Surfactants, nanomedicines and nanocarriers: a critical evaluation on clinical trials

Advances, perspectives and innovation in drug delivery have increased in recent years; however, there is limited information available regarding the actual presence of surfactants, nanomed-icines and nanocarriers in investigational medicinal products submitted as part of a request for authorization of clinical trials, particularly for those authorized in the European Economic Area. We retrieve, analyze and report data available at the Clinical Trial Office of the Italian Medicines Agency (AIFA), increasing the transparency and availability of relevant information. An analysis of quality documentation submitted along with clinical trials authorized by the AIFA in 2018 was carried out, focusing on the key terms “surfactant”, “nanomedicine” and “nanocarrier”. Results suggest potential indications and inputs for further reflection and actions for regulators to actively and safely drive innovation from a regulatory perspective and to transpose upcoming evolution of clinical trials within a strong regulatory framework

Rare and Insidious Toxicities from New Combination Therapies in Metastatic Renal Cell Cancer: Lessons Learned from Real-Practice

The advent of immune checkpoint inhibitors in combination with multitarget tyrosine kinase inhibitors has become a standard first-line treatment for metastatic renal cell cancer. Along with survival improvement, new toxicities have emerged. Such adverse events are still complex to be managed and some of them are rare and could be insidious or even fatal. Medical oncologists dispose of guidelines about the management of toxicities from immune checkpoint inhibitors but not for combinations. Therefore, it is still difficult to properly attribute and manage additive or overlapping adverse events. We report two clinical cases regarding rare treatment-related endocrine toxicities—hypophysitis and thyroiditis—with particular focus on their management. To this purpose, immune checkpoint-related toxicities guidelines represent the starting point. However, their implementation with additional measures is needed, considering the increasing complexity of current clinical scenarios. The goal is to correctly recognize adverse events and address side effects, so as not to discontinue effective treatments. We, therefore, aim at discussing the points of proper management of toxicities and individuating potential areas of improvement

A novel free-electron laser single-pulse Wollaston polarimeter for magneto-dynamical studies

Here, we report on the conceptual design, the hardware realization, and the first experimental results of a novel and compact x-ray polarimeter capable of a single-pulse linear polarization angle detection in the extreme ultraviolet photon energy range. The polarimeter is tested by performing time resolved pump-probe experiments on a Ni80Fe20 Permalloy film at the M-2,M-3 Ni edge at an externally seeded free-electron laser source. Comparison with similar experiments reported in the literature shows the advantages of our approach also in view of future experiments

Breaking barriers in triple negative breast cancer (TNBC) – Unleashing the power of antibody-drug conjugates (ADCs)

Antibody-drug conjugates (ADCs) represent a novel class of molecules composed of a recombinant monoclonal antibody targeted to a specific cell surface antigen, conjugated to a cytotoxic agent through a cleavable or non-cleavable synthetic linker. The rationale behind the development of ADCs is to overcome the limitations of conventional chemotherapy, such as the narrow therapeutic window and the emergence of resistance mechanisms. ADCs had already revolutionized the treatment algorithm of HER2-positive breast cancer. Currently, emergent non-HER2 targeted ADCs are gaining momentum, with special focus on triple-negative disease therapeutic landscape. Sacituzumab govitecan (SG) is an ADC consisting of a humanized monoclonal antibody hRS7 targeting trophoblast cell surface antigen 2 (Trop2), linked to the topoisomerase I inhibitor SN-38 by a hydrolysable linker. It currently stands as the only non-HER2 targeted ADC that already received approval for the treatment of unresectable locally advanced or metastatic triple negative breast cancer (TNBC) in patients who had received two or more prior systemic therapies, with at least one for advanced disease. The purpose of these review is to analyze the available evidence regarding ADCs in TNBC, alongside with providing an overview on the ongoing and future research horizons in this field

Valutazione della bontà educativa dei casi clinici di ECCE, il programma di formazione a distanza (FAD) basato sulle evidenze destinato ai medici italiani

OBIETTIVO. Valutare la qualit\ue0 dei percorsi clinici di un programma FAD destinato a tutti i medici italiani verificando le loro propriet\ue0 psicometriche. METODI. AIFA ha lanciato un programma nazionale di sostegno dell\u2019informazione indipendente tramite la distribuzione gratuita ai medici di Clinical Evidence (CE). Sulla base dei contenuti di CE \ue8 stato sviluppato un programma FAD all\u2019interno del sistema di Educazione Continua in Medicina (ECM) dal nome ECCE, anch\u2019esso gratuito. I medici hanno accesso a CE online e ai relativi percorsi clinici. Superandoli il medico ottiene i crediti ECM. Nel corso del 2006 \ue8 stata valutata la qualit\ue0 di un campione di venti percorsi, su un totale di 120. La valutazione formale della qualit\ue0 dei 20 casi selezionati \ue8 avvenuta attraverso le seguenti dimensioni psicometriche: Giudizio generale sui percorsi da parte degli utilizzatori (face validity); Valutazione dei contenuti da parte di clinici esperti (content validity); Valutazione della attendibilit\ue0 del test attraverso un criterio di consistenza interna (internal reliability); Difficolt\ue0 degli items; Capacit\ue0 del test di rilevare una modificazione della conoscenza (responsiveness). RISULTATI: Alcune migliaia di utenti hanno partecipato alla valutazione fornendo esiti contrastanti: mentre la face e content validity sono state valutate positivamente dagli utilizzatori e dai clinici esperti, altri parametri come l\u2019internal reliability e la difficolt\ue0 degli items hanno mostrato grande variabilit\ue0 tra i percorsi. Sette casi mostrano un valore di alpha complessivo inferiore a 0.50 (soglia minima di affidabilit\ue0). I casi si sono dimostrati nel complesso medio-facili. Facendo riferimento solo alle proprie conoscenze i partecipanti rispondevano correttamente a circa a met\ue0 delle domande. La lettura delle fonti era associata a un miglioramento della performance (miglioramento prima-dopo statisticamente significativo, p<0.05 per 19/20 percorsi). CONCLUSIONI: L\u2019importante eterogeneit\ue0 tra percorsi dimostrerebbe come differenti casi possono analizzare in maniera molto disomogenea il domino conoscenza evidence-based derivata dai contenuti di CE

Instrumental activities of daily living in older patients with metastatic prostate cancer: results from the meet-URO network ADHERE prospective study

Instrumental activities of daily living (IADL) are significant health indicators closely related to executive functions and able to detect mild cognitive impairment. A decline in IADL usually precedes ADL limitation, including taking medications, and may therefore predict a cognitive decline. We aimed to investigate the association of patients’ IADL score with other clinical factors, with a particular focus on the presence of a caregiver, and the impact on adherence to androgen receptor pathway inhibitors (ARPIs) and survival outcomes within the Meet-URO 5—ADHERE study. It was a large prospective multicentre observational cohort study monitoring adherence to ARPIs in 234 metastatic castrate-resistant PC (mCRPC) patients aged ≥ 70. We observed an association between impaired IADL and lower geriatric G8 scores (p < 0.01), and lower adherence to ARPIs whether assessed by pill counting (p = 0.01) or self-reported by the patient himself (p = 0.03). The combination of an IADL < 6 and the absence of a caregiver resulted in a significantly high risk of non-adherence to the ARPIs at the multivariable analysis (HR 9.23, 95% confidence interval 2.28–37.43, p = 0.01). IADL alongside the geriatric G8 scales represent essential tools to identify frail and less auto-sufficient patients who are extremely vulnerable particularly if not supported by a caregiver and have the highest risk of nonadherence to ARPIs

The Geriatric G8 Score Is Associated with Survival Outcomes in Older Patients with Advanced Prostate Cancer in the ADHERE Prospective Study of the Meet-URO Network

Introduction: Androgen receptor pathway inhibitors (ARPIs) have been increasingly offered to older patients with prostate cancer (PC). However, prognostic factors relevant to their outcome with ARPIs are still little investigated. Methods and Materials: The Meet-URO network ADHERE was a prospective multicentre observational cohort study evaluating and monitoring adherence to ARPIs metastatic castrate-resistant PC (mCRPC) patients aged ≥70. Cox regression univariable and multivariable analyses for radiographic progression-free (rPFS) and overall survival (OS) were performed. Unsupervised median values and literature-based thresholds where available were used as cut-offs for quantitative variables. Results: Overall, 234 patients were enrolled with a median age of 78 years (73–82); 86 were treated with abiraterone (ABI) and 148 with enzalutamide (ENZ). With a median follow-up of 15.4 months (mo.), the median rPFS was 26.0 mo. (95% CI, 22.8–29.3) and OS 48.8 mo. (95% CI, 36.8–60.8). At the MVA, independent prognostic factors for both worse rPFS and OS were Geriatric G8 assessment ≤ 14 (p < 0.001 and p = 0.004) and PSA decline ≥50% (p < 0.001 for both); time to castration resistance ≥ 31 mo. and setting of treatment (i.e., post-ABI/ENZ) for rPFS only (p < 0.001 and p = 0.01, respectively); age ≥78 years for OS only (p = 0.008). Conclusions: Baseline G8 screening is recommended for mCRPC patients aged ≥70 to optimise ARPIs in vulnerable individuals, including early introduction of palliative care

Regional actorness and interregional relations:ASEAN, the EU and Mercosur

The European Union (EU) has a long tradition of interregional dialogue mechanisms with other regional organisations and is using these relations to project its own model of institutionalised actorness. This is partly motivated by the emerging actorness of the EU itself, which benefits from fostering capable regional counterparts in other parts of the world. This article advances the argument that actorness, which we conceptualise in terms of institutions, recognition and identity, is a relational concept, dependent on context and perception. Taking the Association of Southeast Asian Nations (ASEAN) and the Common Market of the South (Mercosur) and their relations with the EU as case studies, this article demonstrates that the actorness capabilities of all three organisations have been enhanced as result of ASEAN-EU and Mercosur-EU relations. However, there are clear limits to the development of the three components of regional actorness and to the interregional relations themselves. These limits stem both from the type of interregionalism at play and from the different regional models the actors incorporate. While there is evidence of institutional enhancement in ASEAN and Mercosur, these formal changes have been grafted on top of firmly entrenched normative underpinnings. Within the regional organisations, interactions with the EU generate centrifugal forces concerning the model to pursue, thus limiting their institutional cohesion and capacity. In addition, group-to-group relations have reinforced ASEAN and Mercosur identities in contrast to the EU. The formation of such differences has narrowed the scope of EU interregionalism despite the initial success of improved regional actorness

Small tumor necrosis factor receptor biologics inhibit the tumor necrosis factor-p38 signalling axis and inflammation

Anti-TNF therapy has improved the treatment of inflammatory disease but can predispose to infection and malignancy. Here the authors show an anti-TNF biologic peptide that functionally and selectively targets the TNF-p38 pathway in multiple models of inflammation