CT for appendicitis: No more surprises in the abdomen?

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lymphocytes and cytokines generated directly or indirectly after T-cell activation. Disruption of T cell–dependent regulatory mechanisms that normally protect the intestinal mucosa from immune-mediated injury is a feature common to many of the murine models. For example, the occurrence of colitis in mice with gene-targeted disruption of either the a or the b chains of the T-cell receptor or class II MHC is consistent with the existence of a subpopulation of MHC class II–restricted ab1T cells, which are important in preventing mucosal inflammation (Cell 1993;75:274–282). Direct evidence for the existence of T cells in normal mice that can cause colitis and T cells that can normally prevent colitis has been demonstrated experimentally by models in which immunodeficient mice are reconstituted with lymphocyte subsets, best exemplified by the CD45RB transfer model ( J Exp Med 1993;178:237–244, Immunity 1994;1:553–562). In addition to genetically determined defects in T-cell function, the contribution of the enteric microflora to IBD in these murine models has been demonstrated by attenuation of the disease when the animals are raised in a germfree environment or by use of antibiotics (Immunity 1995;3:171–174). It has been tempting to speculate that a subset of mucosal T cells that are reactive with enteric flora are responsible for the tissue injury, but direct proof has been lacking until the present report by Cong et al. They have now established the link between genetic susceptibility, T-cell reactivity to enteric flora, and causation of enteric inflammation, in one model of IBD. To what extent do the findings of immunologic reactivity to enteric flora in the murine experimental model relate to the human chronic IBD? Persuasive evidence from several sources indicates that the luminal contents of the intestine are a stimulus for persistent and relapsing Crohn’s disease. Much of this is derived from comparisons of disease relapse rates postoperatively when the fecal stream is diverted or maintained (Inflam Bowel Dis 1998;4:29–39, Gastroenterology 1998;114:398–407). More direct evidence has been obtained from studies in which mucosal inflammation has been induced in segments of the gastrointestinal tract of patients with Crohn’s disease when challenged with autologous luminal contents (Gut 1985;26:279–284, Br J Surg 1990;77:616–617, Gastroenterology 1998;114:262–267). There is also a strong conviction that much of the immunologic alterations in patients with IBD, such as antineutrophil cytoplasmic antibodies, are caused by cross-reactivity with the enteric flora (Gut 1997;40:557–558). Also, mucosal antibodies directed against intestinal bacteria have been found in patients with IBD (Gut 1996;38:365– 375). The evidence for immune reactivity to enteric bacterial antigens in the pathogenesis of IBD has immediate therapeutic implications. Two potential strategies are obvious from the work of Cong et al.: either the pathogenic effector CD4 T cells or the implicated enteric bacteria could be targeted for selective elimination. Selective elimination of CD4 subsets is technically difficult and potentially hazardous, whereas manipulation of the enteric flora is beginning to generate more enthusiasm. Based on antibody reactivity to bacterial antigens, the data from the Birmingham, Alabama, group suggest that a relatively limited number of bacterial antigens may be involved. Whether this implies that a restricted number of bacterial species are involved, and therefore potentially susceptible to eradication from the enteric luminal contents, is unclear. Alteration of bowel flora with antibiotics seems too simplistic and crude to achieve sustained therapeutic efficacy in IBD, whereas manipulation of bowel flora with probiotics is conceptually more appealing (Gut 1991;32:439–442, Scand J Gastroenterol 1997;32[suppl 222]:28–31, Gut 1998;42:2–7). There is presently a paucity of rigorously controlled and well-designed studies of probiotic therapies for gastrointestinal disorders. This is likely to

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change, and studies like that of Cong et al. and others should provide the stimulus. FERGUS SHANAHAN, M.D. GERALD C. O’SULLIVAN, M.D. J. KEVIN COLLINS, M.D.

CT FOR APPENDICITIS: NO MORE SURPRISES IN THE ABDOMEN? Rao PM, Rhea JT, Novelline RA, Mostafavi AA, McCabe CJ (Departments of Radiology and Surgery, Massachusetts General Hospital, Boston, Massachusetts). Effect of computed tomography of the appendix on treatment of patients and use of hospital resources. N Engl J Med 1998;338:141–146. Literature increasingly indicates that high-resolution computerized tomography (CT) of the appendix can reliably confirm or exclude appendicitis, with an accuracy in the range of 93%–98% (Radiology 1991;180:21–24, AJR 1997;169: 1275–1280). In the current study, Rao et al. analyzed the effects of routine appendiceal CT on both the management of patients with suspected appendicitis and on the use of hospital resources. One hundred patients seen in the emergency department with suspected appendicitis were enrolled in a prospective cohort study. All subjects were evaluated by a surgeon who, on the basis of the history, physical examination, and laboratory data, recommended hospital admission either for urgent appendectomy or for observation for suspected appendicitis. The referring surgeon was asked to estimate the clinical likelihood of appendicitis as definite (80%–100%), probable (60%– 79%), equivocal (40%–59%), or possible (20%–39%). Patients then underwent focused, helical, appendiceal CT after rectal instillation of 3% diatrizoate meglumine–saline. All scans were completed and interpreted by 1 of 3 emergency department radiologists within an hour of being requested. Final outcomes were determined on the basis of findings at surgery, including pathological examination. For those not undergoing surgery, clinical status was assessed for at least 2 months by clinic visits or telephone calls. Costs for removing a normal appendix and for 1 day of hospital observation were determined by retrospective analysis of the hospital’s cost database. Changes in the use of hospital resources were based on a comparison between the treatment actually delivered and the hypothetical outcomes that would have resulted if no CTs had been performed. Fifty-three patients had appendicitis confirmed at surgery. The remaining 47 patients had appendicitis ruled out by appendectomy (3), other surgery (3), or clinical follow-up (41). The CT was interpreted as positive in 53 patients and negative in 47 patients. There was one false-positive and one falsenegative CT finding. Thus, the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of appendiceal CT were all 98%. In contrast, the surgeons’ clinical assessments of the likelihood of appendicitis were relatively inaccurate. The proportion of patients with confirmed appendi-

December 1998

citis was 78% for those rated ‘‘definitely appendicitis,’’ 56% for ‘‘probable appendicitis,’’ 33% for ‘‘equivocally appendicitis,’’ and 44% for cases rated ‘‘possibly appendicitis.’’ The authors report that if CT had been the sole determinant of treatment, there would have been 63 changes in treatment strategy for 59 patients. These would have included the prevention of an unnecessary appendectomy in 13 patients (total savings of $47,281), avoidance of a hospital admission in 18 patients, and prevention of 50 days of inpatient observation (total savings of $20,250). After subtracting the cost of the 100 appendiceal CT scans ($22,800), the projected net savings per patient was $447. The authors conclude that routine appendiceal CT not only improves patient care but also significantly reduces the use of hospital resources. Comment. It has been more than 100 years since Reginald Fitz initially described appendicitis (Am J Med Sci 1886;92:321–346). Since then, despite dramatic advances, the accurate diagnosis of this condition has remained a challenge. Traditionally, the diagnosis of appendicitis has been based on symptoms and physical findings. Diagnostic studies have generally been considered ancillary. To improve on the accuracy of clinical judgment, numerous scoring systems have been developed and tested (Eur J Surg 1997;163:831– 838). Unfortunately, none has consistently been shown to improve on the clinical acumen of an experienced surgeon. Neither has ultrasonography proven routinely useful in diagnosis. It has a sensitivity of only about 75%, and it is least sensitive in patients with perforation (N Engl J Med 1987;317:666–669). Rao et al. now present the strongest challenge yet to the doctrine that the diagnosis of appendicitis is strictly a clinical one. Building on their earlier studies on appendiceal CT, they have developed a rapid technique that avoids the need for oral or intravenous contrast while preserving a high degree of accuracy (Radiology 1997;202:139–144). They show that a focused scan of the appendix not only reduces the number of unnecessary appendectomies—a laudable goal—but also saves resources. Most of the projected cost savings that accrued in this study came from avoiding unnecessary appendectomies, which averaged 16 times the cost of an appendiceal CT. Savings were further augmented by the reduced costs for a limited appendiceal CT compared with a complete abdominal study, and from a reduction in unnecessary days of inpatient observation. Although the conclusions of the study are provocative, it is important to consider the possible sources of bias that could have influenced the results. It is well-known that diagnostic tests are often less effective in clinical practice than they had been in preceding clinical trials ( JAMA 1995;274:645–651). The design of the current study makes it particularly susceptible to verification bias. This occurs when patients with positive diagnostic test results are preferentially referred to receive verification by the gold standard. In this study, the test being evaluated (appendiceal CT) influenced the decision to perform the reference standard (appendectomy with pathology). The fact that patients were well 2 months after enrollment does not entirely exclude the possibility of self-limited appendicitis. Thus, some scans may have been falsely negative had the patients undergone surgery while they were symptomatic. That such abortive episodes of appendicitis occur is fairly well accepted (Am Surg 1994;60:217). In fact, the authors suggest that their one falsely positive CT report may have represented a case of appendicitis that spontaneously resolved without surgery (AJR 1997;169:1275–1280).

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The study design may also have contributed to inaccurate calculation of cost saving. Had the patients been randomized to two groups, then cost data could have been gathered prospectively to assess resource utilization. In the absence of this, the investigators substituted assumptions regarding utilization that may have been incorrect. For example, most of the savings are calculated from the 13 patients who ‘‘avoided unnecessary appendectomy’’ because of a negative appendiceal CT. In reality, 3 patients underwent appendectomy despite a negative scan. In practice, it is likely that surgeons will occasionally operate in spite of the CT results. This reality is not reflected in the utilization analysis. Similarly, significant savings were calculated for the group of patients who underwent immediate surgery after a positive scan, rather than inpatient observation. The savings are based on two assumptions: that a positive scan results in immediate surgery and that without the scan patients would have been hospitalized for a full day before undergoing an appendectomy. However, it is likely that not all appendectomies were immediate, and that in many cases, clinical progression of patients under observation would have dictated the need for surgery before 24 hours had elapsed, thus eroding much of the cost savings. Finally, the authors calculate the savings of 1 day of hospital observation in 18 patients with negative scans. Yet it is unclear what additional hospital resources these patients may have utilized either before or after their discharge. Only a study with careful prospective clinical follow-up could exclude cost shifting to the outpatient venue. Aside from concerns about methodology, there are reasons to anticipate that the results of this study may not be generalizable to other practice settings. For starters, helical CT scan may not be available at all institutions. Further, the scans were interpreted by 3 radiologists who are widely published in this area, very adept at interpreting appendiceal CT, and available in the emergency department around the clock. Whether the high level of proficiency Rao et al. have achieved can be duplicated by others remains to be seen. Further, if equipment and staff are not always immediately available, it is unclear whether appendiceal CT would have the same impact when performed and interpreted later in the course of this rapidly evolving disease. In addition, cost and efficacy data from this study are not necessarily applicable to patients who undergo complete abdominal CT scanning or to those who receive alternate methods of contrast administration. Finally, there is the important issue of whether local community surgeons will accept and act on the CT results. In light of the above, where should appendiceal CT fit in the evaluation of patients with suspected appendicitis? Should CT be performed uniformly, or should it only be applied in equivocal cases? The investigators appear to favor universal application and would cite that even subjects who were rated ‘‘definitely appendicitis’’ had a 22% chance of not having the disease at all. Nonetheless, those charged with the direct management of these patients would argue that there would always remain a group of patients for whom an exploratory laparotomy is considered a surgical imperative, regardless of radiological findings. Given the above, and the fact that there is currently no evidence to suggest that any one subset of patients is more likely to benefit from appendiceal CT than another (Arch Surg 1998;133:373– 377), this debate will most certainly continue. Although gastroenterologists are not often involved in the initial management of patients with appendicitis, they are occasionally asked to see a patient with undiagnosed abdominal pain who is considered unlikely to have a ‘‘surgical’’ abdomen. Choosing to admit such a patient for observation is becoming increasingly difficult to justify, particularly when the costs for a day of hospitalization often exceed those for a CT scan. Early appendiceal (or abdominal) CT performed

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by a skilled radiologist should facilitate identification of those patients who can be safely discharged, as well as those who indeed do require the skills of a surgeon. DOUGLAS J. ROBERTSON, M.D. IAN S. GRIMM, M.D.

Reply. Drs. Robertson and Grimm nicely encapsulate the major findings of our recent paper and raise the concerns that diagnostic tests are often less effective in clinical practice than in preceding clinical trials, and that helical CT and experienced interpreters are not currently available everywhere at all hours. These are important issues, and I hope that over time most centers will have the equipment and personnel available most or all hours of the day to offer clinicians and patients this useful imaging procedure. They also raise concern about CT false-negative results in patients with normal CT findings but self-limited appendicitis. In practice, nearly all patients with appendicitis excluded at CT have a patent lumen appendix and/or an alternative condition demonstrated; these patients cannot reasonably be thought to have appendicitis. This summary points out several potential causes of overestimation of cost savings. The costs cited in our article are indeed estimates and are based on several assumptions. However, other cost savings were not quantified, including reduction in disability and in lost productivity that would occur with more timely diagnoses and better patient care. Widespread availability and frequent use of appendiceal CT has the potential to provide immediate, definitive, and correct diagnoses in patients with clinically suspected appendicitis. Patient management is improved, mainly because of marked reduction in unnecessary appendectomies. Resource expenditure is lessened, mainly because of the large disparity in the costs of appendiceal CT compared with an unnecessary appendectomy. The potential for simultaneous improvement in patient care and reduction in hospital costs argues strongly for implementation and frequent use of appendiceal CT. PATRICK M. RAO, M.D.

TUMOR PROGRESSION IN THE INTESTINE: SMAD ABOUT YOU Takaku K, Oshima M, Miyoshi H, Matsui M, Seldin MF, Taketo MM (Banyu Tsukuba Research Institute, Tsukuba, Japan; Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo Japan; and Department of Biological Chemistry, University of California, Davis, California). Intestinal tumorigenesis in compound mutant mice of both Dpc4 (Smad 4) and Apc genes. Cell 1998;92:645–656. Colorectal cancers arise through a multistep process during which genetic changes occur over long periods of time (Cell 1996;87:159–170). Chromosomal abnormalities have been reported in colorectal carcinomas for more than a decade, and identification of allelic losses, particularly at chromosome locations 5q, 17p, and 18q provided early clues to the presence of tumor-suppressor genes in the colon. The rate-limiting step for initiation of most colorectal cancers is mutation of the adenomatous polyposis coli (APC) gene on chromosome 5 that acts as a gatekeeper of colonic epithelial proliferation. APC functions to integrate signals from a variety of sources, transmitting them to the nucleus through b-catenin, a downstream effector of the Wnt/Tcf signaling pathway (Science

1997;275:1787–1790). APC is mutated in the earliest lesions in both inherited and sporadic adenomas. However, the progression from adenoma to invasive carcinoma requires additional genetic alterations, and the presence of a tumorsuppressor gene on chromosome 18q is suggested by frequent loss of heterozygosity of DNA markers at this location in colorectal cancers (Science 1990;247:49–56). Indeed, patients whose tumors have deletions of chromosome 18q may have a worse prognosis than patients with this region intact in their tumors (N Engl J Med 1994;331:213–221, Gastroenterology 1998;114:1180–1187). An early candidate for the tumorsuppressor gene on chromosome 18 was the DCC (deleted in colon cancer) gene. DCC is lost in more than 70% of colorectal cancers, and its homology to neural cell adhesion molecules suggested a role in cell–cell adhesion. Recently DCC has been shown to be a receptor for the axonal chemoattractant netrin 1, however, making its role as a tumor-suppressor suspect (Nature 1997;386:796–804). DPC4 (SMAD4) is another candidate tumor-suppressor gene whose inactivation may play a role in development of colorectal, pancreatic, and other cancers. DPC4 belongs to the SMAD gene family involved in the signal transduction pathways activated through the transforming growth factor (TGF)-b family receptors (Trends Cell Biol 1997;7:187–192). The present study by Takaku et al. (Cell 1998;92:645–656) provides convincing evidence that mutations in DPC4 (SMAD4) play a significant role in the malignant progression of some colorectal tumors. ApcD716 knockout mice contain a mutation in Apc, the mouse homologue of APC, and are a model for human familial adenomatous polyposis (FAP) (Cell 1996;87:803–809). These mice develop numerous adenomatous polyps in the small intestine and colon, but actual carcinomas are uncommon (Proc Natl Acad Sci USA 1995;92:4482–4486, Cancer Res 1997;57: 1644–1649). To determine the role of mutations in DPC4 in colonic carcinogenesis, Takaku et al. constructed knockout mice in which the mouse homologue Dpc4 was inactivated by homologous recombination and introduced the mutation into ApcD716 mice. In mice, both Dpc4 and Apc are located on chromosome 18, and the investigators constructed compound heterozygotes (Dpc4 and Apc cis–compound heterozygotes) in which both genes are inactivated in tumors by loss of heterozygosity (LOH). This is most likely due to the loss of the entire chromosome 18 containing the wild-type alleles of Apc and Dpc4, followed by reduplication of the remaining chromosome with the knockout alleles for both genes. Thus, conditional mutant mice were created in which both Apc and Dpc4 are totally inactivated in tumor cells (cis-ApcD716 [6] Dpc4 [6]). Adenomatous polyps in the double mutant mice (ciscompound heterozygotes) were much larger than in control mice containing only the mutation in Apc, although fewer in number. Importantly, tumors in these cis-compound heterozygotes developed into malignant adenocarcinomas with heterogeneous types of cells, including mucinous signet-ring cells, and showed marked submucosal invasion. The invasive pattern in tumors increased with age in the cis-compound heterozy-