[Screening for alpha1-antitrypsin deficiency using dried blood spot: Assessment of the first 20 months]. / Dépistage du déficit en alpha1-antitrypsine sur sang capillaire recueilli sur papier-filtre : bilan des 20 premiers mois.

INTRODUCTION: Alpha1-antitrypsin deficiency is a predisposing factor for pulmonary disease and under-diagnosis is a significant problem. The results of a targeted screening in patients with respiratory symptoms possibly indicative of severe deficiency are reported here. METHODS: Data were collected from March 2016 to October 2017 on patients who had a capillary blood sample collected during a consultation with a pulmonologist and sent to the laboratory for processing to determine alpha1-antitrypsin concentration, phenotype and possibly genotype. RESULTS: In 20 months, 3728 test kits were requested by 566 pulmonologists and 718 (19 %) specimens sent: among these, 708 were analyzable and 613 were accompanied by clinical information. Of the 708 samples, 70 % had no phenotype associated with quantitative alpha1- antitrypsin deficiency, 7 % had a phenotype associated with a severe deficiency and 23 % had a phenotype associated with an intermediate deficiency. One hundred and eight patients carried at least one PI*Z allele which is considered to be a risk factor for liver disease. CONCLUSIONS: The results of this targeted screening program for alpha1- antitrypsin deficiency using a dried capillary blood sample reflect improvement in early diagnosis of this deficiency in lung disease with good adherence of the pulmonologists to this awareness campaign.

Small bowel polyp resection using device-assisted enteroscopy in Peutz-Jeghers Syndrome: Results of a specialised tertiary care centre.

INTRODUCTION: Enteroscopy resection of small bowel polyps in Peutz-Jeghers syndrome has only been described in small case series. Herein, we aimed to assess the efficacy of enteroscopy resection of small bowel polyps within a specialised tertiary care centre and the impact on intraoperative enteroscopy. METHODS: This was an observational single-centre study. All adult Peutz-Jeghers syndrome patients followed in the Predisposition Digestive Ile-de-France network who underwent an endoscopic resection of at least one small bowel polyp ≥ 1 cm by enteroscopy between 2002-2015 were included. Small bowel polyps were detected under a dedicated screening programme by previous capsule endoscopy and/or magnetic resonance enterography, performed every 2-3 years. Complete treatment was defined as the absence of polyps ≥ 1 cm after conventional endoscopic resection. Intraoperative enteroscopy or surgical resection were indicated in incomplete treatments. The overall complete treatment rate including conventional enteroscopy and intraoperative enteroscopy was also considered. RESULTS: Endoscopic resection of 216 small bowel polyps (median: 8.6 per patient, size: 6-60 mm) was performed by 50 enteroscopies in 25 patients (mean age: 36 years, range: 18-71, 56% male) with small bowel polyp ≥ 1 cm. Twenty-three patients (92%) underwent 42 screening capsule endoscopies and 14 (57%) had 23 magnetic resonance enterographies during a median follow-up of 60 months. Complete treatment was achieved in 76%. Intraoperative enteroscopy and surgical resection were performed in four (16%) and two (8%) patients. Intraoperative enteroscopy improved by 16% the complete treatment rate and the overall rate was 92%. The complication rate was 6%. CONCLUSION: This long-term study confirmed the efficacy and safety of endoscopic resection of small bowel polyps in Peutz-Jeghers syndrome. Intraoperative enteroscopy can be a complementary approach in selected cases.

Heavy+light chain monitoring correlates with clinical outcome in multiple myeloma patients.

Novel anti-myeloma agents have improved patient response rates, which are historically based on reductions of the M-protein. These methods can be inaccurate for quantifying M-proteins at low concentrations. We compared the consistency and clinical impact of response assignment by electrophoretic and heavy+light chain (HLC) immunoassays post-consolidation in 463 newly diagnosed patients. The two methods gave similar assignments in patients with partial (PR; 79% agreement) or complete response (⩾CR; 92%). However, in patients achieving very good PR (VGPR) there was poor concordance between methods (45%). Median progression-free survival (PFS) for standard VGPR patients was 34.5 months; HLC responses stratified these patients further into PR, VGPR and ⩾CR, with median PFS of 21.3, 28.9 months and not reached, respectively; P<0.001. At this time, abnormal HLC ratios had better concordance with multiparametric flow cytometry (sensitivity 10-4) (37 and 34% positive, respectively), compared to immunofixation (62% positive). In addition, HLC-pair suppression was identified in 38% of patients and associated with shorter PFS (30.6 months vs not reached; P<0.001). We conclude that HLC monitoring could augment electrophoretic assessments in patients achieving VGPR. The prognostic significance of HLC responses might partly depend on the patients' ability to recover their immune system, as determined by normalisation of HLC measurements.

Randomized clinical trial of sacral nerve stimulation for refractory constipation.

BACKGROUND: Open studies have reported favourable results for sacral nerve stimulation in the treatment of refractory constipation. Here, its efficacy was assessed in a double-blind crossover RCT. METHODS: Patients with at least two of the following criteria were included: fewer than three bowel movements per week; straining to evacuate on more than 25 per cent of attempts; or sensation of incomplete evacuation on more than 25 per cent of occasions. Response to therapy was defined as at least three bowel movements per week and/or more than 50 per cent improvement in symptoms. Responders to an initial 3-week peripheral nerve evaluation were offered permanent implantation of a pulse generator and were assigned randomly in a crossover design to two 8-week intervals of active or sham stimulation. At the end of the two trial periods, the patients received active stimulation until the final evaluation at 1 year. RESULTS: Thirty-six patients (34 women; mean(s.d.) age 45(14) years) underwent peripheral nerve evaluation. Twenty responded and received a permanent stimulator. A positive response was observed in 12 of 20 and 11 of 20 patients after active and sham stimulation periods respectively (P = 0·746). Pain related to the device occurred in five patients and wound infection or haematoma in three, leading to definitive removal of the pulse generator in two patients. At 1 year, 11 of the 20 patients with an implanted device continued to respond. Stimulation had no significant effect on colonic transit time. CONCLUSION: These results do not support the recommendation of permanent implantation of a pulse generator in patients with refractory constipation who initially responded to temporary nerve stimulation. Registration number: NCT01629303 (http://www.clinicaltrials.gov).

Creation of a model to predict survival in patients with refractory coeliac disease using a multinational registry.

BACKGROUND: Refractory coeliac disease is a severe complication of coeliac disease with heterogeneous outcome. AIM: To create a prognostic model to estimate survival of patients with refractory coeliac disease. METHODS: We evaluated predictors of 5-year mortality using Cox proportional hazards regression on subjects from a multinational registry. Bootstrap resampling was used to internally validate the individual factors and overall model performance. The mean of the estimated regression coefficients from 400 bootstrap models was used to derive a risk score for 5-year mortality. RESULTS: The multinational cohort was composed of 232 patients diagnosed with refractory coeliac disease across seven centres (range of 11-63 cases per centre). The median age was 53 years and 150 (64%) were women. A total of 51 subjects died during a 5-year follow-up (cumulative 5-year all-cause mortality = 30%). From a multiple variable Cox proportional hazards model, the following variables were significantly associated with 5-year mortality: age at refractory coeliac disease diagnosis (per 20 year increase, hazard ratio = 2.21; 95% confidence interval, CI: 1.38-3.55), abnormal intraepithelial lymphocytes (hazard ratio = 2.85; 95% CI: 1.22-6.62), and albumin (per 0.5 unit increase, hazard ratio = 0.72; 95% CI: 0.61-0.85). A simple weighted three-factor risk score was created to estimate 5-year survival. CONCLUSIONS: Using data from a multinational registry and previously reported risk factors, we create a prognostic model to predict 5-year mortality among patients with refractory coeliac disease. This new model may help clinicians to guide treatment and follow-up.

[DEFI-ALPHA cohort and POLYGEN DEFI-ALPHA clinical research hospital programme. A study about clinical, biological and genetics factors associated with the occurrence and the evolution of hepatic complications in children with alpha-1 antitrypsin deficiency]. / Cohorte DEFI-ALPHA et projet hospitalier de recherche clinique POLYGEN DEFI-ALPHA. Étude des facteurs cliniques, biologiques et génétiques associés à l'apparition et à l'évolution de complications hépatiques chez les enfants présentant un déficit en alpha-1 antitrypsine.

INTRODUCTION: The alpha-1 antitrypsin (α1-AT) deficiency, most frequently caused by homozygosity for the Z variant (SERPINA1: c.1096 G>A; Glu342Lys), can give rise to two clinical patterns: (i) respiratory impairment with emphysema (mainly in adulthood) because of a pulmonary quantitative defect in anti-elastase activity; (ii) hepatic impairment (mainly in childhood) due to the misfolding of the PiZ protein which accumulates in hepatocytes thus providing cytotoxicity. CURRENT KNOWLEDGE: To date, the clinical and genetic factors responsible for the development of major hepatic injuries (fibrosis and portal hypertension) during childhood in PiZ patients are not known. METHODS: The DEFI-ALPHA cohort, created in 2008, aims to inventory and prospectively study all α1-AT deficient children diagnosed and included after occurrence of a hepatic sign. The POLYGEN DEFI-ALPHA PHRC has recently (2013) been added to the project to identify modifiers genes by two complementary approaches: (i) the candidate genes strategy with the SERPINA1, CFTR (cystic fibrosis gene), MAN1B1 and SORL1 genes, these two latter being implied in the degradation of misfolding proteins; (ii) the whole exome sequencing (WES) strategy in families in which the PiZ proband has a PiZ brother or sister free of any hepatic sign. EXPECTED RESULTS: The clinical parameter we want to explain is the apparition of a portal hypertension in PiZ children. In the DEFI-ALPHA project, three criteria will be tested: (i) age of inclusion in the cohort, (ii) the way of inclusion (neo-natal icterus or later hepatic impairment) and (iii) treatment or not with ursodesoxycholic acid and, if so, its duration. Genetically, polymorphisms on the SERPINA1 and MAN1B1 genes have already been associated in the literature with different clinical evolutions of the A1ATD but very inconstantly. Our study thus aims to confirm or not this association. The CFTR and SORL1 genes have never been studied in the α1-AT deficiency. Finally, the whole exome sequencing strategy could allow the discovery of new unexpected modifiers genes in this disease.

Enteropathy-associated T-cell lymphoma: improving treatment strategies.

Enteropathy-associated T-cell lymphoma (EATL) is a rare and usually rapidly fatal intestinal T-cell non-Hodgkin lymphoma. It arises from intraepithelial lymphocytes and has a high association with coeliac disease. The high mortality of EATL is associated not only with the very aggressive and often chemotherapy-refractory nature of the lymphoma. The poor condition of patients due to prolonged and severe malnutrition compromises the ability to deliver chemotherapy. There are no standardized treatment protocols, and the optimal therapy for EATL remains unclear. The primary step of treatment consists of local debulking, preferably as early as possible after EATL diagnosis. Morbidity and mortality seem to rise with advanced stages of disease due to tumour size progression, worse nutritional status and a higher risk of emergency surgery due to perforation. Standard induction therapy for EATL is anthracycline-based chemotherapy, preferably resumed between 2 and 5 weeks after surgery (depending on clinical condition). Intensification of therapy using high-dose chemotherapy followed by consolidation with BEAM and autologous stem cell transplantation is associated with better outcome. Notably, this treatment strategy has only been applied in patients eligible for this aggressive regimen which might reflect selection bias. Unfortunately, prognosis of EATL remains poor; 5-year survival varies from 8 to 60% depending on the eligibility to receive additional steps of therapy. New treatment strategies are urgently needed for a better prognosis of this lethal complication of coeliac disease. Brentuximab vedotin (anti-CD30) might be promising when added to conventional chemotherapy and is suggested as upfront treatment in EATL.

[Pseudotumoral soft tissue masses in children and adolescents]. / Masses des tissus mous d'allure tumorale de l'enfant et de l'adolescent.

INTRODUCTION: Pseudotumoral soft tissue masses in children and adolescents are a frequent reason for consultation and a diagnostic dilemma. Soft tissue malignancies are relatively uncommon, unlike the large number of benign lesions that may be seen in the superficial tissue and that can be diagnosed with clinical characteristics. MATERIALS AND METHODS: This retrospective study concerns 161 children and adolescents less than 20 years old, referred for a soft tissue mass between 2007 and 2011. It describes their epidemiology, clinical characteristics, and course of care to validate a diagnostic strategy for such masses. RESULTS: Final diagnoses were malignant tumors (44%), benign tumors (32%), and pseudotumoral lesions (24%). Clinical features were similar between these three groups except for age and tumor location, with more benign thoracic masses in younger children. Clinical and radiological association led to an accurate diagnosis for 50% of benign masses and with cytological analysis contribution in 79% of benign tumors and 86% of pseudotumoral lesions. Malignant tumors were suspected in only 39% of cases with radiological exams and in 89% after fine-needle aspiration, an essential additional diagnostic tool. Final diagnoses were formally established through simple standard clinical and radiological evaluation in 19 patients (11.8%; benign tumors, seven patients; malformations, eight patients; post-traumatic lesions, two patients; infection and inflammation, one patient each); ultrasound exam in five patients (3.1%; hemangioendotheliomas, two patients, fascial dehiscence, hemangioma, and vascular malformation, one patient each); MRI in four patients (2.5%; three vascular malformations and one lipoma); CT in two cases (1.2%; vascular malformation and myositis ossificans), and radiological examinations associated with cell aspiration in 15 cases (9.3%; ten benign tumors and five malignant tumors). CONCLUSIONS: A multidisciplinary approach should be requested from oncological, radiological, and pathologic experts to optimize soft tissue mass management as soon as initial investigations start. The authors advise a diagnostic strategy for children with pseudotumoral soft tissue masses.

[Clinical manifestations of adult celiac disease]. / Manifestations de la maladie cœliaque de l'adulte.

Celiac disease is an enteropathy due to gluten intake in genetically predisposed persons (HLA DQ2/DQ8). Celiac disease occurs in adults and children at rates approaching 1% of population in Europe and USA. Celiac disease is extremely various and anaemia, oral aphthous stomatis, amenorrhea or articular symptoms may be the only revealing symptoms. Diagnosis releases on evidence of histological villous atrophy in proximal small bowel and presence of specific serum antibodies. Treatment relies on eviction of gluten. Gluten free diet allows prevention of malignant complications such as small bowel adenocarcinoma and lymphoma and osteopenia. The main cause of resistance to gluten free diet is its bad observance. On the contrary, serious complications of celiac disease, such as clonal refractory celiac sprue and intestinal T-cell lymphoma need to be screen.

Long-term outcome of patients treated with double balloon enteroscopy for small bowel vascular lesions.

OBJECTIVES: Early rebleeding rate after endoscopic therapy with double balloon enteroscopy (DBE) of hemorrhagic small bowel vascular lesions (SBVL) varies between 10 and 50%. In recent reports, long-term follow-up of patients have been described but rebleeding risk factors are still not well established. The aim of the current study was to identify long-term treatment success rate and rebleeding risk factors after DBE therapy in a large cohort. METHODS: We conducted a single-center, retrospective cohort study in a large French tertiary-referral center between January 2004 and December 2007. RESULTS: Among 261 patients presenting with obscure gastrointestinal bleeding (OGIB), SBVL was present in 133 patients and was treated successfully in 129 (97%) using mainly argon plasma coagulation. Ninety-eight patients were followed up for a mean period of 22.6±13.9 months (range 1-52). Rebleeding rate was 46% (45/98 patients) at 36 months. On multivariate analysis, the total number of observed lesions (hazard ratio (HR): 1.15, 95% confidence interval (CI): 1.06-1.25, P=0.001) and the presence of a valvular and/or arrhythmic cardiac disease (HR: 2.50, 95% CI: 1.29-4.87, P=0.007) were significantly associated with the risk of rebleeding. Complication rate of therapeutic DBE was 2.3% with no mortality. CONCLUSIONS: Endoscopic therapy using DBE for SBVL in patients with recurrent OGIB allows a long-term remission in more than half of the patients. Independent rebleeding risk factors after a first endoscopic therapy are an increased number of SBVL and an associated valvular/arrhythmic heart disease.

Laryngeal abnormalities are frequent in the 22q11 deletion syndrome.

OBJECTIVES: The 22q11 microdeletion is a chromosomal disorder detected by fluorescence in situ hybridization (FISH). It has been known since the 80s, and is involved in many malformative syndromes (DiGeorge sequence, VCFS syndrome, etc.). Airway abnormalities are frequently localized in the larynx, as reported in the following series. METHODS: A retrospective chart review of laryngeal abnormalities and 22q11 deletion in a tertiary referral center. RESULTS: Five cases of laryngeal abnormalities associated to 22q11 deletion syndrome (DS) were found in a series of 35 cases. Abnormalities encountered were subglottic stenosis (3%), glottic web (9%), laryngeal paralysis (9%), vocal nodule (3%), laryngomalacia (3%) associated with bronchial malposition (3%). CONCLUSION: Laryngeal abnormalities are relatively common (14% in this series) and important to recognize with the 22q11 deletion syndrome, especially if cardiac surgery is planed. Conversely, in case of laryngeal abnormalities associated to other malformation (like facial dysmorphia or cardiac malformation), the 22q11 deletion must be searched.

Endoscopic submucosal dissection in a European setting. A multi-institutional report of a technique in development.

BACKGROUND AND STUDY AIMS: Endoscopic submucosal dissection (ESD) is a technique for "en bloc" resection of superficial tumors of the gastrointestinal tract. In France, experience with this technique is still limited. We wanted to assess the development of ESD in France, with special attention to short term outcomes. PATIENTS AND METHODS: Members of the Société Française d'Endoscopie Digestive (SFED) who declared performing ESD reported their cases prospectively on a voluntary basis. Demographic, clinical, and technical data, and the results of immediate complications were collected. Case reports were completed prospectively by each investigator before pooled analysis. RESULTS: A total of 188 consecutive case reports were collected from 16 centers. The median case mix per center was 6 patients (range 1-43). The lesion sites treated by ESD were the stomach (n = 75), esophagus (n = 27), duodenum (n = 1), cecum (n = 2), right colon (n = 3), transverse colon (n = 5), sigmoid (n = 3), and rectum (n = 72). The median size of the lesions was 26 mm (range 2-150 mm). En bloc resection was achieved in 77.1% of cases, with complete R0 resection in 72.9%. Histopathology results showed high grade dysplasia or superficial cancer in 71.2%. The median duration of ESD was 105 minutes (range 20-450 minutes). The short term morbidity was 29.2% including 34 cases of perforation (18.1%), and 21 hemorrhages (11.2%) during the 24 hours following ESD, 89% of which were managed conservatively or endoscopically. CONCLUSION: In this early experience, the feasibility of ESD appeared to be good but R0 resection and complication rates did not match those reported by Japanese authors and must be improved by an extended practice.

Colon capsule endoscopy vs. colonoscopy in patients at average or increased risk of colorectal cancer.

BACKGROUND: Colon capsule endoscopy (CCE) is a new, non-invasive technology. AIM: To conduct a prospective, multicentre trial to compare CCE and colonoscopy in asymptomatic subjects enrolled in screening or surveillance programmes for the detection of colorectal neoplasia. METHODS: Patients underwent CCE on day one and colonoscopy (gold standard) on day two. CCE and colonoscopy were performed by independent endoscopists. RESULTS: A total of 545 patients were recruited. CCE was safe and well-tolerated. Colon cleanliness was excellent or good in 52% of cases at CCE. Five patients with cancer were detected by colonoscopy, of whom two were missed by CCE. CCE accuracy for the detection of polyps ≥ 6 mm was 39% (95% CI 30-48) for sensitivity, 88% (95% CI 85-91) for specificity, 47% (95% CI 37-57) for positive predictive value and 85% (95% CI 82-88) for negative predictive value. CCE accuracy was better for the detection of advanced adenoma, in patients with good or excellent cleanliness and after re-interpretation of the CCE videos by an independent expert panel. CONCLUSIONS: Although well-tolerated, CCE cannot replace colonoscopy as a first line investigation for screening and surveillance of patients at risk of cancer. Further studies should pay attention to colonic preparation (Clinicaltrial.gov number NCT00436514).

Enteropathy-associated T-cell lymphoma: a review on clinical presentation, diagnosis, therapeutic strategies and perspectives.

INTRODUCTION: Enteropathy-associated T-cell lymphoma (EATL) is a rare complication of celiac disease (<1% of lymphomas) and has a poor prognosis. METHODS: International literature review with PubMed search (up to January 2009) of pathophysiological, clinical and therapeutic data. RESULTS: EATL is found in patients with a mean age of 59 years, often with a complication that signals its diagnosis. Refractory celiac disease (RCD), equivalent to low-grade intraepithelial T-cell lymphoma, could be an intermediary between celiac disease and high-grade invasive T-cell lymphoma. The median survival is 7 months, with no significant difference between stages; the cumulative 5-year survival is less than 20%. The poor prognosis is determined by disease that has often spread before it is diagnosed (50%), multifocal involvement of the small bowel (50%), poor general health status and undernutrition, and recurrence of complications (infections, perforations, gastrointestinal haemorrhages, occlusions), thus delaying the chemotherapy and contributing to frequent chemotherapy resistance. There is currently no effective and consensual treatment: preventive surgery for complications is controversial, and the results of chemotherapy are disappointing. The classic CHOP protocol (combination of doxorubicin-cyclophosphamide-vincristine-prednisone) does not have satisfactory results and survival remains poor, especially in patients with underlying RCD. High-dose chemotherapy with autotransplantion seems to only improve the prognosis in localised forms. Allogeneic bone marrow transplantation was not evaluated. In all, 1/3 of patients, being unfit for treatment, die before 3 months and half of treated patients stop chemotherapy prematurely due to inefficacy, intolerance and/or complications. CONCLUSION: Improvement of the prognosis requires collaboration in order to compose a national cohort, to evaluate new diagnostic and therapeutic strategies and to define prognostic factors.

Small-bowel capsule endoscopy diagnoses early and advanced neoplasms in asymptomatic patients with Lynch syndrome.

BACKGROUND AND STUDY AIMS: Patients with Lynch syndrome are at increased risk of developing small-bowel adenocarcinoma, which usually has a bad prognosis and needs to be diagnosed early. Our aim was to evaluate the yield of capsule endoscopy and CT enteroclysis in this situation. PATIENTS AND METHODS: We performed a prospective, blinded, comparative study of capsule endoscopy and CT enteroclysis in five academic centers. Thirty-five consecutive asymptomatic patients with Lynch syndrome, all with one proven deleterious mutation, were included. A double reading was performed blind for both types of examination. RESULTS: Histologically confirmed small-bowel neoplasms were diagnosed in three patients (8.6 %): one adenocarcinoma (T3N0M0) and two adenomas with low-grade dysplasia. Capsule endoscopy identified all neoplasms. CT enteroclysis raised suspicion of one neoplasm (adenocarcinoma) but missed the two others. Concordance between the two capsule readings was high with a κ value of 0.78 (95 %CI 0.55 to 1.0), which was not the case for CT enteroclysis, where the κ value was 0.15 (95 %CI -0.27 to 0.58). CONCLUSION: Curable early or advanced neoplasms in asymptomatic patients with Lynch syndrome using capsule endoscopy can be detected with a better reproducibility than with CT enteroclysis. The clinical usefulness of systematic small-bowel screening in these patients should be confirmed through large prospective studies.

Prolonged hemodialysis for acute kidney injury in myeloma patients.

OBJECTIVE: Cast nephropathy, due to free light chain (FLC) toxicity, is the main cause of acute kidney injury in multiple myeloma, with about 10% of patients requiring dialysis. In these patients, in addition to chemotherapy that prevents FLC production, daily hemodialysis using high cutoff or adsorptive membranes, showed promising results by decreasing quickly toxic serum FLC concentrations. CASE HISTORY: We report here the case of 2 patients presenting with acute kidney injury and high FLC serum concentration and M-components one with IgG Kappa and the other with IgD lambda. Both were treated with bortezomib and dexamethasone and received a 24-h continuous hemodialysis using a high and sharp cutoff (around 35,000 Daltons) polysulfone membrane (ultraflux® HD 1000, Fresenius Medical Care GmbH, Bad Homburg, Germany) with citrate regional anticoagulation using a safe and dedicated device (multi filtrate Ci-Ca®). CONCLUSION: Despite similar range of depuration, serum plasma FLC decreased importantly in the patient with the kappa type who recovered but was unchanged in the lambda type patient who remained under maintenance dialysis. Further studies are needed to confirm this new approach therapy.

CYP2C9*3 Loss-of-Function Allele Is Associated With Acute Upper Gastrointestinal Bleeding Related to the Use of NSAIDs Other Than Aspirin.

Nonsteroidal anti-inflammatory drugs (NSAIDs), other than aspirin, are to some extent metabolized by cytochrome P450 2C9 (CYP2C9). The CYP2C9 359Leu (CYP2C9*3) loss-of-function allele could be a risk factor for acute upper gastrointestinal bleeding (AUGIB) related to the use of NSAIDs other than aspirin. To test this hypothesis, we performed a prospective, multicenter, case-case study in patients hospitalized for AUGIB related to the use of NSAIDs. A total of 131 patients had been treated with aspirin and 57 patients had been treated with an NSAID other than aspirin (non-ASP). In the aspirin group, 12 patients (9.2%) had the CYP2C9 359Leu allele as compared with 19 (33.3%) in the non-ASP group (odds ratio (OR) = 5.0; 95% confidence interval 2.2-11.1, P < 0.0001). In a multivariate analysis, CYP2C9 359Leu remained associated with the non-ASP group (OR = 7.2 (2.6-20.3), P = 0.0002) even though 40% of these patients were under treatment with antiulcer drugs at the time of admission. Therefore the results of the study support the hypothesis that the CYP2C9 359Leu allele is a robust risk factor for AUGIB related to the use of NSAIDs other than aspirin.