Exploring the role of PARP1 inhibition in enhancing antibody-drug conjugate therapy for acute leukemias: insights from DNA damage response pathway interactions.

Background: The introduction of antibody-drug conjugates represents a significant advancement in targeted therapy of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Our study aims to investigate the role of the DNA damage response pathway and the impact of PARP1 inhibition, utilizing talazoparib, on the response of AML and ALL cells to Gemtuzumab ozogamicin (GO) and Inotuzumab ozogamicin (INO), respectively.

Methods: AML and ALL cells were treated with GO, INO and γ-calicheamicin in order to induce severe DNA damage and activate the G2/M cell-cycle checkpoint in a dose- and time-dependent manner.

Liquid Chromatography-Tandem Mass Spectrometry Method for Therapeutic Drug Monitoring of Dalbavancin in Plasma of Pediatric and Young Adult Patients.

Background: Dalbavancin, an antimicrobial lipoglycopeptide, is authorized in Europe for treating acute bacterial infections of the skin and skin structures in adults and pediatric patients aged 3 months and older. However, off-label dosing regimens have been proposed for various indications beyond acute bacterial infections of the skin and skin structures. This study presents a novel bioanalytical method using liquid chromatography-tandem mass spectrometry to quantify dalbavancin in low-volume plasma samples (50 μL).

Measurement of 3-O-methyldopa from dried plasma microsamples by high-resolution mass spectrometry: A tool for the diagnosis of patients with high-risk neuroblastoma.

Background: Risk assessment at diagnosis is crucial for neuroblastoma (NB) in order to address patients at high-risk to the most timely and appropriate treatments. 3-O-methyldopa (3-OMD), a direct metabolite of L-Dopa, is a promising biomarker of NB at diagnosis able to stratify high-risk patients.

Methods: We show the development and validation of a method for measuring 3-OMD from dried plasma samples (DPS) and plasma using liquid chromatography coupled with high resolution mass spectrometry (LC-HRMS) on a Thermo Fisher Scientific Orbitrap Exploris 120.

Early bone marrow alterations in patients with adenosine deaminase 2 deficiency across disease phenotypes and severities.

Background: Deficiency of adenosine deaminase 2 (DADA2) is a complex monogenic disease caused by recessive mutations in the ADA2 gene. DADA2 exhibits a broad clinical spectrum encompassing vasculitis, immunodeficiency, and hematologic abnormalities. Yet, the impact of DADA2 on the bone marrow (BM) microenvironment is largely unexplored.

Dried plasma spot as an innovative approach to therapeutic drug monitoring of apixaban: Development and validation of a novel liquid chromatography-tandem mass spectrometry method.

Apixaban, a direct oral anticoagulant drug (DOAC), typically does not require routine therapeutic drug monitoring (TDM), yet recent guidelines propose its use in specific clinical scenarios. While various antifactor Xa (anti-FXa) chromogenic assays serve as useful proxies for measuring plasma exposure to apixaban in emergencies, they lack specificity compared with chromatographic methods. This research project is intended to the development and validation of a standardized protocol of liquid chromatography-tandem mass spectrometry (LC-MS/MS) in conformity with the ICH guidelines M10 for the measurement of apixaban in both plasma and dried plasma spots (DPSs).

VESCL: an open source 2D vessel contouring library.

Purpose: VESCL (pronounced 'vessel') is a novel vessel contouring library for computer-assisted 2D vessel contouring and segmentation. VESCL facilitates manual vessel segmentation in 2D medical images to generate gold-standard datasets for training, testing, and validating automatic vessel segmentation.

Methods: VESCL is an open-source C++ library designed for easy integration into medical image processing systems.

Real-World Safety and Outcome of First-Line Pembrolizumab Monotherapy for Metastatic NSCLC with PDL-1 Expression ≥ 50%: A National Italian Multicentric Cohort ("" Study).

Results from the phase III clinical trial established pembrolizumab monotherapy as the first-line standard of care for patients with metastatic NSCLC who have PD-L1 expression ≥ 50%, , and wild-type tumors. However, given the differences between patients treated in routine clinical practice and those treated in a clinical trial, real-world data are needed to confirm the treatment benefit in standard practice. Given the lack of data on large cohorts of patients with long follow-ups, we designed an observational retrospective study of patients with metastatic NSCLC who were treated with pembrolizumab, starting from its reimbursement eligibility until December 2020.

Pharmacy Workload in Clinical Trial Management: A Preliminary Complexity Assessment Tool for Sponsored Oncology and Haematology Trials.

Investigational drug services need to be organised in a structured approach, especially for sites with a large number of ongoing clinical trials. The aim of this study was to develop a tool to assess the complexity of pharmacy involvement in a sponsored oncology clinical trial. Categorisation into ordinal complexity categories was used to assess the complexity of the clinical trials for consistent pharmacy grant applications.

Innovative LC-MS/MS method for therapeutic drug monitoring of fenfluramine and cannabidiol in the plasma of pediatric patients with epilepsy.

We present a novel liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for quantifying fenfluramine (FFA), its active metabolite norfenfluramine (norFFA), and Epidyolex®, a pure cannabidiol (CBD) oral solution in plasma. Recently approved by the EMA for the adjunctive treatment of refractory seizures in patients with Dravet and Lennox-Gastaut syndromes aged above 2 years, FFA and CBD still do not have established therapeutic blood ranges, and thus need careful drug monitoring to manage potential pharmacokinetic and pharmacodynamic interactions. Our method, validated by ICH guidelines M10, utilizes a rapid extraction protocol from 100 µL of human plasma and a reversed-phase C-18 HPLC column, with deuterated internal standards.

Single suture-mediated closure system after transfemoral transcatheter aortic valve implantation: A single-center real-world experience.

Background: Despite the use of two crossed Perclose ProGlide™ (Abbott Vascular Devices) is the most widespread technique to close the main arterial access in transfemoral transcatheter aortic valve implantation (TF-TAVI), the safest and most effective strategy still remains much debated.

Aims: The aim of the present study was to evaluate the performance of a single Perclose ProGlide suture-mediated closure device to obtain femoral hemostasis after sheathless implantation of self-expanding transcatheter heart valves through their 14 F-equivalent fix delivery systems.

Methods: This prospective observational study included 439 patients undergoing TF-TAVI at the "Montevergine" Clinic of Mercogliano, Italy.

A real-world retrospective, observational study of first-line pembrolizumab plus chemotherapy for metastatic non-squamous non-small cell lung cancer with PD-L1 tumor proportion score < 50% (PEMBROREAL).

Introduction: The phase III Keynote-189 trial established a first-line treatment combining pembrolizumab with pemetrexed and platinum as a standard treatment for patients with stage IV non-small cell lung cancer (NSCLC) without known and driver mutations and independent of programmed cell death ligand 1 (PD-L1) expression. However, in Italy, eligibility for the National Health Service payment program is limited to patients with PD-L1 <50%. The PEMBROREAL study assesses the real-world effectiveness and safety of pembrolizumab in patients eligible for the National Health Service payment program.

Role of HIV-1 Tat Protein Interactions with Host Receptors in HIV Infection and Pathogenesis.

Each time the virus starts a new round of expression/replication, even under effective antiretroviral therapy (ART), the transactivator of viral transcription Tat is one of the first HIV-1 protein to be produced, as it is strictly required for HIV replication and spreading. At this stage, most of the Tat protein exits infected cells, accumulates in the extracellular matrix and exerts profound effects on both the virus and neighbor cells, mostly of the innate and adaptive immune systems. Through these effects, extracellular Tat contributes to the acquisition of infection, spreading and progression to AIDS in untreated patients, or to non-AIDS co-morbidities in ART-treated individuals, who experience inflammation and immune activation despite virus suppression.

Dose optimization and target attainment of vancomycin in children.

Vancomycin is a glycopeptide antibiotic that has been adopted in clinical practice to treat gram-positive infections for more than 70 years. Despite vancomycin's long history of therapeutic use, optimal dose adjustments and pharmacokinetic/pharmacodynamic (PK/PD) target attainment in children are still under debate. Therapeutic drug monitoring (TDM) has been widely integrated into pediatric clinical practice to maximize efficacy and safety of vancomycin treatment.

Fluoroscopy Time as a New Predictor of Short-Term Outcomes after Transcatheter Aortic Valve Replacement.

Background: Transcatheter aortic valve replacement (TAVR) is an almost totally cine-fluoroscopic guided procedure. The amount of radiation used during the procedure is strictly related to the fluoroscopy time (FT), that has already been demonstrated to be associated with outcomes and complexity of coronary procedures. The aim of our study is to demonstrate the relationship between FT and the short-term outcomes after TAVR defined by to the Valve Academic Research Consortium (VARC)-2 and -3 consensus documents.

A Novel LC-MS/MS Method for Therapeutic Drug Monitoring of Baricitinib in Plasma of Pediatric Patients.

Background: Janus kinase inhibitors are antirheumatic immunosuppressive drugs that target intracellular Janus kinases (JAKs). Baricitinib is a selective and reversible orally administered JAK1/JAK2 inhibitor approved for treating rheumatoid arthritis, atopic dermatitis, and alopecia areata in adult patients. Expanded access to baricitinib has been approved for treating pediatric patients affected by rare Mendelian autoinflammatory diseases with type I interferon-mediated damage.

Intracoronary Pacing during "Chimney Technique" in Transcatheter Aortic Valve-in-Valve Implantation: An Alternative Temporary Rapid Ventricular Stimulation?

Temporary rapid ventricular pacing (TRVP) is required during transcatheter aortic valve implantation (TAVI) in order to reduce cardiac output and to facilitate balloon aortic valvuloplasty, prosthesis deployment, and post-deployment balloon dilation. The two most frequently used TRVP techniques are right endocardial (RE)-TRVP and retrograde left endocardial temporary rapid ventricular pacing (RLE)-TRVP. The first one could be responsible for cardiac tamponade, one of the most serious procedural complications during TAVI, while the second one could often be unsuccessful.

Biological Fluid Microsampling for Therapeutic Drug Monitoring: A Narrative Review.

Therapeutic drug monitoring (TDM) is a specialized area of laboratory medicine which involves the measurement of drug concentrations in biological fluids with the aim of optimizing efficacy and reducing side effects, possibly modifying the drug dose to keep the plasma concentration within the therapeutic range. Plasma and/or whole blood, usually obtained by venipuncture, are the "gold standard" matrices for TDM. Microsampling, commonly used for newborn screening, could also be a convenient alternative to traditional sampling techniques for pharmacokinetics (PK) studies and TDM, helping to overcome practical problems and offering less invasive options to patients.

Altered plasma levels of apixaban in major gastrointestinal tract surgery: A case report and review of the literature.

Altered direct oral anticoagulant (DOAC) plasma levels can lead either to spontaneous hemorrhagic or thrombotic complications. We describe a case of suspected altered apixaban disposition in a patient with an upper gastrointestinal cancer resection treated with apixaban for non-valvular atrial fibrillation. Diagnosis of ischemic stroke for left hemiparesis was confirmed due to recent emergence of a hypodense area in the posterior capsular nucleus of ischemic reference in a context of binuclear capsular lacunar lesions.

Surgical Mortality Risk Scores in Transcatheter Aortic Valve Implantation: Is Their Early Predictive Value Still Strong?

Background: Surgical mortality risk scores, even if not properly designed and rarely tested in the transcatheter aortic valve implantation (TAVI) setting, still guide the heart team in managing significant aortic stenosis.

Methods: After splitting 1763 consecutive patients retrospectively based on their mortality risk thresholds, the composite endpoint early safety (ES) was adjudicated according to Valve Academic Research Consortium (VARC)-2 and -3 consensus documents.

Results: ES incidence was higher if VARC-2 rather than VARC-3 defined.

Simultaneous Quantification of Ivacaftor, Tezacaftor, and Elexacaftor in Cystic Fibrosis Patients' Plasma by a Novel LC-MS/MS Method.

The new breakthrough cystic fibrosis (CF) drug combination of ivacaftor (IVA), tezacaftor (TEZ), and elexacaftor (ELX), namely "caftor" drugs, directly modulates the activity and trafficking of the defective CF transmembrane conductance regulator protein (CFTR) underlying the CF disease. The role of therapeutic drug monitoring (TDM) of caftor drugs in clinical settings has recently been established. The availability of reliable and robust analytical methods for the quantification of IVA, TEZ, and ELX is essential to support dose-concentration-effect studies.

Development and Validation of a Novel LC-MS/MS Method for a TDM-Guided Personalization of HSCT Conditioning with High-Dose Busulfan in Children.

Personalization of busulfan (Bu) exposure via therapeutic drug monitoring (TDM) is recommended for patients treated with high-dose conditioning regimens. Several laboratories' developed methods are available in the literature with a lack of standardization. The aim of this study is to develop a new standardized LC-MS/MS method and validate it according to the international ICH M10 (EMA) guidelines.

Early acute kidney injury after transcatheter aortic valve implantation: predictive value of currently available risk scores.

Background: Acute kidney injury (AKI) after transcatheter aortic valve implantation (TAVI) is a frequent complication associated with adverse outcomes and mortality. Various scores have been developed to predict this complication in the coronary setting. However, none have ever been tested in a large TAVI population.

Single-timepoint low-dimensional characterization and classification of acute versus chronic multiple sclerosis lesions using machine learning.

Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease characterized by the appearance of focal lesions across the central nervous system. The discrimination of acute from chronic MS lesions may yield novel biomarkers of inflammatory disease activity which may support patient management in the clinical setting and provide endpoints in clinical trials. On a single timepoint and in the absence of a prior reference scan, existing methods for acute lesion detection rely on the segmentation of hyperintense foci on post-gadolinium T1-weighted magnetic resonance imaging (MRI), which may underestimate recent acute lesion activity.