Clinical Eligibility Criteria Research Articles

Uptake of community- versus clinic-based antiretroviral therapy dispensing in the Central Chronic Medication Dispensing and Distribution program in South Africa.

IntroductionSouth Africa's government‐led Central Chronic Medication Dispensing and Distribution (CCMDD) program offers people living with HIV the option to collect antiretroviral therapy at their choice of community‐ or clinic‐based pick‐up points intended to increase convenience and decongest clinics. To understand CCMDD pick‐up point use among people living with HIV, we evaluated factors associated with uptake of a community‐ versus clinic‐based pick‐up point at CCMDD enrolment.MethodsWe collected baseline data from October 2018 to March 2020 on adults (≥18 years) who met CCMDD clinical eligibility criteria (non‐pregnant, on antiretroviral therapy for ≥1 year and virologically suppressed) as part of an observational cohort in seven public clinics in KwaZulu‐Natal. We identified factors associated with community‐based pick‐up point uptake and fit a multivariable logistic regression model, including age, gender, employment status, self‐perceived barriers to care, self‐efficacy, HIV‐related discrimination, and perceived benefits and challenges of CCMDD.Results and DiscussionAmong 1521 participants, 67% were females, with median age 36 years (IQR 30–44). Uptake of a community‐based pick‐up point was associated with younger age (aOR 1.18 per 10‐year decrease, 95% CI 1.05–1.33), being employed ≥40 hours per week (aOR 1.42, 95% CI 1.10–1.83) versus being unemployed, no self‐perceived barriers to care (aOR 1.42, 95% CI 1.09–1.86) and scoring between 36 and 39 (aOR 1.44, 95% CI 1.03–2.01) or 40 (aOR 1.91, 95% CI 1.39–2.63) versus 10–35 on the self‐efficacy scale, where higher scores indicate greater self‐efficacy. Additional factors included more convenient pick‐up point location (aOR 2.32, 95% CI 1.77–3.04) or hours (aOR 5.09, 95% CI 3.71–6.98) as perceived benefits of CCMDD, and lack of in‐clinic follow‐up after a missed collection date as a perceived challenge of CCMDD (aOR 4.37, 95% CI 2.30–8.31).ConclusionsUptake of community‐based pick‐up was associated with younger age, full‐time employment, and systemic and structural factors of living with HIV (no self‐perceived barriers to care and high self‐efficacy), as well as perceptions of CCMDD (convenient pick‐up point location and hours, lack of in‐clinic follow‐up). Strategies to facilitate community‐based pick‐up point uptake should be tailored to patients’ age, employment, self‐perceived barriers to care and self‐efficacy to maximize the impact of CCMDD in decongesting clinics.

Augmenting Real-World Data Through Modeling Key Clinical Trial Eligibility Criteria: An Example of Patients With Non-small-Cell Lung Cancer Treated With Pembrolizumab.

To compare and characterize baseline characteristics and overall survival (OS) differences by key oncology eligibility criteria for real-world patients from the Flatiron Health database with advanced non-small-cell lung cancer (NSCLC) who received pembrolizumab monotherapy. Real world data (RWD) were from the Flatiron Health advanced NSCLC database and include patients who initiated pembrolizumab monotherapy (first, second, or third line of therapy) by November 30, 2019. At the data cutoff (May 31, 2020), the median survival follow-up time was 8.4 months. Eligible patients satisfy the criteria of Eastern Cooperative Oncology Group performance status of 0/1 and laboratory values indicative of adequate organ function. RWD were analyzed for all patients and patients with a programmed cell death ligand-1 tumor proportion score ≥ 1%. Patients were divided into three categories: ineligible, eligible, and unknown (who satisfy all observed criteria, with at least one missing). An augmented population was also formed, which combines the latter two groups through a propensity-based adjustment. At the data cutoff, N = 3,877 patients with NSCLC received pembrolizumab monotherapy (1L = 2,682, 2L = 946, and 3L = 249). OS was consistently lower for the ineligible with similar survival for the eligible and augmented. Among all patients, the median OS in months (95% CI) was 8.2 (7.5 to 9.6), 16.3 (14.5 to 18.4), 16.4 (15.1 to 19.3), and 16.8 (15.6 to 18.5) for the ineligible (47%, n = 1,827), unknown (27%, n = 1,045), eligible (26%, n = 1,005), and augmented, respectively. The results were similar for patients with a programmed cell death ligand-1 tumor proportion score ≥ 1%. Real-world patients who received pembrolizumab monotherapy and meet key clinical eligibility criteria exhibited similar baseline characteristics and OS profiles as the unknown and augmented patient groups. Population augmentation is a feasible approach for improving the power of RWD analysis.

Clinical Prioritization of Antispike Monoclonal Antibody Treatment of Mild to Moderate COVID-19

Clinical Prioritization of Antispike Monoclonal Antibody Treatment of Mild to Moderate COVID-19

National Cancer Institute (NCI) implementation of the American Society of Clinical Oncology (ASCO) and Friends of Cancer Research (Friends) broadening clinical trials eligibility criteria.

6518 Background: The 2017 ASCO/Friends eligibility criteria guidelines recommend inclusiveness to promote generalizable trial results and clear rationale for necessary exclusion. These guidelines focused on brain metastases, minimum age for enrollment, HIV infection, and organ dysfunction and prior and concurrent malignancies. In September 2018, the NCI Cancer Therapy Evaluation Program (CTEP) implemented modernized protocol template language to operationalize these criteria. We evaluated utilization of the new language among CTEP-sponsored treatment trials. Methods: We evaluated protocols first approved by CTEP between 11/01/2018 and 4/30/2020. The most recent approved protocol version was evaluated for consistency with the new template language for brain metastases, HIV infection, prior or concurrent malignancies, minimum age, and cardiac, liver and kidney function. If a particular criterion was not relevant for a trial, it was not included in the analysis. We did not score age in pediatric or adult-specific trials (e.g. prostate). Results: 122 trials (71% early and 29% late phase) were identified and included in the analysis. Compliance with the new criteria language ranged from a high of 87.7% for liver function to a low of 11.5% for “new or progressive brain metastases” (table). Modernized criteria language was lacking in nearly 46% of trials in the use of concurrent or prior malignancy criteria and 31% of trials for the cardiac criteria. Of the 87 trials for non-localized disease or non-brain tumor trials, 64.4% did not address brain metastases, leaving it to investigator discretion. Thus, 75.9% of trials could theoretically enroll patients with brain metastases. Only 6 trials were considered relevant for patients < 18 years old; 50% were consistent with the age criterion (not shown in table). Conclusions: Implementing ASCO/Friends eligibility criteria requires focused reviews during protocol development to ensure compliance. CTEP is using these findings to continue to improve its protocol review processes to broaden eligibility in clinical trials. Maximizing opportunities for diverse populations to participate in trials is a priority for the National Cancer Institute and CTEP will continue efforts to achieve this goal.[Table: see text]

AGREEing on clinical practice guidelines for idiopathic steroid-sensitive nephrotic syndrome in children

BackgroundNephrotic syndrome is the most common kidney disease in children worldwide. Our aim was to critically appraise the quality of recent Clinical Practice Guidelines (CPGs) for idiopathic steroid-sensitive nephrotic syndrome (SSNS) in children in addition to summarize and compare their recommendations.MethodsSystematic review of CPGs. We identified clinical questions and eligibility criteria and searched and screened for CPGs using bibliographic and CPG databases. Each included CPG was assessed by four independent appraisers using the Appraisal of Guidelines for REsearch & Evaluation II (AGREE-II) instrument. We summarized the recommendations in a comparison practical table.ResultsOur search retrieved 282 citations, of which three CPGs were eligible and appraised: Kidney Disease: Improving Global Outcomes (KDIGO) 2012, Japan Society for Pediatric Nephrology (JSPN) 2014, and American Academy of Pediatrics (AAP) 2009. Among these, the overall assessment of two evidence-based CPGs scored > 70% (KDIGO and JSPN), which was consistent with their higher scores in the six domains of the AGREE II Instrument. In domain 3 (rigor of development), KDIGO, JSPN, and AAP scored 84%, 74%, and 41%, respectively. In domain 5 (applicability), they scored 22%, 16%, and 19%, respectively, and in domain 6 (editorial independence), they scored 94%, 65%, and 88%, respectively.ConclusionsThe methodological quality of the KDIGO CPG was superior, followed by JSPN and AAP CPGs with the relevant recommendations for use in practice.Systematic review registrationThe protocol was registered in the Center for Open Science (OSF) DOI: 10.17605/OSF.IO/6QTMD and in the International prospective register of systematic reviews PROSPERO 2020 CRD42020197511.

Semantic categorization of Chinese eligibility criteria in clinical trials using machine learning methods

BackgroundSemantic categorization analysis of clinical trials eligibility criteria based on natural language processing technology is crucial for the task of optimizing clinical trials design and building automated patient recruitment system. However, most of related researches focused on English eligibility criteria, and to the best of our knowledge, there are no researches studied the Chinese eligibility criteria. Thus in this study, we aimed to explore the semantic categories of Chinese eligibility criteria.MethodsWe downloaded the clinical trials registration files from the website of Chinese Clinical Trial Registry (ChiCTR) and extracted both the Chinese eligibility criteria and corresponding English eligibility criteria. We represented the criteria sentences based on the Unified Medical Language System semantic types and conducted the hierarchical clustering algorithm for the induction of semantic categories. Furthermore, in order to explore the classification performance of Chinese eligibility criteria with our developed semantic categories, we implemented multiple classification algorithms, include four baseline machine learning algorithms (LR, NB, kNN, SVM), three deep learning algorithms (CNN, RNN, FastText) and two pre-trained language models (BERT, ERNIE).ResultsWe totally developed 44 types of semantic categories, summarized 8 topic groups, and investigated the average incidence and prevalence in 272 hepatocellular carcinoma related Chinese clinical trials. Compared with the previous proposed categories in English eligibility criteria, 13 novel categories are identified in Chinese eligibility criteria. The classification result shows that most of semantic categories performed quite well, the pre-trained language model ERNIE achieved best performance with macro-average F1 score of 0.7980 and micro-average F1 score of 0.8484.ConclusionAs a pilot study of Chinese eligibility criteria analysis, we developed the 44 semantic categories by hierarchical clustering algorithms for the first times, and validated the classification capacity with multiple classification algorithms.

Cornerstones of ‘fair’ drug coverage: appropriate cost sharing and utilization management policies for pharmaceuticals

At the heart of all health insurance programs lies ethical tension between maximizing the freedom of patients and clinicians to tailor care for the individual and the need to make healthcare affordable. Nowhere is this tension more fiercely debated than in benefit design and coverage policy for pharmaceuticals. This paper focuses on three areas over which there is the most controversy about how to judge whether drug coverage is appropriate: cost-sharing provisions, clinical eligibility criteria, and economic-step therapy andrequired switching. In each of these domains we present 'ethical goals for access' followed by a series of 'fair design criteria' that can be used by stakeholders to drive more transparent and accountable drug coverage.

Artificial intelligence based Chinese clinical trials eligibility criteria classification

Subject recruitment is a key component that affects the progress and results of clinical trials, and generally conducted with eligibility criteria (includes inclusion criteria and exclusion criteria). The semantic category analysis of eligibility criteria can help optimizing clinical trials design and building automated patient recruitment system. This study explored the automatic semantic categories classification of Chinese eligibility criteria based on artificial intelligence by academic shared task. We totally collected 38 341 annotated eligibility criteria sentences and predefined 44 semantic categories. A total of 75 teams participated in competition, with 27 teams having submitted system outputs. Based on the results, we found out that most teams adopted mixed models. The mainstream resolution was applying pre-trained language models capable of providing rich semantic representation, which were combined with neural network models and used to fine-tune the models with reference to classifier tasks, and finally improved classification performance could be obtained by ensemble modeling. The best-performing system achieved a macro F1 score of 0.81 by using a pre-trained language model, i.e. bidirectional encoder representations from transformers (BERT) and ensemble modeling. With the error analysis we found out that from the point of data processing steps the data pre-processing and post-processing were very important for classification, while from the point of data volume these categories with less data volume showed lower classification performance. Finally, we hope that this study could provide a valuable dataset and state-of-the-art result for the research of Chinese medical short text classification.

Towards clinical data-driven eligibility criteria optimization for interventional COVID-19 clinical trials.

ObjectiveThis research aims to evaluate the impact of eligibility criteria on recruitment and observable clinical outcomes of COVID-19 clinical trials using electronic health record (EHR) data.Materials and MethodsOn June 18, 2020, we identified frequently used eligibility criteria from all the interventional COVID-19 trials in ClinicalTrials.gov (n = 288), including age, pregnancy, oxygen saturation, alanine/aspartate aminotransferase, platelets, and estimated glomerular filtration rate. We applied the frequently used criteria to the EHR data of COVID-19 patients in Columbia University Irving Medical Center (CUIMC) (March 2020–June 2020) and evaluated their impact on patient accrual and the occurrence of a composite endpoint of mechanical ventilation, tracheostomy, and in-hospital death.ResultsThere were 3251 patients diagnosed with COVID-19 from the CUIMC EHR included in the analysis. The median follow-up period was 10 days (interquartile range 4–28 days). The composite events occurred in 18.1% (n = 587) of the COVID-19 cohort during the follow-up. In a hypothetical trial with common eligibility criteria, 33.6% (690/2051) were eligible among patients with evaluable data and 22.2% (153/690) had the composite event.DiscussionBy adjusting the thresholds of common eligibility criteria based on the characteristics of COVID-19 patients, we could observe more composite events from fewer patients.ConclusionsThis research demonstrated the potential of using the EHR data of COVID-19 patients to inform the selection of eligibility criteria and their thresholds, supporting data-driven optimization of participant selection towards improved statistical power of COVID-19 trials.

Sustained Lung Inflation in Pre-term Infants at Birth: A Randomized Controlled Trial.

Invasive mechanical ventilation (IMV) of pre-term infants may be associated with high rate of mortality and iatrogenic complications in low- and middle-income countries. Sustained lung inflation (SLI) may help to reduce their need for IMV. This randomized controlled trial included 160 infants with gestational age (GA) ≥27 and ≤32 weeks who were randomly assigned to receive either SLI; using a pressure of 20 cmH2O for 15 s followed by nasal continuous positive airway pressure (CPAP) of 5 cmH2O or nasal CPAP alone, through an appropriate mask and a T-piece resuscitator. Primary outcome was the need for IMV in the first 72 h of life. There was no difference in the primary outcome between SLI group; 55% (44 out of 80) and the control group; 65% (52 out of 80) [odds ratio (OR): 0.623, 95% confidence interval (CI): 0.33-1.18; p = 0.145]. However, SLI significantly reduced the primary outcome in the sicker infants; who had clinical eligibility criteria (CEC; OR: 0.224, 95% CI: 0.076-0.663; p = 0.005) and in the smaller babies; whose GA was <30 weeks (OR: 0.183, 95% CI: 0.053-0.635; p = 0.005). SLI was not harmful. Although, it did not lead to reduction in the need for IMV in the first 72 h of life in pre-term infants with GA ≥27 and ≤32 weeks, SLI reduced this outcome in the subgroup of infants with CEC and those with GA <30 weeks. Future trials are needed to investigate the effect of SLI on these two subgroups. Clinical trials.gov, NCT03518762. https://www.clinicaltrials.gov/ct2/show/NCT03518762?term=NCT03518762&rank=1.

Heregulin (HRG) assessment for clinical trial eligibility testing in a molecular registry (PRAEGNANT) in Germany

BackgroundEligibility criteria are a critical part of clinical trials, as they define the patient population under investigation. Besides certain patient characteristics, clinical trials often include biomarker testing for eligibility. However, patient-identification mostly relies on the trial site itself and is often a time-consuming procedure, which could result in missing out on potentially eligible patients. Pre-selection of those patients using a registry could facilitate the process of eligibility testing and increase the number of identified patients. One aim with the PRAEGNANT registry (NCT02338167) is to identify patients for therapies based on clinical and molecular data. Here, we report eligibility testing for the SHERBOC trial using the German PRAEGNANT registry.MethodsHeregulin (HRG) has been reported to identify patients with better responses to therapy with the anti-HER3 monoclonal antibody seribantumab (MM-121). The SHERBOC trial investigated adding seribantumab (MM-121) to standard therapy in patients with advanced HER2-negative, hormone receptor–positive (HR-positive) breast cancer and HRG overexpression. The PRAEGNANT registry was used for identification and tumor testing, helping to link potential HRG positive patients to the trial. Patients enrolled in PRAEGNANT have invasive and metastatic or locally advanced, inoperable breast cancer. Patients eligible for SHERBOC were identified by using the registry. Study aims were to describe the HRG positivity rate, screening procedures, and patient characteristics associated with inclusion and exclusion criteria.ResultsAmong 2769 unselected advanced breast cancer patients, 650 were HER2-negative, HR-positive and currently receiving first- or second-line treatment, thus potentially eligible for SHERBOC at the end of current treatment; 125 patients also met further clinical eligibility criteria (e.g. menopausal status, ECOG). In the first/second treatment lines, patients selected for SHERBOC based on further eligibility criteria had a more favorable prognosis than those not selected. HRG status was tested in 38 patients, 14 of whom (36.8%) proved to be HRG-positive.ConclusionUsing a real-world breast cancer registry allowed identification of potentially eligible patients for SHERBOC focusing on patients with HER3 overexpressing, HR-positive, HER2-negative metastatic breast cancer. This approach may provide insights into differences between patients eligible or non-eligible for clinical trials.Trial registrationClinicaltrials, NCT02338167, Registered 14 January 2015 - retrospectively registered.

Do eligibility criteria restrict access to clinical trials?

94 Background: Stringent eligibility criteria may be a barrier to oncology clinical trial enrollment. We examined patients meeting basic trial eligibility criteria defined in a clinical pathway where the trial was not selected, and then performed a thorough review of full trial eligibility. Methods: Locally available trials are embedded into a pathways tool used at the point of care by medical oncologists at a tertiary cancer center. The physician can choose to have the patient fully screened for the recommended trial or bypass it. Patients where the physician bypassed the trial for eleven Phase 2 and 3 solid tumor trials from April 2018 to December 2019 were reviewed for trial eligibility. Basket trials and adoptive cellular therapy trials were excluded. Trials selected for the audit were presented for more than 20 patients and were bypassed in 80% or more cases. For each trial a random set of 20% of cases or a minimum of 15 cases minimum were reviewed. Results: Among the 184 cases reviewed, 149 (81%) were trial ineligible based upon one or more criteria. The most common reasons for patients' ineligibility were the wrong biomarker profile, prior drug treatment, and health conditions including co-morbidities, autoimmune diseases, other cancers and poor performance status. Conclusions: The majority of patients meeting basic eligibility in a clinical pathways system did not meet strict eligibility criteria. This suggests the trials may not be reflective of the needs of the cancer population being treated and may limit the applicability of trial results to the general cancer population. Use of the pathway program to define eligibility is limited by the numerous and nuanced eligibility criteria that cannot be programmed into the pathways system. Clinical trials eligibility criteria and pathway tools need to adapt to the patient population to help advance cancer research. [Table: see text]

Significance of revised criteria for chronic active T cell-mediated rejection in the 2017 Banff classification: Surveillance by 1-year protocol biopsies for kidney transplantation.

Diagnostic criteria for chronic active T cell-mediated rejection (CA-TCMR) were revised in the Banff 2017 consensus, but it is unknown whether the new criteria predict graft prognosis of kidney transplantation. We enrolled 406 kidney allograft recipients who underwent a 1-year protocol biopsy (PB) and investigated the diagnostic significance of Banff 2017. Interobserver reproducibility of the 3 diagnosticians showed a substantial agreement rate of 0.68 in Fleiss's kappa coefficient. Thirty-three patients (8%) were classified as CA-TCMR according to Banff 2017, and 6 were previously diagnosed as normal, 12 as acute TCMR, 10 with borderline changes, and 5 as CA-TCMR according to Banff 2015 criteria. Determinant factors of CA-TCMR were cyclosporine use (vs tacrolimus), previous acute rejection, and BK polyomavirus-associated nephropathy. In survival analysis, the new diagnosis of CA-TCMR predicted a composite graft endpoint defined as doubling serum creatinine or death-censored graft loss (log-rank test, P<.001). In multivariate analysis, CA-TCMR was associated with the second highest risk of the composite endpoint (hazard ratio: 5.42; 95% confidence interval, 2.02-14.61; P<.001 vs normal) behind antibody-mediated rejection. In conclusion, diagnosis of CA-TCMR in Banff 2017 may facilitate detecting an unfavorable prognosis of kidney allograft recipients who undergo a 1-year PB.

Effectiveness of a brief lay counsellor-delivered, problem-solving intervention for adolescent mental health problems in urban, low-income schools in India: a randomised controlled trial

SummaryBackgroundMental health problems are a leading cause of disability in adolescents worldwide. Problem solving is a well-tested mental health intervention in many populations. We aimed to investigate the effectiveness of a brief, transdiagnostic problem-solving intervention for common adolescent mental health problems when delivered by non-specialist school counsellors in New Delhi, India.MethodsThis randomised trial was done in six government-run schools (three all-boys schools, two all-girls schools, and one co-educational school) that serve low-income communities. We recruited participants from grades 9 to 12 (ages 12–20 years) by selecting students with persistently elevated mental health symptoms accompanied by distress or functional impairment. Clinical eligibility criteria were assessed by research assistants using the Hindi-language version of the Strengths and Difficulties Questionnaire (SDQ), with reference to locally validated borderline cutoff scores of 19 or greater for boys and 20 or greater for girls on the SDQ Total Difficulties scale, an abnormal score of 2 or more on the SDQ Impact scale, and persistence of more than 1 month on the SDQ Chronicity index. Participants were randomly allocated (1:1) to problem solving delivered through a brief (2–3 week) counsellor-led intervention with supporting printed materials (intervention group), or problem solving delivered via printed booklets alone (control group). Primary outcomes were adolescent-reported mental health symptoms (SDQ Total Difficulties scale) and idiographic psychosocial problems (Youth Top Problems [YTP]) at 6 weeks. Primary analyses were done on an intention-to-treat basis at the 6-week endpoint. The trial is registered with ClinicalTrials.gov, NCT03630471.FindingsParticipants were enrolled between Aug 20, and Dec 4, 2018. 283 eligible adolescents were referred to the trial, and 251 (89%) of these were enrolled (mean age 15·61 years; 174 [69%] boys). 125 participants were allocated to each group (after accounting for one participant in the intervention group who withdrew consent after randomisation). Primary outcome data were available for 245 (98%) participants. At 6 weeks, the mean YTP scores were 3·52 (SD 2·66) in the intervention group and 4·60 (2·75) in the control group (adjusted mean difference –1·01, 95% CI –1·63 to –0·38; adjusted effect size 0·36, 95% CI 0·11 to 0·61; p=0·0015). The mean SDQ Total Difficulties scores were 17·48 (5·45) in the intervention group and 18·33 (5·45) in the control group (–0·86, –2·14 to 0·41; 0·16, –0·09 to 0·41; p=0·18). We observed no adverse events.InterpretationA brief lay counsellor-delivered problem-solving intervention combined with printed booklets seemed to have a modest effect on psychosocial outcomes among adolescents with diverse mental health problems compared with problem-solving booklets alone. This counsellor-delivered intervention might be a suitable first-line intervention in a stepped care approach, which is being evaluated in ongoing studies.FundingWellcome Trust.

Value of multigene panel retesting of families with BRCA1/2 mutation-negative hereditary breast and ovarian cancer (HBOC).

1582 Background: Despite the use of clinical eligibility criteria and mutation predictive models, a great proportion of families are negative for germline mutations in BRCA1/2 genes. Traditionally, risk assessment of inconclusive results included the recommendation of high-risk surveillance protocol, the update of incident cancer cases in the family and the consideration of additional testing to rule out the possibility of phenocopy. More recently, next generation sequencing multigene panels have become a standard practice in cancer genetics clinics worldwide. We addressed the value of multigene panel retesting of BRCA1/2 negative HBOC families in our institution. Methods: After genetic counseling session and informed consent, a total of 137 individuals (119 probands and 18 extra cancer-affected relatives) from distinct BRCA1/2 negative families were retested using a panel containing 11 breast and ovarian cancer susceptibility genes ( BRCA1/2, PALB2, ATM, CHEK2, PTEN, TP53, STK11, BRIP1, RAD51C, RAD51D). Results: According to the BOADICEA model, the remaining probability of mutation in BRCA1/2 or PALB2 genes in our cohort was 5.5% (0.1-61). The reasons for considering retesting were the addition of any incident cancer diagnosis in 33 cases (24%), a prior study with a low sensitivity screening technique (dHPLC) in 6 families (5%) and the expansion of the study to other putative breast and ovarian susceptibility genes in 98 families (71%). Overall, 3 pathogenic (2 BRCA2, 1 CHEK2) and 8 likely pathogenic variants (1 BRCA2, 4 CHEK2 and 3 ATM) were found. The prevalence was 8%. The detection rate among 19 families with a &gt; 10% remaining probability of mutation in BRCA1/2 and PALB2 genes was 26%. The 3 clinically significant variants in BRCA2 were detected in 2 families and 1 updated cancer family history (BOADICEA remaining probability of 59, 61 and 12%, respectively). Cascade testing was subsequently done in 15 relatives resulting 8 in mutation carriers and 9 true negatives. Conclusions: Our results support the value of updating cancer incident cases and considering expanded panels in selected families.

Eligibility and implementation of disease-modifying therapy for primary progressive multiple sclerosis in a UK cohort

BackgroundAs disease-modifying therapies become approved for primary progressive multiple sclerosis (PPMS), services must be aligned in readiness. MethodsIn this paper we use population and clinic-based data to estimate eligibility rates for ocrelizumab, and the extent of additional service requirements necessary to ensure its widespread introduction in PPMS. ResultsOverall population estimates for the incidence and prevalence of people with PPMS who are eligible for ocrelizumab are 1.6 and 4.2 per 100,000 respectively. The majority (87%) of incident cases of PPMS satisfied clinical eligibility criteria for ocrelizumab but lacked radiological evidence of disease activity due to a historical tendency not to routinely monitor using MRI in this group. The majority of prevalent patients did not satisfy clinical eligibility criteria for ocrelizumab, mainly because of advanced disease duration or disability. ConclusionsThese findings illustrate the fact that there has been a tendency for people with PPMS not to receive routine clinical and radiological monitoring. Additional planning or resources will be required to facilitate contemporary disease re-evaluation and surveillance at a population level.

Eligibility for intravenous thrombolysis in acute ischemic stroke patients presenting in the 4.5-9h window.

Recent randomized-controlled clinical trials have provided preliminary evidence for expanding the time window of intravenous thrombolysis (IVT) in acute ischemic stroke (AIS) patients by applying certain neuroimaging criteria. We prospectively assessed the potential eligibility for IVT in the extended time window (4.5-9h) among consecutive AIS patients treated in a comprehensive stroke center during a nine-month period. Potential eligibility for IVT in the extended time window was evaluated by using inclusion criteria from the EXTEND trial. All patients were underwent baseline emergent neurovascular imaging using either computed tomography angiography/computed tomography perfusion (CTA/CTP) or magnetic resonance angiography/magnetic resonance perfusion (MRA/MRP). Images were post processed by the automated software RAPID. Our study population consisted of 317 AIS patients, and, among them, 31 (9.8%) patients were presented in the time window of 4.5-9h. Seven patients (2.2%) fulfilled the EXTEND neuroimaging criteria. Four patients (1.3%) were treated with IVT because they fulfilled both clinical and neuroimaging EXTEND criteria. Patients eligible for EXTEND neuroimaging criteria had no ischemic core lesion, whereas the mean volume of critical hypoperfusion was relatively small (17.0 ± 11.8ml). There was no hemorrhagic complication in any of the patients treated with IVT. The median mRS score at three months was 0 (range: 0-3) among patients who were eligible for EXTEND neuroimaging criteria. Our everyday clinical practice experience suggests 9.8% of consecutive AIS patients present in the 4.5-9h window and 2.2% adhere to EXTEND neuroimaging eligibility criteria for IVT. Only 1.3% of AIS is eligible for IVT according to EXTEND neuroimaging and clinical eligibility criteria.

Quality improvement of lung cancer patient selection using clinic-based spirometry.

282 Background: Coordinating lung cancer screening requires risk assessment for patient selection. Optimal selection can reduce costs and improve efficiency of low dose computed tomography (LDCT) screening of lung cancer. This study evaluated clinic-based spirometry as a tool to improve patient selection for lung cancer screening. Methods: Eligibility criteria for three large LDCT screening studies were retrospectively applied to the highest risk patients enrolled in the Princess Margaret Lung Cancer Screening Program who had received clinic-based research spirometry. The three studies were: Danish Lung Cancer Screening Trial (DLST), National Lung Screening Trial (NLST), and the Ontario Lung Cancer Screening Program (OLCS). Lung cancer incidence was compared between those who would were included by the screening study eligibility criteria (Group I), those who were excluded by the eligibility criteria but demonstrated obstruction on spirometry (defined as a Forced Expiratory Volume in 1 Second % Predicted (FEV1%) &lt; 90%) (Group II), and those who did not meet eligibility criteria and had no obstruction (FEV1% ≥90) (Group III). Results: The 321 highest risk participants of the screening program had a mean age of 65 years and were 39% male. The median number of pack years in this group was 39. After undergoing spirometry, this cohort was screened using LDCT for a median of 3.3 years (range 1–8.1 years). Under DLST criteria, Groups I and II had virtually identical lung cancer incidences detected by screening at 13.1% and 13.6% of the individuals screened, respectively; Group III had a substantially lower incidence at 6.3%. Results were similar by NLST criteria where the incidence of screen-detected lung cancer were 13.7% for Groups I, 11.1% for Group II, and 8.6% for Group III. Under OLCS criteria, these values were 13.4% (Group I), 13.5% (Group II), and 8.2% (Group III). Conclusions: Individuals who were excluded from LDCT screening because they lacked other clinical eligibility criteria, but had a FEV1 &lt; 90%, had similar lung cancer incidence as patients who had met screening study eligibility criteria. Coordinating care for screening of at-risk individuals could be improved by incorporating spirometric tools.

Does a history of malignancy impact the survival of a subsequent endometrial adenocarcinoma? Should clinical trials eligibility criteria be revisited?

We aimed at finding the impact of prior malignancies on the survival of patients with endometrial adenocarcinoma using SEER database (from 1973 to 2014). We identified 127,988 patients who were diagnosed with endometrial adenocarcinoma (6485 had a prior malignancy), and we compared the overall and cancer-specific survival based on the presence or absence of a prior malignancy and the latency period between the two diagnoses using Kaplan–Meier test and Cox models. Adjusted cox models showed that a history of a prior malignancy neither affected the overall survival nor the cancer-specific survival of stage IV cases in all latency groups except the one diagnosed within 1 year of the first cancer. Therefore, there is no rational explanation for excluding stage IV endometrial adenocarcinoma patients with a prior malignancy from clinical trials except for the group that was diagnosed with endometrial adenocarcinoma within 1 year from the first cancer.Impact statementWhat is already known on this subject? Not enough evidence is found on the impact of prior malignancies on the survival of patients with subsequent endometrial adenocarcinoma.What do the results of this study add? History of a prior malignancy neither affects the overall survival of stage IV endometrial adenocarcinoma nor the cancer-specific survival. Only patients who had their second malignancy diagnosed within one year of the first malignancy should be excluded from clinical trials, while patients diagnosed within one to five years of the first cancer should be encouraged to enrol in clinical trials as they have an enhanced survival than patients without a history of malignancy.What are the implications of these findings for clinical practice and/or further research? We recommend that future researchers should consider including the aforementioned group of patients in their trials to achieve more accurate results and in order not to strip the patients of potential therapeutic benefits of enrolling in clinical trials.

P2-141 - Exclusion of stage IV transitional cell carcinoma of the bladder with prior cancers from clinical trials. Is it valid?

Background: Most clinical trials on stage IV transitional cell carcinoma of the bladder (TCC) exclude stage IV TCC cases with any history of a prior malignancy. However, no evidence is present to support this practice. The aim of our study is investigate the effects of a prior malignancy on survival outcomes of the stage IV TCC, and to question the benefits of including/excluding patients with prior malignancies in the clinical trials. Methods: The Surveillance, Epidemiology, and End Results (SEER) Program was accessed to review patients with stage IV TCC cases diagnosed between 1973 and 2014. We calculated overall and bladder cancer-specific survival of patients with/without prior cancers using unadjusted Kaplan-Meier and cox regression models. Results: We reviewed 8,275 patients with stage IV TCC, of which 798 had a history of a prior cancer. Overall survival of patients with prior cancers was not significantly difference from patients without prior cancers (P=.204). Adjustment for sex, age, race, marital status, grade of TCC, and undergoing surgery, showed similar results (HR = 1.033, 95%CI= .949-1.125, P=.452). When patients with prior cancers were divided according to the site of the prior cancer or the latency groups between the two diagnoses, none of site and latency groups showed significant difference in overall survival from patients with no prior cancers. Conclusion: Our study showed that a history of a prior malignancy had no significant effect on the survival of stage IV TCC. Based on these results, we recommend the reconsideration of clinical trials eligibility criteria regarding patients with prior malignancies. However, prior exposure to systemic treatment may still be needed to be taken into consideration. Further and more detailed studies are required to determine the best approaches.