Randomised, open-label, multicentric phase III trial to evaluate the safety and efficacy of palbociclib in combination with endocrine therapy, guided by ESR1 mutation monitoring in oestrogen receptor-positive, HER2-negative metastatic breast cancer patients: study design of PADA-1.

Introduction: The combination of a CDK4/6 inhibitor with an aromatase inhibitor (AI) has recently become the gold standard for AI-sensitive first line treatment of oestrogen receptor-positive (ER+) HER2-negative (HER2-) advanced breast cancer. However, most patients receiving this combination will ultimately progress and require further therapies.Several studies have demonstrated that the onset of a gene mutation lead to AIs resistance in the advanced setting.

Identification of distinct cytotoxic granules as the origin of supramolecular attack particles in T lymphocytes.

Cytotoxic T lymphocytes (CTL) kill malignant and infected cells through the directed release of cytotoxic proteins into the immunological synapse (IS). The cytotoxic protein granzyme B (GzmB) is released in its soluble form or in supramolecular attack particles (SMAP). We utilize synaptobrevin2-mRFP knock-in mice to isolate fusogenic cytotoxic granules in an unbiased manner and visualize them alone or in degranulating CTLs.

Pseudoprogression in Glioblastoma: Role of Metabolic and Functional MRI-Systematic Review.

Background: Glioblastoma is the most frequent malignant primitive brain tumor in adults. The treatment includes surgery, radiotherapy, and chemotherapy. During follow-up, combined chemoradiotherapy can induce treatment-related changes mimicking tumor progression on medical imaging, such as pseudoprogression (PsP).

SAR442085, a novel anti-CD38 antibody with enhanced antitumor activity against multiple myeloma.

Anti-CD38 monoclonal antibodies (mAbs) represent a breakthrough in the treatment of multiple myeloma (MM), yet some patients fail to respond or progress quickly with this therapy, highlighting the need for novel approaches. In this study we compared the preclinical efficacy of SAR442085, a next-generation anti-CD38 mAb with enhanced affinity for activating Fcγ receptors (FcγR), with first-generation anti-CD38 mAb daratumumab and isatuximab. In surface plasmon resonance and cellular binding assays, we found that SAR442085 had higher binding affinity than daratumumab and isatuximab for FcγRIIa (CD32a) and FcγRIIIa (CD16a).

Comparison of Two Types of Amino Acid Solutions on Lu-Dotatate Pharmacokinetics and Pharmacodynamics in Patients with Metastatic Gastroenteropancreatic Neuroendocrine Tumors.

Background: Lu-Dotatate is used in the treatment of somatostatin-receptor-positive inoperable progressive gastroenteropancreatic neuroendocrine tumors. A co-infusion of amino acids (AAs) is administered to prevent renal toxicity.

Objective: This study aimed to quantify the impact of two types of AA cocktails on the pharmacokinetics and toxicity of Lu-Dotatate.

Radiomics-Based Detection of Radionecrosis Using Harmonized Multiparametric MRI.

In this study, a radiomics analysis was conducted to provide insights into the differentiation of radionecrosis and tumor progression in multiparametric MRI in the context of a multicentric clinical trial. First, the sensitivity of radiomic features to the unwanted variability caused by different protocol settings was assessed for each modality. Then, the ability of image normalization and ComBat-based harmonization to reduce the scanner-related variability was evaluated.

Challenging the traditional approach for interpreting genetic variants: Lessons from Fabry disease.

Fabry disease (FD) is an X-linked genetic disease due to pathogenic variants in GLA. The phenotype varies depending on the GLA variant, alpha-galactosidase residual activity, patient's age and gender and, for females, X chromosome inactivation. Over 1000 variants have been identified, many through screening protocols more susceptible to disclose non-pathogenic variants or variants of unknown significance (VUS).

From Immune Dysregulations to Therapeutic Perspectives in Myelodysplastic Syndromes: A Review.

The pathophysiology of myelodysplastic syndromes (MDSs) is complex and often includes immune dysregulation of both the innate and adaptive immune systems. Whereas clonal selection mainly involves smoldering inflammation, a cellular immunity dysfunction leads to increased apoptosis and blast proliferation. Addressing immune dysregulations in MDS is a recent concept that has allowed the identification of new therapeutic targets.

PKCθ-mediated serine/threonine phosphorylations of FAK govern adhesion and protrusion dynamics within the lamellipodia of migrating breast cancer cells.

The cytoskeleton and cell-matrix adhesions constitute a dynamic network that controls cellular behavior during development and cancer. The Focal Adhesion Kinase (FAK) is a central actor of these cell dynamics, promoting cell-matrix adhesion turnover and active membrane fluctuations. However, the initial steps leading to FAK activation and subsequent promotion of cell dynamics remain elusive.

Analysis of mRNA Translation by Polysome Profiling.

mRNA translation is a key step in gene expression that allows the cell to qualitatively and quantitatively modulate the cell's proteome according to intra- or extracellular signals. Polysome profiling is the most comprehensive technique to study both the translation state of mRNAs and the protein machinery associated with the mRNAs being translated. Here we describe the procedure commonly used in our laboratory to gain insights into the molecular mechanisms underlying translation regulation under pathophysiological conditions.

Evaluation of two modalities of perioperative treatment in the management of extremity and truncal soft tissue sarcomas: neoadjuvant concurrent chemoradiotherapy and sequential treatment.

Purpose: Patients with locally advanced grade 2-3 extremity/truncal soft tissue sarcomas (STS) are at high risk of recurrence. The objective of this study was to assess the efficacy and feasibility of neoadjuvant concurrent chemoradiotherapy (cCRT) in selected grade 2-3 patients with limb or trunk wall STS, and to compare this schedule to a sequential approach combining neoadjuvant chemotherapy and adjuvant radiotherapy.

Methods: We retrospectively included patients who underwent neoadjuvant cCRT at two comprehensive cancer centers from 1992-2016.

CD158k and PD-1 expressions define heterogeneous subtypes of Sezary syndrome.

Sezary syndrome (SS) is a rare leukemic form of cutaneous T-cell lymphoma. Diagnosis mainly depends on flow cytometry, but results are not specific enough to be unequivocal. The difficulty in defining a single marker that could characterize Sezary cells may be the consequence of different pathological subtypes.

Immunopathogenesis and proposed clinical score for identifying Kelch-like protein-11 encephalitis.

In this study, we report the clinical features of Kelch-like protein 11 antibody-associated paraneoplastic neurological syndrome, design and validate a clinical score to facilitate the identification of patients that should be tested for Kelch-like protein 11 antibodies, and examine in detail the nature of the immune response in both the brain and the tumour samples for a better characterization of the immunopathogenesis of this condition. The presence of Kelch-like protein 11 antibodies was retrospectively assessed in patients referred to the French Reference Center for paraneoplastic neurological syndrome and autoimmune encephalitis with (i) antibody-negative paraneoplastic neurological syndrome [limbic encephalitis ( = 105), cerebellar degeneration ( = 33)] and (ii) antibody-positive paraneoplastic neurological syndrome [Ma2-Ab encephalitis ( = 34), antibodies targeting N-methyl-D-aspartate receptor encephalitis with teratoma ( = 49)]. Additionally, since 1 January 2020, patients were prospectively screened for Kelch-like protein 11 antibodies as new usual clinical practice.

Low-grade epilepsy-associated neuroepithelial tumours with a prominent oligodendroglioma-like component: The diagnostic challenges.

Aims: We searched for recurrent pathological features and molecular alterations in a retrospective series of 72 low-grade epilepsy-associated neuroepithelial tumours (LEATs) with a prominent oligodendroglioma-like component, in order to classify them according to the 2021 World Health Organization (WHO) classification of central nervous system (CNS) tumours.

Methods: Centralised pathological examination was performed as well as targeted molecular analysis of v-Raf murine sarcoma viral oncogene homologue B (BRAF) and fibroblast growth factor receptor 1 (FGFR1) by multiplexed digital polymerase chain reaction (mdPCR). DNA methylation profiling was performed in cases with sufficient DNA.

Transcription-associated DNA breaks and cancer: A matter of DNA topology.

Transcription is an essential cellular process but also a major threat to genome integrity. Transcription-associated DNA breaks are particularly detrimental as their defective repair can induce gene mutations and oncogenic chromosomal translocations, which are hallmarks of cancer. The past few years have revealed that transcriptional breaks mainly originate from DNA topological problems generated by the transcribing RNA polymerases.

MAIT cells numbers and frequencies in patients with acute myeloid leukemia at diagnosis: association with cytogenetic profile and gene mutations.

Harnessing or monitoring immune cells is actually a major topic in pre-clinical and clinical studies in acute myeloid leukemia (AML). Mucosal-Associated Invariant T cells (MAIT) constitute one of the largest subset of innate-like, cytotoxic T cell subsets in humans. Despite some papers suggesting a role for MAIT cells in cancer, their specific involvement remains unclear, especially in myeloid malignancies.

Pharmacologic and genetic inhibition of cholesterol esterification enzymes reduces tumour burden: A systematic review and meta-analysis of preclinical models.

Cholesterol esterification proteins Sterol-O acyltransferases (SOAT) 1 and 2 are emerging prognostic markers in many cancers. These enzymes utilise fatty acids conjugated to coenzyme A to esterify cholesterol. Cholesterol esterification is tightly regulated and enables formation of lipid droplets that act as storage organelles for lipid soluble vitamins and minerals, and as cholesterol reservoirs.