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BJOG : An International Journal of... Jan 2023Fifteen percent of patients with endometrial cancer (EC) have advanced stage disease or develop a recurrence. Progestins have been applied as systemic treatment for... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Fifteen percent of patients with endometrial cancer (EC) have advanced stage disease or develop a recurrence. Progestins have been applied as systemic treatment for decades, but there is limited evidence on response prediction with biomarkers and toxicity.
OBJECTIVES
To review the response and toxicity of progestin therapy and stratify response to progesterone receptor (PR) expression and tumour grade.
SEARCH STRATEGY
We used the search terms 'Endometrial cancer', 'Progestins', 'Disease progression', 'Recurrence' and related terms in Pubmed, Embase and Cochrane databases.
SELECTION CRITERIA
Studies on patients with advanced stage or recurrent EC treated with progestin monotherapy were included. Studies on adjuvant therapy, with fewer than ten cases and with sarcoma histology were excluded.
DATA COLLECTION AND ANALYSIS
Evaluation for bias was performed with the Revised Cochrane RoB2 tool for randomised studies and the ROBINS-I tool for non-randomised studies. A random effects meta-analysis was performed with the overall response rate (ORR), clinical benefit rate and toxicity as primary outcome measures.
MAIN RESULTS
Twenty-six studies (1639 patients) were included. The ORR of progestin therapy was 30% (95% CI 25-36), the clinical benefit rate was 52% (95% CI 42-61). In PR-positive EC, the ORR was 55%, compared with 12% in PR-negative disease (risk difference 43%, 95% CI 15-71). Severe toxicity occurred in 6.5%.
CONCLUSIONS
Progestin therapy is a viable treatment option in patients with advanced stage and recurrent EC with low toxicity and high ORR in PR-positive disease. The role of PR expression in relation to progression-free survival and overall survival is unclear.
Topics: Female; Humans; Progestins; Neoplasm Recurrence, Local; Endometrial Neoplasms
PubMed: 36264251
DOI: 10.1111/1471-0528.17331 -
Medecine Sciences : M/S Mar 2022In Brazil, women have free access to contraception through the public health system, the Unified Health System (SUS) which offers the following contraceptive methods:...
In Brazil, women have free access to contraception through the public health system, the Unified Health System (SUS) which offers the following contraceptive methods: Male and female condoms, diaphragm, spermicide, copper intrauterine device (IUD), combined oral and injectable contraceptive hormones, progestin-only contraceptives and injections of medroxyprogesterone acetate (DMPA), emergency pill, female sterilization and vasectomy. However, difficulties in scheduling appointments, women's lack of information about contraceptive methods, and the limited availability of different methods all contribute to high rates of unintended pregnancies. The rate of contraceptive use by Brazilian women aged 18 to 49 is approximately 62%; poorer parts of the country and low levels of education are among the main factors associated with lower rates of contraceptive method use. There are therefore challenges to be taken up to minimize the rates of unwanted pregnancies, which are still too high, such as better distribution, better offer of different contraceptive methods for all regions of the country and better training of professionals involved in women's health care.
Topics: Adolescent; Adult; Brazil; Contraception; Female; Humans; Male; Middle Aged; Pregnancy; Young Adult
PubMed: 35333165
DOI: 10.1051/medsci/2022029 -
Cells Mar 2022Cachexia may be caused by congestive heart failure, and it is then called cardiac cachexia, which leads to increased morbidity and mortality. Cardiac cachexia also... (Review)
Review
Cachexia may be caused by congestive heart failure, and it is then called cardiac cachexia, which leads to increased morbidity and mortality. Cardiac cachexia also worsens skeletal muscle degradation. Cardiac cachexia is the loss of edema-free muscle mass with or without affecting fat tissue. It is mainly caused by a loss of balance between protein synthesis and degradation, or it may result from intestinal malabsorption. The loss of balance in protein synthesis and degradation may be the consequence of altered endocrine mediators such as insulin, insulin-like growth factor 1, leptin, ghrelin, melanocortin, growth hormone and neuropeptide Y. In contrast to many other health problems, fat accumulation in the heart is protective in this condition. Fat in the heart can be divided into epicardial, myocardial and cardiac steatosis. In this review, we describe and discuss these topics, pointing out the interconnection between heart failure and cardiac cachexia and the protective role of cardiac obesity. We also set the basis for possible screening methods that may allow for a timely diagnosis of cardiac cachexia, since there is still no cure for this condition. Several therapeutic procedures are discussed including exercise, nutritional proposals, myostatin antibodies, ghrelin, anabolic steroids, anti-inflammatory substances, beta-adrenergic agonists, medroxyprogesterone acetate, megestrol acetate, cannabinoids, statins, thalidomide, proteasome inhibitors and pentoxifylline. However, to this date, there is no cure for cachexia.
Topics: Cachexia; Ghrelin; Heart; Heart Failure; Humans; Obesity
PubMed: 35326490
DOI: 10.3390/cells11061039 -
American Journal of Reproductive... Mar 2020Injectable contraceptive use may impact immune cell responsiveness and susceptibility to infection. We measured responsiveness of T-cells from women before and after...
PROBLEM
Injectable contraceptive use may impact immune cell responsiveness and susceptibility to infection. We measured responsiveness of T-cells from women before and after initiating depot medroxyprogesterone acetate (DMPA) or norethisterone enanthate (Net-En).
METHOD OF STUDY
Peripheral blood mononuclear cells collected from women aged 18-34 years prior to, at steady state, and nadir concentrations after initiating DMPA (n = 30) or Net-En (n = 36) and from women initiating copper intrauterine device (CU-IUD; n = 32) were stimulated with phorbol myristate acetate and analyzed using flow cytometry. We evaluated percentage change in T-cells expressing programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte associated protein-4 (CTLA-4).
RESULTS
Compared to baseline, there were decreased numbers of CD4+CTLA4+ (P < .001) and CD8+CTLA4+ (P < .01) T-cells following ex vivo stimulation challenge at steady state DMPA concentrations and no differences at nadir concentrations (P = .781 and P = .463, respectively). In Net-En users, no differences in CD4+CTLA4+ T-cells at steady state (P = .087) and nadir concentrations (P = .217) were observed. DMPA users had fewer CD4+PD-1+ (P < .001) and CD8+PD-1+ (P < .001) T-cells at nadir concentrations. Number of CD4+PD-1+ and CD8+PD-1+ T-cells decreased at steady state concentration (P = .002 and P = .001, respectively) and at nadir concentrations after Net-En initiation (P < .001 and P < .001). In CU-IUD users, there were no changes in number of CD4+CTLA4+ (P = .426) and CD8+CTLA4+ (P = .169) and no changes in CD4+PD-1+ (P = .083) and CD8+PD-1+ (P = .936) compared to baseline.
CONCLUSION
Activation of T-cells in response to ex vivo stimulation is suppressed at steady state DMPA concentration and resolves at nadir concentration, suggesting DMPA immunosuppressive effects may be transient.
Topics: Adolescent; Adult; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; CTLA-4 Antigen; Cells, Cultured; Contraceptive Agents, Female; Female; Humans; Immunophenotyping; Lymphocyte Activation; Medroxyprogesterone Acetate; Norethindrone; Programmed Cell Death 1 Receptor; Young Adult
PubMed: 31729087
DOI: 10.1111/aji.13210 -
Journal For Immunotherapy of Cancer Jun 2023Progress in breast cancer (BC) research relies on the availability of suitable cell lines that can be implanted in immunocompetent laboratory mice. The best studied...
BACKGROUND
Progress in breast cancer (BC) research relies on the availability of suitable cell lines that can be implanted in immunocompetent laboratory mice. The best studied mouse strain, C57BL/6, is also the only one for which multiple genetic variants are available to facilitate the exploration of the cancer-immunity dialog. Driven by the fact that no hormone receptor-positive (HR) C57BL/6-derived mammary carcinoma cell lines are available, we decided to establish such cell lines.
METHODS
BC was induced in female C57BL/6 mice using a synthetic progesterone analog (medroxyprogesterone acetate, MPA) combined with a DNA damaging agent (7,12-dimethylbenz[a]anthracene, DMBA). Cell lines were established from these tumors and selected for dual (estrogen+progesterone) receptor positivity, as well as transplantability into C57BL/6 immunocompetent females.
RESULTS
One cell line, which we called B6BC, fulfilled these criteria and allowed for the establishment of invasive estrogen receptor-positive (ER) tumors with features of epithelial to mesenchymal transition that were abundantly infiltrated by myeloid immune populations but scarcely by T lymphocytes, as determined by single-nucleus RNA sequencing and high-dimensional leukocyte profiling. Such tumors failed to respond to programmed cell death-1 (PD-1) blockade, but reduced their growth on treatment with ER antagonists, as well as with anthracycline-based chemotherapy, which was not influenced by T-cell depletion. Moreover, B6BC-derived tumors reduced their growth on CD11b blockade, indicating tumor sustainment by myeloid cells. The immune environment and treatment responses recapitulated by B6BC-derived tumors diverged from those of ER TS/A cell-derived tumors in BALB/C mice, and of ER E0771 cell-derived and MPA/DMBA-induced tumors in C57BL/6 mice.
CONCLUSIONS
B6BC is the first transplantable HR BC cell line derived from C57BL/6 mice and B6BC-derived tumors recapitulate the complex tumor microenvironment of locally advanced HR BC naturally resistant to PD-1 immunotherapy.
Topics: Mice; Female; Animals; Progesterone; Epithelial-Mesenchymal Transition; Mice, Inbred BALB C; Mice, Inbred C57BL; Cell Line, Tumor; Carcinoma; Tumor Microenvironment
PubMed: 37344100
DOI: 10.1136/jitc-2023-007117 -
Chinese Medical Journal Nov 2023Steroid receptor-associated and regulated protein (SRARP) suppresses tumor progression and modulates steroid receptor signaling by interacting with estrogen receptors...
BACKGROUND
Steroid receptor-associated and regulated protein (SRARP) suppresses tumor progression and modulates steroid receptor signaling by interacting with estrogen receptors and androgen receptors in breast cancer. In endometrial cancer (EC), progesterone receptor (PR) signaling is crucial for responsiveness to progestin therapy. The aim of this study was to investigate the role of SRARP in tumor progression and PR signaling in EC.
METHODS
Ribonucleic acid sequencing data from the Cancer Genome Atlas, Clinical Proteomic Tumor Analysis Consortium, and Gene Expression Omnibus were used to analyze the clinical significance of SRARP and its correlation with PR expression in EC. The correlation between SRARP and PR expression was validated in EC samples obtained from Peking University People's Hospital. SRARP function was investigated by lentivirus-mediated overexpression in Ishikawa and HEC-50B cells. Cell Counting Kit-8 assays, cell cycle analyses, wound healing assays, and Transwell assays were used to evaluate cell proliferation, migration, and invasion. Western blotting and quantitative real-time polymerase chain reaction were used to evaluate gene expression. The effects of SRARP on the regulation of PR signaling were determined by co-immunoprecipitation, PR response element (PRE) luciferase reporter assay, and PR downstream gene detection.
RESULTS
Higher SRARP expression was significantly associated with better overall survival and disease-free survival and less aggressive EC types. SRARP overexpression suppressed growth, migration, and invasion in EC cells, increased E-cadherin expression, and decreased N-cadherin and Wnt family member 7A ( WNT7A ) expression. SRARP expression was positively correlated with PR expression in EC tissues. In SRARP -overexpressing cells, PR isoform B (PRB) was upregulated and SRARP bound to PRB. Significant increases in PRE-based luciferase activity and expression levels of PR target genes were observed in response to medroxyprogesterone acetate.
CONCLUSIONS
This study illustrates that SRARP exerts a tumor-suppressive effect by inhibiting the epithelial-mesenchymal transition via Wnt signaling in EC. In addition, SRARP positively modulates PR expression and interacts with PR to regulate PR downstream target genes.
Topics: Female; Humans; Receptors, Progesterone; Proteomics; Cell Line, Tumor; Endometrial Neoplasms; Cell Proliferation; Luciferases; Gene Expression Regulation, Neoplastic
PubMed: 37144734
DOI: 10.1097/CM9.0000000000002537 -
Hematology. American Society of... Dec 2022Estrogen exposure, in the setting of pregnancy, the postpartum state, combined hormonal contraceptives (CHCs), or hormone therapy use, has been clearly associated with...
Estrogen exposure, in the setting of pregnancy, the postpartum state, combined hormonal contraceptives (CHCs), or hormone therapy use, has been clearly associated with increased rates of venous thromboembolism (VTE). Although recurrence rates are low in these settings, up to 70% of anticoagulated menstruating individuals experience abnormal or heavy menstrual bleeding (HMB), which commonly results in iron deficiency with or without anemia. Patients taking rivaroxaban appear to experience higher rates of HMB compared with those on apixaban, dabigatran, or warfarin. HMB can often be diagnosed in a single visit with a good menstrual history assessing for factors with a known association with increased or heavy bleeding, such as changing pads or tampons more often than every 2 hours, clots larger than a quarter, and iron deficiency (ferritin <50 ng/mL). HMB can be managed with hormonal therapies, including those associated with VTE risk, such as CHCs and depot-medroxyprogesterone acetate (DMPA). In many cases, continuing CHCs or DMPA while a patient is therapeutically anticoagulated is reasonable, so long as the therapy is discontinued before anticoagulation is stopped. Modification of the anticoagulation regimen, such as decreasing to a prophylactic dose in the acute treatment period, is not currently recommended. For patients who are currently pregnant, low-molecular-weight heparin (LMWH) is still standard of care during pregnancy; routine monitoring of anti-factor Xa levels is not currently recommended. Warfarin or LMWH may be considered in the postpartum setting, but direct-acting oral anticoagulants are currently not recommended for lactating patients.
Topics: Pregnancy; Humans; Female; Heparin, Low-Molecular-Weight; Lactation; Anticoagulants; Venous Thromboembolism; Warfarin; Menorrhagia; Iron Deficiencies
PubMed: 36485151
DOI: 10.1182/hematology.2022000401 -
Heliyon Dec 2023Canine Pyometra, also known as cystic endometrial hyperplasia complex, is a common reproductive issue in bitches. This study aimed to identify associated risk factors,...
Canine Pyometra, also known as cystic endometrial hyperplasia complex, is a common reproductive issue in bitches. This study aimed to identify associated risk factors, hematological variation, bacteria involved, and the most potent anti-bacterial against bacterial isolates of canine pyometra. Forty-five bitches of different habitats, breeds, and ages infected with pyometra were included in the study. The samples were cultured to isolate bacteria associated with the pyometra and antibiotic sensitivity was done for each bacterial isolates to get antibiogram. The study findings showed that potential risk factors such as age group, medroxyprogesterone acetate administration, and changes in the white blood cells parameters were significantly associated (P < 0.05) with the type of pyometra. Closed cervix pyometra in dogs showed significantly higher prevalence of clinical signs including depression, vomiting, abdominal enlargement, and fever compared to the open cervix pyometra. Low levels of red blood cells, pack cell volume, and hemoglobin indicated that the pyometra-infected dogs were more likely to have normocytic, normochromic, and non-regenerative anemia. Pyometra was attributed to an increase in AST (Aspertate aminotransferase), ALT (Alanine transaminase), ALP (Alkaline phosphatase), BUN (Blood Urea Nitrogen), and Creatinine while a decrease in serum albumin. Of the all bacterial isolates, (35.55%) was the most common pathogen isolated from canine pyometra, followed by spp. (26.66%). and spp. were susceptible to Imipenem, Amikacin, and Gentamicin while highly resistant to Ampicillin and Erythromycin. Imipenem, Amikacin, and Gentamicin were the most sensitive antibiotics, while Ampicillin and Erythromycin were the most resistant antibiotics for the bacterial strain isolated from canine pyometra. Multidrug resistant was observed in 26 of the isolated bacteria, indicating acquired resistance due to improper and uncontrolled use. Hence early diagnosis and close monitoring of antimicrobial susceptibility before therapeutic intervention is indispensable in preventing the global threat of antimicrobial resistance.
PubMed: 38076069
DOI: 10.1016/j.heliyon.2023.e22368 -
Lancet (London, England) Feb 2020
Topics: Contraception; Female; HIV Infections; Humans; Incidence; Intrauterine Devices, Copper; Levonorgestrel; Medroxyprogesterone Acetate
PubMed: 32035557
DOI: 10.1016/S0140-6736(19)33107-1 -
Clinical Immunology (Orlando, Fla.) Oct 2023Although effective contraceptives are crucial for preventing unintended pregnancies, evidence suggests that their use may perturb the female genital tract (FGT). A... (Randomized Controlled Trial)
Randomized Controlled Trial
Although effective contraceptives are crucial for preventing unintended pregnancies, evidence suggests that their use may perturb the female genital tract (FGT). A comparative analysis of the effects of the most common contraceptives on the FGT have not been evaluated in a randomized clinical trial setting. Here, we evaluated the effect of three long-acting contraceptive methods: depot medroxyprogesterone acetate(DMPA-IM), levonorgestrel(LNG) implant, and a copper intrauterine device (Cu-IUD), on the endocervical host transcriptome in 188 women from the Evidence for Contraceptive Options and HIV Outcomes Trial (ECHO) trial. Cu-IUD usage showed the most extensive transcriptomic changes, and was associated with inflammatory and anti-viral host responses. DMPA-IM usage was enriched for pathways associated with T cell responses. LNG implant had the mildest effect on endocervical gene expression, and was associated with growth factor signaling. These data provide a mechanistic basis for the diverse influence that varying contraceptives have on the FGT.
Topics: Pregnancy; Female; Humans; Copper; Levonorgestrel; Intrauterine Devices, Copper; Contraceptive Agents; Systems Analysis
PubMed: 37660744
DOI: 10.1016/j.clim.2023.109750