METHODS In this phase 3, open-label study, we randomly assigned previously untreated patients in East Asia who had advanced pulmonary adenocarcinoma and who were nonsmokers or former light smokers to receive gefitinib (250 mg per day) (609 patients) or carboplatin (at a dose calculated to produce an area under the curve of 5 or 6 mg per milliliter per minute) plus paclitaxel (200 mg per square meter of body-surface area) (608 patients). The primary end point was progression-free survival. RESULTS The 12-month rates of progression-free survival were 24.9% with gefitinib and 6.7% with carboplatin–paclitaxel. The study met its primary objective of showing the noninferiority of gefitinib and also showed its superiority, as compared with carboplatin– paclitaxel, with respect to progression-free survival in the intention-to-treat population (hazard ratio for progression or death, 0.74; 95% confidence interval [CI], 0.65 to 0.85; P<0.001). In the subgroup of 261 patients who were positive for the epidermal growth factor receptor gene (EGFR) mutation, progression-free survival was significantly longer among those who received gefitinib than among those who received carboplatin–paclitaxel (hazard ratio for progression or death, 0.48; 95% CI, 0.36 to 0.64; P<0.001), whereas in the subgroup of 176 patients who were negative for the mutation, progression-free survival was significantly longer among those who received carboplatin–paclitaxel (hazard ratio for progression or death with gefitinib, 2.85; 95% CI, 2.05 to 3.98; P<0.001). The most common adverse events were rash or acne (in 66.2% of patients) and diarrhea (46.6%) in the gefitinib group and neurotoxic effects (69.9%), neutropenia (67.1%), and alopecia (58.4%) in the carboplatin–paclitaxel group. CONCLUSIONS Gefitinib is superior to carboplatin–paclitaxel as an initial treatment for pulmonary adenocarcinoma among nonsmokers or former light smokers in East Asia. The presence in the tumor of a mutation of the EGFR gene is a strong predictor of a better outcome with gefitinib. (ClinicalTrials.gov number, NCT00322452.)

https://www.nejm.org/doi/pdf/10.1056/NEJMoa0810699

Gefitinib or Carboplatin–Paclitaxel in Pulmonary Adenocarcinoma

Context The joint cardiovascular practice guidelines of the American College of Cardiology (ACC) and the American Heart Association (AHA) have become important documents for guiding cardiology practice and establishing benchmarks for quality of care. Objective To describe the evolution of recommendations in ACC/AHA cardiovascular guidelines and the distribution of recommendations across classes of recommendations and levels of evidence. Data Sources and Study Selection Data from all ACC/AHA practice guidelines issued from 1984 to September 2008 were abstracted by personnel in the ACC Science and Quality Division. Fifty-three guidelines on 22 topics, including a total of 7196 recommendations, were abstracted. Data Extraction The number of recommendations and the distribution of classes of recommendation (I, II, and III) and levels of evidence (A, B, and C) were determined. The subset of guidelines that were current as of September 2008 was evaluated to describe changes in recommendations between the first and current versions as well as patterns in levels of evidence used in the current versions. Results Among guidelines with at least 1 revision or update by September 2008, the number of recommendations increased from 1330 to 1973 (+48%) from the first to the current version, with the largest increase observed in use of class II recommendations. Considering the 16 current guidelines reporting levels of evidence, only 314 recommendations of 2711 total are classified as level of evidence A (median, 11%), whereas 1246 (median, 48%) are level of evidence C. Level of evidence significantly varies across categories of guidelines (disease, intervention, or diagnostic) and across individual guidelines. Recommendations with level of evidence A are mostly concentrated in class I, but only 245 of 1305 class I recommendations have level of evidence A (median, 19%). Conclusions Recommendations issued in current ACC/AHA clinical practice guidelines are largely developed from lower levels of evidence or expert opinion. The proportion of recommendations for which there is no conclusive evidence is also growing. These findings highlight the need to improve the process of writing guidelines and to expand the evidence base from which clinical practice guidelines are derived.

/pdf/scientific-evidence-underlying-the-acc-aha-clinical-practice-2t4rs2r2cr.pdf

Scientific Evidence Underlying the ACC/AHA Clinical Practice Guidelines

https://www.cdc.gov/genomics/translation/file/print/translationGIM.pdf

The continuum of translation research in genomic medicine: how can we accelerate the appropriate integration of human genome discoveries into health care and disease prevention?

Context Obesity has been implicated as a risk factor for pancreatic cancer. Objective To demonstrate the association of excess body weight across an age cohort and the risk, age of onset, and overall survival of patients with pancreatic cancer. Design, Setting, and Participants A case-control study of 841 patients with pancreatic adenocarcinoma and 754 healthy individuals frequency matched by age, race, and sex. The study was conducted at a university cancer center in the United States from 2004 to 2008. Height and body weight histories were collected by personal interview starting at ages 14 to 19 years and over 10-year intervals progressing to the year prior to recruitment in the study. Main Outcome Measures The associations between patients’ body mass index (BMI) and risk of pancreatic cancer, age at onset, and overall survival were examined by unconditional logistic regression, linear regression, and Cox proportional hazard regression models, respectively. Results Individuals who were overweight (a BMI of 25-29.9) from the ages of 14 to 39 years (highest odds ratio [OR], 1.67; 95% confidence interval [CI], 1.20-2.34) or obese (a BMI 30) from the ages of 20 to 49 years (highest OR, 2.58; 95% CI, 1.703.90) had an associated increased risk of pancreatic cancer, independent of diabetes status. The association was stronger in men (adjusted OR, 1.80; 95% CI, 1.45-2.23) by mean BMI from the ages of 14 to 59 years than in women (adjusted OR, 1.32; 95% CI, 1.02-1.70) and in ever smokers (adjusted OR, 1.75; 95% CI, 1.37-2.22) than in never smokers (adjusted OR, 1.46; 95% CI, 1.16-1.84). The populationattributable risk percentage of pancreatic cancer based on the mean BMI from the ages of 14 to 59 years was 10.3% for never smokers and 21.3% for ever smokers. Individuals who were overweight or obese from the ages of 20 to 49 years had an earlier onset of pancreatic cancer by 2 to 6 years (median age of onset was 64 years for patients with normal weight, 61 years for overweight patients [P=.02], and 59 years for obese patients [P.001]). Compared with those with normal body weight and after adjusting for all clinical factors, individuals who were overweight or obese from the ages of 30 to 79 years or in the year prior to recruitment had reduced overall survival of pancreatic cancer regardless of disease stage and tumor resection status (overweight patients: hazard ratio, 1.26 [95% CI, 0.94-1.69], P=.04; obese patients: hazard ratio, 1.86 [95% CI, 1.35-2.56], P.001).

https://jamanetwork.com/journals/jama/articlepdf/184143/joc90052_2553_2562.pdf

Body Mass Index and Risk, Age of Onset, and Survival in Patients With Pancreatic Cancer

Allan Best and Bev Holmes4HEWAYWETHINKABOUTHOWRESEARCH POLICY ANDPRACTICEINFORMANDINTERACTWITHEACHOTHERSHAPESOUREFFORTSTOIMPROVEHEALTHANDSOCIALOUTCOMES)NTHISPAPERWEDESCRIBELINEAR RELATIONSHIPANDSYSTEMSMODELSWITHREGARDTOHOWTHEYAPPROACHBRIDGINGEVIDENCEANDPOLICYPRACTICE ORTURNINGKNOWLEDGEINTOACTION7 ECONTRIBUTETOTHEKNOWLEDGETOACTION+4! SYSTEMSTHINKINGDISCUSSIONBYHIGHLIGHTINGFOURINTERCONNECTEDASPECTSOFTHISMODELWEBELIEVEMERITEXP LORATIONE VIDENCEAND KNOWLEDGE LEA DERSHIP NET WORKSANDCOMMUNICATIONS7ECONCLUDEWITHTHECHALLENGEOFDEVELOPINGMEASUREMENTMETHODSFORSYSTEMSRESEARCHTOBETTERUNDERSTANDTHE+4!PROCESS

Systems thinking, knowledge and action: towards better models and methods

The clinical research infrastructure of the United States is currently
at a critical crossroads. To leverage the enormous biomedical research gains
made in the past century efficiently, a drastic need exists to reengineer
this system into a coordinated, safe, and more efficient and effective enterprise.
To accomplish this task, clinical research must be transformed from its current
state as a cottage industry to an enterprise-wide health care pipeline whose
function is to bring the novel research from both government and private entities
to the US public. We propose the establishment of a unique public-private
partnership termed the National Clinical Research Enterprise (NCRE). Its agenda
should consist of informed public participation, supportive information technologies,
a skilled workforce, and adequate funding in clinical research. Devoting only
0.25% of the budgets from all health care stakeholders to support the NCRE
would permit adequate funding to build the infrastructure required to address
these problems in an enterprise fashion. All participants in the US health
care delivery system must come together to focus on system-wide improvements
that will benefit the public.

Clinical research in the United States at a crossroads: proposal for a novel public-private partnership to establish a national clinical research enterprise.

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Clinical research in the United States at a crossroads: proposal for a novel public-private partnership to establish a national clinical research enterprise.