Various experimental models are used to study brain development and degeneration. They range from whole animal models, which preserve anatomical structures but strongly limit investigations at the ...cellular level, to dissociated cell culture systems that allow detailed observation of cell phenotypes but lack the highly ordered physiological neuron connection architecture. We describe here a platform comprising independent cell culture chambers separated by an array of "axonal diodes". This array involves asymmetric micro-channels, imposing unidirectional axon connectivity with 97% selectivity. It allows the construction of complex, oriented neuronal networks not feasible with earlier platforms. Different neuronal subtypes could be co-cultivated for weeks, and sequential seeding of different cell populations reproduced physiological network development. To illustrate possible applications, we created and characterized a cortico-striatal oriented network. Functional synaptic connections were established. The activation of striatal differentiation by cortical axons, and the synchronization of neural activity were demonstrated. Each neuronal population and subcompartment could be chemically addressed individually. The directionality of neural pathways being a key feature of the nervous system organization, the axon diode concept brings in a paradigmatic change in neuronal culture platforms, with potential applications for studying neuronal development, synaptic transmission and neurodegenerative disorder such as Alzheimer and Parkinson diseases at the sub-cellular, cellular and network levels.
Between 30% and 70% of patients with breast cancer have pre-existing chronic conditions, and more than half are on long-term non-cancer medication at the time of diagnosis. Preliminary ...epidemiological evidence suggests that some non-cancer medications may affect breast cancer risk, recurrence, and survival. In this nationwide cohort study, we assessed the association between medication use at breast cancer diagnosis and survival. We included 235,368 French women with newly diagnosed non-metastatic breast cancer. In analyzes of 288 medications, we identified eight medications positively associated with either overall survival or disease-free survival: rabeprazole, alverine, atenolol, simvastatin, rosuvastatin, estriol (vaginal or transmucosal), nomegestrol, and hypromellose; and eight medications negatively associated with overall survival or disease-free survival: ferrous fumarate, prednisolone, carbimazole, pristinamycin, oxazepam, alprazolam, hydroxyzine, and mianserin. Full results are available online from an interactive platform ( https://adrenaline.curie.fr ). This resource provides hypotheses for drugs that may naturally influence breast cancer evolution.
Survival disparities persist in ovarian cancer and may be linked to the environments in which patients live. The main objective of this study was to analyze the global impact of the area of residence ...of ovarian cancer patients on overall survival. The data were obtained from the Surveillance, Epidemiology and End Results (SEER) database. We included all the patients with epithelial ovarian cancers diagnosed between 2010 and 2016. The areas of residence were analyzed by the hierarchical clustering of the principal components to group similar counties. A multivariable Cox proportional hazards model was then fitted to evaluate the independent effect of each predictor on overall survival. We included a total of 16,806 patients. The clustering algorithm assigned the 607 counties to four clusters, with cluster 1 being the most disadvantaged and cluster 4 having the highest socioeconomic status and best access to care. The area of residence cluster remained a statistically significant independent predictor of overall survival in the multivariable analysis. The patients living in cluster 1 had a risk of death more than 25% higher than that of the patients living in cluster 4. This study highlights the importance of considering the sociodemographic factors within the patient's area of residence when developing a care plan and follow-up.
A better understanding of cancer biology has led to the development of molecular targeted therapy, which has dramatically improved the outcome of some cancer patients, especially when a biomarker of ...efficacy has been used for patients' selection. In head and neck oncology, cetuximab that targets epidermal growth factor receptor is the only targeted therapy that demonstrated a survival benefit, both in the recurrent and in the locally advanced settings, yet without prior patients' selection. We herein review the clinical development of targeted therapy in head and neck squamous cell carcinoma in light of the molecular landscape and give insights in on how innovative clinical trial designs may speed up biomarker discovery and deployment of new molecular targeted therapies. Given the recent approval of immune checkpoint inhibitors targeting programmed cell death-1 in head and neck squamous cell carcinoma, it remains to be determined how targeted therapy will be incorporated into a global drug development strategy that will inevitably incorporate immunotherapy.
Breast cancer (BC) is the most frequent cancer and the leading cause of cancer-related death in women. The French National Cancer Institute has created a national cancer cohort to promote cancer ...research and improve our understanding of cancer using the National Health Data System (SNDS) and amalgamating all cancer sites. So far, no detailed separate data are available for early BC.
To describe the creation of the French Early Breast Cancer Cohort (FRESH).
All French women aged 18 years or over, with early-stage BC newly diagnosed between 1 January 2011 and 31 December 2017, treated by surgery, and registered in the general health insurance coverage plan were included in the cohort. Patients with suspected locoregional or distant metastases at diagnosis were excluded. BC treatments (surgery, chemotherapy, targeted therapy, radiotherapy, and endocrine therapy), and diagnostic procedures (biopsy, cytology, and imaging) were extracted from hospital discharge reports, outpatient care notes, or pharmacy drug delivery data. The BC subtype was inferred from the treatments received.
We included 235,368 patients with early BC in the cohort (median age: 60 years). The BC subtype distribution was as follows: luminal (80.2%), triple-negative (TNBC, 9.5%);
(10.3%), or unidentifiable (
= 44,388, 18.9% of the cohort). Most patients underwent radiotherapy (
= 200,685, 85.3%) and endocrine therapy (
= 165,655, 70.4%), and 38.3% (
= 90,252) received chemotherapy. Treatments and care pathways are described.
The FRESH Cohort is an unprecedented population-based resource facilitating future large-scale real-life studies aiming to improve care pathways and quality of care for BC patients.
Breast cancer (BC) is the most common cancer in women worldwide. Neoadjuvant chemotherapy (NAC) makes it possible to monitor in vivo response to treatment. Several studies have investigated the ...impact of the seasons on the incidence and detection of BC, on tumor composition, and on the prognosis of BC. However, no evidence is available on their association with immune infiltration and the response to treatment. The objective of this study was to analyze pre- and post-NAC immune infiltration as assessed by TIL levels, the response to treatment as assessed by pathological complete response (pCR) rates, and oncological outcomes as assessed by relapse-free survival (RFS) or overall survival (OS) according to the seasonality of BC diagnoses in a clinical cohort of patients treated with neoadjuvant chemotherapy. Out of 1199 patients, the repartition of the season at BC diagnosis showed that 27.2% were diagnosed in fall, 25.4% in winter, 24% in spring, and 23.4% in summer. Baseline patient and tumor characteristics, including notable pre-NAC TIL levels, were not significantly different in terms of the season of BC diagnosis. Similarly, the pCR rates were not different. No association for oncological outcome was identified. Our data do not support the idea that the seasonality of diagnoses has a major impact on the natural history of BC treated with NAC.
Immunotherapies and immune checkpoint inhibitors (ICI) represent the latest revolution in oncology. Several studies have reported an association between the use of corticosteroids and poorer outcomes ...for patients treated with ICIs. However, it has been never established whether corticoid-induced tumor progression under ICI treatment could be reversible. We report herein transient tumor progression induced by dexamethasone for a patient treated with pembrolizumab for metastatic bladder cancer. An 82-year-old man was treated with pembrolizumab as a second-line treatment for metastatic urothelial carcinoma with stable disease for 8 months as the best tumoral response. He experienced severe coronavirus disease 2019 (COVID-19) infection and was treated with high-dose dexamethasone for ten days according to the RECOVERY protocol. Following this episode, radiological CT-scan evaluation showed tumor progression. Pembrolizumab was maintained, and subsequent radiological evaluation showed tumor shrinkage. This case highlights that the antagonistic effect of glucocorticoids with ICI efficacy is transient and can be reverted when corticoids are withdrawn. Clinicians should be aware that tumor progression in the context of the intercurrent use of systemic corticosteroids can be temporary and should be interpreted with caution, and ICI continuation could be considered for some patients. Insights: The antagonistic effect of glucocorticoids with ICI efficacy is transient and can be reverted when corticoids are withdrawn. Tumor progression in the context of the intercurrent use of systemic corticosteroids can be temporary and should be interpreted with caution, and ICI continuation could be considered for some patients.
Kinase inhibitors (KI) have dramatically improved the outcome of treatment in patients with non-small cell lung cancer (NSCLC), which harbors an oncogene addiction. This study assesses KI plasma ...levels and their clinical relevance in patients chronically exposed to KIs. Plasma samples were collected in NSCLC patients receiving erlotinib, gefitinib, osimertinib, crizotinib, or dabrafenib (with or without trametinib) for at least three months between November 2013 and February 2019 in a single institution. KI drug concentrations were measured by ultra-performance liquid chromatography coupled with tandem mass spectrometry and compared to published data defining optimal plasma concentration. The main outcome was the rate of samples with suboptimal KI plasma concentrations. Secondary outcomes included its impact on
mutation emergence in patients receiving a first-generation epidermal growth factor receptor (EGFR) KI. Fifty-one samples were available from 41 patients with advanced NSCLC harboring driver genetic alterations, including
, v-Raf murine sarcoma viral oncogene homolog B (
), anaplastic lymphoma kinase (
) or ROS proto-oncogene 1 (
), and who had an available evaluation of chronic KI plasma exposure. Suboptimal plasma concentrations were observed in 51% (26/51) of cases. In
-mutant cases failing first-generation KIs,
exon 20 p.T790M mutation emergence was detected in 31% (4/13) of samples in optimal vs. none in suboptimal concentration (0/5). Suboptimal plasma concentrations of KIs are frequent in advanced NSCLC patients treated with a KI for at least three months and might contribute to treatment failure.
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