Patient-reported outcomes in randomized clinical trials of systemic therapy for advanced soft tissue sarcomas in adults:A systematic review

Background: This systematic review evaluates reporting of patient-reported outcomes (PROs) within randomized clinical trials (RCTs) for advanced soft tissue sarcoma (STS) patients. Methods: A systematic literature search from January 2000 – August 2022 was conducted for phase II/III RCTs evaluating systemic treatments in adult patients with advanced STS. Quality of PRO reporting was assessed using the CONSORT PRO extension. Results: Out of 7294 abstracts, 59 articles were included; comprising 43 RCTs. Only 15 RCTs (35%) included PROs, none as primary endpoints. Only 10 of these RCTs reported PROs, either in the primary (6/10) or secondary publication (1/10) or in both (3/10), with a median time interval of 23 months. The median CONSORT PRO adherence score was 5.5/14, with higher scores in publications focusing exclusively on PROs. Conclusion: These results highlight the need for improved and more consistent PRO reporting to inform patient care in the setting of advanced STS.</p

Intracerebral adenosine during sleep deprivation : A meta-analysis and new experimental data

Funding Information: The systematic review was funded by The Netherlands Organisation for Health Research and Development (ZonMW; 114024101); R2N, Federal State of Lower Saxony; and the DFG (FOR2591, BL 953/11-1). The microdialysis experiment was funded by Netherlands Organization for Scientific Research (NWO; 051-04-010, to Eus van Some-ren). The HPLC adenosine measurements were funded by the University of Helsinki sleep team and a travel grant from the European Sleep Research Society. Publisher Copyright: © 2018 Ubiquity Press. All rights reserved.The neuroregulator adenosine is involved in sleep-wake control. Basal forebrain (BF) adenosine levels increase during sleep deprivation. Only a few studies have addressed the effect of sleep deprivation on extracellular adenosine concentrations in other brain regions. In this paper, we describe a microdialysis experiment as well as a meta-analysis of published data. The 64 h microdialysis experiment determined the extracellular adenosine and adenosine monophosphate (AMP) concentrations in the medial prefrontal cortex of rats before, during and after 12 h of sleep deprivation by forced locomotion. The meta-analysis comprised published sleep deprivation animal experiments measuring adenosine by means of microdialysis. In the animal experiment, the overall median adenosine concentration was 0.36 nM and ranged from 0.004 nM to 27 nM. No significant differences were observed between the five conditions: 12 h of washout, baseline light phase, baseline dark phase, 12 h of sleep deprivation and 12 h of subsequent recovery. The overall median AMP concentration was 0.10 nM and ranged from 0.001 nM to 7.56 nM. Median AMP concentration increased during sleep deprivation (T = 47; p = 0.047) but normalised during subsequent recovery. The meta-analysis indicates that BF dialysate adenosine concentrations increase with 74.7% (95% CI: 54.1-95.3%) over baseline during sleep deprivation. Cortex dialysate adenosine concentrations during sleep deprivation were so far only reported by 2 publications. The increase in adenosine during sleep deprivation might be specific to the BF. At this stage, the evidence for adenosine levels in other brain regions is based on single experiments and insufficient for generalised conclusions. Further experiments are currently still warranted.Peer reviewe

Measuring endogenous corticosterone in laboratory mice - a mapping review, meta-analysis, and open source database

Evaluating stress in laboratory animals is a key principle in animal welfare. Measuring corticosterone is a common method to assess stress in laboratory mice. There are, however, numerous methods to measure glucocorticoids with differences in sample matrix (e.g., plasma, urine) and quantification techniques (e.g., enzyme immunoassay or radioimmunoassay). Here, the authors present a mapping review and a searchable database, giving a complete overview of all studies mea­suring endogenous corticosterone in mice up to February 2018. For each study, information was recorded regarding mouse strain and sex; corticosterone sample matrix and quantification technique; and whether the study covered the research theme animal welfare, neuroscience, stress, inflammation, or pain (the themes of specific interest in our con­sortium). Using all database entries for the year 2012, an exploratory meta-regression was performed to determine the effect of predictors on basal corticosterone concentrations. Seventy-five studies were included using the predictors sex, time-since-lights-on, sample matrix, quantification technique, age of the mice, and type of control. Sex, time-since-lights-on, and type of control significantly affected basal corticosterone concentrations. The resulting database can be used, inter alia, for preventing unnecessary duplication of experiments, identifying knowledge gaps, and standardizing or heterogenizing methodologies. These results will help plan more efficient and valid experiments in the future and can answer new questions in silico using meta-analyses

Measuring Endogenous Corticosterone in Laboratory Mice - a Mapping Review, Meta-Analysis, and Open Source Database

Evaluating stress in laboratory animals is a key principle in animal welfare. Measuring corticosterone is a common method to assess stress in laboratory mice. There are, however, numerous methods to measure glucocorticoids with differences in sample matrix (e.g., plasma, urine) and quantification techniques (e.g., enzyme immunoassay or radioimmunoassay). Here, the authors present a mapping review and a searchable database, giving a complete overview of all studies measuring endogenous corticosterone in mice up to February 2018. For each study, information was recorded regarding mouse strain and sex; corticosterone sample matrix and quantification technique; and whether the study covered the research theme animal welfare, neuroscience, stress, inflammation, or pain (the themes of specific interest in our consortium). Using all database entries for the year 2012, an exploratory meta-regression was performed to determine the effect of predictors on basal corticosterone concentrations. Seventy-five studies were included using the predictors sex, time-since-lights-on, sample matrix, quantification technique, age of the mice, and type of control. Sex, time-since-lights-on, and type of control significantly affected basal corticosterone concentrations. The resulting database can be used, inter alia, for preventing unnecessary duplication of experiments, identifying knowledge gaps, and standardizing or heterogenizing methodologies. These results will help plan more efficient and valid experiments in the future and can answer new questions in silico using meta-analyses

Software tools for literature screening in systematic reviews in biomedical research

Systematic Reviews (SRs) hold promise for implementing the 3Rs in animal sciences: they can retrieve available alternative models, help refining experiments, and identify insufficiencies, or an excess of, scientific knowledge on a particular topic. Unfortunately, SRs can be labour- and time-intensive, especially the reference screening and data extraction phases. Fortunately, there are several software tools available that help make screening faster and easier. However, it is not always clear which features the tools offer. Therefore, a feature analysis was performed to compare different reference screening tools as objectively as possible. This analysis enables researchers to select the most appropriate tool for their needs. Fifteen different tools were compared: CADIMA, Covidence, DistillerSR, Endnote, Endnote using Bramer's method, EROS, HAWC, Microsoft Excel, Excel using VonVille's method, Microsoft Word, Rayyan, RevMan, SyRF, SysRev.com, and SWIFT Active Screener. Their support of 21 features was tested. Features were categorised as mandatory, desirable, and optional. DistillerSR, Covidence, and SWIFT Active Screener are the tools that support all mandatory features. These tools are preferred for screening references, but none of them are free. The best scoring free tool is Rayyan, which lacks one mandatory function: distinct title/abstract and full-text phases. The lowest scoring tools are those not specifically designed for SRs, like Microsoft Word and Endnote. Their use can only be advised for small and simple SRs. A well-informed selection of SR screening tools will benefit review quality and speed, which can contribute to the advancement of the 3Rs in animal studies

Software tools for literature screening in systematic reviews in biomedical research

Systematic Reviews (SRs) hold promise for implementing the 3Rs in animal sciences: they can retrieve available alternative models, help refining experiments, and identify insufficiencies, or an excess of, scientific knowledge on a particular topic. Unfortunately, SRs can be labour- and time-intensive, especially the reference screening and data extraction phases. Fortunately, there are several software tools available that help make screening faster and easier. However, it is not always clear which features the tools offer. Therefore, a feature analysis was performed to compare different reference screening tools as objectively as possible. This analysis enables researchers to select the most appropriate tool for their needs. Fifteen different tools were compared: CADIMA, Covidence, DistillerSR, Endnote, Endnote using Bramer's method, EROS, HAWC, Microsoft Excel, Excel using VonVille's method, Microsoft Word, Rayyan, RevMan, SyRF, SysRev.com, and SWIFT Active Screener. Their support of 21 features was tested. Features were categorised as mandatory, desirable, and optional. DistillerSR, Covidence, and SWIFT Active Screener are the tools that support all mandatory features. These tools are preferred for screening references, but none of them are free. The best scoring free tool is Rayyan, which lacks one mandatory function: distinct title/abstract and full-text phases. The lowest scoring tools are those not specifically designed for SRs, like Microsoft Word and Endnote. Their use can only be advised for small and simple SRs. A well-informed selection of SR screening tools will benefit review quality and speed, which can contribute to the advancement of the 3Rs in animal studies

Clinical development of WEE1 inhibitors in gynecological cancers: A systematic review

Introduction: The anti-tumor activity of WEE1 inhibitors (WEE1i) in gynecological malignancies has recently been demonstrated in clinical trials and its rationale is based on biological/molecular features of gynecological cancers. With this systematic review, we aim to outline the clinical development and current evidence regarding the efficacy and safety of these targeted agents in in this patient group. Methods: Systematic literature review of trials including patients with gynecological cancers treated with a WEE1i. The primary objective was to summarize the efficacy of WEE1i in gynecological malignancies regarding objective response rate (ORR), clinical benefit rate (CBR), overall survival (OS) and progression-free survival (PFS). Secondary objectives included toxicity profile, Maximum Tolerated Dose (MTD), pharmacokinetics, drug-drug interactions and exploratory objectives such as biomarkers for response. Results: 26 records were included for data extraction. Almost all trials used the first-in-class WEE1i adavosertib; one conference abstract reported about Zn-c3. The majority of the trials included diverse solid tumors (n = 16). Six records reported efficacy results of WEE1i in gynecological malignancies (n = 6). Objective response rates of adavosertib monotherapy or in combination with chemotherapy ranged between 23% and 43% in these trials. Median PFS ranged from 3.0 to 9.9 months. The most common adverse events were bone marrow suppression, gastrointestinal toxicities and fatigue. Mainly alterations in cell cycle regulator genes TP53 and CCNE1 were potential predictors of response. Conclusion: This report summarizes encouraging clinical development of WEE1i in gynecological cancers and considers its application in future studies. Biomarker-driven patient selection might be essential to increase the response rates

Patient-reported outcomes in randomized clinical trials of systemic therapy for advanced soft tissue sarcomas in adults:A systematic review

Background: This systematic review evaluates reporting of patient-reported outcomes (PROs) within randomized clinical trials (RCTs) for advanced soft tissue sarcoma (STS) patients. Methods: A systematic literature search from January 2000 – August 2022 was conducted for phase II/III RCTs evaluating systemic treatments in adult patients with advanced STS. Quality of PRO reporting was assessed using the CONSORT PRO extension. Results: Out of 7294 abstracts, 59 articles were included; comprising 43 RCTs. Only 15 RCTs (35%) included PROs, none as primary endpoints. Only 10 of these RCTs reported PROs, either in the primary (6/10) or secondary publication (1/10) or in both (3/10), with a median time interval of 23 months. The median CONSORT PRO adherence score was 5.5/14, with higher scores in publications focusing exclusively on PROs. Conclusion: These results highlight the need for improved and more consistent PRO reporting to inform patient care in the setting of advanced STS.</p