NO-NSAIDs and cancer: promising novel agents.

Three potential applications of NO-donating NSAIDs in human cancer include their use: as chemopreventive agents; against already developed cancers (chemotherapy); and for the control of cancer symptoms, notably cancer pain. The evidence to date of greater safety and enhanced efficacy of NO-donating NSAIDs underscores their potential to prevent colon cancer and overcome the limitations of traditional NSAIDs. NO-donating NSAIDs affect several pathways critical to colon carcinogenesis and this may explain in part their greater efficacy in colon cancer prevention as assessed in preclinical models.

Effect on treatment outcome of coinfection with SEN viruses in patients with hepatitis C.

The newly discovered SEN D and SEN H viruses are transmitted parenterally and can cause post-transfusion hepatitis. We assessed whether coinfection of patients with chronic hepatitis C and SEN D or SEN H correlates with the outcome of treatment with interferon and ribavirin. Of 31 patients with hepatitis C studied, six were positive for SEN D and seven for SEN H (one was positive for both). All of those positive for SEN D and five of those positive for SEN H failed to respond to therapy. Overall response (RNA titre and alanine aminotransferase concentration after treatment) was lower in SEN-infected patients than uninfected patients (p=0.025). We conclude that coinfection with SEN viruses is frequent in chronic hepatitis C patients and might adversely affect the outcome of treatment with interferon and ribavirin.

Efficacy of high-dose interferon in combination with ribavirin in patients with chronic hepatitis C resistant to interferon alone.

OBJECTIVE: Interferon combined with ribavirin has efficacy in the treatment of patients with chronic hepatitis C virus (HCV) infection. However, its utility in patients who have not responded to prior interferon therapy is not clear. Furthermore, the effect of using an increased dose of interferon in combination with ribavirin in patients with chronic hepatitis C resistant to conventional doses of interferon is not known. The aim of our study was to evaluate the effect of high-dose interferon in combination with ribavirin on the efficacy of treating patients with chronic hepatitis C resistant to interferon monotherapy in a large multicenter trial. METHODS: We randomized 154 patients with chronic hepatitis C who failed to achieve a sustained response with prior interferon therapy to receive either 3 or 5 MU of interferon alpha-2b and ribavirin (1000-1200 mg/day) for 12 months. There were 119 patients who had not responded and 35 who initially responded but relapsed after prior interferon monotherapy. Serum HCV RNA levels were measured at entry, 6, and 12 months of treatment and at the end of a 6-month follow-up period. RESULTS: The mean age of the subjects was 47 yr (range 28-68 yr), and 110 (71.4%) were men. One hundred thirty-two patients (86%) had HCV genotype 1, whereas 21 (14%) had cirrhosis. Eighty-one subjects (53%) were randomized to receive 3 MU of interferon alpha-2b. Fifteen of 35 relapse subjects (43%) and 12 of 119 prior nonresponder entrants (10%) achieved a sustained virological response to the 12-month course of treatment. Overall, 11 of 81 patients (14%) receiving 3 MU, and 16 of 73 patients (22%) receiving 5 MU of interferon maintained an undetectable HCV RNA level after cessation of therapy. The difference in sustained response rates between the two interferon dosage groups did not reach statistical significance (p = 0.09). However, among the nonresponder patients alone, there was an increased sustained response in the high-dose interferon group compared with the standard interferon dose group (15.5% vs 4.9%, p = 0.055). Twenty-six patients discontinued therapy before 6 months, including 10 patients (12.3%) in the 3-MU and 16 patients (21.9%) in the 5-MU groups (p = 0.17). CONCLUSIONS: Sustained virological response to combined interferon alpha-2b and ribavirin was significantly higher in relapse patients than those who did not respond to prior interferon monotherapy. Although, when all treated patients were analyzed, there was no significant difference in sustained response between subjects receiving 3 and 5 MU of interferon, among the prior nonresponder patients, treatment with 5 MU of interferon with ribavirin resulted in a slightly increased response compared with treatment with the standard interferon dosage. The tolerability of the treatment regimens was comparable.

Assessment of hepatitis C virus RNA and genotype from 6807 patients with chronic hepatitis C in the United States.

Hepatitis C virus (HCV) RNA status and HCV genotype have become important tools in the diagnosis and monitoring of therapy in chronic HCV infection. To establish a database with respect to HCV genotype and serum HCV RNA concentrations in chronic hepatitis C patients in the United States, we analysed 6807 chronic hepatitis C patients who had HCV RNA and HCV genotype tests conducted at a central laboratory. The HCV RNA concentration cut-off for the lower 25th percentile of this population (low titre) was 0.9 x 106 copies ml-1. The median HCV RNA concentration was 3.5 x 106 copies ml-1 and the cut-off for the upper 25th percentile (high titre) was 5 x 106 copies ml-1. Male patients had a median HCV RNA concentration of 3.9 x 106 copies ml-1, which was significantly higher than the median HCV RNA level for females (2.75 x 106 copies ml-1; P < 0.001). HCV genotype 1 was detected in 73% of patients; genotype 2 in 14%; genotype 3 in 8%; mixed genotype in 4%; and genotypes 4, 5 and 6 with a frequency of < 1%. Patients from the Northeast, Southeast and Midwest had significantly (P < 0.001) more infections with genotype 1 than patients from the Western and Southern regions. African-American patients were more likely to be infected with genotype 1 when compared with Caucasian, Hispanic or Asian Pacific Islanders (P < 0.001). Patients infected with HCV genotype 1 and mixed HCV genotypes had significantly higher serum HCV RNA concentrations when compared with HCV genotypes 2 and 3 (P < 0.001 for all comparisons).

Concomitant human immunodeficiency virus protease inhibitor therapy markedly reduces tacrolimus metabolism and increases blood levels.

We present the case of a patient with hepatitis C-induced cirrhosis and concomitant human immunodeficiency virus infection who underwent orthotopic liver transplantation. The patient developed severe, prolonged tacrolimus toxicity in the presence of human immunodeficiency virus protease inhibitors. At various times, the patient received saquinavir, ritonavir, and nelfinavir in conjunction with tacrolimus. In each instance, the tacrolimus concentration rose to toxic levels. We hypothesize that the protease inhibitors' competition for binding to cytochrome P450 isoenzyme system CYP3A induced extreme prolongation of tacrolimus metabolism. After stabilization of the patient, reinstitution of treatment with nelfinavir resulted in a >95% reduction in tacrolimus dosing from 4 mg twice per day to 0.5 mg once every 3-5 days.

Pruritus in chronic hepatitis C: association with high serum bile acids, advanced pathology, and bile duct abnormalities.

Pruritus is a common symptom of chronic cholestatic liver diseases but is considered rare in chronic hepatitis. We observed pruritus to be an unusually common complaint in patients with advanced chronic hepatitis C. We reviewed the records of 175 chronic hepatitis C patients to identify patients with severe, diffuse, unexplained pruritus; 12 consecutive prospective patients undergoing liver biopsy for chronic hepatitis C served as controls. Assessment included laboratory biochemical tests and assessment of liver pathology by stage, grade, hepatic activity index, and a bile duct score. Pruritus was present in nine (5.1%) patients. Serum AST, ALT, alkaline phosphatase, GGTP, total bilirubin, and ferritin were similar in pruritics and controls. Pruritics had higher serum bile acids (2028.4 +/- 223.1 mmol/liter vs 423.1 +/- 194.3, P < 0.001), higher transferrin saturation (57.5 +/- 6.8% vs 33.2 +/- 3.3, P < 0.01), and lower HCV RNA by bDNA (24.5 +/- 12.7 x 10(5) vs 172.7 +/- 54.1 x 10(5), P < 0.05). Pathology revealed cirrhosis in 6/9 (66.6%) pruritics vs 1/12 (8.3%) controls (P < 0.01). Pruritics had higher pathologic stage (3.7 +/- 0.2 vs 2.2 +/- 0.4, P < 0.01), grade (4.4 +/- 0.2 vs 2.1 +/- 0.2, P < 0.001), activity index (14.3 +/- 1.9 vs 8.6 +/- 1.9, P < 0.025), and bile duct score (7.6 +/- 0.6 vs 4.7 +/- 0.4, P < 0.01). Of eight pruritics treated with IFN-alpha2b, two had complete ALT response and one relapsed. Pruritus followed a relapsing course and only three patients partially responded despite a variety of interventions. In conclusion, pruritus is a common complication of advanced CHC. Its presence is associated with high serum bile acids, advanced pathology and bile duct abnormalities. The clinical course of pruritus is relapsing and response to therapy is inconsistent. These features suggest that pruritus in CHC has a pathogenesis that may vary from that of chronic cholestatic diseases.

The breakthrough phenomenon during alpha-interferon therapy of chronic hepatitis C: incidence, management, and outcome.

OBJECTIVES: Some patients treated with alpha-interferon (alpha-IFN) for chronic hepatitis C (CHC) initially respond with normalization of ALT only to encounter a rise in ALT while still on the drug. This phenomenon is called breakthrough (BT). We reviewed our experience with BT to clarify its incidence, pathogenesis, management, and outcome. METHODS: Charts from 71 consecutive patients with CHC treated with alpha-IFN were reviewed. Forty of these patients were part of a study of 1-yr escalating dose alpha-IFN, initiated at 2 million units (MU) 3 times per week. Endpoints that were evaluated were: reachievement of normal ALT, complete response (CR) (defined as normal ALT at the end of therapy), and sustained CR maintained for 6 months after therapy. RESULTS: Twenty-one (29.5%) patients sustained 28 BT events. Thirteen (46.4%) BT events occurred during the first 6 months of a course of alpha-IFN therapy, and 15 (53.6%) occurred during months 7 through 12. Of patients experiencing BT, six (28.6%) completed their course of therapy with a CR, of which two (9.5%) were sustained. By comparison, of 22 patients who normalized ALT without BT, all completed their course with a CR by definition (p < 0.0001), and nine (40.9%, p < 0.05) had a sustained CR. Of 28 BT events, 13 (46.4%) were followed by reattainment of normal ALT. Of 16 BT events managed with continuation of the same dose of alpha-IFN, normal ALT was reachieved in seven (43.8%). Of 12 BT events managed with an escalation in alpha-IFN dose, six (50%) reachieved normal ALT. A full sequential series of hepatitis C virus RNA PCR from periods of elevated, normal, and again elevated ALT was available for 12 BT events. The pattern was +/+/+ in six, +/-/+ in five, and +/-/- in one. In one additional patient, an apparent BT was attributable to alpha-IFN-induced autoimmune hepatitis. CONCLUSIONS: BT is a common event that may occur at any point during alpha-IFN therapy of CHC. This may limit the benefits of maintenance strategies. After a BT event, normal ALT can be reestablished in about 50% of cases, although the chance of a sustained CR falls to less than 10%. No advantage was demonstrated for escalating the alpha-IFN dose after a BT event. Therefore, we recommend continuation of the same dose as the initial approach. We suspect that BT relates to nonspecific ALT fluctuation in some patients and to emergence of resistant hepatitis C virus strains in others. Other causes of ALT elevation must also be considered in patients with apparent BT.

Open label study of long-term effectiveness of cisapride in patients with idiopathic gastroparesis.

Cisapride induces acetylcholine release in cells of the myenteric plexus, thus promoting gastrointestinal motility. We studied the effects of cisapride on 11 patients with idiopathic gastroparesis. All had negative gastrointestinal endoscopy, normal glucose, and took no drugs capable of influencing motility. Most (9/11) were prior metoclopramide treatment failures. Patients' symptoms were scored (0-60) for pain, satiety, bloating, nausea, vomiting, and heartburn. All underwent a solid gastric emptying study using a Technetium-99-labeled egg meal and received placebo prior to cisapride. There were 10 females and one male with a mean (+/- SE) age of 37.8 +/- 2.6 years. Disease duration was 7.9 +/- 2.8 years. The dose of cisapride was 30-60 mg/day and the duration of therapy was 12.6 +/- 2.6 months (range 2.5-25 months). The symptom score improved on cisapride from 30.9 +/- 3.6 to 14.4 +/- 2.7 (P < 0.002 signed rank test). Emptying half-time improved from 113 +/- 4 min to 94 +/- 6 min, and 46.9 +/- 2.4% food remaining at 120 min decreased to 35.5 +/- 3.6% (both P < 0.05). Emptying half-time in normals was 68 +/- 5 min with 16.9 +/- 2.9% remaining at 120 min. Nine of 11 patients gained weight, with a mean increase of 6.7 +/- 1.6 lb (range 2-12 lb). We conclude that cisapride significantly reduces gastrointestinal symptoms and promotes weight gain in patients with idiopathic gastroparesis and is associated with improvement in solid gastric emptying. The drug is useful in patients who previously failed metoclopramide.

Hepatitis C in the health care setting. II. Seroprevalence among hemodialysis staff and patients in suburban New York City.

BACKGROUND: Hepatitis C virus (HCV) is a newly identified blood-borne virus that may pose an occupational hazard for health care workers. Hemodialysis nurses could be anticipated to be at high risk for HCV infection because this group of health care workers frequently comes into contact with blood of a patient population with a seroprevalence rate of at least 10%. METHODS: To assess the risk of HCV infection for hemodialysis nurses, serum samples from all of the nurses (22/22, 100%) and patients (125/125, 100%) in one hemodialysis unit (unit A) and 85% (29/34) of nurses from a second unit (unit B), both units in suburban New York City, were tested for HCV antibodies. Samples with positive results of enzyme-linked immunosorbent assay underwent supplemental testing by a first-generation recombinant immunoblot assay. RESULTS: Twenty-four (19%) of the hemodialysis patients in unit A were HCV seropositive. Despite an average of 4.7 years spent working in hemodialysis unit A, none of the nurses tested seropositive for HCV antibody. In unit B, despite an average of 6.4 years working in the unit studied, only one nurse tested seropositive for HCV antibody. This nurse reported a long history of elevated liver function values and a negative HBV core antibody status that predated her hemodialysis nursing career. CONCLUSIONS: In contrast to the experience with hepatitis B virus infection, hemodialysis nurses appear to be at low risk for occupationally acquired HCV infection.

Resolution of radiographic abnormalities with ursodeoxycholic acid therapy of primary sclerosing cholangitis.

Ursodeoxycholic acid therapy has shown encouraging results in relieving symptoms and decreasing liver biochemical abnormalities in patients with primary sclerosing cholangitis. However, established biliary strictures are generally considered irreversible. A case of primary sclerosing cholangitis with extensive intrahepatic biliary as well as pancreatic duct strictures that resolved to near normal on ursodeoxycholic acid therapy is reported. The implications of these findings are discussed.

The safety and efficacy of gi endoscopy in patients with acute-leukemia - a review of 27 cases.

In the course of aggressive treatment for acute leukemia, the ensuing pancytopenia and intensive medical support may be accompanied by severe gastrointestinal (GI) complications. Therefore, to assess the safety and efficacy of GI endoscopy as a means of diagnosis, we analyzed the records of 16 patients undergoing 27 endoscopies a mean (+/-S.D.) of 18.4 +/- 11.9 days post chemotherapy. There were 6 procedures performed in patients with acute lymphocytic, 18 with acute myelogenous, including 3 with acute promyelocytic and 3 with blastic phase chronic myelogenous leukemia. 10/27 procedures were performed in patients with less than 1000 WBC/mm3 and 19/27 had less than 100,000 platelets. 15 patients had 25 upper endoscopies done for: bleeding (twenty-one), abdominal pain (two), and persistent vomiting (two). The principal bleeding sources were: esophagitis (eleven), Mallory Weiss tear (one), gastritis (three), gastric ulcer (one), duodenal ulcer (five). In the non-bleeding cases 2 exams were normal and the others had gastritis (one) and esophagitis (one). 15/25 procedures (64%) resulted in new diagnosis and 20/25 (80%) in additional therapies. 47% of patients undergoing upper GI endoscopy received specific new therapies as a result of that procedure. Nd: YAG laser photocoagulation was effective in stopping bleeding lesions in 4/6 cases. 10/12 bleeding patients had persistent or recurrent bleeding and 2 died from bleeding. None had surgery. Two patients underwent colonoscopy, both for colonic distention. One patient, who had been recently treated for Cl. difficile had submucosal petechiae. The other had non-specific colitis. No biopsies were done and both cases were successfully decompressed..No complications occurred from any GI endoscopy. We conclude that GI endoscopy can be safely performed in patients with acute leukemia, resulting in specific diagnoses and therapies. Esophagitis is a principal cause of GI bleeding in these patients. The role of therapeutic endoscopy in controlling bleeding is promising but requires further evaluation.

Upper gastrointestinal bleeding following open heart surgery. Predominant finding of aggressive duodenal ulcer disease.

We reviewed our experience with endoscopically evaluated severe upper gastrointestinal hemorrhage following open heart surgery. Of 4892 patients undergoing open heart surgery, 18 (0.4%) sustained upper gastrointestinal hemorrhage requiring endoscopic evaluation. Endoscopy identified the source of bleeding in all cases. No significant complications of endoscopy were observed. Duodenal ulcers (DUs) were found in 16 (89%) of cases and were felt to be the source of bleeding in 15 (83%). Aggressive features, such as multiplicity, large size, or distal location were associated with 13 (81%) of the DU cases. Complications necessitated endoscopic or surgical therapy in eight (44%) patients with DUs. We conclude that aggressive DU disease accounts for the majority of severe upper gastrointestinal bleeding following open heart surgery.

Liver diseases unique to pregnancy.

Severe liver diseases occur in less than 0.1% of pregnancies. Accurate diagnosis and appropriate therapy are essential to the health and survival of both the mother and fetus. Because of their low incidence and the fact that most pregnant women are cared for primarily by their obstetricians, gastroenterologists only infrequently encounter these diseases. This review is intended to update the practicing gastroenterologist on the complex spectrum of liver diseases unique to pregnancy.