The Disappearing Gallstone and the National Cooperative Gallstone Study Thistle, Hofmann, and colleagues, in two articles in JAMA (239:1041-1046, 1978, and in this issue, p 1138), have summarized
the total pioneering Mayo Clinic experience with chenodeoxycholic acid (CDC) for dissolution of gallstones, clearly attesting to the efficacy of CDC capsules. They found that the dose of CDC, the size and type of stones, and roentgenographic visualization of the gallbladder were important, though incomplete, determinants of response. In addition, an uncontrolled observation by the Mayo group warranting further study was the disappearance of stones in the common bile duct of five of ten patients treated with CDC orally. The investigators concluded that this agent continues to appear promising as medical therapy for radiolucent gallstones in the
gallbladder.
With
appropriate caution, however, they
indicated the need for more information on specific determinants of efficacy, the long-term safety of CDC, and on the medical management of gallstone recurrence after dissolution. Although CDC currently is on the market in at least 25 countries throughout the world, it probably will not be released by the Food and Drug Administration for prescription use in the United States until completion of the National Cooperative Gallstone Study (NCGS). The current status of the NCGS, therefore, will now be summarized. The primary aim of the NCGS, a randomized, controlled, double-blind, cooperative clinical trial, is to determine the efficacy and safety of CDC in gallstone dissolution. The secondary aims are to identify specific determinants of efficacy and safety, study the frequency and management of recurrence after dissolution, and investigate relevant basic mechanisms. The NCGS, funded by the National Institutes of Health, is composed of the Coordinating Center at Cedars-Sinai Medical Center in Los Angeles; Central Serum, Bile, Radiology, Morphology, and Biostatistical Units; and supporting commit¬ tees (Steering, Advisory, Data Monitoring, Clinical Monitoring, Ancillary Study, Protocol-Publications, and Laboratory). Preliminary activities of the NCGS that have been completed include selection of Canada Packers Pharmaceutical House to supply CDC, animal toxicology studies to satisfy FDA require¬ ments; development of a protocol, procedures manual, forms, and quality control techniques; selection of treatment centers; and initiation of ancillary studies on basic mechanisms of gallstone dissolution. Patients 21 through 79 years old, giving fully informed consent and having radiolucent gallstones without biliary colic or cholecystitis within the previous month, are eligible. Patients with any degree or frequency of nonspecific dyspepsia, however, are acceptable. Women must be unable to bear
New Requirements for Authors.—Congress recently passed The Copyright Revision Act of 1976, which affects JAMA's procedure for acceptance of manuscripts. Please refer to the "Instructions for Authors" page for details.
be more than 40 years old and using a contracep¬ tive intrauterine device. The other major exclusion criteria are primary liver disease, gastric ulcer, and inflammatory bowel disease. Accession of patients to the initial (liver -biopsy) study was completed Sept 1, 1976, at which time the main clinical study was initiated with FDA approval. The initial study involves 100 patients randomized to receive either 375 or 750 mg/day of CDC and undergo pretreatment and posttreatment liver biop¬ sies in addition to the same frequent clinical and laboratory patient-safety monitoring done in the main study. In the main study, which does not include routine liver biopsies, 900 patients (90 at each of ten centers) will be randomized to receive either 375 or 750 mg/day of CDC or placebo; thus far, about 500 patients have entered the main study, and completion of accession of patients is anticipated by March 1, 1978. Each patient will be treated and monitored under predefined efficacy and safety criteria for two years; those patients receiving placebo will have the opportunity, subsequently, to receive CDC if it is proved to be safe and effective. The double-blind nature of the NCGS precludes disclosure of emerging results. The unblinded Data Monitoring Commit¬ tee, however, at its most recent meeting (June 27, 1977), reported: "The Data Monitoring Committee has reviewed data related to the efficacy and safety of CDC therapy received at the Biostatistics Unit through April, 1977, and recommends no change in the NCGS protocol for either the initial (biopsy) study or the main study." This statement indicates that the NCGS, under careful scrutiny, is progressing satisfactorily on schedule toward definitive conclusions regarding the efficacy and safety of CDC.
children,
or
Leslie J. Schoenfield, MD Cedars-Sinai Medical Center
University of California at
Los Angeles School of Medicine Los Angeles
An Argument for Research in the Medical
School Curriculum
the need for change in the medical curriculum, one major deficiency remains uncorrected, the lack of training in medical research. The shortage of
Despite
Address editorial communications to the Editor, 535 N Dearborn St, Chicago, IL 60610.
Downloaded From: http://jama.jamanetwork.com/ by a New York University User on 05/26/2015
the attention
given
to
physicians in this country has pressured medical schools to emphasize the practical rather than the theoretical, and students
time to clinical work than to the study of subjects. Many medical students believe that research training will be irrelevant to their future work, but training in research could yield practical rewards for all future physicians. Although medical students are aware of the dramatic break\x=req-\ throughs made in the research laboratory by a few physicians, they are often unaware of the other benefits that all may derive from research experience. Performing research helps one to become a better physician by training the mind to think critically and creatively. Just as the researcher draws conclusions from experimental data, the practicing physician must base his decision on the analysis of medical history, physical findings, and laboratory tests. Physicians who have had research experi¬ ence in medical school will be better equipped to state and test a hypothesis and will have developed the habit of examining all data critically and analytically. Also, a physician with research training would more readily notice, in daily practice, possible cause-and-effect relationships, which could occasionally lead to notable discoveries. Physicians in the academic community are, after all, practicing physicians. Such physicians have made great contributions, for example, to our understanding of infectious diseases, fluid and electrolyte disorders, hématologie disease, and surgical therapy.1 A good research background would enable the physician to better evaluate new techniques and drugs as they are intro¬ duced. Many theories have been "sold" to the medical commu¬ nity during the last 30 years, only to have been discredited within a few years of inception. The internal mammary artery ligation as a means of treating heart disease2 and gastric freezing as a cure for peptic ulcers3 are examples of techniques that achieved popularity quickly without sufficient evaluation. Only after much money was spent applying them to many patients were these techniques shown to be useless. Perhaps more critical evaluation of new ideas by physicians might prevent some of these unfortunate medical fads from reaching such a large number of patients. The rapid proliferation of new devices and techniques places unprecedented responsibility on the physician. To be able to survive in the maze of new techniques, drugs, and theories, the physician must be familiar with the old methods and techniques of basic and clinical research. Research also helps to reinforce a student's knowledge gained from textbooks. I have had the opportunity to partici¬ pate in medical research during the past several years.4'' By assisting in research projects studying heart disease, using dogs as laboratory subjects, many facts were learned about cardio¬ vascular anatomy, physiology, pharmacology, and pathology. I now
basic
devote
more
gained firsthand experience in the application of various drugs and techniques used in the treatment of coronary heart disease. I also acquired a better understanding of the physiologic
mechanism of the heart, far better than could be obtained merely by studying textbooks. Learning by doing and observing is the best way to master the textbook material. Without being unnecessarily specific, three possible ways are suggested by which research could be introduced into the medical school curriculum. First, the student could participate in laboratory research in his school, where research projects are currently being performed. Second, a student could do clinical research, studying and analyzing the many actual cases that came to his attention in the course of the clinical portion of the curriculum. Third, the student might perform a "record room" research project, making statistical analyses of case histories and symptoms without actually meeting the patients involved. The latter two types of research have the advantage of costing little; indeed, the major investment would be not in laboratory equipment to be purchased, but rather in the time required to be spent by the students. Not only would such research projects be for the most part inexpensive, but they could give students valuable training and an opportunity to contribute to the store of medical knowledge. The training that the student would receive in the use of the scientific method is in some ways more important than the factual knowledge obtained in medical school. Facts learned may be quickly forgotten if they are not immediately used. A mind well trained in the scientific method, however, is an asset that a physician is likely to long retain, and the method itself is one that he is likely to use continually. Indeed, since medicine is always changing with new discoveries being made every day, many facts learned in medical school often become obsolete. Methods of organized and critical thinking never become obsolete. Robert N. Greenberg
Hahnemann Medical and Hospital
College
Philadelphia
1. Beeson PB: The development of clinical knowledge: With a few words about targeted vs basic research. JAMA 237:2209-2212, 1977. 2. Wangensteen OH, Peter ET, Nicoloff DM, et al: Achieving "physiologic
gastrectomy" by gastric freezing. JAMA 180:439-444, 1962. 3. Glover RP, Kitchell JR, Davila JC, et al: Bilateral ligation of the internal mammary artery in the treatment of angina pectoris. Am J Cardiol 6:937-945, 1960.
4. Greenberg RN, Angelakos ET, Reed E, et al: Distribution of tracer microspheres during acute coronary occlusion in the intact dog. Presented at the 60th Annual Meeting of the Federation of American Societies for Experimental Biology, Anaheim, Calif, April 11-16, 1976. 5. Greenberg RN, Cassel J, Satinsky VP: Histological studies of various
anode and cathode electrodes. Presented at the 27th Annual Conference Engineering in Medicine and Biology, Philadelphia, Oct 6-10, 1974.
Downloaded From: http://jama.jamanetwork.com/ by a New York University User on 05/26/2015
on
the total pioneering Mayo Clinic experience with chenodeoxycholic acid (CDC) for dissolution of gallstones, clearly attesting to the efficacy of CDC capsules. They found that the dose of CDC, the size and type of stones, and roentgenographic visualization of the gallbladder were important, though incomplete, determinants of response. In addition, an uncontrolled observation by the Mayo group warranting further study was the disappearance of stones in the common bile duct of five of ten patients treated with CDC orally. The investigators concluded that this agent continues to appear promising as medical therapy for radiolucent gallstones in the
gallbladder.
With
appropriate caution, however, they
indicated the need for more information on specific determinants of efficacy, the long-term safety of CDC, and on the medical management of gallstone recurrence after dissolution. Although CDC currently is on the market in at least 25 countries throughout the world, it probably will not be released by the Food and Drug Administration for prescription use in the United States until completion of the National Cooperative Gallstone Study (NCGS). The current status of the NCGS, therefore, will now be summarized. The primary aim of the NCGS, a randomized, controlled, double-blind, cooperative clinical trial, is to determine the efficacy and safety of CDC in gallstone dissolution. The secondary aims are to identify specific determinants of efficacy and safety, study the frequency and management of recurrence after dissolution, and investigate relevant basic mechanisms. The NCGS, funded by the National Institutes of Health, is composed of the Coordinating Center at Cedars-Sinai Medical Center in Los Angeles; Central Serum, Bile, Radiology, Morphology, and Biostatistical Units; and supporting commit¬ tees (Steering, Advisory, Data Monitoring, Clinical Monitoring, Ancillary Study, Protocol-Publications, and Laboratory). Preliminary activities of the NCGS that have been completed include selection of Canada Packers Pharmaceutical House to supply CDC, animal toxicology studies to satisfy FDA require¬ ments; development of a protocol, procedures manual, forms, and quality control techniques; selection of treatment centers; and initiation of ancillary studies on basic mechanisms of gallstone dissolution. Patients 21 through 79 years old, giving fully informed consent and having radiolucent gallstones without biliary colic or cholecystitis within the previous month, are eligible. Patients with any degree or frequency of nonspecific dyspepsia, however, are acceptable. Women must be unable to bear
New Requirements for Authors.—Congress recently passed The Copyright Revision Act of 1976, which affects JAMA's procedure for acceptance of manuscripts. Please refer to the "Instructions for Authors" page for details.
be more than 40 years old and using a contracep¬ tive intrauterine device. The other major exclusion criteria are primary liver disease, gastric ulcer, and inflammatory bowel disease. Accession of patients to the initial (liver -biopsy) study was completed Sept 1, 1976, at which time the main clinical study was initiated with FDA approval. The initial study involves 100 patients randomized to receive either 375 or 750 mg/day of CDC and undergo pretreatment and posttreatment liver biop¬ sies in addition to the same frequent clinical and laboratory patient-safety monitoring done in the main study. In the main study, which does not include routine liver biopsies, 900 patients (90 at each of ten centers) will be randomized to receive either 375 or 750 mg/day of CDC or placebo; thus far, about 500 patients have entered the main study, and completion of accession of patients is anticipated by March 1, 1978. Each patient will be treated and monitored under predefined efficacy and safety criteria for two years; those patients receiving placebo will have the opportunity, subsequently, to receive CDC if it is proved to be safe and effective. The double-blind nature of the NCGS precludes disclosure of emerging results. The unblinded Data Monitoring Commit¬ tee, however, at its most recent meeting (June 27, 1977), reported: "The Data Monitoring Committee has reviewed data related to the efficacy and safety of CDC therapy received at the Biostatistics Unit through April, 1977, and recommends no change in the NCGS protocol for either the initial (biopsy) study or the main study." This statement indicates that the NCGS, under careful scrutiny, is progressing satisfactorily on schedule toward definitive conclusions regarding the efficacy and safety of CDC.
children,
or
Leslie J. Schoenfield, MD Cedars-Sinai Medical Center
University of California at
Los Angeles School of Medicine Los Angeles
An Argument for Research in the Medical
School Curriculum
the need for change in the medical curriculum, one major deficiency remains uncorrected, the lack of training in medical research. The shortage of
Despite
Address editorial communications to the Editor, 535 N Dearborn St, Chicago, IL 60610.
Downloaded From: http://jama.jamanetwork.com/ by a New York University User on 05/26/2015
the attention
given
to
physicians in this country has pressured medical schools to emphasize the practical rather than the theoretical, and students
time to clinical work than to the study of subjects. Many medical students believe that research training will be irrelevant to their future work, but training in research could yield practical rewards for all future physicians. Although medical students are aware of the dramatic break\x=req-\ throughs made in the research laboratory by a few physicians, they are often unaware of the other benefits that all may derive from research experience. Performing research helps one to become a better physician by training the mind to think critically and creatively. Just as the researcher draws conclusions from experimental data, the practicing physician must base his decision on the analysis of medical history, physical findings, and laboratory tests. Physicians who have had research experi¬ ence in medical school will be better equipped to state and test a hypothesis and will have developed the habit of examining all data critically and analytically. Also, a physician with research training would more readily notice, in daily practice, possible cause-and-effect relationships, which could occasionally lead to notable discoveries. Physicians in the academic community are, after all, practicing physicians. Such physicians have made great contributions, for example, to our understanding of infectious diseases, fluid and electrolyte disorders, hématologie disease, and surgical therapy.1 A good research background would enable the physician to better evaluate new techniques and drugs as they are intro¬ duced. Many theories have been "sold" to the medical commu¬ nity during the last 30 years, only to have been discredited within a few years of inception. The internal mammary artery ligation as a means of treating heart disease2 and gastric freezing as a cure for peptic ulcers3 are examples of techniques that achieved popularity quickly without sufficient evaluation. Only after much money was spent applying them to many patients were these techniques shown to be useless. Perhaps more critical evaluation of new ideas by physicians might prevent some of these unfortunate medical fads from reaching such a large number of patients. The rapid proliferation of new devices and techniques places unprecedented responsibility on the physician. To be able to survive in the maze of new techniques, drugs, and theories, the physician must be familiar with the old methods and techniques of basic and clinical research. Research also helps to reinforce a student's knowledge gained from textbooks. I have had the opportunity to partici¬ pate in medical research during the past several years.4'' By assisting in research projects studying heart disease, using dogs as laboratory subjects, many facts were learned about cardio¬ vascular anatomy, physiology, pharmacology, and pathology. I now
basic
devote
more
gained firsthand experience in the application of various drugs and techniques used in the treatment of coronary heart disease. I also acquired a better understanding of the physiologic
mechanism of the heart, far better than could be obtained merely by studying textbooks. Learning by doing and observing is the best way to master the textbook material. Without being unnecessarily specific, three possible ways are suggested by which research could be introduced into the medical school curriculum. First, the student could participate in laboratory research in his school, where research projects are currently being performed. Second, a student could do clinical research, studying and analyzing the many actual cases that came to his attention in the course of the clinical portion of the curriculum. Third, the student might perform a "record room" research project, making statistical analyses of case histories and symptoms without actually meeting the patients involved. The latter two types of research have the advantage of costing little; indeed, the major investment would be not in laboratory equipment to be purchased, but rather in the time required to be spent by the students. Not only would such research projects be for the most part inexpensive, but they could give students valuable training and an opportunity to contribute to the store of medical knowledge. The training that the student would receive in the use of the scientific method is in some ways more important than the factual knowledge obtained in medical school. Facts learned may be quickly forgotten if they are not immediately used. A mind well trained in the scientific method, however, is an asset that a physician is likely to long retain, and the method itself is one that he is likely to use continually. Indeed, since medicine is always changing with new discoveries being made every day, many facts learned in medical school often become obsolete. Methods of organized and critical thinking never become obsolete. Robert N. Greenberg
Hahnemann Medical and Hospital
College
Philadelphia
1. Beeson PB: The development of clinical knowledge: With a few words about targeted vs basic research. JAMA 237:2209-2212, 1977. 2. Wangensteen OH, Peter ET, Nicoloff DM, et al: Achieving "physiologic
gastrectomy" by gastric freezing. JAMA 180:439-444, 1962. 3. Glover RP, Kitchell JR, Davila JC, et al: Bilateral ligation of the internal mammary artery in the treatment of angina pectoris. Am J Cardiol 6:937-945, 1960.
4. Greenberg RN, Angelakos ET, Reed E, et al: Distribution of tracer microspheres during acute coronary occlusion in the intact dog. Presented at the 60th Annual Meeting of the Federation of American Societies for Experimental Biology, Anaheim, Calif, April 11-16, 1976. 5. Greenberg RN, Cassel J, Satinsky VP: Histological studies of various
anode and cathode electrodes. Presented at the 27th Annual Conference Engineering in Medicine and Biology, Philadelphia, Oct 6-10, 1974.
Downloaded From: http://jama.jamanetwork.com/ by a New York University User on 05/26/2015
on
