Iron and Vitamin B12 Deficiency in Patients with Autoimmune Gastritis and Helicobacter pylori Gastritis: Results from a Prospective Multicenter Study.

INTRODUCTION: Iron and vitamin B12 deficiencies are common in patients with atrophic gastritis, but there are limited data on the prevalence of these deficiencies in different types of atrophic gastritis. METHODS: This multicenter, prospective study assessed micronutrient concentrations in histologically confirmed autoimmune gastritis (AIG, n = 45), Helicobacter pylori-related non-autoimmune gastritis (NAIG, n = 109), and control patients (n = 201). A multivariate analysis was performed to determine factors influencing those deficiencies. RESULTS: The median vitamin B12 concentration was significantly lower in AIG (367.5 pg/mL, Q1, Q3: 235.5, 524.5) than in NAIG (445.0 pg/mL, Q1, Q3: 355.0, 565.0, p = 0.001) and control patients (391.0 pg/mL, Q1, Q3: 323.5, 488.7, p = 0.001). Vitamin B12 deficiency was found in 13.3%, 1.5%, and 2.8% of AIG, NAIG, and control patients, respectively. Similarly, the median ferritin concentration was significantly lower in AIG (39.5 ng/mL, Q1, Q3: 15.4, 98.3 ng/mL) than in NAIG (80.5 ng/mL, Q1, Q3: 43.6, 133.9, p = 0.04) and control patients (66.5 ng/mL, Q1, Q3: 33.4, 119.8, p = 0.007). Iron deficiency and iron deficiency adjusted to CRP were present in 28.9% and 33.3% of AIG, 12.8% and 16.5% of NAIG, and 12.9% and 18.4% of controls, respectively. Multivariate analysis demonstrated that AIG patients had a higher risk of developing vitamin B12 deficiency (OR: 11.52 [2.85-57.64, p = 0.001]) and iron deficiency (OR: 2.92 [1.32-6.30, p = 0.007]) compared to control patients. Factors like age, sex, and H. pylori status did not affect the occurrence of vitamin B12 or iron deficiency. CONCLUSION: Iron and vitamin B12 deficiencies are more commonly observed in patients with AIG than in those with NAIG or control patients. Therefore, it is essential to screen for both iron and vitamin B12 deficiencies in AIG patients and include the treatment of micronutrient deficiencies in the management of atrophic gastritis patients.

Atrophic Gastritis and Autoimmunity: Results from a Prospective, Multicenter Study.

Despite a global decrease, gastric cancer (GC) incidence appears to be increasing recently in young, particularly female, patients. The causal mechanism for this "new" type of GC is unknown, but a role for autoimmunity is suggested. A cascade of gastric precancerous lesions, beginning with chronic atrophic gastritis (CAG), precedes GC. To test the possible existence of autoimmunity in patients with CAG, we aimed to analyze the prevalence of several autoantibodies in patients with CAG as compared to control patients. Sera of 355 patients included in our previous prospective, multicenter study were tested for 19 autoantibodies (anti-nuclear antibodies, ANA, anti-parietal cell antibody, APCA, anti-intrinsic factor antibody, AIFA, and 16 myositis-associated antibodies). The results were compared between CAG patients (n = 154), including autoimmune gastritis patients (AIG, n = 45), non-autoimmune gastritis patients (NAIG, n = 109), and control patients (n = 201). ANA positivity was significantly higher in AIG than in NAIG or control patients (46.7%, 29%, and 27%, respectively, p = 0.04). Female gender was positively associated with ANA positivity (OR 0.51 (0.31-0.81), p = 0.005), while age and H. pylori infection status were not. Myositis-associated antibodies were found in 8.9% of AIG, 5.5% of NAIG, and 4.4% of control patients, without significant differences among the groups (p = 0.8). Higher APCA and AIFA positivity was confirmed in AIG, and was not associated with H. pylori infection, age, or gender in the multivariate analysis. ANA antibodies are significantly more prevalent in AIG than in control patients, but the clinical significance of this finding remains to be established. H. pylori infection does not affect autoantibody seropositivity (ANA, APCA, AIFA). The positivity of myositis-associated antibodies is not increased in patients with CAG as compared to control patients. Overall, our results do not support an overrepresentation of common autoantibodies in patients with CAG.

Serum pepsinogens can help to discriminate between H. pylori-induced and auto-immune atrophic gastritis: Results from a prospective multicenter study.

BACKGROUND: Serum pepsinogen (PG) testing is recommended by the European guidelines for diagnosis of chronic atrophic gastritis (CAG). However, wide variations in diagnostic performances are observed, due to the differences in the extent of gastric atrophy, and possibly in its origin (Helicobacter pylori-, autoimmune (AIG)). AIM: To analyze the diagnostic performances of PGs testing according to these different parameters, using enzyme-linked-immunosorbent serologic assay (ELISA) and chemiluminescent immunoassay (CLEIA). METHODS: Serum samples from patients having undergone gastroscopy with biopsies in five French centers were collected prospectively. Sensitivity (Se), specificity (Sp), and Area Under Curve were analyzed according to the extent and origin of CAG. RESULTS: Overall, 344 patients (156 males [45%]; mean age 58.8 [±14.2] years) were included, among whom 44 had AIG. Diagnostic performances of PG I for the detection of corpus CAG were excellent, with Se and Sp of 92.7% and 99.1% for ELISA and 90.5% and 98.2% for CLEIA, respectively. For AIG, corresponding values were 97.7% and 97.4% for ELISA, and 95.6% and 97.1% for CLEIA. In multivariate analysis, PG levels were associated with the auto-immune origin (p<0.001) but not with the extent of the atrophic gastritis. CONCLUSIONS: Pepsinogens are highly efficient for the diagnosis of corpus-limited CAG and allow to discriminate AIG from H. pylori-induced gastritis.

Neglected Comorbidity of Chronic Heart Failure: Iron Deficiency.

Iron deficiency is a significant comorbidity of heart failure (HF), defined as the inability of the myocardium to provide sufficient blood flow. However, iron deficiency remains insufficiently detected. Iron-deficiency anemia, defined as a decrease in hemoglobin caused by iron deficiency, is a late consequence of iron deficiency, and the symptoms of iron deficiency, which are not specific, are often confused with those of HF or comorbidities. HF patients with iron deficiency are often rehospitalized and present reduced survival. The correction of iron deficiency in HF patients is associated with improved functional capacity, quality of life, and rehospitalization rates. Because of the inflammation associated with chronic HF, which complicates the picture of nutritional deficiency, only the parenteral route can bypass the tissue sequestration of iron and the inhibition of intestinal iron absorption. Given the negative impact of iron deficiency on HF progression, the frequency and financial implications of rehospitalizations due to decompensation episodes, and the efficacy of this supplementation, screening for this frequent comorbidity should be part of routine testing in all HF patients. Indeed, recent European guidelines recommend screening for iron deficiency (serum ferritin and transferrin saturation coefficient) in all patients with suspected HF, regular iron parameters assessment in all patients with HF, and intravenous iron supplementation in symptomatic patients with proven deficiency. We thus aim to summarize all currently available data regarding this common and easily improvable comorbidity.

A neglected comorbidity of chronic heart failure: iron deficiency / Carence martiale sans anémie : première comorbidité curable de l'insuffisance cardiaque.

The functioning of the heart muscle is particularly sensitive to iron deficiency, the easily curable comorbidity most frequently associated with heart failure. Iron-deficient heart failure patients are more often rehospitalized and have reduced survival. Heart muscle function is particularly susceptible to martial deficiency. Recent randomized studies have shown that exogenous iron intake is accompanied by improved functional capacity (walking test), quality of life, and re-hospitalization rate in these patients. The symptoms of iron deficiency are not very specific and often confused with those of heart failure or other comorbidities, which explains why management is often too late. Anemia is only a late consequence of this iron deficiency. Due to the inflammatory state associated with chronic heart failure, only the parenteral route can bypass the macrophage tissue sequestration of iron and inhibit its intestinal absorption. Recent European guidelines recommend screening for iron deficiency (serum ferritin and transferrin saturation coefficient) in all patients with suspected heart failure, routine iron parameters assessment in all patients with heart failure, and intravenous iron supplementation in case of deficiency in symptomatic patients. Given the pejorative nature of iron deficiency on disease progression, the frequency and financial impact of hospitalizations linked to episodes of decompensation, as well as the effectiveness of simple supplementation, screening for this comorbidity, screening for this frequent comorbidity should now be part of routine testing in all heart failure patients.

Serum Pepsinogens Combined with New Biomarkers Testing Using Chemiluminescent Enzyme Immunoassay for Non-Invasive Diagnosis of Atrophic Gastritis: A Prospective, Multicenter Study.

BACKGROUND: Analysis of serum biomarkers for the assessment of atrophic gastritis (AG), a gastric precancerous lesion, is of growing interest for identification of patients at increased risk of gastric cancer. The aim was to analyze the diagnostic performance of serum pepsinogen testing using another method, chemiluminescent enzyme immunoassay (CLEIA), as well as of other new potential biomarkers. MATERIAL AND METHODS: The sera of patients considered at increased risk of gastric cancer and undergoing upper endoscopy collected in our previous prospective, multicenter study were tested for pepsinogen I (PGI) and II (PGII), interleukin-6 (IL-6), human epididymal protein 4 (HE-4), adiponectin, ferritin and Krebs von den Lungen (KL-6) using the CLEIA. The diagnostic performance for the detection of AG was calculated by taking histology as the reference. RESULTS: In total, 356 patients (162 men (46%); mean age 58.6 (±14.2) years), including 152 with AG, were included. For the detection of moderate to severe corpus AG, sensitivity and specificity of the pepsinogen I/II ratio were of 75.0% (95%CI 57.8-87.9) and 92.6% (88.2-95.8), respectively. For the detection of moderate to severe antrum AG, sensitivity of IL-6 was of 72.2% (95%CI 46.5-90.3). Combination of pepsinogen I/II ratio or HE-4 showed a sensitivity of 85.2% (95%CI 72.9-93.4) for the detection of moderate to severe AG at any location. CONCLUSION: This study shows that PG testing by CLEIA represents an accurate assay for the detection of corpus AG. Additionally, IL-6 and HE-4 may be of interest for the detection of antrum AG. MINI-ABSTRACT: Pepsinogens testing by chemiluminescent enzyme immunoassay is accurate for the detection of corpus atrophic gastritis. IL-6 and HE-4 maybe of interest for the detection of antrum atrophic gastritis.

Anti-CEA Pretargeted Immuno-PET Shows Higher Sensitivity Than DOPA PET/CT in Detecting Relapsing Metastatic Medullary Thyroid Carcinoma: Post Hoc Analysis of the iPET-MTC Study.

Pretargeting parameters for the use of anti-carcinoembryonic antigen (CEA) bispecific monoclonal antibody TF2 and the 68Ga-labeled IMP288 peptide for immuno-PET have been optimized in a first-in-humans study performed on medullary thyroid carcinoma (MTC) patients (the iPET-MTC study). The aim of this post hoc analysis was to determine the sensitivity of immuno-PET in relapsing MTC patients, in comparison with conventional imaging and 18F-l-dihydroxyphenylalanine (18F-DOPA) PET/CT. Methods: Twenty-five studies were analyzed in 22 patients. All patients underwent immuno-PET 1 and 2 h after 68Ga-IMP288 injection pretargeted by TF2, in addition to neck, thoracic, abdominal, and pelvic CT; bone and liver MRI; and 18F-DOPA PET/CT. The gold standard was histology or confirmation by one other imaging method or by imaging follow-up. Results: In total, 190 lesions were confirmed by the gold standard: 89 in lymph nodes, 14 in lungs, 46 in liver, 37 in bone, and 4 in other sites (subcutaneous tissue, heart, brain, and pancreas). The number of abnormal foci detected by immuno-PET was 210. Among these, 174 (83%) were confirmed as true-positive by the gold standard. Immuno-PET showed a higher overall sensitivity (92%) than 18F-DOPA PET/CT (65%). Regarding metastatic sites, immuno-PET had a higher sensitivity than CT, 18F-DOPA PET/CT, or MRI for lymph nodes (98% vs. 83% for CT and 70% for 18F-DOPA PET/CT), liver (98% vs. 87% for CT, 65% for 18F-DOPA PET/CT, and 89% for MRI), and bone (92% vs. 64% for 18F-DOPA PET/CT and 86% for MRI), whereas sensitivity was lower for lung metastases (29% vs. 100% for CT and 14% for 18F-DOPA PET/CT). Tumor SUVmax at 60 min ranged from 1.2 to 59.0, with intra- and interpatient variability. Conclusion: This post hoc study demonstrates that anti-carcinoembryonic antigen immuno-PET is an effective procedure for detecting metastatic MTC lesions. Immuno-PET showed a higher overall sensitivity than 18F-DOPA PET/CT for disclosing metastases, except for the lung, where CT remains the most effective examination.

Association between blastocyst morphology and maternal first trimester serum markers in ongoing pregnancies obtained after single fresh blastocyst transfer.

OBJECTIVE: Is there an association between blastocyst morphology and maternal first trimester serum markers in In Vitro Fertilization (IVF) pregnancies obtained after fresh single blastocyst transfer? STUDY DESIGN: This bi-centric retrospective study was conducted between January 2012 and August 2018. We included 122 women aged from 18 to 43 years-old, whose pregnancy progressed at least beyond 13 weeks after a single blastocyst transfer and who participated in the first trimester combined screening test. Day 5 and day 6 blastocysts were evaluated according to Gardner and Schoolcraft classification. Patients were classified into three groups according to blastocysts morphological quality: excellent (≥ 3AA), good (3-6AB, 3-6BA, B2), and medium to poor (3-6BB, 3-6AC, 3-6CA, B1, 3-6CB, 3-6BC). First trimester serum markers were measured in maternal blood between 9 and 11 + 6 gestational weeks. Univariate and multivariate analyses were performed. RESULTS: Female body mass index, smoking status, type of infertility, geographical origin, anti-mullerian hormone level, ovarian stimulation characteristics, pregnancy outcomes and obstetrical complications were comparable between the three groups. Patient's age was not distributed evenly across groups, with women in group "Medium to Poor" appearing to be slightly younger than in other groups. There were no significant differences in mean first trimester serum markers between the three groups (PAPP-A: excellent: 1.23 ± 0.59 MoM; good: 1.45 ± 0.71 MoM; medium to poor: 1.22 ± 0.52 MoM; p = 0,20; free beta-HCG: excellent: 1.66 ± 1.38 MoM; good: 1.19 ± 0.76 MoM; medium to poor: 1.81 ± 1.34 MoM; p = 0,12). No significant difference was found either between mean first trimester serum markers and inner cell mass morphology (PAPP-A: grade A: 1.23 ± 0.58 MoM; grade B: 1.26 ± 0.60 MoM; medium to poor: 1.64 ± 0.87 MoM; p = 0,67 ; free beta-HCG: grade A: 1.66 ± 1.36 MoM; grade B: 1.52 ± 1.10 MoM; medium to poor: 1.57 ± 0.39 MoM p = 0,60), trophectoderm cells morphology (PAPP-A: grade A: 1.25 ± 0.63 MoM; grade B: 1.26 ± 0.51 MoM; medium to poor: not comparable; p = 0,66; free beta-HCG: grade A: 1.60 ± 1.34 MoM; grade B: 1.69 ± 1.14 MoM; medium to poor: not comparable; p = 0,25), or blastocoel expansion (PAPP-A: B1: 1.08 ± 0.51MoM; B2: 1.57 ± 0.70 MoM; B3: 1.26 ± 0.61 MoM; B4: 1.28 ± 0.62 MoM; B5: 1.04 ± 0.38 MoM; p = 0,22; free beta-HCG: B1: 2.01 ± 1.88 MoM; B2: 1.07 ± 0.49 MoM; B3: 1.43 ± 0.87 MoM; B4: 1.68 ± 1.28 MoM ; B5: 1.82 ± 2.03 MoM; p = 0,48). After adjustment on potential confounding factors (female age, type of gonadotropin, parity, number of oocytes retrieved and occurrence of ovarian hyperstimulation syndrome), we did not observe any association between PAPP-A or free beta-HCG levels and blastocyst morphology. CONCLUSION: Our study concluded that first trimester serum markers were not associated with blastocyst morphological characteristics. Although this needs further confirmation, this suggests that blastocyst morphology would not have an impact on placentation. Therefore, these findings are reassuring for couples undergoing IVF and blastocyst transfer.

Initial Clinical Results of a Novel Immuno-PET Theranostic Probe in Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer.

This prospective study evaluated the imaging performance of a novel pretargeting immunologic PET (immuno-PET) method in patients with human epidermal growth factor receptor 2 (HER2)-negative, carcinoembryonic antigen (CEA)-positive metastatic breast cancer, compared with CT, bone MRI, and 18F-FDG PET. Methods: Twenty-three patients underwent whole-body immuno-PET after injection of 150 MBq of 68Ga-IMP288, a histamine-succinyl-glycine peptide given after initial targeting of a trivalent anti-CEA, bispecific, antipeptide antibody. The gold standards were histology and imaging follow-up. Tumor SUVs (SUVmax and SUVmean) were measured, and tumor burden was analyzed using total tumor volume and total lesion activity. Results: The total lesion sensitivity of immuno-PET and 18F-FDG PET were 94.7% (1,116/1,178) and 89.6% (1,056/1,178), respectively. Immuno-PET had a somewhat higher sensitivity than CT or 18F-FDG PET in lymph nodes (92.4% vs. 69.7% and 89.4%, respectively) and liver metastases (97.3% vs. 92.1% and 94.8%, respectively), whereas sensitivity was lower for lung metastases (48.3% vs. 100% and 75.9%, respectively). Immuno-PET showed higher sensitivity than MRI or 18F-FDG PET for bone lesions (95.8% vs. 90.7% and 89.3%, respectively). In contrast to 18F-FDG PET, immuno-PET disclosed brain metastases. Despite equivalent tumor SUVmax, SUVmean, and total tumor volume, total lesion activity was significantly higher with immuno-PET than with 18F-FDG PET (P = 0.009). Conclusion: Immuno-PET using anti-CEA/anti-IMP288 bispecific antibody, followed by 68Ga-IMP288, is a potentially sensitive theranostic imaging method for HER2-negative, CEA-positive metastatic breast cancer patients and warrants further research.

Is severe hypocalcemia immediately life-threatening?

Objective: Severe hypocalcemia (Ca <1.9 mmol/L) is often considered an emergency because of a potential risk of cardiac arrest or seizures. However, there is little evidence to support this. The aim of our study was to assess whether severe hypocalcemia was associated with immediately life-threatening cardiac arrhythmias or neurological complications. Methods: A retrospective observational study was carried out over a 2 years period in the Adult Emergency Department (ED) of Nantes University Hospital. All patients who had a protein-corrected calcium concentration measure were eligible for inclusion. Patients with multiple myeloma were excluded. The primary outcome was the number of life-threatening cardiac arrhythmias and/or neurological complications during the stay in the ED. Results: A total of 41,823 patients had protein-corrected calcium (pcCa) concentrations measured, 155 had severe hypocalcaemia, 22 were excluded because of myeloma leaving 133 for analysis. Median pcCa concentration was 1.73 mmol/L [1.57-1.84]. Seventeen (12.8%) patients presented a life threatening condition, 14 (10.5%) neurological and 3 (2.2%) cardiac during ED stay. However these complications could be explained by the presence of underlying co-morbidities and or electrolyte disturbances other than hypocalcaemia. Overall 24 (18%) patients died in hospital. Vitamin D deficiency, chronic kidney disease and hypoparathyroidism were the most frequently found causes of hypocalcemia. Conclusion: 13% of patients with severe hypocalcaemia presented a life-threatening cardiac or neurological complication on the ED. However a perfectly valid alternative cause could account for these complications. Further research is warranted to define the precise role of hypocalcaemia.

Procalcitonin and C-reactive protein may help to detect invasive bacterial infections in children who have fever without source.

AIM: This study evaluated the epidemiology and performance of biomarkers for identifying bacterial infections in children who presented with fever without source. METHODS: We conducted a prospective cohort study in the paediatric department at the University Hospital of Nantes, France, in 2016. Children older than six days and younger than five years of age were included. RESULTS: A total of 1060 children (52.2% male) with fever without source were admitted, and the median age was 17 months (interquartile range: 6.6-24.3 months). Severe bacterial infections were diagnosed in 127 (11.9%) children and invasive bacterial infections in 11 (1.0%) children: four (0.3%) with bacterial meningitis and seven (0.6%) with bacteraemia. A further 114 (10.7%) had urinary tract infections. We explored the area under the receiver-operating characteristic curves for identifying invasive bacterial infections. The curves for procalcitonin and C-reactive protein assays were better than those for the absolute neutrophil counts and the white blood cell counts. CONCLUSION: This study found that there was a low prevalence of invasive bacterial infections in children who presented with fever without source. It also showed that procalcitonin and C-reactive protein may help to detect invasive bacterial infections in children who have fever without source.

Evaluation of sFlt-1/PlGF Ratio for Predicting and Improving Clinical Management of Pre-eclampsia: Experience in a Specialized Perinatal Care Center.

BACKGROUND: Management of pregnant women at high risk of pre-eclampsia (PE) requires frequent monitoring, with referral to specialized perinatal care centers. Reliable tests are necessary to improve prediction of PE and related complications and to assess disease severity and progression. An imbalance in two biomarkers, soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF), is involved in PE pathogenesis. The sFlt-1 to PlGF ratio is increased in pregnant women before the onset of PE. An elevated ratio is highly predictive of PE, whereas the diagnosis of PE can be ruled out within one week for low ratios. The main objective of this study was to assess whether a low sFlt-1/PlGF ratio, below a cutoff of 38, can predict the absence of PE within one week. METHODS: We performed a prospective, monocentric, observational study to evaluate serum sFlt-1/PlGF ratio (Roche Diagnostics Cobas e411 system) for predicting -PE in a group of 67 high-risk pregnant women (20-37 gestation weeks). RESULTS: Among the 67 patients included, 53 had a sFlt-1/PlGF ratio lower than 38; none developed subsequent PE leading to a negative predictive value of 100%. Eight patients developed clinical PE. The positive predictive value was 21% at one week and 18% at four weeks, in accordance with previous studies. CONCLUSIONS: The serum sFlt-1/PlGF ratio showed highly predictive performances for ruling out PE. Using these biomarkers in routine management of PE may improve clinical care and avoid inappropriate hospitalization, which has a significant economic impact.

Reference ranges for serum S100B neuroprotein specific to infants under four months of age.

BACKGROUND: Minor head traumatisms are a common reason for consultation in paediatric emergency departments. The diagnosis of traumatic brain injuries involves performing a cranial computed tomography (CCT), associated with a risk of cancer due to the radiation. The serum S100B is an effective biomarker used to reduce reliance on CCT. While reference ranges have been determined, the limited number of cases regarding infants less than 4months of age has not allowed this biomarker to be used with this age group. Our study aimed to determine reference ranges for serum S100B based on a larger number of infants from birth to 4months of age. METHODS: Three centres included infants coming to the hospital for whom blood samples were taken. These samples were analysed to determine the upper reference values based on the 95th percentile. RESULTS: 135 samples were analysed. The upper reference value was 0.51µg/L for children aged 0 to 4months. There was no effect of the gender. CONCLUSIONS: This study provides serum S100B reference ranges based on the largest group of neurologically healthy 0 to 4-month-old infants analysed to date. Reliable reference values of S100B for children are now determined. It is the first step towards validation of thresholds for studies integrating S100B into a clinical decision rule for MHT in children.

Pharmacokinetics and Dosimetry Studies for Optimization of Pretargeted Radioimmunotherapy in CEA-Expressing Advanced Lung Cancer Patients.

OBJECTIVES: A phase I pretargeted radioimmunotherapy trial (EudractCT 200800603096) was designed in patients with metastatic lung cancer expressing carcinoembryonic antigen (CEA) to optimize bispecific antibody and labeled peptide doses, as well as the delay between their injections. METHODS: Three cohorts of three patients received the anti-CEA × anti-histamine-succinyl-glycine (HSG)-humanized trivalent bispecific antibody (TF2) and the IMP288 bivalent HSG peptide. Patients underwent a pretherapeutic imaging session S1 (44 or 88 nmol/m(2) of TF2 followed by 4.4 nmol/m(2), 185 MBq, of (111)In-labeled IMP288) and, 1-2 weeks later, a therapy session S2 (240 or 480 nmol/m(2) of TF2 followed by 24 nmol/m(2), 1.1 GBq/m(2), of (177)Lu-labeled IMP288). The pretargeting delay was 24 or 48 h. The dose schedule was defined based on preclinical TF2 pharmacokinetic (PK) studies, on our previous clinical data using the previous anti-CEA-pretargeting system, and on clinical results observed in the first patients injected using the same system in Netherlands. RESULTS: TF2 PK was represented by a two-compartment model in which the central compartment volume (Vc) was linearly dependent on the patient's surface area. PK was remarkably similar, with a clearance of 0.33 ± 0.03 L/h/m(2). (111)In- and (177)Lu-IMP288 PK was also well represented by a two-compartment model. IMP288 PK was faster (clearance 1.4-3.3 L/h). The Vc was proportional to body surface area, and IMP288 clearance depended on the molar ratio of injected IMP288 to circulating TF2 at the time of IMP288 injection. Modeling of image quantification confirmed the dependence of IMP288 kinetics on circulating TF2, but tumor activity PK was variable. Organ-absorbed doses were not significantly different in the three cohorts, but the tumor dose was significantly higher with the higher molar doses of TF2 (p < 0.002). S1 imaging predicted absorbed doses calculated in S2. CONCLUSION: The best dosing parameters corresponded to the shorter pretargeting delay and to the highest TF2 molar doses. S1 imaging session accurately predicted PK as well as absorbed doses of S2, thus potentially allowing for patient selection and dose optimization. TRIAL REGISTRATION: ClinicalTrials.gov NCT01221675 (EudractCT 200800603096).

Activation of the prostaglandin D2 metabolic pathway in Crohn's disease: involvement of the enteric nervous system.

BACKGROUND: Recent works provide evidence of the importance of the prostaglandin D2 (PGD2) metabolic pathway in inflammatory bowel diseases. We investigated the expression of PGD2 metabolic pathway actors in Crohn's disease (CD) and the ability of the enteric nervous system (ENS) to produce PGD2 in inflammatory conditions. METHODS: Expression of key actors involved in the PGD2 metabolic pathway and its receptors was analyzed using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) in colonic mucosal biopsies of patients from three groups: controls, quiescent and active CD patients. To determine the ability of the ENS to secrete PGD2 in proinflammatory conditions, Lipocalin-type prostaglandin D synthase (L-PGDS) expression by neurons and glial cells was analyzed by immunostaining. PGD2 levels were determined in a medium of primary culture of ENS and neuro-glial coculture model treated by lipopolysaccharide (LPS). RESULTS: In patients with active CD, inflamed colonic mucosa showed significantly higher COX2 and L-PGDS mRNA expression, and significantly higher PGD2 levels than healthy colonic mucosa. On the contrary, peroxysome proliferator-activated receptor Gamma (PPARG) expression was reduced in inflamed colonic mucosa of CD patients with active disease. Immunostaining showed that L-PGDS was expressed in the neurons of human myenteric and submucosal plexi. A rat ENS primary culture model confirmed this expression. PGD2 levels were significantly increased on primary culture of ENS treated with LPS. This production was abolished by AT-56, a specific competitive L-PGDS inhibitor. The neuro-glial coculture model revealed that each component of the ENS, ECG and neurons, could contribute to PGD2 production. CONCLUSIONS: Our results highlight the activation of the PGD2 metabolic pathway in Crohn's disease. This study supports the hypothesis that in Crohn's disease, enteric neurons and glial cells form a functional unit reacting to inflammation by producing PGD2.

[Dual role for prostaglandin D2 in intestinal epithelial homeostasis]. / Prostaglandine D2 et homéostasie de la barrière épithéliale intestinale--Une relation équivoque.

Prostaglandin D2 (PGD2) and derivatives are lipid mediators involved in the control of the intestinal epithelial barrier homeostasis. Their involvement in the pathophysiology of chronic inflammatory bowel disease (IBD) is still debated. Several results highlight the duality of PGD2 as an anti- or pro-inflammatory mediator. This duality seems to be related to a differential expression of its receptors by intestinal epithelial cells and the surrounding immunocompetent cells. The enteric glial cells from the enteric nervous system (ENS) express the lipocalin-type-prostaglandin D synthase and secrete PGD2 and 15d-PGJ2. The protective role of the ENS in the homeostatic control of the epithelial intestinal barrier and its involvement in the pathogenesis of IBD have already been demonstrated. Thus, these lipid mediators seem to be new actors of the neuro-glio-epithelial unit and could play a crucial role maintaining gut barrier integrity.

Serum S100ß Neuroprotein Reduces Use of Cranial Computed Tomography in Children After Minor Head Trauma.

Minor head trauma is a common reason for consultation in pediatric emergency departments. In 2009, the Pediatric Emergency Care Applied Research Network (PECARN) published a clinical decision rule for its management. It aimed to help clinicians identify children with a very low risk of developing intracranial lesions, so that unnecessary cranial computed tomography (CCT) scan radiation could be avoided, as such exposure is associated with a rising risk of cancer in this young population. In the meantime, the serum S100ß neuroprotein showed encouraging results, with a 30% potential decrease in CCTs for the management of minor head traumas in adults and children. The aim of this study was to determine if the serum S100ß neuroprotein, associated with the PECARN clinical decision rule, could safely reduce the use of CCTs. We included children who were examined at the pediatric emergency department for minor head trauma, who underwent a CCT, whose blood samples were analyzed to determine the level of the serum S100ß protein. They were managed according to the PECARN clinical decision rule. We afterward assessed the potential decrease in the number of CCTs, according to a modified PECARN clinicobiological decision rule, had we taken into account the result of the blood tests. One hundred nine children were included, and nine of them had clinically important traumatic brain injury. Four of them had a negative S100ß value but were classified as high risk of developing intracranial lesion according to the PECARN clinical decision rule. Had we taken into account the modified PECARN clinicobiological decision rule, none of them would have been missed. However, there were 32 true negatives of the rule, allowing a potential decrease in CCTs rated at 29% (95% confidence interval, 21-38). Integrating the serum S100ß neuroprotein assessment in the PECARN clinical decision rule could avoid deleterious exposure to CCT radiation, with the condition of using a clinicobiological rule to avoid missing clinically important traumatic brain injuries. Those results have yet to be confirmed relying on a large multicentric study.