共查询到20条相似文献,搜索用时 31 毫秒
1.
Simbarashe Takuva Azwidhwi Takalani Ishen Seocharan Nonhlanhla Yende-Zuma Tarylee Reddy Imke Engelbrecht Mark Faesen Kentse Khuto Carmen Whyte Veronique Bailey Valentina Trivella Jonathan Peter Jessica Opie Vernon Louw Pradeep Rowji Barry Jacobson Pamela Groenewald Rob E. Dorrington Ria Laubscher Debbie Bradshaw Harry Moultrie Lara Fairall Ian Sanne Linda Gail-Bekker Glenda Gray Ameena Goga Nigel Garrett Sisonke study team 《PLoS medicine》2022,19(6)
BackgroundReal-world evaluation of the safety profile of vaccines after licensure is crucial to accurately characterise safety beyond clinical trials, support continued use, and thereby improve public confidence. The Sisonke study aimed to assess the safety and effectiveness of the Janssen Ad26.COV2.S vaccine among healthcare workers (HCWs) in South Africa. Here, we present the safety data.Methods and findingsIn this open-label phase 3b implementation study among all eligible HCWs in South Africa registered in the national Electronic Vaccination Data System (EVDS), we monitored adverse events (AEs) at vaccination sites through self-reporting triggered by text messages after vaccination, healthcare provider reports, and active case finding. The frequency and incidence rate of non-serious and serious AEs were evaluated from the day of first vaccination (17 February 2021) until 28 days after the final vaccination in the study (15 June 2021). COVID-19 breakthrough infections, hospitalisations, and deaths were ascertained via linkage of the electronic vaccination register with existing national databases. Among 477,234 participants, 10,279 AEs were reported, of which 138 (1.3%) were serious AEs (SAEs) or AEs of special interest. Women reported more AEs than men (2.3% versus 1.6%). AE reports decreased with increasing age (3.2% for age 18–30 years, 2.1% for age 31–45 years, 1.8% for age 46–55 years, and 1.5% for age > 55 years). Participants with previous COVID-19 infection reported slightly more AEs (2.6% versus 2.1%). The most common reactogenicity events were headache (n = 4,923) and body aches (n = 4,483), followed by injection site pain (n = 2,767) and fever (n = 2,731), and most occurred within 48 hours of vaccination. Two cases of thrombosis with thrombocytopenia syndrome and 4 cases of Guillain-Barré Syndrome were reported post-vaccination. Most SAEs and AEs of special interest (n = 138) occurred at lower than the expected population rates. Vascular (n = 37; 39.1/100,000 person-years) and nervous system disorders (n = 31; 31.7/100,000 person-years), immune system disorders (n = 24; 24.3/100,000 person-years), and infections and infestations (n = 19; 20.1/100,000 person-years) were the most common reported SAE categories. A limitation of the study was the single-arm design, with limited routinely collected morbidity comparator data in the study setting.ConclusionsWe observed similar patterns of AEs as in phase 3 trials. AEs were mostly expected reactogenicity signs and symptoms. Furthermore, most SAEs occurred below expected rates. The single-dose Ad26.COV2.S vaccine demonstrated an acceptable safety profile, supporting the continued use of this vaccine in this setting.Trial registrationClinicalTrials.gov ; Pan African Clinical Trials Registry NCT04838795PACTR202102855526180.Saimbarashe Takuva, Azwi Takalani, and colleagues investigate the frequency and incidence of adverse events reported after receipt of a single dose of the Ad26.COV2.S COVID-19 vaccine among health care workers in South Africa. 相似文献
2.
Pim Cuijpers Eva Heim Jinane Abi Ramia Sebastian Burchert Kenneth Carswell Ilja Cornelisz Christine Knaevelsrud Philip Noun Chris van Klaveren Edith vant Hof Edwina Zoghbi Mark van Ommeren Rabih El Chammay 《PLoS medicine》2022,19(6)
BackgroundMost displaced people with mental disorders in low- and middle-income countries do not receive effective care, and their access to care has deteriorated during the Coronavirus Disease 2019 (COVID-19) pandemic. Digital mental health interventions are scalable when digital access is adequate, and they can be safely delivered during the COVID-19 pandemic. We examined whether a new WHO-guided digital mental health intervention, Step-by-Step, in which participants were supported by a nonspecialist helper, was effective in reducing depression among displaced people in Lebanon.Methods and findingsWe conducted a single-blind, 2-arm pragmatic randomized clinical trial, comparing guided Step-by-Step with enhanced care as usual (ECAU) among displaced Syrians suffering from depression and impaired functioning in Lebanon. Primary outcomes were depression (Patient Health Questionnaire, PHQ-9) and impaired functioning (WHO Disability Assessment Schedule-12, WHODAS) at posttreatment. Secondary outcomes included subjective well-being, anxiety, post-traumatic stress, and self-described problems. A total of 569 displaced people from Syria with depression (PHQ-9 ≥ 10) and impaired functioning (WHODAS > 16) were randomized to Step-by-Step (N = 283; lost to follow-up: N = 167) or ECAU (N = 286; lost to follow-up: 133). Participants were considered to be lost to follow-up when they did not fill in the outcome measures at posttest or follow-up. Recruitment started on December 9, 2019 and was completed on July 9, 2020. The last follow-up assessments were collected in December 2020. The study team had access to the online platform, where they could see treatment arm assignment for each participant. All questionnaires were completed by participants online. Intention-to-treat (ITT) analyses showed intervention effects on depression (standardized mean differences [SMDs]: 0.48; 95% CI: 0.26; 0.70; p < 0.001), impaired functioning (SMD: 0.35; 95% CI: 0.14; 0.56; p < 0.001), post-traumatic stress (SMD: 0.36; 95% CI: 0.16; 0.56; p < 0.001), anxiety (SMD: 0.46; 95% CI: 0.24; 0.68; p < 0.001), subjective well-being (SMD: 0.47; 95% CI: 0.26; 0.68; p < 0.001), and self-identified personal problems (SMD: 0.49; 95% CI 0.28; 0.70; p < 0.001). Significant effects on all outcomes were maintained at 3 months follow-up. During the trial, one serious adverse event occurred, unrelated to the intervention. The main limitation of the current trial is the high dropout rate.ConclusionsIn this study, we found that a guided, digital intervention was effective in reducing depression in displaced people in Lebanon. The guided WHO Step-by-Step intervention we examined should be made available to communities of displaced people that have digital access.Trial registrationClinicalTrials.gov .In a randomized controlled trial, Pim Cuijpers and colleagues evaluate the effects of the Step-by-Step guided digital mental health intervention on depression, impaired functioning, and other mental health outcomes among displaced Syrians living in Lebanon. NCT03720769相似文献
3.
Kiyoaki Tsukahara Akira Kubota Yasuhisa Hasegawa Hideki Takemura Tomonori Terada Takahide Taguchi Kunihiko Nagahara Hiroaki Nakatani Kunitoshi Yoshino Yuichiro Higaki Shigemichi Iwae Takeshi Beppu Yutaka Hanamure Kichinobu Tomita Naoyuki Kohno Kazuyoshi Kawabata Masanori Fukushima Satoshi Teramukai Masato Fujii ACTS-HNC group 《PloS one》2015,10(2)
BackgroundWe conducted a phase III study to evaluate S-1 as compared with UFT as control in patients after curative therapy for stage III, IVA, or IVB squamous-cell carcinoma of the head and neck (SCCHN).ResultsA total of 526 patients were enrolled, and 505 were eligible for analysis. The 3-year DFS rate was 60.0% in the UFT group and 64.1% in the S-1 group (HR, 0.87; 95%CI, 0.66-1.16; p = 0.34). The 3-year OS rate was 75.8% and 82.9%, respectively (HR, 0.64; 95% CI, 0.44-0.94; p = 0.022). Among grade 3 or higher adverse events, the incidences of leukopenia (5.2%), neutropenia (3.6%), thrombocytopenia (2.0%), and mucositis/stomatitis (2.4%) were significantly higher in the S-1 group.ConclusionsAlthough DFS did not differ significantly between the groups, OS was significantly better in the S-1 group than in the UFT group. S-1 is considered a treatment option after curative therapy for stage III, IVA, IVB SCCHN.
Trial Registration
ClinicalTrials.gov NCT00336947http://clinicaltrials.gov/show/ NCT00336947相似文献4.
Cindy H. Chau Douglas K. Price Cathee Till Phyllis J. Goodman Xiaohong Chen Robin J. Leach Teresa L. Johnson-Pais Ann W. Hsing Ashraful Hoque Catherine M. Tangen Lisa Chu Howard L. Parnes Jeannette M. Schenk Juergen K. V. Reichardt Ian M. Thompson William D. Figg 《PloS one》2015,10(5)
ObjectiveIn the Prostate Cancer Prevention Trial (PCPT), finasteride reduced the risk of prostate cancer by 25%, even though high-grade prostate cancer was more common in the finasteride group. However, it remains to be determined whether finasteride concentrations may affect prostate cancer risk. In this study, we examined the association between serum finasteride concentrations and the risk of prostate cancer in the treatment arm of the PCPT and determined factors involved in modifying drug concentrations.MethodsData for this nested case-control study are from the PCPT. Cases were drawn from men with biopsy-proven prostate cancer and matched controls. Finasteride concentrations were measured using a liquid chromatography-mass spectrometry validated assay. The association of serum finasteride concentrations with prostate cancer risk was determined by logistic regression. We also examine whether polymorphisms in the enzyme target and metabolism genes of finasteride are related to drug concentrations using linear regression.
Results and Conclusions
Among men with detectable finasteride concentrations, there was no association between finasteride concentrations and prostate cancer risk, low-grade or high-grade, when finasteride concentration was analyzed as a continuous variable or categorized by cutoff points. Since there was no concentration-dependent effect on prostate cancer, any exposure to finasteride intake may reduce prostate cancer risk. Of the twenty-seven SNPs assessed in the enzyme target and metabolism pathway, five SNPs in two genes, CYP3A4 (rs2242480; rs4646437; rs4986910), and CYP3A5 (rs15524; rs776746) were significantly associated with modifying finasteride concentrations. These results suggest that finasteride exposure may reduce prostate cancer risk and finasteride concentrations are affected by genetic variations in genes responsible for altering its metabolism pathway.Trial Registration
ClinicalTrials.gov NCT00288106相似文献5.
Kawsar R. Talaat Subash Babu Pradeep Menon N. Kumarasamy Jabin Sharma Jeeva Arumugam Kalaivani Dhakshinamurthy Ramalingam Srinivasan S. Poongulali Wenjuan Gu Michael P. Fay Soumya Swaminathan Thomas B. Nutman 《PLoS neglected tropical diseases》2015,9(3)
BackgroundThe disease course of human immunodeficiency virus (HIV) is often altered by existing or newly acquired coincident infections.Conclusions/SignificanceWe were unable to find a significant effect of W. bancrofti infection or its treatment on HIV clinical course or surrogate markers of HIV disease progression though we recognized that our study was limited by the smaller than predicted sample size and by the use of ART in half of the patients. Treatment of W. bancrofti coinfection in HIV positive subjects (as is usual in mass drug administration campaigns) did not represent an increased risk to the subjects, and should therefore be considered for PLWHA living in W. bancrofti endemic areas.
Trial Registration
ClinicalTrials.gov NCT00344279相似文献6.
PARP inhibitors (PARPi) gained major interest among prostate cancer researchers in the last few years, thanks to the outstanding results coming from the PROfound an TRITON2 studies. Following that, PARPi gained approval also in metastatic, castration-resistant prostate cancer (mCRPC) with mutations in homologous repair (HR) – related genes. Nevertheless, some questions still remain unanswered concerning the management of drug resistance and PARPi-sensitivity in patients harboring alterations in various DNA damage response (DDR) related genes, not only BRCA1 and BRCA2.In this perspective article we focus on the key issues concerning PARPi in mCRPC, specifically those related to drug sensitivity and resistance mechanisms, exploring the possible role of combination therapeutic approaches and trying to depict potential future addresses in translational oncology research.Perspective Article (max: 1200 words)The DNA damage repair (DDR) pathway gained major interest between cancer researchers since 2005, when emerging studies demonstrated that the simultaneous inhibition of both Poly(ADP-ribose) polymerase 1 (PARP1) and tumor suppressors Breast Related Cancer Antigens 1 and 2 (BRCA1 and BRCA2) generates excessive DNA instability and, ultimately, leads to cellular death. This process, called synthetic lethal theory, constituted the rationale for the development of drugs targeting PARP1 in BRCA1/2 deficient clones, the PARP inhibitors (PARPi) [1, 2].In normal conditions, PARP1 plays a key role as regulator of multiple cellular processes, including DDR. When a DNA damage occurs, the activation of PARP1 results in the recruitment of several DNA repair factors, including BRCA1 and BRCA2, leading to the restoration of single-strand (SSBs) and double-strand DNA breaks (DSBs) [1,2]. Particularly, BRCA1 and BRCA2 act downstream the PARP1 cascade in one of the two major pathways for DSBs repair, largely error free: the homologous repair (HR). Another crucial mechanism, which sees the synergic contribution of PARP1, BRCA1 and BRCA 2, is the stabilization of replication fork during the S phase of the cell cycle [2]. As a consequence of that, heterozygous germline mutations in DDR genes, especially BRCA1 and BRCA2, dramatically increase the risk of developing multiple neoplasms (e.g. breast, ovarian, prostate and pancreatic cancers )2. In addition, somatic and germline mutations in one of these genes confer a strong sensitivity to DNA-damaging agents (e.g. platinum salts): these fundamental observations led researchers to successfully study and test pharmacological inhibition of the DDR pathway, using PARPi [2].Of note, it has been calculated that approximately 12% of metastatic, castration-resistant prostate cancer (mCRPC) patients harbor germline DDR mutations, while 20–25% harbor somatic DDR mutations. Overall, it is estimated that in almost 22.7% of mCRPC patients could be identified mutations in DDR-related genes, making them a considerable number of people who could take an advantage from PARPi administration [3].In 2014, the U.S. Food and Drug Administration (FDA) granted approval to Olaparib as the first PARPi viable for women suffering from BRCA 1–2 mutated metastatic ovarian cancer both for cases previously treated with three or more lines of chemotherapy, and also as maintenance therapy following platinum-based chemotherapy [2]. Since that, following the consistent results described by subsequent clinical trials, Olaparib and other PARPi (e.g. Rucaparib, Niraparib) gained approval for different clinical settings in ovarian cancer and for BRCA-mutated breast, pancreatic and prostate cancer [2].In 2020, thanks to the outstanding results of the PROFound trial, the FDA approved the administration of Olaparib in patients with metastatic castration-resistant prostate cancer (mCRPC) progressing after therapy with enzalutamide or abiraterone and harboring mutations in HR-related genes [4]. Later the same year, the European Medicines Agency (EMA) recommended Olaparib in the same setting, with a slight but substantial difference: the main requirement was the identification of a BRCA 1 and BRCA 2 mutation (somatic or germline) in prostate cancer patients who have progressed to a prior therapy that included a new hormonal agent [5].Similarly, Rucaparib received the FDA accelerated approval after the publication of the TRITON2 study, that showed consistent overall response rate (ORR) and Prostate Specific Antigen (PSA) response rate values in patients with BRCA 1 and BRCA2 alterations [6].Nevertheless, it is well known that DDR mechanisms, including homologous repair (HR), are characterized by the interplay of a huge number of enzymes, co-factors, and molecules, not only BRCA1 and BRCA2 [2,5]. Specifically, HR requires the intervention of co-factors as PALB2 (Partner And Localizer Of BRCA2) and RAD51 (RAD51 Recombinase) to perform an accurate repair of double strand DNA breaks. In addition, BRCA1 and BRCA2 exhibit a crucial role during the S phase of the cell cycle, as protectors of the replication fork from the degradation activity carried out by nucleases. This is why, although PARPi seem to be more effective against BRCA1 and 2 mutations, data extrapolated from clinical trials suggest a benefit also for people harboring alterations in others genes, such as PALB2, RAD51 and ATM (Ataxia-Telangectasia Mutated) [2]. The PROFound trial, considered as a milestone, enlightened this aspect and its possible implications in prostate cancer: administering Olaparib to the whole cohort of HR-deficient patients could extend the survival benefit to a significant number of people, albeit the subgroup of BRCA1 and BRCA2 mutated cohort might have generated an overestimation of this effect in that trial [7]. Further studies need to be carried out in order to perform a correct prognostic and predictive gene-signature based stratification of patients.One of major concerns related to anti-cancer drugs, particularly targeted therapies, is drug-resistance. Even PARPi, although frequently characterized by initial good responses, ultimately loose their effectiveness, leading to disease relapse [2]. The reason is that cancerous cells learn how to escape from the pharmacological attack of PARPi via several mechanisms: upregulation of drug efflux pumps; mutations of the drug target; recovery of BRCA1 and BRCA2 function; re-establishment of replication fork stability [2,8]. The deep knowledge of these mechanisms could lead to overcome drug resistance: the most appealing hypothesis to get through this barrier appears to combine PARPi with agents affecting HR from other sides, such as Vascular Endothelial Growth Factor (VEGF) inhibitors, for which some encouraging data have been published in a cohort of ovarian cancer patients [2]. An interesting observation is also that HR deficient cancers might exhibit a high tumor mutational burden, often associated with an improved sensitivity to immunotherapy. Thus, clinical trials are now investigating the combination of PARPi and immune check-point inhibitors (ICIs) in mCRPC [9].Furthermore, several trials are ongoing to evaluate the efficacy of the combination of PARPi and new hormone agents (i.e. Abiraterone acetate, Enzalutamide) for metastatic prostate cancer, both in the hormone-sensitive and castration-resistant phases.Unfortunately, most of data concerning combination therapies were extrapolated from preliminary analyses of clinical trials, with many open issues still remaining. Firstly, drug safety: as previously stated in a phase I/II clinical trial, the addition of ICIs to PARPi seems to be well tolerated with no significant increase of severe adverse effects; at the same time, the administration of PARPi plus Abiraterone in mCRPC patients was investigated in a randomized, double-blind, placebo controlled phase II clinical trial, obtaining promising results in term of safety and also efficacy [2,10]. Another major concern regards the need to identify reliable biomarkers predictive of drug response, and this must be one of the addresses of future researches [1,2]. The last issue involves health care costs of such combinations therapies, again emphasizing the importance to perform a thorough stratification of mCRPC patients. [2]. These might be some branches for future researches, to explore where and when to combine PARPi with other agents, and in which patients subgroup [1,2,9].We have now several weapons in our hands, ready to be used, the most important represented by genomic analyses techniques [2]. In addition, following that principle of synthetic lethality, we need to hit cellular DNA repairing system from many sides, employing old and new drugs. The only way to cope with this huge amount of data is to team up with different professional figures (e.g. biotechnologists, pharmacologists, biostatisticians), constructing a cooperative network system. Only by doing this we will make it up to the mountain. Study ID Title Status Phase NCT03732820 Study on Olaparib Plus Abiraterone as First-line Therapy in Men With Metastatic Castration-resistant Prostate Cancer Recruiting 3 NCT01972217 Phase II Study to Evaluate Olaparib With Abiraterone in Treating Metastatic Castration Resistant Prostate Cancer. Active, not recruiting 2 NCT02987543 Study of Olaparib (Lynparza™) Versus Enzalutamide or Abiraterone Acetate in Men With Metastatic Castration-Resistant Prostate Cancer (PROfound) Active, not recruiting 3 NCT03787680 Targeting Resistant Prostate Cancer With ATR and PARP Inhibition (TRAP Trial) Active, not recruiting 2 NCT03834519 Study of Pembrolizumab (MK-3475) Plus Olaparib Versus Abiraterone Acetate or Enzalutamide in Metastatic Castration-resistant Prostate Cancer (mCRPC) (MK-7339–010/KEYLYNK-010) Active, not recruiting 3 NCT03012321 Abiraterone/Prednisone, Olaparib, or Abiraterone/Prednisone + Olaparib in Patients With Metastatic Castration-Resistant Prostate Cancer With DNA Repair Defects Recruiting 2 NCT03434158 Olaparib Maintenance in Patients With MCRPC After Docetaxel Treatment Reaching Partial or Stable Response (IMANOL) Active, not recruiting 2 NCT03516812 Testosterone and Olaparib in Treating Patients With Castration-Resistant Prostate Cancer Active, not recruiting 2 NCT04951492 Olaparib for the Treatment of Castration Resistant Prostate Adenocarcinoma Not yet recruiting 2 NCT02893917 Olaparib With or Without Cediranib in Treating Patients With Metastatic Castration-Resistant Prostate Cancer Active, not recruiting 2 NCT01682772 TOPARP: A Phase II Trial of Olaparib in Patients With Advanced Castration Resistant Prostate Cancer Active, not recruiting 2 NCT05005728 XmAb®20,717 Alone or in Combination With Chemotherapy or Targeted Therapy in Patients With Metastatic Castration-Resistant Prostate Cancer Not yet recruiting 2 NCT03413995 Trial of Rucaparib in Patients With Metastatic Hormone-Sensitive Prostate Cancer Harboring Germline DNA Repair Gene Mutations Recruiting 2 NCT02952534 A Study of Rucaparib in Patients With Metastatic Castration-resistant Prostate Cancer and Homologous Recombination Gene Deficiency (TRITON-2) Active, not recruiting 2 NCT02975934 A Study of Rucaparib Versus Physician''s Choice of Therapy in Patients With Metastatic Castration-resistant Prostate Cancer and Homologous Recombination Gene Deficiency (TRITON-3) Recruiting 3 NCT04455750 A Clinical Study Evaluating The Benefit of Adding Rucaparib to Enzalutamide for Men With Metastatic Prostate Cancer That Has Become Resistant To Testosterone-Deprivation Therapy Recruiting 3 NCT03442556 Docetaxel, Carboplatin, and Rucaparib Camsylate in Treating Patients With Metastatic Castration Resistant Prostate Cancer With Homologous Recombination DNA Repair Deficiency Recruiting 2 NCT04592237 Cabazitaxel, Carboplatin, and Cetrelimab Followed by Niraparib With or Without Cetrelimab for the Treatment of Aggressive Variant Metastatic Prostate Cancer Recruiting 2 NCT04821622 Study of Talazoparib With Enzalutamide in Men With DDR Gene Mutated mCSPC Recruiting 3 NCT02854436 An Efficacy and Safety Study of Niraparib in Men With Metastatic Castration-Resistant Prostate Cancer and DNA-Repair Anomalies Active, not recruiting 2