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Background: Over the last decade, studies unraveled the cancer-immune dialogue in the setting of immune checkpoint inhibitors (ICI) and influenced by the gut microbiota. The first evidence of the key role of the microbiota in ICI modulation was observed during antibiotics (ATB) treatment, where altering the microbiota composition by ATB inhibited ICI responses. DAV132 (DAV) is an orally administered colon-targeted ATB adsorbent capsules designed to prevent ATB-induced dysbiosis. We investigated whether DAV co-administered with ATB could prevent ATB-related dysbiosis and ICI response. Methods: 72 human healthy volunteers (HV) were randomized to receive either IV ceftazidime-avibactam (CZA) or Piperacillin tazobactam (PTZ) alone or in combination with oral DAV. CZA and PTZ plasmatic and fecal pharmacodynamic levels were measured using HPLC-MS/MS. Microbiome was profiled with metagenomics at different timepoints. FMT experiments in germ-free mice were performed using fecal samples from HV from the trial, before (D1) or after 6 days (D6) of CZA or PTZ+/-DAV; subsequently mice were inoculated with MCA205 or B16 tumors and treated with anti-PD-1. Tumor infiltrating lymphocytes (TILs) were analyzed by flow cytometry. Results: DAV did not impact plasmatic CZA or PTZ concentrations, but significantly reduced ceftazidime and piperacillin concentrations in feces compared to ATB groups alone. DAV significantly prevented the reduction in microbiota alpha-diversity at D6 and was associated with a rapid return to baseline microbiota. 50 and 43 metagenomics species were preserved in the CZA+DAV vs CZA, or PTZ-DAV vs PTZ such as Faecalibacterium praunistzii, Alistipes Spp and Blautia obeum. FMT in germ-free mice using feces collected at D1 exhibited a significant anti-PD-1 activity. This anti-tumor response was inhibited in two tumors models in mice transplanted with D6 feces from patients in the CZA or PTZ alone groups. Conversely, the anti-tumor response was maintained in mice transplanted with D6 feces from HV treated with CZA+DAV or PTZ+DAV groups. Flow cytometry on TILs demonstrated that CZA decreased CD8+T cell and CD8+/Treg ratio compared to CZA+DAV. Conclusions: DAV prevented ATB-induced dysbiosis in HV treated with CZA or PTZ without influencing plasmatic concentrations. In avatar mice FMT from HV treated with CZA+DAV was able to preserve anti-PD-1 efficacy. These results provide rationale to launch clinical trials combining DAV in patients on ATB amenable to ICI. Citation Format: Meriem Messaoudene, Nathalie Saint-Lu, Frédérique Sablier-Gallis, Stéphanie Ferreira, Mayra Ponce, Clément Le Bescop, Thomas Loppinet, Tanguy Corbel, Céline Féger, Fabien Vitry, Antoine Andremont, Jean de Gunzburg, Bertrand Routy. Prevention of antibiotic-induced dysbiosis in human volunteers by DAV132 and preservation of responsiveness to anti-PD-1 demonstrated by transplantation of human feces into tumor-bearing mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5882.

Summary Background Genome-edited donor-derived allogeneic anti-CD19 chimeric antigen receptor (CAR) T cells offer a novel form of CAR-T-cell product that is available for immediate clinical use, thereby broadening access and applicability. UCART19 is one such product investigated in children and adults with relapsed or refractory B-cell acute lymphoblastic leukaemia. Two multicentre phase 1 studies aimed to investigate the feasibility, safety, and antileukaemic activity of UCART19 in children and adults with relapsed or refractory B-cell acute lymphoblastic leukaemia. Methods We enrolled paediatric or adult patients in two ongoing, multicentre, phase 1 clinical trials to evaluate the safety and antileukaemic activity of UCART19. All patients underwent lymphodepletion with fludarabine and cyclophosphamide with or without alemtuzumab, then children received UCART19 at 1·1–2·3 × 106 cells per kg and adults received UCART19 doses of 6 × 106 cells, 6–8 × 107 cells, or 1·8–2·4 × 108 cells in a dose-escalation study. The primary outcome measure was adverse events in the period between first infusion and data cutoff. These studies were registered at ClinicalTrials.gov, NCT02808442 and NCT02746952. Findings Between June 3, 2016, and Oct 23, 2018, seven children and 14 adults were enrolled in the two studies and received UCART19. Cytokine release syndrome was the most common adverse event and was observed in 19 patients (91%); three (14%) had grade 3–4 cytokine release syndrome. Other adverse events were grade 1 or 2 neurotoxicity in eight patients (38%), grade 1 acute skin graft-versus-host disease in two patients (10%), and grade 4 prolonged cytopenia in six patients (32%). Two treatment-related deaths occurred; one caused by neutropenic sepsis in a patient with concurrent cytokine release syndrome and one from pulmonary haemorrhage in a patient with persistent cytopenia. 14 (67%) of 21 patients had a complete response or complete response with incomplete haematological recovery 28 days after infusion. Patients not receiving alemtuzumab (n=4) showed no UCART19 expansion or antileukaemic activity. The median duration of response was 4·1 months with ten (71%) of 14 responders proceeding to a subsequent allogeneic stem-cell transplant. Progression-free survival at 6 months was 27%, and overall survival was 55%. Interpretation These two studies show, for the first time, the feasibility of using allogeneic, genome-edited CAR T cells to treat patients with aggressive leukaemia. UCART19 exhibited in-vivo expansion and antileukaemic activity with a manageable safety profile in heavily pretreated paediatric and adult patients with relapsed or refractory B-cell acute lymphoblastic leukaemia. The results this study are an encouraging step forward for the field of allogeneic CAR T cells, and UCART19 offers the opportunity to treat patients with rapidly progressive disease and where autologous CAR-T-cell therapy is unavailable. Funding Servier.

BackgroundIn recent years, the gut microbiome has increasingly emerged as influencing the response to immune checkpoint inhibitors (ICIs).1–3 Antibiotic (ABX) exposure, that leads to microbiome dysbiosis, was further shown in numerous studies to adversely influence the clinical outcomes of cancer patients treated with ICIs, especially in non-small-cell lung cancer (NSCLC).4–6We published in 2020 a meta-analysis confirming that ABX use could hamper survival of NSCLC patients treated with ICIs.7 The present study aims at updating this prior work by incorporating studies published until July 2021 and by studying new clinical outcomes.MethodsPubMed and major oncology conferences’ proceedings were systematically searched to identify studies assessing the impact of ABX on the clinical outcomes of NSCLC patients treated with ICIs. Studies were included when reporting a hazard ratio (HR) or Kaplan–Meier curves for Overall Survival (OS) or Progression-Free Survival (PFS) based on antibiotic exposure, and/or data on treatment response such as Overall Response Rate (ORR) and Progressive Disease Rate (PD) according to antibiotic exposure. Pooled HRs for OS and PFS and Odds Ratios (OR) for ORR and PD were calculated, as well as HRs for OS and PFS according to different time windows of ABX exposure.ResultsOverall, 35 independent cohorts were included for a total of 12,235 patients. The pooled HRs for OS (12,235 patients) and PFS (5,356 patients) were 1.63 [95% Confidence Interval (CI) 1.37–1.94] and 1.49 [95% CI 1.26–1.76], respectively, confirming a significantly reduced survival in patients exposed to ABX. The subgroup analyses of OS and PFS based on the time window of ABX exposure (figures 1 and 2) suggest a harmful effect of ABX when taken around ICI initiation. The pooled OR for ORR (1,992 patients) and PD (1,272 patients) were 0.66 [95% CI 0.44–0.99] and 1.98 [95% CI 1.39–2.8], respectively, reflecting both a decreased odd of treatment response and an almost two-fold increased odd of cancer progression among ABX users (figures 3 and 4). These findings confirm the previously reported deleterious effect of ABX on all clinical outcomes (table 1).Abstract 278 Figure 1Forest plot of hazard ratios for overall survival of patients diagnosed with NSCLC and exposed to antibiotics versus not exposed to antibiotics, according to the time window of antibiotic exposureAbstract 278 Figure 2Forest plot of hazard ratios for progression-free survival of patients diagnosed with NSCLC and exposed to antibiotics versus not exposed to antibiotics, according to the time window of antibiotic exposureAbstract 278 Figure 3Forest plot of odds ratios for overall response rate of patients diagnosed with NSCLC and exposed to antibiotics versus not exposed to antibioticsAbstract 278 Figure 4Forest plot of odds ratios for progressive disease rate of patients diagnosed with NSCLC and exposed to antibiotics versus not exposed to antibioticsAbstract 278 Table 1Summary of the impact of antibiotic use on all clinical outcomesConclusionsAntibiotics were shown to impair clinical outcomes of NSCLC patients treated with ICIs in this study. Two (non mutually exclusive) mechanisms are increasingly discussed in the literature to explain the role of microbiome on immunotherapy response: the immunomodulatory effects of bacterial molecules,8 and antigenic mimicry between commensal bacteria and tumor antigens cross reactive for the same antigen specific T cells.9 10ReferencesGopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets TV, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 5 January 2018;359(6371):97–103.Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Daillère R, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 5 January 2018;359(6371):91–7. Matson V, Fessler J, Bao R, Chongsuwat T, Zha Y, Alegre M-L, et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 5 January 2018;359(6371):104–8. Derosa L, Hellmann MD, Spaziano M, Halpenny D, Fidelle M, Rizvi H, et al. Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small-cell lung cancer. Ann Oncol Off J Eur Soc Med Oncol 1 June 2018;29(6):1437–44.Pinato DJ, Howlett S, Ottaviani D, Urus H, Patel A, Mineo T, et al. Association of prior antibiotic treatment with survival and response to immune checkpoint inhibitor therapy in patients with cancer. JAMA Oncol 1 Décember 2019;5(12):1774–8.Rounis K, Makrakis D, Papadaki C, Monastirioti A, Vamvakas L, Kalbakis K, et al. Prediction of outcome in patients with non-small cell lung cancer treated with second line PD-1/PDL-1 inhibitors based on clinical parameters: results from a prospective, single institution study. PloS One 2021;16(6):e0252537.Lurienne L, Cervesi J, Duhalde L, de Gunzburg J, Andremont A, Zalcman G, et al. NSCLC immunotherapy efficacy and antibiotic use: a systematic review and meta-analysis. J Thorac Oncol Off Publ Int Assoc Study Lung Cancer July 2020;15(7):1147–59.Sepich-Poore GD, Zitvogel L, Straussman R, Hasty J, Wargo JA, Knight R. The microbiome and human cancer. Science 26 March 2021;371(6536):eabc4552.Fluckiger A, Daillère R, Sassi M, Sixt BS, Liu P, Loos F, et al. Cross-reactivity between tumor MHC class I-restricted antigens and an enterococcal bacteriophage. Science 21 août 2020;369(6506):936–42.Bessell CA, Isser A, Havel JJ, Lee S, Bell DR, Hickey JW, et al. Commensal bacteria stimulate antitumor responses via T cell cross-reactivity. JCI Insight 23 avr 2020;5(8):135597.

Background DAV132 (colon-targeted adsorbent) has prevented antibiotic-induced effects on microbiota in healthy volunteers. Objectives To assess DAV132 safety and biological efficacy in patients. Patients and methods An open-label, randomized [stratification: fluoroquinolone (FQ) indication] multicentre trial comparing DAV132 (7.5 g, 3 times a day, orally) with No-DAV132 in hospitalized patients requiring 5–21 day treatment with FQs and at risk of Clostridioides difficile infection (CDI). FQ and DAV132 were started simultaneously, DAV132 was administered for 48 h more, and patients were followed up for 51 days. The primary endpoint was the rate of adverse events (AEs) independently adjudicated as related to DAV132 and/or FQ. The planned sample size of 260 patients would provide a 95% CI of ±11.4%, assuming a 33% treatment-related AE rate. Plasma and faecal FQ concentrations, intestinal microbiota diversity, intestinal colonization with C. difficile, MDR bacteria and yeasts, and ex vivo resistance to C. difficile faecal colonization were assessed. Results Two hundred and forty-three patients (median age 71 years; 96% with chronic comorbidity) were included (No-DAV132, n = 120; DAV132, n = 123). DAV132- and/or FQ-related AEs did not differ significantly: 18 (14.8%) versus 13 (10.8%) in DAV132 versus No-DAV132 patients (difference 3.9%; 95% CI: −4.7 to 12.6). Day 4 FQ plasma levels were unaffected. DAV132 was associated with a >98% reduction in faecal FQ levels (Day 4 to end of treatment; P < 0.001), less impaired microbiota diversity (Shannon index; P = 0.003), increased ex vivo resistance to C. difficile colonization (P = 0.0003) and less frequent FQ-induced VRE acquisition (P = 0.01). Conclusions In FQ-treated hospitalized patients, DAV132 was well tolerated, and FQ plasma concentrations unaffected. DAV132 preserved intestinal microbiota diversity and C. difficile colonization resistance.

2585 Background: In recent years, the gut microbiome has increasingly emerged as influencing the response to immune checkpoint inhibitors (ICIs) and antibiotic (ABX) exposure has repeatedly been shown to impair clinical outcomes of patients suffering from different cancer types and treated with ICIs. We published in 2020 a meta-analysis confirming that ABX use hampered survival of non-small cell lung cancer (NSCLC) patients treated with ICIs. The present study aims to determine whether ABX use also reduces survival of patients receiving ICIs for other cancers. Methods: PubMed and major oncology conferences’ proceedings were systematically searched to identify studies assessing the impact of ABX on the clinical outcomes of cancer patients treated with ICIs. Studies were included when reporting data on Overall Survival (OS), Progression-Free Survival (PFS), Overall Response Rate (ORR) and Progressive Disease Rate (PD), according to ABX exposure. Pooled Hazard Ratios (HRs) for OS and PFS and Odds Ratios (ORs) for ORR and PD were calculated, as well as HRs for OS and PFS according to different cancer types and different ABX exposure time windows (TWs). Results: Overall, 94 independent cohorts were included, representing 26,174 patients suffering from various types of cancer. The pooled HRs for PFS (61 cohorts, 13,224 patients) and OS (88 cohorts, 25,480 patients) were 1.47 [95% Confidence Interval (CI) 1.31-1.66] and 1.66 [95% CI 1.50-1.83], respectively, confirming a significant harmful impact of ABX on patient’ survival, observed across all cancer types (Table). The analyses of OS and PFS based on ABX exposure TWs suggested a stronger deleterious effect of ABX when taken around ICI treatment initiation. The response to treatment among ABX users was also impaired: the pooled ORs for ORR (30 cohorts, 4,590 patients) and PD (33 cohorts, 4,972 patients) were 0.55 [95% CI 0.39-0.77] and 1.97 [95% CI 1.48-2.64], respectively. Conclusions: ABX were shown to impair the clinical outcomes of cancer patients treated with ICIs, regardless of cancer type. [Table: see text]

Homeostasis of the intestinal microbiota is currently recognized as a major contributor to human health. Furthermore, intestinal dysbiosis is associated with a multitude of consequences, including intestinal colonization by antibiotic-resistant or pathogenic bacteria, such as Clostridioides difficile, and reduced efficacy of promising anticancer immunotherapies. By far, the most immediate and drastic exposure leading to dysbiosis is antibiotic treatment. Many attempts have been made to prevent or repair antibiotic-associated dysbiosis. Here, we review these innovations and the difficulties associated with their development.

Background: Acute Myeloid Leukemia (AML) and high-risk Myelodysplastic Syndrome (MDS) patients frequently receive antibiotics (ABX) for febrile neutropenia (prophylaxis or empirical treatment) or for suspected or documented bacterial infections. ABX affect the composition of the human intestinal microbiome and the resulting dysbiosis can have important consequences for patients including Clostridioides difficile infections (CDI). The reported cumulative incidence of CDI in patients with AML varies from 9 to 24% in the first 120 days following the start of induction chemotherapy and from 8 to 31% after allogeneic Hematopoietic Stem Cell Transplant (allo-HSCT). In patients undergoing allo-HSCT, acute Graft-versus-Host Disease (GvHD) and GvHD-related mortality are other important complications associated with intestinal dysbiosis, as shown in experimental studies in mice and retrospective analyses in humans. DAV132 is a microbiome protective therapy that can be administered concomitantly with oral or intravenous ABX. It has been primarily developed for adsorbing antibiotic residues in the distal ileum and colon in order to preserve the integrity of the gut microbiome, without impacting antimicrobial pharmacokinetics. Randomized clinical trials conducted to date, both in heathy volunteers and in patients, showed that DAV132 adsorbed residues of ABX in the colon and protected the intestinal microbiome from the dysbiosis induced by ABX while preserving their bioavailability. In addition, DAV132 was safely used in hospitalized patients receiving (multiple) concomitant drugs. Study Design and Methods: MICROCARE is a multicenter, randomized, placebo-controlled, parallel-arm phase 3 clinical trial. A total of 900 patients (randomized 1:1 to either DAV132 or placebo) are planned to be enrolled in approximately 80 study sites worldwide. The primary objective of this study is to evaluate the efficacy of DAV132 in preventing CDI in patients with newly diagnosed AML or high-risk MDS treated with intensive chemotherapy. In addition, the study aims to determine whether the protection of the intestinal microbiome with DAV132 can reduce the incidence of colonization with multidrug-resistant bacteria, bacteremia, and acute GvHD, and improve the long-term outcomes of transplanted patients. Randomization will be stratified by (i) site, and (ii) use of ABX within 30 days before inclusion and/or history of CDI. During the cycle of induction chemotherapy, DAV132 will be administered to patients every day until neutrophil recovery, regardless of the administration of ABX treatment. After neutrophil recovery and up to day 120, DAV132 will be administered every time an ABX treatment is given, for the length of the ABX treatment plus 2 days. The primary analysis of this study is the comparison of the time to CDI between DAV132 patients versus placebo patients up to 120 days after randomization. This will be analyzed using the cause-specific Cox proportional hazards model, whereby time to CDI is the outcome of interest, and mortality will be considered as competing event. In the primary outcome, a cause-specific Cox model will be used assuming that the impact of DAV132 on mortality is negligible; this will be confirmed in a secondary analysis. Secondary and exploratory endpoints include the rate of patients with ABX-associated diarrhea, the rate of patients with a gut colonization by resistant bacteria or a bloodstream infection, the diversity of the gut microbiome, the incidence of acute GvHD and overall survival. Two interim analyses will be performed at approximately 35 and 50 CDI events. Study status: Recruitment of patients in the study is starting in multiple countries in Europe. A first patient has been randomized in July 2021. Topics: Microbiome; CDI; GvHD; Dysbiosis; Antibiotics Disclosure: This work is supported by the IMI Joint Undertaking (JU) (grant 115523), Combatting Bacterial Resistance in Europe, with resources including financial contribution from the EU's Seventh Framework Programme and in-kind contributions from Da Volterra, a company part of the European Federation of Pharmaceutical Industries and Associations (EFPIA). Disclosures Vehreschild: 3M: Research Funding; Astellas Pharma: Consultancy, Research Funding, Speakers Bureau; Biontech: Research Funding; Da Volterra: Consultancy, Research Funding, Speakers Bureau; Evonik: Research Funding; Gilead Sciences: Consultancy, Research Funding, Speakers Bureau; Glycom: Research Funding; Immunic AG: Consultancy, Research Funding, Speakers Bureau; MaaT Pharma: Consultancy, Research Funding; Merck/MSD: Consultancy, Research Funding, Speakers Bureau; Organobalance: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; Seres Therapeutics: Research Funding; Takeda Pharmaceutical: Research Funding; Alb Fils Kliniken GmbH: Consultancy, Speakers Bureau; Arderypharm: Consultancy, Speakers Bureau; Basilea: Consultancy, Speakers Bureau; Bio-Mérieux: Consultancy, Speakers Bureau; Farmak International Holding GmbH: Consultancy, Honoraria, Speakers Bureau; Ferring: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; SocraTec R&D GmbH: Consultancy, Speakers Bureau. Dane: Da Volterra: Consultancy. Mentré: Da Volterra: Consultancy. Burdet: Da Volterra: Consultancy; Mylan: Consultancy. Sablier-Gallis: Da Volterra: Current Employment, Current holder of individual stocks in a privately-held company. Andremont: Da Volterra: Consultancy, Current holder of individual stocks in a privately-held company, Honoraria. de Gunzburg: Da Volterra: Consultancy, Current holder of individual stocks in a privately-held company. Buffet: Da Volterra: Current Employment. Wilcox: Da Volterra: Consultancy, Research Funding. Cornely: Amplyx, Basilea, BMBF, Cidara, DZIF, EU-DG RTD (101037867), F2G, Gilead, Matinas, MedPace, MSD, Mundipharma, Octapharma, Pfizer, Scynexis: Other: Grants or Contracts. Bonten: Merck/MSD: Research Funding; Janssen Vaccines: Consultancy, Speakers Bureau; OM Pharma: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Takeda: Consultancy, Research Funding. Vitry: Da Volterra: Current Employment.

Background Although incidence and mortality data are numerous, population-based studies including clinical and pathological characteristics of melanoma are rare. Objectives To describe the characteristics of melanoma in a rural French region during 2004–2008 and to identify differences according to age, gender and geographical areas. Methods Pathology reports of cutaneous melanomas diagnosed in residents from the Champagne-Ardenne region during 2004–2008 were anonymously collected from pathology laboratories. Demographic, clinical and pathological data were extracted and analysed by experts, including dermatologists, pathologists and epidemiologists. Results One hundred and seventy-seven in situ melanomas were diagnosed in 177 patients (female/male ratio : 1.72). Patients with head and neck in situ melanomas were older than patients with melanomas in other locations (72 vs. 54 years; P

Interleukin 10 (IL10) is associated with maternal immunotolerance. IL10 also down-regulates decidual cell tissue factor expression, the main molecule triggering coagulation activation: this antithrombotic effect may protect the umbilicoplacental vasculature from the 10th wk of gestation onward. IL10 downregulation may thus dispose to early pregnancy loss (PL) due to maternal immunotolerance defect or late pregnancy failure due to placental vascular insufficiency. IL10 gene promoter polymorphisms associated with cytokine down-regulation may help to identify the actual and probable mechanisms of IL10 modulation in pregnancy outcomes. We investigated the following four IL10 promoter polymorphisms associated with IL10 down-regulation: two single-nucleotide polymorphisms rs1800871 and rs1800872 and two polymorphic CA repeat microsatellites IL10 X78437.2:g8134CA(14_29) and IL10 X78437.2:g.5325CA(11_15). Each microsatellite was analyzed as a biallelic polymorphism. Based on a review of the literature, we define a short allele and a long allele for each microsatellite. We compared their frequencies in early PL occurring before 10 wk of amenorrhea (n ¼ 342) and in PL occurring later on (n ¼ 123). The mutated alleles rs1800871T (odds ratio, 3.083; 95% confidence interval, 1.984–4.792) and rs1800872A (odds ratio, 3.013; 95% confidence interval, 1.924–4.719) were associated with early PL. The haplotype rs1800872A/rs1800871T/ X78437.2:g.8134CA[14_25]/X78437.2:g.5325CA[11_13], which includes the two mutated alleles, was significantly associated with the risk of early PL in a dose-dependent manner. Positivity for one haplotype was significantly associated with a 5.6-fold increase in the risk of early pregnancy failure, and positivity for two haplotypes was associated with an 8-fold increase in risk. In women with PL, some polymorphisms of the IL10 gene promoter seem to be constitutional risk factors for early (embryonic) pregnancy failure. cytokines, genetic polymorphism, immunity, immunology, interleukin 10, pregnancy loss, risk factor

Summary Background Recent studies have shown an increased risk of colorectal neoplasia in patients with duodenal neoplasia. The aim of this retrospective case-control study was to confirm this risk. Patients and methods Rate of colorectal neoplasia in 29 patients with one or more duodenal adenomas were compared with controls matched for gender and age, but without duodenal adenomas (one case to two controls). Patients with neoplasia of the ampulla, familial adenomatous polyposis or other known hereditary conditions of the digestive tract were excluded. Indications for upper and lower gastrointestinal endoscopy in controls were abdominal pain or changes in bowel habits. Controls with anemia or digestive bleeding were not included. Neoplastic lesions found at colonoscopy were classified as adenomas, advanced adenomas (size ≥ 10 mm, villous component, high-grade dysplasia), cancers and advanced neoplasia (cancers and advanced adenomas). Comparison between groups was by Fisher's exact test or Student's t test. Odds-ratios (OR) and 95% confidence intervals were calculated, if the difference was significant. Results Mean age of the 29 cases (seven women, 22 men) was 63.2 years and that of the 58 controls (14 women, 44 men) was 62.5 years. First-degree family history of colorectal cancer was present in four cases (13.8%) and eight controls (13.8%) (NS). Colonoscopy showed at least one adenoma in 15 cases (51.7%) and 11 controls (19%) (P = 0.0027; OR 1.87, 1.0–3.49), advanced adenomas in four cases (13.8%) and three controls (5.2%) (NS), and colonic adenocarcinoma in three cases (10.3%) and no controls (0%) (P = 0.03). Advanced neoplasia was present in seven cases (24.1%) and three controls (5.2%) (P = 0.014; OR 2.86, 0.96–8.52). Results were not significantly modified after the exclusion of patients with a family history of colorectal cancer. Conclusion Although lacking in statistical power, these results confirm that patients with sporadic duodenal adenoma are at high risk of colonic adenoma and advanced neoplasia, warranting systematic colonoscopy.

Le suivi habituel d'un anevrysme de l'aorte abdominale (AAA) apres traitement par endoprothese (EVAR) comporte la surveillance de son diametre et la detection d'une endofuite. Parmi les autres parametres proposes au clinicien pour identifier les AAA restant a risque de rupture, figure la compliance de l'AAA mais son interet n'est pas clairement defini. Le doppler tissulaire (TDI) est une modalite echographique permettant la mesure des deplacements des parois de l'AAA. Le but de cette etude etait d'analyser la compliance des AAA avant et apres EVAR, et d'en decrire l'evolution chez des patients ayant plus d'un mois de suivi. Vingt cinq patients consecutifs traites par EVAR entre fevrier 2005 et juin 2007 ont donne leur consentement eclaire pour avoir une analyse prospective du mouvement des parois de l'AAA par TDI avant EVAR et lors de chaque visite au cours du suivi. Le suivi moyen (ET) etait de 13,7 (9,7) mois. La dilatation segmentaire maximale moyenne (MMSD), la compliance segmentaire, la dilatation au diametre maximal, le module elastique de contrainte de pression (Ep) et l'indice de raideur etaient compares entre trois periodes (avant EVAR, avant la sortie et lors du dernier controle) et leur relation avec le diametre de l'AAA etait analysee. La compliance des AAA diminuait significativement immediatement apres une implantation reussie et restait stable au cours du suivi, alors que le diametre des AAA diminuait progressivement et etait statistiquement plus petit lors du dernier controle comparativement au diametre initial. La MMSD, la compliance segmentaire et la dilatation au diametre maximal etaient correlees positivement au diametre de l'AAA. Cela signifie que plus le diametre de l'AAA etait large apres EVAR reussi, plus la compliance etait elevee. A l'oppose, les pourcentages de diminution du diametre de l'AAA et de la MMSD n'etaient pas correles: il n'y avait pas de parallelisme entre la perte de compliance et la retraction de l'AAA. Cela signifie qu'il existe des modeles de perte de compliance et de retraction variables d'un AAA a l'autre au cours du suivi. Meme si la comparaison des patients sans et avec endofuite etait difficile du fait du petit effectif de ce dernier groupe (5 patients), la compliance tendait a etre plus importante en cas d'endofuite. Les mouvements de paroi d'un AAA apres EVAR reussi refletent des interactions complexes entre les composants de l'AAA traite, eux meme evolutifs au cours du temps, incluant la compliance vraie de la coque de l'AAA, la pression intrasacculaire avec des effets possiblement differents entre la pression maximale, la pression moyenne et la pression pulsee, le remodelage du thrombus, les caracteristiques de l'endoprothese et la pression systemique intra aortique. Une mesure combinee de la MMSD et de la pression intrasacculaire chez des patients sans et avec endofuite pourrait permettre d'avancer dans la comprehension du mecanisme des mouvements de parois de l'AAA apres EVAR.

Las tecnicas de imagen habituales tras la reparacion endovascular de los aneurismas (REVA) en casos de aneurismas aorticos abdominales (AAA) estan destinadas a monitorizar el diametro del AAA y detectar endofugas. Entre los parametros predictivos adicionales propuestos para identificar mejor los subgrupos de AAA que siguen presentando riesgo de rotura, se ha estudiado la motilidad de la pared tras la REVA, pero no se ha establecido de forma clara su utilidad. La eco-Doppler tisular (TDI) es una modalidad ecografica que permite realizar mediciones de la motilidad parietal a lo largo de un segmento arterial. El objetivo de este estudio fue analizar la motilidad de la pared del AAA mediante TDI antes y despues de la REVA y describir su evolucion en los pacientes con un seguimiento mayor de 1 mes. Se obtuvo el consentimiento informado de 25 pacientes consecutivos sometidos a REVA entre febrero de 2005 y junio de 2007 para ser estudiados de forma prospectiva mediante el sistema TDI antes de la REVA y en cada visita del seguimiento. La media del seguimiento fue de 13,7 (DE 9,7) meses. La media de la dilatacion maxima del segmento (MDMS), la distensibilidad del segmento, la dilatacion, el modulo elastico presion-deformacion (Ep), y la rigidez se compararon entre 3 periodos (antes de la colocacion del stent, antes del alta, y en el ultimo seguimiento), y se analizo su relacion con el diametro del AAA. Se observo una reduccion significativa en la distensibilidad del AAA inmediatamente tras la REVA, que permanecio estable durante el seguimiento posterior. Por otro lado, el diametro del AAA disminuyo progresivamente con el tiempo y fue estadisticamente menor en el ultimo control en comparacion con los valores iniciales. La MDMS, la distensibilidad del segmento, y la dilatacion del diametro maximo estuvieron relacionadas directamente con el diametro del AAA. Esto significa que cuanto mayor es el diametro del AAA tras la colocacion del stent, mayor es la magnitud que cabe esperar para estos parametros. Por el contrario, los porcentajes de reduccion del diametro del AAA y de la MDMS no estuvieron relacionados tras una REVA satisfactoria. No existio ningun paralelismo entre la perdida de distensibilidad y la reduccion del diametro a lo largo del tiempo, y no existe un unico patron respecto al diametro del AAA y la evolucion de la distensibilidad tras la REVA. A pesar de que la comparacion entre pacientes con y sin endofugas fue debil debido al tamano reducido de la muestra del primer grupo (5 pacientes con endofuga), la distensibilidad tendio a ser mayor en casos de endofuga. La motilidad de la pared del AAA tras una REVA satisfactoria refleja las complejas interacciones entre todos los componentes del aneurisma tratado con endoprotesis que evolucionan a lo largo del tiempo, incluida la distensibilidad real de la propia pared del aneurisma; la presion del saco intraaneurismatico con diferentes posibles efectos en cuanto a la presion maxima, media y del pulso; el remodelado del trombo; las caracteristicas de rigidez del implante; y la presion sistemica. La combinacion de los registros simultaneos de la MDMS con las determinaciones reales de la presion intrasacular en los pacientes con y sin endofuga mejoraria nuestro conocimiento del mecanismo de la pulsatilidad clinica en el AAA tras la REVA.

OBJECTIVE Vectorized internal radiation therapy using lipiodol-labelled with iodine-131 (131 I-lipiodol) is an effective treatment for inoperable hepatocellular carcinomas. However, few dosimetric data are available based on this approach. We have developed a dosimetric protocol based on scintiscan imaging and that is designed to calculate the tumoural absorbed dose during the treatment of hepatocarcinoma by 131 I-lipiodol. METHODS This concept was developed on a gamma-camera coupled to a computed tomography scanner. It integrates corrections for attenuation phenomena, scattering and dead time. The tumoural absorbed dose calculation was carried out according to the Medical Internal Radiation Dose Committee formalism. This protocol was applied to a series of 41 patients in the framework of a retrospective study. RESULTS The mean tumoural absorbed dose with the first treatment is 248 Gy (+/-176), as opposed to 152 Gy (+/-122) during the second. We highlighted a correlation between the tumoural absorbed dose, calculated in tomographic mode, and the morphological response to the first treatment (P=0.0071). Moreover, a tumoural absorbed dose of 280 Gy seems to be an effective absorbed dose threshold in our population. Above this absorbed dose, 84% of the patients are responders after the first treatment, whereas no responses are recorded below this threshold. CONCLUSION These results are promising because, for the first time, they allow us to predict the effectiveness of a treatment by 131 I-lipiodol. They are required to be validated on a broader exploratory trial, including a dosimetric study of the critical organs, so an individualized dosimetry can be defined for each patient.

Aims Although underestimated by interventional cardiologists for a long time, radiation exposure of operators and patients is currently a major concern. The objective of the present operator-blinded registry was to compare related-peripheral arterial route radiation exposure of operators. Methods and results During 420 consecutive coronary angiograms (CAs) and percutaneous coronary interventions (PCIs), four interventional cardiologists were blindly screened. Radiation exposures were assessed using electronic personal dosimeters. Protection of operator was ensured using a lead apron, low leaded flaps, and leaded glass. Radiation exposure of operators was significantly higher using the radial route when compared with the femoral route for both CAs and CAs followed by ad hoc PCIs: 29.0 [1.0–195.0] µSv vs. 13.0 [1.0–164.0] µSv; P < 0.0001 and 69.5 [4.0–531.0] µSv vs. 41.0 [2.0–360.0] µSv; P = 0.018, respectively. Similarly, radiation exposure of patients was significantly higher using the radial route when compared with the femoral route for both CAs and CAs followed by ad hoc PCIs. Moreover, procedural durations and fluoroscopy times were significantly higher throughout the radial route. Conclusions Although the radial route decreases peripheral arterial complication rates, increased radiation exposure of operators despite extensive use of specific protection devices is currently a growing problem for the interventional cardiologist health. Radial route indication should be promptly reconsidered in the light of the present findings.

Summary Objective To assess the efficacy of percutaneous laser disc decompression for patients with radicular pain due to lumbar disc hernia and to identify factors that may predict outcome. Methods The study included all patients treated with percutaneous laser disc decompression from May 2003 through May 2005 at Reims University Hospital and the Courlancy Clinic of Reims. Each patient had previous undergone at least six weeks of conventional medical treatment. The same technique, with either a laser diode or Nd: YAG, was used under endoscopic control and with neuroleptanalgesia. They were seen at 1, 3, 6 and 12 months. The principal evaluation criteria were the course of radicular pain, return to work, and need for surgery. Results We reexamined 149 patients 1 month after the procedure, 135 after 3 months, 102 after 6 months and 59 a year after the procedure. At a month after surgery, radicular pain had decreased by at least half, and sometimes even completely disappeared in 63.1% of patients at 1 month, 66.6% at 3 months, 73.5% at 6 months, and 83.1% at 12 months, while 24%, 50,4%, 61.2%, and 67.3%, respectively, had returned to work. No patient had serious complications. Finally, 45 of the 149 (30.2%) patients chose to have a traditional surgical procedure after percutaneous laser disc decompression. Conclusion Percutaneous laser disc decompression is effective, noninvasive and well tolerated for patients with radicular pain due to lumbar disc hernia.

HemoCue Hb 201+ is a portable photometric analyser providing easy, rapid and accurate determination of hemoglobin from arterial, venous or capillary blood. It is worth that dialysis units have knowledge of its use for a close hematologic monitoring of their patients and a judicious management of erythropoietin (EPO). For the autodialysis > centers, it allows a flexibility that private laboratories cannot have in daily practice. Therefore authors present this device and the evaluation they obtained from 148 hemoglobin measures. Then they expose the advantages and the indications of its use.

The aim of this study was to determine the course of pregnancy and the neonatal outcome of fetuses with cystic hygroma diagnosed at 10-14 weeks' gestation.Maternal and fetal data (nuchal translucency, karyotype, pregnancy outcome) in cases of fetal cystic hygroma, admitted or referred to our antenatal diagnostic centre, were prospectively entered into a computer database. Paediatric outcome was analysed when relevant.Some 72 fetuses had cystic hygroma. The mean size of the cystic hygroma was 7.9 mm. Chromosomal abnormalities were present in 52.7% of cases (38/72), including 14 cases (36.8%) of Down syndrome. A total of 34 chromosomally normal pregnancies gave rise to 18 live births (52.9%), with no visible serious structural abnormalities. The outcome of pregnancy was unfavourable (miscarriage, elective termination, serious structural abnormalities) in 77.7% of cases (56/72). The 18 live-born infants were followed up for 17-98 months. Sixteen infants developed normally, while 1 developed Noonan's syndrome and 1 had a urinary tract abnormality (pyelo-ureteral junction; PUJ).These data suggest that the prognosis of fetal cystic hygroma detected during the first trimester is poor, and show that sonographic evaluation of fetal nuchal translucency thickness in the first trimester is crucial.

Plasma homocysteine is a modifiable cardiovascular risk factor related to the extent of both coronary and carotid atherosclerosis (1)(2)(3)(4). Plasma homocysteine has been shown to predict the occurrence of cardiac events and mortality in patients with coronary atherosclerosis (5)(6)(7). The predictive value of homocysteine on restenosis after percutaneous coronary intervention (PCI) has been debated (8)(9)(10). Recent evidence, however, indicated that the pre-PCI homocysteine plasma concentration was an independent predictor of death, nonfatal myocardial infarction (MI), and target lesion revascularization (11). Cardiac troponins provide prognostic information in patients with acute coronary syndrome (ACS) (12). Several studies have demonstrated that PCI induces MI as assessed by increases in cardiac troponins, particularly in the case of ACS (13)(14)(15). Furthermore, increased cardiac troponin concentrations after PCI are associated with poor clinical outcome (16)(17)(18)(19). We therefore hypothesized that the pre-PCI plasma homocysteine concentration could be related to the occurrence of MI after PCI, as assessed by changes in plasma cardiac troponin I (cTnI) concentration. Consecutive admissions for nonemergency PCI were studied prospectively. All patients had a stenosis >70% in 1 or more coronary arteries. Two groups were examined: patients with stable angina (SA) pain and those with ACS. The SA pain group had myocardial ischemia during exercise stress testing (n = 29). The ACS group included patients admitted with unstable angina without a subsequent increase in troponin concentrations (n = 28) and those with a definite MI with a documented cTnI increase and electrocardiogram changes that had occurred 7–14 days previously (n = 39). Patients with inflammatory diseases, as well as those being treated with corticosteroids or nonsteroidal antiinflammatory or immunosuppressive drugs, were excluded to minimize potential bias. This study complies …

Objective To investigate the diagnostic value of commercially available BP230 and BP180-NC16a enzyme-linked immunosorbent assays (ELISAs) in routine practice in patients with bullous pemphigoid (BP). Design Single-center retrospective study. Setting French academic dermatology department. Patients The study population comprised 138 patients, who were admitted from January 1998 through December 2008. Interventions Sera samples were analyzed by ELISA; clinical and immunopathological data were recorded from the patients' medical charts. Main Outcome Measures BP230 and BP180-NC16a ELISA scores were evaluated with respect to clinical characteristics (number of blisters, mucosal involvement, localized or generalized disease, and outcome) and routine indirect immunofluorescence (IF). Results Of the 138 study patients, 81 (59%) had a positive BP230 ELISA result and 119 (86%) had a positive BP180 ELISA result. There was no relationship between a positive ELISA BP230 result and the disease extent at diagnosis or the presence of mucosal involvement. Serum anti–basement membrane zone autoantibodies (indirect IF) were more frequently detected when the BP230 ELISA result was positive ( P P P = .01) and the mean number of blisters ( P = .03) but was not associated with mucosal involvement. Conclusions The currently available BP230 ELISA is a reliable although less-sensitive test than BP180 ELISA in BP, and its diagnostic added value compared with BP180 ELISA alone is approximately 5%. Our results support the predominant contribution of the BP230-specific autoantibodies to anti–basement membrane zone antibody titer as detected by indirect IF.

BACKGROUND There is no consensus regarding the therapeutic utility of sentinel lymph node biopsy (SLNB) versus that of nodal observation (NO) in melanoma. OBJECTIVE To prospectively evaluate a standardized counseling procedure and its effect on patient choices to undergo SLNB or NO. METHODS In four centers, patients with melanoma eligible for SLNB or NO received a complete counseling procedure that included verbal information from dermatologists and surgeons, a detailed information sheet, and a written consent form. Data collected included patient and tumor characteristics, counseling conditions, and specialties of informing doctors. Factors influencing patients' choices were studied using multivariate analysis. RESULTS Of 343 consecutive patients, 309 were offered SLNB and NO and received complete verbal and written information from a dermatologist alone (62%) or in association with a surgeon (38%). Approximately half took advice from trusted persons, and half asked for additional time before making a decision; 268 (86.7%) ultimately decided to undergo SLNB. Multivariate analysis showed that older patients, those with a head and neck melanoma, and those informed without a surgeon present were more likely to prefer NO. CONCLUSIONS This counseling procedure was easily implemented in clinical practice. Patients favored SLNB but were able to understand uncertainties and express preferences.

International audience; OBJECTIVES: To describe circumstances of the diagnosis and access to dermatological care for patients with cutaneous melanoma (CM) and to investigate factors associated with early detection. DESIGN: Retrospective population-based study of incident cases of invasive CM in 2004, using questionnaires to physicians and a survey of cancer registries and pathology laboratories. SETTING: Five regions in northeastern France. PATIENTS: Six hundred fifty-two patients who were referred to dermatologists by general practitioners (group 1) or by other specialists (group 2), who directly consulted a dermatologist for CM (group 3), or who were diagnosed as having CM during a prospective follow-up of nevi (group 4) or when consulting a dermatologist for other diseases (group 5). MAIN OUTCOME MEASURES: Characteristics of patients, tumors, and patients' residence in each group, including the geographical concentration of dermatologists. We performed multivariate analysis of these factors to determine association with Breslow thickness. RESULTS: Age, tumor location, Breslow thickness, ulceration, histological type, and geographical concentration of dermatologists significantly differed among groups. Patients consulting dermatologists directly formed the largest group (45.1%). Those referred by general practitioners (26.1%) were the oldest and had the highest frequency of thick (>3 mm), nodular, and/or ulcerated CM. Patients from groups 4 (8.4%) and 5 (14.1%) had the thinnest CMs. Ulcerated and/or thick tumors were absent in group 4. In multivariate analysis, histological types superficial spreading melanoma and lentigo maligna melanoma, younger age, high concentration of dermatologists, and detection by dermatologists were significantly associated with thinner CMs. CONCLUSION: Easy access of patients to dermatologists, information campaigns targeting elderly people, and education of general practitioners are complementary approaches to improving early detection.

Background: Cutaneous drug eruptions are common side-effects. The imputation score combining intrinsic (chronology, clinical and paraclinical signs) and extrinsic criteria used in Pharmacovigilance Centres is insufficient alone to identify with certainty a responsible drug. Objective: To evaluate the imputation score before and after performing skin testing in patients with cutaneous drug eruptions. Patients/Methods: A single-centre retrospective study was performed on 339 patients tested between 2001–2006. Imputation scores were calculated before and after skin tests for each cutaneous drug eruption according to the clinical type of skin eruption and the type of drug. Results: Among 121 patients meeting inclusion criteria, 46% showed an increase of the imputation score as shown by 25/41 cases of maculo-papular exanthema, 4/11 cases of acute generalized exanthematous pustulosis and 17/41 cases of urticaria/anaphylaxis. The imputation score increased in 25/70 cases of the tested antibiotic drugs, in 14/56 cases of cardiovascular drugs, and it increased in 19 patients (34%) with I1 or I2 imputation scores before skin testing and in 29 (52%) with an I3 imputation score before skin testing. Conclusions: Drug skin testing appeared useful in investigating cutaneous drug eruptions in routine practice, including not only drugs with a high imputation score (I3) but also those with a lower score (I1, I2). Drug skin testing should lead to oral rechallenge of drugs with negative tests in order to determine which drugs may be used safely.

BACKGROUND: Schizophrenia has been associated with a rate of premature mortality that is 2 to 3 times higher than that in the general population. Although the role of cancer in this excess mortality remains unclear, previous incidence or mortality studies found contradictory results. METHODS: In 1993, a large prospective study was initiated in a cohort of 3470 patients with schizophrenia to examine cancer-related mortality and predictors. Standardized mortality ratios (SMRs) were calculated, adjusting for age and sex relative to a representative sample of the French general population. RESULTS: During the 11-year follow-up, 476 (14%) patients died; the mortality rate was thus nearly 4-fold higher than in the general population. Cancer was the second most frequent cause of mortality (n = 74), with a global SMR of 1.5 (95% confidence interval [95% CI], 1.2-1.9). For all cancers, the SMRs were 1.4 (not significant) for men and 1.9 (95% CI, 1.4-2.8) for women. For men, lung cancer was the most frequent localization (n = 23; 50%), with an SMR of 2.2 (95% CI, 1.6-3.3). For women, breast cancer was the most frequent localization (n = 11; 39%), with an SMR of 2.8 (95% CI, 1.6-4.9). In comparison with patients who did not die of cancer, there were 2 significant baseline predictors of death by lung cancer in the final logistic regression model: duration of smoking and age >38 years. CONCLUSIONS: The results of the current study demonstrated an increased risk of mortality by cancer in patients with schizophrenia, especially for women from breast cancer and for men from lung cancer. Cancer 2009. © 2009 American Cancer Society.

Objective To identify prognostic factors for relapse in the first year after cessation of therapy in bullous pemphigoid (BP). Design Prospective, multicenter, cohort study (January 1, 2000, through December 31, 2006). Setting Fifteen French dermatology departments. Patients Patients with BP in remission under low doses of topical or systemic corticosteroids. Interventions Cessation of corticosteroid treatment (day 0) followed by a systematic clinical and immunologic follow-up. Main Outcome Measures The end point was clinical relapse within the first year after cessation of therapy. Associations of clinical, biological, and immunologic (including direct immunofluorescence, serum anti–basement membrane zone autoantibodies, and serum BP180 autoantibodies by enzyme-linked immunosorbent assay [ELISA] on day 0) variables with clinical relapse were assessed by means of univariate and multivariate analyses. Results On day 0, 30 of 114 patients (26.3%) still had a positive result of direct immunofluorescence, 63 of 112 (56.3%) had circulating anti–basement membrane zone autoantibodies, and 34 of 57 (60%) had anti-BP180 antibodies by ELISA. At month 12, 22 patients were dead (n = 11) or lost to follow-up (n = 11), 51 were in remission, and 45 had had relapses (mean interval to relapse, 3.2 months). Factors predictive of relapse within 12 months after cessation of therapy were a positive result of direct immunofluorescence microscopy ( P = .02), a greater age ( P = .01), and high-titer ELISA scores ( P = .02) on day 0. In multivariate analysis, the only factor independently predictive of relapse was a high-titer ELISA score on day 0 (odds ratio, 11.00; 95% confidence interval, 1.29-93.76). Conclusions High-titer anti-BP180 ELISA score and, to a lesser degree, a positive direct immunofluorescence finding are good indicators of further relapse of BP. At least 1 of these tests should be performed before therapy is discontinued.

Interleukin 10 (IL10) is associated with maternal immunotolerance. IL10 also down-regulates decidual cell tissue factor expression, the main molecule triggering coagulation activation: this antithrombotic effect may protect the umbilicoplacental vasculature from the 10th wk of gestation onward. IL10 down-regulation may thus dispose to early pregnancy loss (PL) due to maternal immunotolerance defect or late pregnancy failure due to placental vascular insufficiency. IL10 gene promoter polymorphisms associated with cytokine down-regulation may help to identify the actual and probable mechanisms of IL10 modulation in pregnancy outcomes. We investigated the following four IL10 promoter polymorphisms associated with IL10 down-regulation: two single-nucleotide polymorphisms rs1800871 and rs1800872 and two polymorphic CA repeat microsatellites IL10 X78437.2:g8134CA(14_29) and IL10 X78437.2:g.5325CA(11_15). Each microsatellite was analyzed as a biallelic polymorphism. Based on a review of the literature, we define a short allele and a long allele for each microsatellite. We compared their frequencies in early PL occurring before 10 wk of amenorrhea (n = 342) and in PL occurring later on (n = 123). The mutated alleles rs1800871T (odds ratio, 3.083; 95% confidence interval, 1.984-4.792) and rs1800872A (odds ratio, 3.013; 95% confidence interval, 1.924-4.719) were associated with early PL. The haplotype rs1800872A/rs1800871T/X78437.2:g.8134CA[14_25]/X78437.2:g.5325CA[11_13], which includes the two mutated alleles, was significantly associated with the risk of early PL in a dose-dependent manner. Positivity for one haplotype was significantly associated with a 5.6-fold increase in the risk of early pregnancy failure, and positivity for two haplotypes was associated with an 8-fold increase in risk. In women with PL, some polymorphisms of the IL10 gene promoter seem to be constitutional risk factors for early (embryonic) pregnancy failure.

Background Previous studies showed that at the individual level, positron emission tomography (PET) has some benefits for patients and physicians in terms of cancer management and staging. We aimed to describe the benefits of (PET) in the management of solitary pulmonary nodules (SPNs) in a population level, in terms of the number of diagnostic and invasive tests performed, time to diagnosis and factors determining PET utilization. Methods In an observational study, we examined reports of computed tomography (CT) performed and mentioning "spherical lesion", "nodule" or synonymous terms. We found 11,515 reports in a before-PET period, 2002–2003, and 20,075 in an after-PET period, 2004–2005. Patients were followed through their physician, who was responsible for diagnostic management. Results We had complete data for 112 patients (73.7%) with new cases of SPN in the before-PET period and 250 (81.4%) in the after-PET period. Patients did not differ in mean age (64.9 vs. 64.8 years). The before-PET patients underwent a mean of 4 tests as compared with 3 tests for the after-PET patients (p = 0.08). Patients in the before-PET period had to wait 41.4 days, on average, before receiving a diagnosis as compared with 24.0 days, on average, for patients in the after-PET period who did not undergo PET (p < 0.001). In the after-PET period, 11% of patients underwent PET during the diagnostic process. A spiculated nodule was more likely to determine prescription for PET (p < 0.001). Multivariate analysis revealed that patients in both periods underwent fewer tests when PET was prescribed by general practitioners (p < 0.001) and if the nodule was not spiculated (p < 0.001). The proportion of unnecessary invasive approaches prescribed (47% vs. 49%) did not differ between the groups. Conclusion In our study, 1 year after the availability of PET, the technology was not the first choice for diagnostic management of SPN. Even though we observed a tendency for reduced number of tests and mean time to diagnosis with PET, these phenomena did not fully relate to PET availability in health communities. In addition, the availability of PET in the management of SPN diagnosis did not reduce the overall rate of unnecessary invasive approaches.

International audience; AGEs (advanced glycation end-products) accumulate in collagen molecules during uraemia and diabetes, two diseases associated with high susceptibility to bacterial infection. Because neutrophils bind to collagen during their locomotion in extravascular tissue towards the infected area we investigated whether glycoxidation of collagen (AGE-collagen) alters neutrophil migration. Type I collagen extracted from rat tail tendons was used for in vitro glycoxidation (AGE-collagen). Neutrophils were obtained from peripheral blood of healthy adult volunteers and were used for the in vitro study of adhesion and migration on AGE- or control collagen. Glycoxidation of collagen increased adhesion of neutrophils to collagen surfaces. Neutrophil adhesion to AGE-collagen was inhibited by a rabbit anti-RAGE (receptor for AGEs) antibody and by PI3K (phosphoinositide 3-kinase) inhibitors. No effect was observed with ERK (extracellular-signal-regulated kinase) or p38 MAPK (mitogen-activated protein kinase) inhibitors. AGE-collagen was able to: (i) induce PI3K activation in neutrophils, and (ii) inhibit chemotaxis and chemokinesis of chemoattractant-stimulated neutrophils. Finally, we found that blocking RAGE with anti-RAGE antibodies or inhibiting PI3K with PI3K inhibitors restored fMLP (N-formylmethionyl-leucyl-phenylalanine)-induced neutrophil migration on AGE-collagen. These results show that RAGE and PI3K modulate adhesion and migration rate of neutrophils on AGE-collagen. Modulation of adhesiveness may account for the change in neutrophil migration rate on AGE-collagen. As neutrophils rely on their ability to move to perform their function as the first line of defence against bacterial invasion, glycoxidation of collagen may participate in the suppression of normal host defence in patients with diabetes and uraemia.

The purpose of our study was to prospectively compare unenhanced ultrasonography (US) to contrast-enhanced US (CEUS) in the detection of hepatic metastases from carcinoid tumor. Thirty patients with carcinoid tumor prospectively underwent US, CEUS, and magnetic resonance imaging (MRI). Differences in sensitivity at US and CEUS were compared using a combination of the results of MR imaging, fine-needle biopsy, and follow-up imaging. Lesion conspicuity was assessed subjectively for US and CEUS. Seventeen patients had a total of 69 hepatic metastases. The addition of CEUS improved the detection of individual metastases from 47 (Se 68%; 95% CI: 57.0, 79.0) to 68 (Se 99%; 99% CI: 96.7, 100.0). Contrast enhancement improved the subjective conspicuity of metastases in 85% of patients. CEUS showed one more metastasis than did MRI in one patient, and MRI showed one more than did CEUS in one patient. CEUS is more sensitive than US in the detection of carcinoid liver metastases.

International audience; OBJECTIVE: To describe current management of cutaneous melanoma (CM) and identify factors accounting for disparities. DESIGN: Retrospective population-based study using survey of cancer registries and pathology laboratories, and questionnaires to physicians. SETTING: Five regions covering 19.2% of the French territory and including 8.2 million inhabitants. PATIENTS: Incident cases of patients with stage I to stage II (hereinafter, stage I-II) tumors staged according to the American Joint Committee on Cancer Staging guidelines and nodal stage III CM in 2004. MAIN OUTCOME MEASURES: Modalities of diagnosis and excision, surgical margins, sentinel lymph node biopsy, adjuvant therapies and surveillance procedures, and their variations according to age, sex, residence, location of primary CM, Breslow thickness, type of physicians, modalities of decisions, and health care patterns. RESULTS: Clinical stage I-II CMs (n = 710 cases) slightly predominated in females (53%), with a lower mean Breslow thickness (1.4 mm) than in males (1.9 mm). Initial excisions were most often performed by private dermatologists and wide excisions by surgeons. Narrow margins (8%) were associated with advanced age, higher Breslow thickness, and head location. Sentinel lymph node biopsy was performed in 34% of CMs thicker than 1.0 mm, depending on geographical regions, distance from reference centers, and health care patterns. Adjuvant therapies (mainly low-dose interferon) were proposed in 53% of thick CMs (>1.5 mm), depending on the patient's age and geographical region. In contrast with French recommendations, surveillance procedures frequently included systematic medical imaging. Stage III nodal CMs (n = 89 cases) predominated in males (62%). After lymphadenectomy, adjuvant therapies (including high-dose interferon in 32% of cases and chemotherapies in 24% of cases) were proposed in 68% of cases, depending on the patient's age and geographical region. A complete 1-year high-dose interferon regimen was administered in less than 10% of cases. CONCLUSION: Large disparities still exist in the management of CM in France, depending to a greater extent on medical and geographical environment than on the characteristics of either patients or tumors.

Thiopurine S-methyltransferase (TPMT) activity is inversely related to the risk of developing severe hematopoietic toxicity in patients treated with azathioprine. The aim of this study was to evaluate the usefulness of TPMT genotyping in severe cases of autoimmune bullous diseases treated with azathioprine. A retrospective study of TPMT genotyping was performed in patients with autoimmune bullous diseases hospitalized in a single centre between 1999 and 2006 and susceptible of being treated by azathioprine. Among 75 patients tested, 70 (93%) had a high TPMT activity and 5 (7%) an intermediate activity. TPMT genotyping was performed in 33/34 patients currently treated with azathioprine. Haematopoietic side-effects (usually moderate) were observed in 12/34 patients treated with a mean dosage of 2.7 mg/kg/day and occurred, despite a high predicted TPMT activity. No myelotoxicity was observed in the two patients with intermediate predicted TPMT activity (mean dosage: 1.7 mg/kg/day), who obtained a clinically complete remission. Although strongly recommended before azathioprine treatment, predicting TPMT activity appears only marginally helpful in patients with autoimmune bullous diseases, mainly for adjusting the azathioprine dosage. In addition, a normal TPMT genotyping is not a guarantee against the occurrence of haematological side-effects.

International audience; Usual imaging after endovascular aneurysm repair (EVAR) of abdominal aortic aneurysm (AAA) consists of AAA diameter monitoring and endoleak detection. Among additional predictor parameters previously proposed to help clinicians in better identifying subgroups of AAA still at risk of rupture, AAA wall motion after EVAR has been studied, but its value was not clearly established. Tissue Doppler imaging (TDI) is an ultrasonographic modality which allows wall motion measurements along an arterial segment. The aim of the current study was to analyze AAA wall motion with TDI before and after EVAR and to describe its evolution in patients with more than 1 month of follow-up. Twenty-five consecutive patients undergoing EVAR between February 2005 and June 2007 gave informed consent to be prospectively investigated with the TDI system before EVAR and at each visit during follow-up. The mean (SD) follow-up was 13.7 (9.7) months. Maximum mean segmental dilation (MMSD), segmental compliance, dilation at maximum diameter, pressure strain elastic modulus (Ep), and stiffness were compared between three periods (before stenting, before discharge, and at last follow-up), and their relation with AAA diameter was analyzed. A significant decrease in AAA compliance was immediately observed after successful EVAR and remained stable during later follow-up. On the other hand, AAA diameter progressively decreased along time and was statistically lower at the last control compared to the initial value. MMSD, segmental compliance, and dilation at maximum diameter were positively related to AAA diameter. This means that the larger the AAA diameter after stenting, the higher the value for these parameters can be expected. On the contrary, percentage of AAA diameter decrease and percentage of MMSD decrease were not related after successful EVAR. There was no parallelism between loss in compliance and diameter decrease along time, and there is not a unique pattern of AAA diameter and compliance evolution after EVAR. Even if comparison between patients without and with endoleak was weak due to the small sample of the latter group (five patients with endoleak), compliance tended to be greater in case of endoleak. AAA wall motion after successful EVAR reflects complex interactions between all the components of the stented aneurysm which evolve over time, including true compliance of the aneurysm wall itself; intra-aneurysm sac pressure with possible different effects for peak, mean, and pulse pressures; remodeling of the thrombus; stiffness characteristics of the graft; and systemic pressure. Combining simultaneous MMSD records with actual intrasaccular pressure measurements in patients with and without endoleak would improve our understanding of the clinical pulsatility mechanism within AAA after EVAR.

Aims In-stent restenosis is related to neointimal hyperplasia. Heating reduces neointimal hyperplasia but promotes constrictive remodeling after balloon angioplasty. We aimed to assess the ability of local heating in inhibiting restenosis and in-stent neointimal hyperplasia and its potential side effects on arterial thrombosis. Methods and results Atherosclerotic-like lesions were induced in iliac rabbit arteries. One month later, both iliac rabbit arteries were stented. In each animal, one artery was randomized to local heating at four temperatures (50, 60, 80, and 100°C). The contra lateral artery was used as control. Angiographic and histomorphometric analysis were performed 42 days after angioplasty. Immunohistochemistry was performed 3, 15, and 42 days after angioplasty. Angiographic significant reduction of in-stent restenosis after moderate heating (50°C) was related to in-stent neointimal hyperplasia trend to be lower after moderate local heating when compared with controls. In contrast, in-stent thrombosis was similar to controls. Higher temperatures (i.e. 80 and 100°C) also reduced in-stent neointimal hyperplasia but were most frequently associated with severe in-stent thrombosis. Local heating was associated with decreased cell proliferation, collagen density, and increased smooth muscle cell apoptosis and heat shock protein expression. Conclusion Moderate heating represents a promising approach to prevent in-stent restenosis via the limitation of the proliferative response without thrombosis induction.

BACKGROUND The AN69 ST haemodialysis membrane, a new membrane resulting from coating polyethyleneimine upon the polyacrylonitrile surface, binds heparin. In patients at risk of bleeding, a pilot study has demonstrated the efficient anticoagulant effect of this heparin-coated membrane. Study design. In chronic haemodialyzed patients, we evaluated whether this anticoagulant effect can be validated in a controlled, prospective, open study. Pragmatically, we tested the hypothesis of no difference of the massive clotting rate in two groups of patients haemodialyzed either with 50% reduced standard doses of nonfractionated heparin using the heparin-coated AN69 ST or with a full dose of heparin (100%) using another type of dialysis membrane that does not bind heparin. Secondary objectives included evaluation of partial clotting, changes in haemoglobin levels, erythropoietin consumption and dialyzer performances. RESULTS One hundred and eighty-four patients were elected and 170 finally included in an 18-month follow-up study. They were allocated to one of the two arms of the study. In the heparin-reduced group (n = 85, mean age: 73 +/- 11 years), 12 472 sessions were performed after priming the AN69 ST dialyzer with 2 L of heparinized saline (5000 IU/L heparin) and using 50% reduced doses of previously administered heparin. In the control group with standard heparin (n = 85, mean age: 74 +/- 13 years), 14 154 sessions were analysed (NS), and mean heparin doses were 2718 +/- 1388 and 4800 +/- 1564 IU per session, respectively (P < 0.001). In the heparin-reduced group, massive clotting occurred in 1.4 per 1000 sessions, whereas it occurred in 1.6 per 1000 sessions in the standard heparin group (P < 0.05). Mild to moderate partial clotting in the venous drip chamber and in the dialyzer was evaluated in a subset of patients, on a visual scale. It was more frequent in the experimental group than in the control group (P < 0.001). Platelets, haemoglobin levels, erythropoietin needs and dialyzer performances remained unchanged in both groups. The global mean death rate was 16.8% per year and did not differ significantly between groups. CONCLUSION The use of the heparin-coated AN69 ST membrane allows a 50% reduction of standard doses of nonfractionated heparin administration for routine haemo- dialysis without increasing the risk of massive clotting of the extracorporeal circuit. This result needs confirmation since massive clotting questions clinical practice and is team dependent.

BackgroundChronic obstructive pulmonary disease (COPD) is characterized by abnormal lung inflammation that exceeds the protective response. Various culture models using epithelial cell lines or primary cells have been used to investigate the contribution of bronchial epithelium in the exaggerated inflammation of COPD. However, these models do not mimicin vivosituations for several reasons (e.g, transformed epithelial cells, protease-mediated dissociation of primary cells, etc.). To circumvent these concerns, we developed a new epithelial cell culture model.MethodsUsing non transformed non dissociated bronchial epithelium obtained by bronchial brushings from COPD and non-COPD smokers, we developed a 3-dimensional culture model, bronchial epithelial spheroids (BES). BES were analyzed by videomicroscopy, light microscopy, immunofluorescence, and transmission electron microscopy. We also compared the inflammatory responses of COPD and non-COPD BES. In our study, we chose to stimulate BES with lipopolycaccharide (LPS) and measured the release of the pro-inflammatory mediators interleukin-8 (IL-8) and leukotriene B4 (LTB4) and the anti-inflammatory mediator prostaglandin E2 (PGE2).ResultsBES obtained from both COPD and non-COPD patients were characterized by a polarized bronchial epithelium with tight junctions and ciliary beating, composed of basal cells, secretory cells and ciliated cells. The ciliary beat frequency of ciliated cells was not significantly different between the two groups. Of interest, BES retained their characteristic features in culture up to 8 days. BES released the inflammatory mediators IL-8, PGE2 and LTB4 constitutively and following exposure to LPS. Interestingly, LPS induced a higher release of IL-8, but not PGE2 and LTB4 in COPD BES (p < 0.001) which correlated with lung function changes.ConclusionThis study provides for the first time a compelling evidence that the BES model provides an unaltered bronchial surface epithelium. More importantly, BES represent an attractive culture model to investigate the mechanisms of injuring agents that mediate epithelial cell inflammation and its contribution to COPD pathogenesis.

Background: During percutaneous coronary intervention, the technique of stent implantation (both direct and complementary stenting) is guided using both clinical and angiographic features. We assessed potential relationships between procedural parameters and angioplasty-induced variations in inflammatory parameters in patients treated by these two different techniques. Methods: A total of 85 consecutive patients due to undergo stent implantation were prospectively enrolled. Inflammation was assessed in terms of C-reactive protein, fibrinogen, erythrocyte sedimentation rate and leukocyte count in samples taken before and 24 h after angioplasty. Patients were classified based on whether they underwent complementary (n=47) or direct stenting (n=38). Results: Inflammation after complementary stenting was related to the duration of inflation (r=0.59; p

Colorectal cancers (CRC) with high level of microsatellite instability (MSI-H) are characterized by lower metastasis propensity and better prognosis than their stable microsatellite (MSS) counterpart. It was hypothesized that the difference in cancer progression might be related to distinct gelatinase-tissue inhibitors of metalloproteinase (TIMPs) balance in MSI-H and MSS sporadic CRC.Levels of gelatinase-A (MMP-2) and -B (MMP-9), TIMP-1 and -2 and membrane-type matrix metallo-proteinase-1 (MT1-MMP) were compared in tumors and normal mucosa from patients with MSI-H and MSS CRC.Active levels of MMP-2 and -9, normalized to normal mucosa, were lower in MSI-H than MSS CRC. There was a trend for higher levels of TIMP-1 and TIMP-2 within MSI-H tumors compared with MSS tumors (p=0.08 and p=0.15, respectively), while TIMP-2 amounts were significantly higher in adjacent normal tissue (p0.001) in patients with MSI-H vs. MSS cancers. There was also a trend for lower MT1-MMP activity in MSI-H than in MSS CRC.Our data suggest that the distinct invasive and metastatic behaviors of MSI-H and MSS CRC may be related to different patterns of gelatinase secretion and regulation.

SummaryThe human interleukin-10 promoter gene is highly polymorphic. IL-10 polymorphisms have been associated with various autoimmune and lymphoproliferative disorders. Although IL-10 has been shown to modulate thrombin generation in several experimental models, it is not known whether IL-10 polymorphisms could be a risk factor for venous thrombosis. We therefore conducted a case-control study comparing 74 consecutive patients who experienced at least one episode of documented venous thromboembolic event and 100 healthy controls. All subjects were Caucasians. Five polymorphisms of the IL-10 promoter gene were studied: two highly polymorphic dinucleotide repeats, IL-10 R and IL-10G, and three single nucleotide polymorphisms at position −1082, −819 and −592. Factor VG1691C Leiden mutation was systematically determined. Multivariate logistic regression analysis showed that IL-10 G13 and G10 alleles are independent risk factors for venous thrombosis (Odds ratio:OR = 3.33, p = 0.003 and OR = 2.83, p = 0.03, respectively). Furthermore, IL-10 G10 allele is more frequent in recurrent disease.

HemoCue Hb 201+ is a portable photometric analyser providing easy, rapid and accurate determination of hemoglobin from arterial, venous or capillary blood. It is worth that dialysis units have knowledge of its use for a close hematologic monitoring of their patients and a judicious management of erythropoietin (EPO). For the autodialysisout hospitalcenters, it allows a flexibility that private laboratories cannot have in daily practice. Therefore authors present this device and the evaluation they obtained from 148 hemoglobin measures. Then they expose the advantages and the indications of its use.

To assess the efficacy of percutaneous laser disc decompression for patients with radicular pain due to lumbar disc hernia and to identify factors that may predict outcome.The study included all patients treated with percutaneous laser disc decompression from May 2003 through May 2005 at Reims University Hospital and the Courlancy Clinic of Reims. Each patient had previous undergone at least six weeks of conventional medical treatment. The same technique, with either a laser diode or Nd: YAG, was used under endoscopic control and with neuroleptanalgesia. They were seen at 1, 3, 6 and 12 months. The principal evaluation criteria were the course of radicular pain, return to work, and need for surgery.We reexamined 149 patients 1 month after the procedure, 135 after 3 months, 102 after 6 months and 59 a year after the procedure. At a month after surgery, radicular pain had decreased by at least half, and sometimes even completely disappeared in 63.1% of patients at 1 month, 66.6% at 3 months, 73.5% at 6 months, and 83.1% at 12 months, while 24%, 50,4%, 61.2%, and 67.3%, respectively, had returned to work. No patient had serious complications. Finally, 45 of the 149 (30.2%) patients chose to have a traditional surgical procedure after percutaneous laser disc decompression.Percutaneous laser disc decompression is effective, noninvasive and well tolerated for patients with radicular pain due to lumbar disc hernia.

Meprobamate is a carbamate, main active metabolite of carisoprodol [1], used as an anxiolytic agent and prescribed in Europe and the USA. Carisoprodol is a prescribed centrally active muscle relaxant analgesic. Carisoprodol is extensively converted to meprobamate. Meprobamate plasmatic levels exceed those of carisoprodol 2.5 h after oral administration of 700 mg of carisoprodol to healthy volunteers [2]. Meprobamate is involved in 7% of psychotropic poisonings [3]. Meprobamate has a barbiturate-like mode of action at the GABAA receptor and at high concentrations is able to cause chloride ion infuse. Well-known toxic effects of a meprobamate overdose include central nervous system (CNS) depression, weakness, clonus and hyperactive reflexes, tachycardia, hypotension and respiratory depression. Meprobamate produces CNS-depressing symptoms [4]. Meprobamate intoxications are often serious and sometimes fatal (5%), resulting from haemodynamic disturbance and circulatory collapse, secondary to severe acute cardiac failure [3]. The mechanism of cardiac toxicity is unknown. An overdose of meprobamate results in coma, generally estimated by the Glasgow Coma Scale (GCS). Only one study, including few patients (n= 21), has evaluated the relationship between meprobamate plasmatic concentrations and GCS [5]. Classically, a nonsevere coma appears with meprobamate concentration between 60 and 120 mg l−1 and deep coma >120 mg l−1. We have studied the relationship between GCS and meprobamate plasma concentration in meprobamate intoxication and evaluated the pertinence of determining the meprobamate plasma level. We have reviewed all toxicological analyses made from January 2002 to September 2007. All patients with a plasma concentration of meprobamate higher than normal (>20 mg l−1) have been included. Blood samples were collected when the patient was admitted to the Emergency Department of the University Hospital. Meprobamate plasma concentrations and GCS were analysed. Meprobamate plasma concentrations were determined by a simplified, rapid and accurate gas chromatographic method [6], using a Delsi Instrument Series 30 gas chromatograph equipped with a flame ionization detector and split-splitless injection. GCS was classified into three groups: as severe group A (GCS 3–8); moderate group B (GCS 9–12); and mild group C (GCS 13–15). Statistical analysis was conducted using an analysis of variance (anova) and the Kruskal–Wallis test, with a level of significance P= 0.05. The research was conducted in compliance with the requirements of our Institutional Review Board. A total of 59 cases were collected. Mean age was 43 years (range 16–69) with a male : female ratio of 0.6. The mean plasma meprobamate concentration was 99.9 ± 13 mg l−1 (therapeutic range 10–25 mg l−1) with a maximal concentration of 271 mg l−1. Mean GCS was 7.1 ± 0.95 (range 3–15). The GCS partition was group A, n= 42; group B, n= 9; and group C, n= 8. In 87% of cases (n= 51), meprobamate had been ingested with concomitant drugs, mainly benzodiazepines (n= 35) or alcohol (n= 17). In 25 cases, the drug involved was the associated meprobamate/aceprometazine, brand name Mepronizine® in France. Meprobamate was the only drug detected in eight cases. Combination with tricyclic antidepressants was found in three cases. Concomitant ingestion of benzodiazepine was equally distributed among the three groups. Fifty-eight patients recovered. One fatal outcome was observed in a 57-year-old woman with a plasma level of meprobamate of 147 mg l−1, associated with a lethal concentration of propranolol of 1260 µg l−1, (therapeutic range 50–150 µg l−1). A high concentration of meprobamate was associated with low GCS (P= 0.0194) (Table 1). Table 1 Analysis by groups For patients with GCS = 3, meprobamate was detected in three cases, with a plasma concentration from 37 to 177 mg l−1. At a high level of consciousness (GCS = 15) a patient presented a meprobamate plasma concentration of 95 mg l−1. In the fatal case, the cause of death could not be attributed to meprobamate alone. According to the American Association of Poison Control Centers, propranolol is responsible for 71% of fatal β-blocker ingestion [7]. In our study, some interindividual variations were observed. Genetics differences have been studied only with carisoprodol. The study about CYP2C19 genotype and the pharmacokinetics of carisoprodol [8] concluded that there are no significant differences with respect to normal and nonfunctional CYP2C19 alleles in acute impairing effects of a single dose of carisoprodol. Conscious patients, with high meprobamate concentrations, are probably addicted to this drug. GCS, as a surrogate marker of meprobamate toxicity, is inferior to direct objective serum measurement and meprobamate levels, despite a high correlation based upon patient sample. Meprobamate concentration determination remains essential for the diagnosis of poisoning and ensures appropriate care of patients (electrocardiogram, intensive care). In our hospital, when meprobamate intoxication is suspected, we systematically determine the dosage of plasma meprobamate. This attitude may explain the absence of fatal outcomes.