René Fiasse

Inflammatory Bowel Disease A Positive Response to Infliximab in Crohn Disease: Association with a Higher Systemic Inflammation Before Treatment But Not With -308 TNF Gene Polymorphism

Background: Two-thirds to three-fourths of patients with either refractory luminal or fistulizing Crohn disease respond to infliximab treatment. The ability or inability to respond seems to persist over time. Biological characteristics and/or genetic background can influence the response to treatment. The aim was to assess the value of C-reactive protein and TNF- α serum levels before treatment as well as the TNF -308 gene polymorphism in the prediction of response to infliximab treatment in Crohn disease. Methods: Two-hundred-and-twenty-six Crohn disease patients treated in the setting of an expanded access programme to infliximab in Belgium were studied. There were 136 refractory luminal diseases and 90 refractory fistulizing diseases. Luminal diseases were treated with one single infusion; fistulizing diseases with three infusions at weeks 0, 2 and 6. A clinical response to treatment was defined as either a Crohn disease activity index <150 (complete) or a drop of 70 points (partial) at week 4, for luminal disease, and as either complete fistula healing (complete) or a decrease of at least 50% of the number of draining fistulas on two consecutive visits between weeks 0 and 18, for fistulizing disease. CRP and serum TNF- α levels were measured at week 0 before treatment and were compared between responders and non-responders. Patients were genotyped for the-308 TNF gene polymorphism, and allelic as well as genotype frequencies were compared between responders and non-responders. Results: There were 73.2% responders (46.4% complete and 26.8% partial) and 26.8% non-responders. Response rates were similar in luminal and fistulizing diseases. CRP level before treatment was significantly higher in responders than in non-responders (16.8 mg/l (5-160) versus 9.6 mg/l (5-143); P = 0.02). Furthermore, response rate was significantly higher in patients with elevated CRP (>5 mg/l) than in patients with a normal CRP value (<5 mg/l) before treatment (76% versus 46%; P = 0.004; OR: 0.26 (0.11-0.63)). Allelic and genotype frequencies for-308 TNF gene polymorphism were not significantly different between responders and non-responders - with the exception of a slightly higher TNF2 frequency in nonresponders in luminal disease (22.1% versus 11.6%; P = 0.04). However, this was not associated with a significant difference in genotype frequencies. Conclusion: A positive clinical response to infliximab was associated with a higher CRP level before treatment in our population of Crohn disease patients, but there was no relevant association with-308 TNF gene polymorphism. We therefore suggest that CRP level may help to identify better candidates for infliximab treatment.

Skeletonizing en bloc esophagectomy for cancer.

ObjectiveTo evaluate the long-term outcome of patients with esophageal cancer after resection of the extraesophageal component of the neoplastic process en bloc with the esophageal tube. Summary Background DataOpinions are conflicting about the addition of extended resection of locoregional lymph nodes and soft tissue to removal of the esophageal tube. MethodsEsophagectomy performed en bloc with locoregional lymph nodes and resulting in a real skeletonization of the nonresectable anatomical structures adjacent to the esophagus was attempted in 324 patients. The esophagus was removed using a right thoracic (n = 208), transdiaphragmatic (n = 39), or left thoracic (n = 77) approach. Lymphadenectomy was performed in the upper abdomen and lower mediastinum in all patients. It was extended over the upper mediastinum when a right thoracic approach was used and up to the neck in 17 patients. Esophagectomy was carried out flush with the esophageal wall as soon as it became obvious that a macroscopically complete resection was not feasible. Neoplastic processes were classified according to completeness of the resection, depth of wall penetration, and lymph node involvement. ResultsSkeletonizing en bloc esophagectomy was feasible in 235 of the 324 patients (73%). The 5-year survival rate, including in-hospital deaths (5%), was 35% (324 patients); it was 64% in the 117 patients with an intramural neoplastic process versus 19% in the 207 patients having neoplastic tissue outside the esophageal wall or surgical margins (P < .0001). The latter 19% represented 12% of the whole series. The 5-year survival rate after skeletonizing en bloc esophagectomy was 49% (235 patients), 49% for squamous cell versus 47% for glandular carcinomas (P = .4599), 64% for patients with an intramural tumor versus 34% for those with extraesophageal neoplastic tissue (P < .0001), and 43% for patients with fewer than five metastatic nodes versus 11% for those with involvement of five or more lymph nodes (P = .0001). ConclusionsThe strategy of attempting skeletonizing en bloc esophagectomy in all patients offers long-term survival to one third of the patients with resectable extraesophageal neoplastic tissues. These patients represent 12% of the patients with esophageal cancer suitable for esophagectomy and 19% of those having neoplastic tissue outside the esophageal wall or surgical margins.

Controlled Trial of Cimetidine in Reflux Esophagitis

In an eight-week double-blind trial, the effectiveness of cimetidine (1.6 g/day) was compared to placebo in 34 patients with symptomatic esophagitis confirmed by endoscopy with biopsies and/or by acid infusion test. Patients treated with cimetidine had significantly less symptomatic days during the first six weeks and less symptomatic nights during the first two weeks, and they consumed less antacids during the whole trial period. Endoscopic evaluation of 17 patients on cimetidine and of 15 patients on placebo did not show any significant difference in severity and extent of esophageal lesions after eight weeks, but histological assessment of 16 patients on cimetidine and 13 patients on placebo showed a significant improvement after eight weeks of cimetidine (P<0.025). These results show that cimetidine has a rapid effect on symptoms of reflux esophagitis and that, in some cases, it may reduce the esophageal lesions after eight weeks.

Crohn's disease stable remission after human immunodeficiency virus infection

We retrospectively assessed the clinical coursein four patients with long-standing Crohns disease whobecame infected with human immunodeficiency virus (HIV).The duration of active Crohns disease was 21, 10, 4, and 4 years in our four patients.They experienced a stable remission of Crohns diseasesymptoms after HIV infection. In three patients Crohnsdisease was in stable remission for 5, 8, and 8 years after HIV infection and all three diedfrom acquired immunodeficiency syndrome-related disease.One patient was still alive without recurrence ofCrohns disease symptoms 7 years following HIVdetection. Our observations of a spontaneous improvementin the clinical course of Crohns disease after HIVinfection, suggests that the integrity of the immuneresponse, especially that of CD4 T cells, plays a major role in the tissue injury mechanism in Crohnsdisease.

Healing of severe esophagitis improves esophageal peristaltic dysfunction

Reflux esophagitis is frequently associated withperistaltic dysfunction, which increases with theseverity of inflammatory lesions. In order to assessperistaltic dysfunction with more accuracy before and after healing, we used a 24-hr pH andpressure recording method. Nineteen patients (medianage: 65, range: 33-77) with stage II and III(Savary-Miller classification) esophagitis andperistaltic dysfunction were treated with 40 mg omeprazole for three tosix months until complete endoscopic healing wasachieved. Before treatment, median contraction amplitudewas significantly lower than median contraction amplitude of a control group of comparable age[31 (21-53) versus 42 (21-77) mm Hg, P < 0.01], aswell as median percentage of peristaltic contractions[27 (16-63) versus 44 (11-56), P < 0.01]. At the end of treatment, a statisticallysignificant improvement of esophageal motor functionswas observed for both median contraction amplitude [38(26-55), P = 0.001] and median percentage of peristaltic waves [45 (23-68), P = 0.0001]. Theposttreatment values, although still low, were notsignificantly different from control values. Inconclusion, complete healing of grade II and IIIesophagitis improves peristalsis. Inflammatory processes related tosevere esophagitis may be involved in failed peristalsisand low contraction amplitude.

Purification and Amino-acid-sequence of Human Motilin Isolated From a Motilin Containing Liver Metastasis

The acid extract of a liver metastasis from a patient with elevated plasma motilin levels contained large quantities of motilin (3.37 micrograms/ml). The extract was concentrated on a C18-column and motilin was isolated by gel chromatography (Sephadex G-50) followed by cation ion exchange chromatography (HR5/5 Mono-S) and three successive steps of reverse phase chromatography (Nucleosil 300-5 C18). The pure peptide was sequenced and the identity of porcine and human motilin was confirmed. This is the first report of a tumor containing large amounts of motilin.

Control of AA amyloidosis complicating Crohn's disease: a clinico-pathological study.

Immunosuppressive drugs may prevent or partially reverse progression of renal AA‐amyloidosis, a rare complication of Crohns disease, often fatal due to renal failure.

Faecal bile acid analysis and intestinal absorption in Crohn's disease before and after ileal resection

Abstract. Faecal bile acids were analysed by gas chromatography in 104 patients. Total bile acids exceeded 1.5 mmol/24 h in 33% of forty‐five unoperated patients and in 90% of those having undergone an ileal resection. Lithocholic and deoxycholic fractions were lower in the unoperated patients than in the control group (P < 0.05 and P < 0.005) and much lower after ileal resection than in unoperated patients (P < 0.001). A significant correlation (r= 0.58; P < 0.001) was found between total bile acids and relative proportions of primary bile acids in operated patients, untreated by antibiotics or sulfasalazine. Dihydroxy bile acids (predominantly chenodeoxycholic acid) correlated with faecal weight in unoperated patients (r= 0.47, P < 0.01) and in 0–50 cm (r= 0.69, P < 0.001) and 50–100 cm (r= 0–63, P < 0.01) ileal resection groups. Our results suggest that the frequently altered bile acid composition is related to a shortening of colonic transit time which reduces the exposure of primary bile acids to bacterial 7α‐dehydroxylase.

An unusual metastatic motilin-secreting neuroendocrine tumour with a 20-year survival. Pathological, biochemical and motility features.

Motilin-secreting neuroendocrine tumours have been rarely described. Immunohistochemical, biochemical and motility investigations were performed in a 62-year-old man with liver and bone metastases of a motilin-secreting neuroendocrine tumour originating from a rectal polyp removed 14 years previously. Symptoms related to liver metastases were reduced by a right hepatectomy whereas plasma motilin levels were decreased. The patient also underwent two operations for spinal cord decompression and survived 6 more years under medical treatment, mainly octreotide. Immunohistochemistry revealed predominant expression of motilin-containing cells, with rare cells expressing somatostatin and pancreatic polypeptide, and staining for only one panendocrine marker, neurone-specific enolase. A liver tumour extract contained 17.9 µg motilin per gram of tissue, which permitted to isolate and characterize human motilin, which was identical to porcine motilin. Plasma column gel chromatography revealed a main peak corresponding apparently to porcine motilin. The patient had no symptoms of disturbed motility. Gastric emptying and gastroduodenojejunal motility were found within normal limits. The absence of alterations of gut motility was perhaps related to sustained autonomous motilin production. The long evolution of this type of tumour suggests that plasma motilin determination should be added to the investigations for neuroendocrine tumours.

Effect of a 2 g cimetidine infusion on twenty-four-hour intragastric pH in critically ill patients.

We evaluated the effect of a cimetidine continuous infusion (2 g in 24 h) on the intragastric pH of 16 critically ill patients (11 men, 5 women, mean age 45 years). During the 24 h pre-trial period and the subsequent 24 h cimetidine infusion, an intragastric combined electrode was placed in the fundus and the pH recorded with a portable pH module and data collection unit. In each patient, the cimetidine infusion induced a prolonged rise of intragastric pH. For all patients the mean percentage of readings above pH 4.0 was 11% pre-trial and 75% during the cimetidine 24 h infusion (p<0.001). The percentages of readings above 5.0, 6.0, 7.0 were also significantly higher during infusion than pre-trial in the 16 patients. After starting the cimetidine infusion, there was a concomitant rise of median plasma cimetidine and median intragastric pH in the 7 patients studied. After 6 h, median plasma cimetidine remained above 1 mcg/ml. These results and recent data from the literature suggest that in critically ill patients a continuous infusion of cimetidine might prevent stress ulcerations better than bolus injections by maintaining intragastric pH above 4.0 during longer time intervals.