ERANET JTC 2011: Submission and Activation of an International Academic Translational Project in Advanced Breast Cancer. Experience From the ET-FES Study

Background: Academic research is important to face unmet medical needs. The Oncological community encounters many hurdles in setting up multicenter investigator-driven trials mainly due to administrative complexity. The purpose of a network organization at a multinational level is to facilitate clinical trials through standardization, coordination, and education for drug development and regulatory approval.Methods: The application of an European grant foresees the creation of a consortium which aims at facilitating multi-center academic clinical trials.Results: The ERA-NET TRANSCAN Call 2011 on “Validation of biomarkers for personalized cancer medicine” was released on December 2011. This project included Italian, Spanish, French and German centers. The approval process included Consortium constitution, project submission, Clinical Trial Submission, and activation on a national level. The different timescales for submitting study documents in each Country and the misalignment of objections by each Competent Authority CA, generated several requests for changes to the study documents which meant amendments had to be made; as requested by the 2001/20/EC Directive, the alignment of core documents is mandatory. This procedure impacted significantly on study activation timelines. Time to first patient in was 14, 10, 28, and 31 months from the date of submission in Italy, France, Spain, and Germany, respectively. Accrual was stopped on 22nd January 2021 due to an 18F FES shortage as the primary reason but also for having exceeded the project deadlines with consequent exhaustion of the funds allocated for the project.Conclusions: Pharmaceutical companies might be reluctant to fund research projects aimed at treatment individualization if the approval for a wider indication has already been achieved. Academic trials therefore become fundamental for promoting trials which are not attractive to big pharma. It was very difficult and time consuming to activate an academic clinical trial, for this reason, a study may become “old” as new drugs entered into the market. National institutions should promote the development of clinical research infrastructures and network with competence in regulatory, ethical, and legal skills to speed up academic research.

Chronopharmacology in Therapeutic Drug Monitoring—Dependencies between the Rhythmics of Pharmacokinetic Processes and Drug Concentration in Blood

The objective of the optimization of pharmacotherapy compliant with the basic rules of clinical pharmacology is its maximum individualization, ensuring paramount effectiveness and security of the patient’s therapy. Thus, multiple factors that are decisive in terms of uniqueness of treatment of the given patient must be taken into consideration, including, but not limited to, the patient’s age, sex, concomitant diseases, special physiological conditions (e.g., pregnancy, lactation, extreme age groups), polypharmacotherapy and polypragmasia (particularly related to increased risk of drug interactions), and patient’s phenotypic response to the administered drug with possible genotyping. Conducting therapy while monitoring the concentration of certain drugs in blood (Therapeutic Drug Monitoring; TDM procedure) is also one of the factors enabling treatment individualization. Furthermore, another material, and yet still a marginalized pharmacotherapeutic factor, is chronopharmacology, which indirectly determines the values of drug concentrations evaluated in the TDM procedure. This paper is a brief overview of chronopharmacology, especially chronopharmacokinetics, and its connection with the clinical interpretation of the meaning of the drug concentrations determined in the TDM procedure.

A Mathematical Model of Thyroid Disease Response to Radiotherapy

We present a mechanistic biomathematical model of molecular radiotherapy of thyroid disease. The general model consists of a set of differential equations describing the dynamics of different populations of thyroid cells with varying degrees of damage caused by radiotherapy (undamaged cells, sub-lethally damaged cells, doomed cells, and dead cells), as well as the dynamics of thyroglobulin and antithyroglobulin autoantibodies, which are important surrogates of treatment response. The model is presented in two flavours: on the one hand, as a deterministic continuous model, which is useful to fit populational data, and on the other hand, as a stochastic Markov model, which is particularly useful to investigate tumor control probabilities and treatment individualization. The model was used to fit the response dynamics (tumor/thyroid volumes, thyroglobulin and antithyroglobulin autoantibodies) observed in experimental studies of thyroid cancer and Graves’ disease treated with 131I-radiotherapy. A qualitative adequate fitting of the model to the experimental data was achieved. We also used the model to investigate treatment individualization strategies for differentiated thyroid cancer, aiming to improve the tumor control probability. We found that simple individualization strategies based on the absorbed dose in the tumor and tumor radiosensitivity (which are both magnitudes that can potentially be individually determined for every patient) can lead to an important raise of tumor control probabilities.

Platelet Function Testing and Genotyping for Tailoring Treatment in Complex PCI Patients

Dual antiplatelet therapy (DAPT), comprising aspirin and a P2Y12 receptor inhibitor, is considered the cornerstone of treatment in patients who have undergone percutaneous coronary intervention (PCI). Patients with complex PCI (C-PCI) constitute a special PCI subpopulation, characterized by increased ischemic risk. Identifying the optimal DAPT strategy is often challenging and remains controversial in this setting. In an attempt to balance ischemic and bleeding risks in C-PCI patients receiving DAPT, treatment individualization regarding potency and duration has evolved as a feasible approach. Platelet function testing and genotyping have been evaluated in several trials with conflicting and mostly neutral results. The aim of this review is to critically appreciate the role of these tools for antiplatelet treatment tailoring specifically in C-PCI patients. Because existing evidence is limited, dedicated future studies are warranted to elucidate the utility of platelet function testing and genotyping in C-PCI.

Arterial Hypertension: Individual Therapeutic Approaches—From DNA Sequencing to Gender Differentiation and New Therapeutic Targets

The aim of this paper is to provide an accurate overview regarding the current recommended approach for antihypertensive treatment. The importance of DNA sequencing in understanding the complex implication of genetics in hypertension could represent an important step in understanding antihypertensive treatment as well as in developing new medical strategies. Despite a pool of data from studies regarding cardiovascular risk factors emphasizing a worse prognosis for female patients rather than male patients, there are also results indicating that women are more likely to be predisposed to the use of antihypertensive medication and less likely to develop uncontrolled hypertension. Moreover, lower systolic blood pressure values are associated with increased cardiovascular risk in women compared to men. The prevalence, awareness and, most importantly, treatment of hypertension is variable in male and female patients, since the mechanisms responsible for this pathology may be different and closely related to gender factors such as the renin–angiotensin system, sympathetic nervous activity, endothelin-1, sex hormones, aldosterone, and the immune system. Thus, gender-related antihypertensive treatment individualization may be a valuable tool in improving female patients’ prognosis.