COX-2 expression in sulindac-sulfone and placebo treated familial adenomatous polyposis patients

COX-2 expression in sulindac-sulfone and placebo treated familial adenomatous polyposis patients

AJG – September, Suppl., 2001 Purpose: Mucosal cell activity within the GI tract may follow a specific cyclical pattern throughout the day. Circadian...

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AJG – September, Suppl., 2001

Purpose: Mucosal cell activity within the GI tract may follow a specific cyclical pattern throughout the day. Circadian rhythms of DNA synthesis and cell proliferation have been documented in human epidermal, buccal, and rectal mucosa. Such circadian variation may have implications for chemotherapy and its damaging effects upon normal mucosa. Topoisomerase II-alpha, an indicator of DNA activity, is a common target for some chemotherapeutic regimens, which alter the activity of this enzyme to induce DNA damage. The variation of topoisomerase II-alpha acivity within normal rectal mucosa has not been determined. Characterization of such a rhythm within topoisomerase II-alpha expression could lead to safer administration of cell cycle targeted chemotherapy. Methods: Between March 2000 and August 2000, ten healthy male adults between the ages of 18 –27 (mean 20 years) underwent 24 hour studies. These patients had no underlying GI diseases nor prior GI surgeries. Biopsies of rectal mucosa were obtained at pre-determined 4 hour intervals over the 24 hour period. Approximately 6 mucosal biopsies were performed at each time point. Tissue was placed in neutral buffered formalin, processed, and stained for anti-topoisomerase II-alpha. All histological specimens were read by the same pathologist. Only properly oriented and stained crypts were counted. Results: Topo II-alpha staining was found in epithelial cell nuclei in the bottom one third to one half of the crypts. A significant circadian rhythm in nuclear topo II-alpha expression in rectal crypt mucosa was found in both the raw(p ⫽ .0004) and normalized values (p ⫽ .01). Mean peak staining occurred at 0723 (⫹/⫺ 45 minutes). The mean rate of change (difference between peak and trough expression) was 40%. Conclusions: There is a distinct circadian rhythm within topoisomerase II-alpha expression in rectal mucosa. The expression may vary individually but consistently peaks in early morning. This is, to our knowledge, the first evidence of a circadian variation in topoisomerase II-alpha expression. This finding suggests that late afternoon or evening administration of topoisomerase-based chemotherapeutic agents (e.g. doxorubicin) might diminish their ability to cause mucositis.

Abstracts

S169

531 Low salt bowel cleansing (LoSo prep) preparation for colonoscopy Vino J Verghese, M.D., Kamran Ayub, M.D., Waqar A Qureshi, M.D., Tina Taupo, R.N. and David Y Graham, M.D., MACG*. 1Medicine, VA Medical Center, Houston, TX, United States; and 2Baylor College of Medicine, Houston, TX, United States. Purpose: Currently available colon cleansing preparations are either poorly tolerated by patients due to large volumes and taste or have limited usage due to electrolyte disturbances. In a pilot study, we evaluated the efficacy of a low salt prep (LoSo prep, EZ-M) based on the premise that the low volume (8 oz.) and better taste may improve patient compliance and the prep experience. Methods: Patients scheduled for colonoscopy at a large VA hospital were offered the LoSo prep which consisted of 34 g of magnesium citrate and 4 bisacodyl tablets at 4 P.M the day before the procedure and one bisacodyl suppository at 6 A.M on the day of the procedure. At endoscopy, the patients completed a questionnaire regarding preparation tolerability. Three endoscopists individually assessed the quality of the preparation by viewing videotape recordings of the procedures and scored the quality of the preparation. Results: 20 patients (12 inpatients, 8 outpatients, age range 49 – 81, all males) were entered. There were no significant side effects or discomforts associated with the prep. All rated the taste as “tolerable or better”. 4 patients who had received PEG preparation for prior colonoscopy, all rated the study prep as more tolerable. Examination was considered adequate with no limitations in 17 patients (85%) and scored as good to excellent (no solid stool) in 11 (55%), acceptable (small amounts of solid stool) in 6 (30%), and poor in 3 (15%: 2 inpatients and 1 inpatient). Importantly, 2 of the failures then received a standard PEG prep and again failed to have adequate colon preparation. Conclusions: This pilot study showed that the low salt colon cleansing preparation was an effective alternative for preparation for colonoscopy. The prep is especially useful for those who cannot tolerate standard prep solutions and those with volume overloaded clinical states.

530 Hydrogen breath test as an indicator of the quality of colonic preparation for colonoscopy Yoshihisa Urita1, Kazuo Hike1, Naotaka Torii1, Yoshinori Kikuchi1, Masahiko Sasajima1 and Kazumasa Miki1*. 1First Department of Internal MedicineToho University School of Medicine, Toho University School of Medicine, Tokyo, Tokyo, Japan. Purpose: Fasting breath hydrogen has been measured to evaluate the intestinal bacterial overgrowth. After ingestion of polyethylene glycol (PEG), it is expected that the breath hydrogen level decreases, reflecting the reduction of colonic bacteria. Then we evaluated the change of breath hydrogen levels after ingestion of PEG that could be used to predict the quality of colonic preparation before the procedure. Methods: After fasting overnight and collecting a 100ml of breath sample, at 9 a.m. 41 patients ingested PEG, containing 12g lactulose, 50ml every 5 minutes for 2 hours. During ingestion of PEG, breath samples were taken at 15-min intervals for 240 min. Breath hydrogen concentration was measured using TGA-2000 (TERAMECS, Kyoto). Colonic preparation was rated as excellent, fair, or poor. Results: Seven (17%) patients were found to have poor colonic preparation, and 34 (83%) had excellent or fair preparation. The breath hydrogen level at 240 min in excellent group was 1.6⫾2.2 ppm, and 43.4⫾29.3ppm in poor group. Conclusions: Patients undergoing colonoscopy after PEG preparation who have poor colonic preparation have significantly higher breath hidrogen levels at 240 min compared to patients who have excellent preparation. Hydrogen breath test is useful as an indicator of the quality of colonic preparation for colonoscopy.

532 COX-2 expression in sulindac-sulfone and placebo treated familial adenomatous polyposis patients Christoph Woerlein, MD, FACG and Scott Kuwada, MD. University of Utah, Health Sciences Center, Salt Lake City, Utah. Purpose of Study: Cyclooxygenase-2 (COX-2) is overexpressed in colonic neoplasms and is a major target for nonsteroidal anti-inflammatory drugs (NSAIDs) in colon cancer chemoprevention. The well-studied NSAID sulindac is converted into sulfide and sulfone metabolites in humans. Both metabolites cause apoptosis of colon cancer cells in vitro. While the sulfide inhibits COX activity, the sulfone does not. AIM: We hypothesized that treatment of familial adenomatous polyposis (FAP) patients with the sulindac sulfone alone should cause regression of polyps regardless of COX-2 expression. Methods: 12 FAP patients with subtotal colectomies were randomized to placebo (4 patients) or sulindac sulfone (8 patients, 600mg/day) for 12 months. At baseline and every 6 months thereafter, all of the polyps were removed endoscopically. Sections of the polyps were processed for COX-2 immuno-staining and COX-2 expression was graded by a single blinded observer. Grading was based on a scale of 0 –3, with 3 being the highest levels of COX-2 expression. COX-2 expression was compared between placebo- and drug-treated patients. Results: COX-2 Expression No. of Polyps (sulfone) No. of Polyps (placebo) p-value

0 1 2 0.6

1 8 15 0.8

2 4 7 0.9

3 4 9 0.9

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Abstracts

AJG – Vol. 96, No. 9, Suppl., 2001

Conclusions: There was no statistically significant difference in the proportion of polyps overexpressing COX-2 between the placebo- and sulfonetreated patients. This suggests that NSAIDs have a chemopreventive effect independent of COX-2 activity. 533 Clinical significance of quantitative assessment of rectal anal inhibitory reflex (RAIR) in patients with constipation Xiaohong XuM.S., PJ Pasricha, M.D., S Jafri M.D. and JDZ Chen, Ph.D, FACG. Division of Gastroenterology, University of Texas Medical Branch, Galveston, TX. The aim of this study was to evaluate the diagnostic value of quantitative assessment of RAIR in patients with constipation. Methods: 48 patients complained of pelvic floor disorders were enrolled and classified into two groups according to their primary complaints: constipation group (CO, 15F, 7M, mean age: 50 yrs) and fecal incontinence group (FI, 24F, 2M, mean age: 56yrs). An anorectal manometric probe with 4 pressure sensors staggered at a longitudinal interval of 1 cm and a balloon at the tip was inserted into the rectum with the most proximal sensor 1 cm from the anal verge. RAIR was solicited by inflating the balloon with various volumes from 10ml to 50ml. The percentage of relaxation was determined based on the rectal baseline pressure, resting sphincter pressure and sphincter pressure with the balloon distention. It is generally accepted that patients with FI do not have impaired RAIR and thus may be considered as the controls when evaluating RAIR in patients with CO. Results: 1) In patients with FI, additional inhibition achieved was only about 8% when the distention volume was increased by 70% from 30ml to 50ml (see table), suggesting that the maximum inhibition of the internal sphincter was probably reached at the distention of 50ml. 2) Percent of relaxation induced by rectal distention was significantly lower in CO than in FI at volumes from 20ml to 50ml (see table). 3) The volume of distention required to achieve a relaxation of 50% was significantly higher in patients with CO than FI (37.3⫾14.9 ml vs. 26.3⫾11.9 ml, p ⬍ 0.05). Conclusions: 1) A maximum relaxation of sphincter pressure induced by rectal distention is about 80%, suggesting that about 20% of the resting pressure measured from the manometry may be attributed to the external sphincter. 2) Patients with CO have impaired RAIR in comparison with patients with F1. 3) Quantitative assessment of RAIR is valuable in the diagnosis of patients with CO and may have pathophysiological implications.

CO FI P

10 ml

20 ml

30 ml

40 ml

50 ml

23.8 ⫾ 23.5 27.2 ⫾ 23.9 ⬎0.05

35.7 ⫾ 24.5 51.7 ⫾ 26.1 ⬍0.05

45.0 ⫾ 28.3 72.3 ⫾ 25.1 ⬍0.05

53.5 ⫾ 24.2 78.2 ⫾ 22.3 ⬍0.05

57.7 ⫾ 27.8 81.0 ⫾ 23.3 ⬍0.05

534 Screening colonoscopy prior to orthotopic liver transplantation (OLT) Mahmoud M Yousfi1, David D Douglas1, William T Savage III1, Vijayan Balan1, Hugo Vargas1, LeaAnn Nelson1, Adyr A Moss1, David C Mulligan1, Jorge Rakela1 and M. Edwyn Harrison1*. 1Transplantation Medicine, Mayo Clinic, Phoenix, AZ, United States. Purpose: Comprehensive preoperative assessment of patients undergoing OLT is crucial in selecting the most suitable candidates in an environment of limited supply of donors. The incidence of colon polyps and cancer in patients with liver cirrhosis does not differ from the general population. The aim of our study was to determine the clinical utility of screening colonoscopy in the preoperative assessment of patients undergoing OLT. Methods: We conducted a descriptive observational study on all patients undergoing preoperative evaluation for OLT in our center from 1999 – 2001. Screening colonoscopy was performed on all patients greater than 45 years old. Patients with a prior history of colorectal cancer or total colectomy were excluded. For each colonoscopy, we reviewed the quality of

preparation, completion of exam (intubation of cecum), endoscopic findings of polyps or cancer, and pathologic findings. The quality of the preparation was considered good or excellent when thorough examination of the colon was achieved; fair when small lesions might have been missed due to retained fluid or stool; and poor when examination was inadequate due to incomplete preparation. We compared the results to a control group of sequential patients undergoing colonoscopy during the same period in our center. Results: 186 patients were studied (93 in each group). The colon preparation in the group evaluated prior to OLT was reported as poor, fair, and good/excellent in 25%, 44%, and 31%, respectively, compared to 3%, 33%, and 59% in the control group, respectively. 23 patients evaluated prior to OLT had incomplete colon examination (19/23 had poor preparation) compared to none in the control group. In the OLT group, polyps were found in 25% (17% hyperplastic and 8% adenomatous), no cases of colorectal cancer were detected, and 32 patients were transplanted. None developed colorectal cancer post OLT. Conclusions: Adenomatous polyps were found in 8% of the patients screened by colonoscopy prior to OLT. Routine colorectal cancer screening guidelines apply to patients undergoing OLT evaluation. Poor preparation and incomplete colonoscopy occur more frequently in screening examinations prior to OLT than in comparably matched controls. A more vigorous colon preparation is required to screen patients effectively prior to OLT, and so to protect our scarce donor organ supply. Colonoscopy Results Poor preparation Incomplete exam

OLT group (n ⴝ 93)

Control group (n ⴝ 93)

P value

25% 25%

8% 0

⬍0.001 ⬍0.001

CLINICAL VIGNETTES 535 Primary lymphoma of the liver Emad M Abu-Hamda MD and John R Stroehlein MD*. 1 Gastroenterology, University of Texas, Houston, Health Science Center, Houston, Texas, United States. Primary lymphoma of the liver is a very rare malignancy. To date less than 100 cases have been reported in the world literature. Most patients with primary lymphoma of the liver present with a discrete liver mass or masses. We report here on an atypical presentation of an extremely rare malignancy that presented as a diffuse lesion and with fulminant hepatic failure. The case is of an 82 year old Caucasian man that was transferred to our institution with a 3 week history of jaundice, fevers and new onset confusion. A diagnosis of ascending cholangitis was made at an outside institution but the attempt at drainage by endoscopic retrograde cholanglopancreatography was unsuccessful. The ERCP was repeated in our institution and was normal as was the CT of the abdomen. Due to the patients mild pancytopenia, a bone marrow aspirate and biopsy were performed which showed a reactive lymphocytosis. Liver biopsy was subsequently performed and the histopathology was consistent with a B-cell non-Hodgkins lymphoma. The bone marrow biopsy was later read as B-cell non-Hodgkins lymphoma. Unfortunately, the patients condition deteriorated and he developed hypotension and acute renal failure. Chemotherapy was started with CHOP however his condition continued to deteriorate and the patient expired several days later. The case described in this report supports previous observations that primary lymphoma of the liver may present as diffuse organ involvement. In the few similar cases described in the literature they were rapidly fatal. This is in contrast to the majority of cases of this rare disorder that present as focal lesions in the liver and carry a more favorable prognosis.