Entry Criteria For Clinical Trials Research Articles

ACTING EARLY TO PROTECT RENAL: BEYOND GLYCEMIC CONTROL OF SGLT2 INHIBITORS

Type 2 Diabetes Mellitus (T2DM) is the leading cause of chronic kidney disease (CKD), accounting for almost half of all cases of kidney failure that necessitate replacement therapy. Cardiovascular disease (CVD) is the leading cause of death in patients with T2DM and CKD. To lower blood glucose levels by inhibiting glucose reabsorption in the proximal tubule, sodium/glucose cotransporter 2 inhibitors (SGLT2-i) were developed. Consistent reductions in risks for secondary kidney disease end points (albuminuria and a composite of serum creatinine doubling or 40% estimated glomerular filtration rate decline, kidney failure, or death) were recognized in clinical trials designed to demonstrate the CVD safety of SGLT2i in type 2 diabetes mellitus (T2DM), as well as reductions in CVD events. The DECLARE-TIMI58 (Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58, or DECLARE) trial in patients with T2DM, urinary albumin-creatinine ratio >300 mg/g, and estimated glomerular filtration rate of 30 to 90 mL/min/1.73 m2 established the kidney and CVD benefits of dapagliflozin in patients with CKD. SGLT2i boost glomerular hemodynamic function and are figured to augment other local and systemic processes that contribute to the development of CKD and CVD. According to latest Indonesian Society of Endocrinologist’s guideline, patients with T2DM was recommended to use SGLT2i to reduce their risk of CKD and CVD, in accordance with the clinical trial entry criteria. To achieve widespread use of these life-saving medications, effective implementation strategies are required.

Re‐examining the impact of adjusting for education and sex the RBANS delayed memory score: Implications on the cut‐offs used to detect cognitive impairment in prodromal Alzheimer’s disease. Data from the EPAD‐LCS study.

AbstractBackgroundthe RBANS is a multilingual brief cognitive battery commonly used in both clinical practice and research. Its delayed memory index has been used as entry criteria for clinical trials in early stages of Alzheimer’s disease (AD). Although several studies reported a significant effect of education and sex in RBANS scores, the published normative data only provide adjustments by age. We aimed at exploring the impact of sex and education in the age‐adjusted scores and studying the percentage of change in the classification of memory impairment, along with the association with AD biomarker status after adjusting for education and sex.MethodsWe analyzed data from the EPAD baseline Longitudinal Cohort Study (n = 1,716 [Clinical Dementia Rating [CDR] = 0 n = 1,233; CDR = 0.5 n = 483]), see Table 1. We used multiple regression to assess the impact of years of education and sex on the age‐adjusted delayed memory index within the CDR = 0 sample. The coefficients obtained were used to generate sex‐, education‐ and age‐adjusted scores. The whole sample was classified as having/not having memory impairment (<85 points) with published and full adjusted scores. Within CDR = 0.5 group, the concordance between presence of memory impairment and pathologic amyloid‐β (A+; cut‐off = 1000 pg/ml) and p‐tau levels (T+; cut‐off = 27 pg/ml) in cerebrospinal fluid was assessed.ResultsEducation and sex (being a woman) had significant positive effects (p<0.001) on the age‐adjusted delayed memory scores (Partial eta2 = 0.035 and 0.010). We observed a change of up to 10 points after sex and education adjustment (mean[SD] change = 0.83 [2.6]). The use of fully adjusted scores increased the number of individuals classified as having memory impairment by 1.7%. Within the CDR = 0.5 group, these scores identified 2.5% individuals with memory impairment that were considered within the normal range using the regular norms, and increased the concordance between memory impairment and A+T+ biomarkers by almost 5% (regular norms = 65.2%, adjusted norms = 69.7%).ConclusionAlthough small, education and sex exert a relevant effect in the delayed memory score of the RBANS and improve clinical and biomarker concordance of the conclusions on the cognitive status derived from them. Adding education and sex adjustments to the RBANS measures may improve the selection of individuals for clinical trials.

A Large Gap in Patients' Characteristics and Outcomes between the Real-World and Clinical Trial Settings in Community-Acquired Pneumonia and Healthcare-Associated Pneumonia.

(1) Introduction: Evidence-based medicine (EBM) is necessary to standardize treatments for infections because EBM has been established based on the results of clinical trials. Since entry criteria for clinical trials are very strict, it may cause skepticism or questions on whether the results of clinical trials reflect the real world of medical practice. (2) Methods: To examine how many patients could join any randomized clinical trials for the treatment of community-acquired pneumonia (CAP) and healthcare-associated pneumonia (HCAP). We reviewed all the pneumonia patients in our institute during 2014–2017. The patients were divided into two groups: patients who were eligible for clinical trials (participation-possible group), and those who were not (participation-impossible group). Exclusion criteria for clinical trials were set based on previous clinical trials. (3) Results: A total of 406 patients were enrolled in the present study. Fifty-seven (14%) patients were categorized into the participation-possible group, while 86% of patients belonged to the participation-impossible group. Patients in the participation-possible group had less comorbidities and more favorable outcomes than those with the participation-impossible group. As for the outcomes, there were significant differences in the 30-day and in-hospital mortality rates between the two groups. In addition, the participation-possible group showed a longer overall survival time than the participation-impossible group (p < 0.001 by Log-Rank test). (4) Conclusion: There is a difference in patients’ profile and outcomes between clinical trials and the real world. Though EBM is essential to advance medicine, we should acknowledge the facts and the limits of the clinical trials.

To what degree could clinical trials in evidence based medicine reflect reality in the treatment of candidemia?

Evidenced based medicine (EBM) is necessary to standardize or treatment for infection since EBM is established based on the results of clinical trials. Entry criteria for clinical trials are very strict, and many patients have difficulties in being enrolled in any clinical trials regarding candidemia. It is questionable if the results of clinical trials reflect the real world of general medicine in this case. For the purpose of examining how many patients could join any randomized clinical trials for the treatment of candidemia, we reviewed all the candidemia patients in our institute during 2014-2018. The patients were divided into two groups: patients who were eligible for clinical trials (participation possible group), and those who were not (participation impossible group). Exclusion criteria for clinical trials were set based on previous clinical trials. A total of 70 patients was enrolled in this study. The median age was 73 years (range 36-93 years). Of these, 41 patients (59%) were male. As for site of infections, catheter related blood stream infection was most frequently seen in 37 (53%). Seventeen patients (24%) were classified as participation possible group and 53 patients (76%) were participation impossible group. Comparing the two groups, participation possible group patients have much better performance status, have less comorbidities and have longer overall survival times than participation impossible group patients. Only 24% of candidemia patients were eligible for the clinical trials. Thus, we can see that clinical trials might not correctly reflect the real world among candidemia patients.

SGLT2 Inhibition for CKD and Cardiovascular Disease in Type 2 Diabetes: Report of a Scientific Workshop Sponsored by the National Kidney Foundation

Diabetes is the most frequent cause of chronic kidney disease (CKD), leading to nearly half of all cases of kidney failure requiring replacement therapy. The principal cause of death among patients with diabetes and CKD is cardiovascular disease (CVD). Sodium/glucose cotransporter 2 (SGLT2) inhibitors were developed to lower blood glucose levels by inhibiting glucose reabsorption in the proximal tubule. In clinical trials designed to demonstrate the CVD safety of SGLT2 inhibitors in type 2 diabetes mellitus (T2DM), consistent reductions in risks for secondary kidney disease end points (albuminuria and a composite of serum creatinine doubling or 40% estimated glomerular filtration rate decline, kidney failure, or death), along with reductions in CVD events, were observed. In patients with CKD, the kidney and CVD benefits of canagliflozin were established by the CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) trial in patients with T2DM, urinary albumin-creatinine ratio>300mg/g, and estimated glomerular filtration rate of 30 to<90mL/min/1.73m2. To clarify and support the role of SGLT2 inhibitors for treatment of T2DM and CKD, the National Kidney Foundation convened a scientific workshop with an international panel of more than 80 experts. They discussed the current state of knowledge and unanswered questions to propose therapeutic approaches and delineate future research. SGLT2 inhibitors improve glomerular hemodynamic function and are thought to ameliorate other local and systemic mechanisms involved in the pathogenesis of CKD and CVD. SGLT2 inhibitors should be used when possible by people with T2DM to reduce risks for CKD and CVD in alignment with the clinical trial entry criteria. Important risks of SGLT2 inhibitors include euglycemic ketoacidosis, genital mycotic infections, and volume depletion. Careful consideration should be given to the balance of benefits and harms of SGLT2 inhibitors and risk mitigation strategies. Effective implementation strategies are needed to achieve widespread use of these life-saving medications.

SGLT2 Inhibition for CKD and Cardiovascular Disease in Type 2 Diabetes: Report of a Scientific Workshop Sponsored by the National Kidney Foundation.

Diabetes is the most frequent cause of chronic kidney disease (CKD), leading to nearly half of all cases of kidney failure requiring replacement therapy. The principal cause of death among patients with diabetes and CKD is cardiovascular disease (CVD). Sodium/glucose cotransporter 2 (SGLT2) inhibitors were developed to lower blood glucose levels by inhibiting glucose reabsorption in the proximal tubule. In clinical trials designed to demonstrate the CVD safety of SGLT2 inhibitors in type 2 diabetes mellitus (T2DM), consistent reductions in risks for secondary kidney disease end points (albuminuria and a composite of serum creatinine doubling or 40% estimated glomerular filtration rate decline, kidney failure, or death), along with reductions in CVD events, were observed. In patients with CKD, the kidney and CVD benefits of canagliflozin were established by the CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) trial in patients with T2DM, urinary albumin-creatinine ratio >300 mg/g, and estimated glomerular filtration rate of 30 to <90 mL/min/1.73 m2. To clarify and support the role of SGLT2 inhibitors for treatment of T2DM and CKD, the National Kidney Foundation convened a scientific workshop with an international panel of more than 80 experts. They discussed the current state of knowledge and unanswered questions in order to propose therapeutic approaches and delineate future research. SGLT2 inhibitors improve glomerular hemodynamic function and are thought to ameliorate other local and systemic mechanisms involved in the pathogenesis of CKD and CVD. SGLT2 inhibitors should be used when possible by people with T2DM to reduce risks for CKD and CVD in alignment with the clinical trial entry criteria. Important risks of SGLT2 inhibitors include euglycemic ketoacidosis, genital mycotic infections, and volume depletion. Careful consideration should be given to the balance of benefits and harms of SGLT2 inhibitors and risk mitigation strategies. Effective implementation strategies are needed to achieve widespread use of these life-saving medications.

Lung cancer in African-Americans and analysis of estrogen plus progestin use.

e18258 Background: The 15-year Women’s Health Initiative (WHI) sponsored by the NIH has provided a robust dataset on health risks for post-menopausal black women (BW), including the impact of hormone therapy (HRT) on cancer risk. Women enrolled in the WHI randomized, placebo-controlled trial and taking HRT demonstrated no increase in lung cancer incidence, but a statistically significant increase in mortality. However, effects of estrogen plus progestin on non-small cell lung cancer (NSCLC) incidence and outcomes has not been extensively examined, especially in African Ancestry (AA) and smoking history. Methods: Study participants were identified who met WHI clinical trial entry criteria. Cox regression models and Kaplan-Meier method plots were utilized. Analyses adjusted for age, BMI, education, smoking status, alcohol use, health status, and physical activity. A secondary analysis was performed on BW based on AA via Affymetrix Human SNP Array. Results: 161, 808 pts were enrolled from October 1993 to December 1998 (after exclusions total analytic cohort = 142,503). 128,682 (90%) were white (WW) and 13,821 (10%) were BW. BW had lower incidence of NSCLC compared to WW (HR 0.68; P &lt; .0001). HRT participants had a 55% increase in incidence of NSCLC (p &lt; .0001). Former alcohol users had highest risk of NSCLC incidence (HR 2.72; p &lt; 0.0001). Age groups (55-59 years; 60-69 years; 70-79 years) were significantly less associated with BW compared to the youngest(50-54 years; P &lt; .0001). HRT participants were more likely BW (OR 1.17; p &lt; .0001). More current smokers were BW compared to WW (OR 1.75; p &lt; .0001). HRT participants had increased risk of death to NSCLC (HR 1.29; p &lt; .001). There was a trend for survival (p = 0.3667) in WW participants compared to BW (32 vs 28.0 months, respectively). BW who had &gt; 80% AA had a decreased incidence NSCLC trend compared to BW with &lt; 80% AA (HR 0.81; p = 0.2806). Conclusions: BW, especially those with high levels of AA had decreased incidence of NSCLC. Those patients who received HRT had higher incidence and death from NSCLC. Further investigations are required to understand the mechanisms that AA and HRT alter risks associated with NSCLC.

Normative Standards for HRpQCT Parameters in Chinese Men and Women.

Assessing bone architecture using high-resolution peripheral quantitative computed tomography (HRpQCT) has the potential to improve fracture risk assessment. The Normal Reference Study aimed to establish sex-specific reference centile curves for HRpQCT parameters. This was an age-stratified cross-sectional study and 1072 ambulatory Chinese men (n = 544) and women (n = 528) aged 20 to 79 years, who were free from conditions and medications that could affect bone metabolism and had no history of fragility fracture. They were recruited from local communities of Hong Kong. Reference centile curves for each HRpQCT parameter were constructed using generalized additive models for location, scale, and shape with age as the only explanatory variable. Patterns of reference centile curves reflected age-related changes of bone density, microarchitecture, and estimated bone strength. In both sexes, loss of cortical bone was only evident in mid-adulthood, particularly in women with a more rapid fashion probably concurrent with the onset of menopause. In contrast, loss of trabecular bone was subtle or gradual or occurred at an earlier age. Expected values of HRpQCT parameters for a defined sex and age and a defined percentile or Z-score were obtained from these curves. T-scores were calculated using the population with the peak values as the reference and reflected age- or menopause-related bone loss in an older individual or the room to reach the peak potential in a younger individual. These reference centile curves produced a standard describing a norm or desirable target that enables value clinical judgements. Percentiles, Z-scores, and T-scores would be helpful in detecting abnormalities in bone density and microarchitecture arising from various conditions and establishing entry criteria for clinical trials. They also hold the potential to refine the diagnosis of osteoporosis and assessment of fracture risk. © 2018 American Society for Bone and Mineral Research.

NCCN Guidelines Insights: Central Nervous System Cancers, Version 1.2017

For many years, the diagnosis and classification of gliomas have been based on histology. Although studies including large populations of patients demonstrated the prognostic value of histologic phenotype, variability in outcomes within histologic groups limited the utility of this system. Nonetheless, histology was the only proven and widely accessible tool available at the time, thus it was used for clinical trial entry criteria, and therefore determined the recommended treatment options. Research to identify molecular changes that underlie glioma progression has led to the discovery of molecular features that have greater diagnostic and prognostic value than histology. Analyses of these molecular markers across populations from randomized clinical trials have shown that some of these markers are also predictive of response to specific types of treatment, which has prompted significant changes to the recommended treatment options for grade III (anaplastic) gliomas.

New Perspectives in Rheumatology: Biomarkers as Entry Criteria for Clinical Trials of New Therapies for Systemic Lupus Erythematosus: The Example of Antinuclear Antibodies and Anti-DNA.

New Perspectives in Rheumatology: Biomarkers as Entry Criteria for Clinical Trials of New Therapies for Systemic Lupus Erythematosus: The Example of Antinuclear Antibodies and Anti-DNA.

Circulating tumor cell (CTC) enumeration in patients with metastatic neuroendocrine prostate cancer (NEPC) and castration-resistant prostate cancer (CRPC).

204 Background: Neuroendocrine prostate cancer (NEPC) is an aggressive variant of prostate cancer. Circulating tumor cell (CTC) counts as measured by CellSearch are prognostic for large groups with metastatic prostate cancer (PC), but are not well described in NEPC. Methods: With institutional review board approval, we retrospectively identified patients with metastatic PC and available CTC enumeration (CellSearch methodology) and compared counts/7.5 mL blood and overall survival (OS), measured from the first recorded CTC count until death or last follow up. Entry criteria for clinical trials were used to define NEPC, including histology (small cell/neuroendocrine carcinoma or adenocarcinoma with more than 50% NE staining), serum chromogranin greater than 5x ULN and/or neuron specific enolase greater than 2x ULN, and/or predominant liver/brain metastases with lack of prostate-specific antigen [Beltran ASCO 2013, clinicaltrials.gov NCT01799278 ]. Frequency of detectable and unfavorable counts was tabulated and OS was compared across groups. Results: Sixty one patients were identified: 21 NEPC with median age 73.7 and 40 patients with castration-resistant prostate cancer (CRPC) with median age 73.9 over contemporary time periods 2009 to 2012. Median OS for the entire group was 22.6 months (mo), with a trend for shorter OS in NEPC (20.7 mo) than CRPC (22.7 mo), p=0.11. 47.6% of NEPC and 55% of CRPC had detectable CTC counts (p=0.58); 38.1% of NEPC and 40.0% of CRPC had greater than or equal to five CTCs (p=0.89). CTC counts of 0 to 4 versus greater than or equal to five were prognostic for both groups: NEPC with 0 to 4 CTCs had median OS of 22.6 versus 6.6 mo for CTCs greater than or equal to 5 (p&lt;0.001) and CRPC with 0 to 4 CTCs median OS not reached (mean 40.6 mo) versus 11.2 mo for those with greater than or equal to five CTCs (p&lt;0.001). Conclusions: Patients with NEPC have similar frequency of detectable and elevated CTC counts by CellSearch methodology as compared to an overall CRPC population. CTC counts are prognostic for both groups.

Clinical disease activity and acute phase reactant levels are discordant among patients with active rheumatoid arthritis: acute phase reactant levels contribute separately to predicting outcome at one year

IntroductionClinical trials of new treatments for rheumatoid arthritis (RA) typically require subjects to have an elevated acute phase reactant (APR), in addition to tender and swollen joints. However, despite the elevation of individual components of the Clinical Disease Activity Index (CDAI) (tender and swollen joint counts and patient and physician global assessment), some patients with active RA may have normal erythrocyte sedimentation rate (ESR) and/or C-reactive protein (CRP) levels and thus fail to meet entry criteria for clinical trials. We assessed the relationship between CDAI and APRs in the Consortium of Rheumatology Researchers of North America (CORRONA) registry by comparing baseline characteristics and one-year clinical outcomes of patients with active RA, grouped by baseline APR levels.MethodsThis was an observational study of 9,135 RA patients who had both ESR and CRP drawn and a visit at which CDAI was >2.8 (not in remission).ResultsOf 9,135 patients with active RA, 58% had neither elevated ESR nor CRP; only 16% had both elevated ESR and CRP and 26% had either ESR or CRP elevated. Among the 4,228 patients who had a one-year follow-up visit, both baseline and one-year follow-up modified Health Assessment Questionnaire (mHAQ) and CDAI scores were lowest for patients with active RA but with neither APR elevated; both mHAQ and CDAI scores increased sequentially with the increase in number of elevated APR levels at baseline. Each individual component of the CDAI followed the same trend, both at baseline and at one-year follow-up. The magnitude of improvement in both CDAI and mHAQ scores at one year was associated positively with the number of APRs elevated at baseline.ConclusionsIn a large United States registry of RA patients, APR levels often do not correlate with disease activity as measured by joint counts and global assessments. These data strongly suggest that it is appropriate to obtain both ESR and CRP from RA patients at the initial visit. Requiring an elevation in APR levels as a criterion for inclusion of RA patients in studies of experimental agents may exclude some patients with active disease.

Metabolomics and the search for biomarkers in Parkinson's disease

One of the most sought after goals in Parkinson disease (PD) research is establishment of a therapeutic regimen that can slow or halt disease progression prior to onset of significant motor symptom disability. Achievement of this goal will require better strategies for diagnosis in the early or preclinical phases of the disease. Identification of biological markers, or biomarkers, defined as “characteristic(s) that are objectively measured and evaluated as indicator(s) of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention”1 is the most promising approach for early diagnosis of PD. In addition to aiding in early diagnosis, biomarkers also have the potential to better characterize subsets of Parkinson's disease, monitor response to therapeutic or neuromodulatory interventions, identify patients who are more or less likely to respond to such interventions, improve clinical trial design and better define clinical trial entry criteria, and contribute to better understanding of disease pathophysiology2. To date, the ideal biomarker, or set of biomarkers, is unknown and the best approach for identifying biomarkers in PD has not yet been established. Potential methods include the use of clinical markers, such as those related to motor or non-motor symptoms; brain or other (e.g., cardiac) imaging; genomics; proteomics; and metabolomics (quantification of small molecular weight compounds)2, 3. In this issue, Lewitt and colleagues describe the use of metabolomic analysis to compare postmortem lateral ventricular CSF samples from PD patients and controls 4. Although Bogdanov and colleagues previously reported the use of metabolomics to evaluate blood5, 6, the study of CSF is novel. The authors take advantage of clinically well-characterized samples available through the Arizona PD consortium to compare PD and control CSF using ultra high performance liquid and gas chromatography linked to mass spectrometry (UHPLC-MS). This technique allows for untargeted screening of the samples and is advantageous because it offers high sample resolution and is capable of rapid rates of analysis2, 7. Additionally, there are extensive reference databases available for sample analysis2, including the Metabolon reference library employed by the authors of this study. Using these techniques for metabolomic profiling, the authors identified 19 compounds that differentiated between Parkinson's disease and control samples. Among these changes was a reduction in oxidized glutathione, a reassuring result consistent with previous studies8, 9. They also found changes in 3-hydroxykynurenine, an excitotoxin previously found to be increased in the tissue samples from the putamen10. Biomarkers can also be used as a panel, rather than singly, and multivariate analysis using the 19 identified metabolites yielded classifiers with high sensitivity and specificity when applied to the data set. This study is a first step towards metabolomics profiling in PD CSF, and it is important to recognize the limitations. First, confirmatory studies are needed. The authors performed an extensive internal cross validation; while this is useful, it is not the same as replication of the results in an independent sample. Second, although the brains of PD patients from which the CSF was derived were very well characterized, the samples are post-mortem and it will be important to validate the changes in living patients. Third, even if validated it is likely that these 19 compounds are only the “tip of the iceberg” and that there are networks of alterations in biochemical metabolism in PD. Greater numbers of subjects along with measures to address the heterogeneity of the disease will be needed to reveal the larger picture. Despite these unanswered questions, the findings reported herein are intriguing in that they provide potential direction for further study, particularly with more intensive investigation of not only the compounds with known connections to PD pathogenesis such as glutathione, but also some of the unidentified compounds or those without previously established roles in the disease process. Although several promising candidates have been proposed, the ideal biomarker or group of biomarkers for PD remains elusive3, 11. Metabolomic analysis has the potential for identification of biochemical pathways and discovery of metabolic profiles that could be used in PD for making preclinical diagnosis, following progression of disease, or monitoring response to therapy. Future study in this field will be needed to determine how biomarker profiles differ among patients with differing disease characteristics and how the profiles change in response to treatment or with progression of disease. It will also be important to determine if biomarkers in CSF can be correlated with biomarkers or profiles in serum2. It is also possible, and perhaps likely, that a single method may not identify the ideal biomarker for PD. Rather, achieving this goal may require a combination approach, with information gained from imaging, genetics, proteomics, metabolomics, and potentially some yet unidentified technique12. Although questions remain, the current study by Lewitt and colleagues opens the door for the use of metabolomics to analyze CSF profiles in patients with Parkinson's disease.

Abstract 3152: CanSeq: prospective clinical whole-exome sequencing of FFPE tumor samples.

Abstract INTRODUCTION: Knowledge of tumor genomic alterations that may predict therapeutic responses represents a growing clinical need. Although there has been an increase in the use of hotspot genotyping and targeted sequencing panels of small numbers of genes, the use of clinical whole exome sequencing (WES) remains underdeveloped. Prospective WES in cancer patients presents several logistical and scientific challenges, including (i) generating robust sequencing data from small amounts of FFPE tumor tissue, (ii) establishing a clinically relevant turnaround time, (iii) achieving clinical interpretation of genomic alterations, and (iv) communicating results to the clinical team and patients. Here, we describe CanSeq, a clinical WES platform to detect genomic alterations in FFPE tumor samples and identify clinically actionable and biologically meaningful alterations in order to aid clinical decision-making and inform future research. METHODS: We performed prospective WES on tumor and germline DNA from patients with advanced refractory cancer. Sequencing was performed at the Broad Institute using the Illumina HiSeq, starting with 100 ng of DNA or less from FFPE tumor tissue and matched normal blood. Data were analyzed using a novel algorithm to highlight clinically actionable mutations, indels, and copy number alterations. These were annotated and assigned levels of evidence, and an interactive web-based report was generated for review by clinicians. RESULTS: The average turnaround time from sample receipt to data delivery was 16 days. Each tumor sample was sequenced at 90X or greater depth of coverage with more than 80% of exons with at least 30X coverage. Analysis of the first 15 patients revealed at least one plausibly actionable somatic mutation in 14 samples. These alterations include “standard of care” alterations (BRAF, EGFR), entry criteria for clinical trials (PIK3CA, KRAS, PTEN), potentially actionable alterations based on more limited evidence (STK11, ATM, CRKL, CTNNB1, PDGFRA, CDK4, CDKN2A, SMARCB1, TP53), and alterations that were theoretically targetable (JAK3, SYK). Additional biologically relevant somatic alterations and notable germline alterations were also identified. For several patients, actionable alterations were confirmed in a CLIA lab and impacted clinical decision-making, including enrollment in clinical trials. CONCLUSION: We have developed a prospective clinical WES platform to robustly detect genomic alterations in archival FFPE tumor samples (using &amp;lt;100 ng DNA) in a clinically appropriate time frame (&amp;lt;3 wks). The platform enables rapid identification of clinically relevant information from vast numbers of somatic and germline events. The ability to use real world biopsy samples could facilitate the routine incorporation of WES into the care of cancer patients, speeding the advent of precision cancer medicine by identifying the actionable genetic changes in each patient's tumor. Citation Format: Nikhil Wagle, Eliezer Van Allen, Danielle Perrin, Dennis Friedrich, Sheila Fisher, Gregory Kryukov, Lauren Ambrogio, Daniel Auclair, Stacy Gray, Steven Joffe, Pasi Janne, Judy Garber, Laura Macconaill, Neal Lindeman, Barrett Rollins, Phillip Kantoff, Gad Getz, Stacey Gabriel, Levi A. Garraway. CanSeq: prospective clinical whole-exome sequencing of FFPE tumor samples. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3152. doi:10.1158/1538-7445.AM2013-3152

P70 Does meeting the clinical criteria for the systemic inflammatory response syndrome equate to biochemical inflammation following cardiac surgery?

Introduction and ObjectivesThe systemic inflammatory response syndrome (SIRS) criteria were developed in part as entry criteria for clinical trials of generalised inflammation from various causes. Despite being commonly used to...

ALS clinical trials

To assess the effect of eligibility criteria in amyotrophic lateral sclerosis (ALS) clinical trials on the representativeness of the enrolled population. Patients enrolled in 8 placebo-controlled clinical trials in our ALS center from 2003 to 2008 were compared 1) to the patients included a prospective epidemiologic register (Piemonte and Valle d'Aosta register for ALS, PARALS) in the same period and 2) the subset of PARALS patients who met the usual criteria for inclusion in clinical trials (PARALS-ct) (definite, probable, probable laboratory-supported ALS; age between 18 and 75 years; disease duration <36 months; vital capacity at diagnosis ≥70%; score ≥3 at the items swallowing and respiratory insufficiency at the Amyotrophic Lateral Sclerosis Functional Rating Scale-revised scale; riluzole therapy). A total of 164 patients were enrolled in 8 different clinical trials. The PARALS cohort included 813 patients, of whom 539 (66.3%) met the entry criteria for clinical trials. Patients enrolled in clinical trials were different from both epidemiologic cohorts, since they were younger, had a longer diagnostic delay, and were more likely to have a spinal onset, and to be men. Tracheostomy-free survival was significantly longer in the group of patients enrolled in clinical trials (median survival time, trial patients, 3.9 years [95% confidence interval (CI) 3.4-4.4]; PARALS, 2.6 [2.4-2.8]; PARALS-ct, 2.9 [2.7-3.1]). Patients enrolled in clinical trials do not satisfactorily represent the ALS population; consequently, the findings of ALS trials lack of external validity (generalizability). Efforts should be made to improve patients' recruitment in trials, particularly enrolling incident rather than prevalent cases.

638 Outcomes of primary prevention implantable cardioverter defibrillator (ICD) recipients with vs without clinical trial entry criteria: Observations from a comprehensive provincial ICD registry

There is increasing interest in the degree to which primary prevention ICDs conform to evidence. We examined the frequency of ICD implants that did not meet MADIT2 or SCD-HeFT inclusion/exclusion criteria in a population-based single-payer health system, and the frequency of appropriate defibrillator therapies in patients who were implanted with an ICD but did not meet clinical trial criteria.

1418 PROGNOSTIC TOOL TO HELP IDENTIFY PT1-3N0 PATIENTS LIKELY TO BENEFIT FROM ADJUVANT CHEMOTHERAPY AFTER RADICAL CYSTECTOMY

1418 PROGNOSTIC TOOL TO HELP IDENTIFY PT1-3N0 PATIENTS LIKELY TO BENEFIT FROM ADJUVANT CHEMOTHERAPY AFTER RADICAL CYSTECTOMY

Ten reasons why we should NOT use severity scores as entry criteria for clinical trials or in our treatment decisions*

Severity scores such as Acute Physiology and Chronic Health Evaluation II have been advocated as entry criteria for clinical trials and in clinical decision-making. We present ten reasons why we believe this approach is not appropriate and may even be detrimental. Available relevant literature from authors' personal databases and personal knowledge of past and future clinical trial development. Severity scores were not designed for use in individual patients or for therapeutic decision-making for specific interventions. Difficulties with the time window needed to calculate these scores and the need to administer therapies early further limit their use in this context. The complex nature of the scores makes it difficult to use them at the bedside and there is considerable interobserver variability in score calculation. Inclusion of chronic health and age points in severity scores may prevent younger, previously healthy patients, with similar acute physiological dysfunction and therefore total lower severity scores, from trial inclusion or from receiving therapies that may be beneficial. We believe severity of illness scores are poor surrogates for risk stratification and should not be used as a criterion for patient enrollment into clinical trials or as the basis for individual treatment decisions.

Caring for the Critically Ill Patient

FOR A QUARTER CENTURY, JAMA HAS SERVED AS A VENUE for articles relating to care of critically ill patients, beginning with the Concepts in Emergency and Critical Care section, in which these fields were initially described as “spanking new medical disciplines.” At the time, knowledge of the biology of critical illness was rudimentary, the focus was on initial patient care, such as airway management and resuscitation, and the few physicians trained in emergency or critical care medicine worked mainly in large teaching hospitals. During the following years, critical care and emergency medicine grew rapidly, training and accreditation became more standardized, and the focus changed to the definition, management, and outcome of postresuscitation syndromes, such as sepsis, shock, and organ dysfunction. Approximately 10 years ago, the section name was changed to Caring for the Critically Ill Patient, ushering in increased focus on high-quality multicenter randomized trials, organization and delivery of care, and attention to patient-centered outcomes. Today, the Caring for the Critically Ill Patient section of JAMA is devoted to publication of important articles in critical and emergency care at a time when the clinical and research landscape has shifted again. Advances in molecular biology now provide a wealth of information on the humoral and cellular responses to acute trauma, infection, and ischemia. This understanding has helped delineate the mechanisms of shock, sepsis, and organ dysfunction syndromes, such as acute respiratory distress syndrome (ARDS), acute renal failure, and traumatic brain injury, generating a plethora of therapeutic targets. The scale of critical care and emergency medicine services has also changed. Every acute care hospital in the United States boasts an intensive care unit (ICU), half of the nation’s ICU beds are located in small hospitals, and many teaching hospitals have built huge ICU services, often with 60 or more beds. Six million Americans, or 2% of the population, are admitted to the ICU each year, severe sepsis and ARDS affect hundreds of thousands of individuals annually, and 1 in 5 Americans receive ICU care at the end of life. All this care is provided by a workforce of hundreds of thousands of highly trained physicians, nurses, and allied health care personnel who function in integrated team systems, not just in the ICU and emergency department, but increasingly on hospital general units and in the community. With substantial investment of resources and advancement in knowledge, care of critically ill patients has no doubt improved. Mortality appears to have decreased for sepsis and ARDS, and headway has been made toward safer, quicker, more effective care. However, considerable challenges lie ahead on the path from basic science to improved public health, including a translational block between basic science and clinical trials; challenges in conducting clinical trials in critically ill patients; failure of clinical research to fully frame health issues facing critically ill patients; an inadequate evidence base for many aspects of care; and public health policy that is either lacking or uninformed by evidence. The first challenge, overcoming translation from basic science to clinical trials, is exemplified by the sepsis syndromes. Among the more than 30 large trials involving agents designed to modify the host response to infection, only 2 were positive (and neither of these are considered definitive). While trial design may be partly to blame, the problems run deeper. Severe sepsis, the subset of sepsis with acute organ dysfunction, is often difficult to define and encompasses a highly heterogeneous group of patients. Outcome and probably response to therapy are linked to multiple host, pathogen, and health care–related factors that neither in vitro nor in vivo models adequately address. Therapies enter clinical trials with little information on appropriate dosing or methods to monitor their biologic activity. A particular challenge for sepsis and other critical illnesses is that the pathways targeted for modification are as often helpful as harmful, and current clinical trial entry criteria provide no guarantee that the host response pathway of interest is either active in a particular patient or behaving in an injurious manner. Thus, clinical research needs better tools to select and monitor patients and their therapies, and basic science needs