Drug-specific risk of non-tuberculosis opportunistic infections in patients receiving anti-TNF therapy reported to the 3-year prospective French RATIO registry.

BACKGROUND: Anti-tumour necrosis factor (TNF) therapy may be associated with opportunistic infections (OIs). OBJECTIVE: To describe the spectrum of non-tuberculosis OIs associated with anti-TNF therapy and identify their risk factors. METHODS: A 3-year national French registry (RATIO) collected all cases of OI in patients receiving anti-TNF treatment for any indication in France. A case-control study was performed with three controls treated with anti-TNF agents per case, matched for gender and underlying inflammatory disease. RESULTS: 45 cases were collected of non-TB OIs in 43 patients receiving infliximab (n=29), adalimumab (n=10) or etanercept (n=4) for rheumatoid arthritis (n=26), spondyloarthritides (n=3), inflammatory colitis (n=8), psoriasis (n=1) or other conditions (n=5). One-third (33%) of OIs were bacterial (4 listeriosis, 4 nocardiosis, 4 atypical mycobacteriosis, 3 non-typhoid salmonellosis), 40% were viral (8 severe herpes zoster, 3 varicella, 3 extensive herpes simplex, 4 disseminated cytomegalovirus infections), 22% were fungal (5 pneumocystosis, 3 invasive aspergillosis, 2 cryptococcosis) and 4% were parasitic (2 leishmaniasis). Ten patients (23%) required admission to the intensive care unit, and four patients (9%) died. Risk factors for OIs were treatment with infliximab (OR=17.6 (95% CI 4.3 - 72.9); p<0.0001)or adalimumab (OR=10.0 (2.3 to 44.4); p=0.002) versus etanercept, and oral steroid use >10 mg/day or intravenous boluses during the previous year (OR=6.3 (2.0 to 20.0); p=0.002). CONCLUSION: Various and severe OIs, especially those with intracellular micro-organisms, may develop in patients receiving anti-TNF treatment. Monoclonal anti-TNF antibody rather than soluble TNF receptor therapy and steroid use >10 mg/day are independently associated with OI.

Effects of therapeutic doses of lactulose vs. polyethylene glycol on isotopic colonic transit.

BACKGROUND: Lactulose and polyethylene glycol are osmotic agents used to treat idiopathic chronic constipation. AIM: To compare the effects of low doses of lactulose and PEG 4000 on transit time measured by scintigraphy in normal subjects. METHODS: For 5 days, 10 healthy subjects received either 10 g b.d. of lactulose or PEG 4000 in a randomized, double-blind, crossover study. On the evening of day 4, they took a capsule containing Amberlite resin pellets labelled with (111)In. On day 5, after a 1000 kcal test meal labelled with 99 Tcm, gastric, small bowel and colonic transits were measured. RESULTS: Gastric emptying and small bowel transit time were not different. Ascending colon emptying curve was significantly accelerated with lactulose in comparison with polyethylene glycol (P = 0.001) and, respectively, 50 +/- 18% vs. 35 +/- 18% of the radioactivity had left the ascending colon at the end of the study (P < 0.05). The descending colon filling curves, variations in the geometric centre and numbers of scintigraphic movements were not different. CONCLUSIONS: In healthy subjects, in comparison to PEG 4000, usual therapeutic doses of lactulose significantly accelerate ascending colon emptying. This result supports a stimulating motor effect of colonic fermentation of lactulose.

Low-dose lactulose produces a tonic contraction in the human colon.

Lactulose (10-20 g day(-1)) is used to treat constipation. At this therapeutic dose, its effects on colonic motility remain unknown. Twenty-two healthy subjects swallowed a probe with an infusion catheter, six perfused catheters and a balloon connected to a barostat. Colonic phasic and tonic motor activity was recorded in fasting state. In group 1, four volunteers ingested 15 g lactulose and motility was recorded for 5 h after entry of lactulose into the caecum; in group 2, motility was recorded during (3 h) and 2 h after intracolonic infusion of isoosmotic and isovolumetric solutions containing sodium chloride alone (n = 9) or with 15 g lactulose (n = 9). In a last group of volunteers, isotopic colonic transit after ingestion of lactulose (10 g,n = 9) was assessed and compared with a control group (n = 17). Ingestion or intracolonic infusion of 15 g lactulose significantly decreased barostat bag volume (maximal decrease: 45 +/- 12% and 35 +/- 9% of basal value respectively). Phasic contractions remained unchanged. Tonic and phasic motility was unchanged by the isotonic and isovolumetric infusion of saline. Ingestion of lactulose significantly accelerated isotopic colonic transit time compared with the control group. We conclude that in healthy humans, 10-15 g ingestion or intracaecal infusion of lactulose produces a prolonged tonic contraction that may be involved in the laxative effect of lactulose.

Prognosis of malignant intraductal papillary mucinous tumours of the pancreas after surgical resection. Comparison with pancreatic ductal adenocarcinoma.

BACKGROUND: Although the prognosis in malignant resectable intraductal papillary mucinous tumours of the pancreas (IPMT) is often considered more favourable than for ordinary pancreatic ductal adenocarcinoma, the long term outcome remains ill defined. AIMS: To assess prognostic factors in patients with malignant IPMT after surgical resection, and to compare long term survival rates with those of patients surgically treated for ductal adenocarcinoma. METHODS: Seventy three patients underwent surgery for malignant IPMT in four French centres. Clinical, biochemical, and pathological features and follow up after resection were recorded. Patients with invasive malignant IPMT were matched with patients with pancreatic ductal adenocarcinoma, according to age and TNM stages; survival rates after resection were compared. RESULTS: Surgical treatment for IPMT were pancreaticoduodenectomy (n=46), distal (n=14), total (n=11), or segmentary (n=2) pancreatectomy. The operative mortality rate was 4%. IPMT corresponded to in situ (n=22) or invasive carcinoma (n=51). In the latter group, 17 had lymph node metastases. Overall median survival was 47 months. Five year survival rates in patients with in situ and invasive carcinoma were 88% and 36%, respectively. On univariate analysis, abdominal pain, preoperative high serum carbohydrate antigen 19.9 concentrations, caudal localisation, invasive carcinoma, lymph node metastases, peripancreatic extension, and malignant relapse were associated with a fatal outcome. Using multivariate analysis, lymph node metastases were the only prognostic factor (OR 7.5; 95% CI: 3.4 to 16.4). Overall five year survival rate was higher in patients with malignant invasive IPMT compared with those with pancreatic ductal carcinoma (36 v 21%, p=0.03), but was similar in the subset of stage II/III tumours. CONCLUSIONS: The prognosis of patients with resected in situ/invasive stage I malignant IPMT is excellent. In contrast, prognosis of locally advanced forms is as poor as in patients with pancreatic ductal adenocarcinoma.

Long-term outcome of patients with gastrointestinal bleeding of obscure origin explored by push enteroscopy.

BACKGROUND AND STUDY AIMS: Little is known of the long-term outcome in patients with gastrointestinal bleeding of obscure origin, who undergo investigation by means of push enteroscopy. The aim of this study was to assess the rate of recurrent bleeding and its predictive factors in patients with gastrointestinal bleeding of obscure origin, after exploration by push enteroscopy. PATIENTS AND METHODS: 105 patients with gastrointestinal bleeding of obscure origin (iron-deficiency anemia: n = 56; overt bleeding: n = 49) underwent exploration by push enteroscopy from December 1994 to December 1998. They were classified into three groups according to enteroscopy findings: no lesion found (group A; 56 patients), arteriovenous malformations (group B; 18 patients), and other gastrointestinal lesions (group C; 31 patients). Actuarial rates of rebleeding during follow-up were calculated and factors associated with rebleeding were assessed by means of univariate and multivariate analysis. RESULTS: Follow-up data were obtained for 101 patients (96 %). The mean follow-up was 29 months (6 - 54 months). The 2-year actuarial rate of rebleeding was 31 % in the overall population, and 27.6 %, 56 % and 24 % in groups A, B, and C, respectively (P = 0.13). The number of previous bleeding episodes and the number of packed red cell units transfused were two independent factors predictive of recurrent bleeding. The modality of recurrent bleeding (anemia or overt bleeding) was similar to that of the initial episode in 94 % of cases. In group A, a gastrointestinal lesion was found after rebleeding in one of the 12 patients with iron-deficiency anemia, and in four of the five patients with overt bleeding. CONCLUSION: Recurrent bleeding occurs in about one-third of patients who undergo investigation by push enteroscopy for gastrointestinal bleeding of obscure origin, with a trend towards more frequent rebleeding in patients with arteriovenous malformations. Frequent previous bleeding episodes and transfusion requirements are predictive of recurrent bleeding.

Bifidobacterium animalis strain DN-173 010 shortens the colonic transit time in healthy women: a double-blind, randomized, controlled study.

BACKGROUND: A previous study has suggested that Bifidobacterium animalis DN-173 010 shortens the colonic transit time in women. AIM: To confirm this effect and to determine whether modifications of the faecal bacterial mass and/or faecal secondary bile salts may be the explanation. METHODS: A double-blind, cross-over study was performed. Thirty-six healthy women were studied in four consecutive 10-day periods. During periods 2 and 4, they ingested three 125 g cups per day of a fermented milk which was either a product containing B. animalis DN-173 010 or a control without bifidobacteria. Periods 1 and 3 were run-in and washout periods, respectively. The total and segmental colonic transit times were assessed using a pellet method. In 12 subjects, all stools were collected and analysed for pH, faecal weight, bacterial mass and bile acids. RESULTS: The total and sigmoid transit times were significantly shorter during dosing with B. animalis compared to the control period. The other transit times, faecal weight, pH, bacterial mass and bile acids were not significantly affected. CONCLUSIONS: B. animalis DN-173 010 shortens the colonic transit time in healthy women. This effect is not explained by modifications of the faecal bacterial mass or secondary bile acids.

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.

Is push enteroscopy useful in patients with malabsorption of unclear origin?

OBJECTIVE: The aim of this study was to determine the diagnostic value of push enteroscopy in patients with chronic diarrhea and malabsorption of unclear origin. METHODS: From January, 1997, to September, 1999, 16 consecutive patients with chronic diarrhea and biological signs of intestinal malabsorption but no evidence of celiac disease were explored by push enteroscopy. Previous duodenal histological findings had been normal in seven patients and abnormal but inconclusive in nine patients. Endoscopic and histological findings in the duodenum and in the jejunum were compared. RESULTS: Push enteroscopy with jejunal biopsy yielded a diagnosis in comparison with duodenal biopsy in two of 16 (12%) patients, respectively, in two of the nine (22%) patients with abnormal but inconclusive findings on duodenal biopsy, and none of the seven patients with normal duodenal histology. In the two patients in whom jejunal biopsy had diagnostic value but duodenal biopsy did not, the final diagnoses were invasive intestinal lymphoma and microsporidiosis. CONCLUSION: Push enteroscopy had diagnostic value in only 12% of patients with malabsorption of unclear origin, all of whom had had abnormal but inconclusive duodenal histological findings. Push enteroscopy with jejunal biopsy appears to have limited diagnostic value in patients with chronic diarrhea and malabsorption, especially when duodenal biopsies are histologically normal.

Biliary varices on endoscopic ultrasonography: clinical presentation and outcome.

BACKGROUND AND STUDY AIMS: Bile duct varices are not a well-recognized feature of portal venous obstruction. The aim of the present study was to describe the clinical and endosonographic features of biliary involvement in patients with extrahepatic portal venous obstruction (EPVO). PATIENTS AND METHODS: A retrospective study was conducted of the clinical features, outcome, and endosonographic findings (using Olympus EUM-3 or EUM-20 probes) in 21 patients with EPVO and endosonographic features of biliary varices. Biliary varices were defined as multiple, large, serpiginous, anechoic vascular channels in and/or surrounding the extrahepatic biliary tracts. RESULTS: Biliary varices have not previously been visible using conventional imaging methods (computed tomography and ultrasonography). They were identified using EUS in the wall of the common bile duct in 16 patients (76%), surrounding the common bile duct (CBD) in 11 patients (52%), and in the gallbladder in nine (43%). The varices were the cause of obstructive jaundice in three of the 21 patients (14%), but only when they were in the wall of the CBD. Two of these patients were treated using portosystemic shunting, and the other received a biliary endoprosthesis. The EUS examination also provided evidence of unrecognized pancreatic or biliary tumors in three other patients with EPVO of undetermined origin. CONCLUSIONS: EUS can serve to diagnose biliary varices in patients with EPVO and jaundice. Although biliary varices are mainly asymptomatic, they may cause obstructive jaundice when they are located in the wall of the CBD. EUS can also detect unrecognized malignant tumors in patients with EPVO of undetermined origin.

Outcome after surgical resection of intraductal papillary and mucinous tumors of the pancreas.

OBJECTIVE: Treatment of intraductal papillary and mucinous tumors of pancreas (IPMT) usually requires surgery. The objective of this study was to evaluate the risk of recurrence in patients after surgery according to the histological nature of the neoplasm and the type of surgery. METHODS: The outcome of 45 patients who underwent partial pancreatectomy (n = 35) or total pancreatectomy (n = 10) for IPMT was studied according to the nature of the neoplasm (invasive carcinoma or noninvasive neoplasm), type of surgery (partial or total pancreatectomy), and lymph nodes status. RESULTS: The overall 3-yr actuarial survival rate was 83%. Death occurred in seven of 20 (35%) patients with invasive carcinoma and in one of 26 (4%) patients with noninvasive tumors (p<0.05). There were two recurrences in the seven patients with noninvasive neoplasm who underwent partial pancreatectomy with involved resection margins, and none in the 13 patients with disease-free margins. In patients with invasive carcinoma, there was one recurrence after total pancreatectomy, six after partial pancreatectomy with disease-free margins and six after partial pancreatectomy with involved margins. In patients with invasive carcinoma, total pancreatectomy and the absence of lymph nodes involvement were independently associated with a low risk of recurrence. CONCLUSIONS: IPMT may be managed as follows: 1) in patients with noninvasive neoplasms, partial pancreatic resection should be guided by frozen section examination until disease-free margins are obtained; and 2) in patients with invasive carcinoma, total pancreatectomy seems most likely to cure the patient, but should be discussed according to the general status and the age.

Right colonic involvement is associated with severe forms of ischemic colitis and occurs frequently in patients with chronic renal failure requiring hemodialysis.

OBJECTIVE: The aim of this study was to identify factors associated with severe outcome in patients with ischemic colitis. METHODS: The files of 60 consecutive inpatients (34 women, 26 men, mean age 67 yr) with ischemic colitis were reviewed. The following data were analyzed: age, sex, smoking, medications, history of cardiovascular disease, metabolic disease, chronic renal failure and hemodialysis, the time elapsed between the first symptoms and the diagnosis, and the site and extension of their colonic involvement. Patients were divided into two groups according to outcome: those with severe disease, including those who died from ischemic colitis (n = 3) or who required surgical resection (n = 21); and those with mild forms of colitis who were treated successfully without surgery (n = 36). The two groups were compared by means of univariate and multivariate analysis to identify factors associated with unfavorable outcomes. Only patients who had a complete examination of the colon (n = 51) were entered into the statistical analysis. RESULTS: By univariate analysis, chronic renal failure (p = 0.03), hemodialysis (p = 0.01), short delay between symptoms and diagnosis (p = 0.01), and right colonic involvement (p = 0.002) were significantly more common in the patients with severe colitis. By logistic regression, right colonic involvement was the only factor independently associated with severity (p = 0.01). Right-sided lesions were present in 82% of patients on dialysis but in only 26% of patients not on dialysis (p = 0.0005). CONCLUSIONS: Right colonic involvement is associated with severe forms of ischemic colitis and occurs frequently in patients with chronic renal failure requiring hemodialysis.

Metastatic jejunal VIPoma: beneficial effect of combination therapy with interferon-alpha and 5-fluorouracil.

The VIPoma syndrome is rare. It is usually caused by a neuroendocrine tumor located in the pancreas. Somatostatin analogs and interferon-a can be helpful in the symptomatic control of the disease, but the efficacy of chemotherapy in metastatic disease is limited. We report the case of a 32-yr-old patient who had a primary intestinal VIPoma with peritoneal carcinomatosis and hepatic metastases. Somatostatin analogs and conventional chemotherapy regimens were not effective on VIPoma syndrome and tumor progression. The combination of 5- fluorouracil and interferon-alpha was associated with a major clinical improvement and tumor regression. Further investigations should evaluate the place of such a combination as a first line treatment for patients with metastatic neuroendocrine tumors.

Endosonographic features predictive of benign and malignant gastrointestinal stromal cell tumours.

BACKGROUND/AIM: Some endoscopic ultrasonographic (EUS) features have been reported to be suggestive of malignancy in gastrointestinal stromal cell tumours (SCTs). The aim of this study was to assess the predictive value of these features for malignancy. METHODS: A total of 56 histologically proven cases of SCT studied by EUS between 1989 and 1996 were reviewed. There were 42 gastric tumours, 12 oesophageal tumours, and two rectal tumours. The tumours were divided into two groups: (a) benign SCT, comprising benign leiomyoma (n = 34); (b) malignant or borderline SCT (n = 22), comprising leiomyosarcoma (n = 9), leiomyoblastoma (n = 9), and leiomyoma of uncertain malignant potential (n = 4). The main EUS features recorded were tumour size, ulceration, echo pattern, cystic spaces, extraluminal margins, and lymph nodes with a malignant pattern. The two groups were compared by univariate and multivariate analysis. RESULTS: Irregular extraluminal margins, cystic spaces, and lymph nodes with a malignant pattern were most predictive of malignant or borderline SCT. Pairwise combinations of the three features had a specificity and positive predictive value of 100% for malignant or borderline SCT, but a sensitivity of only 23%. The presence of at least one of these three criteria had 91% sensitivity, 88% specificity, and 83% predictive positive value. In multivariate analysis, cystic spaces and irregular margins were the only two features independently predictive of malignant potential. The features most predictive of benign SCTs were regular margins, tumour size < or = 30 mm, and a homogeneous echo pattern. When the three features were combined, histology confirmed a benign SCT in all cases. CONCLUSIONS: The combined presence of two out of three EUS features (irregular extraluminal margins, cystic spaces, and lymph nodes with a malignant pattern) had a positive predictive value of 100% for malignant or borderline gastrointestinal SCT. Tumours less than 30 mm in diameter with regular margins and a homogeneous echo pattern are usually benign.

[Acute pancreatitis revealing cystic fibrosis in an adult]. / Pancréatite aiguë révélatrice de mucoviscidose chez une adulte.

We report a case of pancreatitis as the first symptom of cystic fibrosis in a 22-year-old woman. The diagnosis was suspected upon the history of nasal polyposis and severe episodes of respiratory infections in infancy. The diagnosis was confirmed by sweat test. Genotyping showed a compound heterozygosity for mutations delta F508 and 5T. Acute pancreatitis is a rare manifestation of cystic fibrosis and an exceptional mode of initial presentation of the disease. It occurs in pancreatic sufficient patients, especially in young adults. This exceptional case shows that cystic fibrosis should be suspected in each case of idiopathic pancreatitis. Indications of cholecystectomy in patients with associated gallbladder lithiasis is discussed.

Push enteroscopy in celiac sprue and refractory sprue.

BACKGROUND: The aim of this study was to determine in patients with sprue whether jejunal endoscopy improves the diagnostic yield or provides information that may modify management, when compared with evaluation limited to the duodenum. METHODS: From January 1994 to June 1998, a total of 31 patients (6 men, 25 women, mean age 41 years) were prospectively evaluated by push enteroscopy. They were divided into two groups: (1) celiac disease at different stages of activity (n = 23) and (2) refractory sprue (n = 8). The endoscopic and histologic findings in the duodenum and in the jejunum were compared. RESULTS: Celiac disease: In 19 patients, endoscopic and histologic findings in the duodenum and jejunum were similar; in four patients villous atrophy was more severe in the duodenum than in the jejunum. Refractory sprue: In 5 of 8 patients, enteroscopy revealed ulcerative jejunitis, whereas ulcerations were found in the duodenum in only one case. CONCLUSION: In refractory sprue, push enteroscopy with jejunal biopsies was of diagnostic value in 50% of cases demonstrating ulcerative jejunitis, whereas it did not modify the management of patients with responsive celiac disease.