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The Delphi method was successful in gaining a consensus on risks relevant to CAR T-cell clinical trials in a geographically diverse expert association. It is hoped that this work can benefit future risk-based quality management in clinical trials and can potentially promote the better development of CAR T-cell therapy products.

The Delphi method was successful in gaining a consensus on risks relevant to CAR T-cell clinical trials in a geographically diverse expert association. It is hoped that this work can benefit future risk-based quality management in clinical trials and can potentially promote the better development of CAR T-cell therapy products.Uveal melanoma (UM) is the most common intraocular malignancy in adults. So far, no systemic therapy or standard treatment exists to reduce the risk of metastasis and improve overall survival of patients. With the increased knowledge regarding the molecular pathways that underlie the oncogenesis of UM, it is expected that novel therapeutic approaches will be available to conquer this disease. This review provides a summary of the current knowledge of, and progress made in understanding, the pathogenesis, genetic mutations, epigenetics, and immunology of UM. With the advent of the omics era, multi-dimensional big data are publicly available, providing an innovation platform to develop effective targeted and personalized therapeutics for UM patients. Indeed, recently, a great number of therapies have been reported specifically for UM caused by oncogenic mutations, as well as other etiologies. In this review, special attention is directed to advancements in targeted therapies. In particular, we discuss the possibilities of targeting GNAQ/GNA11, PLCβ, and CYSLTR2 mutants; regulators of G-protein signaling; the secondary messenger adenosine diphosphate (ADP)-ribosylation factor 6 (ARF6); downstream pathways, such as those involving mitogen-activated protein kinase/MEK/extracellular signal-related kinase, protein kinase C (PKC), phosphoinositide 3-kinase/Akt/mammalian target of rapamycin (mTOR), Trio/Rho/Rac/Yes-associated protein, and inactivated BAP1; and immune-checkpoint proteins cytotoxic T-lymphocyte antigen 4 and programmed cell-death protein 1/programmed cell-death ligand 1. Furthermore, we conducted a survey of completed and ongoing clinical trials applying targeted and immune therapies for UM. Although drug combination therapy based on the signaling pathways involved in UM has made great progress, targeted therapy is still an unmet medical need.

To compare the efficacy, safety, and tolerability of abemaciclib plus endocrine therapy (ET)

ET alone in postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) from China, Brazil, India, and South Africa.

This randomized, double-blind, phase III study was conducted between 9 December 2016 and 29 March 2019. Postmenopausal women with HR-positive, HER2-negative ABC with no prior systemic therapy in an advanced setting (cohort A) or progression on prior ET (cohort B) received abemaciclib (150 mg twice daily) or placebo plus anastrozole (1 mg/day) or letrozole (2.5 mg/day) (cohort A) or fulvestrant (500 mg per label) (cohort B). The primary endpoint was progression-free survival (PFS) in cohort A, analyzed using the stratified log-rank test. Secondary endpoints were PFS in cohort B (key secondary endpoint), objective response rate (ORR), and safety. This interim analysis was planned after 119 PFS events in cohort A.

bserved in this population.

ClinicalTrials.gov identifier NCT02763566.

The addition of abemaciclib to ET demonstrated significant and clinically meaningful improvement in PFS and ORR, without new safety signals observed in this population.Trial Registration ClinicalTrials.gov identifier NCT02763566.

The programmed death-1/programmed death-ligand-1 (PD-1/PD-L1) axis may represent a target for cervical cancer; however, it is poorly understood in human immunodeficiency virus (HIV)-infected patients.

We evaluated HIV-positive (

 = 42) and HIV-negative (

 = 110) women with locally advanced cervical cancer regarding their PD-L1 expression, determined by combined positive score (CPS) ⩾ 1 and tumor proportion score (TPS) ⩾ 25%, and PD-L1 copy number alterations, assessed by fluorescence

hybridization.

Regardless of HIV status, 84.9% and 44.8% of cases were PD-L1-positive according to CPS ⩾ 1 and TPS ⩾ 25%. Per CPS ⩾ 1, PD-L1 positive rate was similar between HIV-positive and HIV-negative women, whereas a significant difference was seen per TPS ⩾ 25%. Tumor size and parametrial invasion were correlated with PD-L1 positivity in HIV-negative women, whereas anti-retroviral therapy (ART) was correlated with TPS < 25%. Low CD4-positive cell counts were associated with CPS < 1 in HIV-positive women. No ification and polysomy are the strongest drivers of PD-L1 expression in cervical cancer, and could represent prognostic biomarkers for anti-PD-1/PD-L1 therapy. PF-03084014 molecular weight Cervical cancer biology may be modulated by HIV infection, CD4-positive cells, and HIV treatments.Childhood maltreatment types (neglect and psychological, physical, or sexual abuse) are associated with many poor outcomes in adulthood. Yet, research mainly focuses on the cumulative adversity burden rather than specificities and commonalities of associations with adult outcomes and intervening pathways. To build understanding of life-course pathways to a range of outcomes, this overview summarises evidence from several original research studies using the 1958 British Birth Cohort on specific maltreatment types, child development trajectories, adult intermediaries and outcomes. About one-in-five participants were identified as neglected or abused in childhood (~10% were identified for neglect, 10% for psychological abuse, 6% for physical abuse and 1.4% for sexual abuse). Neglect was associated with key dimensions of development, for example, slower height growth, delayed maturation, faster BMI gain, and poorer emotional and cognitive development. Associated adulthood outcomes included harmful behaviours (notably smoking), poorer physical health (e.