Pharmacology and pharmacokinetic of peptide YSNSG

Le peptide YSNSG est un cyclopeptide antagoniste de l’intégrine alpha v beta 3 actif par inhibition de la migration tumorale et de l'angiogénèse. Ces propriétés ont été démontrées in vitro sur diverses lignées cellulaires et in vivo chez des souris C57BL/6 avec xénogreffe de mélanome. Nos travaux se sont intéressés à la pharmacologie et à la pharmacocinétique du YSNSG. Dans un premier temps, nous avons étudié sa pharmacocinétique plasmatique et tissulaire (cerveau et sous-cutané) chez des rats Wistar en utilisant la microdialyse tissulaire. Elle a permis la détermination des principaux paramètres plasmatiques et tissulaire. Le taux de pénétration du peptide au niveau tissulaire est apparu élevé au niveau sous-cutané et faible au niveau cérébral. L’analyse compartimentale de ces données a permis de valider un modèle de type PB-PK pour simuler différents débits de perfusion permettant d’atteindre au niveau tissulaire des concentrations actives. Dans un second temps, nous avons étudiés la distribution intra—tumorale du peptide YSNSG sur le modèle de souris C57BL/6 xénogreffé. A l’aide de la microdialyse tissulaire, nous avons étudié la distribution du peptide YSNSG au sein de deux régions intra-tumorales distinctes, respectivement au centre et en périphérie de la tumeur pour discuter du rôle de l’hétérogénéité intra-tumorale dans la distribution intra-tissulaire des anticancéreux. Notre approche n’a pas permis de mettre en évidence de différence significative dans la distribution du peptide entre les deux régions mais a permis de montrer une faible distribution. Dans une troisième et dernière approche, nous présentons les résultats de la nanoencapsulation du peptide YSNSG à l’aide de particules de type PLGA +/- F-68 à l’aide de méthodes spectroscopiques (Raman), microscopiques (confocale) et in vivo (comparaison de l’efficacité du peptide encapsulé ou non sur l’inhibition de la croissance tumorale sur le modèle animal précédemment utilisé).Peptide YSNSG is a cyclopeptide addressed against integrins growth tumor inhibition and neoangiogenesis. These properties were highlighted in vitro on several cell lines and in vivo in syngeneic mice C57BL/6 with B16F1 melanoma xenograft. In order to describe the pharmacology and pharmacokinetic of peptide YSNSG we first studied plasma and tissue pharmacokinetic (cerebral and subcutaneous) in healthy Wistar rats using microdialysis. We finded main plasma and tissue parameters and a high penetration rate in subcutaneous and a low penetration rate of peptide YSNSG in cerebral tissue, respectively. Compartment analysis of our data allowed assessing a physiologically-based pharmacokinetic model in order to simulate different administration flow rate required to reach pharmacological active concentrations. Secondly we investigated the intra-tumoral distribution of peptide YSNSG the same syngeneic mice C57BL/6 model previously described, using microdialysis. Distribution was assessed in two distinct regions of melanoma tumor (central and peripheral) for the study of the impact of intra-tumoral heterogeneity on YSNSG peptide distribution. This approach did not found any significant difference in term of penetration rate and, moreover, found a low penetration rate in the melanoma tumor in discordance with previous subcutaneous distribution in healthy rat. In a third chapter we describe results of nanoencapsulation tests of YSNSG peptide using PLGA +/- F-68 with spectroscopic method (Raman), microscopic (confocal) and in vivo experimentation (growth tumor inhibition level in the same mice model with or without nanoencapsulation of YSNSG peptide)

BRAF V600-Mutated Metastatic Melanoma and Targeted Therapy Resistance: An Update of the Current Knowledge

Melanoma is the most common cause of death in skin cancer due to its high metastatic potential. While targeted therapies have improved the care of patients with metastatic melanoma harboring the BRAFV600E mutation, these treatments are associated with a high frequency of resistance. Resistance factors are related to cellular adaptation as well as to changes in the tumor microenvironment. At the cellular level, resistance involves mutations, overexpression, activation, or inhibition of effectors involved in cell signaling pathways such as MAPK, PI3K/AKT, MITF, and epigenetic factors (miRNAs). In addition, several components of the melanoma microenvironment, such as soluble factors, collagen, and stromal cells also play a crucial role in this resistance. In fact, extracellular matrix remodeling impacts the physical and chemical properties with changes in the stiffness and acidity, respectively of the microenvironment. The cellular and immune components of the stroma are also affected, including immune cells and CAF. The aim of this manuscript is to review the mechanisms responsible for resistance to targeted therapies in BRAFV600E-mutated metastatic melanoma

Deep learning for the prediction of the chemotherapy response of metastatic colorectal cancer: comparing and combining H&E staining histopathology and infrared spectral histopathology

International audienceColorectal cancer is a global public health problem with one of the highest death rates. It is the second most deadly type of cancer and the third most frequently diagnosed in the world. The present study focused on metastatic colorectal cancer (mCRC) patients who had been treated with chemotherapy-based regimen for which it remains uncertainty about the efficacy for all eligible patients. This is a major problem, as it is not yet possible to test different therapies in view of the consequences on the health of the patients and the risk of progression. Here, we propose a method to predict the efficacy of an anticancer treatment in an individualized way, using a deep learning model constructed on the retrospective analysis of the primary tumor of several patients. Histological sections from tumors were imaged by standard hematoxylin and eosin (HE) staining and infrared spectroscopy (IR). Images obtained were then processed by a convolutional neural network (CNN) to extract features and correlate them with the subsequent progression-free survival (PFS) of each patient. Separately, HE and IR imaging resulted in a PFS prediction with an error of 6.6 and 6.3 months respectively (28% and 26% of the average PFS). Combining both modalities allowed to decrease the error to 5.0 months (21%). The inflammatory state of the stroma seemed to be one of the main features detected by the CNN. Our pilot study suggests that multimodal imaging analyzed with deep learning methods allow to give an indication of the effectiveness of a treatment when choosing

First plasma and tissue pharmacokinetic study of the YSNSG cyclopeptide, a new integrin antagonist, using microdialysis

International audienc

Is antihistaminergic H2 really useful in prevention of hypersensitivity induced by paclitaxel?

International audienceNo abstract availabl

Association of Low Handgrip Strength with Chemotherapy Toxicity in Digestive Cancer Patients: A Comprehensive Observational Cohort Study (FIGHTDIGOTOX)

In the FIGHTDIGO study, digestive cancer patients with dynapenia experienced more chemotherapy-induced neurotoxicities. FIGHTDIGOTOX aimed to evaluate the relationship between pre-therapeutic handgrip strength (HGS) and chemotherapy-induced dose-limiting toxicity (DLT) or all-grade toxicity in digestive cancer patients. HGS measurement was performed with a Jamar dynamometer. Dynapenia was defined according to EWGSOP2 criteria (<27 kg (men); <16 kg (women)). DLT was defined as any toxicity leading to dose reduction, treatment delay, or permanent discontinuation. We also performed an exploratory analysis in patients below the included population’s median HGS. A total of 244 patients were included. According to EWGSOP2 criteria, 23 patients had pre-therapeutic dynapenia (9.4%). With our exploratory median-based threshold (34 kg for men; 22 kg for women), 107 patients were dynapenic (43.8%). For each threshold, dynapenia was not an independent predictive factor of overall DLT and neurotoxicity. Dynapenic patients according to EWGSOP2 definition experienced more hand-foot syndrome (p = 0.007). Low HGS according to our exploratory threshold was associated with more all-grade asthenia (p = 0.014), anemia (p = 0.006), and asthenia with DLT (p = 0.029). Pre-therapeutic dynapenia was not a predictive factor for overall DLT and neurotoxicity in digestive cancer patients but could be a predictive factor of chemotherapy-induced anemia and asthenia. There is a need to better define the threshold of dynapenia in cancer patients

Clinical and Organizational Impacts of Medical Ordering Settings on Patient Pathway and Community Pharmacy Dispensing Process: The Prospective ORDHOSPIVILLE Study

During the dispensing process of medical orders (MOs), community pharmacists (CPs) can manage drug-related problems (DRPs) by performing pharmacist interventions (PIs). There is little evidence that the PI rate is higher with MOs from hospitals (MOHs) than ambulatory (MOAs) settings, and their impact on the patient and community pharmacy is unknown. The primary objective of this study was to compare the MOH and MOA PI rates. The secondary objective was to describe PIs and their clinical and organizational impacts on patient and community pharmacy workflow. A total of 120 CPs participated in a prospective study. Each CP included 10 MOH and 10 MOA between January and June 2020. DRP and PI description and clinical and organizational impacts between MOH and MOA were assessed and compared. We analyzed 2325 MOs. PIs were significantly more frequent in MOH than in MOA (9.7% versus 4.7%; p < 0.001). The most reported PI was the difficulty of contacting hospital prescribers (n = 45; 52.2%). MOHs were associated with a longer dispensing process time and a greater impact on patient pathway and community pharmacy workflow than MOAs. Lack of communication between hospital and primary care settings partly explains the results. Implementation of clinical pharmacy activities at patient discharge could alleviate these impacts

The Role of Community Pharmacists in the Detection of Clinically Relevant Drug-Related Problems in Chronic Kidney Disease Patients

Community pharmacists (CPs) have traditionally had limited access to patients’ estimated glomerular filtration rate (eGFR) during the medication-dispensing process. The increasing access to shared electronic health records is making eGFR available, but the skills needed to detect and manage clinically relevant drug-related problems (DRPs) are poorly documented. The primary objective of this study was to investigate the role of CPs in the medication-dispensation process for elderly patients with renal impairment. A total of 70 CPs participated in this 6 month study. Community pharmacists asked all patients ≥65 years to bring their laboratory test values for the next medication-dispensing process. Drug-related problem detection rates were compared between CPs (prospective period) and expert pharmacists (retrospectively). The clinical relevance of each DRP was assessed by nephrologists and general practitioners using an appropriate tool. Community pharmacists recruited n = 442 patients with eGFR &lt; 60 mL/min/1.73 m2 and detected n = 99 DRPs, whereas expert pharmacists detected n = 184 DRPs. The most frequently detected DRPs were dosage problems and contraindications. According to assessment by clinicians, CPs and expert pharmacists identified 54.0% and 84.7% of clinically relevant DRPs, respectively. This study suggests a positive impact of the systematic availability of eGFR to CPs on the detection of several DRPs with clinical relevance

Predictive factors for clinically significant pharmacist interventions at hospital admission

International audiencePharmaceutical care activities at hospital admission have a significant impact on patient safety. The objective of this study was to identify predictive factors for clinically significant pharmacist interventions (PIs) performed during medication reconciliation and medication review at patient hospital admission. A 4-week prospective study was conducted in 4 medicine wards. At hospital admission, medication reconciliation and medication review were conducted and PIs were performed by the pharmaceutical team. The clinical impact of PIs was determined using the clinical economic and organizational (CLEO) tool. Clinical characteristics, laboratory results, and medication data for each patient were collected and analyzed as potential predictive factors of clinically significant PIs. Univariate and multivariate binary logistic regression were subsequently used to identify independent predictive factors for clinically relevant PIs. Among 265 patients admitted, 150 patients were included. Among 170 PIs performed at hospital admission, 71 were related to unintentional discrepancies (41.8%) during medication reconciliation, and 99 were related to drug-related problems (DRPs) (58.8%) during medication review. Overall, 115 PIs (67.7%) were considered to have a clinical impact. By multivariate analysis, number of medications ≥5 (P = .01) based on the best possible medication history, and Charlson comorbidity index score ≥2 (P < .01) were found to be independent predictive factors of clinically significant PIs at hospital admission. Identifying predictive factors of clinically significant PIs is valuable to optimize clinical pharmacist practices at hospital admission during both medication reconciliation and medication review. These 2 steps of the pharmaceutical care process improve medication safety at hospital admission. Abbreviations: ATC = anatomical therapeutics classification, BPMH = best possible medication history, CKD EPI = chronic kidney disease epidemiology collaboration, CLEO = clinical economic and organizational, DRPs = drug related problems, NCC MERP = National Coordinating Council for Medication Error Reporting and Prevention, OTC = over the counter, PIs = pharmacist interventions, SFPC = French Society of Clinical Pharmacy, TdP = Torsade de Pointe

Dynapenia could predict chemotherapy-induced dose-limiting neurotoxicity in digestive cancer patients

Abstract Background FIGHTDIGO study showed the feasibility and acceptability of handgrip strength (HGS) measure in routine in 201 consecutive patients with digestive cancer treated with ambulatory chemotherapy. The present study focuses on the second aim of FIGHTDIGO study: the relationships between pre-therapeutic dynapenia and chemotherapy-induced Dose-Limiting Toxicities (DLT). Methods In this ancillary prospective study, DLT were analyzed in a sub-group of 45 chemotherapy-naive patients. Two bilateral consecutive measures of HGS were performed with a Jamar dynamometer before the first cycle of chemotherapy. Dynapenia was defined as HGS < 30 kg (men) and < 20 kg (women). DLT and/or Dose-Limiting Neurotoxicity (DLN) were defined as any toxicity leading to dose reduction, treatment delays or permanent treatment discontinuation. Results Two-thirds of chemotherapies were potentially neurotoxic (n = 31 [68.7%]) and 22 patients (48.9%) received FOLFOX (5FU, leucovorin plus oxaliplatin) regimen chemotherapy. Eleven patients (24.4%) had pre-therapeutic dynapenia. The median number of chemotherapy cycles was 10 with a median follow-up of 167 days. Twenty-two patients experienced DLT (48.9%). There was no significant association between pre-therapeutic dynapenia and DLT (p = 0.62). Nineteen patients (42.2%) experienced DLN. In multivariate analysis, dynapenia and tumoral location (stomach, biliary tract or small intestine) were independent risk factors for DLN (HR = 3.5 [1.3; 9.8]; p = 0.02 and HR = 3.6 [1.3; 10.0]; p = 0.01, respectively). Conclusions Digestive cancer patients with pre-therapeutic dynapenia seemed to experience more DLN. HGS routine measurement may be a way to screen patients with frailty marker (dynapenia) who would require chemotherapy dose adjustment and adapted physical activity programs. Trial registration NCT02797197 June 13, 2016 retrospectively registered