Pivotal trial characteristics and types of endpoints used to support Food and Drug Administration rare disease drug approvals between 2013 and 2022.

Background/aims: Rare disease drug development faces unique challenges, such as genotypic and phenotypic heterogeneity within small patient populations and a lack of established outcome measures for conditions without previously successful drug development programs. These challenges complicate the process of selecting the appropriate trial endpoints and conducting clinical trials in rare diseases. In this descriptive study, we examined novel drug approvals for non-oncologic rare diseases by the U.

A New Antibody-Cytokine Construct Targeting Natural Killer Cells: An Immunotherapeutic Approach to Chronic Lymphocytic Leukemia.

In chronic lymphocytic leukemia (CLL), natural killer (NK) cells show a dysfunctional phenotype that correlates with disease progression. Our aim was to restore NK cell functionality in CLL through a specifically targeted IL15-stimulating activity; IL15 targeting could, in fact, potentiate the activity of NK cells and reduce off-target effects. We designed and developed a cis-acting immunocytokine composed of an anti-CD56 single-chain Fragment variable (scFv) and IL15, labeled scFvB1IL15.

TBC1D24 interacts with the v-ATPase and regulates intraorganellar pH in neurons.

The vacuolar ATPase (v-ATPase) is essential for acidification of intracellular organelles, including synaptic vesicles. Its activity is controlled by cycles of association and dissociation of the ATP hydrolysis (V) and proton transport (V) multi-protein subunits. Mutations in genes coding for both v-ATPase subunits and TBC1D24 cause neurodevelopmental disorders with overlapping syndromes; therefore, it is important to investigate their potentially interrelated functions.

Checkpoint based immunotherapy in non-small cell lung cancer: a real-world retrospective study.

Introduction: Immune checkpoint inhibitor (ICI)-based immunotherapy targeting programmed cell death 1 (PD-1) or its ligand 1 (PD-L1) has radically changed the management of many types of solid tumors including non-small cell lung cancer (NSCLC). Many clinical trials have demonstrated that ICIs improve the survival and the quality of life of patients with advanced non oncogene NSCLC as compared to standard therapies. However, not all patients achieve a clinical benefit from this immunotherapeutic approach.

KRAS mutations in advanced non-small cell lung cancer: From biology to novel therapeutic strategies.

Kristen rat sarcoma viral oncogene homolog (KRAS) mutations play a major role in the carcinogenesis of many types of solid tumors including non-small cell lung cancer (NSCLC). Among KRAS mutations, p.G12C single-nucleotide variant (KRAS) is the most frequently reported in NSCLC patients, with a prevalence of about 12-13 %.

ATP6V1A is required for synaptic rearrangements and plasticity in murine hippocampal neurons.

Aim: Understanding the physiological role of ATP6V1A, a component of the cytosolic V domain of the proton pump vacuolar ATPase, in regulating neuronal development and function.

Methods: Modeling loss of function of Atp6v1a in primary murine hippocampal neurons and studying neuronal morphology and function by immunoimaging, electrophysiological recordings and electron microscopy.

Results: Atp6v1a depletion affects neurite elongation, stabilization, and function of excitatory synapses and prevents synaptic rearrangement upon induction of plasticity.

Human DNA topoisomerase I poisoning causes R loop-mediated genome instability attenuated by transcription factor IIS.

DNA topoisomerase I can contribute to cancer genome instability. During catalytic activity, topoisomerase I forms a transient intermediate, topoisomerase I-DNA cleavage complex (Top1cc) to allow strand rotation and duplex relaxation, which can lead to elevated levels of DNA-RNA hybrids and micronuclei. To comprehend the underlying mechanisms, we have integrated genomic data of Top1cc-triggered hybrids and DNA double-strand breaks (DSBs) shortly after Top1cc induction, revealing that Top1ccs increase hybrid levels with different mechanisms.

Neutrophil to lymphocyte ratio in myelofibrosis patients treated with ruxolitinib may predict prognosis and rate of discontinuation.

Background: Myelofibrosis (MF) is a clonal Philadelphia chromosome negative myeloproliferative neoplasm (Ph-MPN). MF is featured by an inflammatory condition that can also drive the progression of disease. Ruxolitinib (ruxo) is the-first-in-class Jak1/2 inhibitor approved for treatment of MF, proved to reduce spleen volume and decrease symptom burden.

Ibrutinib as first line therapy in chronic lymphocytic leukemia patients over 80 years old: A retrospective real-life multicenter Italian cohort.

Although chronic lymphocytic leukemia (CLL) predominantly affects the elderly, limited data exists about the outcomes of over 80-year-old patients, usually underrepresented in clinical trials. We conducted a multicenter study enrolling 79 consecutive CLL patients ≥80 years at the time of frontline therapy, all treated with ibrutinib. Nearly 48% of cases exhibited unmutated IGHV genes, 32% 17p deletion, and 39.

Geodetic imaging of magma ascent through a bent and twisted dike during the Tajogaite eruption of 2021 (La Palma, Canary Islands).

On Sept. 19th, 2021, the largest historical eruption on the island of La Palma began, which had a significant scientific, social, and economic impact. The 2021 Tajogaite eruption was characterised by short precursors, lasting only 8 days.

Evaluation of Potential Predictive Biomarkers for Defining Brain Radiotherapy Efficacy in Non-Small Cell Lung Cancer Patients with Brain Metastases: A Case Report and a Narrative Review.

Non-small cell lung cancer (NSCLC) is the second most common cancer worldwide, resulting in 1.8 million deaths per year. Most patients are diagnosed with a metastatic disease.

Prior Anti-Angiogenic TKI-Based Treatment as Potential Predisposing Factor to Nivolumab-Mediated Recurrent Thyroid Disorder Adverse Events in mRCC Patients: A Case Series.

Immune checkpoint inhibitors (ICIs) targeting programmed cell death 1 (PD-1) or its ligand 1 (PD-L1) have revolutionized the management of many types of solid tumors, including metastatic renal cell carcinoma (mRCC). Both sequential and combinatorial therapeutic strategies utilizing anti-PD-1 monoclonal antibodies (mAbs) and anti-angiogenic tyrosine kinase inhibitors (TKIs) have demonstrated to improve the survival of patients with mRCC as compared to standard therapies. On the other hand, both ICIs and TKIs are well known to potentially cause thyroid disorder adverse events (TDAEs).

Different Prognostic Role of Soluble PD-L1 in the Course of Severe and Non-Severe COVID-19.

Understanding the link between COVID-19 and patient immune characteristics is crucial. We previously demonstrated that high levels of the soluble Programmed Death-Ligand1 (sPD-L1) at the beginning of the infection correlated with low lymphocyte number and high C-reactive protein (CRP), longer length of stay (LOS), and death. This study investigated whether sPD-L1 can be a prognosis biomarker during COVID-19.

Validation of imatinib therapy failure score (IMTF) in chronic phase chronic myeloid leukemia in real life practice.

The outcome of chronic myeloid leukemia (CML) patients improved in the last decade. Clinical prognostic scoring systems aim to provide information about survival in the long-term, without determining from baseline the subset of patients who require a strictly monitoring because at increased risk of failure. Imatinib, the first-generation tyrosine kinase inhibitor (TKI), is still widely used as frontline treatment: recently, the imatinib therapy failure (IMTF) score was proposed to identify the failure free survival.

Complication of Gastric Cancer Surgery: A Single Centre Experience.

Background/aim: Gastric cancer surgery is still characterised by high morbidity and mortality. However, in 2018 an online platform, GASTRODATA has been proposed in Europe to standardize the recording of gastric surgery complications. The aim of the study was to present a single center experience regarding incidence and grading of acute postoperative complications in a population of patients treated surgically for gastric cancer on the basis of the gastrodata online platform.