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A 76-year-old female patient presented with an iodine-refractory papillary thyroid carcinoma (PTC), diagnosed eight years earlier, with several lymph node recurrences requiring successive surgeries. Fluorodeoxyglucose ([ 18 F]FDG) positron emission tomography/computed tomography (PET/CT) imaging revealed a new unresectable loco-regional recurrence. The patient was diagnosed with a somatic BRAF V600E mutation. Therefore, dabrafenib and trametinib combination therapy was introduced and closely monitored by a dedicated multidisciplinary team, involving pharmaceutical consultations. As early as six weeks after treatment initiation, the patient reported multiple adverse events (AEs) to the clinical pharmacy team, who provided advice on resolving AEs or improving tolerance. Close interprofessional collaboration among healthcare workers involved in the care pathway allowed for the identification of the most opportune times for temporary suspension of treatment (four suspensions over seven months) or dose reduction (two reductions over 3.5 months). This resulted in a total treatment duration (one year) longer than the average times reported in the literature. The patient showed a rapid and excellent response to treatment immediately after initiation, culminating in a complete metabolic response assessed by [ 18 F]FDG PET/CT imaging at nine months. Twenty-five months after treatment discontinuation, the disease remained controlled. Overall, dabrafenib and trametinib combination could offer excellent outcomes in selected patients with refractory BRAF-mutated PTC, with additional clinical pharmacy initiatives allowing for the optimized management of AEs and prolonged treatment periods.

Purpose: To ensure the safe use of oral anticancer drugs, oncology pharmacy consultations (OPCs) have been established in France. They are conditioned by the needs, expectations, and involvement of the patients in their care. Thus, it is essential to elicit their preferences. The discrete-choice experiment (DCE) is a method recommended by the ISPOR for such a task. The "selection and validation of attributes and their values" step is fundamental in this process. In this context, the aim of this study was to present our research approach to identify and validate the attributes that characterize an OPC and their values., Methods: Due to the lack of relevant published data in the literature, the focus-group method was used in accordance with good research practices for the application of conjoint-analysis of the ISPOR. The two-round Delphi method was used to validate the attributes and their values identified by the focus-group method., Results: The focus-group method enabled identification of nine attributes. Thirty-seven healthcare professionals at a national level, including 30 pharmacists and seven physicians, were selected to take part in the Delphi procedure. Seven attributes (frequency, planification, operation mode, duration, content, written support, and report) and their values were thus validated., Conclusion: Based on these results, the next step will be to elicit patient preferences for OPCs and to then shed light on the issues of pharmaceutical support for patients by comparing their preferences with those of informal caregivers and, in particular, those of the healthcare professionals involved in their care., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Oral targeted therapies (OTTs) are widely used for cancer management. However, there is no consensus on OTT dose adaptation in older patients with cancer., Methods: This noninterventional, retrospective study was a real-life assessment of dose adaptation for six OTTs (afatinib, everolimus, palbociclib, pazopanib, sorafenib and sunitinib), at baseline and during treatment, and the reasons for the changes, in ≥70-year-old patients treated between February 2016 and August 2019. Data were compared with univariate models fitted with all variables., Results: Among the 986 patients treated with OTT, the group of ≥70-year-old patients (n = 122) received afatinib (15.6%), everolimus (14.8%), palbociclib (50.8%), pazopanib (9.8%), sorafenib (5.8%) or sunitinib (3.2%). At baseline, the prescribed OTT dose was adapted (reduction) in 29% of ≥70-year-old patients (35/122). These 35 patients were significantly older (mean age 80 vs 74 years, P < .001), and more frequently had a performance status score ≥2 (P < .01) than the other patients (n = 87). In the standard dose group, higher toxicity grades (P = .18) and subsequent dose reduction (41% of patients, 36/87) tended to be more frequent compared with the baseline adapted dose group (26%, 9/35, P = .1). At the study end, 53% of patients in the whole cohort (65/122) were taking a lower dose than the recommended one., Conclusion: At OTT initiation, dose was adapted in 29% of older adults with cancer, rarely after a formal oncogeriatric evaluation (6.5% of all patients). In the absence of recommendations, clinical studies are needed to evaluate the efficacy and safety of baseline OTT dose reduction in older adults with cancer., (© 2022 British Pharmacological Society.)

Palbociclib is a good candidate for therapeutic drug monitoring (TDM) due to its narrow therapeutic range and frequency of toxicities, particularly high-grade neutropenia. In this prospective, bicentric clinical trial, we evaluated the palbociclib exposure−toxicity relationship and determined the relevant sources of palbociclib pharmacokinetic variability, including drug−drug interactions (DDI). We followed 58 patients (mean age: 62.9 years) for 1 year. The geometric median of palbociclib plasma trough concentration (Ctrough) was 74.1 ng/mL. Neutropenia occurred in 70.7% of patients (high grade in 67.2% of patients). High-grade neutropenia occurrence during the first two palbociclib cycles was higher in patients with lower neutrophil count at initiation (p = 0.002). Palbociclib plasma Ctrough was correlated with high-grade neutropenia occurrence during the first two cycles (p = 0.024, OR 5.51). Co-treatment with agents that may interfere with palbociclib PK significantly influenced palbociclib Ctrough (p < 0.05). CYP3A4/P-glycoprotein inhibitors increased by 25% palbociclib Ctrough (p = 0.035), while antacids reduced it by 20% (p = 0.036). However, DDI did not have any significant effect on high-grade neutropenia occurrence (p > 0.05). This study confirms the major role of TDM to manage palbociclib safe use from the first week of treatment, particularly the significant incidence of hematological toxicity. Moreover, this first dedicated prospective study confirmed the importance of characterizing co-treatments to limit the DDI risk with oral-targeted therapies.

Purpose: Pharmacist consultation is unfrequently performed in oncology clinical trials that include patients who often have many co-treatments increasing the risk of drug-drug interactions (DDI). The aim of this study was to determine whether best possible medication history (BPMH) by hospital pharmacist at inclusion and therapeutic drug monitoring could be used for DDI risk evaluation and for current oral targeted therapy management., Methods: A prospective clinical trial (ALCINA 2, NCT04025541) was carried out in metastatic breast cancer cohort treated by palbociclib to conduct pharmacokinetics-toxicity correlation study. BPMH was prospectively performed by the hospital pharmacist at each trial inclusion, followed by a contact to the patient's community pharmacy to complete the collected data. Pharmacokinetic analysis was performed on blood samples collected at day 15 of cycle 1 of palbociclib treatment., Results: Pharmacist interventions indicated that at inclusion, current medications were incomplete for 63% of the enrolled patients (32/51). It allowed the real-time management of high-risk DDI detected in third of patients. The palbociclib C trough geometric median (min-max) was significantly higher in cohort with potential DDI [106 ng/mL (66.7-113)], than cohort without potential DDI [70.1 ng/mL (54.1-89.7)], p = 0.0284., Conclusion: This is the first prospective study evaluating the relevance of proactive BPMH by pharmacist with contact to the community pharmacy during the inclusion step of a clinical trial to ensure the efficacy and safety of the investigated drug. This investigation was thus able to highlight the statistically significant impact of these DDI on palbociclib plasma concentration variation during the clinical trial., Trial Registration: Clinicaltrials.gov identifier NCT04025541., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Resistance to castration is a crucial issue in the treatment of metastatic prostate cancer. Kinase inhibitors (KIs) have been tested as potential alternatives, but none of them are approved yet. KIs are subject of extensive metabolism at both the hepatic and the tumor level. Here, we studied the role of PXR (Pregnane X Receptor), a master regulator of metabolism, in the resistance to KIs in a prostate cancer setting. We confirmed that PXR is expressed in prostate tumors and is more frequently detected in advanced forms of the disease. We showed that stable expression of PXR in 22Rv1 prostate cancer cells conferred a resistance to dasatinib and a higher sensitivity to erlotinib, dabrafenib, and afatinib. Higher sensitivity to afatinib was due to a ~ 2-fold increase in its intracellular accumulation and involved the SLC16A1 transporter as its pharmacological inhibition by BAY-8002 suppressed sensitization of 22Rv1 cells to afatinib and was accompanied with reduced intracellular concentration of the drug. We found that PXR could bind to the SLC16A1 promoter and induced its transcription in the presence of PXR agonists. Together, our results suggest that PXR could be a biomarker of response to kinase inhibitors in castration-resistant prostate cancers.

Introduction : Two-thirds of advanced breast cancers are hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative (HR+/HER2-). Gene mutations in PIK3CA , encoding the PI3K catalytic subunit alpha of phosphatidyl-inositol 3-kinase (PI3K), are a frequent event in this population and are implicated in hormone therapy resistance. Alpelisib is a PI3K-alpha inhibitor and is the first PI3K inhibitor approved, in association with fulvestrant, by the FDA and EMA, based on improved progression-free survival (PFS) versus fulvestrant alone in a randomized phase III trial in HR+/HER2-, PIK3CA -mutated tumors following progression on/after HT. Areas covered : The scientific rationale, preclinical development, pharmacokinetics, and clinical efficacy/safety of alpelisib-fulvestrant are summarized. The role of alpelisib in the clinical setting is discussed, referencing current therapeutic options and clinical challenges associated with alpelisib's safety profile. Expert opinion : Alpelisib is an option for patients with HR+/HER2-, PIK3CA -mutated tumors whose disease progressed during/after aromatase inhibitor treatment. The PFS benefit appears clinically significant over fulvestrant alone, with a 7.9 months, non-significant, improvement in overall survival. Its safety profile requires strict patient selection, mainly based on baseline glycemic status, and close monitoring.

Immune check-point inhibitors are drugs that are markedly different from other anticancer drugs because of their indirect mechanisms of antitumoral action and their apparently random effect in terms of efficacy and toxicity. This marked pharmacodynamics variability in patients calls for reconsidering to what extent approved dosing used in clinical practice are optimal or whether they should require efforts for customization in outlier patients. To better understand whether or not dosing could be an actionable item in oncology, in this review, preclinical and clinical development of immune checkpoint inhibitors are described, particularly from the angle of dose finding studies. Other issues in connection with dosing issues are developed, such as the flat dosing alternative, the putative role therapeutic drug monitoring could play, the rise of combinatorial strategies, and pharmaco-economic aspects.

The CDK4/6 inhibitors palbociclib and ribociclib are kinase inhibitors used in association with hormonal therapy for the management of patients with metastatic breast cancer. Like most kinase inhibitors, therapeutic drug monitoring may be used for personalize their dosage. To this aim, we developed and validated a sensitive and specific HPLC-MS/MS method for palbociclib and ribociclib quantification in blood samples. We then quantified exposure to palbociclib (plasma trough concentration; C trough ) in a real-life cohort of patients with locally invasive or metastatic breast cancer (n = 18) at day 15 of the first cycle of palbociclib treatment to characterize palbociclib concentration at steady state (Clinicaltrials.gov identifier NCT04025541, IdRCB n° 2018-A00064-51, 03/07/2018). The geometric mean (± standard deviation [min-max]) of palbociclib plasma C trough was 88.58 ng/mL (± 26.4 [46.5 ng/mL - 133 ng/mL]) at day 15. Some covariates, such as drug-drug interactions, could explain the concentration variations observed in our Caucasian cohort. These first results in real-life settings obtained with our HPLC-MS/MS method give important information on palbociclib monitoring and pharmacokinetic variability., Competing Interests: Declaration of Competing Interest No competing interests to declare for all authors/provided financial support for the conduct of the research, (Copyright © 2020 Elsevier B.V. All rights reserved.)

Reformulation of bread in terms of salt content remains an important measure to help achieve a reduction in salt intake in the population and for the prevention of hypertension and elevated blood pressure (BP). Our fundamental studies on the reduction of salt on dough and bread characteristics showed that wheat breads produced with 0.3 g salt/100 g ("low-salt") were found to be comparable quality to that produced with the typical level of salt (1.2%). This food-based intervention trial examined, using a 5 week cross-over design, the potential for inclusion of "low-salt" bread as part of a pragmatic reduced-salt diet on BP, markers of bone metabolism, and plasma lipids in 97 adults with slightly to moderately elevated BP. Assuming all sodium from dietary intake was excreted through the urine, the intake of salt decreased by 1.7 g/day, on average, during the reduced-salt dietary period. Systolic BP was significantly lower (by 3.3 mmHg on average; p < 0.0001) during the reduced-salt dietary period compared to the usual-salt dietary period, but there was no significant difference ( p = 0.81) in diastolic BP. There were no significant differences ( p > 0.12, in all cases) in any of the urinary- or serum-based biochemical indices of calcium or bone metabolism or in plasma lipids between the two periods. In conclusion, a modest reduction in dietary salt intake, in which the use of "low-salt" (i.e., 0.3 g/100g) bread played a key role along with dietary advice, and led to a significant, and clinically meaningful, decrease in systolic, but not diastolic, BP in adults with mildly to moderately elevated BP.

Objectives: There is some controversy surrounding theBRAF V600E mutation in patients with lung adenocarcinomas. Although the BRAF V600E mutation is sensitive to BRAF inhibitors, the efficiency of these inhibitors on patients harboring an EGFR L858R/del19 /EGFR T790M /BRAF V600E pattern remains unknown., Materials and Methods: Here, we presented the case of a patient with initial response followed by progression on osimertinib. Resistance mutations (EGFR T790M , EGFR C797S , BRAF V600E , MET amp and HER2 amp) were assessed in the tissue or plasma DNA using NGS and digital droplet PCR at progression and during osimertinib treatment., Results: Resistance to osimertinib coincided with the emergence of an additional tumor cell subpopulation carrying the knownBRAF V600E resistance mutation. The patient exhibited two tumor subclones (EGFR del19/T790M and BRAF V600E ) that displayed distinct responses to successive tyrosine kinase inhibitors., Conclusion: We report the first successful example of using sequential treatment with dabrafetinib/trametinib and osimertinib. Our finding provided that unique tumor biopsies deliver incomplete genetic information, and highlighted the complementary role of circulating tumor DNA to tissue biopsies and CT-scans to efficiently monitor response to osimertinib., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Oxidative stress is implicated in the etiology of many diseases, but most of clinical trials failed to demonstrate beneficial effects of antioxidant supplementation., Methods: In the present experiment, we assessed the mean-term effect of wheat germ supplementation, as a dietary source of vitamin E, on antioxidant protection in rat., Results: Feeding rats a 20% wheat germ diet significantly increased plasma and liver vitamin E levels, compared to the low vitamin E basal diet. Concurrently, wheat germ diet consumption strongly decreased the susceptibility of heart and liver lipids to oxidation, as well as the plasma. Wheat germ feeding did not change triglycerides (TG) nor total cholesterol concentrations in plasma or liver, resulting in higher vitamin E/TG ratio compared to controls. Similar results were found with a diet in which wheat germ oil provided the same amount of vitamin E., Conclusions: Wheat germ appears thus very effective to improve antioxidant defense status, especially in tissues, irrespective of modifications of lipids status.

Bread is one of the most widely consumed staple foods worldwide. White-wheat bread, largely consumed in France, is made from highly refined flour, which leads to a low nutrient density. Due to a highly porous structure and gelatinised starch, it is easily broken down during digestion, leading to a rapid increase of glucose released into the bloodstream. Low glycaemic responses are considered favourable to health, especially against a background of diabetes. Literature reports show that selection of raw material is an essential factor in decreasing the glycaemic index (GI) of white bread. There are two means of decreasing the rate of starch degradation: either (i) slowing gastric emptying rate and/or glucose diffusion-absorption through the intestinal mucosa, which can be achieved by incorporating soluble fibre or organic acid in bread, or (ii) limiting starch accessibility to alpha-amylase by using high-amylose cereal varieties and/or incorporating intact cereal grains. Studies on cereal products show that preservation of the food structure during digestion seems to be a more important GI-reducing factor than the degree of starch crystallinity or the presence of soluble fibre. Thus, we should look to produce bread with a more compact food structure or higher density, which is the case in leavened wholewheat bread or bread with intact cereal grains. The baking process should also be improved to achieve this goal, by using, for example, a reduced kneading time or less yeast than usual.

The current study was undertaken to provide solutions to optimize the unsaponifiable antioxidants content of bread. We report a complete description of changes in wheat carotenoids and vitamin E content from grain to bread and highlight the most important processing steps affecting their level in wheat bread. Major carotenoids losses occurred during kneading. A close correlation (r(2) = 0.97; P = 0.05) was found between carotenoid pigment losses and lipoxygenase (LOX) activity, both parameters depending on wheat genotype. The use of wheat species exhibiting high carotenoid contents and low LOX activity was shown to preserve significant carotenoid level in the bread. No relation was found between vitamin E losses during doughmaking and LOX activity. In addition, moderate kneading resulted in higher vitamin E retention in comparison with carotenoids (12% and 66% losses, respectively). It is concluded that carotenoids are more susceptible to oxidation by endogenous lipoxygenase than vitamin E during breadmaking. This study showed that bread nutritional quality, in terms of antioxidant content, could be improved by selecting suitable cereal genotypes, if this potential is preserved by milling and baking processes.

Whole wheat bread is an important source of minerals but also contains considerable amounts of phytic acid, which is known to impair their absorption. An in vitro trial was performed to assess the effect of a moderate drop of the dough pH (around 5.5) by way of sourdough fermentation or by exogenous organic acid addition on phytate hydrolysis. It was shown that a slight acidification of the dough (pH 5.5) with either sourdough or lactic acid addition allowed a significant phytate breakdown (70% of the initial flour content compared to 40% without any leavening agent or acidification). This result highlights the predominance of wheat phytase activity over sourdough microflora phytase activity during moderate sourdough fermentation and shows that a slight drop of the pH (pH value around 5.5) is sufficient to reduce significantly the phytate content of a wholemeal flour. Mg "bioaccessibility"of whole wheat dough was improved by direct solubilization of the cation and by phytate hydrolysis.

Whole cereal products are the main source of magnesium in human nutrition. Even if wholemeal bread is an important source of Mg, it also contains considerable amounts of phytic acid (PA), a natural chelator that lowers the absorption of trace elements such as Fe or Zn as well as Ca or Mg in cereal products. Significant Mg bioavailability improvement in bread could be supplied by the choice of raw materials and the baking processes of cereals. Improvement in the Mg content of wheat grain was proved possible by traditional plant selection. Bread making using sourdough improves the nutritional properties of bread by reducing the amounts of phytic acid and phytate breakdown, which is mainly explained by the acidity level in the sourdough process that promotes greater efficiency in the wheat phytase activity. A slight acidification due to sourdough effectively reduces the phytate content and improves Mg bioavaibility.

The physiologic importance of ferulic acid (FA), and notably its antioxidant properties, depends upon its availability for absorption and subsequent interaction with target tissues. Because FA is widely present in cereals, the aim of the present study was to investigate its intestinal and hepatic metabolism in rats by in situ intestinal perfusion model (from 10 to 50 nmol/min), and its bioavailability in supplemented diets (from 10 to 250 micromol/d) or in a complex cereal matrix, i.e., whole flours from Valoris (Triticum aestivum) or Duriac (T. durum) cultivars and bran or white flour from the Valoris cultivar. In perfused rat intestine, net FA absorption was proportional to the perfused dose (R2 = 0.997); once absorbed, FA was completely recovered as conjugated forms in plasma and bile secretion (representing 5-7% of the perfused dose). In rats fed FA-enriched semipurified diets, FA absorption was quite efficient because approximately 50% of the ingested dose was recovered in urine. This extensive elimination by kidneys limited FA accumulation in plasma (typically 1 micromol/L in rats fed 50 micromol FA/d). In contrast, in rats fed cereal diets providing 56-81 micromol FA/d, urine excretion was 90-95% lower than in rats fed FA-enriched semipurified diets, and plasma concentrations were approximately 0.2-0.3 micromol/L. Thus, the cereal matrix appears to severely limit FA bioavailability. This inherently low bioavailability of FA in cereals likely reflects FA association with the fiber fraction through cross-linking with arabinoxylans and lignins.