Quality and transparency of evidence for implantable cardiovascular medical devices assessed by the CORE-MD consortium.

BACKGROUND AND AIMS: The European Union Medical Device Regulation 2017/745 challenges key stakeholders to follow transparent and rigorous approaches to the clinical evaluation of medical devices. The purpose of this study is a systematic evaluation of published clinical evidence underlying selected high-risk cardiovascular medical devices before and after market access in the European Union (CE-marking) between 2000 and 2021. METHODS: Pre-specified strategies were applied to identify published studies of prospective design evaluating 71 high-risk cardiovascular devices in seven different classes (bioresorbable coronary scaffolds, left atrial appendage occlusion devices, transcatheter aortic valve implantation systems, transcatheter mitral valve repair/replacement systems, surgical aortic and mitral heart valves, leadless pacemakers, subcutaneous implantable cardioverter-defibrillator). The search time span covered 20 years (2000-21). Details of study design, patient population, intervention(s), and primary outcome(s) were summarized and assessed with respect to timing of the corresponding CE-mark approval. RESULTS: At least one prospective clinical trial was identified for 70% (50/71) of the pre-specified devices. Overall, 473 reports of 308 prospectively designed studies (enrolling 97 886 individuals) were deemed eligible, including 81% (251/308) prospective non-randomized clinical trials (66 186 individuals) and 19% (57/308) randomized clinical trials (31 700 individuals). Pre-registration of the study protocol was available in 49% (150/308) studies, and 16% (48/308) had a peer-reviewed publicly available protocol. Device-related adverse events were evaluated in 82% (253/308) of studies. An outcome adjudication process was reported in 39% (120/308) of the studies. Sample size was larger for randomized in comparison to non-randomized trials (median of 304 vs. 100 individuals, P < .001). No randomized clinical trial published before CE-mark approval for any of the devices was identified. Non-randomized clinical trials were predominantly published after the corresponding CE-mark approval of the device under evaluation (89%, 224/251). Sample sizes were smaller for studies published before (median of 31 individuals) than after (median of 135 individuals) CE-mark approval (P < .001). Clinical trials with larger sample sizes (>50 individuals) and those with longer recruitment periods were more likely to be published after CE-mark approval, and were more frequent during the period 2016-21. CONCLUSIONS: The quantity and quality of publicly available data from prospective clinical investigations across selected categories of cardiovascular devices, before and after CE approval during the period 2000-21, were deemed insufficient. The majority of studies was non-randomized, with increased risk of bias, and performed in small populations without provision of power calculations, and none of the reviewed devices had randomized trial results published prior to CE-mark certification.

The impact of baseline 18F-FDG PET-CT on the management and outcome of patients with gastric cancer: a systematic review.

OBJECTIVE: CT and staging laparoscopy are routinely used to stage patients with gastric cancer, however the role of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) combined with CT (PET-CT) is uncertain. This systematic review synthesised the evidence regarding the impact of baseline PET-CT staging on treatment decisions and patient outcomes. METHODS: Systematic database searches were performed without date restriction. Studies reporting data in patients with gastric adenocarcinoma who underwent radiological staging were included. One reviewer screened titles and abstracts for suitability and two reviewers extracted data from included articles. Primary outcome was the reported change in management after PET-CT. Secondary outcomes were the rates of recurrence and overall survival between patients staged with and without PET-CT. Risk of bias was assessed using the ROBINS-I tool. PROSPERO registration (CRD42022304314). RESULTS: Data from 11 studies recruiting 2101 patients between 2012 and 2021 were included. PET-CT was performed in 1422 patients. Change of management varied between 3% and 29% of cases. No studies compared recurrence or survival rates between patients staged with or without PET-CT. Adenocarcinoma of intestinal subtype tended to be more FDG-avid compared to diffuse or signet-ring subtypes. No randomised data existed, and studies were considered low quality with high risk of bias. CONCLUSION: Evidence for the additional value of PET-CT in the gastric cancer staging pathway is limited. All studies reported a positive impact by preventing those with undetected metastatic disease on CT undergoing futile surgery. Future national guidelines should consider routine staging PET-CT in gastric cancer. ADVANCES IN KNOWLEDGE: Studies indicated that FDG PET-CT added benefit in gastric cancer staging by detecting more distant metastases, but these studies were generally of low quality and at high risk of bias. Intestinal subtype of gastric adenocarcinoma tended to be more FDG-avid and therefore more distant metastases were subsequently detected.

Risk of developing gallbladder cancer in patients with gallbladder polyps detected on transabdominal ultrasound: a systematic review and meta-analysis.

OBJECTIVE: To estimate the risk of malignancy in gallbladder polyps of incremental sizes detected during transabdominal ultrasound (TAUS). METHODS: We searched databases including MEDLINE, Embase, and Cochrane Library for eligible studies recording the polyp size from which gallbladder malignancy developed, confirmed following cholecystectomy, or by subsequent follow-up. Primary outcome was the risk of gallbladder cancer in patients with polyps. Secondary outcome was the effect of polyp size as a prognostic factor for cancer. Risk of bias was assessed using the Quality in Prognostic Factor Studies (QUIPS) tool. Bayesian meta-analysis estimated the median cancer risk according to polyp size. This study is registered with PROSPERO (CRD42020223629). RESULTS: 82 studies published since 1990 reported primary data for 67,837 patients. 67,774 gallbladder polyps and 889 cancers were reported. The cumulative median cancer risk of a polyp measuring 10 mm or less was 0.60% (99% credible range 0.30-1.16%). Substantial heterogeneity existed between studies (I2 = 99.95%, 95% credible interval 99.86-99.98%). Risk of bias was generally high and overall confidence in evidence was low. 13 studies (15.6%) were graded with very low certainty, 56 studies (68.3%) with low certainty, and 13 studies (15.6%) with moderate certainty. In studies considered moderate quality, TAUS monitoring detected 4.6 cancers per 10,000 patients with polyps less than 10 mm. CONCLUSION: Malignant risk in gallbladder polyps is low, particularly in polyps less than 10 mm, however the data are heterogenous and generally low quality. International guidelines, which have not previously modelled size data, should be informed by these findings. ADVANCES IN KNOWLEDGE: This large systematic review and meta-analysis has shown that the mean cumulative risk of small gallbladder polyps is low, but heterogeneity and missing data in larger polyp sizes (>10 mm) means the risk is uncertain and may be higher than estimated.Studies considered to have better methodological quality suggest that previous estimates of risk are likely to be inflated.

Response rate and diagnostic accuracy of early PET-CT during neo-adjuvant therapies in oesophageal adenocarcinoma: A systematic review and meta-analysis.

PURPOSE: Only 25% of oesophageal adenocarcinoma (OAC) patients have a pathological response to neo-adjuvant therapy (NAT) before oesophagectomy. Early response assessment using PET imaging may help guide management of these patients. We performed a systematic review and meta-analysis to synthesise the evidence detailing response rate and diagnostic accuracy of early PET-CT assessment. METHODS: We systematically searched several databases including MEDLINE and Embase. Studies with mixed cohorts of histology, tumour location and a repeat PET-CT assessment after more than one cycle of NAT were excluded. Reference standard was pathological response defined by Becker or Mandard classifications. Primary outcome was metabolic response rate after one cycle of NAT defined by a reduction in maximum standardised uptake value (SUVmax) of 35%. Secondary outcome was diagnostic accuracy of treatment response prediction, defined as the sensitivity and specificity of early PET-CT using this threshold. Quality of evidence was also assessed. Random-effects meta-analysis pooled response rates and diagnostic accuracy. This study was registered with PROSPERO (CRD42019147034). RESULTS: Overall, 1341 articles were screened, and 6 studies were eligible for analysis. These studies reported data for 518 patients (aged 27-78 years; 452 [87.3%] were men) between 2005 and 2020. Pooled sensitivity of early metabolic response to predict pathological response was 77.2% (95% CI 53.2%-100%). Significant heterogeneity existed between studies (I2  = 80.6% (95% CI 38.9%-93.8%), P = .006). Pooled specificity was 75.0% (95% CI 68.2%-82.5%), however, no significant heterogeneity between studies existed (I2  = 0.0% (95% CI 0.0%-67.4%), P = .73). CONCLUSION: High-quality evidence is lacking, and few studies met the inclusion criteria of this systematic review. The sensitivity of PET using a SUVmax reduction threshold of 35% was suboptimal and varied widely. However, specificity was consistent across studies with a pooled value of 75.0%, suggesting early PET assessment is a better predictor of treatment resistance than of pathological response. Further research is required to define optimal PET-guided treatment decisions in OAC.

Intravesical Bacillus Calmette-Guérin versus mitomycin C for Ta and T1 bladder cancer.

BACKGROUND: People with urothelial carcinoma of the bladder are at risk for recurrence and progression following transurethral resection of a bladder tumour (TURBT). Mitomycin C (MMC) and Bacillus Calmette-Guérin (BCG) are commonly used, competing forms of intravesical therapy for intermediate- or high-risk non-muscle invasive (Ta and T1) urothelial bladder cancer but their relative merits are somewhat uncertain. OBJECTIVES: To assess the effects of BCG intravesical therapy compared to MMC intravesical therapy for treating intermediate- and high-risk Ta and T1 bladder cancer in adults. SEARCH METHODS: We performed a systematic literature search in multiple databases (CENTRAL, MEDLINE, Embase, Web of Science, Scopus, LILACS), as well as in two clinical trial registries. We searched reference lists of relevant publications and abstract proceedings. We applied no language restrictions. The latest search was conducted in September 2019. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared intravesical BCG with intravesical MMC therapy for non-muscle invasive urothelial bladder cancer. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the literature, extracted data, assessed risk of bias and rated the quality of evidence according to GRADE per outcome. In the meta-analyses, we used the random-effects model. MAIN RESULTS: We identified 12 RCTs comparing BCG versus MMC in participants with intermediate- and high-risk non-muscle invasive bladder tumours (published from 1995 to 2013). In total, 2932 participants were randomised. Time to death from any cause: BCG may make little or no difference on time to death from any cause compared to MMC (hazard ratio (HR) 0.97, 95% confidence interval (CI) 0.79 to 1.20; participants = 1132, studies = 5; 567 participants in the BCG arm and 565 in the MMC arm; low-certainty evidence). This corresponds to 6 fewer deaths (40 fewer to 36 more) per 1000 participants treated with BCG at five years. We downgraded the certainty of the evidence two levels due to study limitations and imprecision. Serious adverse effects: 12/577 participants treated with BCG experienced serious non-fatal adverse effects compared to 4/447 participants in the MMC group. The pooled risk ratio (RR) is 2.31 (95% CI 0.82 to 6.52; participants = 1024, studies = 5; low-certainty evidence). Therefore, BCG may increase the risk for serious adverse effects compared to MMC. This corresponds to nine more serious adverse effects (one fewer to 37 more) with BCG. We downgraded the certainty of the evidence two levels due to study limitations and imprecision. Time to recurrence: BCG may reduce the time to recurrence compared to MMC (HR 0.88, 95% CI 0.71 to 1.09; participants = 2616, studies = 11, 1273 participants in the BCG arm and 1343 in the MMC arm; low-certainty evidence). This corresponds to 41 fewer recurrences (104 fewer to 29 more) with BCG at five years. We downgraded the certainty of the evidence two levels due to study limitations, imprecision and inconsistency. Time to progression: BCG may make little or no difference on time to progression compared to MMC (HR 0.96, 95% CI 0.73 to 1.26; participants = 1622, studies = 6; 804 participants in the BCG arm and 818 in the MMC arm; low-certainty evidence). This corresponds to four fewer progressions (29 fewer to 27 more) with BCG at five years. We downgraded the certainty of the evidence two levels due to study limitations and imprecision. Quality of life: we found very limited data for this outcomes and were unable to estimate an effect size. AUTHORS' CONCLUSIONS: Based on our findings, BCG may reduce the risk of recurrence over time although the Confidence Intervals include the possibility of no difference. It may have no effect on either the risk of progression or risk of death from any cause over time. BCG may cause more serious adverse events although the Confidence Intervals once again include the possibility of no difference. We were unable to determine the impact on quality of life. The certainty of the evidence was consistently low, due to concerns that include possible selection bias, performance bias, given the lack of blinding in these studies, and imprecision.

A systematic review of dose-volume predictors and constraints for late bowel toxicity following pelvic radiotherapy.

BACKGROUND: Advanced pelvic radiotherapy techniques aim to reduce late bowel toxicity which can severely impact the lives of pelvic cancer survivors. Although advanced techniques have been largely adopted worldwide, to achieve their aim, knowledge of which dose-volume parameters of which components of bowel predict late bowel toxicity is crucial to make best use of these techniques. The rectum is an extensively studied organ at risk (OAR), and dose-volume predictors of late toxicity for the rectum are established. However, for other components of bowel, there is a significant paucity of knowledge. The Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC) reviews recommend dose-volume constraints for acute bowel toxicity for peritoneal cavity and bowel loops, although no constraints are recommended for late toxicity, despite its relevance to our increasing number of survivors. This systematic review aims to examine the published literature to seek dose-volume predictors and constraints of late bowel toxicity for OARs (apart from the rectum) for use in clinical practice. METHODS: A systematic literature search was performed using Medline, Embase, Cochrane Library, Web of Science, Cinahl and Pubmed. Studies were screened and included according to specific pre-defined criteria. Included studies were assessed for quality against QUANTEC-defined assessment criteria. RESULTS: 101 studies were screened to find 30 relevant studies. Eight studies related to whole bowel, 11 to small bowel, and 21 to large bowel (including 16 of the anal canal). The anal canal is an important OAR for the development of late toxicity, and we recommend an anal canal Dmean <40Gy as a constraint to reduce late incontinence. For other components of bowel (sigmoid, large bowel, intestinal cavity, bowel loops), although individual studies found statistically significant parameters and constraints these findings were not corroborated in other studies. CONCLUSIONS: The anal canal is an important OAR for the development of late bowel toxicity symptoms. Further validation of the constraints found for other components of bowel is needed. Studies that were more conclusive included those with patient-reported data, where individual symptom scores were assessed rather than an overall score, and those that followed statistical and endpoint criteria as defined by QUANTEC.

Diagnostic accuracy of image-guided biopsies in small (<4 cm) renal masses with implications for active surveillance: a systematic review of the evidence.

OBJECTIVE:: To determine the safety and diagnostic accuracy of renal tumour biopsies in a defined population of small renal masses (SRMs) only <4 cm using 3 × 2 table, intention to diagnose approach. 3 × 2 table approach examines indeterminate results as a separate category rather than pushing these through traditional 2 × 2 table (four-cell matrix) approach. METHODS:: A highly sensitive search was performed in the Cochrane Library, Database of Abstracts of Reviews of Effects; MEDLINE and MEDLINE in Process, EMBASE and conference proceedings (1966-2016) for the acquisition of data on the diagnostic accuracy and complications of RTB in patients with SRM <4 cm. Methodological quality and risk of bias was assessed using QUADAS-2. Test characteristics were calculated using conventional 2 × 2 contingency table analysis excluding non-diagnostic biopsies, and an intention-to-diagnose approach with a 3 × 2 table for pooled estimates of the sensitivity and specificity. RESULTS:: A total of 20 studies were included with a total sample size of 974. The pooled estimates for sensitivity and specificity of RTB based upon univariate analysis using 2 × 2 table observed sensitivity 0.952 [confidence interval (CI) 0.908-0.979] and specificity 0.824 (CI 0.566-0.962). Using the 3 × 2 table and intention-to-diagnose principle, sensitivity 0.947 (CI 0.925-0.965) and specificity 0.609 (CI 0.385-0.803) decreased. CONCLUSION:: RTB in SRMs (<4 cm) is associated with a high diagnostic sensitivity but poor specificity when non-diagnostic results are included by a 3 × 2 table for analysis (intention to diagnose approach). Risk of non-diagnostic results and poor quality of research need addressing through future studies, preferably by a well-designed prospective study appropriately powered for diagnostic accuracy using valid reference standards. ADVANCES IN KNOWLEDGE:: A comprehensive synthesis of literature on image-guided biopsies in SRMs using a different methodology and study design.

Primary cryotherapy for localised or locally advanced prostate cancer.

BACKGROUND: Traditionally, radical prostatectomy and radiotherapy with or without androgen deprivation therapy have been the main treatment options to attempt to cure men with localised or locally advanced prostate cancer. Cryotherapy is an alternative option for treatment of prostate cancer that involves freezing of the whole prostate (whole gland therapy) or only the cancer (focal therapy), but it is unclear how effective this is in comparison to other treatments. OBJECTIVES: To assess the effects of cryotherapy (whole gland or focal) compared with other interventions for primary treatment of clinically localised (cT1-T2) or locally-advanced (cT3) non-metastatic prostate cancer. SEARCH METHODS: We updated a previously published Cochrane Review by performing a comprehensive search of multiple databases (CENTRAL, MEDLINE, EMBASE), clinical trial registries (ClinicalTrials.gov, World Health Organization International Clinical Trials Registry Platform) and a grey literature repository (Grey Literature Report) up to 6 March 2018. We also searched the reference lists of other relevant publications and conference proceedings. We applied no language restrictions. SELECTION CRITERIA: We included randomised or quasi-randomised trials comparing cryotherapy to other interventions for the primary treatment of prostate cancer. DATA COLLECTION AND ANALYSIS: Two independent reviewers screened the literature, extracted data, and assessed risk of bias. We performed statistical analyses using a random-effects model and interpreted them according to the Cochrane Handbook for Systematic Reviews of Interventions. We rated the quality of evidence (QoE) according to the GRADE approach. MAIN RESULTS: We included only one comparison of whole gland cryotherapy versus external beam radiotherapy, which was informed by two trials with a total of 307 randomised participants. The median age of the included studies was around 70 years. The median follow-up of included studies ranged from 100 to 105 months.Primary outcomes: we are uncertain about the effect of whole gland cryotherapy compared to radiation therapy on time to death from prostate cancer; hazard ratio (HR) of 1.00 (95% confidence interval (CI) 0.11 to 9.45; 2 trials, 293 participants; very low QoE); this would correspond to zero fewer death from prostate cancer per 1000 men (95% CI 85 fewer to 520 more). We are equally uncertain about the effect of quality of life-related urinary function and bowel function (QoL) at 36 months using the UCLA-Prostate Cancer Index score for which higher values (range: 0 to 100) reflect better quality of life using minimal clinically important differences (MCID) of 8 and 7 points, respectively; mean difference (MD) of 4.4 (95% CI -6.5 to 15.3) and 4.0 (95% CI -73.96 to 81.96), respectively (1 trial, 195 participants; very low QoE). We are also uncertain about sexual function-related QoL using a MCID of 8 points; MD of -20.7 (95% CI -36.29 to -5.11; 1 trial, 195 participants; very low QoE). Lastly, we are uncertain of the risk for major adverse events; risk ratio (RR): 0.91 (95% CI 0.47 to 1.78; 2 trials, 293 participants; very low QoE); this corresponds to 10 fewer major adverse events per 1000 men (95% CI 58 fewer to 86 more). SECONDARY OUTCOMES: we are very uncertain about the effects of cryotherapy on time to death from any cause (HR 0.99, 95% CI 0.05 to 18.79; 2 trials, 293 participants; very low QoE), and time to biochemical failure (HR 2.15, 95% CI 0.07 to 62.12; 2 trials, 293 participants; very low QoE). Rates of secondary interventions for treatment failure and minor adverse events were either not reported in the trials, or the data could not be used for analyses.We found no trials that compared whole gland cryotherapy or focal cryotherapy to other treatment forms such as radical surgery, active surveillance, watchful waiting or other forms of radiotherapy. AUTHORS' CONCLUSIONS: Based on very low quality evidence, primary whole gland cryotherapy has uncertain effects on oncologic outcomes, QoL, and major adverse events compared to external beam radiotherapy. Reasons for downgrading the QoE included serious study limitations, indirectness due to the use of lower doses of radiation in the comparison group than currently recommended, and serious or very serious imprecision.

WITHDRAWN: Systemic treatments for metastatic cutaneous melanoma.

BACKGROUND: Systemic therapies for metastatic cutaneous melanoma, the most aggressive of all skin cancers, remain disappointing. Few lasting remissions are achieved and the therapeutic aim remains one of palliation.Many agents are used alone or in combination with varying degrees of toxicity and cost. It is unclear whether evidence exists to support these complex regimens over best supportive care / placebo. OBJECTIVES: To review the benefits from the use of systemic therapies in metastatic cutaneous melanoma compared to best supportive care/placebo, and to establish whether a 'standard' therapy exists which is superior to other treatments. SEARCH METHODS: Randomised controlled trials were identified from the MEDLINE, EMBASE and CCTR/CENTRAL databases. References, conference proceedings, and Science Citation Index/Scisearch were also used to locate trials. Cancer registries and trialists were also contacted. SELECTION CRITERIA: Randomised controlled trials of adults with histologically proven metastatic cutaneous melanoma in which systemic anti-cancer therapy was compared with placebo or supportive care. DATA COLLECTION AND ANALYSIS: Study selection was performed by two independent reviewers. Data extraction forms were used for studies which appeared to meet the selection criteria and, where appropriate, full text articles were retrieved and reviewed independently. MAIN RESULTS: No randomised controlled trials were found comparing a systemic therapy with placebo or best supportive care in metastatic cutaneous melanoma. AUTHORS' CONCLUSIONS: There is no evidence from randomised controlled clinical trials to show superiority of systemic therapy over best supportive care / placebo in the treatment of malignant cutaneous melanoma.Given that patients with metastatic melanoma frequently receive systemic therapy, it is our pragmatic view that a future systematic review could compare any systemic treatment, or combination of treatments, to single agent dacarbazine.

Outcomes of non-invasive diagnostic modalities for the detection of coronary artery disease: network meta-analysis of diagnostic randomised controlled trials.

OBJECTIVE: To evaluate differences in downstream testing, coronary revascularisation, and clinical outcomes following non-invasive diagnostic modalities used to detect coronary artery disease. DESIGN: Systematic review and network meta-analysis. DATA SOURCES: Medline, Medline in process, Embase, Cochrane Library for clinical trials, PubMed, Web of Science, SCOPUS, WHO International Clinical Trials Registry Platform, and Clinicaltrials.gov. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Diagnostic randomised controlled trials comparing non-invasive diagnostic modalities in patients presenting with symptoms suggestive of low risk acute coronary syndrome or stable coronary artery disease. DATA SYNTHESIS: A random effects network meta-analysis synthesised available evidence from trials evaluating the effect of non-invasive diagnostic modalities on downstream testing and patient oriented outcomes in patients with suspected coronary artery disease. Modalities included exercise electrocardiograms, stress echocardiography, single photon emission computed tomography-myocardial perfusion imaging, real time myocardial contrast echocardiography, coronary computed tomographic angiography, and cardiovascular magnetic resonance. Unpublished outcome data were obtained from 11 trials. RESULTS: 18 trials of patients with low risk acute coronary syndrome (n=11 329) and 12 trials of those with suspected stable coronary artery disease (n=22 062) were included. Among patients with low risk acute coronary syndrome, stress echocardiography, cardiovascular magnetic resonance, and exercise electrocardiograms resulted in fewer invasive referrals for coronary angiography than coronary computed tomographic angiography (odds ratio 0.28 (95% confidence interval 0.14 to 0.57), 0.32 (0.15 to 0.71), and 0.53 (0.28 to 1.00), respectively). There was no effect on the subsequent risk of myocardial infarction, but estimates were imprecise. Heterogeneity and inconsistency were low. In patients with suspected stable coronary artery disease, an initial diagnostic strategy of stress echocardiography or single photon emission computed tomography-myocardial perfusion imaging resulted in fewer downstream tests than coronary computed tomographic angiography (0.24 (0.08 to 0.74) and 0.57 (0.37 to 0.87), respectively). However, exercise electrocardiograms yielded the highest downstream testing rate. Estimates for death and myocardial infarction were imprecise without clear discrimination between strategies. CONCLUSIONS: For patients with low risk acute coronary syndrome, an initial diagnostic strategy of stress echocardiography or cardiovascular magnetic resonance is associated with fewer referrals for invasive coronary angiography and revascularisation procedures than non-invasive anatomical testing, without apparent impact on the future risk of myocardial infarction. For suspected stable coronary artery disease, there was no clear discrimination between diagnostic strategies regarding the subsequent need for invasive coronary angiography, and differences in the risk of myocardial infarction cannot be ruled out. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registry no CRD42016049442.

Alvimopan for recovery of bowel function after radical cystectomy.

BACKGROUND: Alvimopan is used in abdominal surgery to reduce postoperative ileus in patients undergoing small bowel resections with primary anastomosis. The role and efficacy of alvimopan in patients undergoing radical cystectomy with urinary diversion is not well understood. OBJECTIVES: To assess the effects of alvimopan in the context of enhanced recovery pathways compared to enhanced recovery pathways alone for perioperative bowel dysfunction in patients undergoing radical cystectomy. SEARCH METHODS: The terms alvimopan and cystectomy were used to search the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase. We also reviewed abstracts from the past four years (2013 to 2016) of the American Urologic Association, Society of Urologic Oncology, and American Society of Clinical Oncology Genitourinary Cancers. SELECTION CRITERIA: We searched for randomized controlled trials that compared alvimopan to placebo. DATA COLLECTION AND ANALYSIS: This study was based on a published protocol. We performed a comprehensive search of multiple databases including CENTRAL in the Cochrane Library, MEDLINE, Embase, LILACS, Web of Science, Scopus and Biosis, which we last updated on 6 February 2017. We also searched abstract proceedings for major relevant meetings (2013 to 2016), databases of the grey literature, trial registries, citations of relevant reviews and contacted clinical experts and the drug manufacturer.Two independent reviewers screened the literature in two stages (title and abstract, full-text) using Covidence software. Two independent reviewers assessed the risk of bias on a 'per outcome' basis using the Cochrane 'Risk of bias; tool and rated the quality of evidence according to GRADE. Results of the single eligible trial were reported in a 'Summary of findings' table based on an intention-to-treat analysis. MAIN RESULTS: Based on a single trial and moderate-quality evidence, alvimopan reduced the time to reach a composite endpoint of tolerance of solid food and documented bowel movements (hazard ratio (HR) 1.77, 95% confidence interval (CI) 1.41 to 2.23). This represents 165 more patients (109 more to 207 more) per 1000 meeting this endpoint within 10 days of surgery. Based on moderate-quality evidence, alvimopan reduced the time to hospital discharge (HR 1.67, 95% CI 1.38 to 2.01). This represents 138 more patients (82 more to 198 more) per 1000 being discharged within 10 days of surgery. Also based on moderate-quality evidence, alvimopan was associated with a reduced risk of major adverse events (risk ratio (RR) 0.28, 95% CI 0.18 to 0.44) representing 355 fewer patients (404 fewer to 276 fewer) with major adverse events per 1000. We downgraded this outcome for indirectness as it included adverse events that we did not consider major.In terms of secondary outcomes, alvimopan did not appear to alter the rate of readmission (RR 0.89, 95% CI 0.59 to 1.33), change the rate of any cardiovascular event (RR 0.54, 95% CI 0.27 to 1.05) or alter the mean narcotic pain medication use (mean difference 0, 95% CI 14.08 fewer to 14.08 more morphine equivalents). The quality of evidence was moderate for all three outcomes. Based on high-quality evidence, alvimopan reduced the rate of nasogastric tube replacement (RR 0.31, 95% CI 0.16 to 0.59). We did not find evidence for the drug's impact on rates of parenteral nutrition. All outcomes were short term and limited to a 30-day time horizon.Based on the existence of only one trial, we were unable to perform any subgroup or sensitivity analyses. AUTHORS' CONCLUSIONS: In patients undergoing radical cystectomy and urinary diversion, the use of alvimopan administered as part of an enhanced recovery pathway for a limited duration (up to 15 doses for up to seven days) probably reduces the time to tolerance of solid food, time to hospital discharge and rates of major adverse events. Readmission rates, rates of cardiovascular events and narcotic pain requirements are probably similar. The need for reinsertion of nasogastric tubes is reduced. We found no evidence for the impact on rates of parenteral nutrition within 30 postoperative days.

Update on Neoadjuvant Regimens for Patients with Operable Oesophageal/Gastrooesophageal Junction Adenocarcinomas and Squamous Cell Carcinomas.

Survival outcomes following multimodal treatment of operable oesophageal and gastrooesophageal cancer remain disappointingly poor. Although an appreciation of the impact of both tumour location and histological subtype is now shaping the design of clinical trials, there has been a lack of consensus of the optimal neoadjuvant treatment strategy. This update article will review recent advances in the use of both neoadjuvant chemotherapy and chemoradiotherapy. The emerging role of PET imaging to direct appropriate neoadjuvant treatment regimens and the additive benefit of biological agents are also discussed.

Education and training to enhance end-of-life care for nursing home staff: a systematic literature review.

BACKGROUND: The delivery of end-of-life care in nursing homes is challenging. This situation is of concern as 20% of the population die in this setting. Commonly reported reasons include limited access to medical care, inadequate clinical leadership and poor communication between nursing home and medical staff. Education for nursing home staff is suggested as the most important way of overcoming these obstacles. OBJECTIVES: To identify educational interventions to enhance end-of-life care for nursing home staff and to identify types of study designs and outcomes to indicate success and benchmark interventions against recent international guidelines for education for palliative and end-of-life care. DESIGN: Thirteen databases and reference lists of key journals were searched from the inception of each up to September 2014. Included studies were appraised for quality and data were synthesised thematically. RESULTS: Twenty-one studies were reviewed. Methodological quality was poor. Education was not of a standard that could be expected to alter clinical behaviour and was evaluated mainly from the perspectives of staff: self-reported increase in knowledge, skills and confidence delivering care rather than direct evidence of impact on clinical practice and patient outcomes. Follow-up was often short term, and despite sound economic arguments for delivering effective end-of-life care to reduce burden on the health service, no economic analyses were reported. CONCLUSIONS: There is a clear and urgent need to design educational interventions that have the potential to improve end-of-life care in nursing homes. Robust evaluation of these interventions should include impact on residents, families and staff and include economic analysis.

Palliative radiotherapy regimens for patients with thoracic symptoms from non-small cell lung cancer.

BACKGROUND: Palliative radiotherapy to the chest is often used in patients with lung cancer, but radiotherapy regimens are more often based on tradition than research results. This is an update of a Cochrane review first published in 2001 and previously updated in 2006. OBJECTIVES: The two objectives of this review were:1. To assess the effects of different palliative radiotherapy regimens on improving thoracic symptoms in patients with locally advanced or metastatic non-small cell lung cancer who are not suitable for radical RT given with curative intent.2. To assess the effects of radiotherapy dose on overall survival in patients with locally advanced or metastatic non-small cell lung cancer who are not suitable for radical RT given with curative intent. SEARCH METHODS: The electronic databases MEDLINE (1966 - Jan 2014), EMBASE and the Cochrane Central Register of Controlled Trials, reference lists, handsearching of journals and conference proceedings, and discussion with experts were used to identify potentially eligible trials, published and unpublished.Two authors (FM and RS) independently identified all studies that may be suitable for inclusion in the review.We updated the search up to January 2014. SELECTION CRITERIA: Randomised controlled clinical trials comparing different regimens of palliative thoracic radiotherapy in patients with non-small cell lung cancer. DATA COLLECTION AND ANALYSIS: The reviewers assessed search results independently and possible studies were highlighted and the full text obtained. Data were extracted and attempts were made to contact the original authors for missing information.The primary outcome measure was improvement in major thoracic symptoms (degree and duration). Secondary outcome measures were short and long term toxicities, effect on quality of life and overall survival.Patient reported outcomes were reported descriptively. Quantitative data such as survival and toxicity were analysed as dichotomous variables and reported using relative risks (RR).For this update of the review a meta-analysis of the survival data was carried out. MAIN RESULTS: Fourteen randomised controlled trials (3576 patients) were included, with no new studies added in this update.There were important differences in the doses of radiotherapy investigated, the patient characteristics including disease stage and performance status and the outcome measures.The doses of RT investigated ranged from 10 Gy in 1 fraction (10Gy/1F) to 60 Gy/30F over six weeks, with a total of 19 different dose/ fractionation regimens.Potential biases were identified in some studies. Methods of randomisation, assessment of symptoms and statistical methods used were unclear in some papers. Withdrawal and drop-outs were accounted for in all but one study.All 13 studies that investigated symptoms reported that major thoracic symptoms improved following RT.There is no strong evidence that any regimen gives greater palliation. Higher dose regimens may give more acute toxicity and some regimens are associated with an increased risk of radiation myelitis. Variation in reporting of toxicities, in particular the absence of clear grading, means results of the meta-analysis should be treated with caution.Meta-analysis of overall survival broken down by performance status, a key variable, is included in this update. Further information was sought from all the original authors if stratified data was not included in the original publication. Three published studies contained sufficient data and seven authors were able to provide further information which represented 1992 patients (56% of all patients). The absence of data for nearly half of the patients has affected the quality of evidence.The meta-analysis showed no significant difference in 1-year overall survival between regimens with fewer radiotherapy fractions compared with regimens with more when patients were stratified by performance status. The results of the meta-analysis of 1-year overall survival for patients with good performance status (WHO performance status 0-1) showed moderately high heterogeneity and a summary result was not thought meaningful. The results of 1-year overall survival for patients with poor performance status was RR 0.96 (95% CI 0.91 to 1.02; moderate quality of evidence). AUTHORS' CONCLUSIONS: Radiotherapy for patients with incurable non-small cell lung cancer can improve thoracic symptoms. Care should be taken with the dose to the spinal cord to reduce the risk of radiation myelopathy. The higher dose, more fractionated palliative radiotherapy regimens do not provide better or more durable palliation and their use to prolong survival is not supported by strong evidence. More research is needed into reducing the acute toxicity of large fraction regimens and into the role of radical compared to high dose palliative radiotherapy. In the future, large trials comparing different RT regimens may be difficult to set up because of the increasing use of systemic chemotherapy. Trials looking at how best to integrate these two modalities, particularly in good PS patients, need to be carried out.

Should we involve terminally ill patients in teaching medical students? A systematic review of patient's views.

OBJECTIVE: To review available published research that has explored how terminally ill patients feel about being involved in undergraduate medical teaching. METHODS: A systematic review using narrative synthesis. Qualitative or quantitative publications were included if they directly explored the views of adult patients, with a terminal diagnosis, about their involvement in undergraduate clinical teaching. RESULTS: Seven publications met the inclusion criteria: one case report, one qualitative study and five questionnaire-based studies. A total of 269 patients were included across all studies. Patients were predominantly studied in a hospice or hospice day care setting. Both patients who had, and who had not, previously been involved in student teaching were captured by the included publications. In general, the views of patients were highly positive: overall 85%-100% were in favour of involvement in teaching. There were also some negative aspects, such as: concerns about being physically examined by a student; finding involvement in teaching tiring; feeling unable to decline consent to participate. CONCLUSIONS: An assumption that clinical undergraduate medical teaching involving terminally ill patients may be too burdensome is not reflected overall in studies that have sought the views of the patients themselves. Understanding the patient's perspective provides a number of practical points in relation to how clinical teaching should be adapted in this patient group; for example, using smaller student group sizes; direct supervision if physical examination performed; short encounters with multiple patients rather than a longer encounter with one patient; adequate informed consent beforehand and without the students automatically being present.

The assessment and impact of sarcopenia in lung cancer: a systematic literature review.

OBJECTIVES: There is growing awareness of the relationship between sarcopenia (loss of muscle mass and function), and outcomes in cancer, making it a potential target for future therapies. In order to inform future research and practice, we undertook a systematic review of factors associated with loss of muscle mass, and the relationship between muscle function and muscle mass in lung cancer, a common condition associated with poor outcomes. DESIGN: We conducted a computerised systematic literature search on five databases. Studies were included if they explored muscle mass as an outcome measure in patients with lung cancer, and were published in English. SETTING: Secondary care. PARTICIPANTS: Patients with lung cancer. PRIMARY OUTCOME: Factors associated with loss of muscle mass and muscle function, or sarcopenia, and the clinical impact thereof in patients with lung cancer. RESULTS: We reviewed 5726 citations, and 35 articles were selected for analysis. Sarcopenia, as defined by reduced muscle mass alone, was found to be very prevalent in patients with lung cancer, regardless of body mass index, and where present was associated with poorer functional status and overall survival. There were diverse studies exploring molecular and metabolic factors in the development of loss of muscle mass; however, the precise mechanisms that contribute to sarcopenia and cachexia remain uncertain. The effect of nutritional supplements and ATP infusions on muscle mass showed conflicting results. There are very limited data on the correlation between degree of sarcopenia and muscle function, which has a non-linear relationship in older non-cancer populations. CONCLUSIONS: Loss of muscle mass is a significant contributor to morbidity in patients with lung cancer. Loss of muscle mass and function may predate clinically overt cachexia, underlining the importance of evaluating sarcopenia, rather than weight loss alone. Understanding this relationship and its associated factors will provide opportunities for focused intervention to improve clinical outcomes.

Methodological developments in searching for studies for systematic reviews: past, present and future?

The Cochrane Collaboration was established in 1993, following the opening of the UK Cochrane Centre in 1992, at a time when searching for studies for inclusion in systematic reviews was not well-developed. Review authors largely conducted their own searches or depended on medical librarians, who often possessed limited awareness and experience of systematic reviews. Guidance on the conduct and reporting of searches was limited. When work began to identify reports of randomized controlled trials (RCTs) for inclusion in Cochrane Reviews in 1992, there were only approximately 20,000 reports indexed as RCTs in MEDLINE and none indexed as RCTs in Embase. No search filters had been developed with the aim of identifying all RCTs in MEDLINE or other major databases. This presented The Cochrane Collaboration with a considerable challenge in identifying relevant studies.Over time, the number of studies indexed as RCTs in the major databases has grown considerably and the Cochrane Central Register of Controlled Trials (CENTRAL) has become the best single source of published controlled trials, with approximately 700,000 records, including records identified by the Collaboration from Embase and MEDLINE. Search filters for various study types, including systematic reviews and the Cochrane Highly Sensitive Search Strategies for RCTs, have been developed. There have been considerable advances in the evidence base for methodological aspects of information retrieval. The Cochrane Handbook for Systematic Reviews of Interventions now provides detailed guidance on the conduct and reporting of searches. Initiatives across The Cochrane Collaboration to improve the quality inter alia of information retrieval include: the recently introduced Methodological Expectations for Cochrane Intervention Reviews (MECIR) programme, which stipulates 'mandatory' and 'highly desirable' standards for various aspects of review conduct and reporting including searching, the development of Standard Training Materials for Cochrane Reviews and work on peer review of electronic search strategies. Almost all Cochrane Review Groups and some Cochrane Centres and Fields now have a Trials Search Co-ordinator responsible for study identification and medical librarians and other information specialists are increasingly experienced in searching for studies for systematic reviews.Prospective registration of clinical trials is increasing and searching trials registers is now mandatory for Cochrane Reviews, where relevant. Portals such as the WHO International Clinical Trials Registry Platform (ICTRP) are likely to become increasingly attractive, given concerns about the number of trials which may not be registered and/or published. The importance of access to information from regulatory and reimbursement agencies is likely to increase. Cross-database searching, gateways or portals and improved access to full-text databases will impact on how searches are conducted and reported, as will services such as Google Scholar, Scopus and Web of Science. Technologies such as textual analysis, semantic analysis, text mining and data linkage will have a major impact on the search process but efficient and effective updating of reviews may remain a challenge.In twenty years' time, we envisage that the impact of universal social networking, as well as national and international legislation, will mean that all trials involving humans will be registered at inception and detailed trial results will be routinely available to all. Challenges will remain, however, to ensure the discoverability of relevant information in diverse and often complex sources and the availability of metadata to provide the most efficient access to information. We envisage an ongoing role for information professionals as experts in identifying new resources, researching efficient ways to link or mine them for relevant data and managing their content for the efficient production of systematic reviews.