Archives of Surgery

doi: 10.1001/archsurg.137.9.992pmid: N/A

This ARCHIVES issue attempts to resolve several important issues of surgical practice. We trust that the articles and discussions of these problems will help you determine the best method of dealing with these controversies. First, does the use of computed tomography (CT) and laparoscopy improve the outcome for elderly patients with appendicitis? A retrospective analysis of appendectomy using CT and the laparoscopic approach did not lower the morbidity or mortality rate among the elderly. Emphasis was placed on earlier consideration of the diagnosis in older patients with abdominal pain, followed by prompt surgical consultation and operation. In reviewing the article's discussion, it is apparent that CT can help in determining alternative diagnoses. Article Second, how to deal with the pancreatic stump when the pancreatic duct is small and the residual organ is soft is a problem all pancreatic surgeons consider. Suzuki et al present their algorithm based on 50 consecutive pancreatoduodenectomies, with different procedures used prospectively according to pancreatic texture and duct size (aided by fibrin glue). Behrman's invited critique puts this information into perspective. Article Third, when is the best time for wound excision and grafting in severely burned children? Xiao-Wu et al found that delays in excision were associated with longer hospitalization and delayed wound closure as well as increased rates of invasive wound infection and sepsis. Early excision (within 48 hours) is optimal. Our reviewers warn us of the potential harm of early operative intervention. Article Surgical Treatment of Hyperparathyroidism Improves Health-Related Quality of Life To answer the age-old question, "Can you improve the status of an asymptomatic patient?" Sheldon et al analyzed 74 consecutive patients who underwent parathyroidectomy for primary hyperparathyroidism using the Medical Outcomes Study Short-Form Health Survey (SF-36) as a basis for comparison preoperatively and 1-year postoperatively. They found that surgical treatment, regardless of the preoperative symptoms, was associated with durable, statistically significant improvements in health-related quality of life, whether the operative intervention was bilateral neck exploration, unilateral neck exploration, or a minimally invasive 1-gland exploration. Although one can bicker about the interpretation of asymptomatic, it is difficult to ignore these results. Article Worldwide Trends in the Surgical Treatment of Primary Hyperparathyroidism in the Era of Minimally Invasive Parathyroidectomy Sackett et al have surveyed the members of the International Association of Endocrine Surgeons and have had enough feedback to make the following statements. First, the number of parathyroidectomies performed worldwide increased more than 4-fold in the 20 years from 1980 through 2000 and the average number per endocrine surgeon increased to 45 annually, with more than half of the surgeons using minimally invasive techniques. Second, the most common approach is the focused technique with a small incision, either central or lateral, followed by endoscopic gland retrieval. Third, techniques used to ensure completeness of resection include a quick intraoperative intact parathyroid hormone assay, a same-day intact parathyroid hormone assay, and the nuclear probe. View LargeDownload Article Postoperative Symptoms and Failure After Antireflux Surgery In a series of more than 200 consecutive patients with gastroesophageal reflux disease undergoing a fundoplication, preoperative and postoperative testing was conducted. Only a few patients in the postoperative symptomatic group had abnormal DeMeester scores. Thus, symptomatic assessment appears to be a poor predictor of true pathological reflux in these patients. Article

Fan, S. T.

doi: 10.1001/archsurg.137.9.993pmid: 12215146

Hui, Thomas T.; Major, Kevin M.; Avital, Itzhak; Hiatt, Jonathan R.; Margulies, Daniel R.

doi: 10.1001/archsurg.137.9.995pmid: 12215147

HypothesisElderly patients who have appendicitis have a greater morbidity and mortality rate when compared with younger patients. We hypothesized that recent changes in the diagnosis and management of appendicitis in elderly patients might affect the outcome.DesignRetrospective review.SettingLarge metropolitan teaching hospital.PatientsAll patients aged 70 years and older who underwent appendectomy for appendicitis between January 1, 1991, and December 31, 2000, were divided into groups 1 (those treated from January 1, 1991, through December 31, 1995) and 2 (those treated from January 1, 1996, through December 31, 2000).Main Outcome MeasuresAge, sex, preoperative evaluation, operative duration and findings, postoperative course, duration of hospital stay, and mortality rate. Continuous and categorical variables were analyzed using tand χ2tests, respectively.ResultsNinety-five patients met inclusionary criteria. The mean age (78 years), sex, preoperative suggestion of appendicitis (group 1, 39 [83%] of 47 patients; group 2, 45 [94%] of 48 patients), and duration of the preoperative hospitalization over 24 hours (group 1, 11 patients [23%]; group 2, 9 patients [19%]) were similar in both groups. There was an increasing use of diagnostic computed tomography (group 1, 13 patients [28%]; group 2, 32 patients [67%]; P<.001) and laparoscopy (group 1, 14 patients [30%]; group 2, 23 patients [48%]; P= .02) between the 2 study periods associated with no significant difference in the duration of hospitalization, frequency of appendiceal perforation or abscess, occurrence of complications, or mortality. The length of operating time increased in the second period (ie, January 1, 1996, through December 31, 2000).ConclusionsAppendicitis in elderly patients continues to be a challenging surgical problem. While computed tomography may represent a useful diagnostic tool and laparoscopic appendectomy may be appropriate therapy for selected patients, neither has affected outcome when measured for morbidity and mortality rates. Overall results might improve with earlier consideration of the diagnosis in elderly patients with abdominal pain, followed by prompt surgical consultation and operation.WHILE ACUTE appendicitis is primarily a disease of the younger population, with only 5% to 10% of cases occurring in elderly persons, the incidence of appendicitis in older patients seems to be increasing with an increase in life expectancy.Morbidity and mortality rates are greater in older patients who often have delayed and atypical presentations, leading to increased frequency of perforation and intra-abdominal infection.Diagnostic studies may cause further delays in definitive management, and associated illnesses increase operative risks.The past decade has produced 2 major advances in the diagnosis and treatment of appendicitis. Contrast-enhanced computed tomography (CT) has been shown to be both sensitive and specific in diagnosis.Laparoscopic appendectomy has been shown in some series to offer more rapid recovery and less postoperative pain compared with the open approach.However, these benefits were not demonstrated in all studies and several studies have shown an increased risk of postoperative abscess formation in patients who have perforated appendicitis treated laparoscopically. Laparoscopy has the potential advantage of aiding in diagnosis as well as providing an opportunity for treatment, but it has not been evaluated in older patients. This study was undertaken to evaluate the changes in diagnostic and treatment methods in elderly patients with acute appendicitis over the past decade.PATIENTS, MATERIALS, AND METHODSWe reviewed the medical records of elderly patients (aged ≥70 years) who underwent appendectomy for acute appendicitis at Cedars-Sinai Medical Center, Los Angeles, Calif, a large, private teaching hospital, between January 1, 1991, and December 31, 2000. Variables selected for analysis included age, sex, number of associated illnesses, presenting symptoms, diagnostic studies, operative approach, operative findings, need for postoperative admission to the intensive care unit, duration of hospitalization (total and postoperative), and morbidity and mortality rates. The following definitions were used: fever, a temperature higher than 37.8°C; hypothermia, a temperature lower than 35.6°C; leukocytosis, a white blood cell count higher than 10 × 103/µL; and/or leukopenia, a white blood cell count lower than 4 × 103/µL.Patients were divided into 2 groups for comparison (group 1, those patients admitted to the hospital from January 1, 1991, through December 31, 1995; group 2, those patients admitted to the hospital from January 1, 1996, through December 31, 2000). Further analysis was performed by comparing those patients in whom acute appendicitis was suspected after the initial evaluation with those in whom the diagnosis was unsuspected. Patients undergoing laparoscopy were also compared with those treated with open operation.Sixty-eight patients (72%) were admitted from the emergency department after evaluation by an emergency medicine physician. The remainder were admitted directly to the hospital by an internist or general surgeon. Operative approach was chosen by the attending surgeon. All patients received parenteral antibiotics preoperatively. Cefotetan disodium was the most common antibiotic used. Antibiotics were administered postoperatively for at least 5 days for patients with perforated appendicitis.Computed tomographic scanning of the abdomen and pelvis was performed using 1 of 2 scanners (either the Somatom; Siemens Analyltical X-Ray Instruments, Madison, Wis, or the LightSpeed; General Electric, Waukesha, Wis). All patients received oral and intravenous contrast-enhanced medium; 92 patients (97%) received rectal contrast-enhanced medium. A technician using an ultrasonograph (model HDI 5000; Advanced Technology Laboratory, Best, the Netherlands) performed abdominal ultrasonography. Computed tomographic scans and sonograms were interpreted by a staff radiologist. Enema studies using contrast media were performed by a staff radiologist using water-soluble contrast material under fluoroscopic guidance.All data were entered into a relational database program. Statistical analyses were performed using the ttest for continuous variables and χ2test with the Yate correction for categorical variables. P<.05 was considered statistically significant.RESULTSDuring the study period, 95 elderly patients underwent appendectomy for acute appendicitis (Table 1). Their mean age was 78 years; the sex distribution was nearly equal.Table 1. Presentation and Preoperative Evaluation*VariableTotal (N = 95)Group 1 (n = 47)†Group 2 (n = 48)†PValueAge, mean (SD), y78 (5.6)78 (6.4)78 (4.9).87Female49 (52)23 (49)26 (54).76Symptoms >48 h52 (55)21 (45)31 (65).08No. of associated illnesses, mean (SD)2.3 (1.4)2.5 (1.4)2.0 (1.4).09Appendicitis suspected70 (73)34 (72)36 (75).95Type of diagnostic studyComputed tomography45 (47)13 (28)32 (67)<.001Contrast enema31 (33)23 (43)8 (17).002Ultrasonography16 (17)9 (19)7 (15).75None20 (21)14 (30)6 (13).04Operated on within 24 h75 (79)36 (77)39 (81).82*Data are given as the number (percentage) of elderly patients unless otherwise indicated.†Patients who were aged 70 years and older and who underwent appendectomy for appendicitis were divided into the following groups: group 1, those treated between January 1, 1991, and December 31, 1995; group 2, those treated between January 1, 1996, and December 31, 2000.Associated illness occurred in 71 patients (75%). The average number of associated illnesses was 2.3 per patient and was similar in both groups. Hypertension was present in 42 patients (44%), cardiac disease in 30 patients (32%), diabetes mellitus in 13 patients (14%), chronic obstructive lung disease in 7 patients (7%), renal insufficiency in 3 patients (3%), and myeloma in 1 patient (1%). The mean duration of symptoms was 4 days. More than half of the patients were initially seen with longer than 2 days of symptoms before hospital admission. Symptoms included abdominal pain in 90 patients (95%), nausea in 41 patients (43%), and emesis in 19 patients (20%). Signs included right lower quadrant tenderness in 79 patients (83%), leukocytosis in 68 patients (72%), fever in 29 patients (31%), and leukopenia in 1 patient (1%). No patients had hypothermia. There were no statistically significant differences for any of the presenting signs or symptoms between the 2 groups.After completion of the medical history and physical examination, appendicitis was suggested in only 70 patients (74%). Admission diagnoses in the 25 patients not initially suspected of having appendicitis included small-bowel obstruction (6 patients); nonspecific abdominal pain (6 patients); diverticulitis (3 patients); cholecystitis (2 patients); chest pain (2 patients); and thigh abscess, incarcerated ventral hernia, incarcerated femoral hernia, gastrointestinal hemorrhage, pneumonia, and multiple myeloma (1 patient each).Most (75) patients (79%) underwent diagnostic studies. Contrast enema was the most frequent diagnostic test in the first period (ie, January 1, 1991, through December 31, 1995), while CT was most frequent in the second period (ie, January 1, 1996, through December 31, 2000); use of ultrasonography was similar in both periods. Computed tomography was the most sensitive for the diagnosis of acute appendicitis (91% sensitivity), while ultrasonography was the least sensitive (53%). Contrast enema had a sensitivity of 81%. After testing, suspicion of appendicitis increased to 39 patients (83%) in group 1 and 45 (94%) in group 2 (P= .19). The time from hospital admission to operation was less than 24 hours in 75 patients (79%) and was not significantly different between the 2 groups.Operative therapy is summarized in Table 2. Use of laparoscopy increased significantly in the second period, and the number of open procedures declined correspondingly. Despite the more frequent use of laparoscopy, operative durations were longer in group 2. Most cases were found to be perforated at the time of operation in both groups, and abscesses were present in more than one third of the patients.Table 2. Operative Approach and Findings*VariableTotal (N = 95)Group 1 (n = 47)†Group 2 (n = 48)†PValueAttempted laparoscopic appendectomy41 (43)14 (30)27 (48).02Completed laparoscopically33 (35)12 (26)21 (44).09Converted to open approach8 (8)2 (4)6 (13).28Open appendectomy54 (57)33 (70)21 (44).02Duration of operation, minAll patients, mean (SD)89 (52.0)78 (43.0)100 (57.0).03Laparoscopic appendectomy939591.83Converted to open approach128125129.94Open appendectomy806899.05Perforated appendicitis65 (68)32 (68)33 (69).93Abscess present at operation36 (38)19 (40)17 (35).61*Data are given as the number (percentage) of elderly patients unless otherwise indicated.†Patients who were aged 70 years and older and who underwent appendectomy for appendicitis were divided into the following groups: group 1, those treated between January 1, 1991, and December 31, 1995; group 2, those treated between January 1, 1996, and December 31, 2000.Duration of total hospitalization (group 1 vs group 2, 8.3 vs 11.0 days, P= .15) and postoperative hospitalization (group 1 vs group 2, 7.6 vs 9.4 days, P= .26), intensive care unit admission rate (group 1 vs group 2, 26% vs 21%, P= .76), morbidity rate (group 1 vs group 2, 28% vs 33%, P= .71), and mortality rate (group 1 vs group 2, 2% vs 4%, P= .51) were similar in both groups. Seven patients developed surgical complications (wound infection in 4 patients and intra-abdominal abscess in 3 patients). Other complications in 29 patients included ileus and/or small-bowel obstruction in 9 patients, arrhythmias in 6 patients, pneumonia or respiratory tract failure in 5 patients, urinary retention in 3 patients, generalized sepsis in 2 patients, and acute renal failure in 1 patient. The 3 deaths were due to sepsis syndrome in 2 patients and cardiopulmonary arrest in 1 patient.In 25 (26%) of the 95 patients in this series, appendicitis was not suggested before diagnostic testing (Table 3). Abdominal pain was less frequent in these patients; therefore, operations were delayed, intensive care unit admissions were more frequent, durations of total and postoperative hospitalization were prolonged, and mortality was increased. Twenty-one (22%) of the patients underwent at least 1 diagnostic imaging procedure. A CT scan performed in 16 patients (64%) and contrast enema performed in 9 patients (36%) showed appendicitis in 14 patients (87%) and 4 patients (44%), respectively (P= .04). Only 5 (20%) of these 25 patients underwent a laparoscopic procedure.Table 3. Comparison of Patients by Initial Diagnosis*Those With Suspected Appendicitis (n = 70)Those With Unsuspected Appendicitis (n = 25)P ValueAge, mean (SD), y77 (6.0)80 (5.0).03Abdominal pain70 (100)20 (80)<.001Diagnostic study54 (77)21 (84).66Operated on within 24 h61 (87)9 (36)<.001Laparoscopic appendectomy28 (40)5 (20).12Duration of hospitalization, mean (SD), dTotal7.6 (5.7)15.3 (13.4).01Postoperative7.1 (5.8)12.4 (10.9).03ICU admission11 (16)11 (44).009Complications18 (26)11 (44).15Deaths03.02*Data are given as the number (percentage) of elderly patients unless otherwise indicated. ICU indicates intensive care unit.Comparing patients only by operative approach, those who underwent open appendectomy were older (group 1 vs group 2 mean age, 79 vs 76 years, P= .01) with a higher rate of perforation (group 1 vs group 2, 76% vs 48%, P= .02) and abscess (group 1 vs group 2, 50% vs 15%, P= .002), and duration of postoperative hospitalization was longer (group 1 vs group 2, 9.9 vs 5.0 days, P= .01). Complication and mortality rates were similar between the open and laparoscopic groups.COMMENTThis study was performed to evaluate the changes in the management of 95 elderly patients with acute appendicitis following the introduction of CT for diagnosis and laparoscopy for therapy. The presentation of these patients differs from that of younger patients. The classic triad of right lower quadrant pain of short duration, fever, and leukocytosis was infrequently observed, and more than half of the patients presented with symptoms of longer than 2 days' duration. Despite the report of abdominal pain in 90 (95%) of the 95 patients on presentation, the admitting physician suspected appendicitis in only 70 patients (74%) after the patients' provided a medical history and underwent a physical examination. Imaging tests were helpful in establishing the diagnosis, as the suspicion increased to 88% (84 patients) after testing but prior to operation.The disease process is consistently more advanced in elderly persons. Although most patients underwent operation within 24 hours of hospital admission, the frequency of appendiceal perforation (65 patients [68%]) and intra-abdominal abscess (36 patients [38%]) remained high, similar to observations of other authors.The reasons for delay in presentation may include problems of access to medical care, communication, or fear of hospitalization. Some believe that the physiology differs in the elderly and that the progression to perforation is more rapid owing to decreased lymphoid tissue or blood supply.The wider application of CT for patients with suspected appendicitis has been shown to improve diagnostic accuracy and decrease the negative appendectomy rate,although one study has shown that routine use of CT may lead to delay in definitive management.In the present series, we observed a clear increase in the use of diagnostic CT in the second study period when compared with the first. While we could not evaluate the specificity of CT in diagnosis of appendicitis, because only patients with acute appendicitis were included, the test had excellent sensitivity. There was only 1 false-negative result, and the scans identified the diagnosis in some patients in whom appendicitis had not been considered likely and confirmed the diagnosis in others.Appendicitis was unsuspected after initial evaluation in one quarter of our patients, and the delay in correct diagnosis ultimately resulted in delayed operation and prolonged hospitalization. Abdominal pain was present in 76 (80%) of the 95 patients. While the differential diagnosis of abdominal pain in older patients is broad, these data demonstrate that appendicitis should always be considered, and early surgical consultation is advised.The use of laparoscopic appendectomy also increased in the second study period. The benefit of the laparoscopic approach has not been clearly demonstrated. Several prospective randomized controlled trials have found more rapid recovery and less postoperative pain with the laparoscopic approach,while others have not found a difference in these variables.In the present study, more frequent use of laparoscopic appendectomy was associated with an increase in operating time but no statistically significant difference in the duration of the hospitalization or complications. Patients whose appendectomy was completed laparoscopically were younger and less likely to have appendiceal perforation and abscess. The postoperative hospitalization of these patients was shorter, reflecting the selection of less complicated cases for this subgroup. Similar to our previous study of perforated appendicitis in younger patients,no significant increase in the frequency of postoperative abscess was found in the laparoscopic compared with the open approach group.Comparing the 2 study periods, no significant differences in the interval from presentation to operation, duration of hospitalization, frequency of appendiceal perforation and abscess, postoperative complications, or mortality were observed despite increase use of CT and laparoscopy. This implies that the cost of treating an elderly patient with acute appendicitis has increased without significant outcome improvement. The greatest value of CT is its specificity and its ability to reduce a negative appendectomy rate, which cannot be evaluated in the present series owing to design limitation. This benefit is likely less important in elderly patients because the incidence of acute appendicitis is relatively low. However, CT is much more useful in establishing a diagnosis of appendicitis in patients with atypical presentation if it is ordered in a timely fashion. In the present series, the symptoms of 25 patients were not suggestive of appendicitis after intake of an initial medical history and after undergoing a physical examination. Of these 25 patients, 14 had a CT scan performed demonstrating appendicitis longer than 24 hours after hospital admission.CONCLUSIONSAppendicitis in the elderly continues to be a challenging surgical problem. Patients continued to present late with atypical presentations. The use of CT and laparoscopy has increased significantly but no differences in the frequency of complicated appendicitis, time from the hospital admission to operation, length of hospitalization, and morbidity and mortality rates were observed. Results might improve with earlier consideration of the diagnosis in elderly patients with abdominal pain, followed by prompt surgical consultation and operation.PPeltokallioHTykkaEvolution of the age distribution and mortality of acute appendicitis.Arch Surg.1981;116:153-156.WYLauSTFanTFYiuKWChuJMLeeAcute appendicitis in the elderly.Surg Gynecol Obstet.1985;161:157-160.MCHorattasDPGuytonDWuA reappraisal of appendicitis in the elderly.Am J Surg.1990;160:291-293.DLStromanCVBayouthJAKuhnThe role of the computed tomography in the diagnosis of acute appendicitis.Am J Surg.1999;178:485-489.EJBalthazarAJMegibowSESiegelBABirnbaumAppendicitis: prospective evaluation with high resolution CT.Radiology.1991;180:21-24.PMRaoJTRheaRANovellineAAMostafaviCJMcCabeEffect of computed tomography of the appendix on treatment of patients and use of hospital resources.N Engl J Med.1998;338:141-146.RCFrazeeJWRobertsRESymmondsA prospective randomized trial comparing open versus laparoscopic appendectomy.Ann Surg.1994;219:725-731.RGolubFSiddiquiDPohlLaparoscopic versus open appendectomy: a metaanalysis.J Am Coll Surg.1998;186:545-553.HRFreundERubinsteinAppendicitis in the aged: is it really different?Am Surg.1984;50:573-576.HFallahzadehShould a laparoscopic appendectomy be done?Am Surg.1998;64:231-233.LCMartinIPuenteJLSosaOpen versus laparoscopic appendectomy: a prospective randomized comparison.Ann Surg.1995;222:256-262.FBonanniJReed IIIGHartzellLaparoscopic versus conventional appendectomy.J Am Coll Surg.1994;179:273-278.TMKhaliliJRHiattASavarCLauEHPhillipsDRMarguliesPerforated appendicitis is not a contraindication to laparoscopy.Am Surg.1999;65:965-967.Kenneth Waxman, MD, Santa Barbara, Calif:This interesting study raises important issues. We all hope and believe that we are progressively improving the care that we provide, but we do not often look at this critically. The authors of this study asked whether outcomes of their elderly patients who had appendicitis improved over time. To answer this question, they retrospectively compared 47 elderly patients with appendicitis treated in the first half of the 1990s with 48 patients treated in the second half of the decade.The authors focused on 2 changes in diagnosis and treatment over this period, CT scanning and laparoscopy. Two thirds (32) of the 48 patients had CT scans in the second half of the decade vs only 13 patients (28%) in the first half. Laparoscopy was also more common in the later period, with 23 (48%) of 48 patients having an attempted laparoscopic approach vs 14 (30%) of the 47 patients in the earlier period.The results of the study are interesting: there was no improvement in outcome. Specifically, the death rate was not different, the complication rate was not lower, and the duration of hospitalization was not shorter. Therefore, the answer to the authors' question is that there was no improvement in outcome over this period despite increased use of CT and laparoscopic scanning. The authors conclude that neither CT nor laparoscopy improved outcome. In fact, this conclusion is the title of the paper. However, I believe that this conclusion may be invalid, because of the design of the study.This study is retrospective, and the results must be interpreted carefully because of this. Any outcome difference or lack of difference may be a result of CT or laparoscopy, because there may well have been other changes in treatment that occurred over this period, and these other treatments may have independently affected outcome. For example, was the emergency department busier, resulting in longer time delays? Did more patients in the later period have managed care insurance, and might their insurance status have resulted in delays in treatment? It is theoretically possible that CT and laparoscopy were in fact helpful, but this benefit was offset by other changes. This possibility cannot be excluded from this retrospective study design.In fact, data from this study regarding both CT and laparoscopy suggest possible benefit. Computed tomography correctly diagnosed appendicitis in 86 (91%) of of the 95 cases, with only 2 false-negative results (2%). In contrast, ultrasound was nearly useless, with only 53% (9/17) diagnostic accuracy, and 29% (5/17) false-negative results. Contrast enema fell in between these extremes. We do not have data from this study regarding how many patients with suspected appendicitis had other diagnoses made on CT such as diverticulitis or cancer. (This is an additional value of CT, not addressed by this study.)Laparoscopy was attempted in 41 patients and could be completed in 33. Successful laparoscopic procedures were associated with shorter hospitalizations, although this may well have been influenced by the severity of disease. There were no differences in complications, suggesting that these complications were a result of underlying disease rather than operative approach.As in previous studies of appendicitis in the elderly, the diagnosis of appendicitis in this series was late. Over half the patients had symptoms for longer than 48 hours. In fact, delays in presentation tended to increase over the second half of the decade. Over two thirds of the patients had perforation at the time of operation, and an abscess was present in almost 19 patients (40%). Fifteen (31%) of the 48 patients had complications and 1 patient (3%) died. Hospitalization averaged almost 10 days. From my perspective, the major problem with caring for these patients was their late presentation and their advanced appendicitis at the time of treatment. These issues did not improve over time.I have 3 questions for the authors: First, did the frequency of patients with managed care insurance increase during this study period? Could their insurance plans have affected treatment? Second, has this review influenced your practice; that is, do you now do fewer CT scans or less laparoscopy? Finally, what can you recommend to us and to your own medical community to effect earlier diagnosis and treatment, as these seem to be the critical factors related to outcome?Joshua D. I. Ellenhorn, MD, Duarte, Calif:With the greater advent of the use of CT scanning, there may have been diagnosis of appendicitis in patients in the later years of your study who might have just died septic deaths without ever having a diagnosis of appendicitis had they presented in earlier years. Is the absence of that denominator hiding an actual benefit to CT scanning?John T. Owings, MD, Sacramento, Calif:I enjoyed this study very much. Whenever you ascribe no difference between 2 groups after a statistical analysis, rather than the absence of being able to identify that difference, a type II error is problematic. With this particular study I have this question. Did the authors look, given the very low incidence of mortality in appendicitis, through a power analysis at how many patients they would have expected to need to enroll to demonstrate that truly no difference existed between groups and, thus, avoid a type II error. The same question exists for the relatively low complication rate that is normally seen.Bruce Wolfe, MD, Sacramento:Dr Waxman raised the issue that owing to the methodology, patients with an alternate diagnosis to appendicitis identified by CT scan are excluded from this analysis. The same can be said for laparoscopy. Laparoscopy is used by many of us in patients who have an uncertain diagnosis, and we believe that complete examination of the abdominal cavity is facilitated by laparoscopy as opposed to a small muscle-splitting incision in the right lower quadrant. The patients in whom an alternate diagnosis was established by laparoscopy I presume are also excluded from this study, thereby perhaps omitting a group in which a benefit from this technique may have been missed.Steven C. Stain, MD, Nashville, Tenn:Actually I agree with the authors' conclusion that newer technology probably does not affect outcome. Their study risks omitting patients who had CT scans that were excluded from having appendicitis and never went to operation. My question to the authors is: how did they account for those patients who never had operation and the diagnosis of appendicitis was excluded by CT scan?James J. Peck, MD, Portland, Ore:We recently studied 443 patients who had right lower quadrant pain over an 18-month period. There were 19 patients that were 70 years old or older. Eighteen of 19 patients had a CT scan with a zero percent negative appendectomy rate. One of the important advantages of CT scanning in the older aged group is an alternative diagnosis. In our study of 443 patients, there were 11 patients who had diverticulitis that presented as midline or right-sided abdominal pain. Ten of 11 did not require surgery and, therefore, avoided operative intervention.Your conclusions that older patients need an aggressive approach and early operation supports CT. Only 67% of these patients had a CT scan. If you had done your CT earlier, you may have had a different result. There is no question that the incidence of perforation in this study is related to the delay in presentation rather than in the delay in diagnosis. Sixty-five percent presented longer than 48 hours after their symptoms began. What was your technique of CT scanning? Did you use intravenous and/or oral contrast media? In our study, 57% of the patients had small appendicaliths that can be obscured by a contrast medium.Michael J. Hart, MD, Seattle, WashIt is pretty clear in this group of patients that the delay in initiating therapy is the major issue in their morbidity and mortality rates. One issue is unclear; is this a delay in patient presentation or is this a delay in diagnosis? If it is a delay in diagnosis, is that a delay that occurs on the surgical service or prior to surgical evaluation when patients remain in the emergency department for prolonged observation or are admitted by hospitalists or a nonsurgical service? Where were these patients found? Was the surgeon called when the patient was seen in the emergency room with abdominal pain, or did the patient finally have the surgeon stumble on to him or her several days into the course of things?Ronald G. Latimer, MD, Santa Barbara:Since abscesses were present in 38 (40%) of these 95 patients, how many of the patients did have percutaneous drainage before they underwent their appendectomies?Theodore O'Connell, MD, Los Angeles:I have 1 question also for the authors. I was a little fascinated by the mortality rate which was 2% (1 patient) in the first group and 4% (2 patients) in the second group—3 deaths. I almost cannot remember a death from appendicitis in any age range for about the last 20 years because of the use of modern antibiotics, CT catheter drainage, etc. What were the circumstances of the death in those patients?Dr Margulies:Thank you, Dr Waxman and all the discussants for their questions. Addressing Dr Waxman's questions regarding managed care: most of these patients were covered by Medicare and so I do not think that managed care played a large role in their selection. Similarly, managed care patients in our population had increased in the early 1990s and persisted throughout the later 1990s. Regarding the point that perhaps there are other changes in care that may have contributed, this is possible. However, because there were no statistically significant differences in outcome between the 2 periods, unless these other factors counterbalanced one another, it would be unlikely that they had any significant effect. We chose 2 periods close together to maximize the effect of CT and laparoscopy, which did change, and to minimize effects of other changes.Several questions addressed the use of CT. We believe that the CT scan was useful. Because contrast enema was also sensitive, replacing it with CT did not alter the outcome. Many other questions brought out how it was really the delay in presentation from these patients that established the rate of perforation, the high rate of complications, and their ultimate outcome, and, therefore, very little could be done, even if the diagnosis had been made initially. This is true, is one of the main findings, and points to an area for improvement.Regarding the comment for a type II error, yes, certainly this is possible, but because there was not even a trend toward a difference in outcome between the 2 periods, I do not think that this possibility played a significant role, even if we had had a larger number of patients. Regarding Dr Wolfe's question on the laparoscopic benefits of the diagnosis, actually I agree. There are patients that laparoscopy can benefit and, in fact, the ones in our study who underwent a completely laparoscopic approach had a shorter hospital stay and faired well. Still this was a selected group. There are the additional benefits that alternate diagnoses can be made and treated. We did not find that laparoscopy was a detriment certainly, and in some patients, I think it can be a benefit.Dr Stain, CT scanning certainly could have excluded the diagnosis in certain patients. However, these patients were excluded from our study as all of the patients in this study did have appendicitis. Overall the CT scan was useful and, yes, oral (and rectal) contrast medium were used. Many of these patients certainly did present late. Eighty percent (76/95) were operated on within the first 24 hours, so for most the delay occurred prior to their arrival at the hospital. We did analyze those patients who had a delay in the diagnosis after the hospitalization, and these 25 patients did less well. These patients had alternate diagnoses. For instance, patients with a small-bowel obstruction were treated without the confirming evidence of a CT scan initially and then, when their conditions did not improve, a workup and a CT scan revealed an appendicitis resulting in their being operated on. Therefore, we actually agree that a CT scan was useful and would recommend it even earlier in the course of these patients. As mentioned also, it could result in other diagnoses, for example, diverticulitis and others. So we encourage the use of CT scanning. Still, despite the benefits of both CT and laparoscopy, overall outcomes were not improved between periods in the way we use CT.We did not have any of the patients in this group who had percutaneous drainage prior to the operation. Regarding the question of the deaths, there were 3 in this series. One was an interesting patient who had a presentation with a thigh abscess from necrotizing infection with purulence throughout the muscles of the entire thigh. To exclude a diagnosis of appendicitis as the cause at the time of drainage at his initial operation, a laparotomy was performed and he did have a ruptured retroperitoneal appendicitis that had drained down into the leg. He eventually had a septic course in the intensive care unit with multisystem failure. The other 2 patients were actually initially recovering well and suffered cardiac events that occurred in the postoperative recovery period.This paper was presented at the 73rd Annual Meeting of the Pacific Coast Surgical Association, Las Vegas, Nev, February 16, 2002, and is published after peer review and revision. The discussions are based on the originally submitted manuscript and not the revised manuscript.Corresponding author and reprints: Daniel R. Margulies, MD, Suite 8215, Department of Surgery, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048 (e-mail: [email protected]).

doi: 10.1001/archsurg.137.9.1000pmid: N/A

CME Hiatus: July Through December 2002 CME from JAMA/Archives Journals will be suspended between July and December 2002. Beginning in early 2003, we will offer a new online CME program that will provide many enhancements: Article-specific questions Hypertext links from questions to the relevant content Online CME questionnaire Printable CME certificates and ability to access total CME credits We apologize for the interruption in CME and hope that you will enjoy the improved online features that will be available in early 2003.

Wren, Sherry M.; Stijns, Pascal; Srinivas, Sandy

doi: 10.1001/archsurg.137.9.1001pmid: 12215149

ObjectiveTo assess the value of positron emission tomography (PET) compared with computed tomography (CT) in the initial staging of esophageal cancer.DesignCase series.SettingTertiary care veterans hospital.PatientsPatients with newly diagnosed esophageal cancers from January 1996 through May 2001 who underwent both CT and PET scanning within 4 weeks were included in the study (n = 24). Only patients who underwent pathological or radiographic follow-up were included.Main Outcome MeasuresThe sensitivity, specificity, and negative and positive predictive values of CT and PET were determined based on a criterion standard of pathological staging in 16 patients (67%) and follow-up imaging in 8 patients (33%).ResultsFor staging regional lymph node involvement, CT and PET scans showed no statistically significant difference in sensitivity (57% and 71%, respectively) and specificity (71% and 86%, respectively). For detection of metastatic disease, CT and PET showed no significant difference in sensitivity (83% and 67%, respectively) and specificity (75% and 92%, respectively). There was no significant difference in clinical decision making when the results of both tests were discordant.ConclusionsThere was no significant difference between the 2 imaging modalities in the initial staging of esophageal cancer. The CT scan was a sensitive indicator of distant metastases, whereas PET was more specific. It is unclear what additional role PET scanning should have in the initial screening of patients.THE INCIDENCE of esophageal cancer continues to increase in the United States. In 2002, it is estimated that there will be 13 100 new cases and 12 600 deaths.Treatment can include a number of options, such as surgery, neoadjuvant treatment with chemotherapy and radiation therapy, photodynamic therapy, radiation therapy alone or in combination with chemotherapy, and stent placement. Treatment planning for individual patients should be based on the physician's ability to correctly define the extent of local, regional, and distant disease. The question facing both the clinician and the patient is who achieves the most benefit from which therapy. The role of surgical treatment in palliation is limited, and it is reserved for those patients who may derive some curative benefit from the intervention. The only patients who are candidates for resection are those with no evidence of metastatic disease.The development of neoadjuvant chemotherapy and radiation therapy protocols has influenced the drive for more accurate staging. Esophageal cancer staging encompasses 3 areas: the primary tumor (T stage), regional lymph nodes (N stage), and distant disease (M stage). The current staging modalities include computed tomography (CT), endoscopic ultrasonography (EUS), and positron emission tomography (PET). All 3 modalities give anatomic information; in addition, PET scanning detects metabolically active cancer tissue based on glucose metabolism. The potential to aggressively treat someone with extensive locoregional disease (T3 and/or N1) prior to an operation is an attractive concept. Some clinical trials have demonstrated a possible survival benefit for this type of treatment over surgical treatment alone.More accurate initial staging of the extent of the disease can identify possible candidates for neoadjuvant protocols, which could improve survival in this challenging group. Therefore, other staging modalities, such as EUS and PET, may have an increasing role in the initial staging of esophageal cancer.Each modality has different advantages, depending on which component of the staging is being evaluated. Clearly, primary T stage is the least important for clinical decision making, unless patients are going to be offered neoadjuvant protocols for advanced T3 or T4 lesions; EUS has clearly been shown to be superior at defining the depth of wall invasion, with a sensitivity of 85% to 95% compared with 50% for CT,and PET can show whether primary tumors are present but cannot give the depth of wall invasion. The assessment of regional nodal disease (N stage) is more confusing. Prior studies suggest that CT has limitations, with a sensitivity of only 60% to 87%,whereas EUS is thought to perform better, with a sensitivity of 70% to 80%. A wide range of sensitivity (28%-52%) has been reported for PET.Identification of distant metastases (M stage) is the single most important component of the initial staging. At the time of presentation, it is estimated that 30% to 50% of patients will have advanced (stage IV) disease. In the American Joint Commission on Cancer (AJCC) Cancer Staging Manual, celiac, cervical, and supraclavicular nodal disease, in addition to other distant sites, have been designated as metastatic disease and upstage patients to stage IV.Therefore, accurate staging of patients is critical to identify the subset that will derive the most benefit from surgical resection. The development of PET scanning and its ability to detect metabolically active tumor sites in addition to the anatomic information derived by imaging such as EUS and CT make this an attractive new option. Initial reports demonstrated that CT missed metastases that were then identified by PET scanning in 18% to 29% of patients.The role and true performance of PET scanning in the staging of esophageal cancer has not yet been defined. Based on these initial reports, our institution began using PET scanning to stage esophageal cancer. This article reports our retrospective, nonrandomized data. The final answer will be available when the prospective clinical trial sponsored by the American College of Surgeons has been completed.PATIENTS AND METHODSMedical records were examined for all patients with a new diagnosis of thoracic esophageal cancer at a tertiary medical center from January 1996 through May 2001. Only those patients who underwent both a staging CT scan and PET scan within 4 weeks of each other were included in the analysis. In addition, patients must have had some other follow-up that could be used to determine the nodal and metastatic staging of the tumor. Follow-up material consisted of pathological examination of a biopsy or resection specimen, autopsy examination, or subsequent imaging more than 8 weeks after the initial imaging that demonstrated growth of a lesion when compared with the initial examination. During this time, there were 54 newly diagnosed patients with esophageal cancer at the Palo Alto Veterans Hospital, Palo Alto, Calif, and 24 patients fulfilled the inclusion criteria. Of these 24 patients, 22 received care at the veterans hospital; the other 2 were treated at Stanford University Hospital, Stanford, Calif. The other 30 patients did not fulfill the inclusion criteria, most frequently because they had not undergone a PET scan or follow-up information was not available.Medical record review was performed by 2 of us, a surgical oncologist (S.M.W.) and a medical oncologist (S.S.). Imaging reports were used to generate a CT or PET staging based on the AJCC Cancer Staging Manual, fifth edition.Review of pathological or autopsy material was used in 16 of 24 patients and subsequent imaging in 8 of 24 patients to create a final TNM staging of each patient. Image-based staging for each modality was then compared with the criterion standard TNM staging. In addition, a separate analysis based on metastatic site was performed. Sensitivity, specificity, and positive and negative predictive values were computed using standard definitions. Results were compared using the McNemar analysis. P<.05 was considered significant.All CT scans were performed with a helical scanner, intravenous contrast, and either 7-mm or 10-mm slices. The reports were reviewed for the presence of esophageal-wall thickening, regional lymph node involvement, and distant metastasis. Esophageal-wall thickening was scored as representing primary disease (Tx), lymph nodes of 1 cm or larger were scored as positive, and distant site abnormalities interpreted as probable metastatic disease were scored as M disease. Subsequent imaging had to demonstrate a clear increase in lesion size (>0.5 cm) compared with the initial scan to be scored as pathological disease.All PET scans were performed 30 to 75 minutes after administration of 10 to 16 mCi of fludeoxyglucose F 18. An emission scan was acquired from the base of the skull through the inguinal region in 5 to 6 bed positions at 6 minutes per stop. Emission images were corrected for signal attenuation using a gallium 68 transmission scan acquired immediately before or after the emission scan. Images were reconstructed by filtered back projection using a Hann filter with a 0.3 cycle per pixel cut-off. Images were reviewed on a computer workstation in the transaxial, coronal, and sagittal planes using dedicated software that allowed for adjustment of several viewing parameters. Images were classified as positive or negative for malignancy by the subjective analysis of a single physician with experience in PET. Any focal area of glucose uptake higher than background activity for that region was considered positive for malignancy. All scans were performed at Palo Alto Veterans Hospital.RESULTSThere were 24 patients, all men, with a mean ± SD age of 65.9 ± 10.9 years. Twenty-one patients were white, 2 were African American, and 1 was Latino. Tumor location was in the lower thoracic esophagus (40 cm from incisors) in 19 patients (79%) and the midthoracic (32 cm from upper incisors) in 5 (21%). Tumor histologic diagnosis was adenocarcinoma in 15 (63%), squamous cell in 7 (29%), and other cell types (small cell and sarcoma) in 2 (8%). A total of 21 patients (88%) had invasive cancer, and 3 (13%) had carcinoma in situ.STAGINGRegional Lymph Node Involvement (N Stage)Twenty-one patients (88%) were evaluated for regional lymph node involvement. (Table 1). Of these 21 patients, 7 (33%) had involved regional nodes, and 14 (67%) had nodes that were not involved. The CT scan was correct in 14 patients (67%) and incorrect in 7 patients (33%). Of the 7 for whom the scans were incorrect, 4 would have been upstaged and 3 downstaged by CT. The PET scan was correct in 17 patients (81%) and incorrect in 4 patients (19%). Of those 4, 2 would have been upstaged and 2 downstaged incorrectly. Overall, PET had a higher sensitivity and specificity than CT (71% and 86% vs 57% and 71%, respectively) (Table 1). These differences did not reach statistical significance. Based on an observed regional lymph node involvement prevalence of 33%, both tests had higher negative predictive values (PET, 86%; CT, 77%) than positive predictive values; PET had a better positive predictive value than CT (71% vs 50%), but this difference was not statistically significant.Table 1. Regional Nodal Staging of Esophageal Cancer (N Stage)*StagingCommentsFinalCT†PET‡N0N1N0PET correctN0N1N0PET correctN0N1N0PET correctN1N0N1PET correctN0N0N1CT correctN0N1N1PET and CT overstagedN1N0N0PET and CT understagedN3N0N0PET and CT understagedN0N0N0PET and CT correctN0N0N0PET and CT correctN1N1N1PET and CT correctN0N0N0PET and CT correctN0N0N0PET and CT correctN0N0N0PET and CT correctN0N0N0PET and CT correctN0N0N0PET and CT correctN1N1N1PET and CT correctN1N1N1PET and CT correctN1N1N1PET and CT correctN0N0N0PET and CT correctN0N0N0PET and CT correctNXN0N0NonevaluableNXN1N1NonevaluableNXN1N0Nonevaluable*Each row presents data from 1 of 24 patients. Nonevaluable indicates that we were not able to assign a node status because no pathological or imaging follow-up data were available in these patients; CT, computed tomography; and PET, positron emission tomography.†Sensitivity was 57%; specificity, 71%; positive predictive value, 50%; and negative predictive value, 77%.‡Sensitivity was 71%; specificity, 86%; positive predictive value, 71%; and negative predictive value, 86%.Metastatic Disease (M Stage)All 24 patients could be evaluated for distant metastases (Table 2). There were 12 patients (50%) with metastatic disease; 8 had their metastases confirmed by histologic examination, and 4 had metastases confirmed by imaging studies. Nineteen patients (79%) were correctly staged by CT, and there were 2 false-negative and 3 false-positive results. Nineteen patients (79%) were also correctly staged by PET, and there were 4 false-negative and 1 false-positive results. In 2 patients (8%), CT failed to identify metastatic disease (cervical lymph node in 1 patient and celiac lymph node in another patient) but correctly identified 3 patients (13%) with metastatic disease missed by PET (lung nodule in 1 patient, para-aortic node in a second patient, and celiac lymph node in a third patient). In 4 patients (17%), PET failed to identify metastatic disease (celiac lymph nodes in 2 patients, abdominal lymph node in a third patient, and a lung nodule in a fourth patient) but correctly identified 1 patient with metastatic disease missed by CT (cervical lymph node). Three patients were incorrectly identified by CT as having metastatic disease (lymph nodes in all 3 patients: 1 patient with sarcoidosis and 2 with lymph nodes with no histologic abnormalities). Only 1 of the 3 patients also had a false-positive result on PET. One patient was incorrectly identified by PET as having metastatic disease (colon), but the results of CT were also false positive in this patient (distal node). Overall, CT had a higher sensitivity than PET for identifying patients with metastatic disease (83% vs 67%) but a lower specificity (75% vs 92%). Based on a 50% prevalence of metastatic disease, CT had a lower positive predictive value than PET (77% vs 89%) but a higher negative predictive value (82% vs 73%). None of the differences between CT and PET were statistically significant.Table 2. Distant Metastatic Staging of Esophageal Cancer (M Stage)*StagingCommentsFinalCT†PET‡M0M1aM0PET correctM0M1bM0PET correctM1bM0M1bPET correctM1aM1aM0CT correctM1bM1bM0CT correctM1bM1bM0CT correctM0M1bM1bPET and CT incorrectM1aM0M1bPET and CT incorrectM0M0M0PET and CT correctM0M0M0PET and CT correctM0M0M0PET and CT correctM0M0M0PET and CT correctM0M0M0PET and CT correctM0M0M0PET and CT correctM0M0M0PET and CT correctM1bM1bM1bPET and CT correctM0M0M0PET and CT correctM1bM1bM1bPET and CT correctM1aM1aM1aPET and CT correctM1bM1bM1bPET and CT correctM1bM1bM1bPET and CT correctM0M0M0PET and CT correctM1bM1bM1bPET and CT correctM1bM1bM1bPET and CT correct*Each row presents data from 1 of 24 patients. CT indicates computed tomography; PET, positron emission tomography.†Sensitivity was 83%; specificity, 75%; positive predictive value, 77%; and negative predictive value, 82%.‡Sensitivity was 67%; specificity, 92%; positive predictive value, 89%; and negative predictive value, 73%.LESION ANALYSISLiverOnly 1 patient was found to have a hepatic lesion. This was correctly imaged on both CT and PET scans and was confirmed by subsequent imaging that demonstrated an increase in lesion size and number. This site represents 8% of all metastatic disease.LungThree patients were found to have lung metastases. The CT scan identified metastatic lung disease in 3 of 3 patients, and the PET scan identified metastasis in only 1 of 3. The numbers are too small for statistical comparison. Lesion confirmation was by analysis of a biopsy specimen in 2 patients and subsequent imaging in 1 patient. This site represents 23% of metastatic disease.AdrenalBoth CT and PET scans correctly identified the 1 patient with an adrenal metastasis. Lesion confirmation was by analysis of a biopsy specimen. This site represents 8% of all metastatic disease.BoneTwo patients were positively identified as having bone metastases. The PET scan was the only imaging modality that identified both. One patient had a biopsy specimen that was positive for metastasis, and the other had further imaging with a bone scan and magnetic resonance imaging to confirm the lesion. This site represents 15% of all metastatic disease.Distant Lymph NodeSix patients were proven to have involved distant nodes. Both CT and PET correctly identified 4 of 6 patients. Nodal involvement was confirmed by histologic examination in 5 patients and by subsequent imaging in 1 patient. This site represents 46% of all metastatic disease.CLINICAL DECISION MAKINGThe CT and PET scans had concordant findings in 14 of 24 patients. Both PET and CT were correct in 12 patients and incorrect in 2 patients (Table 3). There were 10 cases in which the CT and PET scan findings were discordant. The PET scan was correct in 5 of 10 discordant cases, 3 of which were for regional node (N stage) disease and 2 for distant (M stage) nodal disease. The CT scan was correct in 3 of 10 discordant cases, all 3 of which were in identifying M stage disease: 1 pulmonary metastasis and 2 distant lymph nodes. In the other 2 discordant cases, both tests incorrectly staged the disease. In analyzing whether CT or PET findings influenced clinical decision making, it is clear that in 4 cases the results of a discordant study did influence management. The CT and PET scans both changed clinical management in 2 cases.Table 3. Concordance Analysis of CT and PET Staging of Esophageal Cancer and Impact on Clinical Decision Making*StagingPET and CT AgreeCorrect TestCT or PET Changed ManagementFinalCTPETT0 N0 M0TX N1 M1aT0 N0 M0NoPETNoT2 N0 M1bTX N0 M0TX N0 M1bNoPETNoT1 N0 M0TX N1 M0TX N0 M0NoPETNoTX N1 M0T4 N0 M0TX N1 M0NoPETNoT2 N0 M0TX N1 M0TX N0 M0NoPETNoTX N1 M1bTX N1 M1bTX N1 M0NoCTYes (chemotherapy and radiation therapy)T3 N0 M1aTX N0 M1aT0 N0 M0NoCTNoTX NX M1bTX N0 M1bTX N0 M0NoCTYes (thoracoscopy)Tis N0 M0T0 N0 M0T0 N0 M0YesPET and CTNoTis N0 M0T0 N0 M0T0 N0 M0YesPET and CTNoTX N0 M0TX N0 M0TX N0 M0YesPET and CTNoTX N0 M1bTX N0 M1bTX N0 M1bYesPET and CTNoT4 N0 M0TX N0 M0TX N0 M0YesPET and CTNoTX NX M1bTX N1 M1bT0 N0 M1bYesPET and CTNoT0 N0 M1bT0 N0 M1bT0 N1 M1bYesPET and CTNoTX N0 M0T0 N0 M0TX N0 M0YesPET and CTNoTX N1 M1bTX N1 M1bTX N1 M1bYesPET and CTNoTX N1 M1aTX N1 M1aTX N1 M1aYesPET and CTNoTX N1 M1bTX N1 M1bTX N1 M1bYesPET and CTNoTX NX M1bT0 N1 M1bTX N1 M1bYesPET and CTNoT3 N1 M0TX N0 M0TX N0 M0YesPET and CT incorrectNoT2 N0 M0TX N0 M1bTX N0 M1bYesPET and CT incorrectYes (colonoscopy)T2 N3 M1aTX N0 M0TX N0 M1bNoPET and CT incorrectYes (bone MRI)Tis N0 M0TX N1 M1bTX N1 M0NoPET and CT incorrectNo*Each row presents data from 1 of 24 patients. CT indicates computed tomography; PET, positron emission tomography; and MRI, magnetic resonance imaging.COMMENTAccurate initial staging of esophageal cancer is of vital importance in treatment planning for individual patients. Patient stratification into those with early-stage disease, advanced local disease, and metastatic disease mirrors the relative benefit of operative therapy in each group. Clearly, only those patients with early-stage disease have any chance for a long-term cure. Those with advanced local disease (T3 and/or N1) may benefit from neoadjuvant treatment, followed by restaging to rule out disease progression, and then resection if no metastases have developed. Lastly, those who present with distant disease are incurable, and the focus should be on palliation and maximizing the remaining quality of life.This retrospective, nonrandomized study compares the abilities of 2 different imaging modalities to stage the initial cancer. The criterion reference standard had been defined as pathological staging in 67% of cases or follow-up imaging analysis in the other 33%. The 2 most common reasons why patients were not included in the analysis were that no PET scan had been obtained or no pathological or follow-up imaging study was available for comparison. Most likely, these patients underwent initial screening with CT, were found to have obvious metastatic disease, and therefore were never referred for PET scanning. Documentation from the cancer registry demonstrates that for this period 51% of newly diagnosed cancers were stage IV. In this study sample, 50% of patients had stage IV disease, and we feel it is a representative sampling of available cases. Because this was a nonprospective case series, we recognize that the data may have some selection bias; it is possible that patients with earlier-stage disease were not included because a PET scan was not performed. We recognize the possible influence on our results but feel that the patients most likely to not have had PET scans ordered were those with CT evidence of stage IV disease.The status of regional lymph node involvement is only clinically relevant if patients are being considered for neoadjuvant treatment protocols. Otherwise, treatment decisions will be based solely on the determination of M stage status. The 57% and 71% sensitivity of detection of regional lymph node involvement by CT and PET were within the range reported by other investigators.The ability of PET scans to accurately detect involvement of regional lymph nodes has been thought to be limited by the poor spatial resolution of PET scans in which the primary tumor cannot be distinguished from regional nodes.In a study by Rankin et al,the sensitivity for regional node identification was better in CT than in PET. They concluded that PET scans might not have been interpreted in combination with CT scans. In our report, PET scans were most often interpreted with full knowledge of and access to the CT scans. This may account for the higher sensitivity and specificity for PET in detection of regional lymph node involvement. The CT sensitivity and specificity reported here are much better than those reported by Flamen et al.In their extensive study, they report no regional lymph node detection by CT when compared with pathological material from resections. One of the problems with this analysis is that sensitivity was computed by comparing CT data with the actual number of positive nodes found during pathological examination of the esophagectomy specimen. Clinically, this may not be as relevant as determining the global regional nodal status, N1 vs N0, not how many regional nodes are involved. The majority of studies agree that EUS has the highest sensitivity for regional lymph node detection (70%-80%), and its specificity can be improved by combining it with fine-needle aspiration of suspicious nodes if that information is important to treatment planning.In the most important aspect of this analysis, identification of metastatic disease, CT performed better than in other series, with a sensitivity of 83% compared with 41% in the series by Flamen et aland 46% in the series by Luketich et al.The 75% specificity rate is within the range reported in these series. The sensitivity and specificity of the PET scan (67% and 92%, respectively) are within the performance range reported in other studies. Most interesting, we did not find the expected 20% of patients in whom PET scans changed clinical management, primarily by detecting novel sites of metastatic disease.In this series, PET identified a single patient (4%) with a metastasis not identified on CT scan. In contrast, CT identified 3 patients (13%) who had metastases that were not detected on the PET scan. There are some possible explanations for the lack of increased benefit of PET scans in our series. In this series, even though 50% of patients had metastatic disease, the most frequent site was nodal, not hepatic, metastasis, as expected in 35% of new patients. This may represent some selection bias in our institution as to who was referred for PET scanning. In addition, supraclavicular lymph node metastases have been a common site where CT has not demonstrated lesions.In the study by Flanagan et al,5 of 7 patients with metastatic disease had supraclavicular nodes as the distant site, none of which were identified by CT but all of which were visible on PET scans. These lymph node beds may not be captured by CT imaging because the neck is not included in routine CT scans. These nodes are also accessible on physical examination, and none of these studies remark on whether the nodes that were identified on PET scan were palpable. In this series, none of our patients had disease in supraclavicular nodes. Another factor in comparing these results is whether the total number of metastases has been used for calculations of sensitivity and specificity. This can result in higher values when compared with calculations based on the presence or absence of any distant disease. The one clear advantage in this study and others is the ability of a PET scan to identify bone metastases. In this series, 15% of patients had documented bone involvement, and PET was the only imaging modality to identify the metastases. Bone has been recognized as a site for distant disease in up to 15% of patients with esophageal cancer.An interesting observation of our series is that only one third of patients had involved regional nodes in contrast with 50% of patients who presented with M1 disease. Of those who had M1 disease, half had metastases in distant lymph nodes. This illustrates some of the problems in interpreting the literature concerning accuracy in detection. Studies use a variety of definitions of what is considered a regional lymph node. Luketich et aldefined distant lymph nodes as those more than 10 cm from the primary lesion. Block et aldefined nodes as either being "adjacent" or "nonadjacent" by proximity to the primary tumor. Data definition and interpretation also influence how PET scans have been evaluated for detection of distant disease. Many centers have adopted a lesion-specific type of analysis comparing how many specific metastases in each patient were identified by each technique. We chose to address a more binary question in this analysis: Is distant disease present or not? We have adopted this approach because that is the clinically relevant information. Once a patient has been diagnosed with metastatic disease, curative surgical treatment is not an option. We are not sure of the clinical relevance of whether a test shows 3 vs 5 lesions once it demonstrates the presence of any distant spread. Therefore, in this analysis we have applied the AJCC definitions of regional nodes and distant metastases to standardize definitions and recreate scenarios of clinical decision making. With such disparate definitions of regional or distant nodes, it is difficult to compare our data with those of other institutions. We would also encourage strict adoption of the AJCC staging criteria because this is a standard nomenclature that has been used to determine which patients are considered for neoadjuvant or other treatment protocols. We recognize the limitations of this type of retrospective analysis. In a recent editorial about PET scanning, Brennancalled for surgeon-run trials to prospectively evaluate new technology to avoid unrealistic expectations based on early reports. We look forward to the prospective American College of Surgeons Oncology Group trial to define the role of this exciting new imaging modality for esophageal cancer staging. In conclusion, we recommend that initial staging continue to be performed with CT scanning. In those patients with no obvious metastases who are candidates for operations, consider performing a PET scan with prospective data collection to evaluate this technology within your own center.American Cancer SocietyCancer Facts and Figures 2002 [report online].Available at: http://www.cancer.org/downloads/STT/CancerFacts&

Khajanchee, Yashodhan S.; O'Rourke, Robert W.; Lockhart, Barbara; Patterson, Emma J.; Hansen, Paul D.; Swanstrom, Lee L.

doi: 10.1001/archsurg.137.9.1008pmid: 12215150

BackgroundOutcomes in patients having surgery for gastroesophageal reflux disease are most commonly determined by symptomatic assessment. Objective testing is usually reserved for symptomatic patients.HypothesisTo evaluate the relationship between symptomatic and objective outcomes after antireflux surgery.DesignRetrospective analysis of prospectively collected data.SettingA tertiary care teaching hospital with a comprehensive esophageal physiology laboratory.InterventionsA 360° (Nissen) fundoplication or a 270° (Toupet) posterior fundoplication was performed based on esophageal motility. Twenty-four–hour pH monitoring was used as a gold standard for assessing postoperative acid reflux.PatientsTwo hundred nine consecutive patients with preoperative and postoperative symptomatic and objective testing performed between January 1, 1996, and June 15, 2001.Main Outcome MeasuresData on preoperative and postoperative symptoms, DeMeester scores, and esophageal motility were prospectively collected. Objective testing was performed after at least 6 months.ResultsThe preoperative median DeMeester score was 50.0 (interquartile [IQ] range, 30.3-87.0). One hundred eighty patients had a Nissen and 29 patients had a Toupet fundoplication. After a median postoperative interval of 7.7 months (IQ range, 6.7-9.5 months), 174 patients (83.3%) had normal DeMeester scores (median, 2.2; IQ range, 0.8-5.0; P<.001). Of 58 patients (27.7%) who had reflux symptoms after surgery, only 17 (29.3%) had abnormal DeMeester scores (median, 36.9; IQ range, 748.4-20.0; P= .001). Eighteen (11.9%) of the 151 asymptomatic patients had abnormal DeMeester scores (median, 32.5; IQ range, 22.2-57.5; P= .006).ConclusionsThere is poor correlation between postoperative reflux symptoms and actual reflux (abnormal DeMeester scores). Surgeons must be careful to define their terms when reporting success or failure rates after antireflux surgery. Routine use of medical therapy for suppressing postoperative gastroesophageal reflux disease symptoms is not supported by these data, and postoperative therapy should be based on objective testing only.GASTROESOPHAGEAL reflux disease (GERD) is the most common upper gastrointestinal tract disorder in the United States.Most patients with symptomatic GERD are treated empirically with antipeptic medication. Patients who fail or refuse medical therapy, or those with severe mucosal injury, are usually considered to be possible candidates for surgical treatment.Laparoscopic antireflux surgery (ARS) is currently the most common operative approach for the treatment of patients with GERD. Referrals for surgery have dramatically increased since the introduction of laparoscopic approaches for fundoplication. The continued popularity of laparoscopic ARS depends on documentation of good outcomes. Patients and referring physicians have been encouraged by early studiesfrom specialty centers that describe an 87% to 98% success rate. There remains some skepticism in the medical community, however, regarding such excellent outcomes. Specifically, questions are raised about the ability to replicate these results outside of high-volume specialty centers,whether early results will translate into long-term success, and whether the outcomes reported by the investigator are accurate.Recent studies that show a high number of postoperative patients returning to chronic medical therapy are widely cited in the medical community and lay press and underscore the need for a better understanding of postsurgical outcomes.Most studies on outcomes after laparoscopic ARS have been based on symptomatic assessment. Objective postsurgical testing is not considered part of routine follow-upbecause of its cost, the time involved, and, partly, the patient's resistance to these uncomfortable tests. Postoperative testing, therefore, is typically applied only to patients with persistent or recurrent symptoms after surgery or those with preoperative documentation of severe mucosal injury or Barrett esophagus and is usually confined to a single test—usually upper GI tract endoscopy. It is common for symptomatic failures to be reported as "surgical failures" without confirmation using 24-hour pH testing despite the fact that similar symptoms are associated with most upper GI tract disorders.The aim of the present study is to evaluate the accuracy of symptomatic assessment in predicting true failure of surgical treatment.PATIENTS, MATERIALS, AND METHODSPATIENTSPatients were selected from a prospective database of individuals who underwent antireflux procedures between January 1, 1996, and June 15, 2001, at the Department of Minimally Invasive Surgery, Legacy Health System, Portland, Ore. Only patients with typical symptoms of GERD (heartburn, acid reflux, or both), preoperative objective testing confirming GERD, and postoperative objective follow-up with 24-hour pH testing of at least 6 months' duration were included in the study. Patients undergoing antireflux procedures for pure paraesophageal (type II) hernia, mixed paraesophageal (type III) hernia with no preoperative subjective or objective documentation of GERD, achalasia, and a history of a previous fundoplication were excluded. A total of 209 consecutive patients were identified who satisfied inclusion criteria.OUTCOME MEASURESAll preoperative, intraoperative, and postoperative data were recorded prospectively on standardized data collection forms, which were transferred into an electronic database system (Microsoft Access 97; Microsoft Corp, Redmond, Wash). All of the patients were interviewed by one of us (L.L.S.).Baseline demographics and preoperative clinical data were obtained at the first office visit. Symptoms of GERD were recorded on a scale from 0 to 4, with higher values representing greater frequency of symptoms (0 indicates never; 1, once or twice a month but not weekly; 2, once or twice a week but not daily; 3, daily but not continuously; and 4, daily and continuously [all the time]). Data were also recorded on preoperative 24-hour pH testing, manometry, upper GI tract endoscopy, and upper GI tract series. Data on operative time, intraoperative complications, American Society of Anesthesiologists grade, surgeon, and type of procedure performed were acquired at the time of surgery.Patients were followed up after the first week and again at 2 to 6 weeks. At 3 months, patients were asked to complete a symptom assessment form and quality-of-life questionnaire (36-Item Short-Form Health Survey). Six months after surgery, all patients were asked to undergo esophageal manometry and 24-hour ambulatory pH testing at no charge. Symptom assessment forms were administered at each visit. Long-term follow-up of all patients was performed by telephone interview every year using the standardized symptom form, and symptomatic patients returned for further testing.Twenty-four–hour pH testing was used as the gold standard to determine failure of surgical treatment. DeMeester scores greater than 14.7 were considered abnormal. Sensitivity, specificity, and positive and negative predictive values of symptomatic assessment in predicting postoperative acid reflux were determined for typical GERD symptoms. Likelihood ratios for negative and positive symptomatic assessment were calculated to determine the odds of ruling out or ruling in true pathologic reflux. Only symptoms of heartburn or acid reflux or a combination of both were considered typical GERD symptoms as these have been shown to have a significant correlation with the results of 24-hour pH testing.Esophageal manometric data were used to further characterize the outcomes.The means of all continuous variables were compared using appropriate parametric or nonparametric tests. Categorical variables and proportions were compared using the χ2test or the Fisher exact test. A P≤.05 is considered statistically significant. All data are reported as percentage of patients, mean ± SD, or median (interquartile [IQ] range).INTERVENTIONSAll procedures were performed by or under the supervision of one of the senior investigators (P.D.H. or L.L.S.). Five trocars were placed in the upper abdomen. The gastroesophageal junction and mediastinal esophagus were widely mobilized while preserving both vagus nerves. The short gastric vessels were routinely divided. Both crura were approximated posteriorly, and a floppy Nissen fundoplication (360°) was performed if preoperative esophageal motility was normal. In patients with impaired esophageal motility (>50% dropped peristalsis or peristaltic amplitudes <30 mm Hg in all manometry leads), a posterior Toupet fundoplication (270°) was considered. All wraps were fashioned around the esophagus after carefully advancing a 54-58 French bougie into the stomach.Esophageal manometry was performed using an 8-channel water-perfused catheter. The lower esophageal sphincter (LES) was located using a stationary pull-through technique, and the resting LES pressure, LES relaxation, and esophageal body contractility were determined for a minimum of 10 wet swallows. A commercial software program (Synectics/Medtronics, Stockholm, Sweden) was used for the interpretation of manometry tracings and for data analysis.Twenty-four–hour pH testing was performed after discontinuation of all peptic medications for 5 days and by positioning the pH electrode 5 cm above the upper border of the LES. The data were recorded by a portable digital data-logger for 24 hours while the patient was ambulatory and were analyzed for calculating the DeMeester score using a standard software program (GastroSOFT; Synectics/Medtronics).RESULTSOf 209 patients, 109 (52%) were men. The mean patient age and weight were 52 ± 13 years and 85 ± 14 kg, respectively. All of the patients had "typical" symptoms (heartburn and reflux) of GERD before surgery and abnormal 24-hour pH scores. The median preoperative symptom scores for heartburn and acid reflux were 3 (IQ range, 2-4) and 2 (IQ range, 0-3). The median preoperative DeMeester score was 50.0 (IQ range, 30.3-87.0), and the median preoperative LES pressure was 9 mm Hg (IQ range, 5-15 mm Hg). Twenty-seven patients (12.9%) had poor esophageal body motility documented by having more than 50% dropped peristalsis. Four patients had severely hypotensive contractions (<20 mm Hg) in the distal esophagus, and 3 patients had a "nutcracker" esophagus.A Nissen fundoplication was performed in 180 patients (86.1%), and 29 (13.9%) underwent posterior Toupet repair. Mean operative time was 146.7 ± 57.0 minutes, and mean intraoperative blood loss was 66.2 ± 52.0 mL. There were no conversions to open surgery in the series, but 2 patients sustained gastric injuries during surgery. Both injuries were repaired with laparoscopic sutures, and there were no sequelae in either patient. Another patient had blood loss of more than 500 mL from a liver retraction injury but did not require a transfusion.Median follow-up duration for objective testing was 7.7 months (IQ range, 6.7-9.5 months). After surgery, 174 patients (83.3%) had normal DeMeester scores (median, 2.2 [IQ range, 0.8-5.0]; P<.001) and 35 (16.7%) had abnormal DeMeester scores (median, 34.5 [IQ range, 20.4-59.3]). Overall, 58 patients (27.8%) had heartburn or reflux symptoms (grades 1-4) after surgery. Based on the presence or absence of postoperative symptoms and normal or abnormal postoperative DeMeester scores, 4 groups were identified. Of 58 patients (27.8%) with typical GERD symptoms after surgery, 17 (29.3%) had abnormal DeMeester scores (true positive) and 41 (70.7%) had normal DeMeester scores (false positive) (Figure 1A). Of 151 asymptomatic patients (72.2%), 133 (88.1%) had normal DeMeester scores (true negative) and 18 (11.9%) had abnormal DeMeester scores (false negative) (Figure 1B).Figure 1.A, Proportion of patients with normal (n = 41) and abnormal (n = 17) DeMeester sores among postoperative symptomatic patients (n = 58). B, Proportion of patients with normal (n = 133) and abnormal (n = 18) DeMeester scores among postoperative asymptomatic patients (n = 151).No statistically significant differences were found in the demographics, preoperative symptom scores, and preoperative manometry data in the 4 groups. The mean preoperative DeMeester scores were significantly higher in true-positive and false-negative patients compared with the other 2 groups (Table 1). After surgery, DeMeester scores for all patients with documented acid reflux were markedly elevated (median, 36.9 [IQ range, 20.0-48.4] for true-positive patients and 32.5 [IQ range, 22.2-57.5] for false-negative patients). These values were low in patients who had no reflux on objective testing: 2.2 (IQ range, 0.8-5.0) and 2.0 (IQ range, 0.7-3.8) for the true-negative and false-positive groups, respectively. Figure 2and Figure 3illustrate the preoperative and postoperative DeMeester scores of the 4 groups. Patients in all groups showed a significant improvement in LES resting pressure after surgery (P<.001). True-positive patients had the lowest median postoperative resting LES pressure, but there were no statistically significant differences among the 4 groups (Figure 4). Postoperative median symptom scores for reflux and heartburn were 1 (IQ range, 0-1) and 2 (IQ range, 1-3), respectively, in true-positive patients. False-positive patients had a median frequency of 0 (IQ range, 0-1) for reflux and of 1 (IQ range, 0-2) for heartburn. This difference in postoperative symptom scores between the 2 groups was not significant (P= .36). Fifteen patients demonstrated disordered esophageal motility, and 4 patients had evidence of nutcracker esophagus after surgery.Table 1. Preoperative Subjective and Objective Data in 209 Patients*OutcomeMedian (Interquartile Range)Patients, No.Heartburn ScoreReflux ScoreLES Pressure, mm HgDeMeester ScoreNissen FundoplicationToupet FundoplicationTotalTrue positive3 (2-4)2 (1-3)4.5 (0-11.5)99.0 (78.0-157.4)†9817False positive3 (2-4)2 (0-3)9 (7-12.5)41.0 (27.5-68.0)‡37441True negative3 (2-4)2 (0-3)10 (5-16)46.3 (28.6-76.0)11914133False negative3 (2-4)2.5 (1-3)9 (3.5-13.2)71.0 (49.0-114.0)‡15318*LES indicates lower esophageal sphincter.†Value is significantly higher than the true-negative (P<.001) and false-positive (P<.001) groups.‡Value is significantly higher than the true-negative (P= .02) and false-positive (P= .01) groups.Figure 2.Median preoperative and postoperative DeMeester scores in the 4 groups. Preoperative DeMeester scores were significantly higher in the true-positive (P<.001) and false-negative groups (P= .01), and there was no statistically significant difference in the postoperative values between these 2 groups (P= .88). Error bars represent interquartile range.Figure 3.Preoperative and postoperative DeMeester scores for individual patients in the 4 groups. A, True-positive patients (n = 17). B, False-positive patients (n = 41). C, False-negative patients (n = 18). D, True-negative patients (n = 133). P<.001 for all.Figure 4.Median preoperative and postoperative resting lower esophageal sphincter (LES) pressures in the 4 groups. There was significant improvement in each group (P<.001), and there was no significant difference in the postoperative mean LES pressure among the 4 groups (P= .06 for true positive vs true negative; P= .09 for true positive vs false positive; P= .65 for false negative vs true negative; P= .66 for false negative vs false positive). Error bars represent interquartile range.Specificity and sensitivity of postoperative symptomatic assessment were 0.77 and 0.48, respectively, when patients with all grades of symptom severity (grades 1-4) were considered (Table 2). The predictive value of positive symptomatic assessment was only 0.29, and the predictive value of negative symptomatic assessment was 0.88. Specificity was 0.94 when only severe symptoms (daily, grades 3 and 4) were considered; however, sensitivity actually decreased to 0.15 in this case (Table 2). The odds of having pathologic reflux were better when patients having only daily symptoms were considered (likelihood ratio of positive symptoms, 2.85) compared with patients with symptoms of all grades (likelihood ratio of positive symptoms, 2.06). However, the likelihood of ruling out the disease was worse when only patients having daily symptoms were considered (likelihood ratio of negative symptoms, 0.89 vs 0.67) (Table 2).Table 2. Sensitivity, Specificity, Predictive Values, and Likelihood RatiosPatientsSpecificitySensitivityPredictive ValueLikelihood RatioPositiveNegativeFor Negative SymptomsFor Positive SymptomsAll patients (grades 1-4)0.770.480.290.880.672.06Patients having daily symptoms only (grades 3-4)0.940.150.350.850.892.85Nissen fundoplication patients only0.770.380.190.880.811.50COMMENTHeartburn and acid regurgitation are considered to be the cardinal symptoms of GERD.However, these symptoms have been found to have a low specificity and sensitivity for the actual diagnosis of GERD.Long-term pH monitoring of the lower esophagus is the best objective tool for measuring abnormal esophageal mucosal acid exposureand is the most recommended test for confirming the diagnosis of GERD.A 24-hour esophageal pH monitoring system quantifies esophageal mucosal acid exposure and provides this information as several variables.The composite scoring system developed by Johnson and DeMeesterand the total time that the pH is less than 4 provides the best assessment for esophageal acid exposure.We used the composite DeMeester scoring system as a gold standard to evaluate our patients because of its higher accuracy and its applicability to both men and women.In this review of 209 patients with GERD—all with classic symptoms and documented acid reflux—70% of the patients who complained of continued GERD symptoms at intermediate follow-up, in fact, had perfectly normal 24-hour pH values. Furthermore, 18 (11.9%) of the 151 asymptomatic patients had significantly higher DeMeester scores, and no statistically significant difference was found in the mean DeMeester score between this group and the symptomatic patients with abnormal DeMeester scores (P= .88).This study shows that symptomatic assessment has relatively high specificity and a high negative predictive value but low sensitivity and a low positive predictive value for abnormal 24-hour pH study findings in the postoperative setting. Our data demonstrate that postoperative symptomatic assessment is an insensitive tool to diagnose failure of the laparoscopic ARS and has a low predictive value of positive assessment and poor diagnostic accuracy. Specifically, symptoms incorrectly identified many patients as having recurrent or residual GERD who had normal pH values on objective testing. This represents approximately 20% of the patients (n = 41) in our study population with postoperative symptoms suggestive of GERD but normal 24-hour pH test results. There were no statistically significant differences in the postoperative symptom frequency scores between false-positive and true-positive groups. All of the patients in these 2 symptomatic groups demonstrated a decrease in the severity of symptoms and a significant improvement in their resting LES pressure, suggesting good surgical correction.Although the role of 24-hour pH testing has been well recognized as the absolute best test to demonstrate pathologic reflux,recurrent or persistent symptoms after surgery are frequently regarded as failures by surgeons(and more so by their patients) without any objective testing to confirm acid reflux. Most surgeons believe that the primary goal of ARS is to improve quality of life and eliminate the symptoms of GERD.Postoperative testing is usually recommended only in patients with persistent or recurrent symptoms after ARS.It is not offered to asymptomatic patients, as routine testing of these patients seems to be unreasonable, particularly in this era of cost containment. In addition, it is commonly presumed that asymptomatic patients have good physiologic control of acid reflux irrespective of the fact that postoperative GERD-specific symptoms and quality of life have poor correlation with the results of postoperative pH testing.Our results suggest that this approach is not appropriate, since most symptomatic patients after surgery will have no pathologic reflux as determined by pH study, whereas a portion of asymptomatic patients will actually have significant pathologic reflux.The present study is not an outcomes analysis, and the higher subjective and objective failure rates do not represent true outcomes of ARS at Legacy Health System. Although we routinely attempt to have all of our patients return for postoperative objective testing after 6 months, it is our experience that symptomatic patients and patients with severe complicated GERD are more likely to return for postoperative objective testing than asymptomatic patients. There is therefore a selection bias in this study for a group of patients with complicated GERD and recurrent symptoms. It is uncertain what the utility of routine objective assessment might be in the entire population of patients with postoperative GERD.Another drawback of the study is that median follow-up was short (7.7 months). This might explain, however, why postoperative symptoms were noted to be more frequent in patients with worse preoperative disease, which could result from residual or healing esophagitis in patients with severe disease in the short term. With time, such symptoms might resolve or dramatically improve. Regardless of the short follow-up in the present study, early pH testing should still distinguish between such patients and those with inadequate antireflux barriers, and could guide further treatment and minimize the time before appropriate treatment can be initiated.One explanation for at least a portion of patients who are symptomatic with negative pH study findings might be the presence of alkaline reflux. We did not use bilirubin probes to determine whether duodenogastroesophageal reflux might be a component of disease in such patients, but such a tool might be well applied to this subset of patients. At the very least, outcomes studies using endoscopy in this and other subsets of patients might define the degree to which an incompetent antireflux mechanism or complications such as wrap herniation or slipped Nissen fundoplication contribute to their symptoms.Of greater concern are the 12% of patients who are asymptomatic but who had significantly high DeMeester scores after surgery. These patients are certainly at risk of disease progression. Symptomatic assessment does not identify this subgroup, whereas routine postoperative objective testing would allow for early identification of such patients before the onset of severe complications of GERD.Our results, therefore, argue for the use of routine objective testing in the postoperative setting for symptomatic patients, many of whom will not have abnormal reflux on pH testing, and for asymptomatic patients, some of whom will have significant reflux. In addition, these results act as an important guide for physicians involved in the follow-up of patients after ARS. Symptomatic assessment is not an accurate predictor of the presence or absence of recurrent or persistent reflux disease, and it is important for physicians caring for such patients to realize this and to alter diagnostic workup appropriately rather than starting antipeptic medications empirically. Finally, these data have important implications for analysis of the literature addressing the efficacy of ARS. Investigators typically use symptomatic assessment as a primary outcome measure of the competency of the antireflux mechanism after fundoplication. These data suggest that symptomatic assessment is inaccurate and that objective testing should be applied more liberally in the analysis of outcomes after ARS.In conclusion, based on these data, symptomatic assessment seems to be a poor predictor of true pathologic reflux in patients who have had ARS. Postoperative GERD symptoms actually indicate acid reflux in only 30% of patients and are not even accurate to rule out acid reflux in patients who are completely free of symptoms after surgery. This is critical information for all involved in the care of these patients. Surgeons should keep this in mind when interpreting their own results and outcomes literature, most of which relies on symptomatic follow-up. Gastroenterologists and primary care physicians also need to understand that most patients who complain of postoperative reflux or heartburn do not have pathologic reflux. These patients need objective testing to determine the actual cause of their symptoms, with treatment directed specifically to the test findings.JHPetersTRDeMeesterIndications, principles of procedure selection, and technique of laparoscopic Nissen fundoplication.Semin Laparosc Surg.1995;2:27-44.MACarlsonCTFrantzidesComplications and results of primary minimally invasive antireflux procedures: a review of 10 735 reported cases.J Am Coll Surg.2001;193:428-439.JGHunterTLTrusGDBranumJPWaringWCWoodA physiologic approach to laparoscopic fundoplication for gastroesophageal reflux disease.Ann Surg.1996;223:673-685.GPerdikisRAHinderRJLundFRaiserNKatadaLaparoscopic Nissen fundoplication: where do we stand?Surg Laparosc Endosc.1997;7:17-21.DIWatsonGGJamiesonRJBaigrieLaparoscopic surgery for gastro-oesophageal reflux: beyond the learning curve.Br J Surg.1996;83:1284-1287.SJWalkerSTBaxterAIMorrisRSuttonReview article: controversy in the therapy of gastro-oesophageal reflux disease: long-term proton pump inhibition or laparoscopic anti-reflux surgery?Aliment Pharmacol Ther.1997;11:249-260.WJHoganRShakerLife after antireflux surgery.Am J Med.2000;108(suppl 4a):181S-191S.SJSpechlerELeeDAhnenLong-term outcome of medical and surgical therapies for gastroesophageal reflux disease: follow-up of a randomized controlled trial.JAMA.2001;285:2331-2338.AGLittleFailed antireflux operations: pathophysiology and treatment.Chest Surg Clin N Am.1994;4:697-704.JCHorrocksFTde DombalDiagnosis of dyspepsia from data collected by a physician's assistant.BMJ.1975;3:421-423.AGKlauserNESchindlbeckSAMuller-LissnerSymptoms in gastro-oesophageal reflux disease.Lancet.1990;335:205-208.NESchindlbeckCHeinrichAKonigADendorferFPaceSAMuller-LissnerOptimal thresholds, sensitivity, and specificity of long-term pH-metry for the detection of gastroesophageal reflux disease.Gastroenterology.1987;93:85-90.MRuthIManssonNSandbergThe prevalence of symptoms suggestive of esophageal disorders.Scand J Gastroenterol.1991;26:73-81.MCostantiniPFCrookesRMBremnerValue of physiologic assessment of foregut symptoms in a surgical practice.Surgery.1993;114:780-786.RMBremnerCGBremnerTRDeMeesterGastroesophageal reflux: the use of pH monitoring.Curr Probl Surg.1995;32:429-558.PJKahrilasEMQuigleyClinical esophageal pH recording: a technical review for practice guideline development.Gastroenterology.1996;110:1982-1996.JRJamiesonHJSteinTRDeMeesterAmbulatory 24-h esophageal pH monitoring: normal values, optimal thresholds, specificity, sensitivity, and reproducibility.Am J Gastroenterol.1992;87:1102-1111.TRDeMeesterCIWangJAWernlyTechnique, indications, and clinical use of 24 hour esophageal pH monitoring.J Thorac Cardiovasc Surg.1980;79:656-670.TRDeMeesterLFJohnsonGJJosephMSToscanoAWHallDBSkinnerPatterns of gastroesophageal reflux in health and disease.Ann Surg.1976;184:459-470.KHFuchsTRDeMeesterMAlbertucciSpecificity and sensitivity of objective diagnosis of gastroesophageal reflux disease.Surgery.1987;102:575-580.EEypaschENeugebauerFFischerHTroidlLaparoscopic fundoplication for gastro-oesophageal reflux disease (GERD): results of a consensus development conference.Surg Endosc.1997;11:413-426.DWRattnerMeasuring improved quality of life after laparoscopic Nissen fundoplication.Surgery.2000;127:258-263.PMMarkusOHorstmannCKleyTNeufangHBeckerLaparoscopic fundoplication: is there a correlation between pH studies and the patient's quality of life?Surg Endosc.2002;16:48-53.VVelanovichRKarmy-JonesMeasuring gastroesophageal reflux disease: relationship between the Health-Related Quality of Life score and physiologic parameters.Am Surg.1998;64:649-653.Peter F. Crookes, MD, Los Angeles, Calif:I have 4 comments and 4 questions for the authors. The first thing that I would like to do is commend the authors for having studied 209 patients with 24-hour pH after surgery. Anybody who has tried to do this type of work will know what a praiseworthy achievement that is. Many of our patients will say when they are coming back for follow-up that the 24-hour pH was the most horrific component of their entire experience, even worse than the operation itself, and it is difficult to persuade them to undergo it. Maybe in the future the new Bravo probe, which is a wireless 24-hour pH monitor, will make this a little easier for us, but for the time being this is all we have, and I commend the authors for having studied the patients so intensively.The second thing is that this message ought to be carried not just to surgeons but to the wider community of gastroenterologists and family practitioners. It is a very common thing, as the authors probably have found out, for patients to return for follow-up already back on proton pump inhibitors. This seems to be something of a knee-jerk response in the gastroenterology community. The patients go back to their family doctor and they are immediately restarted on Prilosec or Prevacid. Even in my own institution I have had a patient with a total gastrectomy who was put back on Prevacid by one of my own colleagues!So this message ought to be carried back to a wider community and when it is published in the Archives of Surgeryit should be extended or summarized in some of the other AMA journals as well because the striking message is that most people who come back with so-called reflux symptoms do not in fact have failure of the operation due to recurrent reflux.Now the third point I want to make is that even in those patients with postoperative reflux, the reflux that was objectively detected was very much reduced from the reflux they started with preoperatively. These true positives were by and large the most severe refluxers with the lowest sphincter pressures and the highest DeMeester scores, sometimes even 2-300. I don't think I have ever seen a DeMeester score of 300, but obviously those are the worst refluxers. One of the things that interested me in the paper is that if you looked in the tables, you had 180 Nissens and 29 Toupets. But only 8 of the Nissens were in this false-positive group; that was 8 out of 180, which is about a 5% risk, whereas 8 of the 29 Toupets were in the positive refluxing group, which means that if you do a Toupet, there is about a 30% chance that they will come back with reflux. I think this emphasizes the inferior protective ability of partial wraps in patients with severe reflux.I was provided with a copy of the printed paper and I note that you speculate about the possibility of bile reflux. I would just like to make the point that bile reflux on its own as an explanation for symptoms when the 24-hour pH is negative is an unlikely explanation. It is very rare to get bile reflux on its own in the absence of concomitant severe acid reflux.So here are my questions for the authors. If the symptoms of heartburn and regurgitation are so hopelessly inaccurate for diagnosing true reflux postoperatively, is there any symptom which can help you? I would speculate, and I ask if you have data to comment on this, that if patients complain that they are totally unable to belch or unable to vomit, probably they are not going to be refluxers and they will have a negative DeMeester score. I don't know if you have data to support that, but it would be interesting to know.The second thing is if you successfully exclude reflux, which you did in 40 out of your 57 symptomatic patients, the patient may then inquire, "Well, if it isn't reflux, what is it?" You show them this beautiful flat tracing and say, "Look—you have no reflux." I would ask you, what was the cause of their symptoms?My third question is, "Was there any anatomical recurrence? Did any studies, short of having to subject them to 24-hour pH, such as endoscopy or barium studies, tell you the reason why they were having symptoms?"The last thing is that if you are faced now with a patient with extremely severe reflux, for example, with a DeMeester score of more than 100, will you now, as a result of this study, warn the patient ahead of time that they are perhaps going to need to remain on medical treatment afterward? Perhaps they will need to continue their proton pump inhibitor afterward or they will need a Nissen rather than a Toupet. Will the presence of that extremely severe reflux change your operative strategy? Those are my questions.Dr Hansen:Dr Swanstrom, who was going to be answering the questions, was unavailable to be here today. Because I am not a member, Dr Susan Orloff has kindly agreed to come up and formally close the paper. I would like to thank Peter for his very insightful and kind comments, and I will do my best to answer his 4 questions.The first question is, if symptoms such as heartburn and reflux are not terribly helpful, are there other symptoms which are more helpful, and the answer to that is, that is not something that we have evaluated yet. We have a tremendous amount of data in the database. We prospectively collected a series of 30 questions on preoperative symptoms on these patients, and I certainly would agree that an inability to either vomit or to burp is probably an indication that their wrap is mechanically intact, and that may be a clue but we don't have any better symptoms at this point.Second question: If we excluded reflux, then what is causing their symptoms? This is going to be one of our next topics for evaluation. Most of these patients are evaluated. As soon as we hear about a patient who is again refluxing, we bring them back in; we usually go ahead and perform the pH manometry fairly quickly on them. If that looks like it is intact, we would move on to an EGD to look anatomically again at whether or not the wrap looks like it is intact internally. We would probably also move on to studies such as gastric emptying studies and find out if there are other mechanical problems or functional problems which are causing their symptoms. One of the issues may be that certain of these patients, especially the patients who had DeMeester scores in the 200 and 300 range, their esophagi may have been sensitized in a way where they just have very severe symptoms with the smallest amount of acid reflux. They may behave differently than say a patient who has had a DeMeester score of 40 and hasn't had such long-standing or severe disease. Again, that is a question we don't know yet. We may find this out in a future study.Other studies again to look at symptoms postoperatively, again as I have just mentioned would be EGD and gastric emptying and in patients who have quite severe reflux, DeMeester's of 2 and 300, do we warn the patients preoperatively? The answer is yes. We definitely feel that those are the patients who are going to be at the highest likelihood for recurring. If you look at the mean DeMeester scores postoperatively in the patients who were true failures, the average preoperative DeMeester score for those patients was around 80 to 90. The average postoperative score was around 40. So we are making an anatomic improvement in those patients, but it is not enough to get them to be symptom free or into the nonrefluxing category. I hope that answers your question.This paper was presented at the 73rd Annual Meeting of the Pacific Coast Surgical Association, Las Vegas, Nev, February 16, 2002, and is published after peer review and revision. The discussions are based on the originally submitted manuscript and not the revised manuscript.Corresponding author: Lee L. Swanstrom, MD, Department of Minimally Invasive Surgery, Legacy Health System, 501 N Graham, Suite 120, Portland, OR 97227 (e-mail: [email protected]).

Cheek, Julie; Lacy, Judith; Toth-Fejel, SuEllen; Morris, Katherine; Calhoun, Kristine; Pommier, Rodney F.

doi: 10.1001/archsurg.137.9.1015pmid: 12215151

HypothesisPatients who receive hormone replacement therapy (HRT) and subsequently develop breast cancer are more likely to be diagnosed by palpation than mammography and have a higher stage of cancer at initial diagnosis.DesignRetrospective case series.SettingUniversity hospital.PatientsTwo hundred ninety-two patients with breast cancer who were postmenopausal.InterventionsClinical examination, mammography, and definitive therapy.Main Outcome MeasuresHormone replacement therapy use, mode of cancer detection, tumor size, nodal status, stage, and survival.ResultsPatients receiving HRT prior to diagnosis had significantly more incidences of mammographically detected tumors, ductal carcinoma in situ, T1 lesions, negative nodes, and better survival rates than nonusers.ConclusionsA history of HRT use had only beneficial and no discernible adverse effects on breast cancer detection and outcomes. These effects of HRT seem to be due to the development of less aggressive tumors rather than earlier detection.HORMONE REPLACEMENT therapy (HRT) is widely used for the relief of menopausal symptoms as well as for the prevention of osteoporosis. Although HRT is beneficial for these reasons, previous studies have reported an increased risk of developing breast cancer in women who have received long-term HRT prior to diagnosis.Another major concern regarding HRT and breast cancer is that patients receiving HRT will have denser breast tissue,making mammographic detection of tumors more difficult. As a result, tumors in patients who have received HRT would be detected more often by palpation as opposed to screening mammography. Palpable tumors are statistically larger and more likely to be node positive. Thus, women who receive HRT and then develop breast cancer would likely have a worse prognosis. Conversely, patients not receiving HRT will have less dense breast tissue and will be more amenable to mammographic detection of small nonpalpable tumors. These tumors are statistically more often node negative, conferring a better prognosis. Contrary to this belief, studies have demonstrated that patients with breast cancer who have received HRT have a better prognosis than those who have never received HRT.Two theories have been presented to describe the mechanism responsible for a better prognosis in patients with breast cancer who have received HRT. First, some authors advocate the theory that HRT users undergo more frequent screening.Second, others state that patients with breast cancer who have received HRT prior to diagnosis develop tumors that behave less aggressively.The aim of our retrospective review of patients with breast cancer who were postmenopausal was 3-fold: to investigate the relationship between HRT and mammographic detection, to examine the theory that breast tumors in HRT users are biologically less aggressive, and to explore the mechanisms by which a history of HRT use improves survival in women diagnosed as having breast cancer.PATIENTS AND METHODSThe medical records of all postmenopausal women diagnosed as having breast cancer at Oregon Health and Science University (Portland) between March 1994 and January 2002 were reviewed. Women were identified as postmenopausal if they had achieved either natural or surgical menopause. Patients were not excluded if they had a history of breast cancer. Collected data included HRT status at the time of diagnosis, method of breast cancer detection, pathologic TNM staging, hormone receptor status, tumor histologic properties, tumor histologic grade, interval between screening mammograms, family history of breast cancer, and status at last follow-up. Hormone receptor status was classified as positive or negative as interpreted by the pathologist. Positive family history was defined as having 1 or more first-degree relatives diagnosed as having breast cancer.Hormone replacement therapy users were defined as patients who had ever received HRT prior to a diagnosis of breast cancer, or who were receiving HRT at the time of diagnosis. Nonusers were defined as patients who had never received HRT. All HRT doses and modes of delivery were accepted. Permission for the study was received from the institutional review board.Hormone replacement therapy status was correlated with patient age at diagnosis, method of tumor detection (screening mammography vs palpation), primary tumor size, pathologic axillary nodal status, pathologic stage, tumor histologic properties, histologic grade, hormone receptor status, and frequency of screening mammograms. Statistical significance (P≤.05) was determined by the Fisher exact test and χ2analysis. Statistical calculations of differences in tumor size and intervals between screening mammograms between the groups was determined by a ttest. Disease-specific survival was determined by the Kaplan-Meier method. The statistical significance of differences in survival distributions was determined by log-rank analysis.RESULTSThere were 292 patients identified. One hundred forty-four women had received HRT at the time of diagnosis and 148 women had not received HRT. Mean patient age at diagnosis was 66 years (range, 38-96 years). There was no significant difference in age at diagnosis between the groups. Mean patient follow-up was 24 months. The mean and median follow-up times for HRT users were 26 and 22 months, respectively, and for nonusers, 22 and 17 months. The mean and median follow-up times for HRT users with tumors detected by mammography were 27 and 22 months, respectively, and for nonusers, 24 and 20 months. The mean and median follow-up times for HRT users with tumors detected by palpation were 25 and 23 months, respectively, and for nonusers, 22 and 17 months. The mean duration of use among the patients who received HRT was 16 years prior to diagnosis.Hormone replacement therapy users had tumors with significantly better prognostic indicators and significantly better survival rates, reflected by differences in mode of detection. Among HRT users, 84 had detection by mammography and 60 had detection by palpation. Among nonusers, 63 had detection by mammography and 85 had detection by palpation (P= .01). The mean time interval between screening mammograms was 22.4 months for HRT users and 23 months for nonusers (P= .85).The percentage of patients with ductal carcinoma in situ (DCIS) varied with HRT status. Among patients who had received HRT, 23 patients were diagnosed as having DCIS. Among patients who had not received HRT, 14 patients were diagnosed as having DCIS. The difference in the incidence of DCIS cases between HRT users and nonusers was statistically significant (P= .04). There were no significant differences in grade or tumor size of DCIS between the groups (Table 1).Table 1. Comparison of Hormone Replacement Therapy (HRT) Users With Nonusers for All Breast Cancer CasesHRT*No HRTPValueOverall cases144 (49)148 (51).01Detected by mammography84 (58)63 (43)Detected by palpation60 (42)85 (57)Ductal carcinoma in situ23 (16)14 (9).04Detected by mammography1910.10Detected by palpation44.25Invasive tumors121 (84)134 (91).04Detected by mammography6553.10Detected by palpation5681.25Stage I tumors68 (56)54 (40).02Detected by mammography4429.05Detected by palpation2425.05T1 lesions84 (69)72 (54).02Detected by mammography5234.03Detected by palpation3238.07Node-negative tumors87 (72)81 (60).02Detected by mammography5441.14Detected by palpation3340.08Family history (mammographically detected invasive tumors)Positive family history12 (18)11 (21).18No family history33 (51)23 (43).11*Data are given as number (percentage) of patients unless otherwise indicated.There were significantly fewer cases of invasive breast tumors among HRT users (P= .04). Additionally, there were significantly higher incidences of T1 lesions, stage I tumors, and node-negative tumors among this group of patients (Table 1).There were no significant differences in overall mean tumor size, number of positive nodes, hormone receptor status, histologic grade, and incidence of stage IV tumors based on HRT status (Table 1and Table 2).Table 2. Comparison of Pathologic Characteristics of Invasive Breast Cancer Tumors Between Hormone Replacement Therapy (HRT) Users and Nonusers*HRTNo HRTPValueInvasive tumor cases detected by mammographyWell differentiated24 (37)16 (30).12Moderately differentiated23 (35)18 (34).15Poorly differentiated9 (14)14 (26).04Unknown9 (14)5 (9).18Invasive tumor nodal statusNegative87 (72)81 (60).02Positive32 (26)52 (39).01Hormone receptor statusNegative19 (13)25 (17).11Positive95 (66)108 (73).11Unknown30 (21)15 (10).002Invasive tumor size, cm<2 (T1)84 (69)72 (54).02>2 (T2 + T3)20 (17)52 (39)<.001Mean2002.39.07*Data are given as number (percentage) of patients unless otherwise indicated.Among mammographically detected tumors, there was a significantly lower incidence of poorly differentiated tumors in HRT users (Table 3). There was no significant difference in the incidence of positive family history of breast cancer between the HRT users and nonusers among mammographically detected tumors (Table 1).Table 3. Summary of Statistically Significant Differences in Breast Cancer Cases Between Hormone Replacement Therapy (HRT) Users and Nonusers*HRTNo HRTPValueMethod of detection.01Mammography84 (58)63 (43)Palpation60 (42)85 (57)Ductal carcinoma in situ23 (16)14 (9).04Invasive tumors121 (84)134 (91).04T184 (69)72 (54).02T2 + T320 (17)52 (39)<.001Node negative87 (72)81 (60).02Stage I tumors68 (56)54 (40).02Invasive tumors detected by mammographyT1 lesions52 (80)34 (64).03Poorly differentiated tumors9 (14)14 (26).04*Data are given as number (percentage) of patients unless otherwise indicated.All disease-specific deaths occurred in patients with invasive tumors. Figure 1shows the survival curves for patients with mammographically detected tumors and for patients with tumors detected by palpation. The 6-year survival rate for patients with mammographically detected tumors was 94%, compared with 78% for patients with palpable tumors (P= .02). The 6-year survival rate for HRT users was 92% compared with 80% for nonusers (P= .05) (Figure 2). Figure 3shows survival curves for patients with tumors detected by palpation. The 6-year survival rate was 79% for HRT users compared with 76% for nonusers (P= .57). For patients with mammographically detected tumors, the 6-year survival rate for HRT users was 100% compared with 87% for nonusers (P= .03) (Figure 4). No differences were observed in any of the survival curves, and there were no changes in any survival-related Pvalues when DCIS cases were included in or omitted from the analysis.Figure 1.Survival curves of patients with mammographically detected tumors (n = 118) and tumors detected by palpation (n = 137); P= .02.Figure 2.Survival curves for hormone replacement therapy (HRT) users (n = 121) compared with nonusers (n = 134); P= .05.Figure 3.Survival curves for patients with palpable tumors comparing hormone replacement therapy (HRT) users (n = 56) with nonusers (n = 81); P= .57.Figure 4.Survival curves for patients with mammographically detected tumors comparing hormone replacement therapy (HRT) users (n = 65) with nonusers (n = 53); P= .03.COMMENTOur series demonstrated that patients who had received HRT had significantly more mammographically detected tumors, a finding that has been reported by others.Conversely, more nonusers had tumors that were diagnosed by palpation.Some authors have explained this finding as being due to more frequent screening in HRT users. For example, patients receiving HRT might be required to obtain annual screening mammograms as a prerequisite to continuing their HRT, whereas no such demand would be placed on patients not receiving HRT.However, our data show that the mean interval between screening mammograms was essentially the same between the groups. In fact, we found the average time interval between screening mammograms to be close to 2 years, as opposed to annually, in both groups. Thus, the increased frequency of mammographically detected tumors among HRT users cannot be attributed to an increased frequency of screening mammograms.Other investigators have reported increased incidences of favorable prognostic features in the tumors of patients who had received HRT. Numerous authors have reported increased numbers of T1 lesions,node-negative tumors,and lower clinical stage at diagnosisin patients with breast cancer who had received HRT. Our data show an increased frequency of T1 lesions, node-negative tumors, and stage I tumors among patients who had received HRT. We also found more cases of DCIS among the HRT users. Conversely, we observed significantly more T2 and T3 lesions among patients who had not received HRT.In our study, these parameters translate into better survival rates for patients with invasive cancer who had received HRT prior to their diagnosis. Other authors have also reported a better prognosis for patients with breast cancer who have received HRT.However, most authors have attributed this better prognosis among HRT users to earlier diagnosis by mammographic detection. Few have considered the possibility that HRT causes tumors to be less aggressive.All of our findings, as well as those of other authors, support the hypothesis that HRT induces a more biologically favorable tumor. When we compared survival between groups of patients with mammographically detected invasive tumors, there was a significant improvement in survival among HRT users. Hormone replacement therapy users had a 100% survival rate at 6 years as opposed to 87% in nonusers. Both groups of tumors were detected by screening mammography, thus detected "early" by current convention. Yet, we observed a survival benefit for those women who had received HRT. We feel that this demonstrates that the differences in outcome are more likely due to the development of less aggressive tumors in HRT users rather than earlier detection by mammography. Hormone replacement therapy was associated with fewer palpable tumors and more mammographically detected tumors as well as more DCIS and less invasive tumors. Although it appears from Figure 3that there was no survival benefit from HRT on palpable tumors, it is critical to note that HRT significantly diminished the number of palpable tumors.To identify the mechanism by which HRT effects these changes, we compared hormone receptor status, tumor histologic properties, and tumor grade between HRT users and nonusers. In concordance with other investigators,we did not find a higher incidence of hormone receptor–positive tumors in our HRT group. We found no significant difference in the frequency of histologic subtypes of breast cancer between the groups. In contrast to other studies, we did not find a higher incidence of well-differentiated tumors among HRT users.We did find significantly fewer poorly differentiated invasive tumors detected by mammography among HRT users, a finding that is supported by other authors.Thus far, there have been no consistent findings that would indicate a clear mechanism by which HRT improves the outcome of breast cancer.Our results have important implications for studies that examine the impact of HRT after a diagnosis of breast cancer. Some studies have reported decreased mortality rates among patients who received HRT after diagnosis and treatment of breast cancer.These studies were not controlled for HRT use before the diagnosis of breast cancer. In one study,68% of patients receiving HRT after a diagnosis of breast cancer had also received HRT prior to their diagnosis. In contrast, only 47% of patients who did not receive HRT after a diagnosis of breast cancer had received HRT prior to their diagnosis. Our study shows an improvement in outcome when HRT was received prior to diagnosis. Therefore, it may be that the patients who received HRT after breast cancer treatment developed low-risk tumors as a result of receiving HRT prior to diagnosis. It is possible that the observed improved survival of patients who received HRT after a diagnosis of breast cancer may be due to HRT use before the diagnosis of breast cancer. Accordingly, future studies of HRT use in patients with a history of breast cancer should be controlled for HRT use prior to diagnosis.The Lancetmeta-analysisshowed that the absolute improvements in survival rates with adjuvant therapy were, at most, 4% for node-negative tumors and 8.6% for node-positive tumors at 10-years' follow-up. The absolute difference in survival rates observed between patients receiving HRT and patients not receiving HRT was 13% at 5 years. Thus, the absolute difference in survival rates cannot be explained by differences in the use of any known adjuvant therapies.Hormone replacement therapy has multiple favorable effects on breast cancer, resulting in a better outcome. We propose that these effects are due to a biological effect rather than early detection. While the mechanism of this beneficial effect of HRT on breast cancer is unclear, we did not demonstrate that it is due to an increased frequency of hormone-sensitive tumors or differing tumor histologic properties or grades.In this study, HRT had only beneficial and no discernible harmful effects on breast cancer detection or outcome. Fears of decreased mammographic detection of breast cancer in patients who received HRT prior to diagnosis were not substantiated in this study. In addition, concern that HRT induces aggressive tumor progression was refuted by improved survival rates. It is plausible that the beneficial effects of HRT on breast cancer could outweigh its reported risk of a slight increase in the incidence of the disease. These findings provide physicians with useful data when counseling patients on the risks and benefits of HRT with respect to breast cancer.PKenemansFScheeleCWBurgerHormone replacement therapy and breast cancer morbidity, mortality and recurrence.Eur J Obstet Gynecol Reprod Biol.1997;71:199-203.HOlssonABladstromCIngvarTRMollerA population-based cohort study of HRT use and breast cancer in southern Sweden.Br J Cancer.2001;85:674-677.JManjerJMalinaGBerglundLBondesonJPGarneLJanzonIncreased incidence of small and well-differentiated breast tumours in post-menopausal women following hormone-replacement therapy.Int J Cancer.2001;92:919-922.Collaborative Group on Hormonal Factors in Breast CancerBreast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer.Lancet.1997;350:1047-1059.ELundstromBWilczekZvon PalffyGSoderqzvistBvon SchoultzMammographic breast density during hormone replacement therapy: differences according to treatment.Am J Obstet Gynecol.1999;181:348-352.MBLayaEBLarsonSHTaplinEWhiteEffect of estrogen replacement therapy on the specificity and sensitivity of screening mammography.J Natl Cancer Inst.1996;88:643-649.MBLayaJCGallagherJSSchreimanEBLarsonPWatsonLWeinsteinEffect of postmenopausal hormonal replacement therapy on mammographic density and parenchymal pattern.Radiology.1995;196:433-437.AMKavanaghHMitchellGGGilesHormone replacement therapy and accuracy of mammographic screening.Lancet.2000;355:270-274.TJAndersonEffects on breast tissue of exogenous oestrogens and progesterons.Acta Obstet Gynecol Scand Suppl.1986:134:9-13.PCStomperBJVan VoorhisVARavnikarJEMeyerMammographic changes associated with postmenopausal hormone replacement therapy: a longitudinal study.Radiology.1990;174:487-490.ZKaufmanWIGarstinRHayesMJMichellMBaumThe mammographic parenchymal patterns of women on hormonal replacement therapy.Clin Radiol.1991;43:389-392.JEBerkowitzOMGatewoodLEGoldblumBWGaylerHormonal replacement therapy: mammographic manifestations.Radiology.1990;174:199-201.MMMcNicholasJPHeneghanMHMilnerTTunneyJBHourihaneDPMacErlainePain and increased mammographic density in women receiving hormone replacement therapy: a prospective study.AJR Am J Roentgenol.1994;163:311-315.KHolliJIsolaJCuzickLow biologic aggressiveness in breast cancer in women using hormone replacement therapy.J Clin Oncol.1998;16:3115-3120.RCDelgadoDMLLopezPrognosis of breast cancers detected in women receiving hormone replacement therapy.Maturitas.2001;38:147-156.CGajdosPTartterABabinszkiBreast cancer diagnosed during hormone replacement therapy.Obstet Gynecol.2000;95:513-518.ESO'MearaMARossingJRDalingJGElmoreWEBarlowNSWeissHormone replacement therapy after a diagnosis of breast cancer in relation to recurrence and mortality.J Natl Cancer Inst.2001;93:754-762.PBonnierFBessenayAJSascoImpact of menopausal hormone-replacement therapy on clinical and laboratory characteristics of breast cancer.Int J Cancer.1998;79:278-282.HJernstromJFrenanderMFernoHOlssonHormone replacement therapy before breast cancer diagnosis significantly reduces the overall death rate compared with never-use among 984 breast cancer patients.Br J Cancer.1999;80:1453-1458.BFowbleAHanlonGFreedmanPostmenopausal hormone replacement therapy: effect on diagnosis and outcome in early-stage invasive breast cancer treated with conservative surgery and radiation.J Clin Oncol.1999;17:1680-1688.MMBilimoriaDJWinchesterSFSenerGMotykieULSehgalDPWinchesterEstrogen replacement therapy and breast cancer: analysis of age of onset and tumor characteristics.Ann Surg Oncol.1999;6:200-207.MWBeckmannDJapSDjahansouziHormone replacement therapy after treatment of breast cancer: effects of postmenopausal symptoms, bone mineral density and recurrence rates.Oncology.2001;60:199-206.AGWileRWOpfellDAMargilethHormone replacement therapy in previously treated breast cancer patients.Am J Surg.1993;165:372-375.PJDiSaiaWRBrewsterAZiogasHAnton-CulverBreast cancer survival and hormone replacement therapy: a cohort analysis.Am J Clin Oncol.2000;23:541-545.Early Breast Cancer Trialists' Collaborative GroupSystemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy.Lancet.1992;339:1,71.Nathalie Johnson, MD, Portland, Ore:This is a very interesting and quite timely paper. Every day I discuss hormone replacement therapy with women who worry about the risk of breast cancer. Many are taking replacement for qualify of life issues, but they do it with an underlying discomfort because of the attendant risk of developing malignancy of the breast. Of course, the next group of patients we encounter are the breast cancer survivors who are dealing with estrogen withdrawal and are searching for answers about use of any hormonal replacement, be it vaginal creams or phytoestrogens.We know that estrogen works at the cellular level to promote the production of growth factors like transforming growth factor α and epidermal growth factor. In addition, it decreases the production of growth inhibitors like transforming growth factor β. Some of estrogen's predilection to encourage malignant degeneration may be mediated by amplification of cell regulatory proteins called cyclins, which encourage abnormal growth by allowing cells to continue through the cycle unchecked and escape normal growth control. This could share similarities with the oncogene protein product HER-2-neu.This brings me to my first question for the authors. In your study, you did not find significant differences in tumor differentiation or hormone receptor status between HRT users and nonusers. Did you collect data on HER-2-neu or p53, and, if not, are you planning to pursue this? If there are differences in the oncogene protein products, it may offer some clues for further study. You also found a trend towards more poorly differentiated tumors in non-HRT users. Were patients in this group younger, and did you find any association with oral contraceptive use?As you stated, mammography in women on hormone replacement has been touted to be more difficult to interpret. Your study was in agreement with others in that there was a higher incidence of tumor detection by mammography in HRT users. The argument that HRT users are screened more frequently also did not hold up in your study, as they were screened at the same interval. Interestingly though, far more palpable tumors developed in the non-HRT group over the same screening interval, which would intuitively suggest that this group of patients had biologically more rapidly growing tumors. You did not control for S-phase, but Holli et al published a study in the Journal of Oncologyin which they did find a statistically significant lower S-phase in patients on HRT.You also found far more DCIS in your HRT users. All of these findings would support your conclusion that HRT seems to lend towards a biologically less aggressive breast malignant transformation. I would ask the authors for their theories on how this may occur and ask what might be some next steps in solving this interesting dilemma.William H. Goodson, MD, San Francisco, Calif:First, it is great that somebody else is looking at the issue of how breast cancer is diagnosed. You can't say often enough that even when you are using mammography, a very large proportion of patients' cancers are first found at palpation. We tend to underestimate the value of palpation; that is very important.I wonder, however, about your results for several reasons. First, only about half of your total patients were first identified by mammography, which is considerably lower than what has been reported in other series. For example, a recent series from the Massachusetts General by Michaelson found that 58% of breast cancers were found by mammography. Our own series has found about 59% by mammography. I am trying to figure out why you have just a hair over half found by mammography. So my first question is why do you think this is so low?My second question is whether this may be related to mode of practice. Were these patients seen by gynecologists? Were they seen by persons who would routinely get a mammogram before an office visit? If you are thinking about that question, and particularly if you are trying to assign a biological meaning to this, the basic question is not whether cancers were first found by mammogram but whether—at the time of diagnosis—did they have a positive mammogram or not? If a physician's practice is to have the patient get the mammogram before they come to the office, some will more often be found first by mammography. However, that doesn't tell you anything about the biology. You have to know whether or not your proportion of cases that had a positive mammogram was actually different in those on HRT or not, because if the proportion is the same, then it is necessary to rethink whether there is a biological effect or not.John A. Butler, MD, Orange, Calif:I have a question concerning your use of the term screening mammography. I noticed that in terms of the patients who were getting mammograms, the mean time was approximately 2 years for both groups. For most postmenopausal women, screening mammography is used yearly. So either the women of Portland were ahead of the curve in terms of the current controversy about the utility of screening mammograms, or maybe some of these people were not actually getting screening mammograms but were getting intermittent mammograms, and I wonder if you have that data concerning how many of these women were actually getting yearly mammograms.The other issue I have is your last result, which talks about the beneficial effects of hormone replacement therapy on breast cancer. You're talking about breast cancers that you diagnosed but you don't really have the denominator in terms of the number of women on hormone replacement and the number of women who are not on hormone replacement who are at risk. Rather than your results showing the benefits of hormone replacement, I think it shows that if you have breast cancer, you are better off if you've had a long history of hormone replacement therapy, which may predict for a more benign clinical course.Steven N. Parks, MD, Fresno, Calif:My questions also relate to the beneficial effects. Since you have shown "a beneficial effect" of hormone replacement on breast cancer, when you see someone with breast cancer today, are you stopping their hormone replacement?The second question is a little more provocative. If in fact it is "beneficial," are you starting hormones when you diagnose breast cancer?I. Benjamin Paz, MD, Duarte, Calif:The questions you bring up are very important. But I have a problem with how you define having ever received hormonal replacement. It's very hard and when you look at all of the studies of hormone replacement, they have the problem of quantifying the amount of estrogen taken. I cannot believe that a woman who took 20 years before estrogen is the same as the woman that is taking current estrogen replacement with Premarin. This could all be circumstantial evidence. A study that looks forward and with a collection tool that really documents how estrogens were used prospectively would probably show that women that did not receive estrogen; with the use of a tool, you will find that many of those women took estrogen and you probably did not know it.David Z.J. Chu, MD, Duarte:I have 2 questions that may help decide whether the findings are due to early detection or a different biology. One is the family history. Are there any differences in terms of family history of breast cancer? The second, the mammographic detection: the time interval has been the same but the real issue is the time of the last mammogram before the diagnosis.Ronald G. Latimer, MD, Santa Barbara, Calif:An observation and then a couple of questions. Some of us are old enough in this room to remember that estrogen was used as adjuvant hormone therapy and a third of breast cancer patients had a remission given just plain estrogen. That was done a long time ago and obviously is not in the present.My question is, with hormone replacement therapy, ie, estrogen and progesterone, did you break it down in those women who were only taking estrogen vs those who were taking the combination? In addition, we do not have a range of how long they were taking the medication from 1 day to 12 years. What is the range?Theodore X. O'Connell, MD, Los Angeles, Calif:I have a question about the design of the study. At the beginning of the talk you said the outcome is better with tumors discovered by mammogram rather than palpation. Obviously patients who have smaller tumors will do better, but those same patients could have had a mammogram 3 months before that was negative and then you discover a palpable tumor. So the only way that you can prove that screening mammograms are good is to have 2 different groups, one a control group not having mammograms and one having a screening mammogram and showing that the outcome is different between the 2 groups. It's the same thing with the study. The only way that you can come to sound conclusions is to have a prospective randomized study with half the women having estrogen replacement and the other half not, and seeing any outcome differences. Otherwise it becomes very difficult to decipher the data.Dr Pommier:To answer Dr Johnson's questions, HER-2-neu was not routinely determined at OHSU until the very end of the study period because it had no therapeutic implications before the advent of herceptin therapy.The poorly differentiated tumors were evenly distributed by age. There were significantly fewer poorly differentiated tumors among women receiving HRT who had mammographically detected tumors but not palpable tumors. We did not look at the role of OCPs. This was a study designed to look at the impact of HRT taken after menopause.Our overall percentage of mammographically detected tumors is about 50%, which is close to the national average. This is an average that results from a 40% rate among the non-HRT group, and a 60% rate in the HRT group. If one's practice has a higher percentage of mammographically detected tumors, then it might mean that there were many women taking HRT in that region.If patients were referred to us with a palpable lump, then the next step would be to get a diagnostic mammogram. Virtually all of the palpable tumors were seen on mammography. However, very few of the tumors that were detected by mammography were palpable by the clinician on concurrent examination.The mammograms should be considered as screening mammograms even if they weren't done annually. I don't think we are achieving the goal of annual mammography anywhere in the country. Even if you look at the data from Sweden, where they have national health care and every woman will have a mammogram paid for annually, the average interval between screening mammograms is actually 18 months. No one is meeting the goal of annual screening mammography for all patients.We currently do tell patients diagnosed with breast cancer to stop their HRT in order to comply with current standards of care and tamoxifen therapy. One of the next steps will be to try to give HRT back to patients after a diagnosis of breast cancer. It is absolutely correct that high-dose estrogen was an effective treatment for breast cancer before tamoxifen, and those who don't know the history of breast cancer treatment are doomed to repeat it.The history of HRT use was consistent and stable. We strived very hard to get these data, and we found them to be simpler than we thought. Essentially, women started HRT at menopause and they continued it for an average of 16 years. The average age at diagnosis was 66, so they essentially took it from the onset of menopause until they had a diagnosis of breast cancer. The other half of the patients were pure nonusers. So the data are really very clean in terms of users and nonusers. In addition, we haven't yet correlated specific HRT regimens with outcomes.The number of patients who had a positive family history was also evenly distributed between the HRT users and the nonusers. There appears to be a significant number of patients who, even though they had a positive family history of breast cancer, decided to use it.I can address all of the remaining questions with the following closing remarks. Recently, there has been a great deal of publicity in the press about the Danish study that concluded that there may be no benefit of screening mammography in women with invasive tumors. These findings are disconcerting because they imply that our pathognomonically Halstedian concept of early detection simply doesn't work. The results of our study persuade me to believe that may actually be true. We need a new paradigm to better fit the data. Perhaps women with mammographically detected tumors don't have better survival because their tumors are caught earlier, as we have all been led to believe, but simply because they are biologically less aggressive tumors than palpable tumors. They are distinctly different than palpable tumors. Intuitively, this should already make sense to us. We have all seen patients with the so-called interval tumors that present as a palpable lump within a few months of a normal mammogram and a normal examination. We know that those tumors are aggressive and that those patients don't do well. The opportunity for early detection in those patients never really existed. Perhaps mammographically detected tumors are a certain percentage of all breast cancers. Intuitively, that also ought to make sense. Nobody seems to question that inflammatory breast cancers are a mere 4% of all cancers. If this is the case, then screening mammography is not the appropriate strategy for changing outcomes because mammograms do nothing to alter that preexisting proportion of mammographically detected tumors.This leaves little that can be done to affect outcomes. However, our study implies that there is something that can be done to affect the outcomes for postmenopausal women and that is to allow them to receive HRT. This actually increases the proportion of mammographically detected tumors. It increases the percentage of well-behaved tumors, as reflected by the increased number of T1 lesions, node-negative tumors, and stage I tumors. All of this is translated into better survival for patients who received HRT.This isn't a matter of early detection. It's a biological effect. All of the benefit of HRT was confined to the group of patients with mammographically detected tumors. All of the mammographically detected tumors would be considered as having been detected early, in the Halstedian concept, by our current standards. Yet, there is an enormous survival advantage seen among the women who took HRT. This isn't due to selection of more hormone-sensitive tumors. There are actually more patients with ER-/PR tumors in the group with mammographically detected tumors that took HRT than in the group that didn't take HRT, but still, the HRT group had absolutely perfect 6-year survival. HRT didn't impact the palpable tumors, which supports the concept that they are different.We simply don't yet know what causes this. The scope of our study was limited in that respect. Whatever the mechanism of HRT, the effect is profound. It yields a 13% improvement in absolute, not relative, survival rates and this is even extended to patients with ER-/PR-tumors. Both effects are more than can be expected from tamoxifen, whether it is adjuvant or preventative.The next step is to look at genetic microarrays, comparing the genes and tumor markers, as Dr Johnson suggested, that are activated between the tumors of patients who are receiving HRT and those who are not, and between mammographically detected tumors and palpable tumors. Probably, that will tell us what the HRT does that is so favorable; possibly, it will tell us what we can do to also improve the outcomes for patients with palpable tumors. Hopefully, it will lead to better treatment and outcomes for all breast cancer patients.This paper was presented at the 73rd Annual Meeting of the Pacific Coast Surgical Association, Las Vegas, Nev, February 17, 2002, and is published after peer review and revision. The discussions are based on the originally submitted manuscript and not the revised manuscript.Corresponding author and reprints: Rodney F. Pommier, MD, 3181 SW Sam Jackson Park Rd, L223A, Portland, OR 97201 (e-mail: [email protected]).

Sheldon, David G.; Lee, Faye T.; Neil, Nancy J.; Ryan, Jr, John A.

doi: 10.1001/archsurg.137.9.1022pmid: 12215152

HypothesisThe surgical treatment of primary hyperparathyroidism results in an improved health-related quality of life.DesignProspective cohort analysis of consecutive patients with primary hyperparathyroidism analyzed preoperatively and 1 year postoperatively.SettingAcademic multispecialty referral clinic.PatientsWe prospectively evaluated 74 consecutive patients who underwent parathyroid exploration for primary hyperparathyroidism during a 15-month period.InterventionsThe Medical Outcomes Study Short-Form Health Survey (SF-36) was administered before consultation with a surgeon. Patients were categorized based on reason for referral as either asymptomatic (group 1; n = 43) or symptomatic (group 2; n = 29). All patients underwent parathyroid exploration and normalization of calcium levels postoperatively. The SF-36 was then re-administered after 1 year.Main Outcome MeasuresStatistical analysis of preoperative and postoperative SF-36 scores, and comparisons with national norms.ResultsThe SF-36 was completed preoperatively and 1 year postoperatively by 72 (97%) of 74 patients. When the results were compared with published national norms, the preoperative population was significantly impaired in 5 of 8 domains, whereas the postoperative one had improved and was nearly indistinguishable from the norm. In 7 of 8 domains, the postoperative scores were significantly improved compared with preoperative scores. Group 1 patients showed significant preoperative impairment in 3 domains and significantly improved in 2, whereas group 2 patients showed significant impairment and improvement in 7 domains.ConclusionThe surgical treatment of primary hyperparathyroidism is associated with durable, statistically significant improvements in health-related quality of life.THE MORBIDITY of primary hyperparathyroidism can range from subtle to severe. Primary hyperparathyroidism is associated with nephrolithiasis, osteoporosis, peptic ulcers, pancreatitis, renal failure, cardiovascular disease, and premature death.Patients without classic symptoms may experience hypertension, depression, and a host of nonspecific neuromuscular symptoms including fatigue.All of these conditions may be reversible with a successful parathyroidectomy.Despite the fact that operation for primary hyperparathyroidism offers the benefit of a cure with minimal morbidity, there is continued controversy concerning the need for intervention in the mildly symptomatic patient. Indications for operative intervention in the asymptomatic patient were proposed at the 1991 National Institutes of Health (NIH) Consensus Development Conference.The conference did not address the neuropsychiatric manifestations of the disease or the health-related quality of life in primary hyperparathyroidism.We believe that most patients with primary hyperparathyroidism have an impaired health-related quality of life. Our hypothesis was that a successful parathyroid operation would improve functional health status. We studied health status before and after parathyroidectomy in all patients referred for primary hyperparathyroidism. The Medical Outcomes Study Short-Form Health Survey (SF-36),a multidimensional health assessment tool, was used to objectively document patients' functional status and compare quality of life with national norms.PATIENTS AND METHODSSeventy-four consecutive patients who were referred to a single surgeon for primary hyperparathyroidism were prospectively studied during a 15-month period. No patient with the diagnosis of primary hyperparathyroidism was excluded. Prior to an initial surgical consultation, informed consent was obtained for study purposes, and patients completed the SF-36. The SF-36 is designed to assess overall functional status and well-being for adult patients compared with age-matched US population norms. The form has 36 questions that assess 8 specific health domains: general health perception, physical function, social function, role limitations attributed to physical problems, role limitations attributed to social problems, bodily pain, mental health, and energy/fatigue. This instrument was selected because it is practical, well suited for clinical use, and inexpensive and has been validated in a variety of disease conditions in adults, including primary hyperparathyroidism.A medical history, physical examination, and appropriate serum and/or urine chemistry values confirmed primary hyperparathyroidism in all patients. All of them underwent preoperative localization studies similar to our previously described protocol.Patients were categorized into 2 groups based on the characterization of their hyperparathyroidism by their referring physician. Group 1 patients were thought to be without symptoms attributable to this condition. We labeled this group "asymptomatic." Group 2 patients were referred by their physician for classic symptoms of hyperparathyroidism. We labeled this group "symptomatic."Parathyroid exploration was then performed in all patients. Type of operative procedure, pathologic results, postoperative morbidity, length of hospital stay, and postoperative serum calcium levels were recorded. One year following the procedure, a second SF-36 questionnaire was mailed to the patient and returned for analysis. Preoperative and postoperative responses were pooled and compared with age-matched national norms. In each domain of the SF-36, we established a 95% confidence interval (±1.96 SEM) based on the scale score for the norm. Statistical significance was defined as a pooled patient score falling outside of the 95% confidence interval in each domain.Quantitative analysis of each patient's preoperative and postoperative SF-36 responses was accomplished using paired comparisons with the Wilcoxon rank sum test.RESULTSThe study population included 72 (97%) of 74 patients who completed both the preoperative and postoperative SF-36 questionnaires. Group 1 (asymptomatic) had 43 patients, and group 2 (symptomatic) had 29 patients. The total population consisted of 21 men and 51 women, with a mean age of 61 years. The type of procedure performed was 4-gland exploration in 27 patients (37%), unilateral neck exploration in 38 patients (53%), and minimally invasive 1-gland exploration in 7 patients (10%). No perioperative complications occurred, and all patients were discharged from the hospital either on the day of their operation or the next morning. The pathologic findings were as follows: 66 solitary adenomas (92%), 4 double adenomas (6%), 1 case of 4-gland hyperplasia (1%), and 1 case of 5-gland hyperplasia (1%). Postoperative serum calcium levels were normalized in 73 (99%) of 74 patients. One patient required a second procedure after unilateral neck exploration to remove an unexpected contralateral adenoma.The reasons for referral to the surgeon are outlined in Table 1. The most common reason for referral was osteoporosis as indicated by an abnormal result on a dual-energy x-ray absorptiometry (DEXA) scan (32/43, or 74% of the patients in group 1).Table 1. Primary Reason for Referral to a Surgeon*No. of PatientsGroup 1: asymptomatic (n = 43)Abnormal DEXA scan result32Persistent hypercalcemia8Young age (<50 y)3Group 2: symptomatic (n = 29)Nephrolithiasis11Fatigue10Mental status changes3Life-threatening hypercalcemia2Fracture2Thirst and polyuria1*Some patients had multiple reasons for referral. The table lists what the referring physician perceived was the primary indication for parathyroidectomy. DEXA indicates dual-energy x-ray absorptiometry.Compared with age-matched national norms, the preoperative study population demonstrated significant impairment in functional health in 5 of 8 domains of the SF-36: physical function, physical role limitations, social function, bodily pain, and energy/fatigue (Table 2). Postoperatively, however, the study population improved and was nearly indistinguishable from the age-matched norms for the general US population. Table 3demonstrates that group 1 (asymptomatic) was significantly impaired preoperatively compared with national norms in 3 domains: physical function, physical role limitations, and energy/fatigue. Table 4demonstrates that group 2 (symptomatic) was significantly impaired preoperatively compared with national norms in 7 of 8 domains: general health perception, physical function, physical role limitations, social function, bodily pain, mental health, and energy/fatigue.Table 2. SF-36 Data for All Patients*DomainNational NormMean Preoperative ScoreMean Postoperative ScoreGeneral health perception726769Physical function847377Role limitation (physical)815974Role limitation (emotional)817688Social function837485Bodily pain756679Mental health757379Energy/fatigue614965*Mean preoperative and postoperative scores highlighted in boldface reached significance at P<.05 compared with national norms. Scores for all patients (N = 72) were measured on a scale of 0 to 100. SF-36 indicates Medical Outcomes Study Short-Form Health Survey.Table 3. Group 1 SF-36 Data*DomainNational NormMean Preoperative ScoreMean Postoperative ScoreGeneral health perception727070Physical function847577Role limitation (physical)816773Role limitation (emotional)818288Social function838286Bodily pain757377Mental health757882Energy/fatigue615566*Mean preoperative and postoperative scores highlighted in boldface reached significance at P<.05 compared with national norms. Scores for asymptomatic patients (n = 43) were measured on a scale of 0 to 100. SF-36 indicates Medical Outcomes Study Short-Form Health Survey.Table 4. Group 2 SF-36 Data*DomainNational NormMean Preoperative ScoreMean Postoperative ScoreGeneral health perception726267Physical function847077Role limitation (physical)814876Role limitation (emotional)816790Social function836383Bodily pain755780Mental health756676Energy/fatigue614165*Mean preoperative and postoperative scores highlighted in boldface reached significance at P<.05 compared with national norms. Scores for symptomatic patients (n = 29) were measured on a scale of 0 to 100. SF-36 indicates Medical Outcomes Study Short-Form Health Survey.Table 5outlines the statistical differences between the postoperative study population and the preoperative study population. There was significant improvement in 7 of 8 domains of the SF-36 after parathyroidectomy. Table 5also demonstrates that the asymptomatic population (group 1) improved significantly in 2 domains: mental health and energy/fatigue. Group 2 (symptomatic) significantly improved in 7 of 8 domains.Table 5. Comparison of the Postoperative Population to the Preoperative Population on the SF-36*DomainAll Patients (N = 72)Group 1: Asymptomatic (n = 43)Group 2: Symptomatic (n = 29)General health perception.10.76.07Physical function.01.17.03Role limitation (physical).01.38.01Role limitation (emotional).03.37.03Social function.001.20.001Bodily pain.001.21.001Mental health<.001.05.001Energy/fatigue<.001.004<.001*The Wilcoxon rank sum test was used to compare individual patients' postoperative responses with their preoperative responses (paired comparisons). Data are presented as Pvalues, which indicate the likelihood of a difference in the postoperative population compared with the preoperative one. Significant Pvalues are shown in boldface. SF-36 indicates Medical Outcomes Study Short-Form Health Survey.COMMENTIn our consecutive series of patients with primary hyperparathyroidism, parathyroidectomy improved health-related quality of life. This finding was consistent whether patients were classified as symptomatic or asymptomatic. Notably, patients characterized by their referring physician as asymptomatic were impaired preoperatively and demonstrated improvement after parathyroidectomy. Our results affirm the argument that few people referred for primary hyperparathyroidism are truly without symptoms.The NIH panel recommended operative intervention in the asymptomatic patient with any of the following factors: markedly elevated serum calcium level, a previous episode of life-threatening hypercalcemia, reduced creatinine clearance, asymptomatic kidney stones, elevated 24-hour urinary calcium excretion, age younger than 50 years, or substantially reduced bone mass. Because the consensus conference did not address health-related quality of life in primary hyperparathyroidism, its recommendations may undertreat a patient population with impaired physical or emotional function and fatigue. Our results imply that an evaluation of health-related quality of life may be helpful in the assessment of patients with hyperparathyroidism.The gains in perceived health status were even more pronounced in the symptomatic group, with the data reaching statistical significance in nearly all domains of the SF-36. This group was more impaired preoperatively and made greater gains in health status after parathyroidectomy.Our findings rely on patient-reported symptoms, and this method is inherently subject to bias. Bias was minimized in several ways. First, no patient with primary hyperparathyroidism was excluded from the prospective study. Previous studies of symptom evaluation in primary hyperparathyroidism have used selected populations or those in which many potential subjects refused to participate.Second, our postoperative evaluation was comprehensive. Based on 97% of consecutive patients responding at 1 year, our data are among the most complete reported in the literature with regard to parathyroid surgery. Third, we minimized the potential for a surgeon's bias to influence the patient's health perception by administering the SF-36 prior to consultation. Similarly, patients completed the follow-up SF-36 by mail so that they did not have to visit the surgeon's office to respond. Fourth, reevaluation 1 year after the procedure limits interventional bias, or the phenomenon of patients wanting and expecting to feel better following an operation. In addition, the 1-year interval assesses the durability of our results.Our study, like others, is subject to referral bias; all patients were selected for operation by either an endocrinologist or a primary care physician. Attributing improvements in quality of life to an operative procedure without a control population is problematic. However, our data demonstrate that patients with primary hyperparathyroidism are a distinct population as compared with age-matched controls. When these patients are cured with parathyroidectomy, they are indistinguishable from the norm. We feel that this is an important finding.Although primary hyperparathyroidism can be a mild disease, the natural history of untreated hyperparathyroidism is not necessarily benign.The absence of symptom progression does not mean that patients with hyperparathyroidism feel healthy. Several recent reports have demonstrated that up to 30% of presumably asymptomatic patients with primary hyperparathyroidism will progress to serious morbidity from their disease.The observation of mild hyperparathyroidism has also been implicated in premature death.The morbidity rate of modern parathyroid surgery is in the 1% to 2% range, with mortality almost nonexistent. With serum analysis and modern imaging techniques, hyperparathyroidism is easily diagnosed using few resources. Additionally, the disease is easily cured and has minimal morbidity, resulting in high patient satisfaction.We believe that a patient with primary hyperparathyroidism should be referred for parathyroidectomy at the time of diagnosis. Although controversy exists concerning the type and extent of procedure, it is clear in this era of ambulatory surgery that parathyroidectomy can be safely performed with minimal risk to the patient.CONCLUSIONSOur consecutive series of patients with primary hyperparathyroidism demonstrated statistically significant impairment regarding preoperative quality of life as measured with the SF-36. Parathyroidectomy significantly improved quality of life, and the effect is durable at 1 year. Most notable are the findings that patients thought to be asymptomatic by the referring physician were preoperatively impaired and that they made improvements in mental health and energy/fatigue levels after parathyroidectomy.DSCorlewSLBrydaELBradley IIIMDiGirolamoObservations on the course of untreated primary hyperparathyroidism.Surgery.1985;98:1064-1071.SLjunghallSJakobssonCJobornLongitudinal studies of mild primary hyperparathyroidism.J Bone Miner Res.1991;6(suppl 2):S111-S124.ELundgrenLLindMPalmerIncreased cardiovascular mortality and normalized serum calcium in patients with mild hypercalcemia followed up for 25 years.Surgery.2001;130:978-985.CJobornJHettaHJohanssonPsychiatric morbidity in primary hyperparathyroidism.World J Surg.1988;12:476-481.CJobornJHettaLLindSelf-rated psychiatric symptoms in patients operated on because of primary hyperparathyroidism and in patients with long-standing mild hypercalcemia.Surgery.1989;105:72-78.CJobornJRastadEStalbergMuscle function in patients with primary hyperparathyroidism.Muscle Nerve.1989;12:87-94.JRastadCJobornGAkerstromSLjunghallIncidence, type and severity of psychic symptoms in patients with sporadic primary hyperparathyroidism.J Endocrinol Invest.1992;15(suppl 6, pt 9):149-156.SJSilverbergEShaneTPJacobsA 10-year prospective study of primary hyperparathyroidism with or without parathyroid surgery.N Engl J Med.1999; 341:1249-1255.Not AvailableNIH conference: diagnosis and management of asymptomatic primary hyperparathyroidism: consensus development conference statement.Ann Intern Med.1991;114:593-597.JEWare JrCDSherbourneThe MOS 36-item short-form health survey (SF-36), I: conceptual framework and item selection.Med Care.1992;30:473-483.REBurneyKRJonesMPetersonSurgical correction of primary hyperparathyroidism improves quality of life.Surgery.1998;124:987-992.SMHaleyCAMcHorneyJEWareEvaluation of the MOS SF-36 physical functioning scale (PF-10), I: unidimensionality and reproducibility of the Rasch item scale.J Clin Epidemiol.1994;47:671-684.CAMcHorneyJEWare JrConstruction and validation of an alternate form general mental health scale for the Medical Outcomes Study Short-Form 36-Item Health Survey.Med Care.1995;33:15-28.CAMcHorneyJEWareJFLuCDSherbourneThe MOS 36-item Short-Form Health Survey (SF-36), III: tests of data quality, scaling assumptions, and reliability across diverse patient groups.Med Care.1994;32:40-66.CAMcHorneyJEWareAERaczekThe MOS 36-Item Short-Form Health Survey (SF-36), II: psychometric and clinical tests of validity in measuring physical and mental health constructs.Med Care.1993;31:247-263.GBTalposHGBone IIIMKleerekoperRandomized trial of parathyroidectomy in mild asymptomatic primary hyperparathyroidism: patient description and effects on the SF-36 health survey.Surgery.2000;128:1013-1021.JARyan JrBEisenbergKMPadoFLeeEfficacy of selective unilateral exploration in hyperparathyroidism based on localization tests.Arch Surg.1997;132:886-891.JEWare JrMKosinskiMSBaylissCAMcHorneyWHRogersARaczekComparison of methods for the scoring and statistical analysis of SF-36 health profile and summary measures: summary of results from the Medical Outcomes Study.Med Care.1995;33(suppl 4):AS264-AS279.OHClarkWWilkesAESipersteinQYDuhDiagnosis and management of asymptomatic hyperparathyroidism: safety, efficacy, and deficiencies in our knowledge.J Bone Miner Res.1991;6(suppl 2):S135-S152.OHClark"Asymptomatic" primary hyperparathyroidism: is parathyroidectomy indicated?Surgery.1994;116:947-953.REBurneyKRJonesJWCoonAssessment of patient outcomes after operation for primary hyperparathyroidism.Surgery.1996;120:1013-1019.AKChanQYDuhMHKatzClinical manifestations of primary hyperparathyroidism before and after parathyroidectomy: a case-control study.Ann Surg.1995;222:402-414.REBurneyKRJonesBChristyNWThompsonHealth status improvement after surgical correction of primary hyperparathyroidism in patients with high and low preoperative calcium levels.Surgery.1999;125:608-614.SJSilverbergJPBilezikianHGBoneTherapeutic controversies in primary hyperparathyroidism.J Clin Endocrinol Metab.1999;84:2275-2285.GHedbackAOdenSurvival of patients operated on for primary hyperparathyroidism.Surgery.1999;125:240-241.GHedbackAOdenLETisellParathyroid adenoma weight and the risk of death after treatment for primary hyperparathyroidism.Surgery.1995;117:134-139.GHedbackAOdenLETisellThe influence of surgery on the risk of death in patients with primary hyperparathyroidism.World J Surg.1991;15:399-407.MPalmerHOAdamiRBergstromMortality after surgery for primary hyperparathyroidism: a follow-up of 441 patients operated on from 1956 to 1979.Surgery.1987;102:1-7.JARyan JrFLeeEffectiveness and safety of 100 consecutive parathyroidectomies.Am J Surg.1997;173:441-444.ELundgrenJRastadPRidefeltLong-term effects of parathyroid operation on serum calcium and parathyroid hormone values in sporadic primary hyperparathyroidism.Surgery.1992;112:1123-1129.Quan-Yang Duh, MD, San Francisco, Calif:Six years ago, Richard Burney of Michigan presented at the American Association of Endocrine Surgeons meeting in Napa Valley, Calif. He was the first to use the SF-36 to show an improved health-related quality of life in patients with primary hyperparathyroidism after parathyroidectomy. At that time, Dr Burney showed that patients with primary hyperparathyroidism had impaired health-related quality of life as measured by the SF-36. Six months after parathyroidectomy, 7 of 8 domains in the SF-36 improved by 10 or more points, and the scores became the same as those for the normal controls. Several more studies since then have confirmed these findings. Some skeptics, however, are still not convinced; they are concerned that the selection of patients can introduce biases; that is, those whose quality of life has improved may be more likely to complete the survey.Dr Sheldon and colleagues addressed this question of patient selection by both including consecutive patients and having a near-perfect survey response. Those of you who have tried to perform surveys know that this is extremely difficult. This paper convincingly demonstrated that this improvement in quality of life is real, and not just an artifact of patient selection.Once the benefit of parathyroidectomy was demonstrated, a second aspect of this paper was to stratify the patients to determine whether some groups may benefit more and others may not. The authors stratified these patients into an "asymptomatic" group and a "symptomatic" group and found that both groups improved in their SF-36 scores 1 year after parathyroidectomy, although the improvement was more significant in the symptomatic group. This stratification seems to help us predict the expected improvement from parathyroidectomy by preoperative symptoms.Since the NIH consensus conference of 1991, there has been a sea change in the field of surgery for the parathyroid. First of all, more unilateral exploration and focused exploration are now done, with results as good as the traditional operation. This was made possible by improved preoperative localization studies, especially sestamibi scan, and intraoperative quick PTH [parathyroid hormone] assay. In addition, our study and others have shown that patients benefit from parathyroidectomy even if they do not fit the so-called NIH criteria. What we have learned over the past 10 years is that (1) parathyroidectomy can be performed safely with less invasiveness, and (2) more patients, especially those with milder disease, can benefit from parathyroidectomy. Dr Sheldon's paper supports this growing opinion among the endocrine surgeons. We all hope that when the NIH revisits this issue in the consensus conference this April, 2 months from now, it will liberalize the indications for parathyroidectomy in patients with less severe primary hyperparathyroidism.I have 2 questions for the authors: (1) Since control group is always an issue, and a randomized study has not yet been done, have you studied a surrogate control group (for example, patients with primary hyperparathyroidism who may have delayed or declined their operations, or patients who have had a thyroidectomy)? (2) Since stratifying patients as "symptomatic" or "asymptomatic," as you have noted, is not precise, have you also stratified the patients differently (for example, either by whether or not they fit the NIH criteria for parathyroidectomy or by the severity of their biochemical abnormalities, such as the calcium or PTH levels)?It is good to know that parathyroidectomy not only prevents morbidity and premature death associated with hyperparathyroidism but also improves the quality of life and makes the patient feel better.John A. Butler, MD, Orange, Calif:The major question addressed by this paper concerns the asymptomatic group. What you showed is that preoperatively they were significantly impaired in 3 of the 8 categories. Postoperatively they improved in 2 of 8, but it was actually only in 1 of the 3 that they were preoperatively impaired. In the other category in which they significantly improved, they were actually better than the norm in the preoperative assessment. Whereas I agree with your bias, I just wonder how strongly you feel your data support your conclusions, particularly in that asymptomatic group.Michael J. Hart, MD, Seattle, Wash:My question is similar to Dr Butler's and has to do with your survey instrument. I assume, and please let me know if this is true, that there has been validation of the SF-36 health questionnaire by using it on the same population over a number of different years to determine the variability in responses. Likewise, the things that you mention most frequently—mental health, fatigue, energy levels—are probably the most nebulous and hardest areas to measure. I'm not sure that if I took that test from year to year I would be all that consistent, or even from day to day. I would like for you to give us a little bit more background about the SF-36 questionnaire and its referencing.Orlo H. Clark, MD, San Francisco:I congratulate Dr Sheldon and colleagues on this excellent paper. They address a currently controversial issue; that is, do "asymptomatic" and "symptomatic" patients benefit symptomatically from successful parathyroidectomy?Most investigations suggest that about 75% to 80% of patients improve following parathyroidectomy. This means that 20% to 25% do not. We have studied whether patients who fit and who did not fit the NIH criteria for parathyroidectomy receive the same psychological improvement after successful parathyroidectomy. We found that both groups benefit.My first question is, did you study the duration of symptoms prior to parathyroidectomy and whether patients who had symptoms for a shorter time preoperatively were more likely to benefit symptomatically? Second, were there any other factors that might help predict whether a patient would improve symptomatically, such as PTH level, calcium level, patient age, or symptom complex? Although other investigations using SF-36 testing support your findings, including those of Burney, Pasieka, Talpos, and colleagues, I believe your new findings not only confirm their studies but also document that the symptomatic benefit of parathyroidectomy continues for at least 1 year.Julie A. Freischlag, MD, Los Angeles, Calif:We administer the SF-36 in our clinic every time a patient comes to visit us. Part of that is for entertainment while they wait in the lobby, but it is also for scientific purposes. Our group of patients that we really worry about are TOS [thoracic outlet syndrome] patients, and we are trying to do a study looking at the SF-36 to see if we really help them. One of the specialists told us, you need to give this survey to your patients and then ask them if there is something you missed, or should you have asked them if something was really bothering them, to know whether this general survey reflects their true improvement. My question to you is, did you ask them about symptoms or feelings that perhaps an instrument may have missed that they would have liked to be asked about?Philip D. Schneider, MD, Sacramento, Calif:It's the closest approximation to the aborted Mayo Clinic trial that was started in the 1960s studying asymptomatic hypercalcemic patients. It really gets at the issue of what may happen to patients who do not have surgery. I have a couple of questions.There were a large number of patients who were referred with abnormal DEXA scans, and I am curious whether they were referred only because the DEXA scan was abnormal and they were known to be hypercalcemic, or whether because they were about to go on hormone replacement therapy, they had a DEXA scan and it had not been appreciated that they were hypercalcemic. Finally, I would be curious if you administered the SF-36 to patients who came to your clinic and then refused surgery, and then had the opportunity to do long-term follow-up on those patients to see if their condition deteriorated.Lawrence Way, MD, San Francisco:I would like to expand on previous comments concerning the possibility of bias. Cognitive psychologists report that people's "mood" influences a variety of subjective assessments, such as those contained in the quality-of-life grid (Psych Res. 1999;88:173). Before their first quality-of-life assessment, the patients in this study, although asymptomatic, would have been told that they had hyperparathyroidism and had probably received conflicting opinions on the significance of the disease and the importance of treatment. The resulting confusion could well have affected their mood and hence their quality-of-life assessments. Since all of this uncertainty would have been relieved by the operation, reported improvement in quality of life might have stemmed, at least in part, from these uncontrolled psychological factors.Dr Ryan:I appreciate the interest in this paper and Dr Quan-Yang Duh's excellent discussion. I will try to answer the questions that were asked, and then I have a short video to show you.Dr Duh asked 3 questions. Did we have a control group of patients not operated on but followed up with the SF-36? No, but Dr Talpos from Henry Ford Hospital has published a randomized trial of patients with mild hyperparathyroidism either operated on or observed showing a benefit in the operative group as judged by the SF-36 (Talpos GB, Bone HG, Kleerekoper M, et al. Randomized trial of parathyroidectomy in mild asymptomatic primary hyperparathyroidism: patient description and effects on the SF-36 health survey. Surgery. 2000;128:1013-1020).Did we stratify the patients by the NIH criteria? No, in our 43 so-called asymptomatic patients, all but 8 of the patients met NIH criteria; most had been referred for abnormal bone marrow density (32), and there were 3 patients less than 50 years of age. However, Drs Burney and Thompson at the University of Michigan did stratify patients by high and low calcium elevations and demonstrated both impairment and postoperative improvement by SF-36 evaluation, independent of calcium level (Burney RE, Jones KR, Christy B, Thompson NW. Health status improvement after surgical correction of primary hyperparathyroidism in patients with high and low preoperative calcium levels. Surgery. 1999;125:608-614).Dr Duh and others complimented the completeness of our long-term evaluation. We have a secret weapon at Virginia Mason, our coauthor and office nurse Faye Lee, RN, who somehow can find patients and get them to respond to long-term evaluations. These patients were referred from over a 5-state area. We realize the importance of having long-term evaluations, and we are fortunate to have someone who is extremely persistent in getting them done.Drs Way, Hart, and Freischlag asked questions about the SF-36 survey. This was a questionnaire that was developed because the HCFA [Health Care Financing Administration] wanted to have a survey for health-related quality of life. The HCFA commissioned the Rand Corporation to form a Medical Outcome Trust to develop a questionnaire that could be used in a variety of situations and diseases. The SF-36 was published in 1992 (Ware JE Jr, Sherbourne CD. The MOS 36-item short-form health survey (SF-36), I: conceptual framework and item selection. Med Care. 1992;30:473-483).No matter what group you are studying, the Medical Outcome Trust gives age- and sex-matched national norms for that group. Perfect health in any of the 8 domains of evaluation is given a score of 100. This questionnaire has been used widely in the last decade and, I believe, has become an accepted standard. Dr Thirlby presented information to the PCSA [Pacific Coast Surgical Association] in 1998 about the SF-36 in Crohn disease.Dr Clark asked about patients who did not improve postoperatively as judged by the SF-36. We did not specifically look at any individual patient, but rather the aggregate of our 72 patients. In fact, although I operated on every patient, I did not see any individual SF-36 results or have any personal involvement with administrating the test. I hope this eliminated a form of bias.Dr Schneider asked about the bone mineral density test. Thirty-two of the 43 so-called asymptomatic patients were referred to us because they had a low bone mineral density. For parathyroid surgeons, this test has been a boon. Physicians who are following patients with slightly elevated calcium levels and the diagnosis of hyperparathyroidism who don't have kidney stones, broken bones, or pancreatitis (any of the traditional indications for referral) do note osteopenia or osteoporosis on a bone mineral density test and at that point feel an obligation to refer the patients to a surgeon.Dr Butler asked 2 pertinent questions. How did we really stratify the patients into the asymptomatic group? The stratification was crucial to our study. We really wanted to see if the patients sent as asymptomatic would improve postoperatively. When patients came to us, we read very carefully their referring notes by either an endocrinologist or primary care doctor, and we asked the patients their perception of why they were sent. If they said they were sent because of an abnormal laboratory value or an abnormal bone density test, then we classified them into the asymptomatic group. Although the classification was somewhat arbitrary, it was done prospectively without any knowledge of SF-36 results and did seem clinically relevant. Dr Butler, who did an advance reading of the manuscript, noted that in the asymptomatic group in the domain of mental health, the comparison of postoperative with preoperative scores showed significant improvement but that the mean for the preoperative score (78) was higher than the national norm (75). (See Table 3in the article.) Those scores were not statistically different. But the aggregate improvement in 43 patients postoperatively to a mean score of 82 was a highly significant improvement when calculated with a Wilcoxon rank sum statistic. Remember that a score of 100 is perfect mental health.This short video demonstrated the long interest that Virginia Mason has had in health-related quality of life in hyperparathyroidism. This movie was made in 1951 by Dr Joel Baker, who of course was president of the PCSA over 30 years ago. Here is Dr Baker talking about a middle-aged woman with hyperparathyroidism. Here she is pictured on the roof of Virginia Mason barely able to climb the steps. Note the view of Puget Sound. Here is the parathyroid at the time of the operation. It was so big that it was localized by barium swallow, and Dr Baker only explored one side of the neck. Here is the patient postoperatively back up on the roof. We didn't have the SF-36, but boy, look how spry this patient is now: up and down the steps, tying her shoes, and giving a huge bow to Dr Baker!Presented at the 73rd Annual Meeting of the Pacific Coast Surgical Association, Las Vegas, Nev, February 17, 2002. The discussions are based on the originally submitted manuscript and not the revised manuscript.Corresponding author: John A. Ryan, Jr, MD, Section of General, Vascular, and Thoracic Surgery, Virginia Mason Medical Center, PO Box 900 C6-GSUR, 1100 Ninth Ave, Seattle, WA 98111 (e-mail: [email protected]).

Pal, Jay D.; Victorino, Gregory P.

doi: 10.1001/archsurg.137.9.1029pmid: 12215153

HypothesisControversy exists regarding the use of diagnostic peritoneal lavage (DPL) vs computed tomography (CT) in the evaluation of blunt abdominal trauma. It has been suggested that one role for DPL is to diagnose bowel injuries in hemodynamically stable patients with an unreliable abdominal examination result. Our hypothesis is that CT is specific and sensitive for diagnosing hollow viscus injuries and is therefore an appropriate diagnostic modality in the hemodynamically stable blunt trauma patient with an unreliable abdominal examination result due to a depressed level of consciousness.DesignRetrospective consecutive case review.SettingAn urban level II trauma center.PatientsThe medical records of 1388 consecutive patients admitted between January 1, 1991, and December 31, 2000, were reviewed. Inclusion criteria included blunt trauma patients who were hemodynamically stable (defined as a systolic blood pressure >90 mm Hg) with unreliable abdominal examination results secondary to a depressed level of consciousness (Glasgow Coma Scale score <11).Main Outcome MeasuresHollow viscus injury diagnosed by CT and missed diagnosis of hollow viscus injury by CT.ResultsOf 1388 patients who met entry criteria, 87 had hollow viscus injuries; CT identified 85 of these injuries. Computed tomography diagnosed intestinal injury with a sensitivity of 97.7%, specificity of 98.5%, and an overall accuracy of 99.4%.ConclusionAt our institution, CT is a reliable and accurate diagnostic modality when used to evaluate hollow viscus injuries in the hemodynamically stable blunt trauma patient with an unreliable abdominal examination result due to a depressed level of consciousness.CONTROVERSY EXISTS regarding the use of computed tomography (CT) vs diagnostic peritoneal lavage (DPL) in the evaluation of blunt abdominal trauma. Diagnostic peritoneal lavage has been criticized for being an overly sensitive and invasive diagnostic tool.Computed tomography has been criticized as an expensive study that has the potential to miss hollow viscus injuries.The concern about hollow viscus injuries is increased due to an unreliable physical examination result in patients with a depressed level of consciousness. These patients may not be able to communicate regarding abdominal pain or identify abdominal tenderness, which may be important first clues of an occult hollow viscus injury. Some authors recommend DPL under such circumstances, whereas others suggest that CT is reliable.We reviewed our experience in hemodynamically stable blunt trauma patients with a depressed level of consciousness. In part owing to the technological improvements and our increased experience with CT, we propose that CT is an appropriate singular diagnostic modality for evaluation of this diagnostically challenging patient population.MATERIALS AND METHODSThe study patient population was drawn from admissions to the trauma service at Alameda County Medical Center in Oakland, Calif, from January 1, 1991, to December 31, 2000. Alameda County Medical Center is a university-based level II trauma center. A retrospective review of the trauma registry, which includes patient demographics, emergency department assessment and treatment records, in-hospital radiographic evaluation, and surgical intervention, was undertaken to identify patients who met the entry criteria. Patients who sustained blunt abdominal trauma and were hemodynamically stable, defined as a systolic blood pressure greater than 90 mm Hg, and demonstrated a depressed mental status as defined by a Glasgow Coma Scale score of less than 11 were considered for enrollment.Initial abdominal and pelvic CT scans were performed within 2 hours after assessment by the trauma service (GE High Speed Advantage CT Scanner; General Electric Medical Co, Milwaukee, Wis). Axial scans with 1-cm cuts were obtained from the diaphragm to the femoral heads after intravenous infusion of Hypaque (Nocamed, Princeton, NJ) contrast after a delay of 70 seconds. Oral contrast was administered at the discretion of the trauma surgeon. The CT scans were initially reviewed by the trauma service with or without the assistance of attending radiologists. Subsequent to initial review, staff radiologists retrospectively reviewed all CT scans. Radiographic signs considered to be suggestive of blunt intestinal injuries were pneumoperitoneum, hemoperitoneum, extravasation of oral contrast, bowel-wall thickening, and focal hematomas. A CT scan result was considered positive if the radiologist's final transcribed report stated that the scan was suggestive of intestinal injuries. A patient was considered to have a hollow viscus injury if there was a bowel perforation documented in the operative report. Mesenteric injuries or serosal tears were not included in this group. The sensitivity, specificity, positive and negative predictive values, and the overall accuracy were calculated.RESULTSDuring the 10-year study period, 1388 consecutive patients met the entry criteria and had complete medical records available for review. There were 87 hollow viscus injuries documented, and CT identified 85 of these injuries. The mechanism of injury for these patients and distribution of bowel injuries are as follows:Injury MechanismPatients, No.Motor vehicle crash44Fall19Assault12Bicycle7Automobile vs pedestrian3Other2Patient demographics of the study population are given in Table 1. There were no significant differences between the entire population and those patients who sustained intestinal injuries.Table 1. Patient Demographics*DemographicBITNo BITPValueAge, y36 ± 1939 ± 16.45M/F, %59/4155/45.33ISS15 ± 914 ± 8.48GCS score8 ± 39 ± 4.41LOS, d9 ± 611 ± 8.19*Data are presented as mean ± SEM unless otherwise indicated. BIT indicates blunt intestinal trauma; ISS, Injury Severity Score; GCS, Glasgow Coma Scale; and LOS, length of stay.The radiology reports were reviewed, and injuries by location were as follows:LocationInjuries, No.Jejunum23Ileum21Jejunal mesentery17Ileal mesentery17Right colon12Mesocolon5Duodenum4Transverse colon2Left colon1Numerous patients had multiple radiographic findings suggestive of bowel injuries. The most common location of injury diagnosed by CT in these patients was the jejunum, with the ileum a close second.Radiographic findings were also extracted from the radiology reports (Table 2). The most common radiographic finding in patients with intestinal injuries was free fluid in the peritoneum. Isolated free fluid was also the most common finding in patients without intestinal injuries and, thus, the least specific of radiographic signs. The most specific finding was pneumoperitoneum. The extravasation of oral contrast was always associated with intestinal injuries. However, the administration of oral contrast was not uniform throughout the study period because there existed a recent trend away from the use of oral contrast in blunt abdominal trauma patients.Table 2. Computed Tomographic Findings in Patients With Bowel InjuriesFindingNo. of PatientsSensitivity, %Specificity, %Free fluid848042Pneumoperitoneum687894Bowel-wall thickening515551Mesenteric hematoma323454The locations of injuries found at laparotomy were as follows:LocationInjuries, No.Jejunum47Ileum45Right colon15Duodenum8Left colon3Transverse colon1There were no nontherapeutic laparotomies in this series. The more severely injured patients often sustained multiple intestinal injuries. The most common site of injury was the distal small bowel. The associated solid organ injuries were as follows:OrganInjuries, No.Spleen27Liver23Kidney13Pancreas6Lacerations and hematomas of the liver and spleen were most commonly associated with blunt intestinal injuries.In the 2 patients in whom the CT scan did not identify a bowel injury, the injuries were identified clinically or by an additional CT scan within 24 hours of admission. The initial scans of these 2 patients were interpreted as having no obvious signs of a hollow viscus injury. On retrospective review and further discussion with staff radiologists, the CT scans were thought to demonstrate subtle signs of hollow viscus injuries, including bowel-wall thickening and free fluid.Seventeen CT scans reviewed by staff radiologists were interpreted as having signs of intestinal injuries. Isolated free fluid was the most commonly reported finding in 13 of 17 cases. All 17 patients were treated nonoperatively based on clinical judgment and had uncomplicated hospital courses, with a mean observation time of 6 ± 5 days. These patients are thought not to have sustained blunt intestinal injuries.The DPLs were completed in only 3 patients enrolled in this study. All results of the 3 DPLs were positive. All 3 patients also had CT scans that were suggestive of hollow viscus injury, and in each case this was documented at laparotomy.The overall incidence of blunt intestinal injury in this series is 6%. Computed tomography diagnosed intestinal injury with a sensitivity of 97.7% and specificity of 98.5%. The positive and negative predictive values are 83.3% and 99.8%, respectively. The overall accuracy is 99.4%.COMMENTThe delayed diagnosis of a hollow viscus injury can be a devastating complication and may lead to sepsis, multiorgan failure, and death. Trauma surgeons make every effort to diagnose these injuries in a timely fashion and often rely on DPL and/or CT to aid in their evaluation. The controversy lies in knowing what study to use and when.A criticism of CT is that it can miss hollow viscus injuries.In the neurologically intact patient, a natural back-up system exists where the clinician can discover a bowel injury missed by CT through physical examination. However, in patients with a depressed level of consciousness whose physical examination result is unreliable, this back-up system does not exist. Therefore, to promptly diagnose all bowel injuries, it has been suggested that DPL may be superior to CT in hemodynamically stable patients with a depressed level of consciousness.The DPL is regarded by some to be the standard screening test for intra-abdominal injuries.However, DPL it is not without its disadvantages. A significant drawback of DPL is the high rate of nontherapeutic laparotomies.In addition, DPL is invasive and may require several hours for the tests to be adequately sensitive for identifying small bowel injuries.Because of improvements in imaging technology and our increased experience with CT, we hypothesized that CT is a reliable and accurate diagnostic modality in the hemodynamically stable patient with a depressed level of consciousness. We reviewed our experience in this clinical situation and found CT to have a sensitivity of 97.7%, a specificity of 98.5%, and an overall accuracy of 99.4%.These results are comparable to a recent study that looked at helical CT scans of all hemodynamically stable blunt trauma patients regardless of level of consciousness.In their study, CT detected 64 of 68 bowel injuries for a sensitivity of 94%. However, in their study, CT had an accuracy of 86%, which was slightly lower than what we found.Improvement in diagnostic imaging technology may be one reason for increased sensitivity of CT as seen in our study. Later model scanners have less motion artifact and better resolution that may allow more accurate diagnoses. The sensitivity of CT as a screening tool for blunt intestinal injury can also be increased when certain diagnostic criteria for a positive scan result are used.When radiographic signs, such as hemoperitoneum, bowel-wall thickening, extravasation of oral contrast, free fluid, and focal hematomas, are used as diagnostic clues, the sensitivity of CT is thought to be comparable to or greater than DPL.The most frequent finding on CT in blunt abdominal trauma was free fluid. However, this finding was not sensitive or specific (80% and 42%, respectively). Pneumoperitoneum was much more specific (98%), but was not sensitive (78%). Bowel-wall thickening performed poorly when used to identify bowel injuries and had a sensitivity of 55% and a specificity of 47%. These figures are comparable to the study by Killeen et alin which free fluid had a sensitivity of 76% and specificity of 39%, pneumoperitoneum had a sensitivity of 76% and specificity of 98%, and bowel-wall thickening had a sensitivity of 44% and specificity of 47%.Given the high diagnostic accuracy of CT in this study, of concern is the subgroup of 17 patients who were interpreted by attending radiologists as having intestinal injuries but did not undergo surgical exploration. Despite CT diagnosis of bowel injury, these patients were treated nonoperatively based on clinical judgment. Thirteen of these patients had isolated free fluid on CT. The presence of isolated free fluid has been suggested to be a strong indication for laparotomy because of therapeutic laparotomy rates of 94% and 54% found in 2 small studiesof 31 and 34 patients each. However, a more recent studyof 90 blunt trauma patients with isolated free fluid on CT showed that only 8% of these patients had intestinal injuries and 92% did not. The mean observation period for these patients was 8 days. The authors concluded that isolated free fluid on CT does not mandate celiotomy. The patients from our study who belonged to this group were observed for a mean of 6 days. All were discharged without consequence and are believed not to have sustained bowel injuries. We agree that isolated free fluid on CT does not mandate laparotomy.The major limitation of the current study is the inability to directly compare the results of DPL and CT scan in the evaluation of blunt trauma patients. Small patient populations have limited previous studies that have attempted to make this comparison partly because the incidence of blunt intestinal injury is approximately 5%. Also inherent in our retrospective design is the inability to assess improvement in patient care using our CT evaluation criteria. This study is also confounded by the variability owing to having several trauma attending physicians, each with a different management guideline, and the bias secondary to the predilection for CT at our institution. Another limitation is the lack of follow-up data on patients with negative CT scan results. However, this group of patients was observed in-house for a mean of 11 days, which is a reasonable period to confidently rule out hollow viscus injuries.We conclude that at our institution CT is a reliable, sensitive, and specific diagnostic modality when used to evaluate hollow viscus injuries in the hemodynamically stable blunt trauma patient with an unreliable abdominal examination result due to a depressed level of consciousness. We find additional diagnostic modalities, such as DPL, to be unnecessary and are not routine in our evaluation of this patient population.JWDavisDBHoytRCMackersieMSMcArdleComplications in evaluating abdominal trauma: diagnostic peritoneal lavage versus computerized axial tomography.J Trauma.1990;30:1506-1509.TFDrostASRosemurgyREKearneyPRobertsDiagnostic peritoneal lavage: limited indications due to evolving concepts in trauma care.Am Surg.1991;57:126-128.JAMarxEEMooreRCJordenJEule JrLimitations of computed tomography in the evaluation of acute abdominal trauma: a prospective comparison with diagnostic peritoneal lavage.J Trauma.1985;25:933-937.YOtomoHHenmiKMashikoNew diagnostic peritoneal lavage criteria for diagnosis of intestinal injury.J Trauma.1998;44:991-997.DMMeyerERThalJAWeigeltHCRedmanEvaluation of computed tomography and diagnostic peritoneal lavage in blunt abdominal trauma.J Trauma.1989;29:1168-1170.PLHennemanJAMarxEEMooreSVCantrillLAAmmonsDiagnostic peritoneal lavage: accuracy in predicting necessary laparotomy following blunt and penetrating trauma.J Trauma.1990;30:1345-1355.DHWisnerYChunFWBlaisdellBlunt intestinal injury: keys to diagnosis and management.Arch Surg.1990;125:1319-1322.SBFrameIWBrowderEKLangNEMcSwain JrComputed tomography versus diagnostic peritoneal lavage: usefulness in immediate diagnosis of blunt abdominal trauma.Ann Emerg Med.1989;18:513-516.JAMarxEEMooreRCJordenJEule JrLimitations of computed tomography in the evaluation of acute abdominal trauma: a prospective comparison with diagnostic peritoneal lavage.J Trauma.1985;25:933-937.MGOchsnerMMKnudsonHLPachterSignificance of minimal or no intraperitoneal fluid visible on CT scan associated with blunt liver and splenic injuries: a multicenter analysis.J Trauma.2000;49:505-510.HDRootPJKeizerJFPerry JrThe clinical and experimental aspects of peritoneal response to injury.Arch Surg.1967;95:531-537.KLKilleenKShanmuganathanPAPolettiCCooperSEMirvisHelical computed tomography of bowel and mesenteric injuries.J Trauma.2001;51:26-36.CRTaylorLDegutisRLangeGBurnsSCohnARosenfieldComputed tomography in the initial evaluation of hemodynamically stable patients with blunt abdominal trauma: impact of severity of injury scale and technical factors on efficacy.J Trauma.1998;44:893-901.HWHarrisDJMorabitoRCMackersieRAHalvorsenWPSchecterLeukocytosis and free fluid are important indicators of isolated intestinal injury after blunt trauma.J Trauma.1999;46:656-659.MACunninghamAHTyrochKLKaupsJWDavisDoes free fluid on abdominal computed tomographic scan after blunt trauma require laparotomy?J Trauma.1998;44:599-602.JHDonohueMPFederleBGGriffithsDDTrunkeyComputed tomography in the diagnosis of blunt intestinal and mesenteric injuries.J Trauma.1987;27:11-17.JSherckCShatneyKSensakiVSelivanovThe accuracy of computed tomography in the diagnosis of blunt small-bowel perforation.Am J Surg.1994;168:670-675.OBlowDBassamKButlerGACephasWBradyJSYoungSpeed and efficiency in the resuscitation of blunt trauma patients with multiple injuries: the advantage of diagnostic peritoneal lavage over abdominal computerized tomography.J Trauma.1998;44:287-290.KJBraselCJOlsonREStaffordTJJohnsonIncidence and significance of free fluid on abdominal computed tomographic scan in blunt trauma.J Trauma.1998;44:889-892.DHLivingstonRFLaveryMRPassannanteFree fluid on abdominal computed tomography after blunt injury does not mandate celiotomy.Am J Surg.2001;182:6-9.Felix D. Battistella, MD, Sacramento, Calif:Initial reports in the 1980s found CT scans lacked the sensitivity needed to reliably diagnose bowel injuries after blunt trauma. This study adds to the growing body of experience that bowel injuries can be accurately diagnosed with the newer generation of high-resolution helical CT scanners. In the hands of experienced physicians, CT scans have a reported sensitivity of 88% to 94%; this study found a 98% sensitivity.However, after hours, scans are frequently interpreted by nonradiologists or less-experienced physicians. Initial misinterpretations that are corrected the next morning can lead to delays in diagnosing bowel injuries. Delays in treating bowel injuries, even as short as 8 hours according to a recently published study, are associated with a significant increase in morbidity and mortality.In your study, you used the radiologist's final interpretation to determine the sensitivity of CT scan. Did you find any differences between the initial and final interpretations of the CT scans? If so, were there delays in diagnosing and treating bowel injuries? DPL has the advantage of giving surgeons prompt, easy-to-interpret information with low morbidity.My second question deals with the 17 patients who had scans that were interpreted by the staff radiologist as having signs of intestinal injury but who did not have an operation. How did you make the decision to manage these patients with an unreliable physical exam nonoperatively? Were the CT findings missed initially and discovered after the patients had been followed for a period during which their neurologic status improved such that you were comfortable with the reliability of their physical examination? What is your recommended treatment for the patient who has an unreliable exam and free intra-abdominal fluid without evidence of solid organ injury?I believe helical CT scans have a high sensitivity for blunt bowel injury, especially when interpreted by experienced physicians who can identify the sometimes subtle findings associated with intestinal injuries. However, a mentor once told me that the answer to a question in the title of a paper is almost always "no." I suggest this applies to your paper. Despite the success of CT scan, I'm not ready to eliminate DPL as a diagnostic tool.George C. Velmahos, MD, Los Angeles, Calif:Although I fully agree that the role of DPL is nearly none for hemodynamically stable patients, my major concern is the hemodynamically unstable patient. I saw in the authors' algorithm that they substituted DPL with FAST [focused abdominal sonography for trauma]. In our hands, and despite the great results that are reported in the literature, FAST is not that reliable. So, I would like to ask the authors, in a patient with multiple injuries and hemodynamic instability, are they ready to dismiss the abdomen as the cause of the hemodynamic instability based on a negative FAST without using DPL?William P. Schecter, MD, San Francisco, Calif:I would like to commend the authors for bringing a clinically critical issue to our attention and that is, how can we exclude hollow viscus injury during the nonoperative management of patients with solid organ injury and free intraperitoneal fluid? This is an excellent study that supports the view that the current generation of helical CT scanners is correct most of the time. The problem is, every time one of these studies is presented, there are always a couple of patients with hollow viscus injury that are missed, and I continue to remain concerned during the nonoperative management of these patients for fear of missing this injury. We need to get an even better imaging study that will do for abdominal surgery what the CT scanner has done for neurosurgery. I don't think we are quite there yet, even with the current generation of helical CT scanners.James J. Peck, MD, Portland, Ore:In the 17 patients who had false-positives, would you do a DPL? Would that help you to make the diagnosis? Would you repeat the CT scan? Repeat CT scan 24 hours later is helpful in detecting evolving inflammation. How many of these cases did you explore for free fluid, but found actually the reason the CT scan was positive was a splenic hilar injury or some other bleed and the intestinal injury was incidental?Lawrence A. Danto, MD, Stockton, Calif:I am sure Dr Organ intended for this paper to be controversial. There is another way of looking at these studies, not just simply as finding indications for operation but also finding indications for observation. In my experience, one of the greatest values of DPL has been to absolutely indicate or identify the patient safe to observe. I wonder if you looked at this in your review.Gail Tominaga, MD, Honolulu, Hawaii:I have a few questions regarding the technique of CT scanning. What type of scanner was used on these patients and were the CT cuts every 10 mm, 5 mm, or 3 mm? Did you use oral contrast and, if so, how long did you wait after giving the oral contrast to scan the patients? Also, according to your algorithm at the beginning, you performed CT scans in all hemodynamically stable patients. Do you think there is a role for a FAST or something else beside CT scan in all hemodynamically stable blunt trauma patients?Claude H. Organ, Jr, MD, Oakland, Calif:The program committee chair, Dr Wilson, will permit Dr Victorino to close and I stand in my closing remarks just to say that I am not an author, but a sponsor of this. I thought after reading the paper it would create some discussion. I would like to thank the program committee for allowing a PGY-1 [postgraduate-year 1] like Dr Pal to present this to this group. It will stimulate other residents to do as he and Dr Sheldon did earlier today in these presentations. There is a negative side to doing reviews. All PGY-1s should do it, because they need to have the experience of looking at incomplete, poorly dictated operative reports and, second, to be able to give the cacography award each year to the trauma surgeon with the worst handwriting.Dr Victorino:Dr Battistella brought up the question about how we extracted the data from the radiologists, and it is in fact the final dictated report. So there may be some circumstances where the trauma team would read the CT scan in the middle of the night and the radiologist would alter that in the morning. We did not extract that information. We definitely agree that time is of the essence in diagnosing these injuries. We do know that in the 2 patients whose injuries we did miss, we picked these up within 24 hours and there were no sequelae from those delays.Dr Battistella also questioned the 17 false-positive patients and how we managed these patients. These patients were managed based on clinical judgment. Most of these patients had minor mechanisms, and the attending surgeon at that time felt that the mechanism was not of severe enough force to cause an intestinal injury. I will say that 13 of these patients had isolated free fluid as their only finding on CT scan. Initially, the problem of isolated free fluid on CT scans was thought to mandate surgical exploration based on 2 studies. These studies had positive therapeutic exploration rates of 90% and 50%. Subsequently, a larger multicenter study has been completed and found 90 patients with isolated free fluid. They reported that 92% of these patients did not have hollow viscus injuries. We like to observe these patients with isolated free fluid as the only finding on CT scan. We admit them for observation, follow the white count and temperature curve, and may repeat the CT scan if indicated.The next question was regarding FAST examination in a hemodynamically unstable patient. At our institution we have had good success with this. We have obtained a portable Sonosite, and our chief residents do a very good job of diagnosing the hemoperitoneum in the hemodynamically unstable patient. The FAST exam is repeatable in equivocal cases. To my knowledge, we have not missed any cases of hemoperitoneum in unstable patients. In those patients where the FAST exam is negative, they do go on to get a CT scan.Dr Schecter mentioned his nervousness in observing this particular patient population. I can't agree more. I get very nervous observing these patients, and we attempt to convey that nervousness to our residents. They are very diligent in following these patients and ensure that we don't miss any of these injuries.The next question was also about the 17 patients who were diagnosed falsely positive by CT scan and if we would recommend DPL or repeat CT scan in this situation. As I mentioned before, we would admit these patients for observation and if there were any question, we would repeat the CT scan. We would not recommend a DPL. There are some authors in the literature, however, recommending that DPL and CT scan are complementary in this particular scenario.A question was asked if any patients were explored for a solid organ injury and then subsequently a hollow viscus injury was found. That did not occur in any of our patients. There was a question about what type of scanner we use. We use the GE high-speed helical scanner. We do not use oral contrast. We have gotten away from that. We think that administration of oral contrast may add unnecessary time to getting these patients properly diagnosed and that it does not appreciably improve the radiographic diagnoses of bowel injuries. It may also increase the aspiration risk.Author's Note:Due to the peer review process, the title of the paper was changed. The initial title of the abstract that was presented at the Pacific Coast Surgical Association meeting was, "Should Diagnostic Peritoneal Lavage (DPL) for Blunt Trauma Be of Historical Interest Only?"This paper was presented at the 73rd Annual Meeting of the Pacific Coast Surgical Association, Las Vegas, Nev, February 17, 2002, and is published after peer review and revision. The discussions are based on the originally submitted manuscript and not on the revised manuscript.Corresponding author and reprints: Gregory P. Victorino, MD, Department of Surgery, University of California–San Francisco, East Bay, 1411 E 31st St, Oakland, CA 94602.

Nunes, Geoffrey C.

doi: 10.1001/archsurg.137.9.1034pmid: 12215154