Can routinely collected administrative data effectively be used to evaluate and validate endpoints used in breast cancer clinical trials? Protocol for a scoping review of the literature.

BACKGROUND: Randomized controlled trials (RCTs) are a critical component of evidence-based medicine and the evolution of patient care. However, the costs of conducting a RCT can be prohibitive. A promising approach toward reduction of costs and lessening of the burden of intensive and lengthy patient follow-up is the use of routinely collected healthcare data (RCHD), commonly called real-world data. We propose a scoping review to identify existing RCHD case definitions of breast cancer progression and survival and their diagnostic performance. METHODS: We will search MEDLINE, EMBASE, and CINAHL to identify primary studies of women with either early-stage or metastatic breast cancer, managed with established therapies, that evaluated the diagnostic accuracy of one or more RCHD-based case definitions or algorithms of disease progression (i.e., recurrence, progression-free survival, disease-free survival, or invasive disease-free survival) or survival (i.e., breast-cancer-free survival or overall survival) compared with a reference standard measure (e.g., chart review or a clinical trial dataset). Study characteristics and descriptions of algorithms will be extracted along with measures of the diagnostic accuracy of each algorithm (e.g., sensitivity, specificity, positive predictive value, negative predictive value), which will be summarized both descriptively and in structured figures/tables. DISCUSSION: Findings from this scoping review will be clinically meaningful for breast cancer researchers globally. Identification of feasible and accurate strategies to measure patient-important outcomes will potentially reduce RCT budgets as well as lessen the burden of intensive trial follow-up on patients. SYSTEMATIC REVIEW REGISTRATION: Open Science Framework ( https://doi.org/10.17605/OSF.IO/6D9RS ).

Impacts of medical and non-medical cannabis on the health of older adults: Findings from a scoping review of the literature.

BACKGROUND: Cannabis legalization has enabled increased consumption in older adults. Age-related mental, physical, and physiological changes may lead to differences in effects of cannabis in older adults compared to younger individuals. OBJECTIVE: To perform a scoping review to map the evidence regarding the health effects of cannabis use for medical and non-medical purposes in older adults. METHODS: Electronic databases (MEDLINE, Embase, PsycINFO, Cochrane Library) were searched for systematic reviews (SRs), randomized controlled trials (RCTs) and non-randomized/observational studies (NRSs) assessing the health effects and associations of cannabis use (medical or non-medical) in adults ≥ 50 years of age. Included studies met age-related inclusion criteria or involved a priori identified health conditions common among older adults. Records were screened using a liberal accelerated approach and data charting was performed independently by two reviewers. Descriptive summaries, structured tables, effect direction plots and bubble plots were used to synthesize study findings. FINDINGS: From 31,393 citations, 133 publications describing 134 unique studies (26 SRs, 36 RCTs, 72 NRSs) were included. Medical cannabis had inconsistent therapeutic effects in specific patient conditions (e.g., end-stage cancer, dementia), with a number of studies suggesting possible benefits while others found no benefit. For medical cannabis, harmful associations outnumbered beneficial, and RCTs reported more negative effects than NRSs. Cannabis use was associated with greater frequencies of depression, anxiety, cognitive impairment, substance use and problematic substance use, accidents/injuries, and acute healthcare use. Studies often were small, did not consistently assess harms, and did not adjust for confounding. DISCUSSION: The effects of medical cannabis are inconsistent within specific patient conditions. For older adults, generally, the available evidence suggests cannabis use may be associated with greater frequencies of mental health issues, substance use, and acute healthcare use, and the benefit-to-risk ratio is unclear. Studies with a balanced assessment of benefits and harms may guide appropriate public health messaging to balance the marketing pressures of cannabis to older adults.

Management of genitourinary symptoms in patients with breast cancer: an updated systematic review of available evidence from randomized trials.

PURPOSE: The purpose of this systematic review update is to synthesize available data on management of genitourinary symptoms (GUS) in breast cancer patients, a common and challenging clinical scenario. METHODS: EMBASE, Ovid Medline, and the Cochrane Library were searched from September 2014 to December 2021 for randomized controlled trials which examined various interventions for GUS in breast cancer patients. Outcomes of interest included improvements in vaginal symptoms (e.g., dryness, pain, dyspareunia, itching), vaginal hormone response measured by validated scales (e.g., Vaginal Health Index, and Vaginal Maturation Index), and Female Sexual Function Index (FSFI). A team of reviewers participated in the processes of study selection, data collection, and risk of bias appraisal. A descriptive approach to synthesis was used. RESULTS: Of 842 unique citations identified (412 from this update, 430 from previous review), eight studies (n = 539) met inclusion criteria. Interventions included 0.005% estriol gel (EG; n = 50), intravaginal testosterone (IVT; n = 21), intravaginal prebiotic (n = 13), hyaluronic acid (HA; n = 12), polyacrylic acid (PA; n = 25), pH-balanced gel (n = 118), Replens® (n = 24), and Lidocaine (n = 22). These were compared to placebo/saline/lubricants/usual care (n = 228). FSFI total score was significantly improved by all interventions except IVT and lidocaine, and not measured for Replens®. Significant improvements in vaginal hormone responses were reported for EG and pH-balanced gel; however, no significant effects were found for IVT, HA, or prebiotics. Vaginal symptoms were significantly improved by EG, IVT, PA, and PH-balanced gel. CONCLUSION: Treatment of GUS remains a challenging issue. It is evident that more prospective trials are needed.

Optimising weight-loss interventions in cancer patients-A systematic review and network meta-analysis.

BACKGROUND: Excess weight has been associated with increased morbidity and a worse prognosis in adult patients with early-stage cancer. The optimal lifestyle interventions to optimize anthropometric measures amongst cancer patients and survivors remain inconsistent. OBJECTIVE: To conduct a systematic review and network meta-analysis (NMA) of randomized controlled trials (RCTs) comparing the effects of exercise and dietary interventions alone or in combination on anthropometric measures of adult cancer patients and survivors. METHODS: A systematic search of Medline, Embase and the Cochrane Trials Registry was performed. Outcomes of interest included changes in weight, body mass index (BMI), and waist circumference. Screening and data collection were performed by two reviewers. Bayesian NMAs were performed. RESULTS: Overall, 98 RCTs were included; 75 were incorporated in NMAs (n = 12,199). Groups of intervention strategies included: 3 exercise interventions, 8 dietary interventions, 7 combination interventions of diet and exercise and standard care. Median intervention duration was 26 weeks. NMA suggested that diet alone (mean difference [MD] -2.25kg, 95% CrI -3.43 to -0.91kg) and combination strategies (MD -2.52kg, 95% CrI -3.54 to -1.62kg) were associated with more weight loss compared to standard care. All dietary interventions achieved a similar magnitude of weight loss (MD range from -2.03kg to -2.52kg). Both diet alone and combination strategies demonstrated greater BMI reductions versus standard care, and each of diet alone, exercise alone and combination strategies demonstrated greater reductions in waist circumference than standard care. CONCLUSION: Diet and exercise alone or in combination are effective lifestyle interventions to improve anthropometric measures in cancer patients and survivors. All reputable diets appear to be similarly effective to achieve weight loss.

Pharmacologic and surgical therapies for patients with Meniere's disease: A systematic review and network meta-analysis.

BACKGROUND: Meniere's disease (MD) is a chronic condition of the inner ear consisting of symptoms that include vertigo attacks, fluctuating sensorineural hearing loss, tinnitus and aural fullness. Despite availability of various interventions, there is uncertainty surrounding their relative efficacy, thus making it difficult to select the appropriate treatments for MD. The objective of this systematic review was to assess the relative effects of the available pharmacologic and surgical interventions in patients with MD with regard to vertigo and other key patient outcomes based on data from randomized clinical trials (RCTs). METHODS: Our published protocol registered with PROSPERO (CRD42019119129) provides details on eligibility criteria and methods. We searched various databases including MEDLINE, Embase and the Cochrane Library from inception to December 10th, 2018. Screening at citation and full-text levels and risk of bias assessment were performed by two independent reviewers in duplicate, with discrepancies resolved by consensus or third-party adjudication. Bayesian network meta-analyses (NMA) were performed for hearing change and vertigo control outcomes, along with pairwise meta-analyses for these and additional outcomes. RESULTS: We identified 2,889 unique citations, that yielded 23 relevant publications describing 18 unique RCTs (n = 1,231 patients). Overall, risk-of bias appraisal suggested the evidence base to be at unclear or high risk of bias. Amongst pharmacologics, we constructed treatment networks of five intervention groups that included placebo, intratympanic (IT) gentamicin, oral high-dose betahistine, IT steroid and IT steroid plus high-dose betahistine for NMAs of hearing change (improvement or deterioration) and complete vertigo control. IT steroid plus high-dose betahistine was associated with the largest difference in hearing improvement compared to placebo, followed by high-dose betahistine and IT steroid (though 95% credible intervals failed to rule out the possibility of no difference), while IT gentamicin was worse than IT steroid. The NMA of complete vertigo control suggested IT gentamicin was associated with the highest probability of achieving better complete vertigo control compared to placebo, followed by IT steroid plus high-dose betahistine. Only two studies related to surgical interventions were found, and data suggested no statistically significant difference in hearing changes between endolymphatic duct blockage (EDB) versus endolymphatic sac decompression (ESD), and ESD with or without steroid injection. One trial reported that 96.5% of patients in EDB group compared to 37.5% of the patients in ESD group achieved complete vertigo control 24 months after surgery (p = 0.002). CONCLUSION: To achieve both hearing preservation and vertigo control, the best treatment option among the pharmacologic interventions compared may be IT steroid plus high-dose betahistine, considering that IT gentamicin may have good performance to control vertigo but may be detrimental to hearing preservation with high cumulative dosage and short interval between injections. However, IT steroid plus high-dose betahistine has not been compared in head-to-head trials against other interventions except for IT steroid alone in one trial, thus future trials that compare it with other interventions will help establish comparative effectiveness with direct evidence.

Comparison of freshly cultured versus freshly thawed (cryopreserved) mesenchymal stem cells in preclinical in vivo models of inflammation: a protocol for a preclinical systematic review and meta-analysis.

BACKGROUND: Mesenchymal stem cells (MSCs) are multipotent cells that demonstrate therapeutic potential for the treatment of acute and chronic inflammatory-mediated conditions. Especially for acute conditions, it is critical to have a readily available freshly thawed (cryopreserved) MSC product for rapid administration. Although controversial, some studies suggest that MSCs may lose their functionality with cryopreservation which in turn could render them non-efficacious. OBJECTIVE: In controlled preclinical in vivo models of inflammation, to determine if there are differences in surrogate measures of preclinical efficacy between freshly cultured and freshly thawed MSCs METHODS/DESIGN: A systematic search for pre-clinical in vivo inflammatory model studies will compare freshly cultured to freshly thawed MSCs from any source. The primary outcomes will include measures of in vivo preclinical efficacy; secondary outcomes will include measures of in vitro MSC potency. Electronic searches for MEDLINE and EMBASE will be constructed and reviewed by the Peer Review of Electronic Search Strategies (PRESS) process. If applicable, study outcomes will be meta-analyzed using a random effects model. Risk of bias will be assessed by the SYRCLE "Risk of Bias" assessment tool for preclinical in vivo studies. DISCUSSION: The results of this systematic review will provide translational scientists, clinical trialists, health regulators, and the clinical and public community with the current pre-clinical evidence base related to the efficacy and potency of freshly cultured versus freshly thawed MSCs, help identify evidence gaps, and guide future related research. SYSTEMATIC REVIEW REGISTRATION: Protocol is submitted to PROSPERO for registration (pending confirmation) and will be submitted to Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies (CAMARADES) for public posting.

A scoping review of network meta-analyses assessing the efficacy and safety of complementary and alternative medicine interventions.

BACKGROUND: Network meta-analysis (NMA) has rapidly grown in use during the past decade for the comparison of healthcare interventions. While its general use in the comparison of conventional medicines has been studied previously, to our awareness, its use to assess complementary and alternative medicines (CAM) has not been studied. A scoping review of the literature was performed to identify systematic reviews incorporating NMAs involving one or more CAM interventions. METHODS: An information specialist executed a multi-database search (e.g., MEDLINE, Embase, Cochrane), and two reviewers performed study selection and data collection. Information on publication characteristics, diseases studied, interventions compared, reporting transparency, outcomes assessed, and other parameters were extracted from each review. RESULTS: A total of 89 SR/NMAs were included. The largest number of NMAs was conducted in China (39.3%), followed by the United Kingdom (12.4%) and the United States (9.0%). Reviews were published between 2010 and 2018, with the majority published between 2015 and 2018. More than 90 different CAM therapies appeared at least once, and the median number per NMA was 2 (IQR 1-4); 20.2% of reviews consisted of only CAM therapies. Dietary supplements (51.1%) and vitamins and minerals (42.2%) were the most commonly studied therapies, followed by electrical stimulation (31.1%), herbal medicines (24.4%), and acupuncture and related treatments (22.2%). A diverse set of conditions was identified, the most common being various forms of cancer (11.1%), osteoarthritis of the hip/knee (7.8%), and depression (5.9%). Most reviews adequately addressed a majority of the PRISMA NMA extension items; however, there were limitations in indication of an existing review protocol, exploration of network geometry, and exploration of risk of bias across studies, such as publication bias. CONCLUSION: The use of NMA to assess the effectiveness of CAM interventions is growing rapidly. Efforts to identify priority topics for future CAM-related NMAs and to enhance methods for CAM comparisons with conventional medicine are needed. SYSTEMATIC REVIEW REGISTRATION: https://ruor.uottawa.ca/handle/10393/35658.

Effects of medical and non-medical cannabis use in older adults: protocol for a scoping review.

INTRODUCTION: With its legalisation and regulation in Canada in 2018, the proportion of Canadians reporting cannabis use in 2019 increased substantially over the previous year, with half of new users being aged 45+ years. While use in older adults has been low historically, as those born in the 1950s and 1960s continue to age, this demographic will progressively have more liberal attitudes, prior cannabis exposure and higher use rates. However, older adults experience slower metabolism, increased likelihood of polypharmacy, cognitive decline and chronic physical/mental health problems. There is a need to enhance knowledge of the effects of cannabis use in older adults. The following question will be addressed using a scoping review approach: what evidence exists regarding beneficial and harmful effects of medical and non-medical cannabis use in adults >50 years of age? Given that beneficial and harmful effects of cannabis may be mediated by patient-level (eg, age, sex and race) and cannabis-related factors (eg, natural vs synthetic, consumption method), subgroup effects related to these and additional factors will be explored. METHODS AND ANALYSIS: Methods for scoping reviews outlined by Arksey & O'Malley and the Joanna Briggs Institute will be used. A librarian designed a systematic search of the literature from database inception to June 2019. Using the OVID platform, Ovid MEDLINE will be searched, including Epub Ahead of Print and In-Process and Other Non-Indexed Citations, Embase Classic+Embase, and PsycINFO for reviews, randomised trials, non-randomised trials and observational studies of cannabis use. The Cochrane Library on Wiley will also be searched. Eligibility criteria will be older adult participants, currently using cannabis (medical or non-medical), with studies required to report a cannabis-related health outcome to be eligible. Two reviewers will screen citations and full texts, with support from artificial intelligence. Two reviewers will chart data. Tables/graphics will be used to map evidence and identify evidence gaps. ETHICS AND DISSEMINATION: This research will enhance awareness of existing evidence addressing the health effects of medical and non-medical cannabis use in older adults. Findings will be disseminated through a peer-reviewed publication, conference presentations and a stakeholder meeting. TRIAL REGISTRATION NUMBER: DOI 10.17605/OSF.IO/5JTAQ.

Cell therapy with intravascular administration of mesenchymal stromal cells continues to appear safe: An updated systematic review and meta-analysis.

BACKGROUND: Characterization of the mesenchymal stromal cell (MSC) safety profile is important as this novel therapy continues to be evaluated in clinical trials for various inflammatory conditions. Due to an increase in published randomized controlled trials (RCTs) from 2012-2019, we performed an updated systematic review to further characterize the MSC safety profile. METHODS: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and Web of Science (to May 2018) were searched. RCTs that compared intravascular delivery of MSCs to controls in adult populations were included. Pre-specified adverse events were grouped according to: (1) immediate, (2) infection, (3) thrombotic/embolic, and (4) longer-term events (mortality, malignancy). Adverse events were pooled and meta-analyzed by fitting inverse-variance binary random effects models. Primary and secondary clinical efficacy endpoints were summarized descriptively. FINDINGS: 7473 citations were reviewed and 55 studies met inclusion criteria (n = 2696 patients). MSCs as compared to controls were associated with an increased risk of fever (Relative Risk (RR) = 2·48, 95% Confidence Interval (CI) = 1·27-4·86; I2 = 0%), but not non-fever acute infusional toxicity, infection, thrombotic/embolic events, death, or malignancy (RR = 1·16, 0·99, 1·14, 0·78, 0·93; 95% CI = 0·70-1·91, 0·81-1·21, 0·67-1·95, 0·65-0·94, 0·60-1·45; I2 = 0%, 0%, 0%, 0%, 0%). No included trials were ended prematurely due to safety concerns. INTERPRETATIONS: MSC therapy continues to exhibit a favourable safety profile. Future trials should continue to strengthen study rigor, reporting of MSC characterization, and adverse events. FUNDING: Stem Cell Network, Ontario Institute for Regenerative Medicine and Ontario Research Fund.

Comparative safety of bowel cleansers: protocol for a systematic review and network meta-analysis.

INTRODUCTION: The US Food and Drug Administration has withdrawn the bowel cleansing kit HalfLytely (PEG 3500) with 10 mg bisacodyl tablets due to an increased risk of ischaemic colitis compared with the same kit with only 5 mg bisacodyl. This is of interest in Canada given that the bowel cleansing kit Bi-Peglyte (PEG 3500) with 15 mg bisacodyl is currently approved for use. The objective is to assess the comparative safety of various bowel cleansers with or without bisacodyl, with a primary interest inpolyethylene glycol (PEG)-based and sodium-picosulfate-based products. METHODS AND ANALYSIS: Given the existing volume of the literature, the review will be conducted in two stages. Stage 1 will consist of a scoping exercise by searching MEDLINE, Embase and the Cochrane Library (up to 21 November 2017) to identify randomised controlled trials, quasirandomised studies and non-randomised studies in which any bowel cleanser regimens were compared among persons undergoing colonoscopy. The outcomes will be mapped to establish a listing of the studies and their comparisons and outcomes currently available in the literature. From this, a data synthesis plan will be determined. In stage 2, a systematic review with meta-analyses will be pursued, focused on the bowel cleanser comparisons and outcomes of interest identified in stage 1. Two reviewers will screen, extract and quality assess the articles. Outcomes of interest include ischaemic colitis, electrolyte imbalances and their consequences, seizures, bowel perforation and patient tolerability. If sufficient data exist and studies are of sufficient homogeneity, network meta-analyses (NMAs) will be performed. ETHICS AND DISSEMINATION: Ethics approval was not necessary due to study design. Updating the safety profile of bowel cleansers among the generally healthy population undergoing colonoscopy is pertinent given recent approval changes. This will be the first NMA within this population. Policy considerations may be reconsidered to minimise risk during bowel cleanser use. PROSPERO REGISTRATION NUMBER: CRD42018084720.