Azathioprine for prevention of postoperative recurrence in Crohn's disease: a retrospective study.

BACKGROUND: The efficacy of azathioprine (AZA) in chronically active Crohn's disease (CD) is well established. Whether this drug is also useful to prevent recurrences after surgery is unknown. We report here our experience of AZA in this therapeutic goal. METHODS: Between 1987 and 1996, 38 patients with CD were treated with AZA to prevent postoperative recurrence. Twenty-three of these had undergone a curative resection with removal of all previously involved parts of the gut. In the other 15 patients, resection was limited to the parts of the gut macroscopically abnormal at the time of surgery; those parts that were previously involved but normal at this time were conserved. The operative procedures were ileocolonic resection (n = 18), subtotal colectomy with ileorectal anastomosis (n = 12), coloproctectomy with ileo-anal anastomosis (n = 4) or ileostomy (n = 2), ileal resection (n = 1) and segmental colectomy (n = 1). Twelve patients had been treated previously with AZA before surgery; in 26 patients, AZA was started within the 2 months following surgery. RESULTS: The median duration of postoperative follow-up was 29 months. Probabilities of clinical recurrence according to the Kaplan-Meier method were 9, 16 and 28% at 1, 2 and 3 years, respectively. For the 25 patients who had a colonoscopy or a small bowel barium X-ray during the follow-up, probabilities of anatomical recurrence were 16, 36 and 59% at 1, 2 and 3 years, respectively. The probability of anatomical recurrence was significantly higher in patients who had segments of the gut previously involved but not removed because they were macroscopically normal at the time of surgery. CONCLUSION: In patients treated with AZA, the rate of postoperative endoscopic recurrence was lower than that previously reported in untreated patients. Our results suggest that AZA should be evaluated prospectively for prevention of postoperative CD recurrence, at least in high-risk patients.

Gastrointestinal lymphoma: prevention and treatment of early lesions.

Gastrointestinal lymphomas comprise a group of distinct clinicopathological entities. Differences in lifestyle and environmental factors between countries could account for the variety in the distribution of the main subtypes: low-grade B-cell lymphomas of the mucosa-associated lymphoid tissue type, alpha-chain disease and enteropathy (coeliac disease)-associated T-cell lymphoma (EATL). The possibility of preventing these lymphomas implies a knowledge of their natural history together with an identification of potential predisposing factors. The development of the lymphoid hyperplasia and subsequently low-grade lymphoma with the possibility of high-grade transformation is a multifactorial process involving both antigenic and host-related factors. The pathogenic role of Helicobacter pylori and gluten has been demonstrated in gastric lymphoma and enteropathy-associated T-cell lymphoma respectively, while environmental factors, especially non-specific bacterial ones, may play a major role in the pathogenesis of alpha-chain disease. The most difficult task in preventing these lymphomas is the recognition of early lesions likely to regress after the removal of the exogenous stimulus.

Intraluminal modulation of gastric sensitivity to distension: effects of hydrochloric acid and meal.

Conscious sensations in response to gut distensions may be modulated by temporospatial interactions among different stimuli. This study investigated whether symptoms induced by gastric distension may be modified by hydrochloric acid (HCl) gastric infusion and meal ingestion. In nine healthy subjects, fixed pressure (isobaric) and fixed volume (isovolumetric) distensions were performed during continuous (4 ml/min) intragastric saline or HCl infusion, during fasting and after meal ingestion, until the maximal distension step defined as discomfort or a predefined maximal volume. During fasting isobaric distensions, the maximal distension step was significantly decreased during HCl compared with saline. The intragastric volumes were not significantly different, but the wall tension was significantly lower during HCl than saline. HCl increased gastric compliance. Meal ingestion relaxed the stomach and decreased the pressure at the maximal distension step during saline, but HCl did not further decrease it compared with fasting. During isovolumetric distensions, HCl also increased gastric compliance, but in both fasted and fed states it did not modify the maximal distension steps. In conclusion, sensations in response to gastric isobaric distensions, but not to isovolumetric distensions, are influenced by gastric acid infusion and meal ingestion. The effects of HCl might be related to a sensitization of mucosal mechanoreceptors.

Resistance of t(11;18) positive gastric mucosa-associated lymphoid tissue lymphoma to Helicobacter pylori eradication therapy.

20-30% of gastric mucosa-associated lymphoid tissue (MALT) lymphoma associated with Helicobacter pylori do not regress after antibiotic therapy. Regression can be assessed only by extended follow-up. To assess whether t(11;18, q21;q21), which results in a chimeric transcript between the AP12 and MLT genes, predicts lymphoma resistance to antibiotic therapy, we screened for the fusion transcript with RT-PCR in ten responsive and 12 non-responsive gastric MALT lymphomas. The AP12-MLT transcript was detected in nine (75%) of 12 patients non-responsive to antibiotic therapy but not in responsive patients. Most H pylori-associated gastric MALT lymphomas that do not respond to antibiotic therapy are associated with t(11;18, q21;q21).

Methotrexate in Crohn's disease: long-term efficacy and toxicity.

OBJECTIVE: A 16-wk, placebo-controlled trial has recently shown weekly low-dose methotrexate to be an effective treatment for patients with chronically active Crohn's disease. The long-term efficacy and safety of this antimetabolite drug, however, are not yet well established and are assessed in this study. METHODS: A total of 49 patients with Crohn's disease who were treated with methotrexate for > or =6 months were studied. All patients had been chronically treated with steroids; but at the time of initiation, only 27 were still on steroids. Of the 49 patients, 42 had previously taken azathioprine but were no longer on this drug because of intolerance or failure. Clinical remission was defined as a Harvey-Bradshaw index of <4. RESULTS: In all, 41 patients achieved complete clinical remission and were maintained on methotrexate for a median of 18 months (range, 7-59 months). In these patients the probabilities of relapse were 29%, 41%, and 48% at 1, 2, and 3 yr, respectively. A higher rate of relapse was observed in women and in patients with ileocolitis. Adverse reactions were recorded in 24 patients, requiring discontinuation of methotrexate in five. A liver biopsy was performed in 11 patients; a mild steatosis was found in five, a slight dilation of the sinusoids in one, a granulomatous hepatitis with a mild portal fibrosis in one, and a slight periportal fibrosis in one patient. CONCLUSIONS: This study suggests a long-term benefit of maintenance treatment with methotrexate in patients with chronically active Crohn's disease, with side effects that are usually only moderate.

Management and long-term results of surgery for localized gastric lymphomas.

BACKGROUND: High- and low-grade gastric lymphomas (GL) differ in their behavior and chemosensitivity. Surgery has to be reevaluated according to the histologic grade of malignancy. We aimed to assess the place of surgery in the management of GL and its results after long-term follow-up. METHODS: Among 54 patients with primary GL prospectively enrolled from 1984 to 1990, 45 with localized disease were studied. Primary resection was done whenever safe. All patients received chemotherapy adapted to the grade of malignancy and/or to the completeness of the resection. RESULTS: Among 18 low- and 27 high-grade GL, 35 patients had primary resections; of those, 23 were complete. The complete response rate for all patients with low- and high-grade GL was 67% and 89%, respectively. After a median follow-up of 8 years, the disease-free survival rates for low-grade GL and high-grade GL were 94% and 89%, respectively. It was better after complete resection. CONCLUSION: Complete resection is a major determinant of prolonged complete remission.

[Isolated jejunal tuberculosis mimicking Crohn disease. Diagnosis by push video-enteroscopy]. / Tuberculose jéjunale isolée simulant une maladie de Crohn. Diagnostic par vidéo-entéroscopie poussée.

Intestinal tuberculosis is relatively unfrequent in Western countries, but immigrants and AIDS patients remain groups at particular risk for this disease. The diagnosis of intestinal tuberculosis is often difficult to establish because of close similarities with other conditions, in particular Crohn's disease. We report a case of jejunal tuberculosis in a 33-year-old man with severe weight loss and unexplained fever. The diagnosis was obtained on histological examination of the distal jejunum biopsies performed during pushed video-enteroscopy. Interestingly, culture of the biopsies and specific PCR remained negative. Dramatic improvement was observed during the first days of antituberculous treatment. The main clinical and paraclinical manifestations of intestinal tuberculosis are also reviewed, as well as recent epidemiologic observations and new developments in diagnosis and treatment.

The clinicopathological features of extensive small intestinal CD4 T cell infiltration.

METHODS: Four patients with clinicopathological features suggesting a new distinct entity defining extensive small intestinal CD4 T cell infiltration were observed. RESULTS: All four patients presented with chronic diarrhoea, malabsorption, and weight loss. Biopsy specimens of the small intestine disclosed extensive and diffuse infiltration of the lamina propria by pleomorphic small T lymphocytes, which were positive for CD3, CD4, CD5, and the beta chain of T cell receptor in all three cases studied and negative for CD103 in all three cases studied. It is notable that, in all invaded areas, the infiltrating cells showed no histological change throughout the whole evolution. In three patients, lymphocyte proliferation was monoclonal and there was extraintestinal involvement. In one patient, lymphoproliferation was oligoclonal and confined to the small intestine. In all four patients, there was no evidence of coeliac disease. Although none of the four patients responded to single or multiple drug chemotherapy, median survival was five years. CONCLUSION: Extensive small intestinal CD4 T cell infiltration is a rare entity, distinct from coeliac disease and associated with prolonged survival.

Long-term survival and parenteral nutrition dependence in adult patients with the short bowel syndrome.

BACKGROUND & AIMS: The short bowel syndrome (SBS) may be associated with either transient or permanent intestinal failure, presently treated by parenteral nutrition (PN). Survival and PN-dependence probabilities, taking into account both small bowel remnant length and the type of the digestive circuit of anastomosis, are not known in adult SBS patients. The aim of this study was to assess such prognostic factors. METHODS: A total of 124 consecutive adults with nonmalignant SBS were enrolled from 1980 to 1992 at 2 home PN centers. They were analyzed for survival and PN-dependence probabilities using the Cox model and for PN dependence using linear discriminant analysis. Data were updated in April 1996. RESULTS: Survival and PN-dependence probabilities were 86% and 49% and 75% and 45% at 2 and 5 years, respectively. In multivariate analysis, survival was related negatively to end-enterostomy, to small bowel length of <50 cm, and to arterial infarction as a cause of SBS, but not to PN dependence. The latter was related negatively to postduodenal small bowel lengths of <50 and 50-99 cm and to absence of terminal ileum and/or colon in continuity. Cutoff values of small bowel lengths separating transient and permanent intestinal failure were 100, 65, and 30 cm in end-enterostomy, jejunocolic, and jejunoileocolic type of anastomosis, respectively. CONCLUSIONS: In adult SBS patients, small bowel length of <100 cm is highly predictive of permanent intestinal failure. Presence of terminal ileum and/or colon in continuity enhances both weaning off PN and survival probabilities. After 2 years of PN, probability of permanent intestinal failure is 94%. These rates may lead to selection of other treatments, especially intestinal transplantation, instead of PN, for permanent intestinal failure caused by SBS.

Antibiotic efficacy in small intestinal bacterial overgrowth-related chronic diarrhea: a crossover, randomized trial.

BACKGROUND & AIMS: No controlled trial has examined the clinical efficacy of antibiotics in small bowel bacterial overgrowth. METHODS: Ten patients with bacterial overgrowth-related diarrhea underwent the following five 7-day treatment periods: untreated (control period), then placebo, and subsequently, in random order and blinded fashion, norfloxacin (800 mg/day), amoxicillin-clavulanic acid (1500 mg/day), and Saccharomyces boulardii (1500 mg/day). A hydrogen breath test was performed on the first and last day of each period. RESULTS: Daily stool frequency was similar during the control and placebo periods (4.2 +/- 0.6 vs. 3.9 +/- 0.6 [mean +/- SEM], respectively). Norfloxacin and amoxicillin-clavulanic acid led to a significant reduction in daily stool frequency (2.3 +/- 0.4 and 3.0 +/- 0.5, respectively; P < 0.01 vs. placebo period) after 2.0 +/- 1.4 and 1.2 +/- 0.4 days, which was maintained for 6.1 +/- 3.7 and 6.0 +/- 9.6 days, respectively. Breath-expired H(2) volume decreased with norfloxacin (37 +/- 8 to 12 +/- 5 mL per 2 hours; P < 0.01) and amoxicillin-clavulanic acid (24 +/- 6 to 8 +/- 4 mL per 2 hours, respectively; P = 0.01), but H(2) breath test result was negative in only 3 and 5 patients. CONCLUSIONS: Norfloxacin and amoxicillin-clavulanic acid are effective in the treatment of bacterial overgrowth-related diarrhea.

[Pregnancy outcome in inflammatory bowel diseases]. / Pronostic de la grossesse au cours des maladies inflammatoires intestinales.

OBJECTIVE: To assess pregnancy outcome in relation to disease activity and maintenance therapy in patients with inflammatory bowel disease. METHODS: A postal questionnaire was sent to every woman of child-bearing age followed for inflammatory bowel disease in three referral centers (Rothschild, Saint-Lazare, Saint-Louis). Response rate was 65%. RESULTS: One hundred and forty-four pregnancies (153 fetuses) in 138 women (122 had Crohn's disease) were reported. Outcome of pregnancy was normal (baby > 2500 g, without malformation) in 115 cases (77%). There were 17 cases of preterm birth (11.5%), 3 cases of hypotrophy, and 14 pregnancy losses (9 miscarriages (6%), 4 therapeutic abortions for major malformation (2.8%)). Percentages of normal pregnancy outcome were not different between patients who continued maintenance therapy and those who stopped: respective percentages were 75 vs 73% in patients receiving mesalamine or olsalazine (n = 30), and 60 vs 75% in patients receiving azathioprine (n = 22). CONCLUSION: In a selected series of women with inflammatory bowel disease, pregnancy outcome is approaching that observed in a normal population, except for an elevated rate of preterm births. There is no need to stop maintenance therapy with 5-aminosalicylates or azathioprine during pregnancy.

Serum antibody responses to Helicobacter pylori and the cagA marker in patients with mucosa-associated lymphoid tissue lymphoma.

The lymphoma of the mucosa-associated lymphoid tissue (MALT) of the stomach has been linked to Helicobacter pylori infection, but the mechanisms involved in B-cell proliferation remain elusive. In a search for putative H. pylori-specific monoclonal immunoglobulin production, an H. pylori strain was isolated from 10 patients with MALT lymphoma and used to detect the specific serum antibody response to the homologous strain by immunoblotting. Moreover, the antigenicity of the different strains was compared by using each of the 10 sera. We found that the different strains induced highly variable patterns of systemic immunoglobulin G antibody response, although several bacterial antigens, such as the 60-kDa urease B, were often recognized by the different sera. The cagA marker was detected in the strains by PCR with specific primers and by dot blot analysis, and the CagA protein was found in the sera of 4 of the 10 patients by immunoblotting. In conclusion, MALT lymphoma patients, like other patients with H. pylori gastritis, exhibit a polymorphic systemic antibody response, despite an apparently similar antigenic profile. The CagA marker of pathogenicity is not associated with this disease.

Bacterial populations contaminating the upper gut in patients with small intestinal bacterial overgrowth syndrome.

OBJECTIVE: Small intestinal bacterial overgrowth syndrome (SIBOS) is characterized by an abnormally high bacterial population level in the upper gut, exceeding 10(5) organisms/ml (5 log colony-forming unit (CFU)/ml). To understand its origin and select an appropriate antibiotic treatment, we have analyzed the bacterial populations contaminating the upper gut in SIBOS patients. METHODS: Jejunal samples of 63 consecutive patients with diarrhea or malabsorption and conditions predisposing to SIBOS were cultured and antibiotic sensitivities determined. RESULTS: Concentrations of total, microaerophilic, and anaerobic bacteria were confirmed in 55 patients with SIBOS (mean +/- SE) 7.6 +/- 0.8, 7.4 +/- 0.9, and 6.1 +/- 0.7 log CFU/ml, respectively. Mean number of bacterial genera was 4.6 +/- 0.8. The main bacteria recovered were (mean +/- SE log CFU/ml) Streptococcus (71%; 6.4 +/- 0.8), Escherichia coli (69%; 7.2 +/- 0.9), Staphylococcus (25%; 6.2 +/- 0.6), Micrococcus (22%; 6.0 +/- 0.7), Klebsiella (20%; 7.1 +/- 0.8), Proteus (11%; 6.1 +/- 0.8) for microaerophilic bacteria, and Lactobacillus (75%; 6.1 +/- 1.1), Bacteroides (29%; 6.9 +/- 1.3), Clostridium (25%; 5.5 +/- 1.0), Veillonella (25%; 5.3 +/- 0.7), Fusobacterium (13%; 4.8 +/- 0.5), and Peptostreptococcus (13%; 6.1 +/- 0.7) for anaerobic bacteria. Amoxicillin-clavulanic acid and cefoxitin were efficient on >90% of strains. CONCLUSIONS: Contaminating flora isolated in SIBOS include commonly identified oropharyngeal and colonic flora, but these occur in SIBOS at different levels from those usually found in their original location. These data may hopefully serve as a starting point to further therapeutic controlled studies.

Regional effects of cholecystokinin octapeptide on colonic phasic and tonic motility in healthy humans.

The aim of this study was to assess in nine healthy subjects the effects of CCK octapeptide (CCK-8) on colonic tonic activity, measured by a barostat, and phasic activity, measured by manometry. On 2 consecutive days, recordings were performed in the unprepared proximal and distal colons during intravenous infusion of saline and CCK-8 at 5, 20, and 40 ng. kg-1. h-1. In the proximal colon CCK-8 induced, at the 20 and 40 ng. kg-1. h-1 doses, a tonic relaxation with an increase in barostat bag volume to 156 +/- 25 and 157 +/- 19% of basal (P < 0.01) and a decrease in phasic activity to 72 +/- 7 and 76 +/- 7% of basal (P < 0.01). In the distal colon, CCK-8 induced, at the 20 and 40 ng. kg-1. h-1 doses, a tonic relaxation (increase in intrabag volume to 133 +/- 12 and 149 +/- 15%, respectively; P < 0.01), whereas phasic activity increased (128 +/- 8 and 132 +/- 6%, respectively; P < 0.01). Effects of CCK-8 on tonic and phasic activities are different according to the colonic segment. Because meals induce colonic tonic contraction, our results suggest that CCK, as a hormone, is not an important mediator of the response of the colon to feeding in humans.

Short-chain fructo-oligosaccharide administration dose-dependently increases fecal bifidobacteria in healthy humans.

Short-chain fructo-oligosaccharides (SC-FOS) are a mixture of oligosaccharides consisting of glucose linked to fructose units (Gfn; n =

[6-mercaptopurine levels and study of blood lymphocyte subsets during azathioprine treatment of Crohn's disease]. / Dosage de la 6-mercaptopurine et étude des sous-populations lymphocytaires sanguines au cours du traitement par l'azathioprine dans la malaide de Crohn.

OBJECTIVES: Our aim was to study the relationships between clinical efficacy of azathioprine, 6-mercaptopurine pharmacokinetics and changes in peripheral blood lymphocyte subpopulations induced by azathioprine treatment in Crohn's disease. METHODS: Twenty-three patients were prospectively followed up for 1 year. Peripheral blood counts, total lymphocytes, CD3+, CD4+, CD8+, CD25+, CD16+CD56+, CD57+ and CD19+ lymphocyte subpopulations were carried out, using flow cytometry, during azathioprine treatment. Pharmacokinetic studies were performed at day 8 and month 3 by measuring 6-mercaptopurine plasma concentration after an oral dose of azathioprine (2 mg/kg). Results were compared in responders (no activity and no steroids) and non-responders. RESULTS: The decrease in peripheral blood leukocytes and neutrophils was significant after 1 month, reaching 49% and 48% of the pre-treatment values at 1 year; the one of lymphocytes was significant after 6 months and reached 41% at 1 year. Percentages of CD3+, CD4+, CD8+, CD57+, CD16+CD56+ and CD19+ lymphocytes remained unchanged whereas percentage of CD25+ lymphocytes increased from 10% to 28% (P < 0.01). There was a high inter and intraindividual variability of 6-mercaptopurine peak plasma concentration and area under the curve. No significant difference was found between responders (n = 14) and non responders (n = 7) for pharmacokinetic parameters and lymphocyte subpopulations; there was no correlation between lymphocyte subpopulation changes and 6-mercaptopurine pharmacokinetics. CONCLUSION: Monitoring of 6-mercaptopurine plasma concentration and blood lymphocyte subpopulations is of little value in Crohn's disease patients treated with azathioprine.

[Paraneoplastic intestinal pseudo-obstruction revealing small cell lung carcinoma: "the anti-Hu syndrome"]. / Pseudo-obstruction intestinale paranéoplasique révélatrice d'un carcinome pulmonaire à petites cellules: le syndrome anti-Hu.

A 67-year-old woman was admitted for intestinal pseudoobstruction associated with peripheral sensitive neuropathy. Jejunal biopsies performed during laparotomy, showed axonal degeneration and lympho-plasmocytic infiltration in myenteric plexus. High titer of seric anti-Hu antibodies suggested a paraneoplastic syndrome. Thoracic CT scan showed mediastinal lymph nodes. Their histological examination confirmed the diagnosis of metastatic small-cell lung carcinoma. Her condition gradually deteriorated despite supportive parenteral nutrition, chemotherapy, steroids and intravenous immunoglobulins. She died 12 months after the onset of symptoms.

Small-intestinal digestion of partially resistant cornstarch in healthy subjects.

The aims of this study were to measure the amount of starch from partially resistant starches (retrograded and complexed high-amylose cornstarches) escaping small-intestinal digestion in healthy humans by use of an intubation method and to compare these data with data obtained by indirect in vitro methods. Experiments were carried out in vivo in 6 healthy humans by using ileal intubation and stool analysis and in vitro by using 3 different methods for analyzing resistant starch. In intubated subjects, 51 +/- 2% of the retrograded and 21 +/- 2% of the complexed starch was delivered to the ileum and was fermented almost completely in the colon. In vitro estimates of the absorption of resistant starch were much lower. We conclude that technologically modified starches may substantially increase the amount of carbohydrate available for colonic fermentation in humans, but that in vitro measurements of resistant starch are inaccurate for predicting malabsorption in healthy humans.

Casein peptide release and passage to the blood in humans during digestion of milk or yogurt.

In adult humans, after milk or yogurt ingestion, many peptides derived from alpha s1-, beta- or kappa-caseins were detected in stomach, including the kappa-caseinoglycopeptide, an inhibitor of platelet aggregation. Smaller peptides derived from casein and lactoferrin were recovered from duodenum. Two long peptides, the kappa-caseinoglycopeptide and the N-terminal peptide of alpha s1-casein, were absorbed and detected in plasma. These results support the concept that food-born peptides could have physiological activities in man.