- Email: [email protected]
Adenomas of the ampulla of vater in familial adenomatous polyposis: Christian Theodore responds
628
CORRESPONDENCE
sons with successful antiretroviral therapy may also suffice to bring about spontaneous clearance.3,4 It will therefore be of great interest to functionally characterize the immunologic and virologic events that attend these uncommon but illuminating cases so that the requisite elements for clearance can be defined and even exploited therapeutically. RAYMOND T. CHUNG MA SOMSOUK Gastrointestinal Unit Massachusetts General Hospital Boston, Massachusetts 1. Berenguer M, Crippin J, Gish R, Bass N, Bostrom A, Netto G, Alonzo J, Garcia-Kennedy R, Rayon JM, Wright TL. A model to predict severe HCV-related disease following liver transplantation. Hepatology 2003;38:34 – 41. 2. Somsouk M, Lauer GM, Casson D, Terella A, Day CL, Walker BD, Chung RT. Spontaneous resolution of chronic hepatitis C virus disease after withdrawal of immunosuppression. Gastroenterology 2003;124:1946 –1949. 3. Yokozaki S, Takamatsu J, Nakano I, et al. Immunologic dynamics in hemophiliac patients infected with hepatitis C virus and human immunodeficiency virus: influence of antiretroviral therapy. Blood 2000;96:4293– 4299. 4. Perez-Olmeda M, Garcia-Samaniego J, Soriano V. Hepatitis C viremia in HIV-HCV co-infected patients having immune restoration with highly active antiretroviral therapy. [letter] AIDS 2000;14:212. doi:10.1053/j.gastro.2003.12.029
Healthy Offspring in Parents Both Receiving Thiopurines Dear Sir: In a recent study Francella et al. investigated the effects of 6-mercaptopurine (6-MP) on the outcome of pregnancy in patients with inflammatory bowel disease (IBD) and on safety of in utero exposed offsprings.1 Among 155 IBD affected females and males 325 pregnancies were examined. All pregnancies occurred after the diagnosis of IBD and were analyzed as to whether the patient had taken 6-MP before or at the time of conception. Outcomes were compared to 84 pregnancies induced before treatment with 6-MP. There was no statistical difference between both groups regarding to conception failures, defined as a spontaneous abortion, abortion secondary to a birth defect, ectopic pregnancy, embryonic pregnancy, embryonic demise, major congenital malformations, neoplasias, or increased infections. The authors concluded that the use of 6-MP before, at the time of conception or during pregnancy appears to be safe and that by discontinuing 6-MP the risk of exacerbation of IBD for fetus and mother would outweigh the potential hazards of maintaining the treatment during pregnancy. We would like to add to the literature the case of a couple of patients with Crohn’s disease (CD) who delivered a healthy baby while both mother and father were exposed to thiopurines at the time of conception. The 35-year-old woman has been treated with azathioprine (AZA) due to chronic active disease since January 2000. After 20 months of AZA treatment at a dosage of 125 mg per day (2 mg/kg bodyweight) she conceived in August 2001 in clinical remission and was advised to continue therapy throughout pregnancy. At the time of conception the 33-year-old father has continuously received 6-MP at a dose of 100 mg/d for chronic active disease since March 2001. In the medical history of the parents no spontaneous abortion was noted. After an uneventful pregnancy a healthy baby was delivered in April 2002 at a gestational age of 39 weeks. The female child had a birth
GASTROENTEROLOGY Vol. 126, No. 2
weight of 3280 g and a length of 50 cm (50th percentile; Apgar score 9/10/10). During pregnancy clinical remission was maintained. We decided to report this case, because data regarding safety of thiopurines during pregnancy in IBD patients are limited and have been discussed controversially leading to a physicians’ uncertainty whether to recommend cessation or maintenance of this immunosuppressive treatment before conceiving. Rajapakse et al. noted an increased incidence of complications of pregnancies and congenital abnormalities when fathers had received 6-MP within 3 months of fertilization.2 Although these data did not provide high evidence, the following report about a baby with a WAGR Syndrome (Wilm’s tumor, Aniridia, Gonadoblastoma, and mental retardation) fathered by an IBD patient receiving AZA intensified precariousness.3 We experienced uneventful pregnancies and observed 7 healthy children fathered by men with AZA therapy, when assessing male fertility in IBD.4 The excellent work by Francella et al. provides data based on an adequate patient cohort that treatment with 6-MP in childbearing females and males with IBD may be regarded as safe. So far, discontinuation of AZA and 6-MP treatment seems to be not longer indicated for patients planning to start a family. Our unique case enriches previous knowledge indicating that an uneventful pregnancy and a birth of a healthy offspring is conceivable when even both parents are exposed to thiopurines during conception. ANNA OEFFERLBAUER-ERNST WALTER REINISCH WOLFGANG MIEHSLER HARALD VOGELSANG CLEMENS DEJACO Department of Internal Medicine IV University of Vienna Vienna, Austria 1. Francella A, Dyan A, Bodian C, Rubin P, Chapman M, Present DH. The safety of 6-mercaptopurine for childbearing patients with inflammatory bowel disease: a retrospective cohort study. Gastroenterology 2003;124:9 –17. 2. Rajapakse RO, Korelitz BI, Zlatanic J, Baiocco PJ, Gleim GW. Outcome of pregnancies when fathers are treated with 6-mercaptopurine for inflammatory bowel disease. Am J Gastroenterol 2000;95:684 – 688. 3. Ben-Neriah Z, Ackerman Z. WAGR syndrome in a baby–the result of 6-MP treatment in a father affected by Crohn’s disease? Am J Gastroenterol 2001;96:251. 4. Dejaco C, Mittermaier C, Reinisch W, Gasche C, Waldhoer T, Strohmer H, Moser G. Azathioprine treatment and male fertility in inflammatory bowel disease. Gastroenterology 2001;121: 1048 –1053. doi:10.1053/j.gastro.2003.12.030
Adenomas of the Ampulla of Vater in Familial Adenomatous Polyposis: Christian Theodore Responds Dear Sir: First, my thanks to Carol Burke for remembering1 my question posed in 1981.2 It is always a pleasure when a woman remembers you more than 20 years later. I don’t know what to do now but I think that it is interesting to report the story of one patient from the study published in 19833 and of his son. This patient, born in 1952, had colectomy with ileorectal anastomosis in 1979 for familial adenomatous polyposis. From 1981 to 1992, the polypoid endoscopic aspect of the ampulla of Vater was
February 2004
CORRESPONDENCE
unchanged with adenomatous lesions without dysplasia on endoscopic biopsies. In 1993, 1995, 1996, the endoscopic biopsies showed adenomatous lesions with moderate dysplasia. Between 1989 and 1996, the patient was treated with sulindac (300 mg/d). In 1996, the posology was increased to 400 mg/d. This treatment was continued until 2003. In 1997 the biopsies showed only mild dysplasia. In 1998, 1999, 2000, 2001, 2002, endoscopic aspect and biopsies were normal. Since 1979, regular endoscopic polypectomies have been made on the rectal stump. The son, born in 1975, had 15 small adenomatous polyps in the caecum in 1997. He refused the colectomy and was treated by sulindac (400 mg/d) since 1997. In 1998, 2000, 2002, coloscopy was normal. In 2002, ampulla of Vater was endoscopically normal and biopsies showed adenomatous lesions with moderate dysplasia. The 2 patients have mutation of the APC gene at codon 1078 in exon 15. These cases show that sulindac can normalize an adenomatous ampulla of Vater and can induce the elimination of moderate dysplasia. If the drug is inefficient, it can be useful to increase the posology. In a given patient the drug can act on ampulla of Vater and not on the colon or the rectum and reciprocally. The future is probably in classic nonsteroidal anti-inflammatory drugs or cyclooxygenase-2 inhibitors4 associated with interventional endoscopy.5 This must be evaluated in prospective studies. CHRISTIAN THEODORE Service de Gastro-Ente´rologie Centre Me´dical de Forcilles Fe´rolles-Attilly, France 1. Burke C. Risk stratification for periampullary carcinoma in patients with familial adenomatous polyposis: does Theodore know what to do now? Gastroenterology 2001;121:1246 –1248. 2. Theodore C, Ronsse H, Leymarios J, Vitaux J, Fournier R, Breil P, Molas G, Paologgi JA. Adenomas of the ampulla of Vater in Gardner’s syndrome. What is to be done? N Engl J Med 1981;304:731. 3. Theodore C, Fournier R, Julien P-E, Molas G, Bard A, Leymarios J, Paolaggi JA. Les le´ sions ade´ nomateuses de la papille dans les polyposes ade´ nomateuses recto-coliques familiales. Inte´ re ˆt de la duode´ noscopie. Gastroenterol Clin Biol 1983;7:864 – 867. 4. Chau I, Cunningham D. Cyclooxygenase inhibition in cancer–a blind alley or a new therapeutic reality? N Engl J Med 2002;346: 1085–1087. 5. Saurin J-C. Prise en charge clinique de la polypose ade´ nomateuse familiale. Gastroenterol Clin Biol 2001;25:B31–B37. doi:10.1053/j.gastro.2003.12.031
Gastric Electrical Stimulation for Refractory Gastroparesis Dear Sir: The recent article regarding gastric electrical stimulation for the treatment of refractory gastroparesis by Abell et al.1 represents the most rigorous published investigation of this therapy to date. The
629
authors are to be congratulated for their ongoing efforts to provide effective symptomatic relief to these unfortunate and difficult patients. The published data are from the Medtronic-sponsored World Wide Anti-Vomiting and Electrical Stimulation Trial and have been previously been submitted to the FDA to obtain a Humanitarian Device Exemption.2 The patient demographics for both reports are identical. There are, however, significant discrepancies in the reported weekly vomiting frequency for the subjects in phase I of the trial randomized to the “device-on” mode. As shown in Table 1, the data submitted to the FDA led to the conclusion that gastric electrical stimulation significantly reduced vomiting severity and the magnitude of reduction was similar with the device turned on or off. This raises the strong possibility of a placebo response. The current iteration of the data leads one to conclude that gastric electrical stimulation effectively reduces vomiting frequency and that this occurs only if the device is functioning. These are very different conclusions. I applaud the efforts of these investigators for their pioneering work in this area. I would now ask them to clarify what appears to be a post hoc change in a primary study endpoint. MICHAEL P. JONES Northwestern University Medical School Division of Gastroenterology Chicago, Illinois 1. Abell T, McCallum R, Hocking M, Koch K, Abrahamsson H, LeBlanc I, Lindberg G, Konturek J, Nowak T, Quigley EMM, Tougas G, Starkebaum W. Gastric electrical stimulation for medically refractory gastroparesis. Gastroenterology 2003;125:421– 428. 2. U.S. Food and Drug Administration. H990014-EnterraTM Therapy System (formerly named Gastric Electrical Stimulation (GES) System). Issued: 31 March 2000; Accessed: 2 August 2003. http://www.fda.gov/cdrh/ode/H990014sum.html. doi:10.1053/j.gastro.2003.12.032
Reply. The issue raised by Jones was also raised by the reviewers prior to publication in GASTROENTEROLOGY. In our early reports on this study presented at DDW, ACG, and AMS as well as the FDA, vomiting frequency derived from the patient diary records was originally computed as follows: For idiopathic patients, we computed vomiting frequency as the total number of vomiting episodes recorded divided by the number of weeks in the diary period (i.e., 2), yielding a “normal average” vomiting frequency. For the diabetic patients, we defined weekly vomiting frequency as the number of episodes in a 7-day window within the 4-week diabetic diary period in which the number of episodes was the maximum for that diary period. The diabetic diary period was 4 weeks because it was felt that vomiting symptoms fluctuate more in diabetic patients than idiopathic patients, and therefore the worst week of the diary period was most representative of the patients overall symptoms. In preparing this manuscript, we decided for the sake of consistency to analyze vomiting frequency for both etiologies in the same way. Thus, for
Table 1. Reported Weekly Vomiting Frequency for all Subjects from the WAVESS Study as Reported to the FDA and Published in GASTROENTEROLOGY FDA Submission
Mean (SD) Median (25th–75th) aP
Gastroenterology Publication
Baseline
ON
OFF
Baseline
ON
OFF
47.6 (52.6) 26.3
23.0 (35.5)a 12.0a
29.0 (38.2)a 14.0a
NR 17.3 (11.8–45.7)
NR 6.8 (3.9–16.5)ab
NR 13.5 (5.5–25.4)
⬍ 0.05 vs. baseline; bP ⬍ 0.05 for “on” vs. “off.”
CORRESPONDENCE
sons with successful antiretroviral therapy may also suffice to bring about spontaneous clearance.3,4 It will therefore be of great interest to functionally characterize the immunologic and virologic events that attend these uncommon but illuminating cases so that the requisite elements for clearance can be defined and even exploited therapeutically. RAYMOND T. CHUNG MA SOMSOUK Gastrointestinal Unit Massachusetts General Hospital Boston, Massachusetts 1. Berenguer M, Crippin J, Gish R, Bass N, Bostrom A, Netto G, Alonzo J, Garcia-Kennedy R, Rayon JM, Wright TL. A model to predict severe HCV-related disease following liver transplantation. Hepatology 2003;38:34 – 41. 2. Somsouk M, Lauer GM, Casson D, Terella A, Day CL, Walker BD, Chung RT. Spontaneous resolution of chronic hepatitis C virus disease after withdrawal of immunosuppression. Gastroenterology 2003;124:1946 –1949. 3. Yokozaki S, Takamatsu J, Nakano I, et al. Immunologic dynamics in hemophiliac patients infected with hepatitis C virus and human immunodeficiency virus: influence of antiretroviral therapy. Blood 2000;96:4293– 4299. 4. Perez-Olmeda M, Garcia-Samaniego J, Soriano V. Hepatitis C viremia in HIV-HCV co-infected patients having immune restoration with highly active antiretroviral therapy. [letter] AIDS 2000;14:212. doi:10.1053/j.gastro.2003.12.029
Healthy Offspring in Parents Both Receiving Thiopurines Dear Sir: In a recent study Francella et al. investigated the effects of 6-mercaptopurine (6-MP) on the outcome of pregnancy in patients with inflammatory bowel disease (IBD) and on safety of in utero exposed offsprings.1 Among 155 IBD affected females and males 325 pregnancies were examined. All pregnancies occurred after the diagnosis of IBD and were analyzed as to whether the patient had taken 6-MP before or at the time of conception. Outcomes were compared to 84 pregnancies induced before treatment with 6-MP. There was no statistical difference between both groups regarding to conception failures, defined as a spontaneous abortion, abortion secondary to a birth defect, ectopic pregnancy, embryonic pregnancy, embryonic demise, major congenital malformations, neoplasias, or increased infections. The authors concluded that the use of 6-MP before, at the time of conception or during pregnancy appears to be safe and that by discontinuing 6-MP the risk of exacerbation of IBD for fetus and mother would outweigh the potential hazards of maintaining the treatment during pregnancy. We would like to add to the literature the case of a couple of patients with Crohn’s disease (CD) who delivered a healthy baby while both mother and father were exposed to thiopurines at the time of conception. The 35-year-old woman has been treated with azathioprine (AZA) due to chronic active disease since January 2000. After 20 months of AZA treatment at a dosage of 125 mg per day (2 mg/kg bodyweight) she conceived in August 2001 in clinical remission and was advised to continue therapy throughout pregnancy. At the time of conception the 33-year-old father has continuously received 6-MP at a dose of 100 mg/d for chronic active disease since March 2001. In the medical history of the parents no spontaneous abortion was noted. After an uneventful pregnancy a healthy baby was delivered in April 2002 at a gestational age of 39 weeks. The female child had a birth
GASTROENTEROLOGY Vol. 126, No. 2
weight of 3280 g and a length of 50 cm (50th percentile; Apgar score 9/10/10). During pregnancy clinical remission was maintained. We decided to report this case, because data regarding safety of thiopurines during pregnancy in IBD patients are limited and have been discussed controversially leading to a physicians’ uncertainty whether to recommend cessation or maintenance of this immunosuppressive treatment before conceiving. Rajapakse et al. noted an increased incidence of complications of pregnancies and congenital abnormalities when fathers had received 6-MP within 3 months of fertilization.2 Although these data did not provide high evidence, the following report about a baby with a WAGR Syndrome (Wilm’s tumor, Aniridia, Gonadoblastoma, and mental retardation) fathered by an IBD patient receiving AZA intensified precariousness.3 We experienced uneventful pregnancies and observed 7 healthy children fathered by men with AZA therapy, when assessing male fertility in IBD.4 The excellent work by Francella et al. provides data based on an adequate patient cohort that treatment with 6-MP in childbearing females and males with IBD may be regarded as safe. So far, discontinuation of AZA and 6-MP treatment seems to be not longer indicated for patients planning to start a family. Our unique case enriches previous knowledge indicating that an uneventful pregnancy and a birth of a healthy offspring is conceivable when even both parents are exposed to thiopurines during conception. ANNA OEFFERLBAUER-ERNST WALTER REINISCH WOLFGANG MIEHSLER HARALD VOGELSANG CLEMENS DEJACO Department of Internal Medicine IV University of Vienna Vienna, Austria 1. Francella A, Dyan A, Bodian C, Rubin P, Chapman M, Present DH. The safety of 6-mercaptopurine for childbearing patients with inflammatory bowel disease: a retrospective cohort study. Gastroenterology 2003;124:9 –17. 2. Rajapakse RO, Korelitz BI, Zlatanic J, Baiocco PJ, Gleim GW. Outcome of pregnancies when fathers are treated with 6-mercaptopurine for inflammatory bowel disease. Am J Gastroenterol 2000;95:684 – 688. 3. Ben-Neriah Z, Ackerman Z. WAGR syndrome in a baby–the result of 6-MP treatment in a father affected by Crohn’s disease? Am J Gastroenterol 2001;96:251. 4. Dejaco C, Mittermaier C, Reinisch W, Gasche C, Waldhoer T, Strohmer H, Moser G. Azathioprine treatment and male fertility in inflammatory bowel disease. Gastroenterology 2001;121: 1048 –1053. doi:10.1053/j.gastro.2003.12.030
Adenomas of the Ampulla of Vater in Familial Adenomatous Polyposis: Christian Theodore Responds Dear Sir: First, my thanks to Carol Burke for remembering1 my question posed in 1981.2 It is always a pleasure when a woman remembers you more than 20 years later. I don’t know what to do now but I think that it is interesting to report the story of one patient from the study published in 19833 and of his son. This patient, born in 1952, had colectomy with ileorectal anastomosis in 1979 for familial adenomatous polyposis. From 1981 to 1992, the polypoid endoscopic aspect of the ampulla of Vater was
February 2004
CORRESPONDENCE
unchanged with adenomatous lesions without dysplasia on endoscopic biopsies. In 1993, 1995, 1996, the endoscopic biopsies showed adenomatous lesions with moderate dysplasia. Between 1989 and 1996, the patient was treated with sulindac (300 mg/d). In 1996, the posology was increased to 400 mg/d. This treatment was continued until 2003. In 1997 the biopsies showed only mild dysplasia. In 1998, 1999, 2000, 2001, 2002, endoscopic aspect and biopsies were normal. Since 1979, regular endoscopic polypectomies have been made on the rectal stump. The son, born in 1975, had 15 small adenomatous polyps in the caecum in 1997. He refused the colectomy and was treated by sulindac (400 mg/d) since 1997. In 1998, 2000, 2002, coloscopy was normal. In 2002, ampulla of Vater was endoscopically normal and biopsies showed adenomatous lesions with moderate dysplasia. The 2 patients have mutation of the APC gene at codon 1078 in exon 15. These cases show that sulindac can normalize an adenomatous ampulla of Vater and can induce the elimination of moderate dysplasia. If the drug is inefficient, it can be useful to increase the posology. In a given patient the drug can act on ampulla of Vater and not on the colon or the rectum and reciprocally. The future is probably in classic nonsteroidal anti-inflammatory drugs or cyclooxygenase-2 inhibitors4 associated with interventional endoscopy.5 This must be evaluated in prospective studies. CHRISTIAN THEODORE Service de Gastro-Ente´rologie Centre Me´dical de Forcilles Fe´rolles-Attilly, France 1. Burke C. Risk stratification for periampullary carcinoma in patients with familial adenomatous polyposis: does Theodore know what to do now? Gastroenterology 2001;121:1246 –1248. 2. Theodore C, Ronsse H, Leymarios J, Vitaux J, Fournier R, Breil P, Molas G, Paologgi JA. Adenomas of the ampulla of Vater in Gardner’s syndrome. What is to be done? N Engl J Med 1981;304:731. 3. Theodore C, Fournier R, Julien P-E, Molas G, Bard A, Leymarios J, Paolaggi JA. Les le´ sions ade´ nomateuses de la papille dans les polyposes ade´ nomateuses recto-coliques familiales. Inte´ re ˆt de la duode´ noscopie. Gastroenterol Clin Biol 1983;7:864 – 867. 4. Chau I, Cunningham D. Cyclooxygenase inhibition in cancer–a blind alley or a new therapeutic reality? N Engl J Med 2002;346: 1085–1087. 5. Saurin J-C. Prise en charge clinique de la polypose ade´ nomateuse familiale. Gastroenterol Clin Biol 2001;25:B31–B37. doi:10.1053/j.gastro.2003.12.031
Gastric Electrical Stimulation for Refractory Gastroparesis Dear Sir: The recent article regarding gastric electrical stimulation for the treatment of refractory gastroparesis by Abell et al.1 represents the most rigorous published investigation of this therapy to date. The
629
authors are to be congratulated for their ongoing efforts to provide effective symptomatic relief to these unfortunate and difficult patients. The published data are from the Medtronic-sponsored World Wide Anti-Vomiting and Electrical Stimulation Trial and have been previously been submitted to the FDA to obtain a Humanitarian Device Exemption.2 The patient demographics for both reports are identical. There are, however, significant discrepancies in the reported weekly vomiting frequency for the subjects in phase I of the trial randomized to the “device-on” mode. As shown in Table 1, the data submitted to the FDA led to the conclusion that gastric electrical stimulation significantly reduced vomiting severity and the magnitude of reduction was similar with the device turned on or off. This raises the strong possibility of a placebo response. The current iteration of the data leads one to conclude that gastric electrical stimulation effectively reduces vomiting frequency and that this occurs only if the device is functioning. These are very different conclusions. I applaud the efforts of these investigators for their pioneering work in this area. I would now ask them to clarify what appears to be a post hoc change in a primary study endpoint. MICHAEL P. JONES Northwestern University Medical School Division of Gastroenterology Chicago, Illinois 1. Abell T, McCallum R, Hocking M, Koch K, Abrahamsson H, LeBlanc I, Lindberg G, Konturek J, Nowak T, Quigley EMM, Tougas G, Starkebaum W. Gastric electrical stimulation for medically refractory gastroparesis. Gastroenterology 2003;125:421– 428. 2. U.S. Food and Drug Administration. H990014-EnterraTM Therapy System (formerly named Gastric Electrical Stimulation (GES) System). Issued: 31 March 2000; Accessed: 2 August 2003. http://www.fda.gov/cdrh/ode/H990014sum.html. doi:10.1053/j.gastro.2003.12.032
Reply. The issue raised by Jones was also raised by the reviewers prior to publication in GASTROENTEROLOGY. In our early reports on this study presented at DDW, ACG, and AMS as well as the FDA, vomiting frequency derived from the patient diary records was originally computed as follows: For idiopathic patients, we computed vomiting frequency as the total number of vomiting episodes recorded divided by the number of weeks in the diary period (i.e., 2), yielding a “normal average” vomiting frequency. For the diabetic patients, we defined weekly vomiting frequency as the number of episodes in a 7-day window within the 4-week diabetic diary period in which the number of episodes was the maximum for that diary period. The diabetic diary period was 4 weeks because it was felt that vomiting symptoms fluctuate more in diabetic patients than idiopathic patients, and therefore the worst week of the diary period was most representative of the patients overall symptoms. In preparing this manuscript, we decided for the sake of consistency to analyze vomiting frequency for both etiologies in the same way. Thus, for
Table 1. Reported Weekly Vomiting Frequency for all Subjects from the WAVESS Study as Reported to the FDA and Published in GASTROENTEROLOGY FDA Submission
Mean (SD) Median (25th–75th) aP
Gastroenterology Publication
Baseline
ON
OFF
Baseline
ON
OFF
47.6 (52.6) 26.3
23.0 (35.5)a 12.0a
29.0 (38.2)a 14.0a
NR 17.3 (11.8–45.7)
NR 6.8 (3.9–16.5)ab
NR 13.5 (5.5–25.4)
⬍ 0.05 vs. baseline; bP ⬍ 0.05 for “on” vs. “off.”