Hotspot DAXX, PTCH2 and CYFIP2 mutations in pancreatic neuroendocrine neoplasms.

Mutations in DAXX/ATRX, MEN1 and genes involved in the phosphoinositide-3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway have been implicated in pancreatic neuroendocrine neoplasms (pNENs). However, mainly mutations present in the majority of tumor cells have been identified, while proliferation-driving mutations could be present only in small fractions of the tumor. This study aims to identify high- and low-abundance mutations in pNENs using ultra-deep targeted resequencing. Formalin-fixed paraffin-embedded matched tumor-normal tissue of 38 well-differentiated pNENs was sequenced using a HaloPlex targeted resequencing panel. Novel amplicon-based algorithms were used to identify both single nucleotide variants (SNVs) and insertion-deletions (indels) present in >10% of reads (high abundance) and in <10% of reads (low abundance). Found variants were validated by Sanger sequencing. Sequencing resulted in 416,711,794 reads with an average target base coverage of 2663 ± 1476. Across all samples, 32 high-abundance somatic, 3 germline and 30 low-abundance mutations were withheld after filtering and validation. Overall, 92% of high-abundance and 84% of low-abundance mutations were predicted to be protein damaging. Frequently, mutated genes were MEN1, DAXX, ATRX, TSC2, PI3K/Akt/mTOR and MAPK-ERK pathway-related genes. Additionally, recurrent alterations on the same genomic position, so-called hotspot mutations, were found in DAXX, PTCH2 and CYFIP2. This first ultra-deep sequencing study highlighted genetic intra-tumor heterogeneity in pNEN, by the presence of low-abundance mutations. The importance of the ATRX/DAXX pathway was confirmed by the first-ever pNEN-specific protein-damaging hotspot mutation in DAXX. In this study, both novel genes, including the pro-apoptotic CYFIP2 gene and hedgehog signaling PTCH2, and novel pathways, such as the MAPK-ERK pathway, were implicated in pNEN.

[Adverse drug reactions in children: 10 years of pharmacovigilance]. / Effets indésirables médicamenteux chez l'enfant : 10ans de pharmacovigilance.

BACKGROUND: Knowledge of drug tolerance and safety in children is limited. The study of spontaneous notifications of adverse events (AEs) can be an important source of information. OBJECTIVE: Describe the characteristics of drug adverse effects (DAEs) in children 0-17 years of age reported to the pharmacovigilance center of Saint-Étienne in 2004-2013. METHODS: This retrospective descriptive study was conducted based on DAE notifications, classified according to age, sex, severity of organ affected (using classification by the System organ class [SOC]) and by suspected drug (Anatomical therapeutic chemical [ATC] drugs). RESULTS: A total of 371 notifications were analyzed. The male:female ratio was 1. Serious cases accounted for 36%, of which 73% resulted in hospitalization or prolongation of hospitalization. The most frequent DAEs were cutaneous (21.1%), infection (13.5%) and general (11.5%). The most frequently involved therapeutic classes were anti-infectives for systemic use (38.7%), mainly vaccines and antibiotics, as well as antineoplastic and immunomodulatory therapy (19.2%) and drugs acting on the nervous system (12.5%). CONCLUSIONS: The analysis of notifications of adverse drug reactions is an important source of information and is underutilized in pediatrics. The data from this study confirm those of European databases with spontaneous reporting. The majority of anti-infectives including antibiotics raises the question of the proper use of this class in this population. Larger studies focused on the drugs at risk would improve the knowledge and safe use of medicines in children.

The PREGVAXGRIP study: a cohort study to assess foetal and neonatal consequences of in utero exposure to vaccination against A(H1N1)v2009 influenza.

BACKGROUND: In October 2009, in the context of an A(H1N1)v2009 influenza pandemic, a vaccination campaign was launched in France, in which one of the priority groups was pregnant women, on account of the high risk of developing complications following infection by this virus. OBJECTIVE: The aim of this multicentric, prospective, observational study was to assess safety and pregnancy outcomes in a cohort of pregnant women when receiving the A(H1N1)v2009 influenza pandemic vaccine. METHODS: This was a prospective study that followed up pregnant women recruited mainly in vaccination centres and maternity departments. Following the expected delivery date, follow-up data were collected concerning the delivery, the infant, and, if appropriate, the reasons why the pregnancy did not reach its term. RESULTS: Between 1 November 2009 and 31 March 2010, 2,415 pregnant women were included at the time of vaccination; 97.6 % of women received a vaccine without adjuvant and 2.4 % received an adjuvanted vaccine. Ninety-two (3.9 %) women were vaccinated during the first trimester of pregnancy, 1,090 (46.5 %) during the second trimester, and 1,162 (49.6 %) during the third trimester. One hundred and thirty-three adverse events (5.5 % of women) were reported, of which 12 were unexpected or serious. There were 2,246 (93.0 %) known pregnancy outcomes with 12 spontaneous abortions (0.5 %), 6 stillbirths (0.3 %), and 4 therapeutic abortions (0.2 %). There were 65 neonates with congenital anomalies, among which 31 were major. But only one congenital malformation (1.4 %) was reported for the 92 women vaccinated in their first trimester. Of the women, 93.3 % were delivered full term and 6.7 % preterm. For 96 (4.2 %) neonates, a disorder was reported in the neonatal period and 130 (5.6 %) were transferred to the neonatology department. CONCLUSIONS: This study suggests that exposure to the A(H1N1)v2009 pandemic influenza vaccine during pregnancy does not increase the risk of adverse pregnancy outcomes. However, because of the relatively small number of women exposed during the first trimester, other studies are needed to exclude an increased risk of malformation.

Antipsychotics: a real or confounding risk factor for venous thromboembolism?

In a meta-analysis of case-control studies, Zhang et al. (2011) found an increased risk of venous thromboembolic events (VTE) in patients exposed to antipsychotics (OR=2.39 [1.71-3.35]). Our updated meta-analysis including the 2 available cohort studies, recognized as a more relevant type of observational study, showed a weaker, but still strong association (OR=1.84 [1.39; 2.44]). In view of the lack of data on the confirmed risk factors for VTE in existing studies, prospective studies including adjustment for these risk factors are warranted to confirm this association and to assess the benefit/risk ratio of antipsychotics in high-risk patients.

[Skin toxicity related to Percutalgine(®): analysis of the French pharmacovigilance database]. / Toxicité cutanée liée à la Percutalgine(®) : analyse de la base nationale de pharmacovigilance.

BACKGROUND: Percutalgine(®) (dexamethasone acetate, salicylamide and hydroxyethyl salicylate) is a topical drug marketed for treatment of benign joint conditions such as mild tendinitis, small joint arthritis and sprains. The aim of the study was to describe the cutaneous side effects of Percutalgine(®) in terms of clinical signs, seriousness and causal relationship of the different components. METHODS: We extracted from the French Pharmacovigilance database all cases of adverse skin reactions occurring after application of Percutalgine(®) and reported for the period between 1st January 2000 and 31st October 2010. The only files selected were those in which Percutalgine(®) was the sole suspected drug and/or allergological tests were positive for Percutalgine(®) or its components. RESULTS: Fifty-three cases were ultimately retained and analysed. The main cutaneous side effect of Percutalgine(®) (n=41) was contact dermatitis with secondary extension in 15 cases. Onset was immediate in 12 cases, delayed in 32 cases and unspecified in eight cases. Twelve patients were hospitalized for inefficiency of the symptomatic treatment, extended lesions or generalized associated signs. Allergological tests were described in 14 cases and were positive for Percutalgine(®) (eight cases), hydroxyethyl salicylate (seven cases), salicylamide (six cases), dexamethasone (three cases), and propylene glycol (two cases). CONCLUSION: Cutaneous side effects with Percutalgine(®) appear to be rare or infrequently reported. They consist chiefly of contact allergy. The component responsible for the reaction can be determined using allergological patch tests.

[Dextropropoxyphene hepatotoxicity: four cases and literature review]. / Dextropropoxyphène et atteintes hépatiques: à propos de 4 cas et revue de littérature.

We report 4 cases of hepatic injury in patients treated with a dextropropoxyphene-paracetamol combination in which the causal relationship with dextropropoxyphene can be suspected. These four cases show similarities with the 29 cases found in international publications. Hepatotoxicity occurs more frequently among old patients and women. Clinically, this condition can mimic a biliary tract disease with sometimes few or no symptoms. Biochemical criteria can show cholestatic, mixed or cytolytic hepatitis. Intrahepatic cholestasis may be found in liver biopsies sometimes suggesting cholangitis. Outcome is favourable on withdrawal of the drug. The mechanism of action of dextropropoxyphene is discussed.

[Drug-induced taste disorders: analysis of the French Pharmacovigilance Database and literature review]. / Troubles du goût d'origine médicamenteuse: analyse de la Banque Nationale de Pharmacovigilance et revue de la littérature.

Taste disorders, generally poorly studied, have various causes. From 1985 to 1997, 305 observations of taste disorders imputed to drugs were notified to Regional Pharmacovigilance Centres. Patients were on average 54.4 years old and 58 per cent were women. Quantitative as well as qualitative disorders have been observed. Drugs mainly found were: angiotensin converting enzyme inhibitors, terbinafine, zopiclone, D-penicillamine, imidazole derivatives, quinolones, macrolides, carbimazole and calcium channel blockers. The outcome was favourable for 60.3 per cent of patients. The possible efficacy of zinc is discussed. It is generally considered that taste disorders are not a serious side-effect, but they can reduce the quality of life and lead to poor compliance with treatment.

[Hemorrhagic syndromes related to selective serotonin reuptake inhibitor (SSRI) antidepressants. Seven case reports and review of the literature]. / Syndromes hémorragiques sous antidépresseurs inhibiteurs sélectifs de la recapture de la sérotonine (ISRS). A propos de sept cas et revue de la littérature.

PURPOSE: Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed. Since their release unexpected adverse effects such as bleeding disorders have been described. METHODS: Thirty patients with either hematoma or muco-cutaneous bleeding have been selected from case reports of the Saint-Etienne Pharmacovigilance center and from a literature review. RESULTS: The female/male sex-ratio was 3:4 and the mean age 42 years. Two newborns who had been exposed in utero to SSRIs were also included in the study. Eleven patients presented an underlying disease or were at risk. Various adverse effects such as bruising, hematoma, petechiae or purpura, epistaxis, and more rarely intestinal hemorrhage, ocular bleeding or cerebral hemorrhage were encountered. Symptoms were sometimes associated with prolonged bleeding time and platelet aggregation disorders and usually resolved within two days to four months after treatment discontinuation. CONCLUSION: Hematoma and muco-cutaneous bleeding would therefore be related to treatment, including selective serotonin reuptake inhibitors. However, these adverse effects are still poorly known and rarely reported. The main mechanism suggested would be a decrease in serotonin platelet leading to a defect in platelet aggregation. However, an increase in capillary fragility or susceptibility related to the patient's condition might be involved. Study of hemostasis history in patients requiring treatment with SSRIs might be of value.

[Delayed drug-induced hepatic injury. Evoking the role of amoxicillin-clavulinic acid combination]. / Hépatite médicamenteuse d'apparition retardée. Evoquer le rôle de l'association amoxicilline-acide clavulanique.

Although infrequent, hepatitis associated with amoxicillin and clavulanic acid combination is probably underestimated. Except for cases with few symptoms, a time interval between stopping treatment and the first manifestations (jaundice in most cases), sometimes of several weeks, may hinder diagnosis. We report 9 patients who exhibited this characteristic. The delay between stopping treatment and the onset of hepatitis varied from 13 days to 6 weeks after stopping the drug. Other causes of jaundice were excluded. Male sex, advancing age, or prolonged treatment (more than 10 days) may increase the risk. Complete recovery occurs within 1 to 4 months after discontinuation of treatment. The mechanism is unclear. Clinical and biological signs of hypersensitivity may suggest an immunoallergic reaction.

[Drug prescription for pregnant women in the department of the Loire] . / Prescription médicamenteuse chez la femme enceinte dans le département de la Loire.

A prospective drug prescription and descriptive study was undertaken in a sample of 214 pregnant women in the department of the Loire. This population was randomized using pregnancy declaration files from the French Health Care Centre. Data recording was retrospective. A total of 2064 drugs have been prescribed; 90 per cent of women received at least one drug during the course of pregnancy with an average of 11.5 drugs per woman. Antispasmodics are mainly prescribed in the first trimester while vitamins, mineral supplements, antianemics and vasoactive agents are found in the third trimester. Prescriptions do not rise with age but increase in urban areas. Use of PDD/DDD (Prescribed Daily Dose/Defined Daily Dose) is an estimation of prescription customs. For ketoprofen, it is 1.6 in the last trimester, although this drug is contra-indicated.

[Adverse effects of quinine in the treatment of leg cramps]. / Effets indésirables de la quinine dans l'indication de crampes musculaires.

In France, three over-the-counter products containing quinine exist to treat cramps. This study aims to analyse data on spontaneous reports to the French System of Pharmacovigilance of adverse reactions to quinine drug products. From 1985 to 1996, we reviewed 58 adverse reaction reports. Most involved hypersensitivity reactions: rash, pruritus, generalized anaphylaxis, thrombopenia and hepatitis. Cinchonism is rarely observed at the usually low dose of quinine in this indication. No fatal outcome has been notified as described in the USA and Australia. The Food and Drug Administration (FDA) decided that prescription of quinine drug products should not be used any longer in the treatment of muscle cramps. Immuno-allergic reactions are potentially serious and must be avoided by giving clear information to patients and prescribers, and looking into the history of such reactions in patients in respect of the quinine drug and also tonic water.

Is lumbar epidural analgesia an alternative in patients who have incomplete colonoscopy with standard premedication?

Total colonoscopy is unsuccessful in about 10% of attempts. In three fourths of the cases, failure is due to the patient's inability to tolerate the procedure and difficulty in negotiating the sigmoid colon. Lumbar epidural analgesia has been used in a series of 29 patients referred for total colonoscopy which had been unsuccessful using intravenous analgesia. The cecum was reached in 27 of 29 examinations. Mean time required to perform total colonoscopy was 10 min and took less than 5 min in one third of the cases. Complete visceral analgesia was responsible for one case of perforation.

The use of peritoneoscopy in the detection of liver metastases.

Peritoneoscopy was carried out in 352 cancer patients with clinical suspicion of liver involvement in most cases. Principally because of patient discomfort, adequate liver biopsy was obtained in only 66% of 240 patients who underwent peritoneoscopy under local anesthesia while, under general anesthesia, biopsies could be taken in 90% of 112 patients. When the liver was macroscopically free of disease, the yield of positive peritoneoscopy was minimal regardless of the number of blind deep biopsies. Peritoneoscopy provided histologic demonstration of hepatic invasion in a total of 55 patients. Seven false-negative examinations out of 19 negative peritoneoscopies (36%) were identified by subsequent laparotomy or autopsy within 2 months. These preliminary data, although difficult to interpret in terms of accuracy of the method, point to the possible contributions of peritoneoscopy in detecting liver metastases.