A core outcome set (COS) is an agreed standardized set of outcomes that should be measured and reported, as a minimum, in specific areas of health or health care. A COS is developed through a ...consensus process to ensure health care outcomes to be measured are relevant to decision-makers, including patients and health-care professionals. Use of COS in guideline development is likely to increase the relevance of the guideline to those decision-makers. Previous work has looked at the uptake of COS in trials, systematic reviews, health technology assessments and regulatory guidance but to date there has been no evaluation of the use of COS in practice guideline development. The objective of this study was to investigate the representation of core outcomes in a set of international practice guidelines.
We searched for clinical guidelines relevant to ten high-quality COS (with focus on the United Kingdom, Germany, China, India, Canada, Denmark, United States and World Health Organisation). We matched scope between COS and guideline in terms of condition, population and outcome. We calculated the proportion of guidelines mentioning or referencing COS and the proportion of COS domains specifically, or generally, matching to outcomes specified in each guideline populations, interventions, comparators and outcome (PICO) statement.
We found 38 guidelines that contained 170 PICO statements matching the scope of the ten COS and of sufficient quality to allow data extraction. None of the guidelines reviewed explicitly mentioned or referenced the relevant COS. The median (range) of the proportion of core outcomes covered either specifically or generally by the guideline PICO was 30% (0%–100%).
There is no evidence that COS are being used routinely to inform the guideline development process, and concordance between outcomes in published guidelines and those in COS is limited. Further work is warranted to explore barriers and facilitators in the use of COS when developing clinical guidelines.
Background
Severe bleeding and coagulopathy are serious clinical conditions that are associated with high mortality. Thromboelastography (TEG) and thromboelastometry (ROTEM) are increasingly used to ...guide transfusion strategy but their roles remain disputed. This review was first published in 2011 and updated in January 2016.
Objectives
We assessed the benefits and harms of thromboelastography (TEG)‐guided or thromboelastometry (ROTEM)‐guided transfusion in adults and children with bleeding. We looked at various outcomes, such as overall mortality and bleeding events, conducted subgroup and sensitivity analyses, examined the role of bias, and applied trial sequential analyses (TSAs) to examine the amount of evidence gathered so far.
Search methods
In this updated review we identified randomized controlled trials (RCTs) from the following electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 1); MEDLINE; Embase; Science Citation Index Expanded; International Web of Science; CINAHL; LILACS; and the Chinese Biomedical Literature Database (up to 5 January 2016). We contacted trial authors, authors of previous reviews, and manufacturers in the field. The original search was run in October 2010.
Selection criteria
We included all RCTs, irrespective of blinding or language, that compared transfusion guided by TEG or ROTEM to transfusion guided by clinical judgement, guided by standard laboratory tests, or a combination. We also included interventional algorithms including both TEG or ROTEM in combination with standard laboratory tests or other devices. The primary analysis included trials on TEG or ROTEM versus any comparator.
Data collection and analysis
Two review authors independently ed data; we resolved any disagreements by discussion. We presented pooled estimates of the intervention effects on dichotomous outcomes as risk ratio (RR) with 95% confidence intervals (CIs). Due to skewed data, meta‐analysis was not provided for continuous outcome data. Our primary outcome measure was all‐cause mortality. We performed subgroup and sensitivity analyses to assess the effect based on the presence of coagulopathy of a TEG‐ or ROTEM‐guided algorithm, and in adults and children on various clinical and physiological outcomes. We assessed the risk of bias through assessment of trial methodological components and the risk of random error through TSA.
Main results
We included eight new studies (617 participants) in this updated review. In total we included 17 studies (1493 participants). A total of 15 trials provided data for the meta‐analyses. We judged only two trials as low risk of bias. The majority of studies included participants undergoing cardiac surgery.
We found six ongoing trials but were unable to retrieve any data from them. Compared with transfusion guided by any method, TEG or ROTEM seemed to reduce overall mortality (7.4% versus 3.9%; risk ratio (RR) 0.52, 95% CI 0.28 to 0.95; I2 = 0%, 8 studies, 717 participants, low quality of evidence) but only eight trials provided data on mortality, and two were zero event trials. Our analyses demonstrated a statistically significant effect of TEG or ROTEM compared to any comparison on the proportion of participants transfused with pooled red blood cells (PRBCs) (RR 0.86, 95% CI 0.79 to 0.94; I2 = 0%, 10 studies, 832 participants, low quality of evidence), fresh frozen plasma (FFP) (RR 0.57, 95% CI 0.33 to 0.96; I2 = 86%, 8 studies, 761 participants, low quality of evidence), platelets (RR 0.73, 95% CI 0.60 to 0.88; I2 = 0%, 10 studies, 832 participants, low quality of evidence), and overall haemostatic transfusion with FFP or platelets (low quality of evidence). Meta‐analyses also showed fewer participants with dialysis‐dependent renal failure.
We found no difference in the proportion needing surgical reinterventions (RR 0.75, 95% CI 0.50 to 1.10; I2 = 0%, 9 studies, 887 participants, low quality of evidence) and excessive bleeding events or massive transfusion (RR 0.38, 95% CI 0.38 to 1.77; I2 = 34%, 2 studies, 280 participants, low quality of evidence). The planned subgroup analyses failed to show any significant differences.
We graded the quality of evidence as low based on the high risk of bias in the studies, large heterogeneity, low number of events, imprecision, and indirectness. TSA indicates that only 54% of required information size has been reached so far in regards to mortality, while there may be evidence of benefit for transfusion outcomes. Overall, evaluated outcomes were consistent with a benefit in favour of a TEG‐ or ROTEM‐guided transfusion in bleeding patients.
Authors' conclusions
There is growing evidence that application of TEG‐ or ROTEM‐guided transfusion strategies may reduce the need for blood products, and improve morbidity in patients with bleeding. However, these results are primarily based on trials of elective cardiac surgery involving cardiopulmonary bypass, and the level of evidence remains low. Further evaluation of TEG‐ or ROTEM‐guided transfusion in acute settings and other patient categories in low risk of bias studies is needed.
Bronchial and gastroenteropancreatic neuroendocrine tumors (NET) are slow-growing tumors, which frequently express somatostatin receptors on their cell membranes. These receptors are targets for ...therapy with Lutetium-177-labeled somatostatin analogues. We have treated over 1,200 patients with peptide receptor radionuclide therapy (PRRT) with
Lu-DOTA
,Tyr
octreotate (
Lu-DOTATATE) since the year 2000 and present the results on efficacy, survival, and toxicity of this therapy.
For safety analysis, 610 patients treated with a cumulative dose of at least 100 mCi (3.7 GBq)
Lu-DOTATATE were included. A subgroup of 443 Dutch patients who were treated with a cumulative dose of at least 600 mCi (22.2 GBq)
Lu-DOTATATE before 2013 was further analyzed for efficacy and survival.
The objective response rate of the total group of patients was 39%. Stable disease was reached in 43% of patients. Progression-free survival (PFS) and overall survival (OS) for all NET patients were 29 months 95% confidence interval (CI), 26-33 months and 63 months (95% CI, 55-72 months). Long-term toxicity included acute leukemia in four patients (0.7%) and myelodysplastic syndrome in nine patients (1.5%). No therapy-related long-term renal or hepatic failure occurred.
PRRT with
Lu-DOTATATE is a favorable therapeutic option in patients with metastatic bronchial and gastroenteropancreatic NETs that express somatostatin receptors. PRRT with
Lu-DOTATATE is safe with few side-effects and shows good response rates with PFS of 29 months and OS of 63 months.
.
The prognostic value and clinical relevance of tertiary lymphoid structures (TLSs) in intrahepatic cholangiocarcinoma (iCCA) remain unclear. Thus, we aimed to investigate the prognostic value and ...functional involvement of TLSs in iCCA.
We retrospectively included 962 patients from 3 cancer centers across China. The TLSs at different anatomic subregions were quantified and correlated with overall survival (OS) by Cox regression and Kaplan-Meier analyses. Multiplex immunohistochemistry (mIHC) was applied to characterize the composition of TLSs in 39 iCCA samples.
A quaternary TLS scoring system was established for the intra-tumor region (T score) and peri-tumor region (P score) respectively. T scores positively correlated with favorable prognosis (p <0.001), whereas a high P score signified worse survival (p <0.001). mIHC demonstrated that both T follicular helper and regulatory T cells were significantly increased in intra-tumoral TLSs compared to peri-tumoral counterparts (p <0.05), and regulatory T cell frequencies within intra-tumoral TLSs were positively associated with P score (p <0.05) rather than T score. Collectively, the combination of T and P scores stratified iCCAs into 4 immune classes with distinct prognoses (p <0.001) that differed in the abundance and distribution pattern of TLSs. Patients displaying an immune-active pattern had the lowest risk, with 5-year OS rates of 68.8%, whereas only 3.4% of patients with an immune-excluded pattern survived at 5 years (p <0.001). The C-index of the immune class was statistically higher than the TNM staging system (0.73 vs. 0.63, p <0.001). These results were validated in an internal and 2 external cohorts.
The spatial distribution and abundance of TLSs significantly correlated with prognosis and provided a useful immune classification for iCCA. T follicular helper and regulatory T cells may play a critical role in determining the functional orientation of spatially different TLSs.
Tertiary lymphoid structures (TLSs) are associated with favorable prognosis in a number of cancers. However, their role in intrahepatic cholangiocarcinoma (iCCA) remains unclear. Herein, we comprehensively evaluated the spatial distribution, abundance, and cellular composition of TLSs in iCCA, and revealed the opposite prognostic impacts of TLSs located within or outside the tumor. This difference could be mediated by the different immune cell subsets present within the spatially distinct TLSs. Based on our analysis, we were able to stratify iCCAs into 4 immune subclasses associated with varying prognoses.
Display omitted
•Tertiary lymphoid structures (TLSs) within and outside the tumor have opposite prognostic impacts on patients with iCCA.•The heterogeneous distribution of Tfh and Treg cells within distinct TLSs might be a determinant of their functional state.•The geographic integration of TLSs stratified iCCAs into 4 immune subclasses with distinct clinical outcomes.
Background
Researchers and organizations often use evidence from randomized controlled trials (RCTs) to determine the efficacy of a treatment or intervention under ideal conditions. Studies of ...observational designs are often used to measure the effectiveness of an intervention in 'real world' scenarios. Numerous study designs and modifications of existing designs, including both randomized and observational, are used for comparative effectiveness research in an attempt to give an unbiased estimate of whether one treatment is more effective or safer than another for a particular population.
A systematic analysis of study design features, risk of bias, parameter interpretation, and effect size for all types of randomized and non‐experimental observational studies is needed to identify specific differences in design types and potential biases. This review summarizes the results of methodological reviews that compare the outcomes of observational studies with randomized trials addressing the same question, as well as methodological reviews that compare the outcomes of different types of observational studies.
Objectives
To assess the impact of study design (including RCTs versus observational study designs) on the effect measures estimated.
To explore methodological variables that might explain any differences identified.
To identify gaps in the existing research comparing study designs.
Search methods
We searched seven electronic databases, from January 1990 to December 2013.
Along with MeSH terms and relevant keywords, we used the sensitivity‐specificity balanced version of a validated strategy to identify reviews in PubMed, augmented with one term ("review" in article titles) so that it better targeted narrative reviews. No language restrictions were applied.
Selection criteria
We examined systematic reviews that were designed as methodological reviews to compare quantitative effect size estimates measuring efficacy or effectiveness of interventions tested in trials with those tested in observational studies. Comparisons included RCTs versus observational studies (including retrospective cohorts, prospective cohorts, case‐control designs, and cross‐sectional designs). Reviews were not eligible if they compared randomized trials with other studies that had used some form of concurrent allocation.
Data collection and analysis
In general, outcome measures included relative risks or rate ratios (RR), odds ratios (OR), hazard ratios (HR). Using results from observational studies as the reference group, we examined the published estimates to see whether there was a relative larger or smaller effect in the ratio of odds ratios (ROR).
Within each identified review, if an estimate comparing results from observational studies with RCTs was not provided, we pooled the estimates for observational studies and RCTs. Then, we estimated the ratio of ratios (risk ratio or odds ratio) for each identified review using observational studies as the reference category. Across all reviews, we synthesized these ratios to get a pooled ROR comparing results from RCTs with results from observational studies.
Main results
Our initial search yielded 4406 unique references. Fifteen reviews met our inclusion criteria; 14 of which were included in the quantitative analysis.
The included reviews analyzed data from 1583 meta‐analyses that covered 228 different medical conditions. The mean number of included studies per paper was 178 (range 19 to 530).
Eleven (73%) reviews had low risk of bias for explicit criteria for study selection, nine (60%) were low risk of bias for investigators' agreement for study selection, five (33%) included a complete sample of studies, seven (47%) assessed the risk of bias of their included studies,
Seven (47%) reviews controlled for methodological differences between studies,
Eight (53%) reviews controlled for heterogeneity among studies, nine (60%) analyzed similar outcome measures, and four (27%) were judged to be at low risk of reporting bias.
Our primary quantitative analysis, including 14 reviews, showed that the pooled ROR comparing effects from RCTs with effects from observational studies was 1.08 (95% confidence interval (CI) 0.96 to 1.22). Of 14 reviews included in this analysis, 11 (79%) found no significant difference between observational studies and RCTs. One review suggested observational studies had larger effects of interest, and two reviews suggested observational studies had smaller effects of interest.
Similar to the effect across all included reviews, effects from reviews comparing RCTs with cohort studies had a pooled ROR of 1.04 (95% CI 0.89 to 1.21), with substantial heterogeneity (I2 = 68%). Three reviews compared effects of RCTs and case‐control designs (pooled ROR: 1.11 (95% CI 0.91 to 1.35)).
No significant difference in point estimates across heterogeneity, pharmacological intervention, or propensity score adjustment subgroups were noted. No reviews had compared RCTs with observational studies that used two of the most common causal inference methods, instrumental variables and marginal structural models.
Authors' conclusions
Our results across all reviews (pooled ROR 1.08) are very similar to results reported by similarly conducted reviews. As such, we have reached similar conclusions; on average, there is little evidence for significant effect estimate differences between observational studies and RCTs, regardless of specific observational study design, heterogeneity, or inclusion of studies of pharmacological interventions. Factors other than study design per se need to be considered when exploring reasons for a lack of agreement between results of RCTs and observational studies. Our results underscore that it is important for review authors to consider not only study design, but the level of heterogeneity in meta‐analyses of RCTs or observational studies. A better understanding of how these factors influence study effects might yield estimates reflective of true effectiveness.
The ability to identify medical reversals and other low-value medical practices is an essential prerequisite for efforts to reduce spending on such practices. Through an analysis of more than 3000 ...randomized controlled trials (RCTs) published in three leading medical journals (the Journal of the American Medical Association, the Lancet, and the New England Journal of Medicine), we have identified 396 medical reversals. Most of the studies (92%) were conducted on populations in high-income counties, cardiovascular disease was the most common medical category (20%), and medication was the most common type of intervention (33%).
Examining the patient's subjective experience in prospective clinical comparative effectiveness research (CER) of oncology treatments or process interventions is essential for informing decision ...making. Patient-reported outcome (PRO) measures are the standard tools for directly eliciting the patient experience. There are currently no widely accepted standards for developing or implementing PRO measures in CER. Recommendations for the design and implementation of PRO measures in CER were developed via a standardized process including multistakeholder interviews, a technical working group, and public comments. Key recommendations are to include assessment of patient-reported symptoms as well as health-related quality of life in all prospective clinical CER studies in adult oncology; to identify symptoms relevant to a particular study population and context based on literature review and/or qualitative and quantitative methods; to assure that PRO measures used are valid, reliable, and sensitive in a comparable population (measures particularly recommended include EORTC QLQ-C30, FACT, MDASI, PRO-CTCAE, and PROMIS); to collect PRO data electronically whenever possible; to employ methods that minimize missing patient reports and include a plan for analyzing and reporting missing PRO data; to report the proportion of responders and cumulative distribution of responses in addition to mean changes in scores; and to publish results of PRO analyses simultaneously with other clinical outcomes. Twelve core symptoms are recommended for consideration in studies in advanced or metastatic cancers. Adherence to methodologic standards for the selection, implementation, and analysis/reporting of PRO measures will lead to an understanding of the patient experience that informs better decisions by patients, providers, regulators, and payers.
Excitement about the dramatic increase in potential successful anticancer medicines in recent years is hampered by the high costs involved as well as the length of time traditional pathways take for ...regulatory approval. The translation of experimental clinical data into real-world evidence is also problematic. While the randomised controlled trial remains the gold standard for assessing efficacy and safety, there is increasing interest in the use of observational data to enable more rapid, informed and widespread availability and access to important anticancer medicines. Taking real-world evidence into account in regulatory and health technology assessment in a thoughtful and balanced fashion will enrich and justify sound decision-making.
•Adding real-world data to randomised controlled trials of anticancer drugs can increase external validity.•Many challenges remain before real-world evidence may become an integrated part of decision-making in drug development.•Even the use of advanced strategies to adjust for confounding factors may lead to biased efficacy estimates.•Use of RWD could reduce costs, minimise patient numbers in randomised trials and supplement or confirm results from RCTs.
To evaluate the study designs and measurement instruments used to assess physical, cognitive, mental health, and quality of life outcomes of survivors of critical illness over more than 40 years old ...as a first step toward developing a core outcome set of measures for future trials to improve outcomes in ICU survivors.
Scoping review.
Published articles that included greater than or equal to one postdischarge measure of a physical, cognitive, mental health, or quality of life outcome in more than or equal to 20 survivors of critical illness published between 1970 and 2013. Instruments were classified using the World Health Organization's International Classification of Functioning, Disability, and Health framework.
ICU survivors.
None.
We reviewed 15,464 abstracts, and identified 425 eligible articles, including 31 randomized trials (7%), 116 cross-sectional studies (27%), and 278 cohort studies (65%). Cohort studies had a median (interquartile range) sample size of 96 survivors (52-209), with 38% not fully reporting loss to follow-up. A total of 250 different measurement instruments were used in these 425 articles. Among eligible articles, 25 measured physical activity limitations (6%), 40 measured cognitive activity limitations (9%), 114 measured mental health impairment (27%), 196 measured participation restriction (46%), and 276 measured quality of life (65%).
Peer-reviewed publications reporting patient outcomes after hospital discharge for ICU survivors have grown from 3 in the 1970s to more than 300 since 2000. Although there is evidence of consolidation in the instruments used for measuring participation restriction and quality of life, the ability to compare results across studies remains impaired by the 250 different instruments used. Most articles described cohort studies of modest size with a single follow-up assessment using patient-reported measures of participation restriction and quality of life. Development of a core outcome set of valid, reliable, and feasible measures is essential to improving the outcomes of critical illness survivors.
Induced pluripotent stem cell (iPSC)-derived dopaminergic (DA) neurons are an expected source for cell-based therapies for Parkinson's disease (PD). The regulatory criteria for the clinical ...application of these therapies, however, have not been established. Here we show the results of our pre-clinical study, in which we evaluate the safety and efficacy of dopaminergic progenitors (DAPs) derived from a clinical-grade human iPSC line. We confirm the characteristics of DAPs by in vitro analyses. We also verify that the DAP population include no residual undifferentiated iPSCs or early neural stem cells and have no genetic aberration in cancer-related genes. Furthermore, in vivo studies using immunodeficient mice reveal no tumorigenicity or toxicity of the cells. When the DAPs are transplanted into the striatum of 6-OHDA-lesioned rats, the animals show behavioral improvement. Based on these results, we started a clinical trial to treat PD patients in 2018.
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