Durvalumab and tremelimumab in combination with metronomic oral vinorelbine for recurrent advanced cervical cancer: an open-label phase I/II study.

Background: The MOVIE phase I/II trial (NCT03518606) evaluated the safety and antitumor activity of durvalumab and tremelimumab combined with metronomic oral vinorelbine in patients with advanced tumors. We present the results of the recurrent advanced cervical cancer cohort.

Methods: Patients received tremelimumab (intravenously, 75 mg, every four weeks (Q4W); four cycles max) plus durvalumab (intravenously, 1,500 mg, Q4W; 26 cycles max) and metronomic oral vinorelbine (40 mg, every three weeks (3QW)) until disease progression.

Pulmonary Consequences of Surgical Treatment in Children's Primary Lung Tumors: A National Retrospective Study.

Background And Aims: Primary lung tumors (PLTs) in children are rare, and surgery remains the key to ensure remission. Here we describe the PLTs clinical characteristics, their management, and the pulmonary outcome following surgery.

Methods: We carried out a French national cohort of pediatric PLTs from 2013 to 2023 from the FRACTURE rare pediatric tumors national database.

Physiologically Based Pharmacokinetic Model of Cefotaxime in Patients with Impaired Renal Function.

Background: Cefotaxime is a widely prescribed cephalosporin antibiotic used to treat various infections. It is mainly eliminated unchanged by the kidney through tubular secretion and glomerular filtration. Therefore, a reduction of kidney function may increase exposure to the drug and induce toxic side effects.

Body mass index affects imatinib exposure: Real-world evidence from TDM with adaptive dosing.

Background: Imatinib is the treatment of elderly or frail patients with chronic myeloid leukemia (CML). Trough levels of around 1000 ng/ml are considered as the target exposure.

Objectives: We searched for baseline parameters associated with imatinib pharmacokinetics, and studied the clinical impact of subsequent adaptive dosing.

A French Multicenter Real-Life Study on the Biological and Clinical Parameters Associated With Response to Immune Checkpoint Inhibitors (ICIs) in Second-Line Treatment of Advanced Urothelial Carcinoma: Impact of Antibiotics Administration at the Time of ICIs Initiation.

Background: After failure of first-line chemotherapy, standard of care for advanced urothelial cancer (aUC) is immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 pathway. Several prognostic models (Bajorin and Bellmunt scores) have been evaluated, but only in the context of chemotherapy.

Objective: To study whether the variables in these scores and new emerging clinical and biological criteria have an impact on the probability of objective response in aUC treated with ICIs in 2nd-line setting and beyond.

Lig3-dependent rescue of mouse viability and DNA double-strand break repair by catalytically inactive Lig4.

Recent studies have revealed a structural role for DNA ligase 4 (Lig4) in the maintenance of a repair complex during non-homologous end joining (NHEJ) of DNA double-strand breaks. In cultured cell lines, catalytically inactive Lig4 can partially alleviate the severe DNA repair phenotypes observed in cells lacking Lig4. To study the structural role of Lig4 in vivo, a mouse strain harboring a point mutation to Lig4's catalytic site was generated.

Separable roles of the DNA damage response kinase Mec1ATR and its activator Rad24RAD17 during meiotic recombination.

During meiosis, programmed DNA double-strand breaks (DSBs) are formed by the topoisomerase-like enzyme, Spo11, activating the DNA damage response (DDR) kinase Mec1ATR via the checkpoint clamp loader, Rad24RAD17. At single loci, loss of Mec1 and Rad24 activity alters DSB formation and recombination outcome, but their genome-wide roles have not been examined in detail. Here, we utilise two strategies-deletion of the mismatch repair protein, Msh2, and control of meiotic prophase length via regulation of the Ndt80 transcription factor-to help characterise the roles Mec1 and Rad24 play in meiotic recombination by enabling genome-wide mapping of meiotic progeny.

Development and validation of the Normalized Organoid Growth Rate (NOGR) metric in brightfield imaging-based assays.

This study focuses on refining growth-rate-based drug response metrics for patient-derived tumor organoid screening using brightfield live-cell imaging. Traditional metrics like Normalized Growth Rate Inhibition (GR) and Normalized Drug Response (NDR) have been used to assess organoid responses to anticancer treatments but face limitations in accurately quantifying cytostatic and cytotoxic effects across varying growth rates. Here, we introduce the Normalized Organoid Growth Rate (NOGR) metric, specifically developed for brightfield imaging-based assays.

Patients' psychosocial attributes and aggressiveness of cancer treatments near the end of life.

Background: While the use of chemotherapy near the end of life (EOL) has been identified as a relevant criterion for assessing quality of cancer care and has been estimated as non-beneficial, a trend of aggressiveness in cancer care during the last period of life remains. Both patients' sociodemographic characteristics and physicians' practice setting are associated with this use. The role of patients' psychosocial characteristics has however been understudied.

Development of an efficient NUPR1 inhibitor with anticancer activity.

Pancreatic cancer is highly lethal and has limited treatment options available. Our team had previously developed ZZW-115, a promising drug candidate that targets the nuclear protein 1 (NUPR1), which is involved in pancreatic cancer development and progression. However, clinical translation of ZZW-115 was hindered due to potential cardiotoxicity caused by its interaction with the human Ether-à-go-go-Related Gene (hERG) potassium channel.

DNA repair and anti-cancer mechanisms in the long-lived bowhead whale.

At over 200 years, the maximum lifespan of the bowhead whale exceeds that of all other mammals. The bowhead is also the second-largest animal on Earth, reaching over 80,000 kg. Despite its very large number of cells and long lifespan, the bowhead is not highly cancer-prone, an incongruity termed Peto's Paradox.

Adaptive dosing of high-dose busulfan in real-world adult patients undergoing haematopoietic cell transplant conditioning.

Aim: To evaluate the effectiveness of a Bayesian adaptive dosing strategy in achieving target busulfan exposure in adult patients undergoing haematopoietic cell transplantation (HCT).

Methods: This study included 71 adult patients scheduled to receive high-dose busulfan. Busulfan was administered to achieve a cumulative area under the curve (AUC) of 66.

A beginner's guide to supervised analysis for mass cytometry data in cancer biology.

Mass cytometry enables deep profiling of biological samples at single-cell resolution. This technology is more than relevant in cancer research due to high cellular heterogeneity and complexity. Downstream analysis of high-dimensional datasets increasingly relies on machine learning (ML) to extract clinically relevant information, including supervised algorithms for classification and regression purposes.

Whole-exome profiles of inflammatory breast cancer and pathological response to neoadjuvant chemotherapy.

Background: Neoadjuvant chemotherapy (NACT) became a standard treatment strategy for patients with inflammatory breast cancer (IBC) because of high disease aggressiveness. However, given the heterogeneity of IBC, no molecular feature reliably predicts the response to chemotherapy. Whole-exome sequencing (WES) of clinical tumor samples provides an opportunity to identify genomic alterations associated with chemosensitivity.

BTN2A1 targeting reprograms M2-like macrophages and TAMs via SYK and MAPK signaling.

Tumor-associated macrophages (TAMs), often adopting an immunosuppressive M2-like phenotype, correlate with unfavorable cancer outcomes. Our investigation unveiled elevated expression of the butyrophilin (BTN)2A1 in M2-like TAMs across diverse cancer types. We developed anti-BTN2A1 monoclonal antibodies (mAbs), and notably, one clone demonstrated a robust inhibitory effect on M2-like macrophage differentiation, inducing a shift toward an M1-like phenotype both in vitro and ex vivo in TAMs from patients with cancer.

Data-centric challenges with the application and adoption of artificial intelligence for drug discovery.

Introduction: Artificial intelligence (AI) is exhibiting tremendous potential to reduce the massive costs and long timescales of drug discovery. There are however important challenges currently limiting the impact and scope of AI models.

Areas Covered: In this perspective, the authors discuss a range of data issues (bias, inconsistency, skewness, irrelevance, small size, high dimensionality), how they challenge AI models, and which issue-specific mitigations have been effective.

Targeting BTN2A1 Enhances Vγ9Vδ2 T-Cell Effector Functions and Triggers Tumor Cell Pyroptosis.

Vγ9Vδ2 T cells are potent but elusive cytotoxic effectors. Butyrophilin subfamily 2 member A1 (BTN2A1) is a surface protein that has recently been shown to bind the Vγ9 chain of the γδ T-cell receptor, but its precise role in modulating Vγ9Vδ2 T-cell functions remains unknown. Here, we show that 107G3B5, a monoclonal BTN2A1 agonist antibody, was able to significantly enhance Vγ9Vδ2 T-cell functions against hematologic or solid cell lines and against primary cells from patients with adult acute lymphoblastic leukemia.