycline-based chemotherapy improved pathological complete response (pCR) rates in patients with triple-negative breast cancer (TNBC). Here, we present survival data and the potential prognostic and predictive role of homologous recombination deficiency (HRD). Patients and Methods
Patients were randomized to paclitaxel plus non-pegylated liposomal doxorubicin (Myocet®) (PM) or PM plus carboplatin (PMCb). The secondary study endpoints disease-free survival (DFS) and overall survival (OS) were analyzed. Median follow-up was 47.3 months. HRD was among the exploratory analyses in GeparSixto and was successfully measured in FFPE tumor samples of 193/315 (61.3%) participants with TNBC. HR deficiency was defined as HRD score ≥42 and/or presence of tumor BRCA mutations (tmBRCA). Results
A significantly better DFS (hazard ratio 0.56, 95%CI 0.34-0.93; P=0.022) was observed in patients with TNBC when treated with PMCb. The improvement of OS with PMCb was not statistically significant. Additional carboplatin did not improve DFS or OS in patients with HER2-positive tumors.HR deficiency was detected in 136 (70.5%) of 193 triple-negative tumors, of which 82 (60.3%) showed high HRD score without tmBRCA. HR deficiency independently predicted pCR (ypT0 ypN0) (odds ratio (OR) 2.60, 95%CI 1.26-5.37, P=0.008). Adding carboplatin to PM significantly increased the pCR rate from 33.9% to 63.5% in HR deficient tumors (P=0.001), but only marginally in HR non-deficient tumors (from 20.0% to 29.6%, P=0.540; test for interaction P=0.327). pCR rates with carboplatin were also higher (63.2%) than without carboplatin (31.7%; OR 3.69, 1.46-9.37, P=0.005) in patients with high HRD score but no tmBRCA. DFS rates were improved with addition of carboplatin, both in HR non-deficient (hazard ratio 0.44, 0.17–1.17, P=0.086) and HR deficient tumors (hazard ratio 0.49, 0.23–1.04, P=0.059). Conclusions
The addition of carboplatin to neoadjuvant PM improved DFS significantly in TNBC. Long-term survival analyses support the neoadjuvant use of carboplatin in TNBC. HR deficiency in TNBC and HRD score in non-tmBRCA TNBC are predictors of response. HRD does not predict for carboplatin benefit.Interpretation of Time-to-event Outcomes in Randomized Trials: an online randomized experiment
Abstract
Background
Multiple features in the presentation of randomized controlled trial (RCT) results are known to influence comprehension and interpretation. We aimed to compare interpretation of cancer RCTs with time-to-event outcomes when the reported treatment effect measure is the hazard ratio (HR), difference in restricted mean survival times (RMSTD), or both (HR+RMSTD). We also assessed the prevalence of misinterpretation of the HR. Patients and methods
We performed a randomized experiment. We selected 15 cancer RCTs with statistically significant treatment effects for the primary outcome. We masked each abstract and created 3 versions reporting either the HR, RMSTD, or HR+RMSTD. We randomized corresponding authors of RCTs and medical residents and fellows to one of 15 abstracts and one of 3 versions. We asked how beneficial the experimental treatment was (0 to 10 Likert scale). All participants answered a multiple-choice question about interpretation of the HR. Participants were unaware of the study purpose. Results
We randomly allocated 160 participants to evaluate an abstract reporting the HR, 154 to the RMSTD, and 155 to both HR+RMSTD. The mean Likert score was statistically significantly lower in the RMSTD group as compared with the HR group (mean difference -0.8, 95% confidence interval, -1.3 to -0.4, p < 0.01) and as compared with the HR+RMSTD group (difference -0.6, -1.1 to -0.1, p = 0.05). In all, 47.2% (42.7% to 51.8%) of participants misinterpreted the HR, with 40% equating it with a reduction in absolute risk. Conclusion
Misinterpretation of the HR is common. Participants judged experimental treatments to be less beneficial when presented with RMSTD as compared with HR. We recommend that authors present RMST-based measures alongside the HR in reports of RCT results.Statistical challenges posed by uncontrolled master protocols: sensitivity analysis of the Vemurafenib study
Abstract
Within the evidentiary hierarchy of experimental inquiry, randomized trials are the gold standard. Oncology patients enter clinical studies with diverse lifestyles, treatment pathways, host tissue environments, and competing co-morbidities. Randomization attempts to balance prognostic characteristics among study arms, thereby enabling statistical inference of "average benefit" and attribution to the studied therapies. In contrast, interpretations of uncontrolled trials require additional scrutiny to attempt to place the findings in the context of external evidence. Counter-factual reasoning and speculation across trials may be obscured by the disproportionate enrollment of prognostic subpopulations which may be unknown from publications of trial reports. Recent modifications to the regulatory environment (Food and Drug Administration Safety and Innovation Act) have elevated the importance of non-comparative trials. Moreover, the emergence of recent innovations in precision medicine have yielded trial designs that partition potentially heterogeneous subpopulations into "statistically exchangeable" cohorts by histologies, or genetic alterations, further elevating the importance of single-cohort analyses. As patient cohorts become ever more refined into smaller targeted subsets, consumers of reports of uncontrolled trials should be further empowered with improvements in reporting practices that better describe the enrolled prognostic subpopulations and importantly their association with study endpoints. This article demonstrates the issue with a sensitivity analysis of the findings reported in a recent trial which was devised to evaluate the preliminary clinical efficacy of vemurafenib in BRAFV600 mutation–positive nonmelanoma cancers.Not Just For Cows Anymore: New Cottonseed Is Safe For People To Eat
Cottonseed is full of protein but toxic to humans and most animals. The USDA has approved a genetically engineered cotton with edible seeds. They could eventually feed chickens, fish — or even people.
(Image credit: Courtesy of Lacey Roberts/Texas A&M University)
Symptoms of premenstrual syndrome in female migraineurs with and without menstrual migraine
Menstrual migraine (MM) and premenstrual syndrome (PMS) are two conditions linked to specific phases of the menstrual cycle. The exact pathophysiological mechanisms are not fully understood, but both condition...
Epidemiology of Nickel Sensitivity: Retrospective Cross-Sectional Analysis of North American Contact Dermatitis Group (NACDG) Data 1994-2014
Detailed analyses of trends in nickel sensitivity in North America are lacking. Clinicians should be aware of a significant increase in nickel sensitivity over time (14.3% to 20.1% from 1994 to 2014) and significant increase in current clinical relevance of reactions over time (44.1% to 51.6% from 1994 to 2014).
Drug repurposing prediction for immune-mediated cutaneous diseases using a word-embedding based machine learning approach
Immune-mediated diseases affect >20% of the population and many autoimmune diseases affect the skin. Drug repurposing (aka repositioning) is a cost-effective approach for revealing drugs that can be used to treat diseases for which they are currently not prescribed. We implemented an efficient bioinformatics approach using "word embedding" to summarize drug information from >20 million articles, and applied machine learning to model the drug-disease relationship. We trained our drug repurposing approach separately on 9 cutaneous diseases (including psoriasis, atopic dermatitis and alopecia areata), as well as 8 other immune-mediated diseases, and obtained a mean AUROC of 0.93 in cross-validation.
Hippocampal-Evoked Feedforward Inhibition in the Nucleus Accumbens
The nucleus accumbens (NAc) is critical for motivated behavior and is rewired following exposure to drugs of abuse. Medium spiny neurons (MSNs) in the NAc express either D1 or D2 receptors and project to distinct downstream targets. Differential activation of these MSNs depends on both excitation from long-range inputs and inhibition via the local circuit. Assessing how long-range excitatory inputs engage inhibitory circuitry is therefore important for understanding NAc function. Here, we use slice electrophysiology and optogenetics to study ventral hippocampal (vHPC)-evoked feedforward inhibition in the NAc of male and female mice. We find that vHPC-evoked excitation is stronger at D1+ than D1– MSNs, whereas inhibition is unbiased at the two cell types. vHPC inputs contact both parvalbumin-positive (PV+) and somatostatin-positive (SOM+) interneurons, but PV+ cells are preferentially activated. Moreover, suppressing PV+ interneurons indicates they are primarily responsible for vHPC-evoked inhibition. Finally, repeated cocaine exposure alters the excitation of D1+ and D1– MSNs, without concomitant changes to inhibition, shifting the excitation/inhibition balance. Together, our results highlight the contributions of multiple interneuron populations to feedforward inhibition in the NAc. Moreover, they demonstrate that inhibition provides a stable backdrop on which drug-evoked changes to excitation occur within this circuit.
SIGNIFICANCE STATEMENT Given the importance of the nucleus accumbens (NAc) in reward learning and drug-seeking behaviors, it is critical to understand what controls the activity of cells in this region. While excitatory inputs to projection neurons in the NAc have been identified, it is unclear how the local inhibitory network becomes engaged. Here, we identify a sparse population of interneurons responsible for feedforward inhibition evoked by ventral hippocampal input and characterize their connections within the NAc. We also demonstrate that the balance of excitation and inhibition that projection neurons experience is altered by exposure to cocaine. Together, this work provides insight into the fundamental circuitry of this region as well as the effects of drugs of abuse.
Early Appearance and Spread of Fast Ripples in the Hippocampus in a Model of Cortical Traumatic Brain Injury
Fast ripples (FRs; activity of >250 Hz) have been considered as a biomarker of epileptic activity in the hippocampus and entorhinal cortex; it is thought that they signal the focus of seizure generation. Similar high-frequency network activity has been produced in vitro by changing extracellular medium composition, by using pro-epileptic substances, or by electrical stimulation. Here we study the propagation of these events between different subregions of the male rat hippocampus in a recently introduced experimental model of FRs in entorhinal cortex–hippocampal slices in vitro. By using a matrix of 4096 microelectrodes, the sites of initiation, propagation pathways, and spatiotemporal characteristics of activity patterns could be studied with unprecedented high resolution. To this end, we developed an analytic tool based on bidimensional current source density estimation, which delimits sinks and sources with a high precision and evaluates their trajectories using the concept of center of mass. With this methodology, we found that FRs can arise almost simultaneously at noncontiguous sites in the CA3-to-CA1 direction, underlying the spatial heterogeneity of epileptogenic foci, while continuous somatodendritic waves of activity develop. An unexpected, yet important propagation route is the propagation of activity from CA3 into the hilus and dentate gyrus. This pathway may cause reverberating activation of both regions, supporting sustained pathological network events and altered information processing in hippocampal networks.
SIGNIFICANCE STATEMENT Fast ripples (FRs) have been considered as a biomarker of epileptic activity and may signal the focus of seizure generation. In a model of traumatic brain injury in the rat, FRs appear in the hippocampus within a couple of hours after an extrahippocampal, cortical lesion. We analyzed the origin and dynamics of the FRs in the hippocampus using massive electrophysiological recordings, allowing an unprecedented high spatiotemporal resolution. We show that FRs originate in distinct and noncontiguous locations within the CA3 region and uncover, with high precision, the extent and dynamics of their current density. This activity propagates toward CA1 but also backpropagates to the hilus and the dentate gyrus, suggesting activation of defined microcircuits that can sustain recurrent excitation.
TOM1 Regulates Neuronal Accumulation of Amyloid-{beta} Oligomers by Fc{gamma}RIIb2 Variant in Alzheimer's Disease
Emerging evidences suggest that intraneuronal Aβ correlates with the onset of Alzheimer's disease (AD) and highly contributes to neurodegeneration. However, critical mediator responsible for Aβ uptake in AD pathology needs to be clarified. Here, we report that FcRIIb2, a variant of Fc-receptor IIb (FcRIIb), functions in neuronal uptake of pathogenic Aβ. Cellular accumulation of oligomeric Aβ1–42, not monomeric Aβ1–42 or oligomeric Aβ1–40, was blocked by Fcgr2b knock-out in neurons and partially in astrocytes. Aβ1–42 internalization was FcRIIb2 di-leucine motif-dependent and attenuated by TOM1, a FcRIIb2-binding protein that repressed the receptor recycling. TOM1 expression was downregulated in the hippocampus of male 3xTg-AD mice and AD patients, and regulated by miR-126-3p in neuronal cells after exposure to Aβ1–42. In addition, memory impairments in male 3xTg-AD mice were rescued by the lentiviral administration of TOM1 gene. Augmented Aβ uptake into lysosome caused its accumulation in cytoplasm and mitochondria. Moreover, neuronal accumulation of Aβ in both sexes of 3xTg-AD mice and memory deficits in male 3xTg-AD mice were ameliorated by forebrain-specific expression of Aβ-uptake-defective Fcgr2b mutant. Our findings suggest that FcRIIb2 is essential for neuropathic uptake of Aβ in AD.
SIGNIFICANCE STATEMENT Accumulating evidences suggest that intraneuronal Aβ is found in the early step of AD brain and is implicated in the pathogenesis of AD. However, the critical mediator involved in these processes is uncertain. Here, we describe that the FcRIIb2 variant is responsible for both neuronal uptake and intraneuronal distribution of pathogenic Aβ linked to memory deficits in AD mice, showing a pathologic significance of the internalized Aβ. Further, Aβ internalization is attenuated by TOM1, a novel FcRIIb2-binding protein. Together, we provide a molecular mechanism responsible for neuronal uptake of pathogenic Aβ found in AD.
Dorsal BNST {alpha}2A-Adrenergic Receptors Produce HCN-Dependent Excitatory Actions That Initiate Anxiogenic Behaviors
Stress is a precipitating agent in neuropsychiatric disease and initiates relapse to drug-seeking behavior in addicted patients. Targeting the stress system in protracted abstinence from drugs of abuse with anxiolytics may be an effective treatment modality for substance use disorders. α2A-adrenergic receptors (α2A-ARs) in extended amygdala structures play key roles in dampening stress responses. Contrary to early thinking, α2A-ARs are expressed at non-noradrenergic sites in the brain. These non-noradrenergic α2A-ARs play important roles in stress responses, but their cellular mechanisms of action are unclear. In humans, the α2A-AR agonist guanfacine reduces overall craving and uncouples craving from stress, yet minimally affects relapse, potentially due to competing actions in the brain. Here, we show that heteroceptor α2A-ARs postsynaptically enhance dorsal bed nucleus of the stria terminalis (dBNST) neuronal activity in mice of both sexes. This effect is mediated by hyperpolarization-activated cyclic nucleotide-gated cation channels because inhibition of these channels is necessary and sufficient for excitatory actions. Finally, this excitatory action is mimicked by clozapine-N-oxide activation of the Gi-coupled DREADD hM4Di in dBNST neurons and its activation elicits anxiety-like behavior in the elevated plus maze. Together, these data provide a framework for elucidating cell-specific actions of GPCR signaling and provide a potential mechanism whereby competing anxiogenic and anxiolytic actions of guanfacine may affect its clinical utility in the treatment of addiction.
SIGNIFICANCE STATEMENT Stress affects the development of neuropsychiatric disorders including anxiety and addiction. Guanfacine is an α2A-adrenergic receptor (α2A-AR) agonist with actions in the bed nucleus of the stria terminalis (BNST) that produces antidepressant actions and uncouples stress from reward-related behaviors. Here, we show that guanfacine increases dorsal BNST neuronal activity through actions at postsynaptic α2A-ARs via a mechanism that involves hyperpolarization-activated cyclic nucleotide gated cation channels. This action is mimicked by activation of the designer receptor hM4Di expressed in the BNST, which also induces anxiety-like behaviors. Together, these data suggest that postsynaptic α2A-ARs in BNST have excitatory actions on BNST neurons and that these actions can be phenocopied by the so-called "inhibitory" DREADDs, suggesting that care must be taken regarding interpretation of data obtained with these tools.
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