Metastatic Potential and Survival of Duodenal and Pancreatic Tumors in Multiple Endocrine Neoplasia Type 1: A GTE and AFCE Cohort Study (Groupe d'étude des Tumeurs Endocrines and Association Francophone de Chirurgie Endocrinienne).

OBJECTIVE: To assess the distant metastatic potential of duodeno-pancreatic neuroendocrine tumors (DP-NETs) in patients with MEN1, according to functional status and size. SUMMARY BACKGROUND DATA: DP-NETs, with their numerous lesions and endocrine secretion-related symptoms, continue to be a medical challenge; unfortunately they can become aggressive tumors associated with distant metastasis, shortening survival. The survival of patients with large nonfunctional DP-NETs is known to be poor, but the overall contribution of DP-NETs to metastatic spread is poorly known. METHODS: The study population included patients with DP-NETs diagnosed after 1990 and followed in the MEN1 cohort of the Groupe d'étude des Tumeurs Endocrines (GTE). A multistate Markov piecewise constant intensities model was applied to separate the effects of prognostic factors on 1) metastasis, and 2) metastasis-free death or 3) death after appearance of metastases. RESULTS: Among the 603 patients included, 39 had metastasis at diagnosis of DP-NET, 50 developed metastases during follow-up, and 69 died. The Markov model showed that Zollinger-Ellison-related tumors (regardless of tumor size and thymic tumor pejorative impact), large tumors over 2 cm, and age over 40 years were independently associated with an increased risk of metastases. Men, patients over 40 years old and patients with tumors larger than 2 cm, also had an increased risk of death once metastasis appeared. CONCLUSIONS: DP-NETs of 2 cm in size or more, regardless of the associated secretion, should be removed to prevent metastasis and increase survival. Surgery for gastrinoma remains debatable.

Is Thrombocytopenia an Early Prognostic Marker in Septic Shock?

OBJECTIVES: To assess whether early thrombocytopenia during septic shock is associated with an increased risk of death at day 28 and to identify risk factors associated with a low platelet count. DESIGN: Prospective, multicenter, observational cohort study. SETTING: Fourteen ICUs from 10 French university teaching and nonacademic hospitals. PATIENTS: Consecutive adult patients with septic shock admitted between November 2009 and September 2011 were eligible. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Of the 1,495 eligible patients, 1,486 (99.4%) were included. Simplified Acute Physiology Score II score of greater than or equal to 56, immunosuppression, age of more than 65 years, cirrhosis, bacteremia (p ≤ 0.001 for each), and urinary sepsis (p = 0.005) were globally associated with an increased risk of thrombocytopenia within the first 24 hours following the onset of septic shock. Survival at day 28 estimated by the Kaplan-Meier method was lower in patients with thrombocytopenia and decreased with thrombocytopenia severity. By multivariate Cox regression, a platelet count of less than or equal to 100,000/mm3 was independently associated with a significantly increased risk of death within the 28 days following septic shock onset. The risk of death increased with the severity of thrombocytopenia (hazard ratio, 1.65; 95% CI, 1.31-2.08 for a platelet count below 50,000/mm3 vs > 150,000/mm3; p < 0.0001). CONCLUSIONS: This is the first study to investigate thrombocytopenia within the first 24 hours of septic shock onset as a prognostic marker of survival at day 28 in a large cohort of ICU patients. Measuring platelet count is inexpensive and easily feasible for the physician in routine practice, and thus, it could represent an easy "alert system" among patients in septic shock.

Low preoperative cholesterol level is a risk factor of sepsis and poor clinical outcome in patients undergoing cardiac surgery with cardiopulmonary bypass.

OBJECTIVES: Systemic inflammatory response syndrome and sepsis frequently occur after cardiac surgery with cardiopulmonary bypass. The aim of the present study was to investigate whether preoperative cholesterol levels can predict sepsis onset and postoperative complications in patients undergoing cardiac surgery with cardiopulmonary bypass. DESIGN: Prospective observational study. SETTING: Surgical ICU of a French university hospital. PATIENTS: Two hundred and seventeen consecutive patients older than 18 years admitted for planned cardiac surgery with cardiopulmonary bypass. INTERVENTIONS: Measurements of plasma blood lipids and inflammation markers before anesthesia induction (baseline), at cardiopulmonary bypass start, at cardiopulmonary bypass end, and 3 and 24 hours after cardiac surgery. Outcomes were compared in systemic inflammatory response syndrome patients with sepsis (n = 15), systemic inflammatory response syndrome patients without sepsis (n = 95), and non-systemic inflammatory response syndrome patients (n = 107). MEASUREMENTS AND MAIN RESULTS: A gradual decrease in plasma cholesterol concentration occurred during surgery with cardiopulmonary bypass but was no longer present after correction for hemodilution. Corrected cholesterol levels were significantly lower at baseline in sepsis patients than in other subgroups, and it remained lower in the sepsis group during and after cardiopulmonary bypass. With regard to sepsis, the discriminatory power of baseline cholesterol was fairly good as indicated by receiver operating characteristic curve analysis (area under the curve, 0.78; 95% CI, 0.72-0.84). The frequency of sepsis progressively decreased with increasing baseline cholesterol level quintiles (18.6% and 0% in the bottom and top quintiles, respectively, p = 0.005). In multivariate analysis, baseline cholesterol levels and cardiopulmonary bypass duration were significant and independent determinants of the 3-hour postcardiopulmonary bypass increase in concentrations of procalcitonin and interleukin-8, but not of interleukin-6. CONCLUSIONS: Low cholesterol levels before elective cardiac surgery with cardiopulmonary bypass may be a simple biomarker for the early identification of patients with a high risk of sepsis.

Clinical and molecular spectrum of renal malformations in Kabuki syndrome.

OBJECTIVE: To determine the frequency and types of renal malformations, and to evaluate renal function in a cohort of patients with Kabuki syndrome (KS). STUDY DESIGN: Renal ultrasound scans and plasma creatinine measurements were collected from a French cohort of 94 patients with genotyped KS. Renal function was evaluated based on the estimated glomerular filtration rate. A genotype-phenotype study was conducted for renal and urinary tract malformations. RESULTS: Renal malformations were present in 22% of cases, and urinary tract anomalies were present in 15%. Renal malformations were observed in 28% of the MLL2 mutation-positive group and in 0% of the MLL2 mutation-negative group (P = .015). No correlation was found between the presence or absence of renal or urinary tract malformations and the location or type of MLL2 mutation. Renal function was normal except for 1 patient with a MLL2 mutation diagnosed in the first days of life and severe renal disease due to unilateral renal agenesia and controlateral severe hypoplasia that progressed to the terminal stage at age 2 years. CONCLUSION: Our study emphasizes the need for ultrasound and renal function screening in children diagnosed with KS.

Associations between cognitive performance and the rehabilitation, medical care and social support provided to French children with Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is a rare genetic neurodevelopmental disorder with a characteristic behavioural phenotype. A multidisciplinary approach to care is required to prevent multiple medical complications in individuals affected by PWS. The aim of this study was to describe the rehabilitation, medical care, educational and social support provided to school-aged French PWS patients with varying neuropsychological profiles. Data were obtained from a French multicentre study that included patients aged 4-20 years with diverse genetic syndromes. Nineteen PWS subjects with a mean age of 9.2 years were included. The mean full-scale intellectual quotient (IQ) was 58 (Wechsler scale). There were frequent dissociations between verbal and performance IQ that were not associated with a specific profile. We also observed lower autonomy and communication scores (5.3 years and 5.9 years equivalent, respectively, Vineland scale), the absence of hyperactivity (Conners scale), and the presence of behavioural abnormalities (CBCL scale). Multidisciplinary medical supervision was generally coordinated by the paediatric endocrinologist and did not always include follow-up with all of the recommended specialists, in particular with a paediatric psychiatrist. Analysis of multidisciplinary rehabilitation conducted in public and private-sector establishment revealed failings in psychological support, occupational therapy and dietary follow-up. Regarding education, most children younger than 10 years were in normal schools, while older individuals were often cared for in medico-social institutions. In conclusion, children and adolescents with PWS generally received appropriate care. Though there have been considerable improvements in the management of children with PWS, reference centres should continue reinforcing the coordination of multidisciplinary supervision.

Phospholipid profiles and hepatocellular carcinoma risk and prognosis in cirrhotic patients.

BACKGROUND: Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. Phospholipids are now well-recognised players in tumour progression. Their metabolic tissue alterations can be associated with plasmatic modifications. The aim of this study was to evaluate the potential of the plasma phospholipid profile as a risk and prognostic biomarker in HCC. METHODS: Ninety cirrhotic patients with (cases) or without HCC (controls) were studied after matching for inclusion centre, age, gender, virus infection, cirrhosis duration and Child-Pugh grade. High-performance liquid chromatography coupled with tandem-mass spectrometry was used to quantify the main species of seven categories of phospholipids in plasma. RESULTS: Elevated concentrations of phosphatidylcholine (PC) 16:0/16:1 (p=0.0180), PC 16:0/16:0 (p=0.0327), PC 16:0/18:1 (p=0.0264) and sphingomyelin (SM) 18:2/24:1 (p=0.0379) and low concentrations of lysophosphatidylcholine 20:4 (0.0093) and plasmalogen-phosphatidylethanolamine (pPE) 16:0/20:4 (p=0.0463), pPE 18:0/20:4 (p=0.0077), pPE 18:0/20:5 (p=0.0163), pPE 18:0/20:3 (p=0.0463) discriminated HCC patients from cirrhotic controls. Two ceramide species were associated with increased HCC risk of death while lysophospholipids, a polyunsaturated phosphatidylinositol, some PC and SM species were associated with low risk of death in HCC patients in 1 and/or 3 years. CONCLUSION: This study identified phospholipid profiles related to HCC risk in liver cirrhotic patients and showed for the first time the potential of some phospholipids in predicting HCC patient mortality.

Impact of a stay in the intensive care unit on the preparation of Advance Directives: Descriptive, exploratory, qualitative study.

BACKGROUND: Our objective was to assess, through a qualitative, exploratory study, the thought processes of patients regarding the formulation of advance directives (AD) after a stay in the ICU. METHODS: The study was conducted from May to July 2016 using telephone interviews performed by four senior ICU physicians. Inclusion criteria were: patients discharged from ICU to home>3 months earlier. Semi-directive interviews with patients focused on 5 main points surrounding AD. RESULTS: In total, among 159 eligible patients, data from 94 (59%) were available for analysis. Among all those interviewed, 83.5% had never heard of "advance directives". Only 2% had executed AD before ICU admission, and 7% expressed a desire to prepare AD further to their ICU stay. Among the barriers to preparation of AD, lack of information was the main reason cited for not executing AD. Patients noted the following in their AD: withdrawal of life-support in case of vegetative/minimally conscious state or when there is no longer any hope, in case of uncontrollable pain, and if impossible to wean from mechanical ventilation. CONCLUSION: The ideal time to engage patients in these discussions is most likely well before an acute health event occurs, although this warrants further investigation both before and after ICU admissions.

Incidence and Predictors of New-Onset Atrial Fibrillation in Septic Shock Patients in a Medical ICU: Data from 7-Day Holter ECG Monitoring.

PURPOSE: We investigated incidence, risk factors for new-onset atrial fibrillation (NAF), and prognostic impact during septic shock in medical Intensive Care Unit (ICU) patients. METHODS: Prospective, observational study in a university hospital. Consecutive patients from 03/2011 to 05/2013 with septic shock were eligible. Exclusion criteria were age <18 years, history of AF, transfer with prior septic shock. Included patients were equipped with long-duration (7 days) Holter ECG monitoring. NAF was defined as an AF episode lasting >30 seconds. Patient characteristics, infection criteria, cardiovascular parameters, severity of illness, support therapies were recorded. RESULTS: Among 66 patients, 29(44%) developed NAF; 10 (34%) would not have been diagnosed without Holter ECG monitoring. NAF patients were older, with more markers of heart failure (troponin and NT-pro-BNP), lower left ventricular ejection fraction (LVEF), longer QRS duration and more nonsustained supra ventricular arrhythmias (<30s) on day 1 than patients who maintained sinus rhythm. By multivariate analysis, age (OR: 1.06; p = 0.01) and LVEF<45% (OR: 13.01, p = 0.03) were associated with NAF. NAF did not predict 28 or 90 day mortality. CONCLUSIONS: NAF is common, especially in older patients, and is associated with low ejection fraction. We did not find NAF to be independently associated with higher mortality.

Very high volume hemofiltration with the Cascade system in septic shock patients.

PURPOSE: We compared hemodynamic and biological effects of the Cascade system, which uses very high volume hemofiltration (HVHF) (120 mL kg(-1) h(-1)), with those of usual care in patients with septic shock. METHODS: Multicenter, prospective, randomized, open-label trial in three intensive care units (ICU). Adults with septic shock with administration of epinephrine/norepinephrine were eligible. Patients were randomized to usual care plus HVHF (Cascade group), or usual care alone (control group). Primary end point was the number of catecholamine-free days up to 28 days after randomization. Secondary end points were number of days free of mechanical ventilation, renal replacement therapy (RRT) or ICU up to 90 days, and 7-, 28-, and 90-day mortality. RESULTS: We included 60 patients (29 Cascade, 31 usual care). Baseline characteristics were comparable. Median number of catecholamine-free days was 22 [IQR 11-23] vs 20 [0-25] for Cascade vs control; there was no significant difference even after adjustment. There was no significant difference in number of mechanical ventilation-free days or ICU requirement. Median number of RRT-free days was 85 [46-90] vs 74 [0-90] for Cascade vs control groups, p = 0.42. By multivariate analysis, the number of RRT-free days was significantly higher in the Cascade group (up to 25 days higher after adjustment). There was no difference in mortality at 7, 28, or 90 days. CONCLUSION: Very HVHF using the Cascade system can safely be used in patients presenting with septic shock, but it was not associated with a reduction in the need for catecholamines during the first 28 days.

Ophthalmic outcomes of congenital toxoplasmosis followed until adolescence.

BACKGROUND: Congenital toxoplasmosis (CT) can elicit severe damage to several organs, especially the eye, and may be manifested at birth or later. We assessed the long-term ocular prognosis in a cohort of congenitally infected children treated according to a standardized protocol and monitored for up to 22 years. METHODS: This prospective study included confirmed cases of CT, which were identified by obligatory antenatal screening at the Lyon (France) reference center between 1987 and 2008. Data obtained through ocular examinations were recorded on a standardized form and confirmed by an independent external committee. Risk factors for retinochoroiditis were identified by using a multivariable Cox model and a flexible model that accounted for changes in the factor effects during follow-up. RESULTS: A total of 477 of 485 infected live-born children were followed for a median of 10.5 years (75th percentile: 15.0 years). During the follow-up, 142 patients (29.8%) manifested at least 1 ocular lesion. Lesions were unilateral in 98 individuals (69.0%) and caused no vision loss in 80.6%. Lesions were first manifested at a median age of 3.1 (0.0-20.7) years. In 48 (33.8%) of the children, recurrences or new ocular lesions occurred up to 12 years after the appearance of the first lesion. Early maternal infection and confirmation of CT in children, prematurity, and nonocular CT lesions at baseline were associated with a higher risk of retinochoroiditis. CONCLUSIONS: Although the consequences of CT are rarely severe in treated children, regular postnatal monitoring is nevertheless justified because of the lifelong persisting risk of new ocular manifestations.