Can extranodal tumour deposits be diagnosed on MRI? Protocol for a multicentre clinical trial (the COMET trial)

IntroductionTumour deposits (TDs) are a poor prognostic marker when seen on pathology, and are worse than lymph node metastases (LNMs). They are now being reported on MRI as discontinuous nodules of extramural venous invasion but this diagnosis has not been validated and it is unclear how it correlates with the diagnosis of TDs on pathology.Methods and analysisThis is a prospective interventional clinical trial which aims to directly map the location of TDs on MRI and correlate what is seen on MRI with the pathology findings at each location. All patients with rectal cancer undergoing resectional surgery are eligible (including those undergoing preoperative therapy). The primary outcome is the prevalence of TDs seen on pathology. Secondary outcomes are to assess radiological and pathological interobserver agreement, assess the effect of TDs on prognosis and carry out exploratory work looking at differences between TDs and LNMs. The estimated sample size is 100 to detect a twofold increase in the pathological diagnosis of TD when MRI mapping is used.Ethics and disseminationEthical approval has been granted from the South Central—Hampshire B Research and Ethics Committee (IRAS 217627). The study will be carried out under standard operative procedures within the Royal Marsden Hospital.Trial registration numberNCT03303547.

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Interobserver variation in the classification of tumor deposits in rectal cancer—is the use of histopathological characteristics the way to go?

Virchows Archiv ◽

10.1007/s00428-021-03197-0 ◽

2021 ◽

Author(s):

Nelleke P. M. Brouwer ◽

A. C. Lord ◽

M. Terlizzo ◽

A. C. Bateman ◽

N. P. West ◽

...

Keyword(s):

Colorectal Cancer ◽

Rectal Cancer ◽

Lymph Node ◽

Perineural Invasion ◽

Interobserver Agreement ◽

Binary Classification ◽

Venous Invasion ◽

Interobserver Variation ◽

Node Metastases

Abstract The focus on lymph node metastases (LNM) as the most important prognostic marker in colorectal cancer (CRC) has been challenged by the finding that other types of locoregional spread, including tumor deposits (TDs), extramural venous invasion (EMVI), and perineural invasion (PNI), also have significant impact. However, there are concerns about interobserver variation when differentiating between these features. Therefore, this study analyzed interobserver agreement between pathologists when assessing routine tumor nodules based on TNM 8. Electronic slides of 50 tumor nodules that were not treated with neoadjuvant therapy were reviewed by 8 gastrointestinal pathologists. They were asked to classify each nodule as TD, LNM, EMVI, or PNI, and to list which histological discriminatory features were present. There was overall agreement of 73.5% (κ 0.38, 95%-CI 0.33–0.43) if a nodal versus non-nodal classification was used, and 52.2% (κ 0.27, 95%-CI 0.23–0.31) if EMVI and PNI were classified separately. The interobserver agreement varied significantly between discriminatory features from κ 0.64 (95%-CI 0.58–0.70) for roundness to κ 0.26 (95%-CI 0.12–0.41) for a lone arteriole sign, and the presence of discriminatory features did not always correlate with the final classification. Since extranodal pathways of spread are prognostically relevant, classification of tumor nodules is important. There is currently no evidence for the prognostic relevance of the origin of TD, and although some histopathological characteristics showed good interobserver agreement, these are often non-specific. To optimize interobserver agreement, we recommend a binary classification of nodal versus extranodal tumor nodules which is based on prognostic evidence and yields good overall agreement.

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Prematurity detection evaluating interaction between the skin of the newborn and light: protocol for the preemie-test multicentre clinical trial in Brazilian hospitals to validate a new medical device

BMJ Open ◽

10.1136/bmjopen-2018-027442 ◽

2019 ◽

Vol 9 (3) ◽

pp. e027442 ◽

Cited By ~ 1

Author(s):

Zilma Silveira Nogueira Reis ◽

Rodney Nascimento Guimarães ◽

Maria Albertina Santiago Rego ◽

Roberta Maia de Castro Romanelli ◽

Juliano de Souza Gaspar ◽

...

Keyword(s):

Clinical Trial ◽

Medical Device ◽

Primary Outcome ◽

Skin Reflectance ◽

Registration Number ◽

Neonatal Skin ◽

The Difference ◽

Nested Case Control ◽

Lung Maturity ◽

Control Study

IntroductionRecognising prematurity is critical in order to attend to immediate needs in childbirth settings, guiding the extent of medical care provided for newborns. A new medical device has been developed to carry out the preemie-test, an innovative approach to estimate gestational age (GA), based on the photobiological properties of the newborn’s skin. First, this study will validate the preemie-test for GA estimation at birth and its accuracy to detect prematurity. Second, the study intends to associate the infant’s skin reflectance with lung maturity, as well as evaluate safety, precision and usability of a new medical device to offer a suitable product for health professionals during childbirth and in neonatal care settings.Methods and analysisResearch protocol for diagnosis, singlegroup, singleblinding and singlearm multicenter clinical trial with a reference standard. Alive newborns, with 24 weeks or more of pregnancy age, will be enrolled during the first 24 hours of life. Sample size is 787 subjects. The primary outcome is the difference between the GA calculated by the photobiological neonatal skin assessment methodology and the GA calculated by the comparator antenatal ultrasound or reliable last menstrual period (LMP). Immediate complications caused by pulmonary immaturity during the first 72 hours of life will be associated with skin reflectance in a nested case–control study.Ethics and disseminationEach local independent ethics review board approved the trial protocol. The authors intend to share the minimal anonymised dataset necessary to replicate study findings.Trial registration numberRBR-3f5bm5.

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Effect of cardiosphere-derived cells on segmental myocardial function after myocardial infarction: ALLSTAR randomised clinical trial

Open Heart ◽

10.1136/openhrt-2021-001614 ◽

2021 ◽

Vol 8 (2) ◽

pp. e001614

Author(s):

Mohammad R Ostovaneh ◽

Raj R Makkar ◽

Bharath Ambale-Venkatesh ◽

Deborah Ascheim ◽

Tarun Chakravarty ◽

...

Keyword(s):

Myocardial Infarction ◽

Clinical Trial ◽

Myocardial Function ◽

Randomised Clinical Trial ◽

Scar Tissue ◽

Left Ventricular ◽

Lv Function ◽

Cardiac Events ◽

Lv Dysfunction ◽

Registration Number

BackgroundMost cell therapy trials failed to show an improvement in global left ventricular (LV) function measures after myocardial infarction (MI). Myocardial segments are heterogeneously impacted by MI. Global LV function indices are not able to detect the small treatment effects on segmental myocardial function which may have prognostic implications for cardiac events. We aimed to test the efficacy of allogeneic cardiosphere-derived cells (CDCs) for improving regional myocardial function and contractility.MethodsIn this exploratory analysis of a randomised clinical trial, 142 patients with post-MI with LVEF <45% and 15% or greater LV scar size were randomised in 2:1 ratio to receive intracoronary infusion of allogenic CDCs or placebo, respectively. Change in segmental myocardial circumferential strain (Ecc) by MRI from baseline to 6 months was compared between CDCs and placebo groups.ResultsIn total, 124 patients completed the 6-month follow-up (mean (SD) age 54.3 (10.8) and 108 (87.1%) men). Segmental Ecc improvement was significantly greater in patients receiving CDC (−0.5% (4.0)) compared with placebo (0.2% (3.7), p=0.05). The greatest benefit for improvement in segmental Ecc was observed in segments containing scar tissue (change in segmental Ecc of −0.7% (3.5) in patients receiving CDC vs 0.04% (3.7) in the placebo group, p=0.04).ConclusionsIn patients with post-MI LV dysfunction, CDC administration resulted in improved segmental myocardial function. Our findings highlight the importance of segmental myocardial function indices as an endpoint in future clinical trials of patients with post-MI.Trial registration numberNCT01458405.

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Assessment of automated clinical trial recruitment and enrolment using patient-facing technology

BMJ Health & Care Informatics ◽

10.1136/bmjhci-2019-100076 ◽

2021 ◽

Vol 28 (1) ◽

pp. e100076

Author(s):

Naomi S Bardach ◽

Regina Lam ◽

Carolyn B Jasik

Keyword(s):

Clinical Trial ◽

Patient Characteristics ◽

Electronic Signature ◽

Study Materials ◽

Study Staff ◽

Surgical Units ◽

Study Implementation ◽

Registration Number ◽

Care Systems ◽

Group Comparisons

ObjectiveInteractive patient care systems (IPCS) at the bedside are becoming increasingly common, but evidence is limited as to their potential for innovative clinical trial implementation. The objective of this study was to test the hypothesis that the IPCS could feasibly be used to automate recruitment and enrolment for a clinical trial.MethodsIn medical-surgical units, we used the IPCS to randomise, recruit and consent eligible subjects. For participants not interacting with IPCS study materials within 48 hours, study staff-initiated recruitment in-person. Eligible study population included all caregivers and any patients >6 years old admitted to medical-surgical units and oncology units September 2015 to January 2016. Outcomes: randomisation assessed using between-group comparisons of patient characteristics; recruitment success assessed by rates of consent; paperless implementation using successful acquisition of electronic signature and email address. We used χ2 analysis to assess success of randomisation and recruitment.ResultsRandomisation was successful (n=1012 randomised, p>0.05 for all between-group comparisons). For the subset of eligible, randomised patients who were recruited, IPCS-only recruitment (consented: 2.4% of n=213) was less successful than in-person recruitment (61.4% of n=87 eligible recruited, p<0.001). For those consenting (n=61), 96.7% provided an electronic signature and 68.9% provided email addresses.ConclusionsOur results suggest that as a tool at the bedside, the IPCS offers key efficiencies for study implementation, including randomisation and collecting e-consent and contact information, but does not offer recruitment efficiencies. Further research could assess the value that interactive technologies bring to recruitment when paired with in-person efforts, potentially focusing on more intensive user-interface testing for recruitment materials.Trial registration numberNCT02491190.

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Hypotension in Preterm Infants (HIP) randomised trial

Archives of Disease in Childhood - Fetal and Neonatal Edition ◽

10.1136/archdischild-2020-320241 ◽

2021 ◽

pp. fetalneonatal-2020-320241

Author(s):

Eugene M Dempsey ◽

Keith J Barrington ◽

Neil Marlow ◽

Colm Patrick Finbarr O'Donnell ◽

Jan Miletin ◽

...

Keyword(s):

Brain Injury ◽

Primary Outcome ◽

Randomised Trial ◽

Intraventricular Haemorrhage ◽

Standard Group ◽

Double Blind ◽

Group Assignment ◽

Standard Management ◽

Postmenstrual Age ◽

Registration Number

ObjectiveTo determine whether restricting the use of inotrope after diagnosis of low blood pressure (BP) in the first 72 hours of life affects survival without significant brain injury at 36 weeks of postmenstrual age (PMA) in infants born before 28 weeks of gestation.DesignDouble-blind, placebo-controlled randomised trial. Caregivers were masked to group assignment.Setting10 sites across Europe and Canada.ParticipantsInfants born before 28 weeks of gestation were eligible if they had an invasive mean BP less than their gestational age that persisted for ≥15 min in the first 72 hours of life and a cerebral ultrasound free of significant (≥ grade 3) intraventricular haemorrhage.InterventionParticipants were randomly assigned to saline bolus followed by either a dopamine infusion (standard management) or placebo (5% dextrose) infusion (restrictive management).Primary outcomeSurvival to 36 weeks of PMA without severe brain injury.ResultsThe trial terminated early due to significant enrolment issues (7.7% of planned recruitment). 58 infants were enrolled between February 2015 and September 2017. The two groups were well matched for baseline variables. In the standard group, 18/29 (62%) achieved the primary outcome compared with 20/29 (69%) in the restrictive group (p=0.58). Additional treatments for low BP were used less frequently in the standard arm (11/29 (38%) vs 19/29 (66%), p=0.038).ConclusionThough this study lacked power, we did not detect major differences in clinical outcomes between standard or restrictive approach to treatment. These results will inform future studies in this area.Trial registration numberNCT01482559, EudraCT 2010-023988-17.

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Protocol for a randomised clinical trial of multimodal postconcussion symptom treatment and recovery: the Concussion Essentials study

BMJ Open ◽

10.1136/bmjopen-2020-041458 ◽

2021 ◽

Vol 11 (2) ◽

pp. e041458

Author(s):

Vicki Anderson ◽

Vanessa C Rausa ◽

Nicholas Anderson ◽

Georgia Parkin ◽

Cathriona Clarke ◽

...

Keyword(s):

Clinical Trial ◽

Randomised Clinical Trial ◽

Normal Activity ◽

Secondary Outcome ◽

Open Label ◽

Human Research Ethics ◽

Postconcussive Symptoms ◽

Study Results ◽

Registration Number ◽

Initial Injury

IntroductionWhile most children recover from a concussion shortly after injury, approximately 30% experience persistent postconcussive symptoms (pPCS) beyond 1-month postinjury. Existing research into the treatment of pPCS have evaluated unimodal approaches, despite evidence suggesting that pPCS likely represent an interaction across various symptom clusters. The primary aim of this study is to evaluate the effectiveness of a multimodal, symptom-tailored intervention to accelerate symptom recovery and increase the proportion of children with resolved symptoms at 3 months postconcussion.Methods and analysisIn this open-label, assessor-blinded, randomised clinical trial, children with concussion aged 8–18 years will be recruited from The Royal Children’s Hospital (The RCH) emergency department, or referred by a clinician, within 17 days of initial injury. Based on parent ratings of their child’s PCS at ~10 days postinjury, symptomatic children (≥2 symptoms at least 1-point above those endorsed preinjury) will undergo a baseline assessment at 3 weeks postinjury and randomised into either Concussion Essentials (CE, n=108), a multimodal, interdisciplinary delivered, symptom-tailored treatment involving physiotherapy, psychology and education, or usual care (UC, n=108) study arms. CE participants will receive 1 hour of intervention each week, for up to 8 weeks or until pPCS resolve. A postprogramme assessment will be conducted at 3 months postinjury for all participants. Effectiveness of the CE intervention will be determined by the proportion of participants for whom pPCS have resolved at the postprogramme assessment (primary outcome) relative to the UC group. Secondary outcome analyses will examine whether children receiving CE are more likely to demonstrate resolution of pPCS, earlier return to normal activity, higher quality of life and a lower rate of utilisation of health services, compared with the UC group.Ethics and disseminationEthics were approved by The RCH Human Research Ethics Committee (HREC: 37100). Parent, and for mature minors, participant consent, will be obtained prior to commencement of the trial. Study results will be disseminated at international conferences and international peer-reviewed journals.Trial registration numberACTRN12617000418370; pre-results.

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Exenatide once weekly over 2 years as a potential disease-modifying treatment for Parkinson’s disease: protocol for a multicentre, randomised, double blind, parallel group, placebo controlled, phase 3 trial: The ‘Exenatide-PD3’ study

BMJ Open ◽

10.1136/bmjopen-2020-047993 ◽

2021 ◽

Vol 11 (5) ◽

pp. e047993

Author(s):

Nirosen Vijiaratnam ◽

Christine Girges ◽

Grace Auld ◽

Marisa Chau ◽

Kate Maclagan ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Primary Outcome ◽

Phase 3 ◽

Double Blind ◽

Treatment Groups ◽

Link Type ◽

South Central ◽

Disease Modifying ◽

Secondary Outcomes

IntroductionParkinson’s disease (PD) is a common neurodegenerative disorder with substantial morbidity. No disease-modifying treatments currently exist. The glucagon like peptide-1 receptor agonist exenatide has been associated in single-centre studies with reduced motor deterioration over 1 year. The aim of this multicentre UK trial is to confirm whether these previous positive results are maintained in a larger number of participants over 2 years and if effects accumulate with prolonged drug exposure.Methods and analysisThis is a phase 3, multicentre, double-blind, randomised, placebo-controlled trial of exenatide at a dose of 2 mg weekly in 200 participants with mild to moderate PD. Treatment duration is 96 weeks. Randomisation is 1:1, drug to placebo. Assessments are performed at baseline, week 12, 24, 36, 48, 60, 72, 84 and 96 weeks.The primary outcome is the comparison of Movement Disorders Society Unified Parkinson’s Disease Rating Scale part 3 motor subscore in the practically defined OFF medication state at 96 weeks between participants according to treatment allocation. Secondary outcomes will compare the change between groups among other motor, non-motor and cognitive scores. The primary outcome will be reported using descriptive statistics and comparisons between treatment groups using a mixed model, adjusting for baseline scores. Secondary outcomes will be summarised between treatment groups using summary statistics and appropriate statistical tests to assess for significant differences.Ethics and disseminationThis trial has been approved by the South Central-Berkshire Research Ethics Committee and the Health Research Authority. Results will be disseminated in peer-reviewed journals, presented at scientific meetings and to patients in lay-summary format.Trial registration numbersNCT04232969, ISRCTN14552789.

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Efficacy and safety of aliskiren combination therapy: a protocol for an umbrella review

BMJ Open ◽

10.1136/bmjopen-2020-043807 ◽

2021 ◽

Vol 11 (3) ◽

pp. e043807

Author(s):

Jiantong Shen ◽

Wenming Feng ◽

Yike Wang ◽

Qiyuan Zhao ◽

Billong Laura Flavorta ◽

...

Keyword(s):

Combination Therapy ◽

Systematic Reviews ◽

Cochrane Library ◽

Umbrella Review ◽

Quality Of Reporting ◽

Ethical Approval ◽

Registration Number ◽

Third Person ◽

Meta Analyses ◽

The Impact

IntroductionEfficacy of aliskiren combination therapy with other antihypertensive has been evaluated in the treatment of patients with hypertension in recent systematic reviews. However, most previous reviews only focused on one single health outcome or one setting, none of them made a full summary that assessed the impact of aliskiren combination treatment comprehensively. As such, this umbrella review based on systematic reviews and meta-analyses is aimed to synthesise the evidences on efficacy, safety and tolerability of aliskiren-based therapy for hypertension and related comorbid patients.Methods and analysisA comprehensive search of PubMed, EMBASE, Cochrane Library, CNKI published from inception to August 2020 will be conducted. The selected articles are systematic reviews which evaluated efficacy, safety and tolerability of aliskiren combination therapy. Two reviewers will screen eligible articles, extract data and evaluate quality independently. Any disputes will be resolved by discussion or the arbitration of a third person. The quality of reporting evidence will be assessed using the Assessment of Multiple Systematic Reviews V.2 tool tool. We will take a mixed-methods approach to synthesising the review literatures, reporting summary of findings tables and iteratively mapping the results.Ethics and disseminationEthical approval is not required for the study, as we would only collect data from available published materials. This umbrella review will be also submitted to a peer-reviewed journal for publication after completion.PROSPERO registration numberCRD42020192131.

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Impact of COVID-19 pandemic on utilisation of healthcare services: a systematic review

BMJ Open ◽

10.1136/bmjopen-2020-045343 ◽

2021 ◽

Vol 11 (3) ◽

pp. e045343

Author(s):

Ray Moynihan ◽

Sharon Sanders ◽

Zoe A Michaleff ◽

Anna Mae Scott ◽

Justin Clark ◽

...

Keyword(s):

Systematic Review ◽

Primary Outcome ◽

Unmet Need ◽

Healthcare Utilisation ◽

Healthcare Services ◽

Risk Of Bias ◽

Secondary Outcome ◽

Severe Illness ◽

Service Utilisation ◽

Registration Number

ObjectivesTo determine the extent and nature of changes in utilisation of healthcare services during COVID-19 pandemic.DesignSystematic review.EligibilityEligible studies compared utilisation of services during COVID-19 pandemic to at least one comparable period in prior years. Services included visits, admissions, diagnostics and therapeutics. Studies were excluded if from single centres or studied only patients with COVID-19.Data sourcesPubMed, Embase, Cochrane COVID-19 Study Register and preprints were searched, without language restrictions, until 10 August, using detailed searches with key concepts including COVID-19, health services and impact.Data analysisRisk of bias was assessed by adapting the Risk of Bias in Non-randomised Studies of Interventions tool, and a Cochrane Effective Practice and Organization of Care tool. Results were analysed using descriptive statistics, graphical figures and narrative synthesis.Outcome measuresPrimary outcome was change in service utilisation between prepandemic and pandemic periods. Secondary outcome was the change in proportions of users of healthcare services with milder or more severe illness (eg, triage scores).Results3097 unique references were identified, and 81 studies across 20 countries included, reporting on >11 million services prepandemic and 6.9 million during pandemic. For the primary outcome, there were 143 estimates of changes, with a median 37% reduction in services overall (IQR −51% to −20%), comprising median reductions for visits of 42% (−53% to −32%), admissions 28% (−40% to −17%), diagnostics 31% (−53% to −24%) and for therapeutics 30% (−57% to −19%). Among 35 studies reporting secondary outcomes, there were 60 estimates, with 27 (45%) reporting larger reductions in utilisation among people with a milder spectrum of illness, and 33 (55%) reporting no difference.ConclusionsHealthcare utilisation decreased by about a third during the pandemic, with considerable variation, and with greater reductions among people with less severe illness. While addressing unmet need remains a priority, studies of health impacts of reductions may help health systems reduce unnecessary care in the postpandemic recovery.PROSPERO registration numberCRD42020203729.

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Perspectives and experiences of people who were randomly assigned to wait-and-see approach in a gluteal tendinopathy trial: a qualitative follow-up study

BMJ Open ◽

10.1136/bmjopen-2020-044934 ◽

2021 ◽

Vol 11 (4) ◽

pp. e044934

Author(s):

Melanie Louise Plinsinga ◽

Rebecca Mellor ◽

Jenny Setchell ◽

Kelsie Ford ◽

Leonard Lynch ◽

...

Keyword(s):

Clinical Trial ◽

Corticosteroid Injection ◽

Imaging Diagnosis ◽

Parallel Group ◽

Data Collection And Analysis ◽

Gluteal Tendinopathy ◽

Semistructured Interviews ◽

Registration Number ◽

Wait And See

ObjectiveTo explore participants’ perspectives on, and experiences of, being assigned to a wait-and-see arm of a gluteal tendinopathy trial.DesignDescriptive qualitative.SettingGeneral community in Brisbane and Melbourne, Australia.ParticipantsFifteen participants who had been randomly allocated to the wait-and-see group in a recent parallel group superiority clinical trial. That trial compared the wait-and-see approach to a physiotherapist-led education plus exercise approach, and an ultrasound-guided corticosteroid injection. The wait-and-see approach involved one physiotherapy session in which participants received reassurance, general advice and encouragement to stay active for the management of gluteal tendinopathy.Data collection and analysisSemistructured interviews were conducted by four interviewers in person or over the internet, audio recorded and transcribed verbatim. Transcripts were coded and data analysed using an inductive thematic approach.ResultsFive themes were extracted from the interview transcripts: (1) Feeling disenfranchised by being assigned to a wait-and-see approach; (2) the importance of having a clinical and imaging diagnosis during screening for inclusion into the clinical trial; (3) feelings regarding the effectiveness of the approach; (4) the convenient and easy to follow nature of the wait-and-see approach and (5) the connotation of wait-and-see not always being perceived as an intervention.ConclusionsParticipants found the wait-and-see approach convenient and easy to follow, yet almost always felt disenfranchised that nothing was being done. Participants highlighted the importance of a definite clinical and imaging diagnosis.Trial registration numberACTRN12612001126808; Post-results.

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