5' Region Large Genomic Rearrangements in the Gene in French Families: Identification of a Tandem Triplication and Nine Distinct Deletions with Five Recurrent Breakpoints.

Background: Large genomic rearrangements (LGR) in consisting of deletions/duplications of one or several exons have been found throughout the gene with a large proportion occurring in the 5' region from the promoter to exon 2. The aim of this study was to better characterize those LGR in French high-risk breast/ovarian cancer families.

Methods: DNA from 20 families with one apparent duplication and nine deletions was analyzed with a dedicated comparative genomic hybridization (CGH) array, high-resolution BRCA1 Genomic Morse Codes analysis and Sanger sequencing.

Cancer cell adaptability: turning ribonucleoprotein granules into targets.

Stress granules (SGs) and processing bodies (P-bodies) are membraneless cytoplasmic condensates of ribonucleoproteins (RNPs). They both regulate RNA fate under physiological and pathological conditions, and are thereby involved in the regulation and maintenance of cellular integrity. During tumorigenesis, cancer cells use these granules to thrive, to adapt to the harsh conditions of the tumor microenvironment (TME), and to protect themselves from anticancer treatments.

A novel leukemic route of mutant NPM1 through nuclear import of the overexpressed long noncoding RNA LONA.

The most frequent genetic alteration in acute myeloid leukemia (AML) is the mutation of nucleophosmin 1 (NPM1). Yet, its downstream oncogenic routes are not fully understood. Here, we report the identification of one long noncoding RNA (lncRNA) overexpressed in NPM1-mutated AML patients (named LONA) whose intracellular localization inversely reflects that of NPM1.

Current and Future Role of Medical Imaging in Guiding the Management of Patients With Relapsed and Refractory Non-Hodgkin Lymphoma Treated With CAR T-Cell Therapy.

Chimeric antigen receptor (CAR) T-cells are a novel immunotherapy available for patients with refractory/relapsed non-Hodgkin lymphoma. In this indication, clinical trials have demonstrated that CAR T-cells achieve high rates of response, complete response, and long-term response (up to 80%, 60%, and 40%, respectively). Nonetheless, the majority of patients ultimately relapsed.

Cytoplasmic LXR expression is an independent marker of poor prognosis for patients with early stage primary breast cancer.

Purpose: The aim of this study was to investigate the expression of liver X receptors α/β (LXR) in primary breast cancer (BC) tissues and to analyze its correlations with clinicopathological parameters including patient survival.

Methods: In a well-characterized cohort of 305 primary BC, subcellular distribution of LXR was evaluated by immunohistochemistry. Correlations with clinicopathological characteristics as well as with patient outcome were analyzed.

p27 controls autophagic vesicle trafficking in glucose-deprived cells via the regulation of ATAT1-mediated microtubule acetylation.

The cyclin-dependent kinase inhibitor p27 (p27) has been involved in promoting autophagy and survival in conditions of metabolic stress. While the signaling cascade upstream of p27 leading to its cytoplasmic localization and autophagy induction has been extensively studied, how p27 stimulates the autophagic process remains unclear. Here, we investigated the mechanism by which p27 promotes autophagy upon glucose deprivation.

Adherence to French and ESGO Quality Indicators in Ovarian Cancer Surgery: An Ad-Hoc Analysis from the Prospective Multicentric CURSOC Study.

Background: Quality Indicators for ovarian cancer (OC) have been developed by the European Society of Gynaecological Oncology (ESGO) and by the French National Cancer Institute (Institut National du Cancer, INCa). The aim of the study was to characterize OC care distribution in France by case-volume and to prospectively evaluate the adherence of high-volume institutions to INCa/ESGO quality indicators.

Methods: The cost-utility of radical surgery in ovarian cancer (CURSOC) trial is a prospective, multicenter, comparative and non-randomized study that includes patients with stage IIIC-IV epithelial OC treated in nine French health care tertiary institutions.

Neutral Sphingomyelinase 2 Heightens Anti-Melanoma Immune Responses and Anti-PD-1 Therapy Efficacy.

Dysregulation of lipid metabolism affects the behavior of cancer cells, but how this happens is not completely understood. Neutral sphingomyelinase 2 (nSMase2), encoded by , catalyzes the breakdown of sphingomyelin to produce the anti-oncometabolite ceramide. We found that this enzyme was often downregulated in human metastatic melanoma, likely contributing to immune escape.

VOTRAGE study: Phase I dose-escalation study of pazopanib in unfit older patients.

Background: Pazopanib is a tyrosine kinase inhibitor given at the approved dose of 800 mg orally once daily (OD), but often requiring individual dose adjustment due to toxicity. Limited data is available to guide prescription in older patients especially the unfit according to geriatric assessment.

Patients And Methods: VOTRAGE is a 3 + 3 dose-escalation, open-label phase I trial of continuous OD oral administration of pazopanib to evaluate safety, PK and PD data in unfit older patients with advanced solid tumors.

Stress Granules in the Post-transcriptional Regulation of Immune Cells.

Immune cell activation triggers transcriptional and translational programs eliciting cellular processes, such as differentiation or proliferation, essential for an efficient immune response. These dynamic processes require an intricate orchestration of regulatory mechanisms to control the precise spatiotemporal expression of proteins. Post-transcriptional regulation ensures the control of messenger RNA metabolism and appropriate translation.

The m6A RNA Demethylase ALKBH5 Promotes Radioresistance and Invasion Capability of Glioma Stem Cells.

Recurrence of GBM is thought to be due to GBMSCs, which are particularly chemo-radioresistant and characterized by a high capacity to invade normal brain. Evidence is emerging that modulation of m6A RNA methylation plays an important role in tumor progression. However, the impact of this mRNA modification in GBM is poorly studied.

Patient-derived glioblastoma stem cells transfer mitochondria through tunneling nanotubes in tumor organoids.

Glioblastoma (GBM) is the most aggressive brain cancer and its relapse after surgery, chemo and radiotherapy appears to be led by GBM stem cells (GSCs). Also, tumor networking and intercellular communication play a major role in driving GBM therapy-resistance. Tunneling Nanotubes (TNTs), thin membranous open-ended channels connecting distant cells, have been observed in several types of cancer, where they emerge to drive a more malignant phenotype.

Urinary diversion after pelvic exenteration for gynecologic malignancies.

Pelvic exenteration combines multiple organ resections and functional reconstruction. Many techniques have been described for urinary reconstruction, although only a few are routinely used. The aim of this review is to focus beyond the technical aspects and the advantages and disadvantages of each technique, and to include a critical analysis of continent techniques in the gynecologic and urologic literature.

Cancer Immunotherapy Dosing: A Pharmacokinetic/Pharmacodynamic Perspective.

Immune check-point inhibitors are drugs that are markedly different from other anticancer drugs because of their indirect mechanisms of antitumoral action and their apparently random effect in terms of efficacy and toxicity. This marked pharmacodynamics variability in patients calls for reconsidering to what extent approved dosing used in clinical practice are optimal or whether they should require efforts for customization in outlier patients. To better understand whether or not dosing could be an actionable item in oncology, in this review, preclinical and clinical development of immune checkpoint inhibitors are described, particularly from the angle of dose finding studies.

Activin A Promotes Regulatory T-cell-Mediated Immunosuppression in Irradiated Breast Cancer.

Increased regulatory T cells (Treg) after radiotherapy have been reported, but the mechanisms of their induction remain incompletely understood. TGFβ is known to foster Treg differentiation within tumors and is activated following radiotherapy. Thus, we hypothesized that TGFβ blockade would result in decreased Tregs within the irradiated tumor microenvironment.

Cancer-Associated Fibroblasts: Accomplices in the Tumor Immune Evasion.

Cancer-associated fibroblasts (CAFs) are prominent cells within the tumor microenvironment, by communicating with other cells within the tumor and by secreting the extracellular matrix components. The discovery of the immunogenic role of CAFs has made their study particularly attractive due to the potential applications in the field of cancer immunotherapy. Indeed, CAFs are highly involved in tumor immune evasion by physically impeding the immune system and interacting with both myeloid and lymphoid cells.

Dendrogenin A Enhances Anti-Leukemic Effect of Anthracycline in Acute Myeloid Leukemia.

Dendrogenin A (DDA), a mammalian cholesterol metabolite with tumor suppressor properties, has recently been shown to exhibit strong anti-leukemic activity in acute myeloid leukemia (AML) cells by triggering lethal autophagy. Here, we demonstrated that DDA synergistically enhanced the toxicity of anthracyclines in AML cells but not in normal hematopoietic cells. Combination index of DDA treatment with either daunorubicin or idarubicin indicated a strong synergism in KG1a, KG1 and MV4-11 cell lines.

Eomes-Dependent Loss of the Co-activating Receptor CD226 Restrains CD8 T Cell Anti-tumor Functions and Limits the Efficacy of Cancer Immunotherapy.

CD8 T cells within the tumor microenvironment (TME) are exposed to various signals that ultimately determine functional outcomes. Here, we examined the role of the co-activating receptor CD226 (DNAM-1) in CD8 T cell function. The absence of CD226 expression identified a subset of dysfunctional CD8 T cells present in peripheral blood of healthy individuals.

CD155 on Tumor Cells Drives Resistance to Immunotherapy by Inducing the Degradation of the Activating Receptor CD226 in CD8 T Cells.

The activating receptor CD226 is expressed on lymphocytes, monocytes, and platelets and promotes anti-tumor immunity in pre-clinical models. Here, we examined the role of CD226 in the function of tumor-infiltrating lymphocytes (TILs) and resistance to immunotherapy. In murine tumors, a large proportion of CD8 TILs had decreased surface expression of CD226 and exhibited features of dysfunction, whereas CD226 TILs were highly functional.

Model-Based Quantification of Impact of Genetic Polymorphisms and Co-Medications on Pharmacokinetics of Tamoxifen and Six Metabolites in Breast Cancer.

Variations in clinical response to tamoxifen (TAM) may be related to polymorphic cytochromes P450 (CYPs) involved in forming its active metabolite endoxifen (ENDO). We developed a population pharmacokinetic (PopPK) model for tamoxifen and six metabolites to determine clinically relevant factors of ENDO exposure. Concentration-time data for TAM and 6 metabolites come from a prospective, multicenter, 3-year follow-up study of adjuvant TAM (20 mg/day) in patients with breast cancer, with plasma samples drawn every 6 months, and genotypes for 63 genetic polymorphisms (PHACS study, NCT01127295).