Repifermin (keratinocyte growth factor-2) for the treatment of active ulcerative colitis: a randomized, double-blind, placebo-controlled, dose-escalation trial.

BACKGROUND: Repifermin (keratinocyte growth factor-2) has been shown to reduce inflammation in animal models of colitis. AIM: To evaluate repifermin for the treatment of active ulcerative colitis. METHODS: Eighty-eight patients with active ulcerative colitis were enrolled in a 6-week, double-blind trial. Patients were randomized to receive treatment for five consecutive days with intravenous repifermin at a dose of 1, 5, 10, 25 or 50 microg/kg, or placebo. The primary objective of the study was to evaluate the safety of repifermin. The primary efficacy outcome was clinical remission at week 4, defined as a score of zero on the endoscopic appearance and stool blood components of the Mayo score and a score of zero or unity on the stool frequency and physician's global assessment components. RESULTS: At week 4, the rates of clinical remission in the 1, 5, 10, 25 and 50 microg/kg repifermin groups were 19%, 9%, 0%, 0% and 0%, respectively, and 11% for the placebo group (P = 0.32 for repifermin vs. placebo). The frequencies of commonly occurring adverse events and severe adverse events were similar in both groups. CONCLUSIONS: Intravenous repifermin at a dose of 1-50 microg/kg was very well tolerated, but there was no evidence that repifermin was effective for the treatment of active ulcerative colitis at these doses. An additional study to determine the efficacy of repifermin at doses of > 50 microg/kg or for a longer treatment duration may be warranted, as the maximally tolerated dose was not reached in the present study.

Randomized, controlled trial of recombinant human interleukin-11 in patients with active Crohn's disease.

BACKGROUND: Interleukin-11 is a mesenchymally derived cytokine with pleiotropic activities. A pilot study suggested therapeutic benefit of recombinant human interleukin-11 (rhIL-11) in patients with Crohn's disease. AIM: To determine the safety and preliminary estimate of efficacy of rhIL-11 in treating active Crohn's disease. METHODS: Patients with mild to moderately active Crohn's disease, defined as a Crohn's disease activity index (CDAI) > or = 220 and < or = 450, were enrolled in a multicentre trial. Stable doses of 5-aminosalicylates, antibiotics, 6-mercaptopurine or azathioprine were permitted with appropriate wash-in periods. Oral, intravenous or rectally administered corticosteroids were not allowed. Patients were randomized to 6 weeks of subcutaneous injection with rhIL-11 15 microg/kg or placebo weekly, or rhIL-11 7.5 microg/kg or placebo twice weekly. The primary end-point was per cent change in CDAI at week 6; the major secondary end-point was the proportion of patients in remission, defined as a 100 point decrease in CDAI and absolute CDAI < or = 150. RESULTS: Baseline characteristics were similar among the 148 evaluated patients (49 placebo, 49 rhIL-11 15 microg/kg once weekly, 50 rhIL-11 7.5 microg/kg twice weekly). Treatment was well-tolerated, with mild injection site reactions occurring more frequently among patients treated with rhIL-11. Headache, oedema, and increased platelet count occurred significantly more often in the rhIL-11 7.5 microg/kg twice weekly group, but not the 15 microg/kg once weekly group. There was a trend toward decreased mean per cent change in CDAI in the rhIL-11 15 micro/kg once weekly group vs. placebo (-31.5% vs. -18.5%, 95% confidence interval for the difference -27.9-1.6%). A significantly greater proportion of patients receiving rhIL-11 15 microg/kg once weekly achieved remission compared to placebo (36.7% vs. 16.3%, 95% confidence interval for the difference 3.4-37.4%; 16.4% for rhIL-11 7.5 microg/kg, N.S.). CONCLUSIONS: Weekly subcutaneous injection with rhIL-11 15 microg/kg is safe and effective in inducing remission in a subset of patients with active Crohn's disease.

Efficacy and safety of sodium phosphate tablets compared with PEG solution in colon cleansing: two identically designed, randomized, controlled, parallel group, multicenter phase III trials.

BACKGROUND: Liquid purgatives for cleansing before colonoscopy often are poorly tolerated. A sodium phosphate tablet has been developed to provide equivalent efficacy with better patient tolerance. These 2 studies compare the safety, efficacy, and patient acceptance of the tablet (Visicol) to a polyethylene glycol (PEG) solution in adults undergoing colonoscopy. METHODS: Two identically designed, randomized, investigator-blinded, multicenter trials were performed. The primary efficacy variable was the overall quality of colon cleansing. Patient tolerance was assessed in terms of compliance with the dosing regimen. Safety assessments included recording of adverse events and changes in biochemical tests, electrocardiogram, and vital signs. RESULTS: Eight hundred forty-five patients participated in the studies; 420 took sodium phosphate tablets and 425 took a PEG solution. The 2 methods of preparation were equivalent in the overall quality of colon cleansing, cleansing in the right colon, and the frequency of inadequate preparation. Overall cleansing was excellent or good in 84.3% of patients in the tablet group and in 76.7% in the PEG group. Patient compliance was greater in the tablet group. There were also significantly fewer GI side effects in this group. CONCLUSIONS: Sodium phosphate tablets, compared with PEG solution, produce equivalent colon cleansing, are associated with fewer GI side effects, and are better tolerated by patients.

Rabeprazole versus ranitidine for the treatment of erosive gastroesophageal reflux disease: a double-blind, randomized clinical trial. Raberprazole Study Group.

OBJECTIVE: The objective of this study was to compare the efficacy and safety of the proton pump inhibitor rabeprazole to that of the histamine-2 (H2)-receptor antagonist ranitidine in the treatment of erosive gastroesophageal reflux disease. The primary indicator of efficacy was the absence of esophageal erosions or ulcerations as determined by posttreatment endoscopy. Secondary indicators of efficacy included improvement in frequency and severity of daytime and nighttime heartburn. METHODS: A total of 338 patients were enrolled and randomly assigned to therapy with rabeprazole 20 mg once daily in the morning or to ranitidine 150 mg four times daily. At baseline and at 4 wk, patients underwent endoscopy for evaluation of esophageal lesions. Patients whose lesions healed by wk 4 had therapy discontinued; others remained on therapy and had repeat endoscopy at 8 wk. Also recorded at study visits were patients' ratings of heartburn symptoms and overall sense of well being, patients' reports of time lost from daily activities, antacid use, and adverse events. Serum gastrin levels were measured and argyrophil enterochromaffin-like cell histology evaluated at baseline and when the patient ended therapy. RESULTS: At wk 4, healing was observed in 59% (98/167) of patients assigned to rabeprazole therapy, compared with 36% (60/169) of those receiving ranitidine (p < 0.001). By 8 wk, healing was seen in 87% (146/167) and 66% (112/169) of patients in the rabeprazole and ranitidine groups, respectively (p < 0.001). There were also significant differences between the two groups favoring rabeprazole with respect to resolution or improvement of heartburn symptoms and improvement in sense of well-being. No drug-related serious adverse events were seen with either therapy; fewer patients assigned to rabeprazole had treatment-emergent signs and symptoms. Serum gastrin levels increased over baseline in the rabeprazole group, but the mean value remained within normal limits. CONCLUSIONS: Rabeprazole was superior to ranitidine in esophageal healing and symptom relief in patients with erosive gastroesophageal reflux disease, and was equally well tolerated.

The ChemTrak Hp Chek fingerstick whole blood serology test for the detection of Helicobacter pylori infection.

OBJECTIVE: To evaluate a new whole blood serology test (Hp Chek; ChemTrak) that detects IgG antibodies to Helicobacter pylori. METHODS: The study was conducted at 10 sites within the United States. Patients undergoing upper endoscopy for dyspepsia were recruited for enrollment. Those treated for H. pylori infection within a year of endoscopy and those who had regularly used proton pump inhibitors, bismuth compounds, or antibiotics within a month of endoscopy were not eligible. During endoscopy, specimens were obtained from the corpus and antrum for histological examination, which was performed by a single experienced pathologist. The Hp Chek was tested using whole blood and serum. Serum was also tested with a reference enzyme-linked immunosorbent assay (ELISA) at a centralized location. Test characteristics for the Hp Chek and ELISA were calculated using histology as the "gold standard." RESULTS: Two hundred eighty-seven patients (140 women and 147 men; mean age 53 +/- 6 yr) were enrolled. The Hp Chek was easy to perform and yielded results 9 min after inoculation of the test cassette with whole blood or serum. When the Hp Chek used with whole blood was compared with histology as the gold standard, the sensitivity was 88%, specificity 85%, positive predictive value 83%, negative predictive value 90%, and percent agreement 86%. There were no statistically significant differences among the results obtained with the Hp Chek using whole blood, the Hp Chek using serum, or reference ELISA. CONCLUSIONS: The Hp Chek whole blood serology test was easy to perform and rapid and yielded performance characteristics comparable to those of a reference ELISA or the Hp Chek used with serum.

A double-blind comparison of oral versus rectal mesalamine versus combination therapy in the treatment of distal ulcerative colitis.

OBJECTIVES: The aim of this study was to compare the efficacy of mesalamine rectal suspension enema (Rowasa) alone, oral mesalamine tablets (Asacol) alone, and the combination of mesalamine enema and mesalamine tablets in patients with active mild-to-moderate distal ulcerative colitis. METHODS: Sixty outpatients with ulcerative colitis at least 5 cm above the anal verge and not more than 50 cm, inclusive, and a total disease activity index (DAI) score between 4 and 10, inclusive, were randomized to either mesalamine rectal enema (n = 18) once nightly, oral mesalamine 2.4 g/day (n = 22), or a combination of both treatments (n = 20). Placebo capsules and enemas were used to maintain a blind procedure. Total DAI scores and abbreviated DAI scores were evaluated at wk 3 and 6, and wk 1 and 2, respectively. Patients recorded the amount of blood in stools, urgency, straining at stools, and abdominal pain in daily diaries. Physicians and patients rated overall improvement at each visit. RESULTS: At wk 6, combination therapy produced a greater improvement (-5.2) in total DAI scores than did either mesalamine enema (-4.4) or mesalamine tablet (-3.9) therapy alone; similar treatment differences were observed at wk 3. Compared with patients given mesalamine enemas or mesalamine tablets, combination-therapy patients reported an absence of blood in stools significantly sooner and, at all visits, the combination therapy group had the highest percentage of patients who reported no blood in their stools. Physicians' and patients' ratings of improvement indicated that combination therapy significantly improved disease status, compared with mesalamine tablet therapy alone. All treatments were well tolerated. CONCLUSIONS: The combination of oral and rectal mesalamine therapy was well tolerated and produced earlier and more complete relief of rectal bleeding than oral or rectal therapy alone.

Omeprazole versus ranitidine or ranitidine/metoclopramide in poorly responsive symptomatic gastroesophageal reflux disease.

OBJECTIVES: To evaluate complete symptom resolution, mucosal healing, and tolerability of omeprazole, ranitidine, or ranitidine/metoclopramide in patients with poorly responsive, symptomatic gastroesophageal reflux disease (GERD). METHODS: Adults with persistent symptomatic GERD after ranitidine treatment were stratified by esophagitis grade and randomized to omeprazole 20 mg once daily, ranitidine HCI 150 mg twice daily, or ranitidine HCI 150 mg twice daily plus metoclopramide HCI 10 mg four times daily. Endoscopies were conducted at baseline and at wk 4 and 8. Patients assessed overall symptom improvement at wk 4 and 8 and evaluated daytime and nighttime heartburn, dysphagia, and acid regurgitation daily. RESULTS: After 1 wk, 13% of patients receiving omeprazole (N = 100) had complete resolution of all GERD symptoms versus 1% and 3% of patients receiving ranitidine (N = 97) or ranitidine/metoclopramide (N = 93), respectively (p < 0.001). More patients receiving omeprazole had complete symptom resolution at wk 4 (33%) and at the end of the study (64%; both p < 0.001) than patients receiving ranitidine (8% and 28%, respectively) or ranitidine/metoclopramide (7% and 29%, respectively). Regardless of baseline esophagitis grade, more patients receiving omeprazole had complete symptom resolution. At wk 8, more than 91% of patients with grade 0 or 1 esophagitis at baseline were still healed irrespective of treatment. At wk 8, 80% of patients with esophagitis grade 2 or higher at entry were healed with omeprazole (p < 0.001 vs ranitidine [40%] and ranitidine/metoclopramide [46%]). Thirty-four percent of patients reported an adverse event. Significantly more patients receiving combination treatment reported an adverse event than patients treated with single agents. CONCLUSIONS: In patients with persistent GERD symptoms after ranitidine, omeprazole (20 mg daily for up to 8 wk) provides faster and more complete resolution of common GERD symptoms than continued ranitidine (300 mg daily) alone or in combination with metoclopramide (40 mg daily). Omeprazole provides significantly higher rates of endoscopic healing than ranitidine alone or with metoclopramide. Omeprazole and ranitidine are generally well tolerated. The addition of metoclopramide to ranitidine significantly increases adverse events.

Mesalamine capsules for the treatment of active Crohn's disease: results of a 16-week trial. Pentasa Crohn's Disease Study Group.

BACKGROUND: Mesalamine is released from sulfasalazine in the colon and benefits colonic Crohn's disease. The mesalamine used in this study releases the drug throughout the small bowel and colon. Therefore, this study was designed to detect benefit for Crohn's disease involving the small bowel alone or both the colon and small bowel. METHODS: This double-blind, randomized, multicenter prospective controlled trial compared placebo and three daily doses of mesalamine in 310 patients. The primary outcome criterion was change in the Crohn's Disease Activity Index (CDAI) from baseline to final study visit. RESULTS: Patients taking 4 g/day mesalamine experienced a decrease of 72 CDAI points compared with 21 points in the placebo group (P < 0.01). Remission occurred in 43% of the 4-g group and 18% of the placebo group. Patients with ileum-only disease showed a 93-point improvement on 4 g mesalamine, compared with a 2-point improvement in similar patients on placebo. Mesalamine in this trial was not associated with clinically significant toxicity. CONCLUSIONS: This controlled-release mesalamine preparation is safe and effective at 4 g/day as a single agent in treatment of active Crohn's disease of the ileum and colon.

Adenocarcinoma of the stomach with invasion limited to the muscularis propria.

Adenocarcinoma of the stomach having invasion limited to the muscularis propria with or without lymph node metastasis, termed PM (proper muscle) gastric cancer by Japanese investigators, has a prognosis superior to that of carcinoma extending to the serosa and approaching that of early gastric cancer in Japan. To evaluate the occurrence and significance of PM gastric cancer in the United States, we analyzed 272 gastric carcinomas resected at our institution between 1964 and 1983. Forty-two PM cancers (15%) were identified. Improved 5-year survival rate was noted for PM cancer when compared with survival rate for 215 neoplasms exhibiting serosal invasion (29% versus 7%, P less than 0.001). In univariate analysis, a survival advantage was also associated with absence of lymph node metastasis, intestinal-type histopathology of the Lauren classification, the expanding pattern of the Ming classification, and polypoid or fungating gross configuration of tumor. In multivariate analysis, depth of tumor invasion remained significantly associated with improved 5-year survival rate independently of other variables, including lymph node metastasis. Using continuous survival curves, the prognostic significance of PM cancer prevailed throughout the 5-year postgastrectomy interval. Our data indicate that PM gastric cancer occurs in the United States and need not be considered "advanced" gastric carcinoma; depth of tumor invasion should be recognized as a nodal metastasis-independent prognosticator of gastric cancer survival.

Liver abscess: a harbinger of Crohn's disease.

A 24-yr-old man with no previous history of Crohn's disease presented with a 5-wk history of fever and malaise. Computed tomographic scan of the abdomen revealed a liver abscess. Upon intraoperative examination, the terminal ileum was noted to have changes characteristic of Crohn's disease. This case report represents the first documented occurrence of liver abscess as the initial manifestation of Crohn's disease.

Prognostic factors in colorectal carcinomas arising in adenomas: implications for lesions removed by endoscopic polypectomy.

Endoscopic polypectomy has become the preferred technique for the removal of most colorectal adenomas. Whether polypectomy alone or segmental colectomy is the appropriate management of the patient whose adenoma contains carcinoma is a controversial issue. We studied 129 colorectal carcinomas that arose in adenomas and in which invasion was no deeper than the submucosa of the underlying colonic wall. The following factors were evaluated: location; gross appearance (sessile versus pedunculated); histologic type of adenoma (tubular, villous, mixed); grade of carcinoma; level of invasion (0--carcinoma confined to the mucosa, 1--head, 2--neck, 3--stalk, 4--submucosa of underlying colonic wall); vascular invasion; and adequacy of excisional margins. Patients were divided into two groups with respect to outcome: adverse (dead from colorectal carcinoma, alive with colorectal carcinoma or positive nodes on colectomy), and favorable (absence of above). Sixty-three patients were treated by polypectomy alone and 66 by colectomy (21 preceded by polypectomy); there were no operative deaths. Mean follow-up was 81 mo. None of 65 patients with carcinoma confined to the mucosa had an adverse outcome, but 8 of 64 patients with invasive carcinoma did. Level 4 invasion (p less than 0.001) and rectal location (p = 0.025) were the only statistically significant adverse prognostic factors. Seven of 28 level 4 lesions and six of 42 rectal lesions had an adverse outcome; level 4 lesions were overrepresented in the rectum (14 of 42; p = 0.032). We conclude that the level of invasion should be the major factor in determining prognosis for the management of carcinoma arising in an adenoma.

Psychogenic vomiting: a review.

Psychogenic vomiting appears to be an exacerbation of a longstanding pattern of episodic stress-related vomiting. A small fraction of these patients has serious psychiatric problems and are in need of specialized treatment. Generally, psychogenic vomiters are very resentful of the suggestion that they should seek psychiatric help and more often than not refuse to be referred. Indeed, the majority of these patients is not seriously psychiatrically disturbed. They respond very well to an opportunity to ventilate their stresses to the treating physician and to supportive contacts to help them over their crisis.

Serum gamma-glutamyl transpeptidase: its specificity and clinical value.

The clinical import of the serum gamma-glutamyl transpeptidase (GGTP) level was evaluted in 162 prospectively studied patients. GGTP is helpful in determining the origin of alkaline phosphatase (AP); it clearly separates increased AP of bone and placental origin from that of liver origin. The GGTP level closely parallels the AP level in most instances, but it may be more sensitive in detecting liver disease in anicteric patients. The finding of significantly increased GGTP in patients with chronic aggressive hepatitis as compared to normal levels found in chronic persistent hepatitis may provide a prognostic clue in cases of unresolved hepatitis. The apparent specificity and sensitivity of the GGTP test, combined with ease of performance and low expense, make it a valuable addition to the evaluation of a patient with hepatic disease.

Hepatitis-B surface antigen (HBsAg) and antibody (anti-HBs) prevalence among laboratory and nonlaboratory hospital personnel.

HBsAg and anti-HBs positivity was determined in hospital laboratory workers and nonlaboratory hospital workers (controls) matched for race and sex and adjusted for age. The combined prevalence of antigen-antibody positivity among white female technicians was 12% versus 0 of controls (P less than 0.005). The highest prevalence (18%) among laboratory workers was found in chemistry technicians, and significantly elevated frequencies also were noted in histocytologic, hematologic, and general laboratory technicians and blood collectors; this was not explained by a history of previous blood transfusions or hepatitis. Prevalence among pathologists (16%) was significantly greater (P less than 0.05) than among radiologists not routinely performing angiography (2%). Prevalence among black female housekeepers, both laboratory (25%) and nonlaboratory (36 %), was the highest, and was significantly greater (P less than 0.05) than among black female technicians (10%). Positivity was not correlated with current residence census tract socioeconomic indicators in black or white females. The data emphasize the need for continued identification of risks and improved protection measures in hospital workers.