prevention is worth a pound of cure). Also the cost in human terms is high; patients with chronic hepatitis C suffer great psychological and physical distress over ...
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receive six injections each (a total of 600 injections) to prevent one case of transmission over 1 year’s time. In conclusion, we now have evidence from several sources that that old standard globulin preparation was protective. It is curious that we come to such a conclusion at the very time when that particular globulin is no longer available. It is certainly far from certain that current preparations, which contain no anti-HCV, will be satisfactory replacements. RONALD L. KORETZ, M.D.
Reply. Dr. Koretz has provided an excellent summary of our work and raises several interesting points. The observation that the two groups were comparable for most features (sex, condom use, and clinical status of HCV-infected patients) indicates that the randomization procedure was on the whole satisfactory. The small differences between the two groups (partners assigned to the IG arm were slightly older etc.) have little effect on our results. In fact, the 7 cases of infection (1 IG and 6 controls) occurred in partners whose average age was above that of the overall population studied. Exposure to risk factors was controlled also by a standardized questionnaire administered every 4 months in all the at-risk partners studied. The rate of sexual transmission of HCV is low. However, in countries with an intermediate-high HCV prevalence, and thus with a substantial number of sexually active HCV-infected subjects, the number of individuals exposed to sexually transmitted infection is not irrelevant. For instance, most of the 1.5 million anti-HCV–positive subjects in Italy are sexually active. Viewed in this light, the prevention of 1 case of infection per year obtained by administering 6 injections of IG to 100 potential at-risk partners takes on greater significance, particularly because treatment is simple, safe, and inexpensive. At the time of the trial, the direct cost of 600 IG injections was about 6 million lira (US$5000). Although difficult to estimate, cases of chronic hepatitis C are costly. In fact, the marginal cost-effectiveness required to gain a year of life in an individual treated with interferon for 12 months varies between $2300 and $53,000 depending on the patients’ age. Liver transplantation costs about $200,000. The marginal cost-effectiveness per gain of 1 year of life is acceptable up to $50,000–$100,000 (Hepatology 1997;25[suppl 1]:152S–155S). In our trial, it cost only $5000 not to gain 1 year of life, but to prevent the disease and its associated costs (an ounce of prevention is worth a pound of cure). Also the cost in human terms is high; patients with chronic hepatitis C suffer great psychological and physical distress over long periods. Moreover, one should not underestimate the impact of IG prophylaxis on the quality of life of both partners in an at-risk relationship when they learn that the risk of sexual transmission of HCV, which is low but nevertheless a reality, can be dramatically reduced. As Dr. Koretz points out, current IG preparations cannot replace the old standard preparations. We were the first to demonstrate that the ‘‘old’’ commercially available intramuscular serum IG contained high titers of neutralizing antibodies against virus C (anti-E2), whereas currently available preparations are totally devoid of these antibodies (Boll Soc Ital Biol Sper 1996;72[1–2]:69–70). The only difference between old and new preparations is that the former originated from a pool of blood containing about 2% of anti-HCV– positive blood units, whereas the latter are prepared from anti-HCV– negative blood units. This led us to conclude that the neutralizing antibodies are concentrated in the anti-HCV–positive blood units that are now discarded. Consequently, preparations obtained from only anti-HCV–positive blood should yield hyperimmune anti-HCV globulin (HCIG) containing a titer of neutralizing antibodies about 50-fold
higher than that found in the old IG. The concentration of neutralizing antibodies could be increased even further if preparations are made from blood units that contain high titers of neutralizing antibodies. HCIG should be inexpensive. In fact, unlike other hyperimmune IG (e.g., HBIG) that is produced from a limited number of selected donors, HCIG should be produced from a very large number of blood units (to contain neutralizing antibodies to different strains of HCV) that are now discarded. HCIG would be even more protective than the IG used in our trial, a smaller number of injections per year would be required, and it could be used in other at-risk situations (e.g., hemodialysis), and, as occurs for hepatitis B, for the prevention of reinfection of the liver after transplantation. MARCELLO PIAZZA, M.D.
ASSOCIATION OF PRIMARY SCLEROSING CHOLANGITIS AND COLORECTAL CANCER IN PATIENTS WITH ULCERATIVE COLITIS: IS IT TRUE AND DOES IT MATTER? Kornfeld D, Ekbom A, Ihre T (University Hospital, Uppsala, and So¨dersjukhuset, Stockholm, Sweden). Is there an excess risk for colorectal cancer in patients with ulcerative colitis and concomitant primary sclerosing cholangitis? A population based study. Gut 1997;41:522–525. Primary sclerosing cholangitis (PSC) has been reported in some but not all studies to be a risk factor for the development of colorectal cancer in patients with ulcerative colitis (UC). The authors report the results of a population-based study of the cumulative risk of colorectal cancer in patients with PSC. A population-based cohort of 125 patients diagnosed with PSC based on findings of endoscopic retrograde cholangiopancreatography and/or percutaneous transhepatic cholangiography was identified. Seventy-nine patients had concomitant inflammatory bowel disease (IBD) before the diagnosis of PSC, including 75 with UC and 4 with indeterminate colitis or Crohn’s colitis. Six additional patients were diagnosed with UC after the diagnosis of PSC. Twenty-one patients underwent a colectomy for IBD before the diagnosis of PSC. Twelve patients had colorectal cancer, including 6 diagnosed before the diagnosis of PSC. Among 104 patients with an intact colon, the cumulative risk of colorectal cancer 10 years after the diagnosis of PSC was 16%. If the analysis was confined to those 58 patients with a prior diagnosis of UC and an intact colon, the risk of colorectal cancer 10 years after the diagnosis of PSC was 25%. Using another analytical approach, the cumulative risk of colorectal cancer after the diagnosis of UC was 10%, 33%, and 44% after 10, 20, and 30 years, respectively. The authors concluded that UC and concomitant PSC seem to constitute a subgroup with high risk for colorectal cancer. Comment. In 1992 Broome et al. reported that 28% of patients with long-standing pancolonic UC who developed dysplasia or DNA aneuploidy while in a colonoscopic surveillance program had concomitant PSC, whereas there were no cases of PSC among patients who did not develop dysplasia or DNA aneuploidy (Gastroenterology 1992;102:
July 1998
1877–1880). This seminal observation led to a flurry of additional studies, which have reported conflicting results. Three studies of patients with UC and colorectal dysplasia, aneuploidy, or cancer reported an increased odds ratio of having concomitant PSC compared with controls (the combined number of patients with PSC in 2 of the studies was 17 [Gastroenterology 1992;102:1877–1880, Am J Gastroenterol 1993;88:1174–1178] and was not stated in the third study [Am J Gastroenterol 1996;91:44– 48]). In contrast, 2 other similar studies of patients with UC and colorectal dysplasia or cancer did not report an increased odds ratio of having concomitant PSC compared with controls (the combined number of patients with PSC in the two studies was 61 [Gastroenterology 1992;103:1707–1708, Cancer 1998;82:822–826]). Looking at the question another way, 5 studies from four centers of patients with concomitant PSC and UC reported an increased relative risk of developing colorectal dysplasia or cancer compared with controls (the combined number of patients with PSC in the 5 studies was 237 [Hepatology 1995;22:1404–1408, Gastroenterology 1996; 110:331–338, Am J Gastroenterol 1997;92:1285–1288, Am J Gastroenterol 1997;92:A1688, Scand J Gastroenterol 1997;32:706–711]). In contrast, 3 other similar studies of patients with PSC and UC did not report an increased relative risk of developing colorectal dysplasia or cancer compared with controls (the combined number of patients with PSC was 372 [Gastroenterology 1992;103:1707–1708, Dis Colon Rectum 1995;38:37–41, Gastroenterology 1996;110:432– 440]). The 2 latter studies used historical control data from other countries. Another variable that may be important in determining the risk of colorectal cancer in patients with PSC and UC is the intervention of liver transplantation for liver failure from PSC followed by triple immunosuppression with azathioprine, cyclosporine or tacrolimus, and corticosteroids to prevent allograft rejection. Several studies have suggested that there may be an increased risk of colorectal dysplasia and cancer in patients with concomitant UC and PSC after liver transplantation (Dis Colon Rectum 1993;36:908–912, Hepatology 1998;27:685–690); however, data are again conflicting (Gastroenterology 1996;110:331–338). In the current study, Kornfeld et al. reported strikingly high rates of colorectal cancer in a population-based cohort of Swedish patients with concomitant PSC and UC. They used historical data from population-based studies of colorectal cancer in Sweden as a control group. Interestingly, half of the observed cancers occurred before the clinical diagnosis of PSC, and the investigators raised the possibility that although PSC and colorectal cancer may be associated, the association may not be causal. Finally, this study showed that 12% of patients who did not have IBD when PSC was diagnosed developed UC during follow-up. The ideal study design to determine whether PSC is an independent risk factor for colorectal cancer in patients with concomitant UC would be a case control study in which one or more controls matched for age of UC onset, duration since UC onset, and previous liver transplantation would be identified for each member of a populationbased cohort of patients with concomitant UC and PSC. Without such a study, the question ‘‘Does the high rate of colorectal cancer in patients with PSC and IBD represent a true association or is PSC simply a surrogate marker for a group of patients with mild long-standing pancolonic UC?’’ cannot be answered. The ‘‘surrogate marker’’ explanation remains a real possibility because UC associated with PSC is nearly always pancolonic and usually has a very mild clinical course that rarely leads to colectomy for disease activity (Dis Colon Rectum 1997;40:451–456).
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To clinicians, the answer to this question may not matter. The population-based data from Kornfeld et al. in patients with concomitant UC and PSC show an ‘‘unprecedented’’ 25% cumulative rate of colorectal cancer 10 years after the diagnosis of UC. While the academics continue to debate the underlying reasons for this observation, clinicians should change their practice. With a 25% colorectal cancer rate at 10 years, it seems reasonable to begin yearly surveillance colonoscopy at the time of diagnosis of PSC in all patients with concomitant IBD, regardless of how long the IBD has been present. In patients with newly diagnosed PSC and an intact colon who do not have a previous diagnosis of IBD, an initial surveillance colonoscopy should be performed to look for subclinical UC (Dis Colon Rectum 1995;38:1301–1305). Finally, asymptomatic patients with PSC and an intact colon who are not found to have IBD at the time that PSC is diagnosed should undergo periodic (although its frequency is uncertain) endoscopic evaluation with either sigmoidoscopy or colonoscopy to watch for the development of subclinical IBD, because such progressions occur at a frequency of 12%. These changes in clinical practice should reduce mortality from colorectal cancer in patients with concomitant UC and PSC. WILLIAM J. SANDBORN, M.D. EDWARD V. LOFTUS, Jr., M.D. DAVID A. AHLQUIST, M.D.
PANCREATODUODENECTOMY FOR CHRONIC PANCREATITIS Traverso LW, Kozarek RA (Departments of General Surgery and Gastroenterology, Virginia Mason Medical Center, Seattle, Washington). Pancreatoduodenectomy for chronic pancreatitis. Ann Surg 1997;226:429–438. The goal of this study was to develop a reference standard for comparing outcomes after surgery for chronic pancreatitis. The authors therefore performed an outcome analysis of 57 consecutive patients undergoing pancreatoduodenectomy for chronic pancreatitis from 1986 to 1996. The primary indication for surgery was intractable pain caused by severe chronic pancreatitis. All patients met the definition of chronic pancreatitis proposed by the Cambridge International Workshop on Pancreatitis (Gyr KE, Singer MV, Sarles H, eds. Pancreatitis: concepts and classification. Amsterdam: Elsevier Science, 1984:239– 241). Using different imaging studies, stricture or obstruction was present in the main pancreatic duct in 55 patients, or a cyst was present and connected to the main pancreatic duct in 2 patients. Each patient in this series underwent computerized tomography (CT) scan and endoscopic retrograde cholangiopancreatography. All but 2 had visualization of the hepatomesenteric blood supply by visceral angiography (n 5 44) or CT angiogram (n 5 11). All patients fulfilled imaging criteria for markedly severe pancreatitis. Forty-seven underwent a standard Whipple or pylorus-preserving Whipple procedure, and 10 underwent total pancreatectomy. The investigators developed a list of positive and adverse outcomes, including death (8 of 57), appearance of diabetes mellitus if it was not present preoperatively (7 of 27), preservation of weight (35 of 43), subjective perception of persistence of pain after surgery (10 of 42), use of pain
