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1.
Cancer Research Conference: American Association for Cancer Research Annual Meeting, ACCR ; 83(7 Supplement), 2023.
Article in English | EMBASE | ID: covidwho-20235730

ABSTRACT

Objective: During the COVID-19 pandemic, cancer patients had restricted access to standard of care tissue biopsy. Liquid biopsy assays using next generation sequencing technology provides a less invasive method for determining circulating tumour mutations (ctDNA) associated with targeted treatments or prognosis. As part of deploying technology to help cancer patients obtain molecular testing, a clinical program was initiated to offer liquid biopsy testing for Canadian patients with advanced or metastatic breast cancer. Method(s): Blood was drawn in two 10 mL StreckTM DNA BCTs and sent to the CAP/CLIA/DAP accredited Imagia Canexia Health laboratory for testing using the clinically validated Follow ItTM liquid biopsy assay. Plasma was isolated using a double spin protocol and plasma cell-free DNA (cfDNA) extracted using an optimized Promega Maxwell RSC method. Extracted cfDNA was amplified using the multiplex amplicon-based hotspot 30 or 38 gene panel and sequenced. An inhouse developed bioinformatics pipeline and reporting platform were used to identify pathogenic single nucleotide variants (SNVs), indels (insertions and deletions), and gene amplification. Included in the panel are genes associated with metastatic breast cancer: AKT1, BRAF, ERBB2, ESR1, KRAS, PIK3CA, TP53. Result(s): To identify biomarkers, 1214 metastatic or advanced breast cancer patient cfDNA samples were tested. There were 15 cases sent for repeat testing. We reported 48% of samples harboring pathogenic ctDNA mutations in TP53 (22%), PIK3CA (19%), ESR1 (18%), AKT1 (2%), ERBB2 (1.5%). Co-occurring variants were identified in samples with ESR1/PIK3CA as well as TP53/PIK3CA (both p-values <0.001). Interestingly, 29% of samples with mutated ESR1 harbored >= 2 ESR1 ctDNA mutations. In 56% of cases, previous molecular testing indicated the cancer subtype as hormone receptor (ER, PR) positive with/without HER2 negative status. In this specific subgroup, 49% harbored ctDNA mutations with 63% of those being PIK3CA and/or ESR1 mutations. Conclusion(s): A population of Canadian women with metastatic breast cancer were tested using a liquid biopsy gene panel during the COVID-19 pandemic for identification of biomarkers for targeted therapeutic options. Over 50% of the samples were identified as hormone positive, with greater than 60% harboring PIK3CA and ESR1 ctDNA mutations. Studies have shown that metastatic PIK3CA mutated ER-positive/HER2-negative tumors are predictive to respond to alpelisib therapy and have FDA and Health Canada approval. Additionally, ESR1 mutations are associated with acquired resistance to antiestrogen therapies, and interestingly we identified 29% of ESR1 mutated samples with multiple mutations possibly indicating resistance subclones. In future studies, longitudinal monitoring for presence of multiple targetable and resistance mutations could be utilized to predict or improve clinical management.

2.
Chinese Pharmacological Bulletin ; 36(9):1309-1316, 2020.
Article in Chinese | EMBASE | ID: covidwho-2323869

ABSTRACT

Aim To explore the active compound of Maxingganshi decoction in treatment of novel coronavirus pneumonia(COVID-19). Methods With the help of TCMSP database, the chemical components and action targets of ephedra, almond, licorice, and gypsum in Maxingganshi decoction were searched, and then a C-T network, protein interaction analysis, GO functional enrichment analysis, and KEGG pathway enrichment were constructed. Analysis was performed to predict its mechanism of action. Results A total of 120 compounds in Maxingganshi decoction corresponded to 222 targets. PTGS2, ESR1, PPARG, AR, NOS2, NCOA2 acted on PI3K-Akt signaling pathway, TNF signaling pathway, IL-17 signaling pathway, T cell receptor signaling pathways, etc. The results of molecular docking showed that the affinity of quercetin, kaempferol, glabridin and other core compounds was similar to recommended drugs in treatment of COVID-19. Conclusions The active compounds of Maxingganshi decoction can target multiple pathways to achieve the therapeutic effect of COVID-19.Copyright © 2020 Publication Centre of Anhui Medical University. All rights reserved.

3.
Journal of Biological Chemistry ; 299(3 Supplement):S135, 2023.
Article in English | EMBASE | ID: covidwho-2314280

ABSTRACT

The presence of estrogenic compounds (endocrine-disruptors, EDCs) in the water supply raises concerns about human and aquatic health. Current methods for detecting estrogen contamination require expensive, time-consuming techniques such as liquid chromatography-mass spectrometry and high-performance liquid chromatography. Previously reported estrogen biosensors required multiple cloning and transformation steps for successful detection in bacteria. Synthetic biology allows for the construction of genetic devises composed of DNA sequences modified to be interchangeable and provide novel functions. New tools and devices are constantly needed to enhance the already extensive list of novel genetic parts. Our approach to the design of an estrogen responsive element uses methodology developed in the Wells lab (Elledge et al, 2021) to detect SARS-CoV-2 antibodies. This methodology takes advantage of the split Nanoluciferase (spLUC) protein divided into two functional domains (designated SmBit and LgBit). Based on rational engineering design we express dimerization dependent LgBit and SmBit fused to the Estrogen Receptor alpha protein (ERalpha) in bacteria cells. These two monomeric proteins will dimerize in the presence of estrogen, reconstitute the split luciferase enzyme and reestablish enzyme activity. Cells can be lysed, and luminescence detected to quantify estrogen present in the sample. We present here the construction strategy and proof of concept data demonstrating the efficiency of this dual-functional biosensor and its effectiveness for detection of estrogenic compounds in contaminated water. NSF-REU-1852150, REU Site: A multisite REU in Synthetic Biology, 2019.Copyright © 2023 The American Society for Biochemistry and Molecular Biology, Inc.

4.
ESMO Open ; Conference: ESMO Breast Cancer 2023. Berlin Germany. 8(1 Supplement 4) (no pagination), 2023.
Article in English | EMBASE | ID: covidwho-2313820

ABSTRACT

Background: The phase III EMERALD trial (NCT03778931) reported significantly prolonged progression-free survival (PFS) and a manageable safety profile with elacestrant vs SoC endocrine therapy (ET) in patients (N=478) with ER+/HER2- advanced or mBC following progression on prior CDK4/6i plus ET. PROs measuring quality of life (QoL) are reported here. Method(s): EMERALD patients (pts) completed 3 PRO tools at prespecified time points: the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), the PRO version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), and the EuroQoL 5 Dimension 5 Level (EQ-5D-5L). Result(s): The ratio of PROs tools completed vs. PROs tools expected was 80-90% through cycle 4 and approximately 70% at cycle 6;likely due to clinical study period overlapping with COVID-19 period. Overall, the EORTC QLQ-C30 scores were similar for elacestrant and SoC, with no differences across all time points for both functional and symptom scales. However, PRO-CTCAE results showed that fewer pts who received elacestrant reported very severe nausea (4.0% vs 14.3% by cycle 6) or very severe vomiting (9.1% vs 50% by cycle 6) compared with SoC. There were no clinically meaningful differences across all time points in adverse events typically observed with pts with cancer on ET, such as fatigue, nausea, vomiting, joint and muscle pain and hot flashes. EQ-5D-5L scores were generally comparable throughout treatment for both study arms, with elacestrant showing numerically better outcomes vs SoC for mobility, self-care and usual activities. Similar trends were observed for the full intent-to-treat population and in pts with detectable estrogen receptor 1 mutations (ESR1m). Conclusion(s): This analysis confirmed that QoL was maintained between treatment groups in the EMERALD trial. Together with the previously described statistically significant prolonged PFS and manageable safety profile, these PRO results provide additional evidence that oral elacestrant is clinically meaningful in this patient population with limited therapeutic options. Clinical trial identification: NCT03778931. Editorial acknowledgement: Jeffrey Walter, IQVIA. Legal entity responsible for the study: Stemline Therapeutics/Menarini Group. Funding(s): Stemline Therapeutics/Menarini Group. Disclosure: J. Cortes: Financial Interests, Personal, Advisory Board: Roche, Celgene, Cellestia, AstraZeneca, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, MERCK SHARP& DOHME, GSK, LEUKO, Bioasis, Clovis oncology, Boehringer Ingelheim, Ellipses, Hibercell, BioInvent, Gemoab, Gilead, Menarini, Zymeworks, Reveal Genomics;Financial Interests, Personal, Invited Speaker: Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, MERCK SHARP& DOHME, Daiichi Sankyo;Financial Interests, Personal, Other, Consulting/advisor: Expres2ion Biotechnologies;Financial Interests, Personal, Stocks/Shares: MedSIR, Nektar Therapeutics;Financial Interests, Institutional, Research Grant: Roche, Ariad Pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, Guardant Health, Merck Sharp & Dohme, Pfizer, Piqur Therapeutics, Puma B, Queen Mary University of London;Other, Travel cost and expenses: Roche, Novartis, Eisai, Daiichi Sankyo, Pfizer, Gilead, AstraZeneca. F.C. Bidard: Financial Interests, Personal, Advisory Role: Pfizer, AstraZeneca, Lilly, Novartis, Radius Health, Menarini;Financial Interests, Institutional, Advisory Role: Menarini;Financial Interests, Personal, Speaker's Bureau: Pfizer, Novartis, AstraZeneca, Roche, Lilly, Rain Therapeutics;Financial Interests, Institutional, Research Grant: Novartis, Pfizer, Menarini Silicon Biosystems, Prolynx;Financial Interests, Institutional, Other, patents: ESR1 & MSI detection techniques;Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Roche, Pfizer, AstraZeneca, Novartis. A. Bardia: Financial Interests, Personal, Advisory Board: Pfizer, Novartis, Genentech, Merck, Sanofi, Eisa , Lilly, Mersana, AstraZeneca/Daiichi, Menarini, Gilead;Financial Interests, Personal, Royalties: UpToDate;Financial Interests, Institutional, Invited Speaker: Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics/Gilead, Daiichi Pharma/AstraZeneca, Eli Lilly.;Non-Financial Interests, Principal Investigator: Gilead, Mersana, AstraZeneca/Daiichi, Novartis, Pfizer, Genentech, Lilly, Merck, Sanofi. V.G. Kaklamani: Financial Interests, Personal, Other, Honoraria: Genentech, Novartis, Pfizer, Genomic Health, Puma Biotechnology, AstraZeneca, Seattle Genetics, Daichi, Gilead Sciences;Financial Interests, Personal, Advisory Role: Amgen, Eisai, Puma Biotechnology, Celldex, AstraZeneca, Athenex, bioTheranostics;Financial Interests, Personal, Speaker's Bureau: Genentech, Novartis, Genomic Health, Puma Biotechnology, Pfizer, AstraZeneca/Daiichi Sankyo;Financial Interests, Personal, Research Grant: Eisai. I. Vlachaki: Financial Interests, Personal, Full or part-time Employment: Menarini Hellas A.E. G. Tonini: Financial Interests, Personal, Full or part-time Employment: Menarini Ricerche S.p.A. N. Habboubi: Financial Interests, Personal, Full or part-time Employment: Stemline Therapeutics;Financial Interests, Personal, Leadership Role: Stemline Therapeutics. P.G. Aftimos: Financial Interests, Personal, Advisory Board: Boehringer Ingelheim, Macrogenics, Roche, Novartis, Amcure, Servier, G1 Therapeutics, Radius, Deloitte, Menarini, Gilead, Novartis, Eisai, Lilly;Financial Interests, Personal, Invited Speaker: Synthon, Amgen;Financial Interests, Institutional, Research Grant: Roche.Copyright © 2023

5.
Reproductive Endocrinology ; 65:38-43, 2022.
Article in Ukrainian | EMBASE | ID: covidwho-2265344

ABSTRACT

Objectives: to determine the clinical and genetic determinants of the severe course of COVID-19 in pregnant women in order to identify a risk group and search for therapeutic targets. Materials and methods. 21 patients (group 1) with a severe course of COVID-19 who required intensive care in the Anesthesiology and Intensive Care Unit (AICU) and 126 pregnant women with moderate severity treated in the Infectious-Obstetrics Unit (IOCU) were examined (group 2). Genomic DNA for molecular genetic analysis of gene variants ACE (I/D, rs 4340), PGR (Alu insertion), ESR1 (A351G, rs 9340799), PON1 (C108T, rs 705379) was isolated from the peripheral blood of patients using a commercial Quick-DNA Miniprep Plus Kit (Zymo Research, USA). Variants of ACE and PGR genes were determined using allele-specific polymerase chain reaction;polymerase chain reaction followed by restriction analysis was used to determine ESR1 and PON1 gene variants. Results. Severe course of COVID-19 is observed in 18.2% of pregnant women, critical condition in 7.5%. A third of AICU patients are over 35 years old. Somatic anamnesis was complicated in 23.8% of patients;thyroid gland pathology (14.3%) and varicose disease (19.0%) prevailed. A significant factor in the severe course of COVID-19 is obesity of the III-IV degree in 28.5% cases. The severe course of the disease was associated with complications of pregnancy (oligohydramnios - 52.4%, ahydramnios - 14.3%, fetal growth retardation syndrome - 33.3%, circulatory disorders - 57.1%, fetal distress - 47.6%, preeclampsia - 14.3%), labor (caesarean section - 57.1%, premature birth - 28.6%), disorders of newborns state (asphyxia - 35.6%). These patients are characterized by anemia (58.7%), thrombocytopenia (23.8%), leukocytosis (33.3%), lymphopenia (90.5%), a shift of the leukocyte formula to the left (an increase of rod-nuclear leukocytes by 85.7%). There were significantly increased levels of transaminases: alanine aminotransferase in 47.6%, aspartate aminotransferase in 76.2%. Prothrombotic changes are indicated by a decrease in prothrombin time and activated partial thromboplastin time in 66.7%, which is confirmed by an increase in D-dimer in 85.7% of patients up to the maximum 15,000 ng/ml in 9.5% of women. An increase in inflammation markers (C-reactive protein and interleukin-6 in all AICU patients, procalcitonin in 66.7%) is a reflection of the destructive effect of inflammatory processes. The genetic determinants of the severe course of COVID-19 in pregnant women can be the ID genotype of the ACE I/D rs4340 polymorphism (81.0%), the T2/T2 PROGINS genotype (19.0%), the ESR1 A351G rs9340799 GG genotype (28.5%). Conclusions. The use of separate clinical, laboratory and genetic indicators in pregnant women with COVID-19 will contribute to the selection of the risk group of a coronavirus severe course and the determination of targets of therapeutic impact.Copyright © 2022 Trylyst. All rights reserved.

6.
Ankara Universitesi Eczacilik Fakultesi Dergisi ; 46(1):144-159, 2022.
Article in English | EMBASE | ID: covidwho-2283034

ABSTRACT

Objective: Traditional medicine is often considered to be a kind of complementary or alternative medicine (CAM) nowadays. Therefore, documenting and identifying the herbs that are effective in treating various diseases is vital for future disease control programs. This study aims to perform a molecular docking analysis of the thirteen plant components in Bauhinia acuminata against the target proteins in lung cancer (PDB IDs: 2ITY), breast cancer (1A52), diabetes (3L4U), obesity (IT02), inflammation (5COX) and corona viral infections (6VYO). Material(s) and Method(s): All the plant components used for the present study were retrieved from the plant Bauhinia acuminata and were evaluated for their biological activity results using molinspiration. Further in-silico docking analysis was performed using AutoDock Vina software and the binding interactions were visualized using Discovery studio program. Result and Discussion: The docking scores and analysis of the interactions of the plant components with targets suggest that all the selected plant components showed excellent binding to the chosen targets when compared to that of the standard drugs. As a result of the docking process on 6 different targets, the selected plant components like Quercetin, Beta-sitosterol, and Rheagenine were observed to show good binding energy values against all the 5 targets except 6VYO as shown in (Table 9). These results can further pave the way for getting better insights in identifying and designing potential lead candidates.Copyright © 2022 University of Ankara. All rights reserved.

7.
J Mol Struct ; 1228: 129433, 2021 Mar 15.
Article in English | MEDLINE | ID: covidwho-2095810

ABSTRACT

Traditional medicines contain natural products (NPs) as main ingredient which always give new direction and paths to develop new advanced medicines. In the COVID-19 pandemic, NPs can be used or can help to find new compound against it. The SARS coronavirus-2 main protease (SARS CoV-2 Mpro) enzyme, arbitrate viral replication and transcription, is target here. The study show that, from the electronic features and binding affinity of all the NPs with the enzyme, the compounds with higher hydrophobicity and lower flexibility can be more favorable inhibitor. More than fifty NPs were screened for the target and one terpenoid (T3) from marine sponge Cacospongia mycofijiensis shows excellent SARS CoV-2 Mpro inhibitory activity in comparison with known peptide based inhibitors. The molecular dynamics simulation studies of the terpenoids with the protein indicates that the complex is stable and hydrogen bonds are involved during the complexation. Considering binding affinity, bioavailability, pharmacokinetics and toxicity of the compounds, it is proposed that the NP T3 can act as a potential drug candidate against COVID-19 virus.

8.
Annals of the Rheumatic Diseases ; 81:1857, 2022.
Article in English | EMBASE | ID: covidwho-2008819

ABSTRACT

Background: Few cases of digital ischemia and gangrene associated with primary solid tumors have been described in literature[3]. The exact mechanism of severe occurrence has not been completely understood and the available treatment options have an extremely limited utility [1,2].In the most cases the patients were elderly women with adenocarcinomas of digestive or gynaecologic apparatuses [4]. Objectives: We describe a new case of digital gangrene as unusual presentation of ovarian cancer in a 36 years old woman. Methods: 36 years old female was admitted to our Reheumatology deparment with blackish Blackish discoloration of the toes of one week duration. She had history of COVID-19 infection 8 months prior to the presentation then developed hemoptysis, picture suggestive of ILD, generalized anasarca and skin rash;accordingly an initial diagnosis of post COVID-19 vasculitis was made by dermatologist. The blood tests were ESR:21 mm/hr, CRP:25.7, D.Dimer:8.8, Ferri-tin:575 ng/ml, lymphopenia:0.9, S.Creatinine:2, 24 h urinary protein: 325 mg/24h and all autoimmune markers were negative except anti nuclear antibody (ANA) with titer:1/160. Further assessment revealed that she had multiple site coag-ulopathy;internal jugular vein thrombosis, bilateral lower limbs Deep Venous Thrombosis (DVT). Neck ultrasound surprisingly showed bilateral enlarged suspicious looking supraclavicular lymph node with lost hilum which was Biopsied for histopathological correlation which revealed focally necrotizing adenocarci-noma with signifcant signet ring differentiation. Searching for the primary malignancy, tumor markers were sent CA125: 584 u/ml (up to 35), Pelvi-abdominal Magnetic resonance imaging (MRI) revealed Left ovarian mass measuring 3.6 x 3.4 x 4.4 cm highly suspicious of malignant neoplastic growth for histopatho-logical correlation, Suspicious looking pelviabdominal lymph nodes mostly representing malignant lymphadenopathy, Scattered peritoneal nodules suspicious of metastatic deposits. Results: During admision the patient received full dose anticoagulation (Low Molecular Weight Heparin: 60 iu/12 h). Upon diagnosis we arrange the transferal to the oncology department to continue her management plan. Unfortunately;the case was terminal for palliative therapy and she died after 2 weeks. Conclusion: Bluish discoloration of digits and toes may be a clue for diagnosis of many diseases not only vasculitis. Malignancy can disturb the immune system in a way that mimic any systemic connective tissue disease. Acute insult aggressive multiple site deep venous thrombosis (DVT) necessitate thinking outside the box and consider other causes of coagulopathy like visceral malignancy.

9.
International Journal of Pharmaceutical Sciences Review and Research ; 73(2):53-61, 2022.
Article in English | EMBASE | ID: covidwho-1863755

ABSTRACT

Traditional medicine is often considered to be a kind of complementary or alternative medicine (CAM) nowadays. Therefore, documenting and identifying the herbs that are effective in treating various diseases is vital for future disease control programs. The study aims to perform Molecular docking analysis of the phytoconstituents of the Bauhinia acuminata named Quercetin, Bauhinone, Beta-sitosterol, and Kaempferol 3-glycoside with the target proteins with PDB IDs namely 2ITY, 1A52, 3L4U, IT02, 5COX, 6VYO involved in Lung cancer, breast cancer, anti-diabetes, anti-obesity, anti-inflammatory, and SARS COV-2. Chemsketch software, the study of the in-silico docking was done using Autodock.4.2 software and the binding interactions are visualized using Discovery studio 3.1. The docking scores and analysis of the interactions of the phytoconstituents with target proteins suggests that all the selected 5 phytoconstituents showed excellent binding to 2ITY and 5-COX as opposed to the standard drugs Erlotinib and Aspirin. In this study, it was concluded that the investigated phytoconstituents showed potent inhibiting activity, and the dock scores as opposed to standard as in Table 6, directly represent possible binding to the target proteins indicating their good biological activity as in lung cancer and anti-inflammatory action.

10.
Chinese Pharmacological Bulletin ; 36(9):1309-1316, 2020.
Article in Chinese | EMBASE | ID: covidwho-1863006

ABSTRACT

Aim To explore the active compound of Maxingganshi decoction in treatment of novel coronavirus pneumonia(COVID-19). Methods With the help of TCMSP database, the chemical components and action targets of ephedra, almond, licorice, and gypsum in Maxingganshi decoction were searched, and then a C-T network, protein interaction analysis, GO functional enrichment analysis, and KEGG pathway enrichment were constructed. Analysis was performed to predict its mechanism of action. Results A total of 120 compounds in Maxingganshi decoction corresponded to 222 targets. PTGS2, ESR1, PPARG, AR, NOS2, NCOA2 acted on PI3K-Akt signaling pathway, TNF signaling pathway, IL-17 signaling pathway, T cell receptor signaling pathways, etc. The results of molecular docking showed that the affinity of quercetin, kaempferol, glabridin and other core compounds was similar to recommended drugs in treatment of COVID-19. Conclusions The active compounds of Maxingganshi decoction can target multiple pathways to achieve the therapeutic effect of COVID-19.

11.
New Zealand Medical Journal ; 134(1547), 2021.
Article in English | EMBASE | ID: covidwho-1812555

ABSTRACT

The proceedings contain 8 papers. The topics discussed include: an exploration of mental health promotion in Aotearoa New Zealand: a qualitative study;vaccination, vaccine hesitancy and COVID-19 in New Zealand, 2018-2021;infra-slow pink noise stimulation can increase default-mode network activity in individuals with early Alzheimer's disease;agmatine attenuates actin dynamic alteration and synaptic dysfunction in aged rats;estrogen receptor alpha activation stimulates the Coolidge effect but has no effect on the sexual refractory period of estrogen-deprived male rats;and dissecting the receptor signaling events responsible for the immune suppressive and immune stimulatory effects of IL-10.

12.
Cancer Research ; 82(4 SUPPL), 2022.
Article in English | EMBASE | ID: covidwho-1779449

ABSTRACT

Background: Aromatase inhibitors (AI) in combination with a CDK 4/6 inhibitor have been established as the standard first line treatment of non AI-resistant hormone receptor-positive (HR+) HER2-metastatic breast cancer (mBC) patients (pts). ESR1 mutations are known drivers of resistance to AIs in the metastatic setting but their actionability remains unknown. The phase 3 PADA-1 trial aimed both at refining the global safety of palbociclib combined to any AI as first line treatment of HR+ HER2-mBC pts, and at evaluating the clinical benefit associated with a switch to fulvestrant-palbociclib upon detection of a rising ESR1 mutation in blood (bESR1mut). Methods: PADA-1 (NCT03079011), a multicenter, randomized, open-label, phase 3 trial, enrolled HR+ HER2-mBC pts with no prior therapy for mBC, in the absence of AI-resistance. In the first step, pts received a combination of any AI and palbociclib at standard recommended doses and underwent centralized bESR1mut screening every two months. In the second step, bESR1mut+ pts with no S clinical/imaging concomitant disease progression were randomized between continuing the same therapy (standard arm) or switching to fulvestrant-palbociclib (experimental arm). The third step consisted in an optional cross-over after tumor progression for patients randomized in the standard arm. PADA-1 co-primary endpoints were global safety of the combination of palbociclib + endocrine therapy in the whole population of patients, throughout the study, with focus on hematological toxicities;and PFS in the second step. We present here the results of the global safety co-primary endpoint. Results: From 3/2017 to 01/2019, 1017 pts were accrued in 83 sites. As per 05/2021, 272 pts were still in step 1, 35 in step 2, and 8 in step 3. The overall follow-up was 33.7 months. 232 pts have deceased. 333 SAEs have been reported, including 21 grade 5, 35 grade 4, 183 grade 3, 53 grade 2, 26 grade 1 and 15 unknown grade. Among the grade 5 cases, 2 have been declared as potentially related to the underlying treatment (Death of unknown cause, pulmonary embolism). No pt died of SARS-CoV2 infection. The main hematological toxicities encountered, as well as selected non-hematological events are described in Table 1. Permanent discontinuation of the treatment due to toxicity occurred in 39 pts/1017 (3.8%). Palbociclib dose decreases occurred in 419 (41.2%) pts. Conclusion: By the number of included patients, PADA-1 is the largest prospective trial with 1st line AI and palbociclib. Data confirm the favorable safety profile of palbociclib when combined to any AI +/-switch to fulvestrant. Hematological toxicity appears limited and is mostly restricted to non-clinically significant neutropenia. Permanent discontinuation was exceptional. Detailed per-step analyses will be presented.

13.
J Family Reprod Health ; 15(3): 150-159, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1498155

ABSTRACT

Objective: Female sex hormones have a pro-inflammatory effect, which may help to minimize inflammation. Estrogen's immunoregulatory properties play a significant role in the bi-directional neuroendocrine-immune activity in females. As a result, sex hormones can play a role in men's high mortality rate from coronavirus-2019 (COVID-19). It is aimed to clarify the role of 17-estradiol (E2) in the battle against COVID-19. Materials and methods: Until April 2021, a study on PubMed was performed. COVID-19, 17-estradiol (E2), immunoregulatory properties, pregnancy, menopausal symptoms, hormonal therapy, ER/ expression on immune cells, and mortality were some of the concepts used in the search. Results: Regulation of pro-inflammatory immune processes against COVID-19 appears to be associated with increased immune function (pro-inflammatory), anti-inflammatory regulation, and antiviral defense. Women with a severe coronavirus infection had higher serum IgG antibody levels than men, and their IgG production was faster in the early stages of infection. 17-estradiol (E2) levels of blood will increase by 100-fold during pregnancy. COVID-19 in pregnant women had a 15-fold lower mortality rate than other women. While menopause replacement therapy (MRT) for pre/post-menopausal women and its effectiveness in reducing COVID-19 infection is debatable. Conclusion: MRT may be considered as a viable treatment option for pre/post-menopause women with coronavirus, referring to the fact that sex hormones reduce inflammatory responses and modulate ACE2 expression. The task's difficulty and achieving the desired outcome seem to be challenging.

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