ABSTRACT
BACKGROUND: Advanced recurrent ovarian cancer (ROC) is the leading cause of gynecologic cancer-related death in developed countries and new treatments are needed. Previous studies of immune checkpoint blockade showed low objective response rates (ORR) in ROC with no identified predictive biomarker. PATIENTS AND METHODS: This phase II study of pembrolizumab (NCT02674061) examined two patient cohorts with ROC: cohort A received one to three prior lines of treatment with a platinum-free interval (PFI) or treatment-free interval (TFI) between 3 and 12 months and cohort B received four to six prior lines with a PFI/TFI of ≥3 months. Pembrolizumab 200 mg was administered intravenously every 3 weeks until cancer progression, toxicity, or completion of 2 years. Primary end points were ORR by Response Evaluation Criteria in Solid Tumors version 1.1 per blinded independent central review by cohort and by PD-L1 expression measured as combined positive score (CPS). Secondary end points included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Cohort A enrolled 285 patients; the first 100 served as the training set for PD-L1 biomarker analysis. Cohort B enrolled 91 patients. ORR was 7.4% for cohort A and 9.9% for cohort B. Median DOR was 8.2 months for cohort A and not reached for cohort B. DCR was 37.2% and 37.4%, respectively, in cohorts A and B. Based on the training set analysis, CPS 1 and 10 were selected for evaluation in the confirmation set. In the confirmation set, ORR was 4.1% for CPS <1, 5.7% CPS ≥1, and 10.0% for CPS ≥10. PFS was 2.1 months for both cohorts. Median OS was not reached for cohort A and was 17.6 months for cohort B. Toxicities were consistent with other single-agent pembrolizumab trials. CONCLUSIONS: Single-agent pembrolizumab showed modest activity in patients with ROC. Higher PD-L1 expression was correlated with higher response. CLINICAL TRIAL NUMBER: Clinicaltrials.gov, NCT02674061.
Subject(s)
Adenocarcinoma, Clear Cell/drug therapy , Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents, Immunological/therapeutic use , Neoplasm Recurrence, Local/drug therapy , Ovarian Neoplasms/drug therapy , Adenocarcinoma, Clear Cell/pathology , Aged , Antibodies, Monoclonal, Humanized/adverse effects , Antineoplastic Agents, Immunological/adverse effects , Cohort Studies , Cystadenocarcinoma, Serous/drug therapy , Cystadenocarcinoma, Serous/pathology , Female , Follow-Up Studies , Humans , Male , Neoplasm Recurrence, Local/pathology , Ovarian Neoplasms/pathology , Prognosis , Survival RateABSTRACT
This review focuses on age-related changes occurring in the female reproductive system and their effect on reproductive material. Aging significantly impact the female reproductive system but, despite this fact, there is nowadays a trend to postpone pregnancy to pursue educational and vocational goals. Therefore a remarkable effort is now being made by the medical establishment to understand the effects of aging in women. The assessment and treatment of this decline in fertility is discussed, as well as assisted reproductive techniques and new therapeutic options.
Subject(s)
Aging/physiology , Infertility, Female/physiopathology , Adult , Age Factors , Female , Humans , Middle AgedABSTRACT
OBJECTIVE: To investigate the potential role of peritoneal fluid (PF) from women with or without endometriosis in implantation in mice with use of the delayed implantation model. DESIGN: A murine experimental model with markers of uterine receptivity and prospective comparison of the effects of human PF on implantation. SETTING: Academic university and hospital program. INTERVENTION(S): PF collected from women with and without endometriosis was injected intraperitoneally into recently mated mice. MAIN OUTCOME MEASURE(S): Implantation sites were counted in treated and untreated animals, and the alphavbeta3 integrin was measured in the pregnant mouse uterus by immunohistochemistry with in situ hybridization. Leukemia inhibitory factor and the beta3 subunit of alphavbeta3 were measured by Northern blot during early pregnancy and after injections of PF. RESULT(S): Animals receiving PF from infertile women with endometriosis had a reduction in the number of implantation sites compared with animals that received PF from fertile women or from patients with recently treated endometriosis. In the mouse, expression of alphavbeta3 and leukemia inhibitory factor peaked at the time of implantation and was reduced by injections of human PF from infertile patients with endometriosis. CONCLUSION(S): Leukemia inhibitory factor and alphavbeta3 are coexpressed at the time of implantation in the mouse. PF from women with endometriosis has a detrimental effect on embryo implantation, perhaps by adversely affecting uterine receptivity.
Subject(s)
Ascitic Fluid , Embryo Implantation , Endometriosis/physiopathology , Interleukin-6 , Animals , Blotting, Northern , Disease Models, Animal , Female , Growth Inhibitors/metabolism , Humans , In Situ Hybridization , Leukemia Inhibitory Factor , Lymphokines/metabolism , Mice , Mice, Inbred Strains , Pregnancy , Receptors, Vitronectin/metabolismABSTRACT
The protozoan myosin Is are widely expressed actin-based motors, yet their in vivo roles remain poorly understood. Molecular genetic studies have been carried out to determine their in vivo function in the simple eukaryote Dictyostelium, an organism that contains a family of four myosin Is. Here we report the characterization of myoC, a gene that encodes a fifth member of this family. Analysis of the deduced amino acid sequence reveals that the myoC gene encodes a myosin that is homologous to the well-described Acanthamoeba myosin Is as well as to Dictyostelium myoB and -D. The expression pattern of the myoC mRNA is similar to that of myoB and myoD, with a peak of expression at times of maximal cell migration, around 6 hours development. Deletion of the myoB gene has been previously shown to result in mutant cells that are defective in pseudopod extension and phagocytosis. However, no obvious differences in cell growth, development, phagocytosis or motility were detected in cells in which the myoC gene had been disrupted by homologous recombination. F-actin localization and ultrastructural organization also appeared unperturbed in myoC- cells. This apparent 'lack' of phenotype in a myosin I single knockout cannot be simply explained by redundancy of function. Our results rather suggest that the present means of assessing myosin I function in vivo are insufficient to identify the unique roles of these actin-based motors.
Subject(s)
Dictyostelium/genetics , Myosins/genetics , Amino Acid Sequence , Animals , Base Sequence , DNA, Fungal/genetics , DNA, Protozoan/genetics , Dictyostelium/physiology , Dictyostelium/ultrastructure , Fungal Proteins/genetics , Gene Deletion , Gene Expression , Genes, Fungal , Genes, Protozoan , Microscopy, Electron , Molecular Biology , Molecular Sequence Data , Myosins/physiology , Protozoan Proteins/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Sequence Homology, Amino AcidABSTRACT
Financial managers expect nursing salaries to reflect declining hospital utilization. Nursing managers, however, expect salaries to reflect the increase in nursing care required by a sicker patient population. With the use of a patient classification system, the cost of the nursing portion of a hospital's operating expenses and the correct amount of nursing labor required by patients can be determined. By determining appropriate staffing levels, high quality nursing care can be delivered in a cost efficient manner.
