Steven Goodman, MD, MHS, PhD is Associate Dean of Clinical and Translational Research and Professor of Epidemiology and Population Health, and Medicine. He is co-founder and co-director of the Meta-research innovation Center at Stanford (METRICS), a group dedicated to examining and improving the reproducibility and efficiency of biomedical research. He led the Stanford CTSA KL2 and TL1 training programs from 2012-2019.
Dr. Goodman's own research concerns the proper measurement, conceptualization and synthesis of research evidence, with particular emphasis on Bayesian approaches to quantitation, and qualitative approaches arising from the philosophy of science. He is also interested in developing methods to use shared data to confirm and extend published science, as well as to explore new hypotheses. He also has worked on the connections between ethics and scientific methods, particularly in the domain of interventional research, and policy making. Finally, he has a strong interest in developing curricula and new models for teaching the foundations of good scientific practice, from question development to proper study design, conduct, analysis and inference. He teaches courses on clinical research methods, foundations of scientific and statistical reasoning, and evaluation of diagnostic and predictive technologies.
He has been a senior statistical editor of Annals of Internal Medicine since 1987 and was Editor of Clinical Trials: Journal of the Society for Clinical Trials from 2004-2013. He is Chair of the Methodology Committee of the Patient Centered Outcomes Research Institute (PCORI), where he led their open science and data sharing efforts, and is scientific advisor for the national Blue Cross–Blue Shield Technology Assessment Program. He has served on numerous Institute of Medicine committees since the mid 1990's, including chairing a 2012 committee on drug safety, and as a committee member on sharing data from clinical trials, whose report was released in January, 2015. He was awarded the 2016 Spinoza Chair in Medicine from the University of Amsterdam for his work in scientific inference, received the 2019 Abraham Lilienfeld award from the American College of Epidemiology for his lifetime research and teaching contributions to the field, and was elected into the National Academy of Medicine in 2020.
From 1989-2011, Steve served on the faculties of the Johns Hopkins Schools of Medicine and Public Health, where he was co-director of the doctoral program in Epidemiology and member (1989-2011) and then director (2007-2011) of the Johns Hopkins cancer center’s Division of Biostatistics and Bioinformatics. At Hopkins, he taught courses on Systematic reviews and Meta-analysis, Diagnostic and prognostic testing, and several courses on epidemiologic, clinical research and inferential methods. He received an AB from Harvard, majoring in Biochemistry and Applied Math, an MD from NYU, trained in pediatrics at Washington University in St. Louis, and received a master’s degree in Biostatistics and PhD in Epidemiology from Johns Hopkins.
Associate Dean of Clinical and Translational Research, Stanford School of Medicine (2011 - Present)
Director, MedScholars Clinical Research Concentration, Stanford School of Medicine (2011 - Present)
Co-Director, Meta-research Innovation Center at Stanford (METRICS) (2013 - Present)
Director of Graduate Studies, Dept. of Epidemiology and Population Health (2019 - Present)
Director, Spectrum Research Education and Training, Stanford School of Medicine (2011 - 2019)
Chief, DIvision of Epidemiology, Dept. of Health Research and Policy (2014 - 2019)
Director, Division of Biostatistics and Bioinformatics, Department of Oncology, Johns Hopkins School of Medicine (2007 - 2010)
Professor of Oncology, Pediatrics, Biostatistics and Epidemiology, Johns Hopkins Schools of Medicine and Public Health (1989 - 2011)
Honors & Awards
Member, National Public Health Honor Society (1989)
Myrto Lefkopoulou Distinguished Lecturer, Harvard Dept of Biostatistics (2000)
Fellow, Society for Clinical Trials (2010)
Spinoza Chair in Medicine, University of Amsterdam (2016)
Abraham Lilienfeld Award, American College of Epidemiology (2019)
Lifetime Fellow, American College of Epidemiology (2019)
Elected Member, National Academy of Medicine (2020)
Boards, Advisory Committees, Professional Organizations
Chair, Methodology Commitee, PCORI (2019 - Present)
Vice-chair, Methodology Committee, Patient Centered Outcomes Research Institute (PCORI) (2011 - 2019)
Senior statistical editor, Annals of Internal Medicine (1987 - Present)
Scientific Advisor and member, Medical Advisory Panel, National Blue Cross-Blue Shield Technology Assessment Program (2001 - Present)
Member, Advisory committee to the NIH director on the National Library of Medicine (2015 - 2015)
Member, Committee on Responsible Sharing of Clinical Trial Data, Institute of Medicine (2013 - 2015)
Co-chair, Committee on Drug Safety, Institute of Medicine (2010 - 2012)
Editor in Chief, Clinical Trials: Journal of the Society for Clinical Trials (2004 - 2013)
Member, Committee on Immunization Safety, Institute of Medicine (2001 - 2004)
PhD, Johns Hopkins School of Public Health, Epidemiology (1989)
MHS, Johns Hopkins School of Public Health, Biostatistics (1987)
Board Certification, General Pediatrics, American Board of Pediatrics, Pediatrics (1985)
Residency, St. Louis Children's Hospital, Washington University School of Medicine, Pediatrics (1984)
MD, New York University, Medicine (1981)
AB, Harvard College, Biochemistry, Applied Math (1976)
Current Research and Scholarly Interests
I am interested in issues relating to the representation and measurement of evidence in medical research, and determinants of the truth of medical findings, using a Bayesian framework. I also do work in evidence synthesis, comparative effectiveness research, and the ethics of clinical research.
- Cinematic Discoveries: A movie-based exploration of research rigor, communication and diversity
BIOS 298 (Aut)
- Epidemiology Research Seminar
EPI 236 (Aut)
- Essentials of Clinical Research at Stanford
EPI 273 (Win)
- Evaluating Technologies for Diagnosis, Prediction and Screening
EPI 219 (Win)
- Foundations of Statistical and Scientific Inference
EPI 264, STATS 264 (Aut)
- Foundations of statistics and reproducible research
BIOS 217 (Aut)
- Intensive Course in Clinical Research
EPI 245 (Aut)
- Stanford CTSA Scholars Seminar
EPI 229 (Aut, Win, Spr, Sum)
Independent Studies (10)
- Directed Reading in Epidemiology
EPI 299 (Aut, Win, Spr, Sum)
- Directed Reading in Health Research and Policy
HRP 299 (Aut)
- Directed Reading in Medicine
MED 299 (Aut, Win, Spr, Sum)
- Early Clinical Experience in Medicine
MED 280 (Aut, Win, Spr, Sum)
- Graduate Research
EPI 399 (Aut, Win, Spr, Sum)
- Graduate Research
HRP 399 (Aut)
- Graduate Research
MED 399 (Aut, Win, Spr, Sum)
- Medical Scholars Research
MED 370 (Aut, Win, Spr, Sum)
- Undergraduate Research
EPI 199 (Aut, Win, Spr, Sum)
- Undergraduate Research
MED 199 (Aut, Win, Spr, Sum)
- Directed Reading in Epidemiology
Prior Year Courses
- Epidemiology Research Seminar
HRP 236 (Aut)
- Essentials of Clinical Research at Stanford
HRP 273 (Win)
- Evaluating Technologies for Diagnosis, Prediction and Screening
HRP 219 (Win)
- Foundations of Statistical and Scientific Inference
HRP 264, STATS 264 (Aut)
- Intensive Course in Clinical Research
HRP 245 (Aut)
- Spectrum Scholars Seminar
HRP 229 (Win, Spr, Sum)
- Epidemiology Research Seminar
HRP 236 (Aut)
- Essentials of Clinical Research at Stanford
HRP 273 (Aut, Win)
- Foundations of Statistical and Scientific Inference
HRP 264 (Aut)
- Intensive Course in Clinical Research
HRP 245 (Aut)
- Spectrum Scholars Seminar
HRP 229 (Aut, Win, Spr, Sum)
- Epidemiology Research Seminar
HRP 236 (Aut)
- Essentials of Clinical Research at Stanford
HRP 273 (Aut, Win)
- Evaluating Technologies for Diagnosis, Prediction and Screening
HRP 219 (Win)
- Foundations of Statistical and Scientific Inference
HRP 264 (Aut)
- Intensive Course in Clinical Research
HRP 245 (Aut)
- Spectrum Scholars Seminar
HRP 229 (Aut, Win, Spr, Sum)
- Epidemiology Research Seminar
Master's Program Advisor
Yan Jiang, Stephanie Lee
- The Role of Masks in Mitigating the SARS-CoV-2 Pandemic: Another Piece of the Puzzle. Annals of internal medicine 2020
- COVID-19 Clinical Trials: A Teachable Moment for Improving Our Research Infrastructure and Relevance. Annals of internal medicine 2020
- Harms From Uninformative Clinical Trials. JAMA 2019
The high resource impact of reformatting requirements for scientific papers.
2019; 14 (10): e0223976
Most research manuscripts are not accepted for publication on first submission. A major part of the resubmission process is reformatting to another journal's specific requirements, a process separate from revising the scientific content. There has been little research to understand the magnitude of the burden imposed by the current resubmission process.We analyzed original research article submission requirements from twelve randomly selected journals in each of eight scientific and clinical focus areas from the InCites Journal Citation Reports database. From the 96 journals selected, we randomly identified three recently published manuscripts and sent surveys to those first and/or corresponding authors (288 total) to solicit information on time spent reformatting resubmissions and opinions on the process.There was significant variation in manuscript submission requirements for journals within the same scientific focus and only 4% of journals offered a fully format-free initial submission. Of 203 authors responding (71.5% response rate), only 11.8% expressed satisfaction with the resubmission process and 91% desired reforming the current system. Time spent on reformatting delays most publications by at least two weeks and by over three months in about 20% of manuscripts. The effort to comply with submission requirements has significant global economic burden, estimated at over $1.1 billion dollars annually when accounting for a research team's time.We demonstrate that there is significant resource utilization associated with resubmitting manuscripts, heretofore not properly quantified. The vast majority of authors are not satisfied with the current process. Addressing these issues by reconciling reformatting requirements among journals or adopting a universal format-free initial submission policy would help resolve a major subject for the scientific research community and provide more efficient dissemination of findings.
View details for DOI 10.1371/journal.pone.0223976
View details for PubMedID 31665156
Inappropriate Statistical Analysis and Reporting in Medical Research: Perverse Incentives and Institutional Solutions.
Annals of internal medicine
View details for PubMedID 30304363
Assessing scientists for hiring, promotion, and tenure
2018; 16 (3): e2004089
Assessment of researchers is necessary for decisions of hiring, promotion, and tenure. A burgeoning number of scientific leaders believe the current system of faculty incentives and rewards is misaligned with the needs of society and disconnected from the evidence about the causes of the reproducibility crisis and suboptimal quality of the scientific publication record. To address this issue, particularly for the clinical and life sciences, we convened a 22-member expert panel workshop in Washington, DC, in January 2017. Twenty-two academic leaders, funders, and scientists participated in the meeting. As background for the meeting, we completed a selective literature review of 22 key documents critiquing the current incentive system. From each document, we extracted how the authors perceived the problems of assessing science and scientists, the unintended consequences of maintaining the status quo for assessing scientists, and details of their proposed solutions. The resulting table was used as a seed for participant discussion. This resulted in six principles for assessing scientists and associated research and policy implications. We hope the content of this paper will serve as a basis for establishing best practices and redesigning the current approaches to assessing scientists by the many players involved in that process.
View details for PubMedID 29596415
What does research reproducibility mean?
SCIENCE TRANSLATIONAL MEDICINE
2016; 8 (341)
The language and conceptual framework of "research reproducibility" are nonstandard and unsettled across the sciences. In this Perspective, we review an array of explicit and implicit definitions of reproducibility and related terminology, and discuss how to avoid potential misunderstandings when these terms are used as a surrogate for "truth."
View details for DOI 10.1126/scitranslmed.aaf5027
View details for PubMedID 27252173
- The Research-Treatment Distinction: A Problematic Approach for Determining Which Activities Should Have Ethical Oversight HASTINGS CENTER REPORT 2013; 43: S4-S15
Causal inference in public health.
Annual review of public health
2013; 34: 61-75
Causal inference has a central role in public health; the determination that an association is causal indicates the possibility for intervention. We review and comment on the long-used guidelines for interpreting evidence as supporting a causal association and contrast them with the potential outcomes framework that encourages thinking in terms of causes that are interventions. We argue that in public health this framework is more suitable, providing an estimate of an action's consequences rather than the less precise notion of a risk factor's causal effect. A variety of modern statistical methods adopt this approach. When an intervention cannot be specified, causal relations can still exist, but how to intervene to change the outcome will be unclear. In application, the often-complex structure of causal processes needs to be acknowledged and appropriate data collected to study them. These newer approaches need to be brought to bear on the increasingly complex public health challenges of our globalized world.
View details for DOI 10.1146/annurev-publhealth-031811-124606
View details for PubMedID 23297653
- An Ethics Framework for a Learning Health Care System: A Departure from Traditional Research Ethics and Clinical Ethics HASTINGS CENTER REPORT 2013; 43: S16-S27
- Ethical Considerations in Studying Drug Safety - The Institute of Medicine Report NEW ENGLAND JOURNAL OF MEDICINE 2012; 367 (10): 959-964
Quasi-random reflections on randomized controlled trials and comparative effectiveness research
2012; 9 (1): 22-26
Comparative effectiveness research (CER) is still an evolving framework for which much needs to be done to improve the ability of randomized controlled trials (RCTs) to supply the necessary evidence. Perhaps, most important is to start with a clearly specified decision and decision maker in mind when the RCTs are designed. Second is to initiate RCTs with clinically relevant outcomes and comparators earlier in the evaluation process. Third is to specify and measure factors that might modify the intervention's effect, subject to logistical constraints of complexity and cost, so the trial is maximally informative, about how and to whom the intervention should be administered. It will be necessary to borrow observational methodologies and approaches to extract meaningful causal and subgroup inferences from such trials. Process variables should be seen as potentially part of that framework of effect-modifying factors, perhaps amenable to embedded experimental assessment with a trial. Perhaps most importantly, we need to improve the nationwide CER infrastructure to allow for rapid initiation and accrual for CER trials to reduce the trade-off that often exists between the speed of evidence development and its quality.
View details for DOI 10.1177/1740774511433285
View details for PubMedID 22334465
The Methods of Comparative Effectiveness Research
ANNUAL REVIEW OF PUBLIC HEALTH, VOL 33
2012; 33: 425-445
This review describes methods used in comparative effectiveness research (CER). The aim of CER is to improve decisions that affect medical care at the levels of both policy and the individual. The key elements of CER are (a) head-to-head comparisons of active treatments, (b) study populations typical of day-to-day clinical practice, and (c) a focus on evidence to inform care tailored to the characteristics of individual patients. These requirements will stress the principal methods of CER: observational research, randomized trials, and decision analysis. Observational studies are especially vulnerable because they use data that directly reflect the decisions made in usual practice. CER will challenge researchers and policy makers to think deeply about how to extract more actionable information from the vast enterprise of the daily practice of medicine. Fortunately, the methods are largely applicable to research in the public health system, which should therefore benefit from the intense interest in CER.
View details for DOI 10.1146/annurev-publhealth-031811-124610
View details for Web of Science ID 000304202700026
View details for PubMedID 22224891
- Metabias: A Challenge for Comparative Effectiveness Research ANNALS OF INTERNAL MEDICINE 2011; 155 (1): 61-U104
Confessions of a chagrined trialist
BMJ QUALITY & SAFETY
2011; 20: I97-I98
As a clinical trialist, I had thought that the methods I employed were far more challenging than those I had thought were needed for quality improvement. However, some personal experiences and participation in the Cliveden conference led me to a new appreciation of the methodological and conceptual challenges faced by those trying to improve medical systems.
View details for DOI 10.1136/bmjqs.2010.046623
View details for Web of Science ID 000289768600023
View details for PubMedID 21450783
- Rethinking Randomized Clinical Trials for Comparative Effectiveness Research: The Need for Transformational Change ANNALS OF INTERNAL MEDICINE 2009; 151 (3): 206-W45
A dirty dozen: Twelve P-value misconceptions
SEMINARS IN HEMATOLOGY
2008; 45 (3): 135-140
The P value is a measure of statistical evidence that appears in virtually all medical research papers. Its interpretation is made extraordinarily difficult because it is not part of any formal system of statistical inference. As a result, the P value's inferential meaning is widely and often wildly misconstrued, a fact that has been pointed out in innumerable papers and books appearing since at least the 1940s. This commentary reviews a dozen of these common misinterpretations and explains why each is wrong. It also reviews the possible consequences of these improper understandings or representations of its meaning. Finally, it contrasts the P value with its Bayesian counterpart, the Bayes' factor, which has virtually all of the desirable properties of an evidential measure that the P value lacks, most notably interpretability. The most serious consequence of this array of P-value misconceptions is the false belief that the probability of a conclusion being in error can be calculated from the data in a single experiment without reference to external evidence or the plausibility of the underlying mechanism.
View details for DOI 10.1053/j.seminhematol.2008.04.003
View details for Web of Science ID 000257501600002
View details for PubMedID 18582619
Stopping at nothing? Some dilemmas of data monitoring in clinical trials
ANNALS OF INTERNAL MEDICINE
2007; 146 (12): 882-887
This commentary reviews the argument that clinical trials with data monitoring committees that use statistical stopping guidelines should generally not be stopped early for large observed efficacy differences because efficacy estimates may be exaggerated and there is minimal information on treatment harms. Overall, the average of estimates from trials that use these boundaries differs minimally from the true value. Estimates from a given trial that seem implausibly high can be moderated by using Bayesian methods. Data monitoring committees are not ethically required to precisely estimate a large efficacy difference if that difference differs convincingly from zero, and the requirement to detect harms and balance efficacy against harm depends on whether the nature of the harm is known or unknown before the trial.
View details for Web of Science ID 000247347100007
View details for PubMedID 17577008
Reproducible research: Moving toward research the public can really trust
ANNALS OF INTERNAL MEDICINE
2007; 146 (6): 450-453
A community of scientists arrives at the truth by independently verifying new observations. In this time-honored process, journals serve 2 principal functions: evaluative and editorial. In their evaluative function, they winnow out research that is unlikely to stand up to independent verification; this task is accomplished by peer review. In their editorial function, they try to ensure transparent (by which we mean clear, complete, and unambiguous) and objective descriptions of the research. Both the evaluative and editorial functions go largely unnoticed by the public--the former only draws public attention when a journal publishes fraudulent research. However, both play a critical role in the progress of science. This paper is about both functions. We describe the evaluative processes we use and announce a new policy to help the scientific community evaluate, and build upon, the research findings that we publish.
View details for Web of Science ID 000245192200007
View details for PubMedID 17339612
- Assessing the unreliability of the medical literature: A response to ?Why most published research findings are false? www.bepress.com/jhubiostat/paper135 2007
Introduction to Bayesian methods I: measuring the strength of evidence
2005; 2 (4): 282-290
Bayesian inference is a formal method to combine evidence external to a study, represented by a prior probability curve, with the evidence generated by the study, represented by a likelihood function. Because Bayes theorem provides a proper way to measure and to combine study evidence, Bayesian methods can be viewed as a calculus of evidence, not just belief. In this introduction, we explore the properties and consequences of using the Bayesian measure of evidence, the Bayes factor (in its simplest form, the likelihood ratio). The Bayes factor compares the relative support given to two hypotheses by the data, in contrast to the P-value, which is calculated with reference only to the null hypothesis. This comparative property of the Bayes factor, combined with the need to explicitly predefine the alternative hypothesis, produces a different assessment of the strength of evidence against the null hypothesis than does the P-value, and it gives Bayesian procedures attractive frequency properties. However, the most important contribution of Bayesian methods is the way in which they affect both who participates in a scientific dialogue, and what is discussed. With the emphasis moved from "error rates" to evidence, content experts have an opportunity for their input to be meaningfully incorporated, making it easier for regulatory decisions to be made correctly.
View details for DOI 10.1191/1740774505cn098oa
View details for Web of Science ID 000232648100004
View details for PubMedID 16281426
A Bayesian approach to randomized controlled trials in children utilizing information from adults: the case of Guillain-Barre syndrome
2005; 2 (4): 305-310
Guillain-Barré syndrome (GBS) is a rare neurologic disease that occurs at all ages, causing a progressive, ascending paralysis that usually resolves over weeks or months. The disease appears to be identical in children and adults, except that children recover more quickly, with fewer residua. For patients who lose the ability to walk independently, the main treatment options are plasmapheresis or intravenous immune globulin (IVIg), treatments that have shown to have identical effectiveness in adults in two large RCTs involving 388 patients. The effectiveness of the treatments in children has only been studied in small, poorly controlled studies. If one could capture all eligible patients in the United States, only about 100-300 children would be available for a trial annually.The goal of this case was to demonstrate how Bayesian methods could be used to incorporate prior information on treatment efficacy from adults to design a randomized noninferiority trial of IVIg versus plasmapheresis in children. A Bayesian normal-normal model on the hazard ratio of time to independent walking was implemented.An evidence-based prior was constructed that was equivalent to 72 children showing exact equivalence between the therapies. A design was constructed based on a Bayesian normal-normal model on the hazard ratio, yielding a sample size of 160 children, with a preposterior analysis demonstrating a "Type I" error rate of 5% and a power of 77%.This case study illustrates a rational approach to constructing an evidence-based prior that would allow information from adults to formally augment data from children to minimize unnecessary pediatric experimentation. The frequentist properties of a Bayesian design can be evaluated and reported as they would be for a standard design. Discussion of the appropriate prior for such designs is both a necessary and desirable feature of Bayesian trials.
View details for DOI 10.1191/1740774505cn102oa
View details for Web of Science ID 000232648100008
View details for PubMedID 16281429
- Of P-values and bayes: A modest proposal EPIDEMIOLOGY 2001; 12 (3): 295-297
Toward evidence-based medical statistics. 2: The Bayes factor
ANNALS OF INTERNAL MEDICINE
1999; 130 (12): 1005-1013
Bayesian inference is usually presented as a method for determining how scientific belief should be modified by data. Although Bayesian methodology has been one of the most active areas of statistical development in the past 20 years, medical researchers have been reluctant to embrace what they perceive as a subjective approach to data analysis. It is little understood that Bayesian methods have a data-based core, which can be used as a calculus of evidence. This core is the Bayes factor, which in its simplest form is also called a likelihood ratio. The minimum Bayes factor is objective and can be used in lieu of the P value as a measure of the evidential strength. Unlike P values, Bayes factors have a sound theoretical foundation and an interpretation that allows their use in both inference and decision making. Bayes factors show that P values greatly overstate the evidence against the null hypothesis. Most important, Bayes factors require the addition of background knowledge to be transformed into inferences--probabilities that a given conclusion is right or wrong. They make the distinction clear between experimental evidence and inferential conclusions while providing a framework in which to combine prior with current evidence.
View details for Web of Science ID 000080894700008
View details for PubMedID 10383350
Toward evidence-based medical statistics. 1: The P value fallacy
ANNALS OF INTERNAL MEDICINE
1999; 130 (12): 995-1004
An important problem exists in the interpretation of modern medical research data: Biological understanding and previous research play little formal role in the interpretation of quantitative results. This phenomenon is manifest in the discussion sections of research articles and ultimately can affect the reliability of conclusions. The standard statistical approach has created this situation by promoting the illusion that conclusions can be produced with certain "error rates," without consideration of information from outside the experiment. This statistical approach, the key components of which are P values and hypothesis tests, is widely perceived as a mathematically coherent approach to inference. There is little appreciation in the medical community that the methodology is an amalgam of incompatible elements, whose utility for scientific inference has been the subject of intense debate among statisticians for almost 70 years. This article introduces some of the key elements of that debate and traces the appeal and adverse impact of this methodology to the P value fallacy, the mistaken idea that a single number can capture both the long-run outcomes of an experiment and the evidential meaning of a single result. This argument is made as a prelude to the suggestion that another measure of evidence should be used--the Bayes factor, which properly separates issues of long-run behavior from evidential strength and allows the integration of background knowledge with statistical findings.
View details for Web of Science ID 000080894700007
View details for PubMedID 10383371
SOME PRACTICAL IMPROVEMENTS IN THE CONTINUAL REASSESSMENT METHOD FOR PHASE-I STUDIES
STATISTICS IN MEDICINE
1995; 14 (11): 1149-1161
The Continual Reassessment Method (CRM) is a Bayesian phase I design whose purpose is to estimate the maximum tolerated dose of a drug that will be used in subsequent phase II and III studies. Its acceptance has been hindered by the greater duration of CRM designs compared to standard methods, as well as by concerns with excessive experimentation at high dosage levels, and with more frequent and severe toxicity. This paper presents the results of a simulation study in which one assigns more than one subject at a time to each dose level, and each dose increase is limited to one level. We show that these modifications address all of the most serious criticisms of the CRM, reducing the duration of the trial by 50-67 per cent, reducing toxicity incidence by 20-35 per cent, and lowering toxicity severity. These are achieved with minimal effects on accuracy. Most important, based on our experience at our institution, such modifications make the CRM acceptable to clinical investigators.
View details for Web of Science ID A1995RE49200001
View details for PubMedID 7667557
ASSOCIATION BETWEEN CIGARETTE-SMOKING AND MUTATION OF THE P53 GENE IN SQUAMOUS-CELL CARCINOMA OF THE HEAD AND NECK
NEW ENGLAND JOURNAL OF MEDICINE
1995; 332 (11): 712-717
Although epidemiologic studies have long associated tobacco and alcohol use with the development of squamous-cell carcinoma of the head and neck, the molecular targets of these carcinogens have yet to be identified. We performed a molecular analysis to determine the pattern of mutations in the p53 gene in neoplasms from patients with squamous-cell carcinoma of the head and neck and a history of tobacco or alcohol use.Sequence analysis of the conserved regions of the p53 gene was performed in tumor samples from 129 patients with primary squamous-cell carcinoma of the head and neck. We then used statistical analysis to identify any patient characteristics associated with mutation of the p53 gene.We found p53 mutations in 42 percent of the patients (54 of 129). Fifty-eight percent of the patients who smoked cigarettes and used alcohol (37 of 64; 95 percent confidence interval, 45 to 70 percent), 33 percent of the patients who smoked but abstained from alcohol (13 of 39; 95 percent confidence interval, 19 to 50 percent), and 17 percent of the patients who neither smoked nor drank alcohol (4 of 24, 95 percent confidence interval, 5 to 37 percent) had p53 mutations (P = 0.001). (Two patients used alcohol but did not smoke, and neither had a p53 mutation.) Furthermore, 100 percent of the mutations in the patients who neither drank nor smoked occurred at sites containing cytidine phosphate guanosine dinucleotides (potentially representing endogenous mutations) within the p53 gene (5 of 5 mutations; 95 percent confidence interval, 48 to 100 percent), whereas only 23 percent of those in cigarette smokers consisted of such changes (12 of 53 mutations; 95 percent confidence interval, 12 to 36 percent; P = 0.001).In our study, a history of tobacco and alcohol use was associated with a high frequency of p53 mutations in patients with squamous-cell carcinoma of the head and neck. Preliminary evidence linked cigarette smoking to p53 mutations at nonendogenous mutation sites. Our findings suggest a role for tobacco in the molecular progression of squamous-cell carcinoma of the head and neck and support the epidemiologic evidence that abstinence from smoking is important to prevent head and neck cancer.
View details for Web of Science ID A1995QL78800004
View details for PubMedID 7854378
THE USE OF PREDICTED CONFIDENCE-INTERVALS WHEN PLANNING EXPERIMENTS AND THE MISUSE OF POWER WHEN INTERPRETING RESULTS
ANNALS OF INTERNAL MEDICINE
1994; 121 (3): 200-206
Although there is a growing understanding of the importance of statistical power considerations when designing studies and of the value of confidence intervals when interpreting data, confusion exists about the reverse arrangement: the role of confidence intervals in study design and of power in interpretation. Confidence intervals should play an important role when setting sample size, and power should play no role once the data have been collected, but exactly the opposite procedure is widely practiced. In this commentary, we present the reasons why the calculation of power after a study is over is inappropriate and how confidence intervals can be used during both study design and study interpretation.
View details for Web of Science ID A1994NY33800008
View details for PubMedID 8017747
P-VALUES, HYPOTHESIS TESTS, AND LIKELIHOOD - IMPLICATIONS FOR EPIDEMIOLOGY OF A NEGLECTED HISTORICAL DEBATE
AMERICAN JOURNAL OF EPIDEMIOLOGY
1993; 137 (5): 485-496
It is not generally appreciated that the p value, as conceived by R. A. Fisher, is not compatible with the Neyman-Pearson hypothesis test in which it has become embedded. The p value was meant to be a flexible inferential measure, whereas the hypothesis test was a rule for behavior, not inference. The combination of the two methods has led to a reinterpretation of the p value simultaneously as an "observed error rate" and as a measure of evidence. Both of these interpretations are problematic, and their combination has obscured the important differences between Neyman and Fisher on the nature of the scientific method and inhibited our understanding of the philosophic implications of the basic methods in use today. An analysis using another method promoted by Fisher, mathematical likelihood, shows that the p value substantially overstates the evidence against the null hypothesis. Likelihood makes clearer the distinction between error rates and inferential evidence and is a quantitative tool for expressing evidential strength that is more appropriate for the purposes of epidemiology than the p value.
View details for Web of Science ID A1993KX52900001
View details for PubMedID 8465801
A COMMENT ON REPLICATION, P-VALUES AND EVIDENCE
STATISTICS IN MEDICINE
1992; 11 (7): 875-879
It is conventionally thought that a small p-value confers high credibility on the observed alternative hypothesis, and that a repetition of the same experiment will have a high probability of resulting again in statistical significance. It is shown that if the observed difference is the true one, the probability of repeating a statistically significant result, the 'replication probability', is substantially lower than expected. The reason for this is a mistake that generates other seeming paradoxes: the interpretation of the post-trial p-value in the same way as the pre-trial alpha error. The replication probability can be used as a frequentist counterpart of Bayesian and likelihood methods to show that p-values overstate the evidence against the null hypothesis.
View details for Web of Science ID A1992HU18300003
View details for PubMedID 1604067
META-ANALYSIS AND EVIDENCE
CONTROLLED CLINICAL TRIALS
1989; 10 (2): 188-204
Meta-analysis is the science of combining evidence from different studies, but traditional statistical techniques contain neither a formal definition nor a measure of evidence. It is argued in this paper that the log-likelihood ratio, as a measure of the "weight of evidence," can be a very useful tool in the meta-analysis. The mathematics and the philosophy behind the use of this index are introduced. The construction and interpretation of "support curves" in fixed and random-effects models are presented. The application of evidential techniques is illustrated on six trials of aspirin therapy previously presented by Canner. The possible dangers of focusing on statistical error rates instead of evidence are discussed.
View details for Web of Science ID A1989U775200005
View details for PubMedID 2666026
EVIDENCE AND SCIENTIFIC-RESEARCH
AMERICAN JOURNAL OF PUBLIC HEALTH
1988; 78 (12): 1568-1574
This commentary reviews the arguments for and against the use of p-values put forward in the Journal and other forums, and shows that they are all missing both a measure and concept of "evidence." The mathematics and logic of evidential theory are presented, with the log-likelihood ratio used as the measure of evidence. The profoundly different philosophy behind evidential methods (as compared to traditional ones) is presented, as well as a comparative example showing the difference between the two approaches. The reasons why we mistakenly ascribe evidential meaning to p-values and related measures are discussed. Unfamiliarity with the technology and philosophy of evidence is seen as the main reason why certain arguments about p-values persist, and why they are frequently contradictory and confusing.
View details for Web of Science ID A1988R635700013
View details for PubMedID 3189634
Association of Rapid Eye Movement Sleep With Mortality in Middle-aged and Older Adults.
Importance: Rapid eye movement (REM) sleep has been linked with health outcomes, but little is known about the relationship between REM sleep and mortality.Objective: To investigate whether REM sleep is associated with greater risk of mortality in 2 independent cohorts and to explore whether another sleep stage could be driving the findings.Design, Setting, and Participants: This multicenter population-based cross-sectional study used data from the Outcomes of Sleep Disorders in Older Men (MrOS) Sleep Study and Wisconsin Sleep Cohort (WSC). MrOS participants were recruited from December 2003 to March 2005, and WSC began in 1988. MrOS and WSC participants who had REM sleep and mortality data were included. Analysis began May 2018 and ended December 2019.Main Outcomes and Measures: All-cause and cause-specific mortality confirmed with death certificates.Results: The MrOS cohort included 2675 individuals (2675 men [100%]; mean [SD] age, 76.3[5.5] years) and was followed up for a median (interquartile range) of 12.1 (7.8-13.2) years. The WSC cohort included 1386 individuals (753 men [54.3%]; mean [SD] age, 51.5[8.5] years) and was followed up for a median (interquartile range) of 20.8 (17.9-22.4) years. MrOS participants had a 13% higher mortality rate for every 5% reduction in REM sleep (percentage REM sleep SD=6.6%) after adjusting for multiple demographic, sleep, and health covariates (age-adjusted hazard ratio,1.12; fully adjusted hazard ratio,1.13; 95% CI, 1.08-1.19). Results were similar for cardiovascular and other causes of death. Possible threshold effects were seen on the Kaplan-Meier curves, particularly for cancer; individuals with less than 15% REM sleep had a higher mortality rate compared with individuals with 15% or more for each mortality outcome with odds ratios ranging from 1.20 to 1.35. Findings were replicated in the WSC cohort despite younger age, inclusion of women, and longer follow-up (hazard ratio,1.13; 95% CI, 1.08-1.19). A random forest model identified REM sleep as the most important sleep stage associated with survival.Conclusions and Relevance: Decreased percentage REM sleep was associated with greater risk of all-cause, cardiovascular, and other noncancer-related mortality in 2 independent cohorts.
View details for DOI 10.1001/jamaneurol.2020.2108
View details for PubMedID 32628261
THE ASSOCIATION BETWEEN REM SLEEP AND RISK OF MORTALITY IN THREE INDEPENDENT COHORTS
OXFORD UNIV PRESS INC. 2020: A19–A20
View details for Web of Science ID 000554588500049
The Predictive Approaches to Treatment effect Heterogeneity (PATH) Statement: Explanation and Elaboration
ANNALS OF INTERNAL MEDICINE
2020; 172 (1): W1–W25
The PATH (Predictive Approaches to Treatment effect Heterogeneity) Statement was developed to promote the conduct of, and provide guidance for, predictive analyses of heterogeneity of treatment effects (HTE) in clinical trials. The goal of predictive HTE analysis is to provide patient-centered estimates of outcome risk with versus without the intervention, taking into account all relevant patient attributes simultaneously, to support more personalized clinical decision making than can be made on the basis of only an overall average treatment effect. The authors distinguished 2 categories of predictive HTE approaches (a "risk-modeling" and an "effect-modeling" approach) and developed 4 sets of guidance statements: criteria to determine when risk-modeling approaches are likely to identify clinically meaningful HTE, methodological aspects of risk-modeling methods, considerations for translation to clinical practice, and considerations and caveats in the use of effect-modeling approaches. They discuss limitations of these methods and enumerate research priorities for advancing methods designed to generate more personalized evidence. This explanation and elaboration document describes the intent and rationale of each recommendation and discusses related analytic considerations, caveats, and reservations.
View details for DOI 10.7326/M18-3668
View details for Web of Science ID 000506650200002
View details for PubMedID 31711094
Calibrating the Scientific Ecosystem Through Meta-Research
Annual Review of Statistics and Its Application
View details for DOI 10.1146/annurev-statistics-031219-041104
How often do leading biomedical journals use statistical experts to evaluate statistical methods? The results of a survey.
2020; 15 (10): e0239598
Scientific claims in biomedical research are typically derived from statistical analyses. However, misuse or misunderstanding of statistical procedures and results permeate the biomedical literature, affecting the validity of those claims. One approach journals have taken to address this issue is to enlist expert statistical reviewers. How many journals do this, how statistical review is incorporated, and how its value is perceived by editors is of interest. Here we report an expanded version of a survey conducted more than 20 years ago by Goodman and colleagues (1998) with the intention of characterizing contemporary statistical review policies at leading biomedical journals. We received eligible responses from 107 of 364 (28%) journals surveyed, across 57 fields, mostly from editors in chief. 34% (36/107) rarely or never use specialized statistical review, 34% (36/107) used it for 10-50% of their articles and 23% used it for all articles. These numbers have changed little since 1998 in spite of dramatically increased concern about research validity. The vast majority of editors regarded statistical review as having substantial incremental value beyond regular peer review and expressed comparatively little concern about the potential increase in reviewing time, cost, and difficulty identifying suitable statistical reviewers. Improved statistical education of researchers and different ways of employing statistical expertise are needed. Several proposals are discussed.
View details for DOI 10.1371/journal.pone.0239598
View details for PubMedID 33002031
Single-cell mass cytometry reveals cross-talk between inflammation-dampening and inflammation-amplifying cells in osteoarthritic cartilage
2020; 6 (11)
View details for DOI 10.1126/sciadv.aay5352
The worldwide clinical trial research response to the COVID-19 pandemic - the first 100 days.
2020; 9: 1193
Background: Never before have clinical trials drawn as much public attention as those testing interventions for COVID-19. We aimed to describe the worldwide COVID-19 clinical research response and its evolution over the first 100 days of the pandemic. Methods: Descriptive analysis of planned, ongoing or completed trials by April 9, 2020 testing any intervention to treat or prevent COVID-19, systematically identified in trial registries, preprint servers, and literature databases. A survey was conducted of all trials to assess their recruitment status up to July 6, 2020. Results: Most of the 689 trials (overall target sample size 396,366) were small (median sample size 120; interquartile range [IQR] 60-300) but randomized (75.8%; n=522) and were often conducted in China (51.1%; n=352) or the USA (11%; n=76). 525 trials (76.2%) planned to include 155,571 hospitalized patients, and 25 (3.6%) planned to include 96,821 health-care workers. Treatments were evaluated in 607 trials (88.1%), frequently antivirals (n=144) or antimalarials (n=112); 78 trials (11.3%) focused on prevention, including 14 vaccine trials. No trial investigated social distancing. Interventions tested in 11 trials with >5,000 participants were also tested in 169 smaller trials (median sample size 273; IQR 90-700). Hydroxychloroquine alone was investigated in 110 trials. While 414 trials (60.0%) expected completion in 2020, only 35 trials (4.1%; 3,071 participants) were completed by July 6. Of 112 trials with detailed recruitment information, 55 had recruited <20% of the targeted sample; 27 between 20-50%; and 30 over 50% (median 14.8% [IQR 2.0-62.0%]). Conclusions: The size and speed of the COVID-19 clinical trials agenda is unprecedented. However, most trials were small investigating a small fraction of treatment options. The feasibility of this research agenda is questionable, and many trials may end in futility, wasting research resources. Much better coordination is needed to respond to global health threats.
View details for DOI 10.12688/f1000research.26707.1
View details for PubMedID 33082937
- Preprint Servers' Policies, Submission Requirements, and Transparency in Reporting and Research Integrity Recommendations. JAMA 2020; 324 (18): 1901–3
THE ASSOCIATION BETWEEN REM SLEEP AND MORTALITY IN THE MROS AND WISCONSIN SLEEP COHORTS
ELSEVIER. 2019: S213
View details for Web of Science ID 000558768400594
- Lost Evidence From Registered Large Long-Unpublished Randomized Controlled Trials: A Survey ANNALS OF INTERNAL MEDICINE 2019; 171 (4): 300-+
- Random-Effects Assumption in Meta-analyses-Reply. JAMA 2019; 322 (1): 82
- Urodynamic factors associated with the large capacity bladder and incomplete emptying after prolapse repair (2009-2015) NEUROUROLOGY AND URODYNAMICS 2019; 38 (5): 1322–31
Urodynamic factors associated with the large capacity bladder and incomplete emptying after prolapse repair (2009-2015).
Neurourology and urodynamics
AIMS: To identify the clinical and urodynamic factors associated with the large capacity bladder and incomplete bladder emptying after prolapse repair.METHODS: We identified 592 women who underwent anterior and/or apical prolapse repair at our institution from 2009 to 2015. Women were stratified by urodynamic capacity. The primary outcome was incomplete emptying at the longest follow-up (postvoid residual [PVR]>200mL). Data were analyzed in the Statistical Analysis System software.RESULTS: Two hundred and sixty-six women (mean age, 61 years) had preoperative urodynamic tracings available for review. After surgery, there were 519 PVRs in 239 women recorded at up to 2949 days (mean, 396) and nine time points (median, 2; IQR, 1-3). The receiver operator curve for predicted probability of longest follow-up PVR greater than 200mL (area under curve=0.67) identified the 600mL cutpoint which defined large capacity bladder. Large capacity bladders (capacity, >600mL [n=79] vs ≤600mL, [n=160]) had a mean: detrusor pressure at maximum flow (21 vs 22cm H2 O; P=0.717), maximum flow rate (19 vs 17mL/s; P=0.148), significantly elevated PVR (202 vs 73mL; P<0.001), and significantly lower voiding efficiency (VE) (74 vs 82%, P<0.05). Following prolapse repair, elevated PVR was associated with large capacity (PVR 101 vs 49mL, P<0.05). Large bladders had a two- to three-fold risk of longest follow-up PVR greater than 200mL (14.3%-20.3% [capacity, >600mL] vs 4.1%-7.0% [capacity, ≤600mL]). VE was similar after surgery regardless of the capacity (87% vs 88%, P=0.772).CONCLUSIONS: The decision to pursue prolapse repair should be individualized and take into account, the bladder capacity and goals for PVR improvement after surgery.
View details for PubMedID 30912192
The Predictive Approaches to Treatment effect Heterogeneity (PATH) Statement.
Annals of internal medicine
Heterogeneity of treatment effect (HTE) refers to the nonrandom variation in the magnitude or direction of a treatment effect across levels of a covariate, as measured on a selected scale, against a clinical outcome. In randomized controlled trials (RCTs), HTE is typically examined through a subgroup analysis that contrasts effects in groups of patients defined "1 variable at a time" (for example, male vs. female or old vs. young). The authors of this statement present guidance on an alternative approach to HTE analysis, "predictive HTE analysis." The goal of predictive HTE analysis is to provide patient-centered estimates of outcome risks with versus without the intervention, taking into account all relevant patient attributes simultaneously. The PATH (Predictive Approaches to Treatment effect Heterogeneity) Statement was developed using a multidisciplinary technical expert panel, targeted literature reviews, simulations to characterize potential problems with predictive approaches, and a deliberative process engaging the expert panel. The authors distinguish 2 categories of predictive HTE approaches: a "risk-modeling" approach, wherein a multivariable model predicts the risk for an outcome and is applied to disaggregate patients within RCTs to define risk-based variation in benefit, and an "effect-modeling" approach, wherein a model is developed on RCT data by incorporating a term for treatment assignment and interactions between treatment and baseline covariates. Both approaches can be used to predict differential absolute treatment effects, the most relevant scale for clinical decision making. The authors developed 4 sets of guidance: criteria to determine when risk-modeling approaches are likely to identify clinically important HTE, methodological aspects of risk-modeling methods, considerations for translation to clinical practice, and considerations and caveats in the use of effect-modeling approaches. The PATH Statement, together with its explanation and elaboration document, may guide future analyses and reporting of RCTs.
View details for DOI 10.7326/M18-3667
View details for PubMedID 31711134
- Why is Getting Rid of P-Values So Hard? Musings on Science and Statistics AMERICAN STATISTICIAN 2019; 73: 26–30
Lost Evidence From Registered Large Long-Unpublished Randomized Controlled Trials: A Survey.
Annals of internal medicine
View details for PubMedID 31060046
Lack of Diagnostic Utility of "Amino Acid Dysregulation Metabotypes".
View details for PubMedID 30595232
Random-Effects Meta-analysis: Summarizing Evidence With Caveats.
View details for PubMedID 30566189
Machine Learning, Health Disparities, and Causal Reasoning.
Annals of internal medicine
View details for PubMedID 30508423
Annals Understanding Clinical Research: Interpreting Results With Large P Values
ANNALS OF INTERNAL MEDICINE
2018; 169 (7): 485-+
View details for PubMedID 30208404
New Principles for Assessing
ISSUES IN SCIENCE AND TECHNOLOGY
2018; 35 (1): 20–23
View details for Web of Science ID 000447682000006
How and why studies disagree about the effects of education on health: A systematic review and meta-analysis of studies of compulsory schooling laws
SOCIAL SCIENCE & MEDICINE
2018; 212: 168–78
Rich literatures across multiple disciplines document the association between increased educational attainment and improved health. While quasi-experimental studies have exploited variation in educational policies to more rigorously estimate the health effects of education, there remains disagreement about whether education and health are causally linked. The aim of this study was to conduct a systematic review and meta-analysis to characterize this literature, with a focus on quasi-experimental studies of compulsory schooling laws (CSLs). Articles from 1990 to 2015 were obtained through electronic searches and manual searches of reference lists. We searched for English-language studies and included manuscripts if: (1) they involved original data analysis; (2) outcomes were health-related; and (3) the primary predictor utilized variation in CSLs. We identified 89 articles in 25 countries examining over 25 health outcomes, with over 600 individual point estimates. We systematically characterized heterogeneity on key study design features and conducted a meta-analysis of studies with comparable health outcome and exposure variables. Within countries, studies differed in terms of birth cohorts included, the measurement of health outcomes within a given category, and the type of CSL variation examined. Over 90% of manuscripts included multiple analytic techniques, such as econometric and standard regression methods, with as many as 31 "primary" models in a single study. A qualitative synthesis of study findings indicated that educational attainment has an effect on the majority of health outcomes-most beneficial, some negative-while the meta-analysis demonstrated small beneficial effects for mortality, smoking, and obesity. Future work could focus on inconsistent findings identified by this study, or review the health effects of other types of educational policies.
View details for PubMedID 30036767
THE LARGE CAPACITY BLADDER OVER 600 ML IS ASSOCIATED WITH ONGOING INCOMPLETE BLADDER EMPTYING FOLLOWING ANTERIOR AND/OR APICAL PROLAPSE REPAIR (2009-2015)
WILEY. 2018: S289–S291
View details for Web of Science ID 000437692900216
Rapid Bedside Evaluation of Seizures in the ICU by Listening to the Sound of Brainwaves: A Prospective Observational Clinical Trial of Ceribell's Brain Stethoscope Function.
BACKGROUND: Patients suffering from non-convulsive seizures experience delays in diagnosis and treatment due to limitations in acquiring and interpreting electroencephalography (EEG) data. The Ceribell EEG System offers rapid EEG acquisition and conversion of EEG signals to sound (sonification) using a proprietary algorithm. This study was designed to test the performance of this EEG system in an intensive care unit (ICU) setting and measure its impact on clinician treatment decision.METHODS: Encephalopathic ICU patients at Stanford University Hospital were enrolled if clinical suspicion for seizures warranted EEG monitoring. Treating physicians rated suspicion for seizure and decided if the patient needed antiepileptic drug (AED) treatment at the time of bedside evaluation. After listening to 30s of EEG from each hemisphere in each patient, they reevaluated their suspicion for seizure and decision for additional treatment. The EEG waveforms recorded with Ceribell EEG were subsequently analyzed by three blinded epileptologists to assess the presence or absence of seizures within and outside the sonification window. Study outcomes were EEG set up time, ease of use of the device, change in clinician seizure suspicion, and change in decision to treat with AED before and after sonification.RESULTS: Thirty-five cases of EEG sonification were performed. Mean EEG setup time was 6±3min, and time to obtain sonified EEG was significantly faster than conventional EEG (p<0.001). One patient had non-convulsive seizure during sonification and another had rhythmic activity that was followed by seizure shortly after sonification. Change in treatment decision after sonification occurred in approximately 40% of patients and resulted in a significant net reduction in unnecessary additional treatments (p=0.01). Ceribell EEG System was consistently rated easy to use.CONCLUSION: The Ceribell EEG System enabled rapid acquisition of EEG in patients at risk for non-convulsive seizures and aided clinicians in their evaluation of encephalopathic ICU patients. The ease of use and speed of EEG acquisition and interpretation by EEG-untrained individuals has the potential to improve emergent clinical decision making by quickly detecting non-convulsive seizures in the ICU.
View details for PubMedID 29923167
Clinical Trial Participants' Views of the Risks and Benefits of Data Sharing
NEW ENGLAND JOURNAL OF MEDICINE
2018; 378 (23): 2202–11
Background Sharing of participant-level clinical trial data has potential benefits, but concerns about potential harms to research participants have led some pharmaceutical sponsors and investigators to urge caution. Little is known about clinical trial participants' perceptions of the risks of data sharing. Methods We conducted a structured survey of 771 current and recent participants from a diverse sample of clinical trials at three academic medical centers in the United States. Surveys were distributed by mail (350 completed surveys) and in clinic waiting rooms (421 completed surveys) (overall response rate, 79%). Results Less than 8% of respondents felt that the potential negative consequences of data sharing outweighed the benefits. A total of 93% were very or somewhat likely to allow their own data to be shared with university scientists, and 82% were very or somewhat likely to share with scientists in for-profit companies. Willingness to share data did not vary appreciably with the purpose for which the data would be used, with the exception that fewer participants were willing to share their data for use in litigation. The respondents' greatest concerns were that data sharing might make others less willing to enroll in clinical trials (37% very or somewhat concerned), that data would be used for marketing purposes (34%), or that data could be stolen (30%). Less concern was expressed about discrimination (22%) and exploitation of data for profit (20%). Conclusions In our study, few clinical trial participants had strong concerns about the risks of data sharing. Provided that adequate security safeguards were in place, most participants were willing to share their data for a wide range of uses. (Funded by the Greenwall Foundation.).
View details for PubMedID 29874542
Statistical Code to Support the Scientific Story
ANNALS OF INTERNAL MEDICINE
2018; 168 (11): 828-+
View details for PubMedID 29404564
Improving the integrity of published science: An expanded taxonomy of retractions and corrections
EUROPEAN JOURNAL OF CLINICAL INVESTIGATION
2018; 48 (4)
View details for PubMedID 29369337
- A serious nonsense publishing proposal NATURE 2018; 553 (7687): 155
- Redefine statistical significance NATURE HUMAN BEHAVIOUR 2018; 2 (1): 6–10
Redefine statistical significance.
Nature human behaviour
2018; 2 (1): 6–10
View details for PubMedID 30980045
- Using big data analytics to extract disease surveillance information from point of care diagnostic machines PERVASIVE AND MOBILE COMPUTING 2017; 42: 470–86
Five ways to fix statistics.
2017; 551 (7682): 557–59
View details for PubMedID 29189798
Using Design Thinking to Differentiate Useful From Misleading Evidence in Observational Research.
2017; 317 (7): 705–7
View details for PubMedID 28241335
Posing Causal Questions When Analyzing Observational Data-Reply.
2017; 318 (2): 201–2
View details for PubMedID 28697249
Sharing Clinical Research Data-Finding the Right Balance.
JAMA internal medicine
2017; 177 (9): 1241–42
View details for PubMedID 28715538
Quantifying over-estimation in early stopped clinical trials and the "freezing effect" on subsequent research
2016; 13 (6): 621-631
Despite the wide use of the design with statistical stopping guidelines to stop a randomized clinical trial early for efficacy, there are unsettled debates of potential harmful consequences of such designs. These concerns include the possible over-estimation of treatment effects in early stopped trials and a newer argument of a "freezing effect" that will halt future randomized clinical trials on the same comparison since an early stopped trial represents an effective declaration that randomization to the unfavored arm is unethical. The purpose of this study is to determine the degree of bias in designs that allow for early stopping and to assess the impact on estimation if indeed future experimentation is "frozen" by an early stopped trial.We perform simulations to study the effect of early stopping. We simulate a collection of trials and contrast the treatment-effect estimates (risk differences and ratios) with the simulation truth. Simulations consider various scenarios of between-study variation, including an empirically derived distribution of effects from the clinical literature.Across the trials whose true effects are sampled from a uniform distribution, estimates from trials that stop early for efficacy deviate minimally from the simulation truth (median bias of the estimate of risk difference is 0.005). Over-estimation becomes appreciable only when the true effect is close to the null value 0 (median bias of the risk difference estimate is 0.04) or when stopping happens with 40% information or less; however, stopping under these situations is rare. We also find slight reverse bias of the estimated treatment effect (median bias of the risk difference estimate is -0.002) among trials that do not cross the early stopping boundaries but continue to the final analysis. Similar results occur with relative risk estimates. In contrast, Bayesian estimation of the treatment effect shrinks the estimate from trials stopping early and pulls back under-estimation from completed trials, largely rectifying any over-estimation among trials that terminate early. Regarding the so-called freezing effect, the pooled effects from meta-analyses that include truncated randomized clinical trials show an unimportant deviation from the true value, even when no subsequent trials are conducted after a truncated randomized clinical trial.Group sequential designs with stopping rules seek to minimize exposure of patients to a disfavored therapy and speed dissemination of results, and such designs do not lead to materially biased estimates. The likelihood and magnitude of a "freezing effect" is minimal. Superiority demonstrated in a randomized clinical trial stopping early and designed with appropriate statistical stopping rules is likely a valid inference, even if the estimate may be slightly inflated.
View details for DOI 10.1177/1740774516649595
View details for PubMedID 27271682
- STATISTICS. Aligning statistical and scientific reasoning. Science 2016; 352 (6290): 1180-1181
Statistical tests, P values, confidence intervals, and power: a guide to misinterpretations
EUROPEAN JOURNAL OF EPIDEMIOLOGY
2016; 31 (4): 337-350
Misinterpretation and abuse of statistical tests, confidence intervals, and statistical power have been decried for decades, yet remain rampant. A key problem is that there are no interpretations of these concepts that are at once simple, intuitive, correct, and foolproof. Instead, correct use and interpretation of these statistics requires an attention to detail which seems to tax the patience of working scientists. This high cognitive demand has led to an epidemic of shortcut definitions and interpretations that are simply wrong, sometimes disastrously so-and yet these misinterpretations dominate much of the scientific literature. In light of this problem, we provide definitions and a discussion of basic statistics that are more general and critical than typically found in traditional introductory expositions. Our goal is to provide a resource for instructors, researchers, and consumers of statistics whose knowledge of statistical theory and technique may be limited but who wish to avoid and spot misinterpretations. We emphasize how violation of often unstated analysis protocols (such as selecting analyses for presentation based on the P values they produce) can lead to small P values even if the declared test hypothesis is correct, and can lead to large P values even if that hypothesis is incorrect. We then provide an explanatory list of 25 misinterpretations of P values, confidence intervals, and power. We conclude with guidelines for improving statistical interpretation and reporting.
View details for DOI 10.1007/s10654-016-0149-3
View details for PubMedID 27209009
Academic criteria for appointment, promotion and rewards in medical research: where's the evidence?
European journal of clinical investigation
It has been argued that incentive systems should be multi-dimensional, including productivity, quality, reproducibility, sharing, and translation potential ("PQRST"),(1) but many current systems weight productivity particularly heavily. These systems directly affect the volume, and indirectly the quality of the scientific publication record. This was recognized at least as far back as the 1980s, with a proposal that promotion committees consider only a handful of a scientist's publications, in the hopes of improving the quality of our "large and largely trivial" literature. This article is protected by copyright. All rights reserved.
View details for PubMedID 26924551
Informatics: Make sense of health data
2015; 527 (7576): 31–32
View details for PubMedID 26536942
Data monitoring committees for pragmatic clinical trials
2015; 12 (5): 530–36
In any clinical trial, it is essential to monitor the accumulating data to be sure that the trial continues to be safe for participants and that the trial is being conducted properly. Data monitoring committees, independent expert panels who undertake regular reviews of the data as the trial progresses, serve an important role in safeguarding the interests of research participants and ensuring trial integrity in many trials. Many pragmatic clinical trials, which aim to inform healthcare decisions by comparing alternate interventions in heterogeneous healthcare delivery settings, will warrant review by an independent data monitoring committee due to their potential impact on clinical practice. However, the very features that make a trial "pragmatic" may pose challenges in terms of which aspects of a trial to monitor and when it is appropriate for a data monitoring committee to intervene. Using the Pragmatic-Explanatory Continuum Indicator Summary tool that draws distinctions between pragmatic and explanatory clinical trials, we review characteristics of pragmatic clinical trials that may have implications for data monitoring committees and interim monitoring plans. These include broad eligibility criteria, a focus on subjective patient-centered outcomes, and in some cases a lack of standardized follow-up procedures across study sites. Additionally, protocol adherence is often purposefully not addressed in pragmatic trials in order to accurately represent the clinical practice setting and maintain practicability of implementation; there are differing viewpoints as to whether adherence should be assessed and acted upon by data monitoring committees in these trials. Some other issues not specifically related to the Pragmatic-Explanatory Continuum Indicator Summary criteria may also merit special consideration in pragmatic trials. Thresholds for early termination of a pragmatic clinical trial might be controversial. The distinguishing features of pragmatic clinical trials require careful consideration when developing interim data monitoring plans, and trial sponsors, investigators, and data monitoring committees should agree on a plan before trial inception. Finally, special expertise, such as an informatics, may be helpful on data monitoring committees for some pragmatic clinical trials. Patient representatives may provide particularly valuable insights in the monitoring process.
View details for PubMedID 26374679
- An interview with David Sackett, 2014-2015. Clinical trials 2015; 12 (5): 540-551
Meta-research: Evaluation and Improvement of Research Methods and Practices
2015; 13 (10)
As the scientific enterprise has grown in size and diversity, we need empirical evidence on the research process to test and apply interventions that make it more efficient and its results more reliable. Meta-research is an evolving scientific discipline that aims to evaluate and improve research practices. It includes thematic areas of methods, reporting, reproducibility, evaluation, and incentives (how to do, report, verify, correct, and reward science). Much work is already done in this growing field, but efforts to-date are fragmented. We provide a map of ongoing efforts and discuss plans for connecting the multiple meta-research efforts across science worldwide.
View details for DOI 10.1371/journal.pbio.1002264
View details for PubMedID 26431313
Random-Effects Meta-analysis of Inconsistent Effects: A Time for Change.
Annals of internal medicine
2014; 160 (4): 267-270
This article has an additional interactive example appended as a Supplement. Please visit the Supplement tab on this page to access the presentation. A primary goal of meta-analysis is to improve the estimation of treatment effects by pooling results of similar studies. This article explains how the most widely used method for pooling heterogeneous studies-the DerSimonian-Laird (DL) estimator-can produce biased estimates with falsely high precision. A classic example is presented to show that use of the DL estimator can lead to erroneous conclusions. Particular problems with the DL estimator are discussed, and several alternative methods for summarizing heterogeneous evidence are presented. The authors support replacing universal use of the DL estimator with analyses based on a critical synthesis that recognizes the uncertainty in the evidence, focuses on describing and explaining the probable sources of variation in the evidence, and uses random-effects estimates that provide more accurate confidence limits than the DL estimator.
View details for DOI 10.7326/M13-2886
View details for PubMedID 24727843
Opening the FDA Black Box
JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION
2014; 311 (4): 361–63
View details for PubMedID 24449313
Discussion: An estimate of the science-wise false discovery rate and application to the top medical literature.
Biostatistics (Oxford, England)
2014; 15 (1): 23–27; discussion 39–45
View details for PubMedID 24068250
Raw data from clinical trials: within reach?
Trends in pharmacological sciences
2013; 34 (12): 645-647
Making raw data from clinical trials widely publically available should reduce selective reporting biases and enhance the reproducibility of and trust in clinical research. The optimal procedures for data sharing are hotly debated. Some of the caveats and limitations in proposed data-sharing policies are potentially restrictive, and we argue in favor of more widespread availability of data from clinical research.
View details for DOI 10.1016/j.tips.2013.10.006
View details for PubMedID 24295825
Handling of Rescue and Missing Data Affects Synthesis and Interpretation of Evidence: The Sodium-Glucose Cotransporter 2 Inhibitor Example
ANNALS OF INTERNAL MEDICINE
2013; 159 (4): 285-?
Confidence in evidence summarized in meta-analyses depends on the strength of the underlying studies. This inherent limitation of syntheses appears in the case of a meta-analysis of sodium-glucose cotransporter 2 inhibitors for the treatment of type 2 diabetes because many of the pertinent randomized trials did not handle patient dropout and "rescue" medication properly. Repudiated statistical methods, such as last observation carried forward, and unsophisticated methods for handling postrescue data produce unreliable summary estimates. Future reports of randomized studies and meta-analyses of those studies must focus on posing precise questions about the treatment effect of interest and then implement appropriate statistical methods to account for missing data, patient dropout, and use of rescue medication.
View details for Web of Science ID 000323421700018
View details for PubMedID 24026261
The Relative Expression of Mig6 and EGFR Is Associated with Resistance to EGFR Kinase Inhibitors
2013; 8 (7)
The sensitivity of only a few tumors to anti-epidermal growth factor receptor EGFR tyrosine kinase inhibitors (TKIs) can be explained by the presence of EGFR tyrosine kinase (TK) domain mutations. In addition, such mutations were rarely found in tumor types other than lung, such as pancreatic and head and neck cancer. In this study we sought to elucidate mechanisms of resistance to EGFR-targeted therapies in tumors that do not harbor TK sensitizing mutations in order to identify markers capable of guiding the decision to incorporate these drugs into chemotherapeutic regimens. Here we show that EGFR activity was markedly decreased during the evolution of resistance to the EGFR tyrosine kinase inhibitor (TKI) erlotinib, with a concomitant increase of mitogen-inducible gene 6 (Mig6), a negative regulator of EGFR through the upregulation of the PI3K-AKT pathway. EGFR activity, which was more accurately predicted by the ratio of Mig6/EGFR, highly correlated with erlotinib sensitivity in panels of cancer cell lines of different tissue origins. Blinded testing and analysis in a prospectively followed cohort of lung cancer patients treated with gefitinib alone demonstrated higher response rates and a marked increased in progression free survival for patients with a low Mig6/EGFR ratio (approximately 100 days, P = 0.01).
View details for DOI 10.1371/journal.pone.0068966
View details for Web of Science ID 000322633700014
View details for PubMedID 23935914
View details for PubMedCentralID PMC3729565
Bayesian methods for evidence evaluation: are we there yet?
2013; 127 (24): 2367-2369
"First they ignore you, then they laugh at you, then they fight you, then you win," a saying reportedly misattributed to Mahatma Ghandi(1), might apply to the use of Bayesian statistics in medical research. The idea that Bayesian approaches might be used to "affirm" findings derived from conventional methods, and thereby be regarded as more authoritative, is a dramatic turnabout from an era not very long ago when those embracing Bayesian ideas were considered barbarians at the gate. I remember my own initiation into the Bayesian fold, reading with a mixture of astonishment and subversive pleasure one of George Diamond's early pieces taking aim at conventional interpretations of large cardiovascular trials of the early 80's.(2) It is gratifying to see that the Bayesian approach, which saw negligible application in biomedical research in the 80's and began to get traction in the 90's, is now not just a respectable alternative to standard methods, but sometimes might be regarded as preferable. That said, it is premature to declare a "win," and the statistical lingua franca of biomedical research is still firmly frequentist, with P-values, confidence intervals and Type I and II errors dominating the journal landscape. It is helpful to use the thoughtful and thorough Bayesian exercise of Bittl et al.(3) to reflect on what Bayesian approaches give us, and what they don't.
View details for DOI 10.1161/CIRCULATIONAHA.113.003193
View details for PubMedID 23674396
- Closing in on the truth about recombinant human bone morphogenetic protein-2: evidence synthesis, data sharing, peer review, and reproducible research. Annals of internal medicine 2013; 158 (12): 916-918
- Advances in regulatory science at the Food and Drug Administration. JAMA-the journal of the American Medical Association 2013; 309 (20): 2103-2104
A decade of Clinical Trials.
Clinical trials (London, England)
2013; 10 (6): 837–39
View details for PubMedID 24287131
- Beyond the Usual Prediction Accuracy Metrics: Reporting Results for Clinical Decision Making ANNALS OF INTERNAL MEDICINE 2012; 157 (4): 294-?
Correlation between BRAF mutation and promoter methylation of TIMP3, RAR beta 2 and RASSF1A in thyroid cancer
2012; 7 (7): 710-719
Our aim was to comprehensively analyze promoter hypermethylation of a panel of novel and known methylation markers for thyroid neoplasms and to establish their relationship with BRAF mutation and clinicopathologic parameters of thyroid cancer. A cohort of thyroid tumors, consisting of 44 cancers and 44 benign thyroid lesions, as well as 15 samples of adjacent normal thyroid tissue, was evaluated for BRAF mutation and promoter hypermethylation. Genes for quantitative methylation specific PCR (QMSP) were selected by a candidate gene approach. Twenty-two genes were tested: TSHR, RASSF1A, RARβ2, DAPK, hMLH1, ATM, S100, p16, CTNNB1, GSTP1, CALCA, TIMP3, TGFßR2, THBS1, MINT1, CTNNB1, MT1G, PAK3, NISCH, DCC, AIM1 and KIF1A. The PCR-based "mutector assay" was used to detect BRAF mutation. All p values reported are two sided. Considerable overlap was seen in the methylation markers among the different tissue groups. Significantly higher methylation frequency and level were observed for KIF1A and RARß2 in cancer samples compared with benign tumors. A negative correlation between BRAF mutation and RASSF1A methylation, and a positive correlation with RARß2 methylation were observed in accordance with previous results. In addition, positive correlation with TIMP3 and a marginal correlation with DCC methylation were observed. The present study constitutes a comprehensive promoter methylation profile of thyroid neoplasia and shows that results must be analyzed in a tissue-specific manner to identify clinically useful methylation markers. Integration of genetic and epigenetic changes in thyroid cancer will help identify relevant biologic pathways that drive its development.
View details for DOI 10.4161/epi.205248
View details for Web of Science ID 000306291900007
View details for PubMedID 22694820
Methodological Standards and Patient-Centeredness in Comparative Effectiveness Research The PCORI Perspective
JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION
2012; 307 (15): 1636-1640
Rigorous methodological standards help to ensure that medical research produces information that is valid and generalizable, and are essential in patient-centered outcomes research (PCOR). Patient-centeredness refers to the extent to which the preferences, decision-making needs, and characteristics of patients are addressed, and is the key characteristic differentiating PCOR from comparative effectiveness research. The Patient Protection and Affordable Care Act signed into law in 2010 created the Patient-Centered Outcomes Research Institute (PCORI), which includes an independent, federally appointed Methodology Committee. The Methodology Committee is charged to develop methodological standards for PCOR. The 4 general areas identified by the committee in which standards will be developed are (1) prioritizing research questions, (2) using appropriate study designs and analyses, (3) incorporating patient perspectives throughout the research continuum, and (4) fostering efficient dissemination and implementation of results. A Congressionally mandated PCORI methodology report (to be issued in its first iteration in May 2012) will begin to provide standards in each of these areas, and will inform future PCORI funding announcements and review criteria. The work of the Methodology Committee is intended to enable generation of information that is relevant and trustworthy for patients, and to enable decisions that improve patient-centered outcomes.
View details for Web of Science ID 000302896100026
- Landmark clinical trials: a new journal series CLINICAL TRIALS 2011; 8 (2): 128-128
- Harry Marks: an appreciation. Clinical trials 2011; 8 (2): 123-127
Diastolic Blood Pressure Levels and Ischemic Stroke Incidence in Older Adults With White Matter Lesions
JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES
2011; 66 (1): 74-81
The optimal blood pressure level to minimize the risk of ischemic stroke (IS) in older adults is undetermined. Cerebral white matter lesions (WML), prevalent in older adults, may be a marker for vulnerability to IS. We aimed at determining the relationship between diastolic blood pressure (DBP) levels and IS in the presence of WML.The Cardiovascular Health Study population (N = 3,345, age ≥ 65 years, N = 3,345) was followed between 1989 and 2002 for IS incidence. Survival analysis included quintiles of DBP analyzed within WML levels controlling for age and cardiovascular disease.DBP had no effect on IS incidence in low WML levels but had a marginally significant J-curve relationship with IS in high WML levels: the adjusted hazard ratio for IS in the lowest (<63 mmHg) and highest (≥ 80) DBP quintiles compared with the third (nadir, 69-73 mmHg) was 1.64 (95% confidence interval: 0.93-2.9) and 1.83 (95% confidence interval: 1.06-3.15), respectively.In older adults with low-grade WML, low DBP may not pose a risk for IS. However, in high-grade WML, IS risk may increase in DBP less than 69 mmHg but is highest more than 80 mmHg. People with high-grade WML may be at risk of IS in high and low DBP.
View details for DOI 10.1093/gerona/glq166
View details for Web of Science ID 000286655300011
View details for PubMedID 21030465
- On making clinical trials possible CLINICAL TRIALS 2010; 7 (6): 621-621
CONSORT 2010 Explanation and Elaboration: Updated guidelines for reporting parallel group randomised trials.
Journal of clinical epidemiology
2010; 63 (8): e1-37
Overwhelming evidence shows the quality of reporting of randomised controlled trials (RCTs) is not optimal. Without transparent reporting, readers cannot judge the reliability and validity of trial findings nor extract information for systematic reviews. Recent methodological analyses indicate that inadequate reporting and design are associated with biased estimates of treatment effects. Such systematic error is seriously damaging to RCTs, which are considered the gold standard for evaluating interventions because of their ability to minimise or avoid bias. A group of scientists and editors developed the CONSORT (Consolidated Standards of Reporting Trials) statement to improve the quality of reporting of RCTs. It was first published in 1996 and updated in 2001. The statement consists of a checklist and flow diagram that authors can use for reporting an RCT. Many leading medical journals and major international editorial groups have endorsed the CONSORT statement. The statement facilitates critical appraisal and interpretation of RCTs. During the 2001 CONSORT revision, it became clear that explanation and elaboration of the principles underlying the CONSORT statement would help investigators and others to write or appraise trial reports. A CONSORT explanation and elaboration article was published in 2001 alongside the 2001 version of the CONSORT statement. After an expert meeting in January 2007, the CONSORT statement has been further revised and is published as the CONSORT 2010 Statement. This update improves the wording and clarity of the previous checklist and incorporates recommendations related to topics that have only recently received recognition, such as selective outcome reporting bias. This explanatory and elaboration document-intended to enhance the use, understanding, and dissemination of the CONSORT statement-has also been extensively revised. It presents the meaning and rationale for each new and updated checklist item providing examples of good reporting and, where possible, references to relevant empirical studies. Several examples of flow diagrams are included. The CONSORT 2010 Statement, this revised explanatory and elaboration document, and the associated website (www.consort-statement.org) should be helpful resources to improve reporting of randomised trials.
View details for DOI 10.1016/j.jclinepi.2010.03.004
View details for PubMedID 20346624
- Bias and Trials Stopped Early for Benefit JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION 2010; 304 (2): 157-157
- Commentary BIOSTATISTICS 2010; 11 (3): 389-390
- CONSORT 2010 Statement Updated Guidelines for Reporting Parallel Group Randomized Trials OBSTETRICS AND GYNECOLOGY 2010; 115 (5): 1063-1070
High-dose cyclophosphamide as single-agent, short-course prophylaxis of graft-versus-host disease
2010; 115 (16): 3224-3230
Because of its potent immunosuppressive yet stem cell-sparing activity, high-dose cyclophosphamide was tested as sole prophylaxis of graft-versus-host disease (GVHD) after myeloablative allogeneic bone marrow transplantation (alloBMT). We treated 117 patients (median age, 50 years; range, 21-66 years) with advanced hematologic malignancies; 78 had human leukocyte antigen (HLA)-matched related donors and 39 had HLA-matched unrelated donors. All patients received conventional myeloablation with busulfan/cyclophosphamide (BuCy) and T cell-replete bone marrow followed by 50 mg/kg/d of cyclophosphamide on days 3 and 4 after transplantation. The incidences of acute grades II through IV and grades III through IV GVHD for all patients were 43% and 10%, respectively. The nonrelapse mortality at day 100 and 2 years after transplantation were 9% and 17%, respectively. The actuarial overall survival and event-free survivals at 2 years after transplantation were 55% and 39%, respectively, for all patients and 63% and 54%, respectively, for patients who underwent transplantation while in remission. With a median follow-up of 26.3 months among surviving patients, the cumulative incidence of chronic GVHD is 10%. These results suggest that high-dose posttransplantation cyclophosphamide is an effective single-agent prophylaxis of acute and chronic GVHD after BuCy conditioning and HLA-matched BMT (clinicaltrials.gov no. NCT00134017).
View details for DOI 10.1182/blood-2009-11-251595
View details for Web of Science ID 000276956500008
View details for PubMedID 20124511
High-dose cyclophosphamide for severe aplastic anemia: long-term follow-up
2010; 115 (11): 2136-2141
Severe aplastic anemia (SAA) is a life-threatening bone marrow failure disorder that can be treated with bone marrow transplantation, immunosuppressive therapy, and high-dose cyclophosphamide. Here, we report long-term follow-up on 67 SAA patients (44 treatment-naive and 23 refractory) treated with high-dose cyclophosphamide. At 10 years, the overall actuarial survival was 88%, the response rate was 71% with the majority being complete, and the actuarial event-free survival was 58% in 44 treatment-naive SAA patients. Patients with refractory SAA fared less well after high-dose cyclophosphamide therapy; at 10 years, overall actuarial survival, response, and actuarial event-free survival rates were 62%, 48%, and 27%, respectively. High-dose cyclophosphamide is highly effective therapy for severe aplastic anemia. Large randomized controlled trials will be necessary to establish how results of high-dose cyclophosphamide compare with either bone marrow transplantation or standard immunosuppressive regimens, such as antithymocyte globulin and cyclosporine.
View details for DOI 10.1182/blood-2009-06-225375
View details for Web of Science ID 000275751400008
View details for PubMedID 20018919
- An Absence of Evidence in "Evidence-Based Rulemaking" AMERICAN JOURNAL OF BIOETHICS 2010; 10 (6): 22-23
- Considering Usual Medical Care in Clinical Trial Design PLOS MEDICINE 2009; 6 (9)
Sensitive digital quantification of DNA methylation in clinical samples
2009; 27 (9): 858-U118
Analysis of abnormally methylated genes is increasingly important in basic research and in the development of cancer biomarkers. We have developed methyl-BEAMing technology to enable absolute quantification of the number of methylated molecules in a sample. Individual DNA fragments are amplified and analyzed either by flow cytometry or next-generation sequencing. We demonstrate enumeration of as few as one methylated molecule in approximately 5,000 unmethylated molecules in DNA from plasma or fecal samples. Using methylated vimentin as a biomarker in plasma samples, methyl-BEAMing detected 59% of cancer cases. In early-stage colorectal cancers, this sensitivity was four times more than that obtained by assaying serum-carcinoembryonic antigen (CEA). With stool samples, methyl-BEAMing detected 41% of cancers and 45% of advanced adenomas. In addition to diagnostic and prognostic applications, this digital quantification of rare methylation events should be applicable to preclinical assessment of new epigenetic biomarkers and quantitative analyses in epigenetic research.
View details for DOI 10.1038/nbt.1559
View details for Web of Science ID 000269751400029
View details for PubMedID 19684580
- Building a Bayesian Bridge From Evidence to Guidelines ARCHIVES OF INTERNAL MEDICINE 2009; 169 (15): 1436-1437
An intervention to improve cancer patients' understanding of early-phase clinical trials.
2009; 31 (3): 1-10
View details for PubMedID 19552233
- Stopping trials for efficacy: an almost unbiased view CLINICAL TRIALS 2009; 6 (2): 133-135
Phase II Study of Risk-Adapted Therapy of Newly Diagnosed, Aggressive Non-Hodgkin Lymphoma Based on Midtreatment FDG-PET Scanning
BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION
2009; 15 (2): 242-248
In newly diagnosed aggressive non-Hodgkin lymphoma (NHL), a positive midtreatment fluorine-18 fluorodeoxyglucose positron emission tomography (PET) scan often carries a poor prognosis, with reported 2-year event-free survival (EFS) rates of 0% to 30% after standard therapy. To determine the outcome of early treatment intensification for midtreatment PET-positive disease, a phase II trial of risk-adapted therapy was conducted. Fifty-nine newly diagnosed patients, 98% with B cell lymphoma, had PET/CT performed after 2 or 3 cycles of first-line chemotherapy. Those with negative PET on semiquantitative visual interpretation completed standard therapy. Those with positive PET received platinum-based salvage chemotherapy, high-dose therapy, and autologous stem cell transplantation (ASCT). Midtreatment PET was positive in 33 (56%); 28 received ASCT with an actuarial 2-year EFS of 75% (95% confidence interval, 60%-93%). On intention-to-treat analysis, 2-year EFS was 67% (53%-86%) in all PET-positive patients and 89% (77%-100%) in PET-negative patients. No association was found between the International Prognostic Index category and the midtreatment PET result. The favorable outcome achieved here in historically poor-risk patients warrants further, more definitive investigation of treatment modification based on early PET scanning.
View details for DOI 10.1016/j.bbmt.2008.11.026
View details for Web of Science ID 000263016600010
View details for PubMedID 19167684
A blinded, crossover study of the efficacy of the ketogenic diet
2009; 50 (2): 322-325
Despite over 80 years of use, the ketogenic diet (KD) has never been tested in a blinded manner. Twenty children with intractable Lennox-Gastaut syndrome (LGS) were fasted 36 h and then randomized to receive the classic KD in conjunction with a solution containing either 60 g/day of glucose or saccharin. Parents and physicians were blinded to both the solution composition and level of ketosis. A crossover to the KD with the alternate solution occurred following the sixth day and a repeat fast. A 24-h electroencephalography (EEG) was obtained at baseline and after each arm. After administration of the solution, there was moderate evidence of a reduction in parent-reported seizures between the glucose and saccharin arms, with a median difference of 1.5 seizures per day (p = 0.07). There was no reduction in the number of EEG-identified events, with a median reduction of 7 events per day (p = 0.33). Ketosis was not completely eliminated in the glucose-added arm.
View details for DOI 10.1111/j.1528-1167.2008.01740.x
View details for Web of Science ID 000262781800018
View details for PubMedID 18717710
RNAi-mediated silencing of nuclear factor erythroid-2-related factor 2 gene expression in non-small cell lung cancer inhibits tumor growth and increases efficacy of chemotherapy
2008; 68 (19): 7975-7984
Nuclear factor erythroid-2-related factor 2 (Nrf2) is a redox-sensitive transcription factor that regulates the expression of electrophile and xenobiotic detoxification enzymes and efflux proteins, which confer cytoprotection against oxidative stress and apoptosis in normal cells. Loss of function mutations in the Nrf2 inhibitor, Kelch-like ECH-associated protein (Keap1), results in constitutive activation of Nrf2 function in non-small cell lung cancer. In this study, we show that constitutive activation of Nrf2 in lung cancer cells promotes tumorigenicity and contributes to chemoresistance by up-regulation of glutathione, thioredoxin, and the drug efflux pathways involved in detoxification of electrophiles and broad spectrum of drugs. RNAi-mediated reduction of Nrf2 expression in lung cancer cells induces generation of reactive oxygen species, suppresses tumor growth, and results in increased sensitivity to chemotherapeutic drug-induced cell death in vitro and in vivo. Inhibiting Nrf2 expression using naked siRNA duplexes in combination with carboplatin significantly inhibits tumor growth in a subcutaneous model of lung cancer. Thus, targeting Nrf2 activity in lung cancers, particularly those with Keap1 mutations, could be a promising strategy to inhibit tumor growth and circumvent chemoresistance.
View details for DOI 10.1158/0008-5472.CAN-08-1401
View details for Web of Science ID 000260029900035
View details for PubMedID 18829555
Circulating mutant DNA to assess tumor dynamics
2008; 14 (9): 985-990
The measurement of circulating nucleic acids has transformed the management of chronic viral infections such as HIV. The development of analogous markers for individuals with cancer could similarly enhance the management of their disease. DNA containing somatic mutations is highly tumor specific and thus, in theory, can provide optimum markers. However, the number of circulating mutant gene fragments is small compared to the number of normal circulating DNA fragments, making it difficult to detect and quantify them with the sensitivity required for meaningful clinical use. In this study, we applied a highly sensitive approach to quantify circulating tumor DNA (ctDNA) in 162 plasma samples from 18 subjects undergoing multimodality therapy for colorectal cancer. We found that ctDNA measurements could be used to reliably monitor tumor dynamics in subjects with cancer who were undergoing surgery or chemotherapy. We suggest that this personalized genetic approach could be generally applied to individuals with other types of cancer.
View details for DOI 10.1038/nm.1789
View details for Web of Science ID 000258988600033
View details for PubMedID 18670422
PURPOSE AND BENEFITS OF EARLY PHASE CANCER TRIALS: WHAT DO ONCOLOGISTS SAY? WHAT DO PATIENTS HEAR?
JOURNAL OF EMPIRICAL RESEARCH ON HUMAN RESEARCH ETHICS
2008; 3 (3): 57-68
CANCER PATIENTS OVERESTIMATE BENEFITS of early phase trials but studies have not reported what oncologists say to patients about trials. We audiotaped oncologists talking to cancer patients about Phase I or II trials and interviewed patients about the purpose and expected outcomes of trials presented to them. Oncologists gave mixed messages, saying Phase I trials measure safety and dosing, yet referring to trials as treatment with uncertain therapeutic effects. Seventeen percent of Phase I respondents said the trial's purpose related to safety/dosing (p = 0.017); 17% of Phase I respondents said the purpose was "to cure my cancer." Patients may find it important to believe trials offer significant benefit. Oncologists, while respecting patients' hopes, should be precise in their language, particularly regarding Phase I trials, distinguishing early stages of research from treatment.
View details for DOI 10.1525/jer.2008.3.3.57
View details for Web of Science ID 000259994900008
View details for PubMedID 19385771
Analysis of mutations in DNA isolated from plasma and stool of colorectal cancer patients
2008; 135 (2): 489-498
Somatic mutations provide uniquely specific markers for the early detection of neoplasia that can be detected in DNA purified from plasma or stool of patients with colorectal cancer. The primary purpose of the present investigation was to determine the parameters that were critical for detecting mutations using a quantitative assay. A secondary purpose was to compare the results of plasma and stool DNA testing using the same technology.We examined DNA purified from the stool of 25 patients with colorectal cancers before surgery. In 16 of these cases, plasma samples also were available. Mutations in stool or plasma were assessed with an improved version of the BEAMing technology.Of the 25 stool DNA samples analyzed, 23 (92%) contained mutations that were present in the corresponding tumors from the same patients. In contrast, only 8 of the 16 (50%) plasma DNA samples analyzed had detectable levels of mutated DNA. We found that the DNA fragments containing mutations in both stool and plasma DNA typically were smaller than 150 bases in size. The sensitivity of the new method was superior to a widely used technique for detecting mutations, using single base extension and sequencing, when assessed on the same samples (92% vs 60%; P = .008, exact McNemar test).When assessed with sufficiently sensitive methods, mutant DNA fragments are detectable in the stool of more than 90% of colorectal cancer patients. DNA purified from stool provides a better template for mutation testing than plasma.
View details for DOI 10.1053/j.gastro.2008.05.039
View details for Web of Science ID 000258439900026
View details for PubMedID 18602395
Systematic review: Gene expression profiling assays in early-stage breast cancer
ANNALS OF INTERNAL MEDICINE
2008; 148 (5): 358-W81
Three gene expression-based prognostic breast cancer tests have been licensed for use.To summarize evidence on the validity and utility of 3 gene expression-based prognostic breast cancer tests: Oncotype DX (Genomic Health, Redwood City, California), MammaPrint (Agendia BV, Amsterdam, the Netherlands), and H/I (AvariaDX, Carlsbad, California).MEDLINE, EMBASE, and Cochrane databases (from 1990 through January 2007), Web sites of test manufacturers, and discussion with the manufacturers.Original data studies published in English that addressed prognostic accuracy and discrimination or treatment benefit prediction of any of the 3 tests in women with breast cancer.Information was extracted about the clinical characteristics of the study population (particularly clinical and therapeutic homogeneity), tumor characteristics, and whether the marketed test or underlying signature was evaluated.The tests are based on distinct gene lists, using 2 different technologies. Overall, the body of evidence showed that this new generation of tests may improve prognostic and therapeutic prediction, but the tests are at different stages of development. Evidence shows that the tests offer clinically relevant, improved risk stratification over standard predictors. Oncotype DX has the strongest evidence, closely followed by MammaPrint and H/I (which is still maturing).For all tests, the relationship of predicted to observed risk in different populations and their incremental contribution over conventional predictors, optimal implementation, and relevance to patients receiving current therapies need further study.Gene expression technologies show great promise to improve predictions of prognosis and treatment benefit for women with early-stage breast cancer. More information is needed on the extent of improvement in prediction, characteristics of women in whom the tests should be used, and how best to incorporate test results into decision making about breast cancer treatment.
View details for Web of Science ID 000253600800005
View details for PubMedID 18252678
Tissue inhibitor of metalloproteinases-3 promoter methylation is an independent prognostic factor for bladder cancer
JOURNAL OF UROLOGY
2008; 179 (2): 743-747
TIMP-3 (tissue inhibitor of metalloproteinases-3) is 1 of 4 members of a family of proteins that were originally classified according to their ability to inhibit matrix metalloproteinases. We analyzed TIMP-3 methylation in 175 urine sediment DNA samples from patients with bladder cancer with well characterized clinicopathological parameters, including patient outcome.We examined urine sediment DNA for aberrant methylation of 9 genes, including TIMP-3, by quantitative fluorogenic real-time polymerase chain reaction.Using an optimal cutoff value by TaqMan(R) quantitation we found that the risk of death was statistically significantly higher in patients with higher TIMP-3 and ARF methylation (HR 1.99, 95% CI 1.12 to 3.27, p = 0.01 and HR 1.66, 95% CI 1.00 to 2.76, p = 0.05, respectively) than in patients without/lower TIMP3 and ARF methylation in urine. A significant correlation was also seen between the risk of death and stage 3 tumor (HR 2.73, 95% CI 1.58 to 4.72, p = 0.003) and metastasis (HR 3.32, 95% CI 1.98 to 5.57, p = 0.0001). Multivariate analysis subsequently revealed that TIMP-3 methylation was an independent prognostic factor for bladder cancer survival with stage and metastasis (p = 0.001 and 0.02, respectively).These results suggest that TIMP-3 promoter methylation could be a clinically applicable marker for bladder cancer progression.
View details for DOI 10.1016/j.juro.2007.09.019
View details for Web of Science ID 000252369600091
View details for PubMedID 18082200
- Systematic reviews are not biased by results from trials stopped early for benefit JOURNAL OF CLINICAL EPIDEMIOLOGY 2008; 61 (1): 95-96
Impact of gene expression profiling tests on breast cancer outcomes.
Evidence report/technology assessment
To assess the evidence that three marketed gene expression-based assays improve prognostic accuracy, treatment choice, and health outcomes in women diagnosed with early stage breast cancer.We evaluated the evidence for three gene expression assays on the market; Oncotype DX, MammaPrint and the Breast Cancer Profiling (BCP or H/I ratio) test, and for gene expression signatures underlying the assays. We sought evidence on: analytic performance of tests, clinical validity (i.e., prognostic accuracy and discrimination), clinical utility (i.e., prediction of treatment benefit), harms, impact on clinical decision making and health care costs.Few papers were found on the analytic validity of the Oncotype DX and MammaPrint tests, but these showed reasonable within-laboratory replicability. Pre-analytic issues related to sample storage and preparation may play a larger role than within-laboratory variation. For clinical validity, studies differed according to whether they examined the actual test that is currently being offered to patients or the underlying gene signature. Almost all of the Oncotype DX evidence was for the marketed test, the strongest validation study being from one arm of a randomized controlled trial (NSABP-14) with a clinically homogeneous population. This study showed that the test, added in a clinically meaningful manner to standard prognostic indices. The MammaPrint signature and test itself was examined in studies with clinically heterogeneous populations (e.g., mix of ER positivity and tamoxifen treatment) and showed a clinically relevant separation of patients into risk categories, but it was not clear exactly how many predictions would be shifted across decision thresholds if this were used in combination with traditional indices. The BCP test itself was examined in one study, and the signature was tested in a variety of formulations in several studies. One randomized controlled trial provided high quality retrospective evidence of the clinical utility of Oncotype DX to predict chemotherapy treatment benefit, but evidence for clinical utility was not found for MammaPrint or the H/I ratio. Three decision analyses examined the cost-effectiveness of breast cancer gene expression assays, and overall were inconclusive.Oncotype DX is furthest along the validation pathway, with strong retrospective evidence that it predicts distant spread and chemotherapy benefit to a clinically relevant extent over standard predictors, in a well-defined clinical subgroup with clear treatment implications. The evidence for clinical implications of using MammaPrint was not as clear as with Oncotype DX, and the ability to predict chemotherapy benefit does not yet exist. The H/I ratio test requires further validation. For all tests, the relationship of predicted to observed risk in different populations still needs further study, as does their incremental contribution, optimal implementation, and relevance to patients on current therapies.
View details for PubMedID 18457476
Disclosure of individual surgeon's performance rates during informed consent - Ethical and epistemological considerations
ANNALS OF SURGERY
2007; 245 (4): 507-513
The purpose of the paper is to examine the ethical arguments for and against disclosing surgeon-specific performance rates to patients during informed consent, and to examine the challenges that generating and using performance rates entail.Ethical, legal, and statistical theory is explored to approach the question of whether, when, and how surgeons should disclosure their personal performance rates to patients. The main ethical question addressed is what type of information surgeons owe their patients during informed consent. This question comprises 3 related, ethically relevant considerations that are explored in detail: 1) Does surgeon-specific performance information enhance patient decision-making? 2) Do patients want this type of information? 3) How do the potential benefits of disclosure balance against the risks?Calculating individual performance measures requires tradeoffs and involves inherent uncertainty. There is a lack of evidence regarding whether patients want this information, whether it facilitates their decision-making for surgery, and how it is best communicated to them. Disclosure of personal performance rates during informed consent has the potential benefits of enhancing patient autonomy, improving patient decision-making, and improving quality of care. The major risks of disclosure include inaccurate and misleading performance rates, avoidance of high-risk cases, unjust damage to surgeon's reputations, and jeopardized patient trust.At this time, we think that, for most conditions, surgical procedures, and outcomes, the accuracy of surgeon- and patient-specific performance rates is illusory, obviating the ethical obligation to communicate them as part of the informed consent process. Nonetheless, the surgical profession has the duty to develop information systems that allow for performance to be evaluated to a high degree of accuracy. In the meantime, patients should be informed of the quantity of procedures their surgeons have performed, providing an idea of the surgeon's experience and qualitative idea of potential risk.
View details for DOI 10.1097/01.sla.0000242713.82125.d1
View details for Web of Science ID 000245232900002
View details for PubMedID 17414595
- Why most published research findings are false: Problems in the analysis PLOS MEDICINE 2007; 4 (4): 773-773
- Rashomon revisited: two views of monitoring the Women's Health Initiative trials CLINICAL TRIALS 2007; 4 (3): 205-206
- Reanalysis of survival of Oscar winners ANNALS OF INTERNAL MEDICINE 2006; 145 (5): 392-392
ANNALS OF INTERNAL MEDICINE
2006; 145 (5): 392-393
View details for Web of Science ID 000240255900012
Quantitation of promoter methylation of multiple genes in urine DNA and bladder cancer detection
JOURNAL OF THE NATIONAL CANCER INSTITUTE
2006; 98 (14): 996-1004
The noninvasive identification of bladder tumors may improve disease control and prevent disease progression. Aberrant promoter methylation (i.e., hypermethylation) is a major mechanism for silencing tumor suppressor genes and other cancer-associated genes in many human cancers, including bladder cancer.A quantitative fluorogenic real-time polymerase chain reaction (PCR) assay was used to examine primary tumor DNA and urine sediment DNA from 15 patients with bladder cancer and 25 control subjects for promoter hypermethylation of nine genes (APC, ARF, CDH1, GSTP1, MGMT, CDKN2A, RARbeta2, RASSF1A, and TIMP3) to identify potential biomarkers for bladder cancer. We then used these markers to examine urine sediment DNA samples from an additional 160 patients with bladder cancers of various stages and grades and from an additional 69 age-matched control subjects. Data were analyzed on the basis of a prediction model and were internally validated using a jacknife procedure. All statistical tests were two-sided.For all 15 patients with paired DNA samples, the promoter methylation pattern in urine matched that in the primary tumors. Four genes displayed 100% specificity. Of the 175 bladder cancer patients, 121 (69%, 95% confidence interval [CI] = 62% to 76%) displayed promoter methylation in at least one of these genes (CDKN2A, ARF, MGMT, and GSTP1), whereas all control subjects were negative for such methylation (100% specificity, 95% CI = 96% to 100%). A logistic prediction model using the methylation levels of all remaining five genes was developed and internally validated for subjects who were negative on the four-gene panel. This combined, two-stage predictor produced an internally validated ROC curve with an overall sensitivity of 82% (95% CI = 75 % to 87%) and specificity of 96% (95% CI = 90% to 99%).Testing a small panel of genes with the quantitative methylation-specific PCR assay in urine sediment DNA is a powerful noninvasive approach for the detection of bladder cancer. Larger independent confirmatory cohorts with longitudinal follow-up will be required in future studies to define the impact of this technology on early detection, prognosis, and disease monitoring before clinical application.
View details for DOI 10.1093/jnci/djj265
View details for Web of Science ID 000239279000013
View details for PubMedID 16849682
Left insular stroke is associated with adverse cardiac outcome
2006; 66 (4): 477-483
After stroke, 10% of patients have adverse cardiac outcomes. Left insular damage may contribute to this by impairing sympathovagal balance (associated with cardiac structural damage and arrhythmias).The authors conducted a prospective study of 32 patients with left insular stroke (Group 1) and 84 patients with non-insular stroke/TIA (Group 2). Adverse cardiac outcomes (cardiac death, myocardial infarction, angina, and heart failure) were assessed over 1 year. Myocardial wall motion was investigated with transesophageal echocardiography.Group 1's cardiac outcome relative risk (RR) compared with Group 2 was 1.75 (95% CI: 1.02, 3.00, p = 0.05). Left insular stroke remained an independent predictor of cardiac outcome in multivariate analyses. Sensitivity analysis excluding TIA and angina showed similar results. For Group 1 patients without symptomatic coronary artery disease (SCAD), cardiac outcome RR = 4.06 (95% CI: 1.83, 9.01, p = 0.002). For Group 1 with SCAD, RR = 0.36 (95% CI: 0.06, 2.13, p = 0.14). Cardiac wall motion impairment was also associated with left insular stroke independent of CAD or nonischemic heart disease. Right insular stroke was not associated with adverse cardiac outcomes or cardiac wall motion impairment.Left insular stroke is associated with an increased risk of adverse cardiac outcome and decreased cardiac wall motion compared to stroke in other locations and TIA. This was particularly marked in patients without symptomatic coronary artery disease (SCAD). In patients with SCAD, the cardioprotective effect of medications, especially beta-blockers alone or combined with ischemic preconditioning, may explain the lack of association in this subgroup.
View details for Web of Science ID 000235645200008
View details for PubMedID 16505298
- Adverse events: The more you search, the more you find ANNALS OF INTERNAL MEDICINE 2006; 144 (4): 298-300
Ethical issues in evidence-based surgery
SURGICAL CLINICS OF NORTH AMERICA
2006; 86 (1): 151-?
Evidence-based medicine, although ostensibly concerned with the research evidence underlying claims of efficacy for surgical procedures,has a direct connection with the ethics of surgical decision making. Questions of whether new procedures should ever be performed on patients outside of a formal research protocol, what the patient should be told about the uncertainties inherent in the use of nonvalidated innovative procedures, when formal evaluation is necessary, what form that evaluation should take, and how the burdens and results of such research can be distributed fairly all involve balancing competing ethical principles. Good ethics requires good facts, and evidence from well-controlled experiments provides best information upon which to base decisions in these areas and to build ethical surgical practice.
View details for DOI 10.1016/j.suc.2005.10.003
View details for Web of Science ID 000235522200012
View details for PubMedID 16442426
Phase I study of low-dose interleukin-2, fludarabine, and cyclophosphamide for previously untreated indolent lymphoma and chronic lymphocytic leukemia
45th Annual Meeting and Exhibition of the American-Society-of-Hematology
AMER ASSOC CANCER RESEARCH. 2005: 8413–17
Fludarabine and cyclophosphamide is an effective combination but increases the risk of opportunistic infections due to depressed lymphocyte counts. In an attempt to preserve CD4 counts, we conducted a phase I, double-blind, placebo-controlled trial of recombinant interleukin-2 (IL-2) added to fludarabine and cyclophosphamide in patients with treatment-naive indolent lymphomas or chronic lymphocytic leukemia.Subcutaneous IL-2 (days 1-21 of each 28-day cycle) was combined with cyclophosphamide (600 mg/m2, day 8) and fludarabine (20 mg/m2, days 8-12) at four dose levels: 0.8, 1.0, 1.2, and 1.4 x 10(6) IU/m2/d. IL-2 dose was escalated in cohorts of four to six patients, with one patient per cohort receiving placebo.Twenty-three patients, median age 50, were enrolled, of whom 30% had chronic lymphocytic leukemia/small lymphocytic lymphoma and 52% had follicular lymphomas. The combination was generally well tolerated, with mainly hematologic toxicities. CD4 counts typically declined substantially during the early weeks of treatment and remained suppressed for months afterward. In the 18 evaluable patients who received IL-2, the mean absolute CD4 count was 999 cells/microL (range, 97-3,776) pretreatment, 379 cells/microL (range, 54-2,599) at day 14, and 98 cells/microL (range, 17-291) at end of treatment. In longitudinal linear models, the changes in CD4 counts were not significantly different across IL-2 dose levels.The addition of low-dose IL-2 to fludarabine and cyclophosphamide does not seem immunoprotective. New approaches are needed to reduce the cellular immunosuppression and infectious complications associated with purine analogues.
View details for DOI 10.1158/1078-0432.CCR-05-1612
View details for Web of Science ID 000233701300027
View details for PubMedID 16322303
Detection and quantification of mutations in the plasma of patients with colorectal tumors
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2005; 102 (45): 16368-16373
The early detection of cancers through analysis of circulating DNA could have a substantial impact on morbidity and mortality. To achieve this goal, it is essential to determine the number of mutant molecules present in the circulation of cancer patients and to develop methods that are sufficiently sensitive to detect these mutations. Using a modified version of a recently developed assay for this purpose, we found that patients with advanced colorectal cancers consistently contained mutant adenomatous polyposis coli (APC) DNA molecules in their plasma. The median number of APC DNA fragments in such patients was 47,800 per ml of plasma, of which 8% were mutant. Mutant APC molecules were also detected in >60% of patients with early, presumably curable colorectal cancers, at levels ranging from 0.01% to 1.7% of the total APC molecules. These results have implications for the mechanisms through which tumor DNA is released into the circulation and for diagnostic tests based on this phenomenon.
View details for Web of Science ID 000233283700044
View details for PubMedID 16258065
- The methodologic ozone effect EPIDEMIOLOGY 2005; 16 (4): 430-435
- The long and creative arm of the drug industry LANCET 2005; 365 (9460): 656-656
- Ethics and evidence in clinical trials CLINICAL TRIALS 2005; 2 (3): 195-196
Role and limitations of epidemiology in establishing a causal association
SEMINARS IN CANCER BIOLOGY
2004; 14 (6): 413-426
Cancer risk assessment is one of the most visible and controversial endeavors of epidemiology. Epidemiologic approaches are among the most influential of all disciplines that inform policy decisions to reduce cancer risk. The adoption of epidemiologic reasoning to define causal criteria beyond the realm of mechanistic concepts of cause-effect relationships in disease etiology has placed greater reliance on controlled observations of cancer risk as a function of putative exposures in populations. The advent of molecular epidemiology further expanded the field to allow more accurate exposure assessment, improved understanding of intermediate endpoints, and enhanced risk prediction by incorporating the knowledge on genetic susceptibility. We examine herein the role and limitations of epidemiology as a discipline concerned with the identification of carcinogens in the physical, chemical, and biological environment. We reviewed two examples of the application of epidemiologic approaches to aid in the discovery of the causative factors of two very important malignant diseases worldwide, stomach and cervical cancers. Both examples serve as paradigms of successful cooperation between epidemiologists and laboratory scientists in the pursuit of the understanding of cancer etiology.
View details for DOI 10.1016/j.semcancer.2004.06.004
View details for Web of Science ID 000224847300004
View details for PubMedID 15489134
Human telomerase reverse transcriptase gene expression and the surgical management of suspicious thyroid tumors
CLINICAL CANCER RESEARCH
2004; 10 (17): 5762-5768
Patients with a preoperative cytologic diagnosis of a suspicious thyroid nodule present a therapeutic dilemma because surgery differs for benign and malignant lesions. To address this issue, several molecular markers, including human telomerase reverse transcriptase (TERT), have been tested as markers of thyroid cancer. Because most studies select cases falling into well-defined categories to test new markers, they may overestimate their discriminatory power when applied to samples that are difficult to classify. Fine-needle aspirates (FNAs) of the thyroid with indeterminate cytology are an example of such cases.We examined whether assessing TERT mRNA by reverse transcription-PCR could have improved the surgical management in a cohort of 100 patients undergoing thyroidectomy for indeterminate FNA results.Ninety percent of 48 cancers were TERT positive, as were 35% of 52 benign lesions. When 10 cases with concomitant lymphocytic thyroiditis were excluded, the overall sensitivity of TERT was 91% (95% confidence interval, 80-98%) and specificity was 79% (64-90%). No clinical or tumor variable contributed to the predictive ability of TERT except for tumor size, which added only marginally. Basing the surgical approach on the TERT assay alone would have reduced lobectomies performed for malignant disease from 11 to 4 cases and reduced total thyroidectomies for benign lesions from to 15 to 9, an overall 50% reduction in suboptimal treatment.The overall performance of preoperative differential diagnosis for thyroid tumors with indeterminate FNA results can be substantially improved by the inclusion of molecular markers such as TERT.
View details for Web of Science ID 000223724700019
View details for PubMedID 15355904
Catalytic asymmetric total syntheses of quinine and quinidine
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
2004; 126 (3): 706-707
The catalytic, asymmetric syntheses of quinine and quinidine were achieved in 16 steps. The recently developed salen(Al)-catalyzed enantioselective Michael addition of methyl cyanoacetate served to set the crucial C4 stereocenter in 92% ee, and a late-stage asymmetric dihydroxylation was used to differentiate the common intermediate and access the two desired diastereomeric products with high selectivity.
View details for DOI 10.1021/ja039550y
View details for Web of Science ID 000188318300006
View details for PubMedID 14733531
Nonsteroidal anti-inflammatory drugs for the prevention of Alzheimer's disease: a systematic review
2004; 23 (4): 159-169
Alzheimer's disease, the most prevalent dementia, is a prominent source of chronic illness in the elderly. Laboratory evidence suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) might prevent the onset of Alzheimer's disease. Since the early 1990s numerous observational epidemiological studies have also investigated this possibility. The purpose of this meta-analysis is to summarize and evaluate available evidence regarding exposure to nonaspirin NSAIDs and risk of Alzheimer's disease using meta-analyses of published studies.A systematic search was conducted using Medline, Biological Abstracts, and the Cochrane Library for publications 1960 onwards. All cross-sectional, retrospective, or prospective observational studies of Alzheimer's disease in relation to NSAID exposure were included in the analysis. At least 2 of 4 independent reviewers characterized each study by source of data and design, including method of classifying exposure and outcome, and evaluated the studies for eligibility. Discrepancies were resolved by consensus of all 4 reviewers.Of 38 publications, 11 met the qualitative criteria for inclusion in the meta-analysis. For the 3 case-control and 4 cross-sectional studies, the combined risk estimate for development of Alzheimer's disease was 0.51 (95% Cl=0.40-0.66) for NSAID exposure. In the prospective studies, the estimate was 0.74 (95% Cl=0.62-0.89) for 4 studies reporting lifetime NSAID exposure and it was 0.42 (95% Cl=0.26-0.66) for the 3 studies reporting a duration of use of 2 or more years.Based on analysis of prospective and nonprospective studies, NSAID exposure was associated with decreased risk of Alzheimer's disease. An issue that requires further exploration in future trials or observational studies is the temporal relationship between NSAID exposure and protection against Alzheimer's disease.
View details for DOI 10.1159/000078501
View details for Web of Science ID 000223490800001
View details for PubMedID 15279021
Quantitative GSTP1 methylation and the detection of prostate adenocarcinoma in sextant biopsies
JOURNAL OF THE NATIONAL CANCER INSTITUTE
2003; 95 (21): 1634-1637
Hypermethylation of the 5' promoter region of the glutathione S-transferase pi gene (GSTP1) occurs at a very high frequency in prostate adenocarcinoma. We compared the results of blinded histologic review of sextant biopsy samples from 72 excised prostates with those obtained using a quantitative methylation-specific polymerase chain reaction assay (QMSP) for GSTP1. Formal surgical pathologic review of the resected prostates was used to determine the number of patients with (n = 61) and without (n = 11) prostate cancer. Histology alone detected prostate carcinoma with 64% sensitivity (95% confidence interval [CI] = 51% to 76%) and 100% specificity (95% CI = 72% to 100%), whereas the combination of histology and GSTP1 QMSP at an assay threshold greater than 10 detected prostate carcinoma with 75% sensitivity (95% CI = 63% to 86%) and 100% specificity (95% CI = 72% to 100%), an 11% improvement (95% CI = 5% to 22%) in sensitivity over histology alone. The combination of histology and GSTP1 QMSP at an assay threshold greater than 5 detected prostate adenocarcinoma with 79% sensitivity (95% CI = 68% to 89%), a 15% improvement (95% CI = 7% to 26%) over histology alone. Thus, GSTP1 QMSP improved the sensitivity of histologic review of random needle biopsies for prostate cancer diagnosis. Further studies should determine whether detection of GSTP1 hypermethylation in a biopsy sample with normal histology indicates the need for an early repeat biopsy at the same site.
View details for DOI 10.1093/jnci/djg082
View details for Web of Science ID 000186327800014
View details for PubMedID 14600096
- Commentary: The P-value, devalued INTERNATIONAL JOURNAL OF EPIDEMIOLOGY 2003; 32 (5): 699-702
Toward protecting the safety of participants in clinical trials
CONTROLLED CLINICAL TRIALS
2003; 24 (3): 256-271
It is a widely held belief that the current system of oversight of clinical research, particularly the means of assessing risks and minimizing harms to participants in clinical trials, could be improved. In particular, the system is inefficient with overemphasis on the monitoring ability of some groups such as research ethics review boards and investigators, underemphasis on others such as data monitoring committees (DMCs) and sponsors, confusion about responsibilities for safety and imperfect communication between these different groups. Research ethics review boards are not able to perform safety monitoring by review of individual adverse events and are often burdened by duplicative reviews of large multicenter studies. There are no standards for DMCs to ensure they can reliably identify safety issues. Sponsors may be overreliant on data audits and slow to disseminate safety data in a coherent summary. Investigators, their staffs and clinical sites may not fully appreciate all the nuances of good clinical practice or may be inattentive to the daily conduct of studies. Regulators, particularly those in the United States, have failed to completely harmonize their policies with each other or with international regulatory agencies. We recommend well-designed monitoring plans for all studies that are appropriate to their scope and risk, more centralized review of large multisite studies and closer local scrutiny of single-institution studies. In addition, sponsors should pay greater attention to monitoring adverse events and keeping up-to-date databases or investigator's brochures emphasizing safety issues. A minimal standard of education or expertise in good clinical practice should be established for investigators, their staffs and research ethics review board members. DMC composition and functions should be standardized and regulations should be harmonized nationally and internationally. Finally, there should be a concerted effort to study the efficacy of various components of the system.
View details for DOI 10.1016/S0197-2456(03)00005-9
View details for Web of Science ID 000183255400002
View details for PubMedID 12757992
Cardiac resynchronization and death from progressive heart failure - A meta-analysis of randomized controlled trials
JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION
2003; 289 (6): 730-740
Progressive heart failure is the most common mechanism of death among patients with advanced heart failure. Cardiac resynchronization, a pacemaker-based therapy for heart failure, enhances cardiac performance and quality of life, but its effect on mortality is uncertain.To determine whether cardiac resynchronization reduces mortality from progressive heart failure.MEDLINE (1966-2002), EMBASE (1980-2002), the Cochrane Controlled Trials Register (Second Quarter, 2002), The National Institutes of Health ClinicalTrials.gov database, the US Food and Drug Administration Web site, and reports presented at scientific meetings (1994-2002). Search terms included pacemaker, pacing, heart failure, dual-site, multisite, biventricular, resynchronization, and left ventricular preexcitation.Eligible studies were randomized controlled trials of cardiac resynchronization for the treatment of chronic symptomatic left ventricular dysfunction. Eligible studies reported death, hospitalization for heart failure, or ventricular arrhythmia as outcomes. Of the 6883 potentially relevant reports initially identified, 11 reports of 4 randomized trials with 1634 total patients were included in the meta-analysis.Trial reports were reviewed independently by 2 investigators in an unblinded standardized manner.Follow-up in the included trials ranged from 3 to 6 months. Pooled data from the 4 selected studies showed that cardiac resynchronization reduced death from progressive heart failure by 51% relative to controls (odds ratio [OR], 0.49; 95% confidence interval [CI], 0.25-0.93). Progressive heart failure mortality was 1.7% for cardiac resynchronization patients and 3.5% for controls. Cardiac resynchronization also reduced heart failure hospitalization by 29% (OR, 0.71; 95% CI, 0.53-0.96) and showed a trend toward reducing all-cause mortality (OR, 0.77; 95% CI, 0.51-1.18). Cardiac resynchronization was not associated with a statistically significant effect on non-heart failure mortality (OR, 1.15; 95% CI, 0.65-2.02). Among patients with implantable cardioverter defibrillators, cardiac resynchronization had no clear impact on ventricular tachycardia or ventricular fibrillation (OR, 0.92; 95% CI, 0.67-1.27).Cardiac resynchronization reduces mortality from progressive heart failure in patients with symptomatic left ventricular dysfunction. This finding suggests that cardiac resynchronization may have a substantial impact on the most common mechanism of death among patients with advanced heart failure. Cardiac resynchronization also reduces heart failure hospitalization and shows a trend toward reducing all-cause mortality.
View details for Web of Science ID 000180886000028
View details for PubMedID 12585952
Lung, cancer screening with helical computed tomography in older adult smokers - A decision and cost-effectiveness analysis
JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION
2003; 289 (3): 313-322
Encouraged by direct-to-consumer marketing, smokers and their physicians are contemplating lung cancer screening with a promising but unproven imaging procedure, helical computed tomography (CT).To estimate the potential benefits, harms, and cost-effectiveness of lung cancer screening with helical CT in various efficacy scenarios.Using a computer-simulated model, we compared annual helical CT screening to no screening for hypothetical cohorts of 100 000 current, quitting, and former heavy smokers, aged 60 years, of whom 55% were men. We simulated efficacy by changing the clinical stage distribution of lung cancers so that the screened group would have fewer advanced-stage cancers and more localized-stage cancers than the nonscreened group (ie, a stage shift). Our model incorporated known biases in screening programs such as lead time, length, and overdiagnosis bias.We measured the benefits of screening by comparing the absolute and relative difference in lung cancer-specific deaths. We measured harms by the number of false-positive invasive tests or surgeries per 100 000 and incremental cost-effectiveness in US dollars per quality-adjusted life-year (QALY) gained.Over a 20-year period, assuming a 50% stage shift, the current heavy smoker cohort had 553 fewer lung cancer deaths (13% lung cancer-specific mortality reduction) and 1186 false-positive invasive procedures per 100 000 persons. The incremental cost-effectiveness for current smokers was $116 300 per QALY gained. For quitting and former smokers, the incremental cost-effectiveness was $558 600 and $2 322 700 per QALY gained, respectively. Other than the degree of stage shift, the most influential parameters were adherence to screening, degree of length or overdiagnosis bias in the first year of screening, quality of life of persons with screen-detected localized lung cancers, cost of helical CT, and anxiety about indeterminate nodule diagnoses. In 1-way sensitivity analyses, none of these parameters was sufficient to make screening highly cost-effective for any of the cohorts. In multiway sensitivity analyses, a program screening current smokers was $42 500 per QALY gained if extremely favorable estimates were used for all of the influential parameters simultaneously.Even if efficacy is eventually proven, screening must overcome multiple additional barriers to be highly cost-effective. Given the current uncertainty of benefits, the harms from invasive testing, and the high costs associated with screening, direct-to-consumer marketing of helical CT is not advisable.
View details for Web of Science ID 000180345100026
View details for PubMedID 12525232
Assessment of plasma DNA levels, allelic imbalance, and CA 125 as diagnostic tests for cancer
JOURNAL OF THE NATIONAL CANCER INSTITUTE
2002; 94 (22): 1697-1703
Allelic imbalance (AI), the loss or gain of chromosomal regions, is found in many cancers. AI can be detected in genomic tumor DNA released into the blood after necrosis or apoptosis. We evaluated plasma DNA concentration, allelic status in plasma DNA, and serum CA 125 level as screening tests for ovarian and other cancers.Plasma samples were obtained from 330 women (44 normal healthy control individuals, 122 patients with various cancers, and 164 control patients with non-neoplastic diseases). Plasma DNA concentration was determined in all samples. Allelic status was determined by digital single nucleotide polymorphism (SNP) analysis with eight SNP markers in plasma DNA from 54 patients with ovarian cancer and 31 control patients. CA 125 was determined in 63 samples. Receiver-operating characteristic (ROC) curves were plotted, and the areas under the ROC curves--a measure of the overall ability of a diagnostic test with multiple cutoffs to distinguish between diseased and nondiseased individuals--were determined.The area under the ROC curve for plasma DNA concentration was 0.90 for patients with neoplastic disease versus healthy control individuals and 0.74 for patients with neoplastic diseases versus control patients with non-neoplastic diseases. For control subjects given a specificity of 100% (95% confidence interval [CI] = 92% to 100%), the highest sensitivity achieved was 57% (95% CI = 49% to 67%). AI in at least one SNP was found in 87% (95% CI = 60% to 98%) of patients with stage I/II ovarian cancer and 95% (95% CI = 83% to 99%) of patients with stage III/IV ovarian cancer, but AI was not found in 31 patients with non-neoplastic diseases (specificity = 100%, 95% CI = 89% to 100%). The area under the ROC curve assessing AI was 0.95. Combining the serum CA 125 level with the plasma DNA concentration increased the area under the ROC curve from 0.78 (CA 125 alone) to 0.84.Plasma DNA concentration may not be sensitive or specific enough for cancer screening or diagnosis, even when combined with CA 125. AI was detected with high specificity in plasma DNA from patients with ovarian cancer and should be studied further as a screening tool.
View details for Web of Science ID 000179265000010
View details for PubMedID 12441325
- The mammography dilemma: A crisis for evidence-based medicine? ANNALS OF INTERNAL MEDICINE 2002; 137 (5): 363-365
Acne therapy: A methodologic review
JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY
2002; 47 (2): 231-240
Acne is a very common problem with significant physical and psychological morbidity. The evidence basis for its treatment had not been systematically reviewed. Therefore, we performed an evidence review to provide researchers a basis for further studies, and to provide clinicians the background needed to interpret current and future clinical studies.We summarize the methodologic state of the acne literature in patients with acne who do not have complicating co-morbidities.This was an expert-advised literature synthesis. We used a structured literature search for English-language controlled trials in Cochrane CENTRAL, MEDLINE, OLDMEDLINE, HSTAT, CINAHL, and PsychInfo. Results underwent a structured data abstraction process, with review by at least 2 reviewers.Out of 1588 unique articles, 250 articles (274 controlled trials) over the past 50 years were reviewed: 57 (21%) trials had at least one major weakness and no strengths; 125 (47%) trials had at least one major strength and at least one major weakness; 48 (18%) trials had at least one major strength, and no major weaknesses. The remaining 16 (6%) were of intermediate quality or did not provide enough information to make a determination. One fourth of studies did not report patient age; one fourth did not report on patient gender. Only 8% mentioned patient race; only 2% mentioned skin type; 0.4% mentioned diet; none scored sexual maturity or insurance status. There were 1237 outcomes. There were more than 25 methods of assessing acne severity and more than 19 methods for counting lesions. There were only two trials that formally assessed psychological outcomes. More than 140 treatments were tested in 251 comparisons.Ranging over 50 years of research, the acne literature evidences great heterogeneity at all levels: patient characteristics, acne severity, outcome assessments, treatments, and comparisons. A list of methodologic recommendations is provided.
View details for DOI 10.1067/mjd.2002.120912
View details for Web of Science ID 000177206300007
View details for PubMedID 12140469
High-resolution scintimarnmography: A pilot study
JOURNAL OF NUCLEAR MEDICINE
2002; 43 (7): 909-915
This study evaluated a novel high-resolution breast-specific gamma camera (HRBGC) for the detection of suggestive breast lesions.Fifty patients (with 58 breast lesions) for whom a scintimammogram was clinically indicated were prospectively evaluated with a general-purpose gamma camera and a novel HRBGC prototype. The results of conventional and high-resolution nuclear studies were prospectively classified as negative (normal or benign) or positive (suggestive or malignant) by 2 radiologists who were unaware of the mammographic and histologic results. All of the included lesions were confirmed by pathology.There were 30 benign and 28 malignant lesions. The sensitivity for detection of breast cancer was 64.3% (18/28) with the conventional camera and 78.6% (22/28) with the HRBGC. The specificity with both systems was 93.3% (28/30). For the 18 nonpalpable lesions, sensitivity was 55.5% (10/18) and 72.2% (13/18) with the general-purpose camera and the HRBGC, respectively. For lesions < or = 1 cm, 7 of 15 were detected with the general-purpose camera and 10 of 15 with the HRBGC. Four lesions (median size, 8.5 mm) were detected only with the HRBGC and were missed by the conventional camera.Evaluation of indeterminate breast lesions with an HRBGC results in improved sensitivity for the detection of cancer, with greater improvement shown for nonpalpable and < or =1-cm lesions.
View details for Web of Science ID 000176853400018
View details for PubMedID 12097461
How statistical expertise is used in medical research
4th International Congress on Peer Review in Biomedical Publication
AMER MEDICAL ASSOC. 2002: 2817–20
Investigation of the nature and frequency of statistician involvement in medical research and its relation to the final editorial decision.Authors of original research articles who submitted to BMJ and Annals of Internal Medicine from May through August 2001 were sent a short questionnaire at the time of manuscript submission. Authors were asked if they received assistance from a person with statistical expertise, the nature of any such contribution, and reasons why, if no statistical input was received.The response rate was 75% (704/943); methodological input was reported for 514 (73%) of these papers. In 435 papers (85%), such input was provided by biostatisticians or epidemiologists and, if deemed significant, was typically associated with authorship. A total of 33 of 122 methodologists (27%) whose main contribution started at the analysis stage received neither acknowledgment nor authorship. Research without methodological assistance was more likely to be rejected without review (71% vs 57%; chi(2) = 10.6; P =.001) and possibly less likely to be accepted for publication (7% vs 11%; chi(2) = 2.37; P =.12).Statistical input to medical research is widely recommended but inconsistently obtained. Individuals providing such expertise are often not involved until the analysis of data and many go unrecognized by either authorship or acknowledgment.
View details for Web of Science ID 000176002200019
View details for PubMedID 12038922
Pancreatic cancer after remote peptic ulcer surgery
JOURNAL OF CLINICAL PATHOLOGY
2002; 55 (5): 340-345
Peptic ulcer surgery may carry an increased risk for pancreatic cancer development. Molecular analysis of K-ras codon 12, frequently mutated in conventional pancreatic cancers, might provide insight into the aetiological mechanisms.The relative risk of pancreatic cancer was computed by multivariate and person-year analysis in a cohort of 2633 patients who had undergone gastrectomy. Lung cancer risk was analysed as an indirect means of assessing smoking behaviour. K-ras codon 12 mutational analysis was performed on 15 postgastrectomy pancreatic cancers.There was an overall increased risk of pancreatic carcinoma of 1.8 (95% confidence interval, 1.3 to 2.6) five to 59 years postoperatively, which gradually increased to 3.6 at 35 years or more after surgery (chi(2) test for trend, p < 0.05). Multivariate analysis indicated that parameters other than postoperative interval did not influence the risk. Lung cancer risk was significantly increased after surgery, but no time trend was observed. The spectrum and prevalence of K-ras codon 12 mutations were comparable to conventional pancreatic cancer.Remote partial gastrectomy is associated with an increased risk of pancreatic cancer. Postgastrectomy and non-postgastrectomy pancreatic cancers may share similar aetiological factors, such as smoking. However, the neoplastic process in patients who have undergone gastrectomy appears to be accelerated by factors related to the surgery itself.
View details for Web of Science ID 000175538200004
View details for PubMedID 11986336
Counting alleles to predict recurrence of early-stage colorectal cancers
2002; 359 (9302): 219-225
Chromosome imbalances occur in many cancers and represent important biological properties of tumours. However, measurements of such imbalances are difficult. We used a new, quantitative approach to investigate the prognostic value of chromosome imbalances in early-stage colorectal cancers.We studied 180 patients with no evidence of lymph-node or distant metastases at the time of surgery. DNA from paraffin-embedded tumours was tested for imbalances of chromosome 8p and 18q by digital SNP (single-nucleotide polymorphism)-a technique in which each allele in a sample is directly counted. Surviving patients had median follow-up of 68 months, and disease recurrence was used as the clinical endpoint.Tumours were divided into three groups: "L" tumours (n=93) had allelic imbalances of chromosomes 8p and 18q, "L/R" tumours (n=60) had allelic imbalances of either chromosome 8p or 18q but not both, and "R" tumours (n=27) retained allelic balance for both chromosomes. 5-year disease-free survival was 100% (95% CI 80-100) for patients with R tumours, 74% (61-87) for patients with L/R tumours, and 58% (47-69) for those with L tumours. These differences were significant (p<0.0001) and were independent of other variables--eg, Duke's stage A tumours of class L were much more likely to recur than Duke's stage B tumours of class R (p=0.002).In patients without metastasis, allelic imbalance is a better predictor of prognosis than histopathological stage.
View details for Web of Science ID 000173350800014
View details for PubMedID 11812558
Hypermethylation of the DNA repair gene O-6-methylguanine DNA methyltransferase and survival of patients with diffuse large B-cell lymphoma
JOURNAL OF THE NATIONAL CANCER INSTITUTE
2002; 94 (1): 26-32
The gene encoding the DNA repair enzyme O(6)-methylguanine DNA methyltransferase (MGMT) is transcriptionally silenced by promoter hypermethylation in several human cancers, including diffuse large B-cell lymphoma (B-DLCL). MGMT promoter hypermethylation is a favorable prognostic marker in patients with brain tumors treated with alkylating agents.In a retrospective cohort study, we used methylation-specific polymerase chain reaction to analyze the MGMT promoter methylation status in tumor DNA of B-DLCL patients receiving cyclophosphamide as part of multidrug regimens. Molecular data were compared with patient response with the use of Student's t test. Disease-free survival and overall survival were estimated by the Kaplan-Meier method and compared with the use of the log-rank test. Multivariable survival analyses were performed with the Cox proportional hazards model. All statistical tests were two-sided.Thirty (36%) of 84 B-DLCL patients showed MGMT promoter hypermethylation in their lymphomas. The presence of MGMT methylation was associated with a statistically significant increase in overall survival (hazard ratio for time to death for nonmethylation versus methylation = 2.8; 95% confidence interval (CI) = 1.2 to 7.5; P =.01) and progression-free survival (hazard ratio for time to progression for nonmethylation versus methylation = 2.6; 95% CI = 1.3 to 5.8; P =.02). MGMT promoter hypermethylation was both independent of and stronger than established prognostic factors, such as age, disease stage, serum lactic dehydrogenase level, and performance status.MGMT promoter hypermethylation appears to be a useful marker for predicting survival in patients with B-DLCL treated with multidrug regimens including cyclophosphamide.
View details for Web of Science ID 000173058600011
View details for PubMedID 11773279
Do basic laboratory tests or clinical observations predict bleeding in thrombocytopenic oncology patients? A reevaluation of prophylactic platelet transfusions.
Transfusion medicine reviews
2002; 16 (1): 34-45
The purpose of this study was to determine which clinical and laboratory features correlate with serious hemorrhage in thrombocytopenic oncology patients. A retrospective review was conducted of all thrombocytopenic adult patients admitted to the Johns Hopkins Oncology Center, Baltimore, MD, over the last 10 years. We performed multiple logistic regression analysis on 2942 patients looking at the frequency of serious bleeding as a function of platelet count and numerous features that may correlate with hemorrhage. Multivariate analyses showed no relationship between either the first morning platelet count or the lowest platelet count of the day and the risk of hemorrhage. Of the other features we examined, several correlated independently with bleeding, including uremia (odds ratio [OR] 1.64; 95% confidence interval [CI], 1.40 to 1.92), hypoalbuminemia (OR 1.54; 95% CI, 1.33 to 1.79), recent bone marrow transplantation (OR 1.32; 95% CI, 1.22 to 1.43), and recent hemorrhage (OR 6.72; 95% CI, 5.53 to 8.18). Leukopenia was associated with a decreased risk of bleeding (OR 0.70; 95% CI, 0.60 to 0.82). Although this large study identified a number of clinical and laboratory features that correlated significantly with bleeding, the ORs of these factors were not large and all were much less than previous bleeding. These findings suggest that the major goal of transfusion support should be the aggressive therapeutic use of blood products rather than prophylactic use based on such weak clinical correlates and on the platelet count, which was not a correlate at all in multivariate analysis.
View details for PubMedID 11788928
Effects of mixed hematopoietic chimerism in a mouse model of bone marrow transplantation for sickle cell anemia
2001; 97 (12): 3960-3965
Sickle cell anemia (SCA) is an inherited disorder of beta-globin, resulting in red blood cell rigidity, anemia, painful crises, organ infarctions, and reduced life expectancy. Allogeneic blood or marrow transplantation (BMT) can cure SCA but is associated with an 8% to 10% mortality rate, primarily from complications of marrow-ablative conditioning. Transplantation of allogeneic marrow after less intensive conditioning reduces toxicity but may result in stable mixed hematopoietic chimerism. The few SCA patients who inadvertently developed mixed chimerism after BMT remain symptom free, suggesting that mixed chimerism can reduce disease-related morbidity. However, because the effects of various levels of mixed chimerism on organ pathology have not been characterized, this study examined the histologic effects of an increasing percentage of normal donor hematopoiesis in a mouse model of BMT for SCA. In lethally irradiated normal mice that were reconstituted with varying ratios of T-cell-depleted marrow from normal and transgenic "sickle cell" mice, normal myeloid chimerism in excess of 25% was associated with more than 90% normal hemoglobin (Hb). However, 70% normal myeloid chimerism was required to reverse the anemia. Organ pathology, including liver infarction, was present in mice with sickle Hb (HbS) levels as low as 16.8% (19.6% normal myeloid chimerism). Histologic abnormalities increased in severity up to 80% HbS, but were less severe in mice with more than 80% HbS than in those with 40% to 80% HbS. Therefore, stable mixed chimerism resulting from nonmyeloablative BMT may reduce the morbidity from SCA, but prevention of all disease complications may require minimizing the fraction of circulating sickle red cells. (Blood. 2001;97:3960-3965)
View details for Web of Science ID 000169164300043
View details for PubMedID 11389040
- Statins and cancer: A case of meta-uncertainty AMERICAN JOURNAL OF MEDICINE 2001; 110 (9): 738-740
Detecting colorectal cancer in stool with the use of multiple genetic targets
JOURNAL OF THE NATIONAL CANCER INSTITUTE
2001; 93 (11): 858-865
Colorectal cancer cells are shed into the stool, providing a potential means for the early detection of the disease using noninvasive approaches. Our goal was to develop reliable, specific molecular genetic tests for the detection of colorectal cancer in stool samples.Stool DNA was isolated from paired stools and primary tumor samples from 51 colorectal cancer patients. Three genetic targets-TP53, BAT26, and K-RAS-were used to detect tumor-associated mutations in the stool prior to or without regard to the molecular analyses of the paired tumors. TP53 gene mutations were detected with a mismatch-ligation assay that detects nine common p53 gene mutations. Deletions within the BAT26 locus were detected by a modified solid-phase minisequencing method. Mutations in codons 12 and 13 of K-RAS were detected with a digital polymerase chain reaction-based method.TP53 gene mutations were detected in the tumor DNA of 30 patients, all of whom had the identical TP53 mutation in their stools. Tumors from three patients contained a noninherited deletion at the BAT26 locus, and the same alterations were identified in these patients' stool specimens. Nineteen of 50 tumors tested had a K-RAS mutation; identical mutations were detected in the paired stool DNA samples from eight patients. In no case was a mutation found in stool that was not also present in the primary tumor. Thus, the three genetic markers together detected 36 (71%) of 51 patients (95% confidence interval [CI] = 56% to 83%) with colorectal cancer and 36 (92%) of 39 patients (95% CI = 79% to 98%) whose tumors had an alteration.We were able to detect the majority of colorectal cancers by analyzing stool DNA for just three genetic markers. Additional work is needed to determine the specificity of these genetic tests for detecting colorectal neoplasia in asymptomatic patients and to more precisely estimate the prevalence of the mutations and sensitivity of the assay.
View details for Web of Science ID 000169105100012
View details for PubMedID 11390535
Nonpalpable breast cancer: Percutaneous diagnosis with 11-and 8-gauge stereotactic vacuum-assisted biopsy devices
2001; 219 (3): 793-796
To compare the accuracy of diagnosis of invasive breast cancer with 11- and 8-gauge stereotactic vacuum-assisted biopsy (SVAB) devices and to correlate lesion diameter and accuracy of breast cancer diagnosis at SVAB.During a 22-month period, 489 SVAB procedures were performed with an 11-gauge probe and 305 with an 8-gauge probe. SVAB and surgical pathologic results of 104 breast carcinomas were reviewed and correlated with lesion size, number of specimens obtained, and type of SVAB probe used.Four of 38 ductal carcinoma in situ (DCIS) lesions diagnosed with 11-gauge SVAB demonstrated invasion at surgery, whereas one of 23 DCIS lesions diagnosed with 8-gauge SVAB demonstrated invasion at surgery (P =.6). A mean of 12 specimens per lesion were obtained in each group. In lesions 30 mm or larger, the underestimation rate for DCIS was 43% (three of seven) with 11-gauge SVAB and 17% (one of six) with 8-gauge SVAB (P =.6). Overall, the rate of underestimation for DCIS was significantly higher in lesions 30 mm or larger (four of 13) than in smaller lesions (one of 48, P =.006).This study demonstrated no difference in breast cancer diagnosis with the 8- and 11-gauge SVAB systems, but the accuracy of breast cancer diagnosis was greater in lesions smaller than 30 mm than in larger lesions.
View details for Web of Science ID 000168864800029
View details for PubMedID 11376271
Pancreatic intraepithelial neoplasia - A new nomenclature and classification system for pancreatic duct lesions
AMERICAN JOURNAL OF SURGICAL PATHOLOGY
2001; 25 (5): 579-586
Proliferative epithelial lesions in the smaller caliber pancreatic ducts and ductules have been the subject of numerous morphologic, clinical, and genetic studies; however, a standard nomenclature and diagnostic criteria for classifying these lesion have not been established. To evaluate the uniformity of existing systems for grading duct lesions in the pancreas, 35 microscopic slides with 35 representative duct lesions were sent to eight expert pathologists from the United States, Canada, and Europe. Kappa values for interobserver agreement could not be calculated initially because more than 70 different diagnostic terms were used by the eight pathologists. In several cases, the diagnoses rendered for a single duct lesion ranged from "hyperplasia," to "metaplasia," to "dysplasia," to "carcinoma in situ." This review therefore demonstrated the need for a standard nomenclature and classification system. Subsequently, during a working group meeting, the pathologists agreed to adopt a single standard system. The terminology pancreatic intraepithelial neoplasia (or PanIN) was selected, and diagnostic criteria for each grade of PanIN were established (http://pathology.jhu.edu/pancreas_panin). This new system was then evaluated by having the eight pathologists rereview the original 35 cases. Only seven different diagnoses were rendered, and kappa values of 0.43, 0.14, and 0.42 were obtained for PanINs 1, 2, and 3 respectively. Cases assigned other diagnoses (e.g., squamous metaplasia) collectively had a kappa value of 0.41. These results show both the potential of the classification system, and also the difficulty of classifying these lesions even with a consistent nomenclature. However, even when there is lack of consensus, having a restricted set of descriptions and terms allows a better understanding of the reasons for disagreement. It is suggested that we adopt and apply this system uniformly, with continued study of its reliability and use, and possibly further refinement. The acceptance of a standard classification system will facilitate the study of pancreatic duct lesions, and will lead ultimately to a better understanding of their biologic importance.
View details for Web of Science ID 000168418500003
View details for PubMedID 11342768
Evidence that genetic instability occurs at an early stage of colorectal tumorigenesis
2001; 61 (3): 818-822
Chromosomal instability is believed to be a common feature of most human tumors, but the stage at which such instability originates has not been defined. At the molecular level, chromosomal instability is characterized by allelic imbalance (AI), representing losses or gains of defined chromosomal regions. We have assessed AI in early colorectal tumors using newly developed methods for assessing AI in complex cell populations. A total of 32 adenomas of average size (2 mm; range, 1-3 mm) were studied. AI of chromosome 5q markers occurred in 55% of tumors analyzed, consistent with a gatekeeping role of the adenomatous polyposis coli tumor suppressor gene located at chromosomal position 5q21. AI was also detected in each of the other four chromosomes tested. The fractions of adenomas with AI of chromosomes 1p, 8p, 15q, and 18q were 10,19, 28, and 28%, respectively. Over 90% of the tumors exhibited AI of at least one chromosome, and 67% had allelic imbalance of a chromosome other than 5q. These findings demonstrate that AI is a common event, even in very small tumors, and suggest that chromosomal instability occurs very early during colorectal neoplasia.
View details for Web of Science ID 000167020100005
View details for PubMedID 11221861
Interferon and ribavirin vs interferon alone in the re-treatment of chronic hepatitis C previously nonresponsive to interferon - A meta-analysis of randomized trials
JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION
2001; 285 (2): 193-199
Hepatitis C is the leading cause of chronic liver disease in the United States. Several trials have found that interferon and ribavirin combination therapy is more efficacious than interferon monotherapy for previously untreated patients and those who relapsed after prior interferon monotherapy, but its effectiveness for nonresponders to prior interferon monotherapy is unclear.To assess the efficacy and safety of interferon and ribavirin vs interferon alone for treatment of patients with chronic hepatitis C who previously did not respond to interferon monotherapy.A systematic search was performed using MEDLINE and the Science Citation Index for publications from 1966 to December 1999. A manual reference search and a manual review of relevant specialty journals also were performed, and input from clinical hepatology experts was sought.Included studies were randomized, controlled clinical trials comparing interferon and ribavirin with interferon alone and reporting virological and biochemical outcomes after a follow-up period. Of 50 identified studies, 12 trials (941 patients) were included in the analysis.Two investigators reviewed trials independently for methods, inclusion and exclusion criteria, and outcomes. Disagreements were resolved by discussion. Abstracted data included study and patient characteristics and virological, biochemical, and histological outcomes. A quality evaluation questionnaire was used to score studies.The pooled virological response rate for combination therapy was 14% (95% confidence interval [CI], 11%-17%), with a risk difference favoring combination therapy of 7% (95% CI, 2%-13%). Use of interferon alfa-2a/2b and ribavirin, 1000 to 1200 mg/d, was associated with a pooled virological response rate of 18% and a risk difference of 16% (95% CI, 11%-21%). When interferon alfa-n/n3 and a lower dosage of ribavirin (600-800 mg/d) were used, the risk difference was 0% (95% CI, -7% to 7%). Combination therapy was associated with more adverse effects and an increased rate of discontinuation of treatment compared with interferon monotherapy.For chronic hepatitis C that is nonresponsive to prior interferon monotherapy, combination therapy is more effective than re-treatment with interferon alone. Response rates remain less than 20% even in the most responsive subgroups, demonstrating a need for better therapeutic options.
View details for Web of Science ID 000166227000028
View details for PubMedID 11176813
Counting alleles reveals a connection between chromosome 18q loss and vascular invasion
2001; 19 (1): 78-81
The analysis of loss of heterozygosity (LOH) is perhaps the most widely used technique in cancer genetics. In primary tumors, however, the analysis of LOH is fraught with technical problems that have limited its reproducibility and interpretation. In particular, tumors are mixtures of neoplastic and nonneoplastic cells, and the DNA from the nonneoplastic cells can mask LOH. We here describe a new experimental approach, involving two components, to overcome these problems. First, a form of digital PCR was employed to directly count, one by one, the number of each of the two alleles in tumor samples. Second, Bayesian-type likelihood methods were used to measure the strength of the evidence for the allele distribution being different from normal. This approach imparts a rigorous statistical basis to LOH analyses, and should be able to provide more reliable information than heretofore possible in LOH studies of diverse tumor types.
View details for Web of Science ID 000166261400025
View details for PubMedID 11135558
Very high risk of cancer in familial Peutz-Jeghers syndrome
2000; 119 (6): 1447-1453
The Peutz-Jeghers syndrome (PJS) is an autosomal dominant polyposis disorder with increased risk of multiple cancers, but literature estimates of risk vary.We performed an individual patient meta-analysis to determine the relative risk (RR) of cancer in patients with PJS compared with the general population based on 210 individuals described in 6 publications.For patients with PJS, the RR for all cancers was 15.2 (95% confidence limits [CL], 2, 19). A statistically significant increase of RR was noted for esophagus (57; CL, 2.5, 557), stomach (213; CL, 96, 368), small intestine (520; CL, 220, 1306), colon (84; CL, 47, 137), pancreas (132; CL, 44, 261), lung (17.0; CL, 5.4, 39), breast (15.2; CL, 7.6, 27), uterus (16.0; CL, 1.9, 56), ovary (27; CL, 7.3, 68), but not testicular or cervical malignancies. Cumulative risk for all cancer was 93% from age 15 to 64 years old.Patients with PJS are at very high relative and absolute risk for gastrointestinal and nongastrointestinal cancers.
View details for DOI 10.1053/gast.2000.20228
View details for Web of Science ID 000165833800007
View details for PubMedID 11113065
Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents
NEW ENGLAND JOURNAL OF MEDICINE
2000; 343 (19): 1350-1354
The DNA-repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) inhibits the killing of tumor cells by alkylating agents. MGMT activity is controlled by a promoter; methylation of the promoter silences the gene in cancer, and the cells no longer produce MGMT. We examined gliomas to determine whether methylation of the MGMT promoter is related to the responsiveness of the tumor to alkylating agents.We analyzed the MGMT promoter in tumor DNA by a methylation-specific polymerase-chain-reaction assay. The gliomas were obtained from patients who had been treated with carmustine (1,3-bis(2-chloroethyl)-1-nitrosourea, or BCNU). The molecular data were correlated with the clinical outcome.The MGMT promoter was methylated in gliomas from 19 of 47 patients (40 percent). This finding was associated with regression of the tumor and prolonged overall and disease-free survival. It was an independent and stronger prognostic factor than age, stage, tumor grade, or performance status.Methylation of the MGMT promoter in gliomas is a useful predictor of the responsiveness of the tumors to alkylating agents.
View details for Web of Science ID 000165152800001
View details for PubMedID 11070098
Efficacy of agents for pharmacologic conversion of atrial fibrillation and subsequent maintenance of sinus rhythm - A meta-analysis of clinical trials
48th Annual Scientific Session of the American-College-of-Cardiology
DOWDEN HEALTH MEDIA. 2000: 1033–46
Physicians have little evidentiary guidance for pharmacologic agent selection for atrial fibrillation (AF).To assess antiarrhythmic agent efficacy for AF conversion and subsequent maintenance of sinus rhythm (MSR).We searched the clinical trial database of the Cochrane Collaboration and MEDLINE encompassing literature from 1948 to May 1998.We selected 36 (28%) articles eligible as randomized trials of nonpostoperative AF conversion or MSR in adults.Study quality; rates of conversion, MSR, and adverse events were extracted.Compared with control treatment (placebo, verapamil, diltiazem, or digoxin), the odds ratio (OR) for conversion was greatest for ibutilide/dofetilide (OR=29.1; 95% confidence interval [CI], 9.8-86.1) and flecainide (OR=24.7; 95% CI, 9.0-68.3). Less strong but conclusive evidence existed for propafenone (OR=4.6; 95% CI, 2.6-8.2). Quinidine (OR=2.9; 95% CI, 1.2-7.0) had moderate evidence of efficacy for conversion. Disopyramide (OR=7.0; 95% CI, 0.3-153.0) and amiodarone (OR=5.7; 95% CI, 1.0-33.4) had suggestive evidence of efficacy. Sotalol (OR=0.4; 95% CI, 0.0-3.0) had suggestive evidence of negative efficacy. For MSR, strong evidence of efficacy existed for quinidine (OR=4.1; 95% CI, 2.5-6.7), disopyramide (OR=3.4; CI, 1.6-7.1), flecainide (OR=3.1; 95% CI, 1.5-6.2), propafenone (OR=3.7; 95% CI, 2.4-5.7), and sotalol (OR=7.1; 95% CI, 3.8-13.4). The only amiodarone data, from comparison with disopyramide, provided moderate evidence of efficacy for MSR. No trial evaluated procainamide. Direct agent comparisons and adverse event data were limited.Although multiple antiarrhythmic agents had strong evidence of efficacy compared with control treatment for MSR, ibutilide/dofetilide and flecainide had particularly strong evidence of efficacy compared with control treatment for AF conversion. There is sparse and inconclusive evidence on direct agent comparisons and adverse event rates. Obtaining information regarding these relative efficacies should be a research priority.
View details for Web of Science ID 000165251700009
View details for PubMedID 11093570
A dose-finding study of liposomal daunorubicin with CVP (COP-X) in advanced NHL
ANNALS OF ONCOLOGY
2000; 11 (6): 691-695
Standard therapy for lymphoma consists of a cyclophosphamide (C), doxorubicin, vincristine (V), and prednisone (P) (CHOP) combination regimen. Liposomal daunorubicin (DaunoXome) is an alternative to doxorubicin for patients with lymphoma because of its more favorable safety profile and potentially more selective uptake in lymphoma. The objectives of this study were to determine the maximum tolerated dose (MTD) of liposomal daunorubucin with CVP (COP-X) and the tolerability of the regimen in patients with indolent lymphoma.Patients with low-grade and intermediate-grade lymphoma having adequate cardiac, hepatic, and renal function were enrolled. Patients received C 750 mg/m2, V 1.4 mg/m2 (maximum 2.0 mg), and liposomal daunorubicin 50-100 mg/m2 i.v. on day 1 and P 100 mg p.o. on days 1-5. MTD was the liposomal daunorubicin dose associated with 20% dose-limiting toxicity (ANC < 500/mm3 for > 5 days or febrile neutropenia).Twenty patients, median age 59 years, were treated. The liposomal daunorubicin MTD combined with CVP was 70-80 mg/m2, depending on patient population. No significant non-hematologic toxicity occurred. Response rate was 44% (2 complete and 5 partial responses).A liposomal daunorubicin dose of 80 mg/m2 in the COP-X regimen was well tolerated with little nonhematologic toxicity.
View details for Web of Science ID 000088219600014
View details for PubMedID 10942057
Management of new onset atrial fibrillation.
Evidence report/technology assessment (Summary)
View details for PubMedID 11471248
Bayesian communication: A clinically significant paradigm for electronic publication
JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION
2000; 7 (3): 254-266
To develop a model for Bayesian communication to enable readers to make reported data more relevant by including their prior knowledge and values.To change their practice, clinicians need good evidence, yet they also need to make new technology applicable to their local knowledge and circumstances. Availability of the Web has the potential for greatly affecting the scientific communication process between research and clinician. Going beyond format changes and hyperlinking, Bayesian communication enables readers to make reported data more relevant by including their prior knowledge and values. This paper addresses the needs and implications for Bayesian communication. FORMULATION: Literature review and development of specifications from readers', authors', publishers', and computers' perspectives consistent with formal requirements for Bayesian reasoning.Seventeen specifications were developed, which included eight for readers (express prior knowledge, view effect size and variability, express threshold, make inferences, view explanation, evaluate study and statistical quality, synthesize multiple studies, and view prior beliefs of the community), three for authors (protect the author's investment, publish enough information, make authoring easy), three for publishers (limit liability, scale up, and establish a business model), and two for computers (incorporate into reading process, use familiar interface metaphors). A sample client-only prototype is available at http://omie.med.jhmi.edu/bayes.Bayesian communication has formal justification consistent with the needs of readers and can best be implemented in an online environment. Much research must be done to establish whether the formalism and the reality of readers' needs can meet.
View details for Web of Science ID 000087055700006
View details for PubMedID 10833162
Quantitative neurologic assessment of ataxia-telangiectasia
2000; 54 (7): 1505-1509
Ataxia telangiectasia (A-T) is a rare disorder with many distinctive neurologic features. Although there is substantial individual variation in the rate of progression of these features, their relationship to one another or to age has not been characterized.We formulated and tested multiple elements that assess different neurologic functions known to be affected by A-T. The overall index was applied to 52 patients with A-T, 2 to 29 years of age.Seven elements items proved to be informative, and three elements were added based on face validity. In a linear regression model of individuals under 19 years of age, controlled for correlation within sibships, age accounted for 87% of the variation in the A-T Index.Despite substantial individual variability of the phenotypic elements of A-T, scores on this multidimensional index have a very high correlation with age, indicating that there is a characteristic rate of progression of the disease, although functional domains in the brain are differentially affected. The pattern of scores suggests that a severe and a mild form of A-T may be distinguished by this quantitative measure. With further development this index may become useful as an outcome measure for treatment studies and prognosis.
View details for Web of Science ID 000086460900022
View details for PubMedID 10751267
The evidence regarding the drugs used for ventricular rate control
JOURNAL OF FAMILY PRACTICE
2000; 49 (1): 47-59
Our goal was to determine what drugs are most efficacious for controlling the ventricular rate in patients with atrial fibrillation.We conducted a systematic review of the literature published before May 1998, beginning with searches of The Cochrane Collaboration's CENTRAL database and MEDLINE.We included English-language articles describing randomized controlled trials of drugs used for heart rate control in adults with atrial fibrillation. DATA COLLECTION/ANALYSIS: Abstracts of trials were reviewed independently by 2 members of the study team. We reviewed English-language abstracts of non-English-language publications to assess qualitative consistency with our results.Forty-five articles evaluating 17 drugs met our criteria for review. In the 5 trials of verapamil and 5 of diltiazem, heart rate was reduced significantly (P <.05), both at rest and with exercise, compared with placebo, with equivalent or improved exercise tolerance in 6 of 7 comparisons. In 7 of 12 comparisons of a beta-blocker with placebo, the beta-blocker was efficacious for control of resting heart rate, with evidence that the effect is drug specific, as nadolol and atenolol proved to be most efficacious. All 9 comparisons demonstrated good heart rate control with beta-blockers during exercise, although exercise tolerance was compromised in 3 of 9 comparisons. In 7 of 8 trials, digoxin administered alone slowed the resting heart rate more than placebo, but it did not significantly slow the rate during exercise in 4 studies. The trials evaluating other drugs yielded insufficient evidence to support their use, but those drugs may yet be promising.The calcium-channel blockers verapamil or diltiazem, or select beta-blockers are efficacious for heart rate control at rest and during exercise for patients with atrial fibrillation without a clinically important decrease in exercise tolerance. Digoxin is useful when rate control during exercise is less a concern.
View details for Web of Science ID 000087077800008
View details for PubMedID 10678340
Prevention of thromboembolism in atrial fibrillation - A meta-analysis of trials of anticoagulants and antiplatelet drugs
JOURNAL OF GENERAL INTERNAL MEDICINE
2000; 15 (1): 56-67
Appropriate use of drugs to prevent thromboembolism in patients with atrial fibrillation (AF) involves comparing the patient's risk of stroke and risk of hemorrhage. This review summarizes the evidence regarding the efficacy of these medications.We conducted a meta-analysis of randomized controlled trials of drugs used to prevent thromboembolism in adults with nonpostoperative AF. Articles were identified through the Cochrane Collaboration's CENTRAL database and MEDLINE until May 1998.Eleven articles met criteria for inclusion in this review. Warfarin was more efficacious than placebo for primary stroke prevention (aggregate odds ratio [OR] of stroke = 0.30, 95% confidence interval [CI] 0.19, 0.48), with moderate evidence of more major bleeding (OR 1.90; 95% CI 0.89, 4.04). Aspirin was inconclusively more efficacious than placebo for stroke prevention (OR 0.56, 95% CI 0.19, 1.65), with inconclusive evidence regarding more major bleeds (OR 0.81, 95% CI 0.37, 1.77). For primary prevention, assuming a baseline risk of 45 strokes per 1,000 patient-years, warfarin could prevent 30 strokes at the expense of only 6 additional major bleeds. Aspirin could prevent 17 strokes, without increasing major hemorrhage. In direct comparison, there was evidence suggesting fewer strokes among patients on warfarin than among patients on aspirin (aggregate OR 0.64, 95% CI 0.43, 0.96), with only suggestive evidence for more major hemorrhage (OR 1.60, 95% CI 0.77,3.35). However, in younger patients, with a mean age of 65 years, the absolute reduction in stroke rate with warfarin compared with aspirin was low (5.5 per 1,000 person-years) compared with an older group (15 per 1,000 person-years).In general, the evidence strongly supports warfarin for patients with AF at average or greater risk of stroke. Aspirin may prove to be useful in subgroups with a low risk of stroke, although this is not definitively supported by the evidence.
View details for Web of Science ID 000084835900009
View details for PubMedID 10632835
Novobiocin in combination with high-dose chemotherapy for the treatment of advanced breast cancer: A phase 2 study
BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION
2000; 6 (3A): 335-343
We conducted the first phase 2 and pharmacologic study to evaluate the combination of novobiocin (a coumeromycin antibiotic that has been shown to augment alkylating agent cytotoxicity in experimental models) and high-dose cyclophosphamide and thiotepa followed by autologous marrow support in women with chemosensitive advanced breast cancer. Its aims were (1) to determine progression-free survival (PFS) and overall survival (OS), (2) to evaluate the pharmacokinetics of cyclophosphamide and thiotepa, and (3) to measure the ability of novobiocin to reverse alkylator drug resistance in vitro. Forty-one women with chemotherapy-responsive advanced breast cancer received cyclophosphamide (4 g/m2) for peripheral blood stem cell mobilization (treatment 1) followed by high-dose cyclophosphamide (1.5 g/m2 per day for 4 days), thiotepa (200 mg/m2 per day for 4 days), and novobiocin (4 g/day orally for 7 days) (treatment 2) and autologous marrow support. The median PFS was 10 months (range, 0.2-70.6 months) and OS, 21.5 months (range, 0.2-70.6 months). There was no statistically significant relationship between PFS or OS and area-under-the-curve values of cyclophosphamide, thiotepa, or 4-hydroxycyclophosphamide. Patient plasma samples (n = 12) obtained during novobiocin therapy were able to reverse alkylator drug resistance in an in vitro colony-forming assay. Correlative laboratory studies in an in vitro model system demonstrated that patient plasma after novobiocin treatment resulted in the magnitude of resistance reversal that had been predicted by prior preclinical experiments. Clinically, however, this activity of novobiocin did not translate into a substantial increase in PFS or OS compared with historical controls treated with high-dose alkylator therapy alone.
View details for Web of Science ID 000090022500006
View details for PubMedID 10905771
A prospective pharmacologic evaluation of age-related toxicity of adjuvant chemotherapy in women with breast cancer
34th Annual Meeting of the American-Society-of-Clinical-Oncology
TAYLOR & FRANCIS INC. 2000: 521–29
Despite increasing evidence of benefit from adjuvant chemotherapy, older women with breast cancer are commonly given less aggressive treatment than younger patients. Conflicting prior data regarding age-related toxicity prompted this prospective study. Forty-four women (aged 35-79 years) with early-stage breast cancer were treated with four cycles of adjuvant therapy with doxorubicin 60 mg/m2 i.v. and cyclophosphamide 600 mg/m2 i.v. every 21 days. They were monitored for myelosuppression, cardiotoxicity, and decrease in quality of life. Pharmacokinetics were analyzed using cycle 1 plasma samples. Bone marrow granulocyte and macrophage colony-forming units (CFU-GM) were assayed in vitro for dose response to 4-hydroperoxycyclophosphamide and doxorubicin before cycle 1. There was moderate evidence of age-related decrease in nadir absolute neutrophil count (ANC) when age was viewed as a continuous variable. On average there was a 10/microliter drop in cycle 1 nadir ANC for every year increase in age (p = 0.02). However, when age was viewed as a categorical variable (age < 65 vs. > or = 65 years), a similar proportion of women in each group reached an ANC < 100 (18% vs. 19%). Neither neutropenic complications, alteration in cardiac function, nor change in quality of life scores were significantly age related (p > 0.12). Pharmacokinetic analyses did not demonstrate age-related differences in the clearance of either doxorubicin or cyclophosphamide (p > 0.8). Pharmacodynamic analysis of individual patient bone marrow progenitor cell sensitivity did not reveal any correlation with age (p > 0.48). In women undergoing adjuvant therapy for breast cancer, no clinically significant age-related trends in toxicity were observed. These data suggest that older age alone should not exclude patients from receiving adjuvant therapy with doxorubicin and cyclophosphamide.
View details for Web of Science ID 000088285900004
View details for PubMedID 10923100
Rectal epithelial apoptosis in familial adenomatous polyposis patients treated with sulindac
1999; 45 (6): 822-828
Sulindac regresses colorectal adenomas in patients with familial adenomatous polyposis (FAP), although the mechanism of polyp regression is unclear.To determine whether differences occur in alteration of rectal epithelial apoptotic index and expression of apoptosis related proteins in FAP patients treated with sulindac compared with placebo.Twenty one FAP patients; 12 had not undergone colectomy.Patients with FAP were treated with sulindac 150 mg orally twice a day for three months (n=10) or placebo (n=11). Colorectal polyp number was determined and biopsies of the normal rectal mucosa were performed before and after three months of treatment. Response to treatment and alteration of the apoptotic ratio (index in base of crypt divided by index in surface epithelium) were evaluated. Bcl-2, bax, p21/WAF-1, and p53 proteins were assessed semiquantitatively by immunohistochemistry.Significant decreases in polyp number and in the apoptotic ratio were seen in patients treated with sulindac compared with controls. The mean percentage change in polyp number from baseline was -46% in the sulindac group and +13% in the placebo group (p=0.005). Mean percentage change in the apoptotic ratio was -8% and +25% in the sulindac and placebo treated patients, respectively (p=0.004). No differences in expression or compartmentalisation of apoptosis related proteins were noted between treatment groups.Sulindac regression of colorectal adenomas is accompanied by alteration of the rectal epithelial apoptotic ratio with relative increase in apoptosis in surface cells compared with the deeper crypt. The utility of the apoptotic ratio as an intermediate biomarker for colorectal tumorigenesis deserves further study.
View details for Web of Science ID 000083947700010
View details for PubMedID 10562579
PGP9.5 as a candidate tumor marker for non-small-cell lung cancer
AMERICAN JOURNAL OF PATHOLOGY
1999; 155 (3): 711-715
PGP9.5 is a neurospecific peptide that functions to remove ubiquitin from ubiquitinated proteins and prevents them from targeted degradation by proteasomes. Using the serial analysis of gene expression method (SAGE), we observed that the PGP9.5 transcript was highly expressed in primary lung cancers and lung cancer cell lines but was not detectable in the normal lung. Here we examined the expression of PGP9.5 protein in normal lung epithelium, lung tumor cell lines, and 98 resected primary non-small-cell lung carcinomas (NSCLCs). We found PGP9.5 reactivity in normal lung in a pattern compatible with K-cells of the diffuse neuroendocrine system. However, the PGP9.5 was present in both small-cell lung cancer (SCLC) and NSCLC cell lines (22/24) independent of neuronal differentiation. In primary NSCLCs, 54% (53/98) of the cases had positive PGP9.5 staining, and the expression of protein was strongly associated with pathological stage of the cancer. It was present in 44% (29/66) of stage I NSCLCs and in 75% (24/32) of stage II and IIIA NSCLCs (p = 0.0032). These results suggest that the increased expression of PGP9.5 is specifically associated with lung cancer development and may serve as a potential marker for the detection of lung cancer.
View details for Web of Science ID 000082537800007
View details for PubMedID 10487828
Genetic epidemiology of mutated K-ras proto-oncogene, altered suppressor genes, and microsatellite instability in colorectal adenomas
1999; 44 (6): 826-833
The genetic epidemiology of colorectal adenomas has not been studied prospectively in colonoscopy patients without cancer.To study genetic alterations in colorectal adenomas and correlate these with patient demographics and adenoma characteristics.Mutations and allelic deletions in 201 adenomas from 60 patients were compared with demographic features, adenoma characteristics, and family history.The most common alteration was K-ras proto-oncogene mutation, present in 35% of adenomas and 65% of patients. Patients 65 years of age and older had a decreased probability of K-ras mutations (26% versus 45%). Overexpression of p53 gene product was present in only 6% of adenomas but was more frequent in villous or tubulovillous adenomas (19% versus 3%). Allelic loss of chromosome 18q was present in only 2% of adenomas and was significantly less frequent than p53 overexpression. DNA replication errors (RER) were present in 7% of adenomas and 15% of patients, including multiple adenomas in four patients (two with hereditary non-polyposis colorectal cancer syndrome). Only 36% of RER positive adenomas had alteration of BAT-26 alleles, none had alteration of BAT-25, and only one (8%) had mutation in the transforming growth factor beta type II receptor gene. RER positive adenomas were more likely to have a K-ras mutation. In patients with multiple adenomas, there was concordance of p53 overexpression and RER but not of K-ras mutations.Genetic progression in colorectal adenomas is heterogeneous, involving factors related to patient age and the presence of RER for the occurrence of ras mutations, but different intraindividual characteristics for the occurrence of p53 alterations and RER.
View details for Web of Science ID 000080513100017
View details for PubMedID 10323885
- Probability at the bedside: The knowing of chances or the chances of knowing? ANNALS OF INTERNAL MEDICINE 1999; 130 (7): 604-606
Statistical reviewing policies of medical journals - Caveat lector?
JOURNAL OF GENERAL INTERNAL MEDICINE
1998; 13 (11): 753-756
To describe the current policies regarding statistical review of clinical research in biomedical journals.Cross-sectional survey.Editors of biomedical journals that publish original clinical research.General policies on statistical review, types of persons used for statistical reviewing, compensation of statistical reviewers, percentage of articles subject to such review, percentage of time statistical review makes an important difference, journal circulation, and selectivity.Of 171 journals, 114 (67%) responded to the survey. About one third of journals had policies that guaranteed statistical review for all accepted manuscripts. In approximately half of the journals, articles were sent for statistical review at the discretion of the editor. There was some evidence that statistical review policies differed between journals of different circulation size. In journals in the top quartile of circulation (> 25,000) the probability of definitely having a statistical review before an acceptance decision was 52%, but it was only 27% in journals in the lower three quartiles (p = .09). The probability of a statistical consultant on staff ranged from 31% in the bottom quarter, to 58% in the middle two, to 82% in the highest quarter (p < .001). Editors judged that statistical review resulted in an important change in a manuscript about half of the time.Except in the largest circulation medical journals, the probability of formal methodologic review of original clinical research is fairly low. As readers and researchers depend on the journals to assess the validity of the statistical methods and logic used in published reports, this is potentially a serious problem. This situation may exist because the cost of such statistical review can be considerable, and because finding appropriate reviewers can be difficult. It may also exist partly because editors or publishers may not regard such review as important. The professions of medical publishing, statistics, epidemiology, and other quantitative disciplines should work together to address this problem.
View details for Web of Science ID 000076927000005
View details for PubMedID 9824521
Perceived value of providing peer reviewers with abstracts and preprints of related published and unpublished papers
3rd International Congress on Peer Review in Biomedical Publication
AMER MEDICAL ASSOC. 1998: 273–74
Many journals provide peer reviewers with written instructions regarding review criteria, such as the originality of results, but little research has been done to investigate ways to improve or facilitate the peer review task.To assess the value that peer reviewers place on receipt of supplemental materials (eg, abstracts of related papers and preprints of related unpublished manuscripts).Questionnaire survey sent to all 733 peer reviewers recruited by the Journal of the National Cancer Institute to review 356 manuscripts consecutively sent out for review from February 24, 1997, through January 16, 1998. The inclusion of supplemental materials with manuscript review packages was optional.The peer reviewers' assessment of the actual or potential usefulness of supplemental materials on the performance of peer review.A total of 481 (66%) of 733 questionnaires were returned. Of the 471 respondents' questionnaires that could be used, 217 (46%) indicated that they received abstracts, and 44 (10%) of 458 respondents indicated that they received preprints. Higher proportions of peer reviewers who received supplemental materials than those who had not received them felt that they were (or would be) useful to them when reviewing the manuscript (63% [95% confidence interval (CI), 57%-69%] vs 45% [95% CI, 38%-52%]; P<.001) and to the peer review process in general (80% [95% CI, 75%-85%] vs 64% [95% CI, 58%-70%]; P<.001).The majority of respondents indicated that supplemental materials helped (or would have helped) them evaluate manuscripts and valued them more highly when they actually received them.
View details for Web of Science ID 000074706000024
View details for PubMedID 9676679
What patients say about medical research.
1998; 20 (4): 1-7
View details for PubMedID 11657084
- Multiple comparisons, explained AMERICAN JOURNAL OF EPIDEMIOLOGY 1998; 147 (9): 807-812
CD34 augmentation improves allogeneic T cell-depleted bone marrow engraftment
JOURNAL OF HEMATOTHERAPY
1998; 7 (2): 151-157
T cell depletion (TCD) performed by elutriation has decreased the incidence of acute and chronic graft-versus-host disease (GvHD) following bone marrow transplantation (BMT). However, as with all forms of TCD, patients may experience graft failure (10%), delayed engraftment, and mixed chimerism. Because 66%-75% of the CD34+ cells coseparate with the small lymphocytes, which are removed by elutriation, we designed a phase I trial in HLA-identical siblings to determine if the readdition of these previously lost small CD34+ cells would improve elutriation's engraftment kinetics. CD34+ cells were isolated from the small cell fraction of 10 consecutive donor grafts and infused into the recipients along with the TCD graft. The positively selected product had a mean T cell content of 1.2 x 10(5)/kg and was 80% CD34+, doubling the CD34+ content of the graft. All patients engrafted promptly with a median time to 500 neutrophils/mm3, untransfused 50,000 platelets/mm3, and discharge from the hospital of 19 (range 10-25), 24 (14-52), and 24 (18-29) days, respectively. Acute GvHD occurred in 2 patients, and no patient had chronic GvHD. Augmenting stem cell dose may be an efficient and safe alternative for overcoming TCD-associated delayed engraftment and graft failure, rather than increasing immunosuppression.
View details for Web of Science ID 000073441200007
View details for PubMedID 9597572
CD44 expression in the stromal matrix of colorectal cancer: Association with prognosis
CLINICAL CANCER RESEARCH
1998; 4 (1): 21-29
CD44, a cell hyaluronate receptor, is implicated in the metastatic behavior of some cancer cells. This study analyzed CD44 expression in topographic tissue sites of colorectal cancers to determine its association with patient survival and clinicopathological characteristics. Immunohistochemical localization of the core CD44 and the v6 splice variant domains was examined by use of paraffin-fixed sections from 133 stage II or III colorectal cancers that previously had been evaluated for other diagnostic markers. Expression in malignant epithelium, stromal matrix, and stromal cells was compared to patient survival by univariate, multivariate, and bootstrap (reproducibility) analysis. Core CD44 staining was present in the malignant epithelium of 85% of tumors, the stromal matrix of 90%, and the stromal cells of 98%. The v6 splice variant domain was present in the epithelium of 77% of tumors but was less frequent in the stromal matrix (12%; P < 0.001) and stromal cells (17%; P < 0.001). Absence of core CD44 immunoreactivity in the stromal matrix was associated with increased death rate (hazard ratio, 2.4; 95% confidence interval, 1.2-4.8; P = 0.02), making this one of the most significant adverse prognostic variables, along with an age of 60 years or older, poor differentiation of the cancer, extramural venous invasion, chromosome 18q allelic loss, and nonwhite race. This study shows that core CD44 and v6 splice variant antigens are differentially expressed in the epithelium and stroma of colorectal cancers. A model that includes core CD44 immunoreactivity in stromal matrix along with other prognostic factors may improve identification of high-risk and low-risk patients.
View details for Web of Science ID 000071623200004
View details for PubMedID 9516948
Tumor-suppressive pathways in pancreatic carcinoma
1997; 57 (9): 1731-1734
During tumorigenesis, positive selection is exerted upon those tumor cells that alter rate-limiting regulatory pathways. A corollary of this principle is that mutation of one gene abrogates the need for alteration of another gene in the same pathway and also that the coexistence in a single tumor of mutations in different genes implies their involvement in distinct tumor-suppressive pathways. We studied 42 pancreatic adenocarcinomas for genetic alterations in the K-ras oncogene and the p16, p53, and DPC4 tumor suppressor genes. All of them had the K-ras gene mutated. Thirty-eight % of the tumors had four altered genes, another 38% had three altered genes, 15% had two altered genes, and 8% of the tumors had one altered gene. Interestingly, we noted a high concordance of DPC4 and p16 inactivations (P = 0.007), suggesting that the genetic inactivation of p16 increases the selective advantage of subsequent mutation in DPC4. No statistically significant association was identified between the alteration of these cancer genes and pathological or clinical parameters. This type of multigenic analysis in human tumors may serve to substantiate experimental tumor models and thus increase our understanding of the truly physiologically relevant tumor-suppressive pathways that are abrogated during human tumorigenesis.
View details for Web of Science ID A1997WW56900022
View details for PubMedID 9135016
p53 mutation and locoregional treatment failure in head and neck squamous cell carcinoma
JOURNAL OF THE NATIONAL CANCER INSTITUTE
1996; 88 (21): 1580-1586
The p53 gene (also known as TP53) may be the most common genetic target involved in the malignant transformation of human cells. Direct sequence analysis has demonstrated that alteration of this gene occurs in approximately 45% of head and neck squamous cell carcinomas. The consequences of p53 mutations in these cancers with respect to tumor behavior and patient survival have not been rigorously determined.We evaluated the implications of p53 mutations in relation to the control of locoregional disease and overall survival following radiation therapy.Data from 110 consecutive patients with invasive disease who were treated with primary radiation therapy (given with curative intent) or with adjuvant radiation therapy (following complete surgical extirpation of gross disease) were included in the analysis. A 1.8-kilobase fragment of the p53 gene encompassing exons 5-9 was amplified from the DNA of stored (frozen) tumor specimens; the amplified DNA was cloned and sequenced by use of standard techniques. Overall survival and locoregional disease-free survival after the completion of radiation therapy were estimated by the Kaplan-Meier method; survival comparisons were made by use of the logrank test or proportional hazards regression models. Reported P values are two-sided.Fortyeight (44%) of the 110 tumors had cells bearing p53 mutations. The risk of locoregional recurrence following either primary or adjuvant radiation therapy was significantly greater (i.e., the time to recurrence was shorter) for patients whose tumors contained mutant p53 genes (univariate model hazard ratio [HR] for p53 mutation versus wild-type = 2.2; 95% confidence interval [CI] = 1.2-4.1; P = .02). The presence of regional lymph node metastases (presence versus absence, HR = 2.0; 95% CI = 1.0-4.2; P = .05) and treatment type (primary radiation therapy versus surgery plus adjuvant radiation therapy, HR = 2.3; 95% CI = 1.2-4.3; P = .01) were also associated with greater risks of locoregional failure. The presence of p53 mutations and lymph node metastases and treatment with primary, as opposed to adjuvant, radiation therapy remained significant risk factors in multivariate regression analysis. No relationship was demonstrated between p53 status and overall survival (mutant versus wild-type, HR = 1.1; 95% CI = 0.6-2.1; P = .66); however, a relationship was shown for tumor stage and overall survival (stages III and IV [more advanced] versus stages I and II [less advanced], HR = 3.3; 95% CI = 1.0-10.8; P = .05). Mutation of the p53 gene was not associated with patient age, sex, tumor stage, primary tumor site, regional lymph node status, degree of tumor cell differentiation, or treatment method.Mutation of the p53 gene is associated with an increased risk of locoregional failure in patients with invasive head and neck squamous cell carcinoma who are treated with radiation therapy.
View details for Web of Science ID A1996VQ46500015
View details for PubMedID 8901856
Relationship between CD44 expression and cell proliferation in epithelium and stroma of colorectal neoplasms
AMERICAN JOURNAL OF PATHOLOGY
1996; 149 (4): 1147-1155
The cell surface glycoprotein CD44 is expressed primarily in the region of cell replication in the lower crypt epithelium of colorectal mucosa, and its expression is markedly increased in colorectal neoplasms, suggesting that expression is linked to proliferation. The association between CD44 expression and replication in individual cells was therefore analyzed by double-label immunohistochemistry for CD44 and the cell-cycle-dependent protein proliferating cell nuclear antigen (PCNA). Enhanced expression of CD44 in colorectal neoplasms occurred not only in epithelial cells but also in stromal cells, including lymphocytes and macrophages. On a topographical basis, the cellular localization of CD44 and PCNA were commonly different. Quantitatively, in all cell types studied (epithelial cells and stroma of colorectal mucosa, adenomas, and carcinomas) PCNA was present most frequently in cells lacking CD44. Statistical analysis by logistic regression models indicated that cells negative for CD44 had a higher probability of being positive for PCNA than did cells positive for CD44 (P < 0.001). These data suggest that the enhanced level of CD44 in colorectal neoplasms is asynchronous with cell replication and reflects mechanisms that act on nonproliferative stromal lymphocytes and other mononuclear cells as well as the epithelial cells.
View details for Web of Science ID A1996VM31400009
View details for PubMedID 8863664
Oral antibiotic treatment of right-sided staphylococcal endocarditis in injection drug users: Prospective randomized comparison with parenteral therapy
AMERICAN JOURNAL OF MEDICINE
1996; 101 (1): 68-76
To compare the efficacy and safety of inpatient oral antibiotic treatment (oral) versus standard parenteral antibiotic treatment (intravenous) for right-sided staphylococcal endocarditis in injection drug users.In a prospective, randomized, non-blinded trial, febrile injection drug users were assigned to begin oral or intravenous (IV) treatment on admission, before blood culture results were available. Oral therapy consisted of ciprofloxacin and rifampin. Parenteral therapy was oxacillin or vancomycin, plus gentamicin for the first 5 days. Antibiotic dosing was adjusted for renal dysfunction. Administration of other antibacterial drugs was not permitted during the treatment or follow-up periods. Bacteremic subjects having right-sided staphylococcal endocarditis received 28 days of inpatient therapy with the assigned antibiotics. Test-of-cure blood cultures were obtained during inpatient observation 6 and 7 days after the completion of antibiotic therapy, and again at outpatient follow-up 1 month later. Criteria for treatment failure and for drug toxicity were prospectively defined.Of 573 injection drug users who were hospitalized because of a febrile illness and suspected right-sided staphylococcal endocarditis, 93 subjects (16.2%) had two or more sets of blood cultures positive for staphylococci; 85 of these bacteremic subjects (14.8%) satisfied diagnostic criteria for at least possible right-sided staphylococcal endocarditis (no other source of bacteremia was apparent) and entered the trial. Forty-four (oral, 19; IV, 25) of these 85 subjects completed inpatient treatment and evaluation including test-of-cure blood cultures. There were four treatment failures (oral, 1 [5.2%]; IV, 3 [12.0%]; not significant, Fisher's exact test). Drug toxicity was significantly more common in the parenterally treated group (oral, 3%; IV, 62%; P < 0.0001), consisting largely of oxacillin-associated increases in liver enzymes.For selected patients with right-sided staphylococcal endocarditis, oral ciprofloxacin plus rifampin is effective and is associated with less drug toxicity than is intravenous therapy.
View details for Web of Science ID A1996UY64700011
View details for PubMedID 8686718
Colorectal cancer in ulcerative colitis: Survival in patients with and without colorectal cancer symptoms
INFLAMMATORY BOWEL DISEASES
1996; 2 (1): 6-10
: Patients with ulcerative colitis are at increased risk for colorectal adenocarcinoma compared with the general population. Although surveillance for colorectal malignancy and dysplasia (a premalignant lesion) has been recommended, a benefit in reducing mortality from colorectal cancer via surveillance or prophylactic colectomy is still being debated. We reviewed the outcome of 40 consecutive patients with ulcerative colitis with colorectal adenocarcinoma diagnosed between 1956 and 1991 at The Johns Hopkins Hospital. The diagnosis of ulcerative colitis and the tumor, node, metastasis (TNM) stage of colorectal cancer were obtained from clinicopathologic records. Follow-up information was complete for all patients. Patients were divided into two groups: 18 asymptomatic patients who had colorectal cancer detected by colonoscopy, biopsies for dysplasia, or barium enema, or had undergone "prophylactic" colectomy as part of a colorectal cancer-prevention strategy (asymptomatic group), whereas 22 patients did not undergo cancer-prevention testing or prophylactic surgery and had symptoms of colorectal cancer (symptomatic group). Colorectal cancer was diagnosed at a statistically significantly earlier cancer stage in the asymptomatic group [12 (67%) of 18 at stage I or II] compared with those in the symptomatic group [two (9%) of 22 at stage I or II] (Wilcoxon test, p < 0.01). Colorectal cancer 5-year survival in the asymptomatic group was 89% [confidence limit (CL), 6197%] and in the symptomatic group, 19% (CL, 6-39%). Patients with ulcerative colitis and asymptomatic colorectal cancer detected as part of a prevention strategy had malignancies that were less invasive and showed greatly increased survival compared with patients with symptomatic colorectal cancer.
View details for Web of Science ID A1996UL03300002
View details for PubMedID 23282450
Immunohistochemical evaluation of HER-2/neu expression in pancreatic adenocarcinoma and pancreatic intraepithelial neoplasms
1996; 27 (2): 119-124
Although several morphological and molecular genetic studies have implicated various grades of pancreatic duct hyperplasia as precursor lesions to infiltrating pancreatic adenocarcinoma, the identity of preinvasive pancreatic neoplasms remains controversial. In the present study, the authors examined the expression of the epidermal growth factor receptor homologue, HER-2/neu (c-erbB-2), in pancreatic duct lesions adjacent to infiltrating pancreas cancers in a series of 19 cases of pancreatic duct adenocarcinoma. HER-2/neu expression was examined because it has been identified in a proportion of infiltrating pancreas cancers and because it may provide early neoplasms with a growth advantage over adjacent nonneoplastic epithelium. In normal pancreatic ducts and ductules, HER-2/neu expression was absent in all but one case. By contrast, HER-2/neu was expressed in 82% (P = .008 vs normal ) of ducts with flat mucinous hyperplasia, 86% (P = .03 vs normal) of ducts with papillary mucinous hyperplasia without atypia, 92% (P = .001 vs normal) of ducts with atypical papillary mucinous hyperplasia, and all specimens with carcinoma in situ. HER-2/neu expression was observed in 69% (P = .002 vs normal) of the moderately differentiated infiltrating carcinomas and none of the poorly differentiated infiltrating carcinomas. These data establish HER-2/neu as a potential mediator of growth factor-related signal transduction in pancreatic duct lesions, and provide additional support for the hypothesis that lesions formerly regarded as various grades of hyperplasia instead may represent intraepithelial neoplasms with the potential for subsequent invasion and metastasis.
View details for Web of Science ID A1996TU85500004
View details for PubMedID 8617452
Can caretakers of children with IDDM accurately measure small insulin doses and dose changes?
1996; 19 (1): 56-59
To determine if caretakers of young children with IDDM could consistently reproduce small incremental measurements of insulin (U100).Fifteen caretakers of children with IDDM were asked to deliver repeated small doses of insulin, including doses separated by only 0.25 U of insulin. A sensitive gravimetric technique was used to determine the error in measurement of these low doses of insulin. Statistical analysis was used to evaluate accuracy and internal consistency of each caretaker at each dose.The means +/- SD at each dose level were as follows: 2.75 +/- 0.13 U at 2.5 U, 3.19 +/- 0.13 U at 3.0 U, 3.55 +/- 0.13 U at 3.25 U, and 3.70 +/- 0.11 U at 3.5 U. All doses were biased toward overadministration. There was as statistically significant difference in the dose delivered when the target doses were varied by only 0.25 U. The average differences and standard errors between 2.5 U and 3.0 U, 3.0 U and 3.25 U, and 3.25 U and 3.5 U were 0.44 +/- 0.20 U, 0.36 +/- 0.018 U, and 0.15 +/- 0.017 U, respectively.Participants were not accurate in measuring small insulin doses, consistently overdrawing insulin by an average of 0.22 U. Caretakers are reasonably internally consistent with a given dose, since participants were able to measure statistically significant differences in 0.25 U dose changes. The error in insulin measurement does not vary with the intended dose level. Caretakers in the same family deliver insulin doses as variable from each other as they are from the population as a whole; however, when two or more individuals are responsible for one insulin dose in a child with IDDM, they have a combined variability that is approximately 40% greater than a single individual's variability.
View details for Web of Science ID A1996TW85800012
View details for PubMedID 8720535
PANCREATICODUODENECTOMY FOR CANCER OF THE HEAD OF THE PANCREAS - 201 PATIENTS
106th Annual Scientific Session of the Southern-Surgical-Association
LIPPINCOTT WILLIAMS & WILKINS. 1995: 721–33
This single-institution study examined the outcome after pancreaticoduodenectomy in patients with adenocarcinoma of the head of the pancreas.In recent years, pancreaticoduodenectomy for adenocarcinoma of the head of the pancreas has been associated with decreased morbidity and mortality and, in some centers, 5-year survival rates in excess of 20%.Two hundred one patients with pathologically verified adenocarcinoma of the head of the pancreas undergoing pancreaticoduodenectomy at The Johns Hopkins Hospital between 1970 and 1994 were analyzed (the last 100 resections were performed between March 1991 and April 1994). This is the largest single-institution experience reported to date.The overall postoperative in-hospital mortality rate was 5%, but has been 0.7% for the last 149 patients. The actuarial 5-year survival for all 201 patients was 21%, with a median survival of 15.5 months. There were 11 5-year survivors. Patients resected with negative margins (curative resections: n = 143) had an actuarial 5-year survival rate of 26%, with a median survival of 18 months, whereas those with positive margins (palliative resections; n = 58) fared significantly worse, with an actuarial 5-year survival rate of 8% and a median survival of 10 months (p < 0.0001). Survival has improved significantly from decade to decade (p < 0.002), with the 3-year actuarial survival of 14% in the 1970s, 21% in the 1980s, and 36% in the 1990s. Factors significantly favoring long-term survival by univariate analyses included tumor diameter < 3 cm, negative nodal status, diploid tumor DNA content, tumor S phase fraction < 18%, pylorus-preserving resection, < 800 mL intraoperative blood loss, < 2 units of blood transfused, negative resection margins, and use of postoperative adjuvant chemotherapy and radiation therapy. Multivariate analyses indicated the strongest predictors of long-term survival were diploid tumor DNA content, tumor diameter < 3 cm, negative nodal status, negative resection margins, and decade of resection.The survival of patients with pancreatic adenocarcinoma treated by pancreaticoduodenectomy is improving. Aspects of tumor biology, such as DNA content, tumor diameter, nodal status and margin status, are the strongest predictors of outcome.
View details for Web of Science ID A1995RF53600011
View details for PubMedID 7794076
EVALUATION OF P53 PROTEIN EXPRESSION AS A MARKER FOR LONG-TERM PROGNOSIS IN COLORECTAL-CARCINOMA
BRITISH JOURNAL OF CANCER
1995; 71 (6): 1257-1262
Mutation of the p53 gene is reported to be of prognostic importance in colorectal carcinomas. Immunohistochemical staining of the accumulated p53 gene product may be a simple alternative for p53 mutation analysis. Previous studies addressing the prognostic importance of p53 expression, however, yielded contradictory results. Therefore, we evaluated the importance of p53 expression as a marker for long-term prognosis in a well-characterised study population of 109 colorectal carcinomas. After antigen retrieval with target unmasking fluid (TUF), immunostaining of p53 was performed with both monoclonal antibody DO7 and polyclonal antibody CM1. Objective quantification of the p53 signal was assessed by a computerised image analyser. p53 expression was higher in non-mucinous tumours than in mucinous tumours (p53 labelling index = 30% and 17% respectively, P = 0.05), and in metastatic tumours compared with non-metastatic tumours (p53 labelling index = 37% and 22% respectively, P = 0.05). Other histopathological features were not related to p53 expression. In multivariate analysis, Dukes' stage (P = 0.02) and histological grade (P = 0.05) stood out as independent markers for prognosis. p53 expression was not an independent marker for prognosis. At present, p53 expression is not a useful marker for long-term prognosis. Further insight into the relationship between p53 mutations and p53 expression is needed to elucidate more precisely the clinical relevance of p53 alterations.
View details for Web of Science ID A1995RB64600025
View details for PubMedID 7779721
MOLECULAR ASSESSMENT OF HISTOPATHOLOGICAL STAGING IN SQUAMOUS-CELL CARCINOMA OF THE HEAD AND NECK
NEW ENGLAND JOURNAL OF MEDICINE
1995; 332 (7): 429-435
Surgical oncologists rely heavily on the histopathological assessment of surgical margins to ensure total excision of the tumor in patients with head and neck cancer. However, current techniques may not detect small numbers of cancer cells at the margins of resection or in cervical lymph nodes.We used molecular techniques to determine whether clonal populations of infiltrating tumor cells harboring mutations of the p53 gene could be detected in histopathologically negative surgical margins and cervical lymph nodes of patients with squamous-cell carcinoma of the head and neck.We identified 25 patients with primary squamous-cell carcinoma of the head and neck containing a p53 mutation who appeared to have had complete tumor resection on the basis of a negative histopathological assessment. In 13 of these 25 patients, molecular analysis was positive for a p53 mutation in at least one tumor margin. In 5 of 13 patients with positive margins by this method (38 percent), the carcinoma has recurred locally, as compared with none of 12 patients with negative margins (P = 0.02 by the log-rank test). Furthermore, molecular analysis identified neoplastic cells in 6 of 28 lymph nodes (21 percent) that were initially negative by histopathological assessment.Among specimens initially believed to be negative by light microscopy, a substantial percentage of the surgical margins and lymph nodes from patients with squamous-cell carcinoma of the head and neck contained p53 mutations specific for the primary tumor. Patients with these positive margins appear to have a substantially increased risk of local recurrence. Molecular analysis of surgical margins and lymph nodes can augment standard histopathological assessment and may improve the prediction of local tumor recurrence.
View details for Web of Science ID A1995QF77000004
View details for PubMedID 7619114
MULTIVARIATE-ANALYSIS OF PROGNOSTIC FEATURES IN MALIGNANT PLEURAL EFFUSIONS FROM BREAST-CANCER PATIENTS
1994; 38 (6): 945-952
To identify prognostic indicators in breast cancer patients with malignant pleural effusions, we analyzed the cytopathologic features of 57 fluids representing the first pathologic diagnosis of a distant metastasis in these women. The specimens were analyzed prior to reviewing the clinical records. The median survival of 55 patients who died of the disease was five months following the effusion diagnosis (range, 1-114). Univariate analysis identified three cytopathologic features that correlated with relatively prolonged survival: arrangement of tumor cells in spheroids, slight nuclear atypia and low mitotic rate. Women whose tumor cells formed spheroids survived a median of 24.5 months as compared to 4 months for women with all other architectural patterns (P = .004). Multivariate analysis revealed that slight nuclear atypia and low mitotic rate strongly correlated with spheroid formation. Since breast cancers that form spheroids in effusions portend a relatively favorable prognosis, we recommend that cytopathologists comment on this pattern when reporting on metastatic breast carcinoma in pleural fluids.
View details for Web of Science ID A1994PX23800012
View details for PubMedID 7992584
DO READERS AND PEER REVIEWERS AGREE ON MANUSCRIPT QUALITY
2nd International Congress on Peer Review in Biomedical Publication
AMER MEDICAL ASSOC. 1994: 117–19
To study readers' judgments of manuscript quality and the degree to which readers agreed with peer reviewers.Cross-sectional study.Annals of Internal Medicine.One hundred thirteen consecutive manuscripts reporting original research and selected for publication. Each of two manuscript versions (one before and one after revision) was judged by two readers, randomly sampled from those who said (based on the title) that they would read the article; one peer reviewer (peer), chosen in the usual way for Annals; and one expert in clinical research methods (expert). Each judge completed an instrument that included a 10-point subjective summary grade of manuscript quality.Agreement on the 10-point summary grade of manuscript quality between reader-expert, reader-peer, and reader-reader.Readers and peers gave high grades (77% and 73% gave a grade of 5 or better, respectively), while experts were more critical (52% gave a grade of 5 or better; P < .0001). Agreement was relatively high among judge groups (in all cases, > 69%) but agreement beyond chance was poor (kappa < 0.04). One third of readers (33%) thought that the manuscript had little relevance to their work.Readers, like most peer reviewers, are generally satisfied with the quality of manuscripts but would like research articles to be more relevant to their clinical practice.
View details for Web of Science ID A1994NV42400009
View details for PubMedID 8015119
TRANSFER OF TECHNOLOGY FROM STATISTICAL JOURNALS TO THE BIOMEDICAL LITERATURE - PAST TRENDS AND FUTURE PREDICTIONS
2nd International Congress on Peer Review in Biomedical Publication
AMER MEDICAL ASSOC. 1994: 129–32
To investigate the speed of the transfer of new statistical methods into the medical literature and, on the basis of current data, to predict what methods medical journal editors should expect to see in the next decade.Influential statistical articles were identified and the time pattern of citations in the medical literature was ascertained. In addition, longitudinal studies of the statistical content of articles in medical journals were reviewed.Cumulative number of citations in medical journals of each article in the years after publication.Annual citations show some evidence of decreasing lag times between the introduction of new statistical methods and their appearance in medical journals. Newer technical innovations still typically take 4 to 6 years before they achieve 25 citations in the medical literature. Few methodological advances of the 1980s seem yet to have been widely cited in medical journals. Longitudinal studies indicate a large increase in the use of more complex statistical methods.Time trends suggest that technology diffusion has speeded up during the last 30 years, although there is still a lag of several years before medical citations begin to accrue. Journals should expect to see more articles using increasingly sophisticated methods. Medical journals may need to modify reviewing procedures to deal with articles using these complex new methods.
View details for Web of Science ID A1994NV42400013
View details for PubMedID 8015123
MANUSCRIPT QUALITY BEFORE AND AFTER PEER-REVIEW AND EDITING AT ANNALS OF INTERNAL-MEDICINE
ANNALS OF INTERNAL MEDICINE
1994; 121 (1): 11-21
To evaluate the effects of peer review and editing on manuscript quality.Editorial offices of Annals of Internal Medicine.Masked before-after study. MANUSCRIPTS: 111 consecutive original research manuscripts accepted for publication at Annals between March 1992 and March 1993.We used a manuscript quality assessment tool of 34 items to evaluate the quality of the research report, not the quality of the research itself. Each item was scored on a 1 to 5 scale. Forty-four expert assessors unaware of the design or aims of the study evaluated the manuscripts, with different persons evaluating the two versions of each manuscript (before and after the editorial process).33 of the 34 items changed in the direction of improvement, with the largest improvements seen in the discussion of study limitations, generalizations, use of confidence intervals, and the tone of conclusions. Overall, the percentage of items scored three or more increased by an absolute 7.3% (95% CI, 3.3% to 11.3%) from a baseline of 75%. The average item score improved by 0.23 points (CI, 0.07 to 0.39) from a baseline mean of 3.5. Manuscripts rated in the bottom 50% showed two- to threefold larger improvements than those in the top 50%, after correction for regression to the mean.Peer review and editing improve the quality of medical research reporting, particularly in those areas that readers rely on most heavily to decide on the importance and generalizability of the findings.
View details for Web of Science ID A1994PN27100003
View details for PubMedID 8198342
The influence of HIV serostatus on physicians' clinical decisions.
AIDS & public policy journal
1994; 9 (2): 93-99
View details for PubMedID 11659840
OVEREXPRESSION OF P53 PROTEIN IN ADENOCARCINOMA OF THE PANCREAS
AMERICAN JOURNAL OF CLINICAL PATHOLOGY
1994; 101 (6): 684-688
Mutations in the p53 tumor suppressor gene are frequently identified in human neoplasms. These mutations may be associated with stabilization and, therefore, with overexpression of the p53 protein product as determined by immunohistochemical staining. Using a new antigen retrieval method and a polyclonal antibody to p53 (CM-1), the authors examined 48 formalin-fixed paraffin-embedded adenocarcinomas of the pancreas for overexpression of the p53 gene product. These 48 carcinomas were obtained from a series of patients with well-documented clinical histories and extensive follow-up. The carcinomas had been analyzed previously for K-ras gene mutations, tumor ploidy, and tumor proliferating index. Specific diffuse nuclear staining for the p53 protein was identified in 19 of the 48 (40%) infiltrating carcinomas examined. Focal or negative staining was seen in the remaining 29 cases (60%). In addition, 17 of the neoplasms contained synchronous in situ carcinomas; two (12%) of these displayed diffuse nuclear staining for the p53 protein. Overexpression of p53 was associated with aneuploidy (P = .05), which had been a poor prognosticator in this series of adenocarcinomas of the pancreas. Although overexpression of p53 appeared to be associated with poor prognosis (hazard ratio, 1.8; P = .07), this was not statistically significant. Overexpression of p53 was not significantly associated with K-ras oncogene mutations or tumor proliferating index. The authors conclude that overexpression of the p53 protein occurs frequently in invasive adenocarcinomas of the pancreas and in some in situ carcinomas, as well.
View details for Web of Science ID A1994NQ30200003
View details for PubMedID 8209852
PERITRANSPLANT INJURY TO THE MYOCARDIUM ASSOCIATED WITH THE DEVELOPMENT OF ACCELERATED ARTERIOSCLEROSIS IN HEART-TRANSPLANT RECIPIENTS
AMERICAN JOURNAL OF SURGICAL PATHOLOGY
1994; 18 (4): 338-346
Accelerated arteriosclerosis is now the major long-term complication of heart transplantation. Defining the risk factors associated with the development of accelerated arteriosclerosis will provide not only a means of identifying patients at risk for this complication but also clues to the etiology of accelerated arteriosclerosis. The purpose of this study was to examine the relationship between peritransplant myocardial ischemic injury and the development of accelerated arteriosclerosis. In a case-control study we examined the first three endomyocardial biopsies from 50 heart transplant recipients and graded the degree of ischemic injury present in these biopsies. The histologic changes graded in the biopsies included contraction band necrosis, coagulative necrosis, and macrophagic removal of ischemically injured myocytes. Of the 50 recipients included in the study, 25 had angiographic evidence of accelerated arteriosclerosis and 25 did not. In multivariate analysis, which included the number of class I major histocompatibility (MHC) antigen mismatches between the donor and the recipient, the recipient's post-transplant cytomegalovirus status, the donor's age, and the number of rejection episodes, the histologic degree of ischemic injury present in the biopsies emerged as the strongest predictor of the development of accelerated arteriosclerosis (RR 2.6, 95% CI 1.2-5.8, p = 0.02). These results suggest that ischemic injury to the heart during the peritransplant period significantly contributes to the development of accelerated arteriosclerosis in heart transplant recipients and that histologic changes in early posttransplant biopsies can be used to identify recipients at risk of developing accelerated arteriosclerosis.
View details for Web of Science ID A1994ND58100002
View details for PubMedID 8141428
Catalysts for conversations about advance directives: the influence of physician and patient characteristics.
journal of law, medicine & ethics : a journal of the American Society of Law, Medicine & Ethics
1994; 22 (1): 29-35
View details for PubMedID 8173657
- CONFIDENCE-LIMITS VS POWER CALCULATIONS EPIDEMIOLOGY 1994; 5 (2): 266-268
EFFICACY OF IMMUNE GLOBULIN IN PREVENTING COMPLICATIONS OF BONE-MARROW TRANSPLANTATION - A METAANALYSIS
BONE MARROW TRANSPLANTATION
1993; 12 (3): 273-282
To assess the efficacy of immune globulin in preventing CMV infection, interstitial pneumonia, GVHD and death after BMT, we reviewed and synthesized data from 12 published studies (with 1282 patients) in which immune globulin was used prophylactically in BMT patients, controls were included and clinical outcomes were assessed. Data synthesis indicates that immune globulin significantly reduces fatal CMV infection (odds ratio (OR) 0.47, 95% confidence interval (CI) 0.23-0.99), CMV pneumonia (OR 0.61, CI 0.42-0.89), non-CMV interstitial pneumonia (OR 0.57, CI 0.35-0.95) and total mortality (OR 0.74, CI 0.55-0.99). The reduction in acute GVHD was not quite significant (OR CI 0.45-1.02). Complications decrease with both hyperimmune and conventional immune globulin. For CMV-negative transplant recipients, immune globulin decreases symptomatic CMV infection (OR 0.55, CI 0.31-0.94) and interstitial pneumonia (OR 0.34, CI 0.15-0.77). For CMV-positive recipients, immune globulin prevents interstitial pneumonia (OR 0.45, CI 0.26-0.80) but not symptomatic CMV infection (CI 0.41-2.80). We conclude that immune globulin is efficacious in preventing major complications of BMT in both CMV-negative and CMV-positive recipients.
View details for Web of Science ID A1993LX82500016
View details for PubMedID 8241987
K-RAS ONCOGENE ACTIVATION IN ADENOCARCINOMA OF THE HUMAN PANCREAS - A STUDY OF 82 CARCINOMAS USING A COMBINATION OF MUTANT-ENRICHED POLYMERASE CHAIN-REACTION ANALYSIS AND ALLELE-SPECIFIC OLIGONUCLEOTIDE HYBRIDIZATION
AMERICAN JOURNAL OF PATHOLOGY
1993; 143 (2): 545-554
We examined 82 surgically resected or biopsied, formalin-fixed, paraffin-embedded primary adenocarcinomas of the pancreas for the presence of activating point mutations in codon 12 of the K-ras oncogene. Mutations were detected using primer-mediated, mutant-enriched, polymerase chain reaction-restriction fragment length polymorphism analysis and characterized further by allele-specific oligonucleotide hybridization. This combination of mutant-enriched polymerase chain reaction-restriction fragment length polymorphism analysis and allele-specific oligonucleotide hybridization results in a rapid and sensitive characterization of the mutations in codon 12 of K-ras. Sixty-eight (83%) of the 82 carcinomas examined harbored a point mutation. Of the 68 mutations, 33 (49%) were guanine to adenine transitions, 27 (39%) were guanine to thymine transversions, and eight (12%) were guanine to cytosine transversions. Mutations were found in carcinomas of the head (61 of 75, 81%) as well as in carcinomas of the body or tail (seven of seven, 100%) of the pancreas. The overall prevalence of K-ras point mutations in adenocarcinomas of the pancreas obtained from patients who smoked cigarettes at some point during their lives (88%; 86% in current smokers and 89% in ex-smokers) was greater than that seen in pancreatic adenocarcinomas from patients who never smoked cigarettes (68%, P = 0.046). The presence of K-ras point mutations did not correlate with tumor ploidy, tumor proliferating index, or patient survival. These results demonstrate that primer-mediated, mutant-enriched polymerase chain reaction-restriction fragment length polymorphism analysis combined with allele-specific oligonucleotide hybridization can be used to detect and characterize mutations in codon 12 of the K-ras oncogene in formalin-fixed, paraffin-embedded tissues, and the results confirm that activating point mutations in codon 12 of the K-ras oncogene occur frequently in adenocarcinomas of the pancreas.
View details for Web of Science ID A1993LQ67500025
View details for PubMedID 8342602
K-RAS ONCOGENE ACTIVATION IN LUNG ADENOCARCINOMAS FROM FORMER SMOKERS - EVIDENCE THAT K-RAS MUTATIONS ARE AN EARLY AND IRREVERSIBLE EVENT IN THE DEVELOPMENT OF ADENOCARCINOMA OF THE LUNG
1993; 72 (2): 432-438
Point mutations in codon 12 of the K-ras protooncogene occur more frequently in lung adenocarcinomas from smokers (30%) than they do in lung adenocarcinomas from nonsmokers (7%), suggesting that smoking is an important factor in the induction of these mutations. The lack of well defined "early" premalignant or in situ glandular neoplasms of the lung, however, has not permitted direct evaluation of the chronology of ras activation in the development of lung adenocarcinomas. To circumvent the need to evaluate precursor lesions, we examined lung adenocarcinomas from former smokers for point mutations in K-ras.Mutations in codon 12 of K-ras were detected using polymerase chain reaction amplification and mutation-specific oligonucleotide probes. The types and frequencies of mutations found in adenocarcinomas obtained from 57 former smokers were compared to those found in 27 adenocarcinomas from patients who never smoked and to those found in 27 adenocarcinomas from patients who were current smokers.The overall prevalence of K-ras point mutations in lung adenocarcinomas obtained from former smokers (32%) was not different from that seen in adenocarcinomas from patients who were current smokers (30%, P = 0.83), and was greater than that seen in adenocarcinomas from patients who never smoked (7%, P = 0.015). This pattern was independent of the duration of abstinence from smoking. Furthermore, the predominant type of mutation found in tumors from former smokers was a guanine-to-thymine transversion, the specific type of mutation induced by benzo(a)pyrene, one of the chemical carcinogens found in tobacco smoke.These findings support previous findings that suggest that codon 12 of the K-ras oncogene may be a specific target of the mutagenic activity of tobacco smoke, and suggest that DNA alterations at this site can occur early and irreversibly during the development of adenocarcinomas of the lung.
View details for Web of Science ID A1993LL90500018
View details for PubMedID 8319174
OVEREXPRESSION OF THE P53-TUMOR SUPPRESSOR GENE-PRODUCT IN PRIMARY LUNG ADENOCARCINOMAS IS ASSOCIATED WITH CIGARETTE-SMOKING
AMERICAN JOURNAL OF SURGICAL PATHOLOGY
1993; 17 (3): 213-220
Mutations in the p53 tumor suppressor gene are frequently observed in primary lung adenocarcinomas, suggesting that these mutations are critical events in the malignant transformation of airway cells. These mutations are often associated with stabilization of the p53 gene product, resulting in the accumulation of p53 protein. In this study, 70 formalin-fixed, paraffin-embedded primary lung adenocarcinomas resected for potential cure were examined for p53 overexpression. These 70 lung adenocarcinomas were obtained from a series of patients with well-documented clinical histories, and all 70 carcinomas had been previously evaluated for point mutations in codon 12 of the K-ras oncogene. Overexpression of the p53 protein was detected using an antigen retrieval system (Target Unmasking Fluid) and the anti-p53 antibody CM-1. CM-1 is a polyclonal antibody directed against the wild-type p53 protein. Overexpression of the p53 protein was found in 23 (33%) of the 70 lung adenocarcinomas. In all 23 cases, overexpression was confined to neoplastic cells. Overexpression of the p53 protein correlated with cigarette smoking: 10 (56%) of the 18 adenocarcinomas from patients who were current smokers overexpressed p53 compared with 13 (33%) of the 40 adenocarcinomas from patients who had quit smoking and 0 (0%) of the 12 adenocarcinomas from patients who had never smoked (p = 0.002, trend test). Overexpression of the p53 protein was also related to the degree of histologic differentiation: 48% of the p53 negative carcinomas were well differentiated, whereas only 13% (p = 0.003) of the carcinomas in which p53 was overexpressed were well differentiated. Overexpression of the p53 protein did not correlate with point mutations in codon 12 of the K-ras oncogene, nor did it correlate with tumor stage or patient survival. These findings indicate that p53 protein is frequently overexpressed in primary lung adenocarcinomas. Furthermore, the association of tobacco smoking with this overexpression suggests that the p53 gene is a target of specific mutagens in tobacco smoke.
View details for Web of Science ID A1993KN93700001
View details for PubMedID 8434702
NEUROBLASTOMA SCREENING DATA - AN EPIDEMIOLOGIC ANALYSIS
AMERICAN JOURNAL OF DISEASES OF CHILDREN
1991; 145 (12): 1415-1422
Neuroblastoma is one of the most common malignant neoplasms in children under age 5 years. Little progress has been made in the prognosis of advanced stage disease in the past three decades. Since the development in the 1960s of a simple urine test to detect neuroblastoma metabolites, there has been hope that mortality from this disease could be reduced by early detection via mass screening of young infants. Encouraging reports from Japan on mass screening programs instituted in the 1970s have been appearing in the medical literature since 1982, resulting in widespread interest in screening. This article applies standard epidemiologic criteria for screening evaluations to the Japanese reports. We find that the data needed to definitively assess the value of screening were not a part of those reports and that the benefits claimed from the reported data could be due to overdiagnosis. In addition, the most recent Japanese data, combined with recent advances in biologic understanding of neuroblastoma, show that screening at age 6 months may not detect tumors with poor prognoses. Even if it could, it is uncertain whether those outcomes could be substantially altered by earlier diagnosis. Although a final verdict on the value of neuroblastoma screening is not yet possible, these neuroblastoma studies are an excellent example of how screening results must be viewed with extreme caution in the absence of age-specific, population-based incidence and mortality rates.
View details for Web of Science ID A1991GZ35000019
View details for PubMedID 1669671
MULTIVARIATE-ANALYSIS OF THE RISK OF STOMACH-CANCER AFTER ULCER SURGERY IN AN AMSTERDAM COHORT OF POSTGASTRECTOMY PATIENTS
AMERICAN JOURNAL OF EPIDEMIOLOGY
1991; 134 (1): 14-21
Although gastric cancer incidence is decreasing in the western world, it remains an important cause of death, and there has been debate about screening persons who have undergone gastrectomy for benign ulcers. The authors analyzed risk factors for stomach cancer mortality in an Amsterdam cohort of 2,633 postgastrectomy patients, followed from their initial surgery between 1931 and 1960 until 1975, with 99.7% complete follow-up. Increased stomach cancer mortality was observed in the study population (compared with the general Dutch population) among males 25 years or more after surgery (observed/expected, 5.0; 95% confidence interval (Cl) 2.8-8.3), and among females 15-24 years postoperatively (observed/expected, 3.5; 95% Cl 1.0-9.0). A multivariate Poisson regression analysis showed that after control for age at time of surgery and calendar year of operation, the most important risk factors were time since surgery (0-4 years, relative risk (RR) = 1.0; 5-14 years, RR = 4.1, 95% Cl 0.93-18.5; 15-24 years, RR = 9.4, 95% Cl 2.1-42.3; and 25-46 years, RR = 55.6, 95% Cl 11.7-265.4) and ulcer location (gastric versus duodenal ulcer, RR = 2.6, 95% Cl 1.4-4.8). Surveillance for postgastrectomy cancer could be considered 15-25 years after a patient undergoes surgery for gastric ulcer disease.
View details for Web of Science ID A1991FX66900002
View details for PubMedID 1853856
INFLUENCE OF DILATED CARDIOMYOPATHY, MYOCARDITIS AND CARDIAC TRANSPLANTATION ON THE RELATION BETWEEN PLASMA ATRIAL-NATRIURETIC-FACTOR AND ATRIAL PRESSURES
AMERICAN JOURNAL OF CARDIOLOGY
1991; 67 (5): 391-397
To determine whether dilated cardiomyopathy, myocarditis or cardiac transplantation affect the relation between plasma immunoreactive atrial natriuretic factor (ANF) and cardiac filling pressures, right atrial plasma ANF concentration, pulmonary arterial wedge pressure and right atrial pressure were measured in patients with dilated cardiomyopathy (n = 48), dilated cardiomyopathy secondary to myocarditis (n = 20) and prior cardiac transplantation (n = 34). ANF level significantly correlated with both pulmonary arterial wedge and right atrial pressures in patients with dilated cardiomyopathy; however, the presence or absence of myocarditis did not significantly alter these relations (p = 0.88 and p = 0.33 for interaction terms, respectively). For the combined group the ANF-pulmonary arterial wedge pressure relation had a slope of 8.1 pg/ml/mm Hg (95% confidence interval (CI), 5.4 to 10.8; p = 0.0001) and the ANF-right atrial pressure relation a slope of 13.6 pg/ml/mm Hg (CI, 8.5 to 18.7; p = 0.0001). Receiver operator curve analysis identified an optimal dividing point of ANF 150 pg/ml with 100% (CI, 72 to 100%) of patients with right atrial pressure greater than or equal to 8 mm Hg having ANF greater than or equal to 150 pg/ml, but only 56% (CI, 42 to 69%) with pressure less than 8 mm Hg having ANF less than 150 pg/ml. Unlike the patients with cardiomyopathy (with or without myocarditis), cardiac transplant recipients displayed no correlation between ANF level and either pulmonary arterial wedge pressure (p = 0.50) or right atrial pressure (p = 0.29) despite similarly elevated ANF concentrations (mean +/- standard deviation 168 (83) pg/ml in transplant patients versus 185 (114) pg/ml in cardiomyopathy patients). It is concluded that left and right intracardiac pressures are important determinants of circulating ANF level unaffected by inflammation in patients with cardiomyopathy.(ABSTRACT TRUNCATED AT 250 WORDS)
View details for Web of Science ID A1991EX48700011
View details for PubMedID 1825259
- HAVE YOU EVER METAANALYSIS YOU DIDNT LIKE ANNALS OF INTERNAL MEDICINE 1991; 114 (3): 244-246
DETECTION OF MINIMAL RESIDUAL T-CELL ACUTE LYMPHOBLASTIC-LEUKEMIA BY FLOW-CYTOMETRY
JOURNAL OF IMMUNOLOGICAL METHODS
1990; 132 (2): 275-286
We have developed a flow cytometric assay for the determination of cellular expression of terminal deoxynucleotidyl transferase (TdT) and applied this to the detection of minimal residual T cell acute lymphoblastic leukemia (T-ALL). The flow cytometric assay for TdT demonstrated requisite specificity: TdT was localized to the nucleus, and was detected in MOLT3 T lymphoblasts, clinical T-ALL samples, and normal bone marrow B lymphoid precursors, but in neither the KG1a myeloid leukemia cell line nor normal myeloid cells. Co-expression of TdT and the pan T cell marker CD5 was used to quantify T lymphoblasts. 0.25 +/- 0.13% of normal adult bone marrow CD5+ cells were TdT+; these may represent early T lymphoid precursors. When admixed with normal bone marrow, CD5+TdT+ leukemic cells could be detected above background levels at an added concentration of 0.035% (95% confidence interval 0.028-0.43%). Long term follow-up of a large number of patients will be required to determine the clinical significance of a minimal burden of leukemic cells.
View details for Web of Science ID A1990DZ70000015
View details for PubMedID 1698878