Inclusion Criteria For Clinical Trials Research Articles

Characterisation and classification of oligometastatic disease: a European Society for Radiotherapy and Oncology and European Organisation for Research and Treatment of Cancer consensus recommendation

Oligometastatic disease has been proposed as an intermediate state between localised and systemically metastasised disease. In the absence of randomised phase 3 trials, early clinical studies show improved survival when radical local therapy is added to standard systemic therapy for oligometastatic disease. However, since no biomarker for the identification of patients with true oligometastatic disease is clinically available, the diagnosis of oligometastatic disease is based solely on imaging findings. A small number of metastases on imaging could represent different clinical scenarios, which are associated with different prognoses and might require different treatment strategies. 20 international experts including 19 members of the European Society for Radiotherapy and Oncology and European Organisation for Research and Treatment of Cancer OligoCare project developed a comprehensive system for characterisation and classification of oligometastatic disease. We first did a systematic review of the literature to identify inclusion and exclusion criteria of prospective interventional oligometastatic disease clinical trials. Next, we used a Delphi consensus process to select a total of 17 oligometastatic disease characterisation factors that should be assessed in all patients treated with radical local therapy for oligometastatic disease, both within and outside of clinical trials. Using a second round of the Delphi method, we established a decision tree for oligometastatic disease classification together with a nomenclature. We agreed oligometastatic disease as the overall umbrella term. A history of polymetastatic disease before diagnosis of oligometastatic disease was used as the criterion to differentiate between induced oligometastatic disease (previous history of polymetastatic disease) and genuine oligometastatic disease (no history of polymetastatic disease). We further subclassified genuine oligometastatic disease into repeat oligometastatic disease (previous history of oligometastatic disease) and de-novo oligometastatic disease (first time diagnosis of oligometastatic disease). In de-novo oligometastatic disease, we differentiated between synchronous and metachronous oligometastatic disease. We did a final subclassification into oligorecurrence, oligoprogression, and oligopersistence, considering whether oligometastatic disease is diagnosed during a treatment-free interval or during active systemic therapy and whether or not an oligometastatic lesion is progressing on current imaging. This oligometastatic disease classification and nomenclature needs to be prospectively evaluated by the OligoCare study.

High MYC mRNA Expression Is More Clinically Relevant than MYC DNA Amplification in Triple-Negative Breast Cancer.

DNA abnormalities are used in inclusion criteria of clinical trials for treatments with specific targeted molecules. MYC is one of the most powerful oncogenes and is known to be associated with triple-negative breast cancer (TNBC). Its DNA amplification is often part of the targeted DNA-sequencing panels under the assumption of reflecting upregulated signaling. However, it remains unclear if MYC DNA amplification is a surrogate of its upregulated signaling. Thus, we investigated the difference between MYC DNA amplification and mRNA high expression in TNBCs utilizing publicly available cohorts. MYC DNA amplified tumors were found to have various mRNA expression levels, suggesting that MYC DNA amplification does not always result in elevated MYC mRNA expression. Compared to other subtypes, both MYC DNA amplification and mRNA high expression were more frequent in the TNBCs. MYC mRNA high expression, but not DNA amplification, was significantly associated with worse overall survival in the TNBCs. The TNBCs with MYC mRNA high expression enriched MYC target genes, cell cycle related genes, and WNT/β-catenin gene sets, whereas none of them were enriched in MYC DNA amplified TNBCs. In conclusion, MYC mRNA high expression, but not DNA amplification, reflects not only its upregulated signaling pathway, but also clinical significance in TNBCs.

Characterizing Inclusion and Exclusion Criteria in Clinical Trials for CAR-T Cellular Therapy Among Adults with Hematologic Malignancies

Introduction: Clinical trial development and enrollment are pivotal to advancing cancer outcomes. Novel treatment modalities such as Chimeric Antigen Receptor (CAR) T-cell therapy is an intensive therapy that has altered the landscape of hematologic malignancy therapies, with several FDA approvals based on Phase I-II studies. Strict eligibility criteria are implemented to ensure safety of trial participants; however, these criteria can lead to barriers to patient enrollment, hinder the generalizability of the study, and result in a population of participants not representative of those who would benefit from therapy. The aim of this proposal is to characterize inclusion and exclusion criteria in clinical trials for CAR-T cellular therapy in adults with hematologic malignancies. Methods: The U.S. National Library of Medicine's Clinical Trial database of privately and publicly funded clinical studies was accessed June 2019 to assemble a list of studies with the following filters applied: hematologic, recruiting, not yet recruiting, not recruiting, active, completed, suspended, terminated studies, interventional studies, CAR, CAR T, chimeric antigen receptor, CAR NK, adult, older adult, early phase 1, phase 1, phase 2, phase 3. From this, 95 studies populated, 84 were utilized in this study and 11 studies excluded due to non-hematologic malignancy. Results: We analyzed 84 CAR-T clinical trials targeting multiple diseases (Table 1) including; acute lymphoblastic (n=7) and myeloid leukemia (n=2); lymphoma (n=6); multiple myeloma (n=40); multiple hematologic malignancies (n=27) and other (n=2). The majority of studies were phase 1 (n=47) or phase 1/2 (n=28). Upper age limit restrictions were in place for 53/84 (63%) of trials. Trials included the AYA population (n=5), ≤ age 65 (n=1), ≤ age 70 or 73 (n=26), ≤ age 75 or 78 (n=12), ≤ age 80 or 85 (n=9). Of the 84 trials, 65 (77%) had performance status inclusion criteria, most commonly was status ECOG 0-2 (n=23) and ECOG 0-1 (n=24). Patients were excluded for a history of a separate or concurrent malignancy in 52/84 (62%) trials, CNS disease was excluded in 45/84 (54%) trials and 70/84 (83%) clinical trials excluded infectious diseases; HIV (n=69) and Hepatitis B/C (n=64). Many studies had restrictions for impairment in organ function; renal impairment (n=66), cardiac deficits (n=67), and abnormal pulmonary function (n=44). Unique to CAR-T trials, 27/84 had restrictions in place for neurological disorders: epilepsy (n=15), history of brain injury (n=10), dementia (n=8), coordination/movement disorder (n=6), cerebellar disease (n=8), psychosis (n=7), paresis (n=6), history of stroke/aphasia (n=21), and active autoimmune or inflammatory disease of the central nervous system (n=3). Conclusion: CAR-T cellular therapy is a tremendous therapeutic advancement in the medical community. This study emphasizes, in detail, highly variable cross-study inclusion/exclusion criteria for early phase CAR-T studies. This new and promising therapy is actively being studied in a highly select group of patients and may not be generalizable to the older adult with hematologic malignancies due to non-uniform trial criteria. The applicability of this modality should be tempered by the understanding that CAR-T trials have overt age caps, ambiguous performance and comorbidity exclusions, and neurologic exclusions and play a role in limiting patient accessibility to novel clinical trial therapy. Confirmatory prospective and observational studies of CAR-T therapy in representative populations are a high priority. 1. Brudno JN, Kochenderfer JN. Toxicities of chimeric antigen receptor T cells: recognition and management. 2016 127:3321-3330. Doi: 10.1182/blood-2016-04-703751 2. Kim ES, Bruinooge SS, Roberts S, et al. Broadening Eligibility Criteria to Make Clinical Trials More Representative: American Society of Clinical Oncology and Friends of Cancer Research Joint Research Statement. J Clin Oncol. 2017;35(33):3737-3744. doi:10.1200/JCO.2017.73.7916 3. Unger JM, Cook E, Tai E, and Bleyer A. The Role of Clinical Trial Participation in Cancer Research: Barriers, Evidence, and Strategies. American Society of Clinical Oncology Educational Book. 2016; 36:185-198. Doi:10.1200/EDBK\_156686 Disclosures Wildes: Janssen: Research Funding; Carevive: Consultancy. Olin:Spectrum: Research Funding; Novartis: Research Funding. Artz:Miltenyi: Research Funding. Jaglowski:Unum Therapeutics Inc.: Research Funding; Kite: Consultancy, Other: advisory board, Research Funding; Juno: Consultancy, Other: advisory board; Novartis: Consultancy, Other: advisory board, Research Funding. William:Guidepoint Global: Consultancy; Defined Health: Consultancy; Techspert: Consultancy; Celgene Corporation: Consultancy; Kyowa Kirin, Inc.: Consultancy. Rosko:Vyxeos: Other: Travel support.

PMU85 LESSONS FOR BREAKING NEW GROUND WITH FIRST-IN-CLASS THERAPIES

To explore the access challenges faced by first-in-class treatments across therapeutic areas and identify optimal evidence and submission strategies to help secure desired reimbursement levels in the top-five European markets. We analysed products approved by the European Medicines Agency (EMA) within the last five years and filtered this list for first-in-class therapies, defined as first-to-market or on the basis of a novel mechanism of action. Our final analogue selection included treatments launched in three major therapeutic areas: rare diseases, non-rare diseases, and oncology. Using a targeted search protocol, we evaluated information on the regulatory label and examined the evidence package, including clinical trial design, inclusion and exclusion criteria, and the efficacy outcomes that supported approval. For each therapy, we compared the regulatory label with the reimbursement outcomes across markets to identify drivers for health technology assessment (HTA) decision-making and barriers to positive reimbursement outcomes. In oncology and non-rare diseases, reimbursement restrictions were imposed in therapies that failed to investigate treatment effect across the full population represented in the label. Similarly, therapies with pivotal trials that lacked inclusion of sub-populations representative of current clinical practice also faced HTA restrictions in these therapy areas. In contrast, HTA bodies were less likely to impose restrictions in treatments for rare diseases with high unmet need and lack of alternative options. First-in-class therapies with a broad regulatory label can achieve widespread unrestricted access only with an evidence package that spans the whole licensed indication. However, HTA bodies might be more lenient when evaluating treatments targeting diseases with high unmet need and lack of treatment options. Therefore, to maximize the success of submissions, manufacturers need to carefully consider the population within the clinical trials, but also ensure they have an accurate reflection of the level of unmet need in the target population.

Characteristics and treatment regimens across ERS SHARP severe asthma registries.

Little is known about the characteristics and treatments of patients with severe asthma across Europe, but both are likely to vary. This is the first study in the European Respiratory Society Severe Heterogeneous Asthma Research collaboration, Patient-centred (SHARP) Clinical Research Collaboration and it is designed to explore these variations. Therefore, we aimed to compare characteristics of patients in European severe asthma registries and treatments before starting biologicals.This was a cross-sectional retrospective analysis of aggregated data from 11 national severe asthma registries that joined SHARP with established patient databases.Analysis of data from 3236 patients showed many differences in characteristics and lifestyle factors. Current smokers ranged from 0% (Poland and Sweden) to 9.5% (Belgium), mean body mass index ranged from 26.2 (Italy) to 30.6 kg·m-2 (the UK) and the largest difference in mean pre-bronchodilator forced expiratory volume in 1 s % predicted was 20.9% (the Netherlands versus Hungary). Before starting biologicals patients were treated differently between countries: mean inhaled corticosteroid dose ranged from 700 to 1335 µg·day-1 between those from Slovenia versus Poland when starting anti-interleukin (IL)-5 antibody and from 772 to 1344 µg·day-1 in those starting anti-IgE (Slovenia versus Spain). Maintenance oral corticosteroid use ranged from 21.0% (Belgium) to 63.0% (Sweden) and from 9.1% (Denmark) to 56.1% (the UK) in patients starting anti-IL-5 and anti-IgE, respectively.The severe asthmatic population in Europe is heterogeneous and differs in both clinical characteristics and treatment, often appearing not to comply with the current European Respiratory Society/American Thoracic Society guidelines definition of severe asthma. Treatment regimens before starting biologicals were different from inclusion criteria in clinical trials and varied between countries.

Clinical outcome measures in SPMS trials: An analysis of the IMPACT and ASCEND original trial data sets

Background: Still too little is known about the natural history of clinical outcome measures beyond the Expanded Disability Status Scale (EDSS), such as the timed 25-foot walk (T25FW) and nine-hole peg test (9HPT) in secondary progressive multiple sclerosis (SPMS). Objective: To describe progression on the EDSS, T25FW, 9HPT, and their combinations. To investigate the association of the baseline characteristics age, sex, EDSS, T25FW, gadolinium-enhancing lesions, and relapse activity with EDSS and T25FW progression. Methods: Using original trial data from the placebo arms of the IMPACT and ASCEND randomized controlled trials, we describe disability progression (with and without 3- or 6-month confirmation). We investigated the association of selected baseline characteristics with EDSS and T25FW progression over 2 years using binary logistic regression. Results: T25FW was the single outcome measure with the largest proportion of patients progressing, followed by EDSS and 9HPT. EDSS and T25FW at baseline were associated with EDSS and T25FW progression in both data sets. Age and relapse activity were only mild and inconsistent predictors, while sex and gadolinium enhancement at baseline did not predict disability progression in either data set. Conclusion: Our analyses inform the selection of primary outcome measures as well as inclusion criteria for clinical trials in SPMS.

Commonly Used Immunosuppressives Affect Mesenchymal Stem Cell Viability and Function: Should We Rethinking Clinical Trial Inclusion and Exclusion Criteria?

Abstract Background Clinical trials utilizing mesenchymal stem cells (MCSs) for the treatment of perianal Crohn disease are expanding. Most enrolled Crohn patients are being actively treated with corticosteroids, immunomodulators, and biologic therapy for their luminal and perianal disease at the time of enrollment and treatment. Aim We sought to broaden the understanding of the effect of corticosteroids, immunomodulators, and biologic therapy on the viability and function of MCSs. This information is important for tailoring inclusion and exclusion criteria of clinical trials. Methods Human adipose–derived mesenchymal stem cells (hAMCSs) were harvested and isolated from healthy patient donors. At Passage 3, hAMCSs were treated with 7 commonly used immunosuppressive therapies used to treat Crohn disease at increasing concentrations: dexamethasone, methotrexate, azathioprine, 6-mercaptopurine, infliximab, vedolizumab, and ustekinumab. Cell proliferation, migration, and cytokine secretion were analyzed at Day 4. Results Dexamethasone and azathioprine and 6-mercaptopurien affected cell proliferation and migration. Dexamethasone even resulted in cell death at high physiologic concentrations. The same drugs also had the most profound impacts on IL-6, IL-8, and monocyte chemoattractant protein-1 secretion profiles. Biologic therapies, including anti-tumor necrosis factor, anti-interleukin, and anti-integrins, had the smallest impact on hAMSC proliferation, migration, and cytokine secretion profile. Conclusions In clinical trials with MCSs, a washout period may be recommended for corticosteroids and immunomodulators to minimize any effect of systemic immunosuppression on MSC function and efficacy.

Definition of Synchronous Oligometastatic Non–Small Cell Lung Cancer—A Consensus Report

IntroductionImproved outcome has been shown in patients with synchronous oligometastatic (sOM) NSCLC when treated with radical intent. As a uniform definition of sOM NSCLC is lacking, we developed a definition and diagnostic criteria by a consensus process. MethodsA pan-European multidisciplinary consensus group was established. Consensus questions were built on the basis of current controversies, and definitions were extracted from a survey, cases and a systematic review. This statement was formulated during a consensus meeting. ResultsIt was determined that definition of sOM NSCLC is relevant when a radical treatment that may modify the disease course (leading to long-term disease control) is technically feasible for all tumor sites with acceptable toxicity. On the basis of the review, a maximum of five metastases and three organs was proposed. Mediastinal lymph node involvement was not counted as a metastatic site. Fludeoxyglucose F 18 positron emission tomography–computed tomography and brain imaging were considered mandatory. A dedicated liver magnetic resonance imaging scan was advised for a solitary liver metastasis, and thoracoscopy and biopsies of distant ipsilateral pleural sites were recommended for a solitary pleural metastasis. For mediastinal staging, fludeoxyglucose F 18 positron emission tomography–computed tomography was deemed the minimum requirement, with pathological confirmation recommended if this influences the treatment strategy. Biopsy of a solitary metastatic location was mandated unless the multidisciplinary team is of the opinion that the risks outweigh the benefits. ConclusionA multidisciplinary consensus statement on the definition and staging of sOM NSCLC has been formulated. This statement will help to standardize inclusion criteria in future clinical trials.

NOVEL DIGITALIZED MARKERS FOR SCREENING AND DISEASE TRAJECTORY TRACKING IN CLINICAL TRIALS

Currently, to enroll participants into pharmaceutical trials strenuous and costly procedures are applied to test whether participants meet inclusion criteria or not; this includes travel to clinics, costly brain imaging, invasive assessments, or costly f2f assessments with experts. Moreover, screening for such inclusion criteria in clinical trials has significant fail rates and significant resources have to be spent on participant screening to enroll only a fraction of them (10%). Standard cognitive assessment typically uses a set of speech-based cognitive tests which have the potential to be conducted remotely in telecommunication settings. However, only recently speech analysis and automatic speech recognition, as well as semantic speech processing have become mature enough to automate such speech-based testing procedures. The European DeepSpA project aims to replace in-person manual pre-screening procedures by remote (semi-)automated analyses methods detecting relevant phenotype for novel Alzheimer trials automatically. To evaluate the feasibility of the phone-based solution in a real-world scenarioand examine the predictive potential for prognostic diagnosis, information extracted over the phone from the participant's speech in cognitive and narrative speech tasks will be analyzed for its usefulness for remote pre-screening. 120 participants at preclinical stages of cognitive impairment will be recruited from the local memory clinic. At baseline, a complete dataset (including speech recordings) will be collected, consisting of clinical data and biobank materials, e.g. blood samples, MRI and cerebrospinal fluid. After 6 months the participants will be called for a brief remote follow up evaluation on the phone consisting of a short interview on subjective cognitive decline, a verbal memory task, and fluency tasks in which speech features will be collected through a semi-automatic phone-based interface. Final data sets will be compared to each other. We expect to obtain comparable results between the telecommunication administration method and the traditional application. First preliminary results as well as a working demo version will be presented at the preconference. Built on existing speech technologies, we expect this first-of-its-kind service to allow to remotely conduct neurocognitive testing thus pre-screening of potential trial participants. This will significantly reduce the overall costs associated with the screening and speed up the trials' preparatory activities.

Subthreshold amyloid and its biological and clinical meaning

The development of in vivo imaging of the pathologic hallmark of Alzheimer disease (AD), β-amyloid (Aβ), altered the framing of its pathophysiology and formulation of inclusion criteria for clinical trials. Recent evidence suggests that in vivo measures of Aβ deposition below a threshold indicative of Aβ positivity carry critical information on future cognitive decline and accumulation of AD pathology, potentially already at a younger age. Here, we integrate the existing literature on histopathology of Aβ and its convergence and divergence with in vivo Aβ imaging. The evidence presented amounts to a reconceptualization, in which we advocate for a closer look into Aβ accumulation rates in earlier life, the factors that promote accumulation, comparative studies with different markers of Aβ, and longitudinal designs to elucidate when AD pathology rises and how it shifts from benign to malignant stages that ultimately define AD. These efforts open a new window of opportunity for disease-modifying interventions.

Changes in Patient Demographics and Outcomes in the Inpatient Rehabilitation Facility Traumatic Brain Injury Population from 2002 to 2016: Implications for Patient Care and Clinical Trials.

Initial studies examining patient demographics and outcomes in traumatic brain injury (TBI) suggest a trend toward increasing patient age and decreasing rehabilitation length of stay, but such studies have not been repeated since the passage of healthcare reform legislation, most notably the Affordable Care Act. This study utilized the Uniform Data System for Medical Rehabilitation® (UDSMR) for patients admitted to medical rehabilitation facilities after sustaining a TBI from January 1, 2002 through December 31, 2016. Trends for demographic and medical data were evaluated. In total, 233,843 patients from 1290 facilities were included; mean patient age increased from 54.1 to 64.8 years, rehabilitation length of stay decreased from 19 to 14.5 days, and mean admission Functional Independence Measure® (FIM) decreased from 56.9 to 54.5. Sex and racial distribution remained relatively stable across all years, as did discharge FIM. There was an increase in Medicare patients from 40.7% to 62.1%, a concomitant decrease in commercially insured patients from 29.2% to 15.4%, and a decrease in unreimbursed patients from 7.2% to 2.6% over the course of the study. Based on these data, medical rehabilitation facilities appear to be admitting an older TBI patient population that is less functional on admission and discharging them after shorter rehabilitation lengths of stay. Similar discharge functional status, despite shorter rehabilitation lengths of stay and an older population may suggest a change in the typical mechanism of injury. Many current TBI patients would fail to meet inclusion criteria for post-acute clinical trials in TBI because of their age, and treatments based on such trials may not be generalizable, which has significant implications on both research and clinical care realms within brain injury rehabilitation.

Prediction of Organ-confined Disease in High- and Very-high-risk Prostate Cancer Patients Staged with Magnetic Resonance Imaging: Implications for Clinical Trial Design

BackgroundHigh-risk (HR) prostate cancer (PCa) is a heterogeneous disease leading to difficulties in designing appropriate inclusion criteria for clinical trials. ObjectiveTo describe clinical predictors of organ-confined disease in HR or very-high-risk (VHR) PCa patients staged with multiparametric magnetic resonance imaging with endorectal coil (mp-MRI-ER). Design, setting, and participantsWe reviewed 366 HR/VHR PCa patients who had preoperative mp-MRI-ER, and underwent radical prostatectomy and extended pelvic lymph node dissection between 2006 and 2015. InterventionRadical prostatectomy with preoperative mp-MRI-ER. Outcome measurements and statistical analysisWe used multivariable logistic regression modeling to assess for associations with ≤ pT2N0 stage and multivariable cox modeling to assess for associations with biochemical failure. Results and limitationsOf 366 patients, 132 had ≤ pT2N0 disease. For the entire cohort, negative staging mp-MRI-ER (odds ratio [OR] 1.73, 95% confidence interval [CI] 1.06–2.83, p = 0.03), lower prostate-specific antigen (PSA; OR 0.98, 95% CI 0.97–1.00, p = 0.02), and fewer cores of Gleason ≥8 cancer (OR 0.86, 95% CI 0.79–0.93, p = 0.0002) were associated with ≤pT2N0 disease. In HR patients only, negative mp-MRI-ER (OR 3.41, 95% CI 1.73–6.72, p = 0.0004) and fewer than four cores of Gleason ≥8 disease (OR 3.38, 95% CI 1.20–9.56, p = 0.02) were still associated with ≤pT2N0 disease. Lack of non–organ-confined disease on MRI was associated with superior biochemical recurrence-free survival (p = 0.02). Limitations of this study include lack of a central review or quality control of the MRI reporting. ConclusionsIn HR PCa, negative staging mp-MRI-ER, fewer positive cores of Gleason >8, and lower PSA were significant predictors of pathologic organ-confined disease. Improved prediction of organ-confined disease in HR patients may allow for their inclusion into studies evaluating treatments from which they would otherwise be excluded based solely on their HR status. Patient summaryIn patients with high-risk prostate cancer, prostate magnetic resonance imaging along with other clinical parameters may help determine which patients are likely to have disease confined to the prostate and thus be eligible for clinical trials that they otherwise might be excluded from based on their high-risk status alone.

Early prediction of acute traumatic coagulopathy: a validation of the COAST score using the German Trauma Registry.

Early identification of trauma patients at risk of developing acute traumatic coagulopathy (ATC) is important for initiating appropriate, coagulopathy-focused treatment. A clinical ATC prediction tool is a quick, simple method to evaluate risk. The COAST score was developed and validated in Australia but is yet to be validated on a European population. We validated the ability of the COAST score to predict coagulopathy and adverse bleeding-related outcomes on a large European trauma population. The COAST score was modified and applied to a retrospective cohort of trauma patients from the German Trauma Registry (TR-DGU). The primary outcome was coagulopathy defined as INR > 1.5 or aPTT > 60s. Secondary outcomes were massive transfusion, blood product requirements, urgent surgery and mortality. The cohort included adult trauma patients with Injury Severity Score > 15 treated in Germany/Austria in 2012-2016. 15,370 cases were included, of which 10.9% were coagulopathic. The COAST score performed with sensitivity 21.6% and specificity 94.2% at a threshold of COAST ≥ 3. The AUROC was 0.625 (95% CI 0.61-0.64). The COAST score also identified patients who had more massive transfusions (15.3% v 1.6%), more emergency surgery (49.6% v 28.2%), and higher early (21.7% v 5.4%) and total in-hospital mortality (38.1% v 14.5%). This large retrospective study demonstrated that the modified COAST score predicts coagulopathy with low sensitivity but high specificity. A positive COAST score identified a group of patients with bleeding-related adverse outcomes. This score appears adequate to act as an inclusion criterion for clinical trials targeting ATC.

Treatment of Patients with Advanced Gastroesophageal Adenocarcinoma: Does Age Matter?

Gastroesophageal cancer is the fourth most frequent malignant disease and, despite significant advances in chemotherapy, the prognosis of unresectable or recurrent gastroesophageal cancer is poor. The majority of patients, nearly two-thirds, are over the age of 65years at diagnosis. Elderly patients are a heterogeneous population and aging occurs at different rates in different individuals. The chronological age of a patient does not necessarily reflect the physiological age. However, elderly patients are more likely to have a number of concomitant diseases and impaired organ function, which should be considered when making treatment decisions. Therefore, treatment in older adults requires particular caution, and physiologic age rather than chronologic age should be considered when deciding for or against systemic therapy. Older patients are generally underrepresented in clinical trials and many elderly patients do not receive effective combination therapies due to concerns with tolerability. Age itself is not a negative predictive factor and treatment should not be omitted just on the basis of chronological age. Older patients who fulfill the standard inclusion criteria of clinical trials seem to have a similar advantage from palliative chemotherapy for gastroesophageal adenocarcinoma as younger patients; however, large prospective trials in the elderly population are needed to guide clinicians in making evidence-based decisions.

Development and external validation of a pathological nodal staging score for patients with clear cell renal cell carcinoma.

To develop and externally validate a model that quantifies the likelihood that a pathologically node-negative patient with clear cell renal cell carcinoma (cRCC) has, indeed, no lymph node metastasis (LNM). Data from 1389 patients treated with radical nephrectomy (RN) and lymph node dissection (LND) were analyzed. For external validation, we used data from 2270 patients in the Surveillance, Epidemiology and End Results (SEER) database. We estimated the sensitivity of pathologic nodal staging using a beta-binomial model and developed a pathological nodal staging score (pNSS), which represents the probability that a patient is correctly staged as node negative as a function of the number of examined lymph nodes (LNs). The mean and median number of LNs removed were 7.0 and 5.0 (standard deviation, SD 6.6; interquartile range, IQR 7.0) in the development cohort and 5.6 and 2.0 (SD 8.6, IQR 5.0) in the validation cohort, respectively. The probability of missing a positive LN decreased with increasing number of LNs examined. In both the validation and the development cohort, the number of LNs needed for correctly staging a patient as node negative increased with higher pathological tumor stage and Fuhrman grade. The number of examined LNs needed for adequate nodal staging in cRCC depends on pathological tumor stage and Fuhrman grade. We developed here and then externally validated a pNSS, which could help to refine patient counseling, decision-making regarding risk-stratified surveillance regimens and inclusion criteria for clinical trials of adjuvant therapy.

Accrual to Clinical Trials (ACT): A Clinical and Translational Science Award Consortium Network.

The Accrual to Clinical Trials (ACT) network is a federated network of sites from the National Clinical and Translational Science Award (CTSA) Consortium that has been created to significantly increase participant accrual to multi-site clinical trials. The ACT network represents an unprecedented collaboration among diverse CTSA sites. The network has created governance and regulatory frameworks and a common data model to harmonize electronic health record (EHR) data, and deployed a set of Informatics for Integrating Biology and the Bedside (i2b2) data repositories that are linked by the Shared Health Research Information Network (SHRINE) platform. It provides investigators the ability to query the network in real time and to obtain aggregate counts of patients who meet clinical trial inclusion and exclusion criteria from sites across the United States. The ACT network infrastructure provides a basis for cohort discovery and for developing new informatics tools to identify and recruit participants for multi-site clinical trials.

Abstract 3664: A workflow to evaluate PD-L1 protein expression on circulating tumor cells (CTCs) from non-small cell lung cancer (NSCLC)

Abstract Introduction Many tumors evade immune surveillance by deploying immunosuppressive mechanisms and co-opting immune checkpoint pathways, such as PD-1/PD-L1. PD-1/PD-L1 pathway blockade is a highly promising therapy and has elicited durable antitumor responses in a variety of cancers. Challenges in advancing immunotherapies lie in patient stratification and monitoring therapy. Evaluation of PD-L1 expression is generally regarded as an inclusion criterion for clinical trials. Current methods rely on the analysis of excisional biopsies, which are invasive and carry associated medical risks. Isolation and analysis of CTCs is a noninvasive alternative that may provide, in real-time, more representative information on tumor biomarkers, and allow the monitoring of treatment effectiveness over time. Here, we present an integrated workflow for the analysis of PD-L1 protein expression on CTCs from metastatic NSCLC patients isolated with the Vortex Biosciences VTX-1 liquid biopsy system. Methods Cell lines expressing various level of PD-L1 and white blood cells prepared from healthy donors were used to optimize the PD-L1 immunostaining assay. Several PD-L1 antibodies were titrated, and their specificity estimated with isotype controls. PD-L1 expression quantification was evaluated using two independent methods i) Zen 2 imaging (Zeiss) and ii) CellProfiler software. Clinical validation was performed on blood samples collected from a cohort of metastatic NSCLC patients (stage IV) with known PD-L1 tumor status. CTCs were isolated using the VTX-1 Liquid Biopsy System, stained (PD-L1, CK, CD45, CD11b, DAPI) and classified, then PD-L1 expression was quantified. Results We have developed a PD-L1 immunofluorescent assay that shows specificity, sensitivity, and very good intra-assay repeatability. The two methods evaluated for the quantification of PD-L1 expression provided equivalent data and could be used interchangeably. The PD-L1 assay was further validated on CTCs isolated from a small cohort of metastatic NSCLC patients. Preliminary data shows heterogeneity in PD-L1 expression levels across CTCs from the same patient. Interestingly, among PD-L1 positive CTCs, both traditional CK+/PD-L1+ and CK-/PD-L1+ cells were observed. To move toward a more automated workflow for immunostaining, imaging, and fluorescence signal analysis, methods to collect CTC on glass slides were evaluated, with cell recovery ranging from 33 to 98%. Conclusion We demonstrated the feasibility of evaluating PD-L1 protein expression on NSCLC's CTCs isolated with the VTX-1 Liquid Biopsy System. While further clinical validation is warranted, this test could represent a simple, non-invasive method to help identify patients most likely to respond to PD-1/PD-L1 immunotherapies. Future work will focus on compatibility of the assay with autostainers and fully automated imaging and analysis platforms. Citation Format: Corinne Renier, Charles L. Wilkerson, SJ Claire Hur, Da Eun Rachel Park, Clementine A. Lemaire, Melissa Matsumoto, James Carroll, Steve Crouse, Jonathan W. Goldman, Edward B. Garon, Dino Di Carlo, Elodie Christen-Sollier. A workflow to evaluate PD-L1 protein expression on circulating tumor cells (CTCs) from non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3664.

Age-Related Changes in Immunological and Physiological Responses Following Pulmonary Challenge.

This review examines the current status of knowledge of sepsis and pneumonia in the elderly population and how the dynamics of the pulmonary challenge affects outcome and consequences. Led by an unprecedented shift in demographics, where a larger proportion of the population will reach an older age, clinical and experimental research shows that aging is associated with certain pulmonary changes, but it is during infectious insult of the lungs, as in the case of pneumonia, that the age-related differences in responsiveness and endurance become obvious and lead to a worse outcome than in the younger population. This review points to the neutrophil, and the endothelium as important players in understanding age-associated changes in responsiveness to infectious challenge of the lung. It also addresses how the immunological set-point influences injury-repair phases, remote organ damage and how intake of drugs may alter the state of responsiveness in the users. Further, it points out the importance of considering age as a factor in inclusion criteria in clinical trials, in vitro/ex vivo experimental designs and overall interpretation of results.

Lack of uniformity in inclusion criteria for clinical trials of atopic dermatitis: A systematic review

Lack of uniformity in inclusion criteria for clinical trials of atopic dermatitis: A systematic review

386 A systematic review of inclusion criteria for clinical trials of atopic dermatitis

386 A systematic review of inclusion criteria for clinical trials of atopic dermatitis