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GIH clinical research 2003–2004: The year in review
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2004;2:1043–1047
REVIEWS GIH Clinical Research 2003–2004: The Year in Review MICHAEL CAMILLERI Mayo Clinic, Rochester, Minnesota
This article summarizes the clinical research advances in gastroenterology and hepatology that were reviewed during the Plenary Session of the American Gastroenterological Association’s Annual Meeting in May 2004 in New Orleans, Louisiana. The clinical research advances included the efficacy of infliximab in the treatment of fistulizing Crohn’s disease, survival after isolated intestinal transplantation, the role of endoscopic treatment of bleeding peptic ulcers and Barrett’s esophagus, the recurrence of cancer after laparoscopic colectomy, the impact of microsatellite instability on the response to adjuvant chemotherapy with 5-fluorouracil (5-FU), the epidemiology of obesity and its response to low-carbohydrate diets, the potential role of gastrointestinal factors in the development of obesity, and, the newly appreciated condition, autoimmune pancreatitis with associated cholangitis. Clinical research advances will impact the management of digestive diseases.
his article highlights a selection of the advances in clinical research in Gastroenterology and Hepatology, published in peer-reviewed journals in 2003 and 2004.
T
Biologics in Inflammatory Bowel Disease The ACCENT II trial report1 assessed the effect of infliximab (anti–tumor necrosis factor-␣1, tumor necrosis factor-␣ antibody) in the treatment of fistulizing Crohn’s disease. In 195 patients whose fistula had responded (closed) at the end of 14 weeks of standard anti–tumor necrosis factor-␣ therapy, a randomized trial was performed to compare maintenance therapy with 5 mg/kg of infliximab vs. placebo. At the end of 1 year of maintenance therapy, infliximab was associated with a significantly longer time (⬎40 vs. 14 wk) to loss of response (recrudescence of fistulas), a higher rate of complete closure of fistulas (36% vs. 19% at wk 54), a decrease in clinical activity of Crohn’s disease (Figure 1), an improvement in the quality of life, and an acceptable safety profile. During the course of the 1-year study, it also was necessary to cross
50 of 99 placebo-treated patients over to the infliximab arm of the study, and 28 of 96 patients initially randomized to 5 mg/kg of infliximab required an increase in the dose to 10 mg/kg. Although infliximab was associated with more infusion reactions and formation of antinuclear antibodies and anti– double-stranded DNA antibodies, the overall prevalence of serious adverse events was greater in the placebo arm of the maintenance study. These data confirm the efficacy of this biologic treatment for the management of fistulae, one of the remaining significant challenges in management of inflammatory bowel disease. Another novel biologic agent that was featured in a trial of patients with mild to moderate ulcerative colitis was recombinant human epithelial growth factor [EGF].2 EGF is a potent mitogenic peptide, produced by salivary and duodenal Brunner’s glands, that stimulates healing. In humans, topical EGF enhances healing of skin wounds and systemic EGF is beneficial for necrotizing enterocolitis in neonates. In the study reported, daily enemas were administered for 14 days containing human recombinant EGF or carrier, expressed in Saccharomyces cerevisiae. The preparation consists of 60% EGF1–52 and 40% EGF1–51. The bioactivity of the recombinant form is equivalent to that of full-length EGF1–53. Patients with mild to moderate ulcerative left-sided colitis or proctitis were allowed to continue mesalamine enemas. Significant improvements in ulcerative colitis disease activity index scores were recorded at 2 and 4 weeks of treatment. The role of this form of treatment alone in mild to moderate disease severity or as adjuvant treatment in severe disease needs to be established.
Abbreviations used in this paper: EGF, epidermal growth factor; 5-FU, 5-fluorouracil. © 2004 by the American Gastroenterological Association 1542-3565/04/$30.00 PII: 10.1053/S1542-3565(04)00448-3
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CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 2, No. 12
coagulation,6 were both shown to effectively treat early adenocarcinoma or high-grade dysplasia in Barrett’s esophagus. These preliminary studies showed endoscopic mucosal resection and photodynamic therapy to be a viable, less-morbid alternative to standard esophagectomy in early Barrett’s adenocarcinoma relative to a concomitant series of esophagectomy-treated patients.5 Argon beam coagulation was associated with similar survival in patients with Barrett’s metaplasia and highgrade dysplasia to that expected of the control population, projected out to 7 years. Figure 1. Time to loss of response among 195 of 282 patients with a response (fistula closure) at randomization treated with maintenance infliximab or placebo. Reprinted with permission from Sands et al.1
Isolated Intestinal Transplantation A paradigm shift in intestinal transplantation is represented by the observations that graft survival and patient survival are enhanced dramatically3 by the use of isolated intestinal transplants (in lieu of the multivisceral approach favored in the past) and the inclusion of sirolimus in the prevention of rejection. These approaches have been applied to patients (adults and children) requiring transplant predominantly for short-gut syndrome. Other indications were tumors and dysmotility and hypersecretory states. The patient and graft survivals were 88% and 71%, respectively, at 3 years, and graft survival was enhanced by the adoption of sirolimus in the immunosuppressive regimens (3-year survival of 88% with sirolimus vs. 50% without sirolimus).
Advances in Endoscopic Therapy for Bleeding Peptic Ulcers and Barrett’s Esophagus A randomized study of 164 patients tested the role of endoscopic therapy in patients receiving omeprazole for bleeding ulcers with nonbleeding visible vessels or adherent clots.4 Rebleeding rates, morbidity, and mortality were compared over the 30 days after admission for the index hemorrhage (Figure 2). Endoscopic therapy significantly decreased the likelihood of rebleeding before hospital discharge (0% vs. 9.9%, P ⫽ .01), or during the first 30 days (1.1% vs. 11.6%, P ⫽ .009), and decreased the median number of units of blood transfused by 1 unit. Mortality was halved from 5.1% for the group treated with omeprazole alone to 2.6% in those receiving combined endoscopic therapy and intravenous omeprazole. Two forms of endoscopic therapy, endoscopic mucosal resection and photodynamic therapy5 or argon beam
Laparoscopic Colectomy for Colorectal Cancer In a noninferiority trial at 48 institutions with 872 patients with adenocarcinoma of the colon randomly assigned to undergo open or laparoscopically assisted colectomy performed by credentialed surgeons, the risk for recurrence of cancer and survival were not different for all stages of cancer. The median follow-up period was 4.4 years. Perioperative recovery was faster in the laparoscopic-surgery group than in the open-colectomy group. This was reflected by a shorter median hospital stay (5 vs. 6 days, P ⬍ .001) and a briefer use of parenteral narcotics (3 vs. 4 days, P ⬍ .001) and oral analgesics (1 vs. 2 days, P ⫽ .02). The rates of intraoperative complications, 30-day postoperative mortality, complications at discharge and 60 days, hospital readmission, and reoperation were very similar between groups. These data suggest that the laparoscopic approach is an acceptable alternative to open surgery for colon cancer.7
Figure 2. Endoscopic treatment in patients on omeprazole for bleeding ulcers with nonbleeding visible vessels or adherent clots. Reprinted with permission from Sung et al.4
December 2004
Figure 3. Effect of low-carbohydrate (n ⫽ 33) vs. conventional (n ⫽ 30) diet for obesity. For the low-carbohydrate (CHO) diet: first 2 weeks, carbohydrate intake 20 g/day, then gradually increased until a stable and desired weight was achieved. Numbers refer to the number of patients completing the study period. Note the significant attrition of participants in each group. Each patient was given a copy of Dr. Atkins’ New Diet Revolution.17 Note the initial promise in weight loss is not maintained at the end of 1 year. Weight loss at 3 months, P ⫽ .001; weight loss at 12 months, P ⫽ .26. Reprinted with permission from Foster et al.16
Microsatellite Instability and Colorectal Cancer Response to Adjuvant Therapy Microsatellites are stretches of DNA in which a short motif (usually 1–5 nucleotides long) is repeated several times. In humans, a dinucleotide repeat of cytosine and adenine, (CA)n, occurs in tens of thousands of locations in the germ line.8 When microsatellites show heritable and stable differences (and hence the term heterozygosity) from person to person in the number of repeats involved, they are termed polymorphic and serve as genetic markers for mapping disease-causing genes by linkage analysis. They also serve for studying genetic deletions in tumors that may be genetic (ie, in the germ line in conditions such as hereditary nonpolyposis colon cancer), or epigenetic (not inherited) change. In the genetic disorder, microsatellites occur in the critical genetic region and virtually everywhere in the genome of the tumor. Thus, in hereditary nonpolyposis colon cancer, microsatellite alleles that have changes in length result in defective DNA-mismatch repair genes such as MSH2, MSH6, or MLH1. Epigenetic (noninherited) change may involve biallelic methylation of the promoter sequences of MLH1. Defective mismatch repair results in rapid accumulation of mutations that inactivate genes with key functions, and occurs in ⬃15% of all colorectal carcinomas. In summary, microsatellite instability involves a somatic change in length in a germ-line microsatellite allele that
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can be detected only if many cells are affected. This may result from clonal expansion typical of a neoplasm and, therefore, lead to a loss of the heterozygosity of the microsatellite alleles that are characteristic of the normal condition.8 Two recent studies8 explored the influence of microsatellite instability on the survival of patients with colorectal cancer treated with 5-fluorouracil (5-FU) adjuvant therapy. Results from the first study showed that the survival advantage from 5-FU is attributable to the beneficial effect in patients with microsatellite stability.9 The second study showed an advantage in survival for stage II or III colorectal cancer with microsatellite stability or low frequency of instability (hazard ratio for death, 0.69; 95% confidence interval, 0.50 – 0.94; P ⫽ .02). For adjuvant 5-FU in patients with high-frequency microsatellite instability, a reverse trend was observed (hazard ratio for death, 2.17; 95% confidence interval, 0.84 –5.55; P ⫽ .10) with an apparent, although nonsignificant, survival disadvantage for the adjuvant 5-FU therapy group.10 These data suggest that testing for microsatellite stability may help identify the likelihood of response in patients with stage II or III colon cancer being considered for adjuvant chemotherapy.
Obesity: Epidemiology, Low-Carbohydrate Diet, and Gut Dysfunctions The increasing prevalence of obesity with the associated increase in diabetes has been documented fully from 1991 to 2001.11 Moreover, there is a higher proportionate increase in prevalence in the higher body mass groups.12 These trends have been associated with increased numbers of bariatric surgery in the United States,
Figure 4. Appetite scores are decreased after PYY3–36 infusion. Reprinted with permission from Batterham et al.18
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predominantly Roux-Y gastric bypass and adjustable gastric banding.13 It is estimated that 2.8% of the US population is eligible for obesity surgery based on National Institutes of Health consensus guidelines. Of these, a disproportionate number are black, poorly educated, or impoverished, and 38% rely on Medicare or Medicaid for their health insurance.14 Two studies explored the efficacy of low-carbohydrate vs. conventional low-fat diets in the treatment of obesity.15,16 Although the low-carbohydrate diet17 trials presented challenges because of low adherence and high attrition rates, general comments can be made to summarize these controlled trials (Figure 3). First, the degree of weight loss was variable and, although significant at 3 and 6 months, longer-term efficacy (1 year) of the lowcarbohydrate diet is not proven, and much of the weight lost was regained. Nevertheless, there are salutary effects of being involved in such trials because the low-carbohydrate diet was associated with increased high-density lipoprotein cholesterol and decreased triglyceride levels, and both low-carbohydrate and low-fat diets significantly decreased diastolic blood pressure and the insulin response to an oral glucose load. The diets themselves seem unimportant; the behavioral and other changes involved may lead to the salutary effects of dieting. The poor efficacy of diets and generally poor results with appetite-reducing pharmacotherapy in the past have led to the strong advocacy for bariatric surgery for severe obesity or for those with moderate obesity associated with risk factors such as diabetes. Surgery is aimed at decreasing the reservoir function of the stomach. Two intriguing studies point to the potential importance of gastrointestinal pathophysiology in obesity. The first observations pertain to the lower plasma peptide YY during fasting and after a standard meal in obese relative to lean controls.18 Second, exogenous PYY3–36 was associated with decreased food intake and appetite over a 12-hour period after infusion (Figure 4).18 Third, satiation during a challenge test was delayed in patients with a larger body mass index, but fasting gastric volume was an independent determinant of satiation (feeling of fullness that stops an individual from eating more19). Taken together, these data suggest that there may be potential for decreasing gastric volume during fasting or retarding gastric emptying in the management of obesity. The effect of neurohormonal modulators on gastric physiology should be explored further as a potential means to modify calorie intake as an alternative to pharmacotherapy or surgery for obesity. Clearly, further studies are necessary and appear to be of high priority, given the prevalence and morbidity associated with obesity.
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 2, No. 12
Figure 5. Percutaneous transhepatic cholangiogram showing multiple strictures of the hilar and intrahepatic bile ducts (right) in a patient with pancreatic strictures (left) caused by autoimmune pancreatitis. Intraductal ultrasound shows marked thickening of the hilar duct wall (arrowheads). Reprinted with permission from Hirano et al.20
Autoimmune Pancreatitis With Cholangitis A syndrome of autoimmune pancreatitis with stricture of the pancreatic duct has been described and is associated with significant biliary involvement with thickening or strictures (Figure 5). This is a subgroup of patients with autoimmune pancreatitis. Strictures are usually at the hilus or intrahepatic ducts and appear in 75% of patients by the 4-year follow-up evaluation.20 Complications include the development of pancreatic mass with lymphoplasmacyte infiltration, severe fibrosis, and acinar cell depletion. Interestingly, there is a similar appearance of liver biopsy specimens, which show lymphoplasmacyte infiltration and fibrosis in the portal area. The fibrotic reaction in the liver may sometimes appear similar to a mass lesion, and may require biopsy examination to exclude malignancy. Interestingly, 5 of 8 patients who received steroids for autoimmune pancreatitis and cholangitis had improvement of the cholangitis and bile duct strictures. Clinicians need to be aware of this diagnosis and the potential of masses including so-called tumefactive pancreatitis that require differentiation from pancreatic tumors.21
Conclusion Several reports on clinical diagnosis, endoscopic and pharmacologic treatments, and surgical intervention in the past year provide new opportunities to translate research advances to the practice of gastroenterology and hepatology.
References 1. Sands BE, Anderson FH, Bernstein CN, Chey WY, Feagan BG, Fedorak RN, Kamm MA, Korzenik JR, Lashner BA, Onken JE,
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2.
3.
4.
5.
6.
7.
8. 9.
10.
11.
Rachmilewitz D, Rutgeerts P, Wild G, Wolf DC, Marsters PA, Travers SB, Blank MA, van Deventer SJ. Infliximab maintenance therapy for fistulizing Crohn’s disease. N Engl J Med 2004;350:876 – 885. Sinha A, Nightingale JMD, West KP, Berlanga-Acosta J, Playford RJ. Epidermal growth factor enemas with oral mesalamine for mild-to-moderate left-sided ulcerative colitis or proctitis. N Engl J Med 2003;349:350 –357. Fishbein TM, Kaufman SS, Florman SS, Gondolesi GE, Schiano T, Kim-Schluger L, Magid M, Harpaz N, Tschernia A, Leibowitz A, LeLeiko NS. Isolated intestinal transplantation: proof of clinical efficacy. Transplantation 2003;76:636 – 640. Sung JY, Chan FKL, Lau JYW, Yung M-Y, Wai-Keung L, Wu JCY, Ng EKW, Chung SSC. The effect of endoscopic therapy in patients receiving omeprazole for bleeding ulcers with nonbleeding visible vessels or adherent clots: a randomized comparison. Ann Intern Med 2003;139:237–243. Pacifico RJ, Wang KK, Wongkeesong L-M, Buttar NS, Lutzke LS. Combined endoscopic mucosal resection and photodynamic therapy versus esophagectomy for management of early adenocarcinoma in Barrett’s esophagus. Clin Gastroenterol Hepatol 2003;1:252–257. Attwood SE, Lewis CJ, Caplin S, Hemming K, Armstrong G. Argon beam plasma coagulation as therapy for high-grade dysplasia in Barrett’s esophagus. Clin Gastroenterol Hepatol 2003;1:258 –263. Nelson H, Sargent DJ, Wieand S, Fleshman J, Anvari M, Stryker SJ, Beart RW Jr, Hellinger M, Flanagan R Jr, Peters W, Ota D (The Clinical Outcomes of Surgical Therapy Study Group). A comparison of laparoscopically assisted and open colectomy for colon cancer. N Engl J Med 2004;350:2050 –2059. de la Chapelle A. Microsatellite instability. N Engl J Med 2003;349:209 –210. Carethers JM, Smith EJ, Behling CA, Nguyen L, Tajima A, Doctolero RT, Cabrera BL, Goel A, Arnold CA, Miyai K, Boland CR. Use of 5-fluorouracil and survival in patients with microsatellite-unstable colorectal cancer. Gastroenterology 2004;126:394 – 401. Ribic CM, Sargent DJ, Moore MJ, Thibodeau SN, French AJ, Goldberg RM, Hamilton SR, Laurent-Puig P, Gryfe R, Shepherd LE, Tu D, Redston M, Gallinger S. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med 2003;349:247–257. Mokdad AH, Ford ES, Bowman BA, Dietz WH, Vinicor F, Bales VS, Marks JS. Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. JAMA 2003;289:76 –79.
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12. Sturm R. Increases in clinically severe obesity in the United States, 1986-2000. Arch Intern Med 2003;163:2146 –2148. 13. Steinbrook R. Surgery for severe obesity. N Engl J Med 2004;350:1075–1079. 14. Livingston EH, Ko CY. Socioeconomic characteristics of the population eligible for obesity surgery. Surgery 2004;135:288 –296. 15. Samaha FF, Iqbal N, Seshadri P, Chicano KL, Daily DA, McGrory J, Williams T, Williams M, Gracely EJ, Stern L. A low-carbohydrate as compared with a low-fat diet in severe obesity. N Engl J Med 2003;348:2074 –2081. 16. Foster GD, Wyatt HR, Hill JO, McGuckin BG, Brill C, Mohammed BS, Szapary PO, Rader DJ, Edman JS, Klein S. A randomized trial of a low-carbohydrate diet for obesity. N Engl J Med 2003;348:2082–2090. 17. Atkins RC. Dr Atkins’ new diet revolution. New York: Avon Books, 1998. 18. Batterham RL, Cohen MA, Ellis SM, Le Roux CW, Withers DJ, Frost GS, Ghatei MA, Bloom SR. Inhibition of food intake in obese subjects by Peptide YY3–36. N Engl J Med 2003;349:941–948. 19. Delgado-Aros S, Cremonini F, Castillo EJ, Chial HJ, Burton DD, Ferber I, Camilleri M. Independent influences of body mass and gastric volumes on satiation in humans. Gastroenterology 2004;126:432– 440. 20. Hirano K, Shiratori Y, Komatsu Y, Yamamoto N, Sasahira N, Toda N, Isayama H, Tada M, Tsujino T, Nakata R, Kawase T, Katamoto T, Kawabe T, Omata M. Involvement of the biliary system in autoimmune pancreatitis: a follow-up study. Clin Gastroenterol Hepatol 2003;1:453– 464. 21. Yadav D, Notahara K, Smyrk TC, Clain JE, Pearson RK, Farnell MB, Chari ST. Idiopathic tumefactive chronic pancreatitis: clinical profile, histology, and natural history after resection. Clin Gastroenterol Hepatol 2003;1:129 –135.
Address requests for reprints to: Michael Camilleri, MD, Mayo Clinic, Charlton 8-110, 200 First Street Southwest, Rochester, Minnesota 55905. e-mail: [email protected] Supported in part by grants #RO1-DK54681 and #K24-DK-02638 from the National Institutes of Health. M.C. has received a research grant (2000 –2003) from Johnson and Johnson, which markets infliximab; however, the grant was for work unrelated to that drug or disease. Presented at the Plenary Session of the American Gastroenterological Association Annual Meeting in New Orleans, Louisiana, in May, 2004.
REVIEWS GIH Clinical Research 2003–2004: The Year in Review MICHAEL CAMILLERI Mayo Clinic, Rochester, Minnesota
This article summarizes the clinical research advances in gastroenterology and hepatology that were reviewed during the Plenary Session of the American Gastroenterological Association’s Annual Meeting in May 2004 in New Orleans, Louisiana. The clinical research advances included the efficacy of infliximab in the treatment of fistulizing Crohn’s disease, survival after isolated intestinal transplantation, the role of endoscopic treatment of bleeding peptic ulcers and Barrett’s esophagus, the recurrence of cancer after laparoscopic colectomy, the impact of microsatellite instability on the response to adjuvant chemotherapy with 5-fluorouracil (5-FU), the epidemiology of obesity and its response to low-carbohydrate diets, the potential role of gastrointestinal factors in the development of obesity, and, the newly appreciated condition, autoimmune pancreatitis with associated cholangitis. Clinical research advances will impact the management of digestive diseases.
his article highlights a selection of the advances in clinical research in Gastroenterology and Hepatology, published in peer-reviewed journals in 2003 and 2004.
T
Biologics in Inflammatory Bowel Disease The ACCENT II trial report1 assessed the effect of infliximab (anti–tumor necrosis factor-␣1, tumor necrosis factor-␣ antibody) in the treatment of fistulizing Crohn’s disease. In 195 patients whose fistula had responded (closed) at the end of 14 weeks of standard anti–tumor necrosis factor-␣ therapy, a randomized trial was performed to compare maintenance therapy with 5 mg/kg of infliximab vs. placebo. At the end of 1 year of maintenance therapy, infliximab was associated with a significantly longer time (⬎40 vs. 14 wk) to loss of response (recrudescence of fistulas), a higher rate of complete closure of fistulas (36% vs. 19% at wk 54), a decrease in clinical activity of Crohn’s disease (Figure 1), an improvement in the quality of life, and an acceptable safety profile. During the course of the 1-year study, it also was necessary to cross
50 of 99 placebo-treated patients over to the infliximab arm of the study, and 28 of 96 patients initially randomized to 5 mg/kg of infliximab required an increase in the dose to 10 mg/kg. Although infliximab was associated with more infusion reactions and formation of antinuclear antibodies and anti– double-stranded DNA antibodies, the overall prevalence of serious adverse events was greater in the placebo arm of the maintenance study. These data confirm the efficacy of this biologic treatment for the management of fistulae, one of the remaining significant challenges in management of inflammatory bowel disease. Another novel biologic agent that was featured in a trial of patients with mild to moderate ulcerative colitis was recombinant human epithelial growth factor [EGF].2 EGF is a potent mitogenic peptide, produced by salivary and duodenal Brunner’s glands, that stimulates healing. In humans, topical EGF enhances healing of skin wounds and systemic EGF is beneficial for necrotizing enterocolitis in neonates. In the study reported, daily enemas were administered for 14 days containing human recombinant EGF or carrier, expressed in Saccharomyces cerevisiae. The preparation consists of 60% EGF1–52 and 40% EGF1–51. The bioactivity of the recombinant form is equivalent to that of full-length EGF1–53. Patients with mild to moderate ulcerative left-sided colitis or proctitis were allowed to continue mesalamine enemas. Significant improvements in ulcerative colitis disease activity index scores were recorded at 2 and 4 weeks of treatment. The role of this form of treatment alone in mild to moderate disease severity or as adjuvant treatment in severe disease needs to be established.
Abbreviations used in this paper: EGF, epidermal growth factor; 5-FU, 5-fluorouracil. © 2004 by the American Gastroenterological Association 1542-3565/04/$30.00 PII: 10.1053/S1542-3565(04)00448-3
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CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 2, No. 12
coagulation,6 were both shown to effectively treat early adenocarcinoma or high-grade dysplasia in Barrett’s esophagus. These preliminary studies showed endoscopic mucosal resection and photodynamic therapy to be a viable, less-morbid alternative to standard esophagectomy in early Barrett’s adenocarcinoma relative to a concomitant series of esophagectomy-treated patients.5 Argon beam coagulation was associated with similar survival in patients with Barrett’s metaplasia and highgrade dysplasia to that expected of the control population, projected out to 7 years. Figure 1. Time to loss of response among 195 of 282 patients with a response (fistula closure) at randomization treated with maintenance infliximab or placebo. Reprinted with permission from Sands et al.1
Isolated Intestinal Transplantation A paradigm shift in intestinal transplantation is represented by the observations that graft survival and patient survival are enhanced dramatically3 by the use of isolated intestinal transplants (in lieu of the multivisceral approach favored in the past) and the inclusion of sirolimus in the prevention of rejection. These approaches have been applied to patients (adults and children) requiring transplant predominantly for short-gut syndrome. Other indications were tumors and dysmotility and hypersecretory states. The patient and graft survivals were 88% and 71%, respectively, at 3 years, and graft survival was enhanced by the adoption of sirolimus in the immunosuppressive regimens (3-year survival of 88% with sirolimus vs. 50% without sirolimus).
Advances in Endoscopic Therapy for Bleeding Peptic Ulcers and Barrett’s Esophagus A randomized study of 164 patients tested the role of endoscopic therapy in patients receiving omeprazole for bleeding ulcers with nonbleeding visible vessels or adherent clots.4 Rebleeding rates, morbidity, and mortality were compared over the 30 days after admission for the index hemorrhage (Figure 2). Endoscopic therapy significantly decreased the likelihood of rebleeding before hospital discharge (0% vs. 9.9%, P ⫽ .01), or during the first 30 days (1.1% vs. 11.6%, P ⫽ .009), and decreased the median number of units of blood transfused by 1 unit. Mortality was halved from 5.1% for the group treated with omeprazole alone to 2.6% in those receiving combined endoscopic therapy and intravenous omeprazole. Two forms of endoscopic therapy, endoscopic mucosal resection and photodynamic therapy5 or argon beam
Laparoscopic Colectomy for Colorectal Cancer In a noninferiority trial at 48 institutions with 872 patients with adenocarcinoma of the colon randomly assigned to undergo open or laparoscopically assisted colectomy performed by credentialed surgeons, the risk for recurrence of cancer and survival were not different for all stages of cancer. The median follow-up period was 4.4 years. Perioperative recovery was faster in the laparoscopic-surgery group than in the open-colectomy group. This was reflected by a shorter median hospital stay (5 vs. 6 days, P ⬍ .001) and a briefer use of parenteral narcotics (3 vs. 4 days, P ⬍ .001) and oral analgesics (1 vs. 2 days, P ⫽ .02). The rates of intraoperative complications, 30-day postoperative mortality, complications at discharge and 60 days, hospital readmission, and reoperation were very similar between groups. These data suggest that the laparoscopic approach is an acceptable alternative to open surgery for colon cancer.7
Figure 2. Endoscopic treatment in patients on omeprazole for bleeding ulcers with nonbleeding visible vessels or adherent clots. Reprinted with permission from Sung et al.4
December 2004
Figure 3. Effect of low-carbohydrate (n ⫽ 33) vs. conventional (n ⫽ 30) diet for obesity. For the low-carbohydrate (CHO) diet: first 2 weeks, carbohydrate intake 20 g/day, then gradually increased until a stable and desired weight was achieved. Numbers refer to the number of patients completing the study period. Note the significant attrition of participants in each group. Each patient was given a copy of Dr. Atkins’ New Diet Revolution.17 Note the initial promise in weight loss is not maintained at the end of 1 year. Weight loss at 3 months, P ⫽ .001; weight loss at 12 months, P ⫽ .26. Reprinted with permission from Foster et al.16
Microsatellite Instability and Colorectal Cancer Response to Adjuvant Therapy Microsatellites are stretches of DNA in which a short motif (usually 1–5 nucleotides long) is repeated several times. In humans, a dinucleotide repeat of cytosine and adenine, (CA)n, occurs in tens of thousands of locations in the germ line.8 When microsatellites show heritable and stable differences (and hence the term heterozygosity) from person to person in the number of repeats involved, they are termed polymorphic and serve as genetic markers for mapping disease-causing genes by linkage analysis. They also serve for studying genetic deletions in tumors that may be genetic (ie, in the germ line in conditions such as hereditary nonpolyposis colon cancer), or epigenetic (not inherited) change. In the genetic disorder, microsatellites occur in the critical genetic region and virtually everywhere in the genome of the tumor. Thus, in hereditary nonpolyposis colon cancer, microsatellite alleles that have changes in length result in defective DNA-mismatch repair genes such as MSH2, MSH6, or MLH1. Epigenetic (noninherited) change may involve biallelic methylation of the promoter sequences of MLH1. Defective mismatch repair results in rapid accumulation of mutations that inactivate genes with key functions, and occurs in ⬃15% of all colorectal carcinomas. In summary, microsatellite instability involves a somatic change in length in a germ-line microsatellite allele that
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can be detected only if many cells are affected. This may result from clonal expansion typical of a neoplasm and, therefore, lead to a loss of the heterozygosity of the microsatellite alleles that are characteristic of the normal condition.8 Two recent studies8 explored the influence of microsatellite instability on the survival of patients with colorectal cancer treated with 5-fluorouracil (5-FU) adjuvant therapy. Results from the first study showed that the survival advantage from 5-FU is attributable to the beneficial effect in patients with microsatellite stability.9 The second study showed an advantage in survival for stage II or III colorectal cancer with microsatellite stability or low frequency of instability (hazard ratio for death, 0.69; 95% confidence interval, 0.50 – 0.94; P ⫽ .02). For adjuvant 5-FU in patients with high-frequency microsatellite instability, a reverse trend was observed (hazard ratio for death, 2.17; 95% confidence interval, 0.84 –5.55; P ⫽ .10) with an apparent, although nonsignificant, survival disadvantage for the adjuvant 5-FU therapy group.10 These data suggest that testing for microsatellite stability may help identify the likelihood of response in patients with stage II or III colon cancer being considered for adjuvant chemotherapy.
Obesity: Epidemiology, Low-Carbohydrate Diet, and Gut Dysfunctions The increasing prevalence of obesity with the associated increase in diabetes has been documented fully from 1991 to 2001.11 Moreover, there is a higher proportionate increase in prevalence in the higher body mass groups.12 These trends have been associated with increased numbers of bariatric surgery in the United States,
Figure 4. Appetite scores are decreased after PYY3–36 infusion. Reprinted with permission from Batterham et al.18
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predominantly Roux-Y gastric bypass and adjustable gastric banding.13 It is estimated that 2.8% of the US population is eligible for obesity surgery based on National Institutes of Health consensus guidelines. Of these, a disproportionate number are black, poorly educated, or impoverished, and 38% rely on Medicare or Medicaid for their health insurance.14 Two studies explored the efficacy of low-carbohydrate vs. conventional low-fat diets in the treatment of obesity.15,16 Although the low-carbohydrate diet17 trials presented challenges because of low adherence and high attrition rates, general comments can be made to summarize these controlled trials (Figure 3). First, the degree of weight loss was variable and, although significant at 3 and 6 months, longer-term efficacy (1 year) of the lowcarbohydrate diet is not proven, and much of the weight lost was regained. Nevertheless, there are salutary effects of being involved in such trials because the low-carbohydrate diet was associated with increased high-density lipoprotein cholesterol and decreased triglyceride levels, and both low-carbohydrate and low-fat diets significantly decreased diastolic blood pressure and the insulin response to an oral glucose load. The diets themselves seem unimportant; the behavioral and other changes involved may lead to the salutary effects of dieting. The poor efficacy of diets and generally poor results with appetite-reducing pharmacotherapy in the past have led to the strong advocacy for bariatric surgery for severe obesity or for those with moderate obesity associated with risk factors such as diabetes. Surgery is aimed at decreasing the reservoir function of the stomach. Two intriguing studies point to the potential importance of gastrointestinal pathophysiology in obesity. The first observations pertain to the lower plasma peptide YY during fasting and after a standard meal in obese relative to lean controls.18 Second, exogenous PYY3–36 was associated with decreased food intake and appetite over a 12-hour period after infusion (Figure 4).18 Third, satiation during a challenge test was delayed in patients with a larger body mass index, but fasting gastric volume was an independent determinant of satiation (feeling of fullness that stops an individual from eating more19). Taken together, these data suggest that there may be potential for decreasing gastric volume during fasting or retarding gastric emptying in the management of obesity. The effect of neurohormonal modulators on gastric physiology should be explored further as a potential means to modify calorie intake as an alternative to pharmacotherapy or surgery for obesity. Clearly, further studies are necessary and appear to be of high priority, given the prevalence and morbidity associated with obesity.
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 2, No. 12
Figure 5. Percutaneous transhepatic cholangiogram showing multiple strictures of the hilar and intrahepatic bile ducts (right) in a patient with pancreatic strictures (left) caused by autoimmune pancreatitis. Intraductal ultrasound shows marked thickening of the hilar duct wall (arrowheads). Reprinted with permission from Hirano et al.20
Autoimmune Pancreatitis With Cholangitis A syndrome of autoimmune pancreatitis with stricture of the pancreatic duct has been described and is associated with significant biliary involvement with thickening or strictures (Figure 5). This is a subgroup of patients with autoimmune pancreatitis. Strictures are usually at the hilus or intrahepatic ducts and appear in 75% of patients by the 4-year follow-up evaluation.20 Complications include the development of pancreatic mass with lymphoplasmacyte infiltration, severe fibrosis, and acinar cell depletion. Interestingly, there is a similar appearance of liver biopsy specimens, which show lymphoplasmacyte infiltration and fibrosis in the portal area. The fibrotic reaction in the liver may sometimes appear similar to a mass lesion, and may require biopsy examination to exclude malignancy. Interestingly, 5 of 8 patients who received steroids for autoimmune pancreatitis and cholangitis had improvement of the cholangitis and bile duct strictures. Clinicians need to be aware of this diagnosis and the potential of masses including so-called tumefactive pancreatitis that require differentiation from pancreatic tumors.21
Conclusion Several reports on clinical diagnosis, endoscopic and pharmacologic treatments, and surgical intervention in the past year provide new opportunities to translate research advances to the practice of gastroenterology and hepatology.
References 1. Sands BE, Anderson FH, Bernstein CN, Chey WY, Feagan BG, Fedorak RN, Kamm MA, Korzenik JR, Lashner BA, Onken JE,
December 2004
2.
3.
4.
5.
6.
7.
8. 9.
10.
11.
Rachmilewitz D, Rutgeerts P, Wild G, Wolf DC, Marsters PA, Travers SB, Blank MA, van Deventer SJ. Infliximab maintenance therapy for fistulizing Crohn’s disease. N Engl J Med 2004;350:876 – 885. Sinha A, Nightingale JMD, West KP, Berlanga-Acosta J, Playford RJ. Epidermal growth factor enemas with oral mesalamine for mild-to-moderate left-sided ulcerative colitis or proctitis. N Engl J Med 2003;349:350 –357. Fishbein TM, Kaufman SS, Florman SS, Gondolesi GE, Schiano T, Kim-Schluger L, Magid M, Harpaz N, Tschernia A, Leibowitz A, LeLeiko NS. Isolated intestinal transplantation: proof of clinical efficacy. Transplantation 2003;76:636 – 640. Sung JY, Chan FKL, Lau JYW, Yung M-Y, Wai-Keung L, Wu JCY, Ng EKW, Chung SSC. The effect of endoscopic therapy in patients receiving omeprazole for bleeding ulcers with nonbleeding visible vessels or adherent clots: a randomized comparison. Ann Intern Med 2003;139:237–243. Pacifico RJ, Wang KK, Wongkeesong L-M, Buttar NS, Lutzke LS. Combined endoscopic mucosal resection and photodynamic therapy versus esophagectomy for management of early adenocarcinoma in Barrett’s esophagus. Clin Gastroenterol Hepatol 2003;1:252–257. Attwood SE, Lewis CJ, Caplin S, Hemming K, Armstrong G. Argon beam plasma coagulation as therapy for high-grade dysplasia in Barrett’s esophagus. Clin Gastroenterol Hepatol 2003;1:258 –263. Nelson H, Sargent DJ, Wieand S, Fleshman J, Anvari M, Stryker SJ, Beart RW Jr, Hellinger M, Flanagan R Jr, Peters W, Ota D (The Clinical Outcomes of Surgical Therapy Study Group). A comparison of laparoscopically assisted and open colectomy for colon cancer. N Engl J Med 2004;350:2050 –2059. de la Chapelle A. Microsatellite instability. N Engl J Med 2003;349:209 –210. Carethers JM, Smith EJ, Behling CA, Nguyen L, Tajima A, Doctolero RT, Cabrera BL, Goel A, Arnold CA, Miyai K, Boland CR. Use of 5-fluorouracil and survival in patients with microsatellite-unstable colorectal cancer. Gastroenterology 2004;126:394 – 401. Ribic CM, Sargent DJ, Moore MJ, Thibodeau SN, French AJ, Goldberg RM, Hamilton SR, Laurent-Puig P, Gryfe R, Shepherd LE, Tu D, Redston M, Gallinger S. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med 2003;349:247–257. Mokdad AH, Ford ES, Bowman BA, Dietz WH, Vinicor F, Bales VS, Marks JS. Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. JAMA 2003;289:76 –79.
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12. Sturm R. Increases in clinically severe obesity in the United States, 1986-2000. Arch Intern Med 2003;163:2146 –2148. 13. Steinbrook R. Surgery for severe obesity. N Engl J Med 2004;350:1075–1079. 14. Livingston EH, Ko CY. Socioeconomic characteristics of the population eligible for obesity surgery. Surgery 2004;135:288 –296. 15. Samaha FF, Iqbal N, Seshadri P, Chicano KL, Daily DA, McGrory J, Williams T, Williams M, Gracely EJ, Stern L. A low-carbohydrate as compared with a low-fat diet in severe obesity. N Engl J Med 2003;348:2074 –2081. 16. Foster GD, Wyatt HR, Hill JO, McGuckin BG, Brill C, Mohammed BS, Szapary PO, Rader DJ, Edman JS, Klein S. A randomized trial of a low-carbohydrate diet for obesity. N Engl J Med 2003;348:2082–2090. 17. Atkins RC. Dr Atkins’ new diet revolution. New York: Avon Books, 1998. 18. Batterham RL, Cohen MA, Ellis SM, Le Roux CW, Withers DJ, Frost GS, Ghatei MA, Bloom SR. Inhibition of food intake in obese subjects by Peptide YY3–36. N Engl J Med 2003;349:941–948. 19. Delgado-Aros S, Cremonini F, Castillo EJ, Chial HJ, Burton DD, Ferber I, Camilleri M. Independent influences of body mass and gastric volumes on satiation in humans. Gastroenterology 2004;126:432– 440. 20. Hirano K, Shiratori Y, Komatsu Y, Yamamoto N, Sasahira N, Toda N, Isayama H, Tada M, Tsujino T, Nakata R, Kawase T, Katamoto T, Kawabe T, Omata M. Involvement of the biliary system in autoimmune pancreatitis: a follow-up study. Clin Gastroenterol Hepatol 2003;1:453– 464. 21. Yadav D, Notahara K, Smyrk TC, Clain JE, Pearson RK, Farnell MB, Chari ST. Idiopathic tumefactive chronic pancreatitis: clinical profile, histology, and natural history after resection. Clin Gastroenterol Hepatol 2003;1:129 –135.
Address requests for reprints to: Michael Camilleri, MD, Mayo Clinic, Charlton 8-110, 200 First Street Southwest, Rochester, Minnesota 55905. e-mail: [email protected] Supported in part by grants #RO1-DK54681 and #K24-DK-02638 from the National Institutes of Health. M.C. has received a research grant (2000 –2003) from Johnson and Johnson, which markets infliximab; however, the grant was for work unrelated to that drug or disease. Presented at the Plenary Session of the American Gastroenterological Association Annual Meeting in New Orleans, Louisiana, in May, 2004.