Clinical experience to date with nilotinib in gastrointestinal stromal tumors.

Nilotinib, a novel tyrosine kinase inhibitor (TKI) that inhibits BCR-ABL, the stem cell factor receptor (KIT), and platelet-derived growth factor receptor-alpha (PDGFRα), is approved for the treatment of patients with newly diagnosed Philadelphia chromosome-positive chronic myelogenous leukemia (CML) and those with CML that is imatinib-resistant or -intolerant. Due to its potent inhibition of KIT and PDGFRα--the two tyrosine kinases that are the central oncogenic mechanisms of gastrointestinal stromal tumors (GIST)--nilotinib also has been investigated for potential efficacy and safety in patients with GIST who have progressed on other approved treatments. Initial results have been encouraging, as nilotinib has demonstrated clinical efficacy and safety in a phase I trial as either a single agent or in combination with imatinib, as well as in heavily pretreated patients with GIST in a compassionate use program. In addition, the phase III trial of nilotinib versus best supportive care (with or without a TKI at the investigator's discretion) indicated that nilotinib may have efficacy in some third-line patients. Furthermore, the Evaluating Nilotinib Efficacy and Safety in Clinical Trials (ENEST g1 trial), a phase III randomized, open-label study comparing the safety and efficacy of imatinib versus nilotinib in the first-line treatment of patients with GIST, is currently under way. Other studies with nilotinib either have been initiated or are in development. Based on published and accruing clinical data, nilotinib shows potential as a new drug in the clinician's armamentarium for the management of GIST.

Primary localized rectal/pararectal gastrointestinal stromal tumors: results of surgical and multimodal therapy from the French Sarcoma group.

BACKGROUND: Rectal and pararectal gastrointestinal stromal tumors (GISTs) are rare. The optimal management strategy for primary localized GISTs remains poorly defined. METHODS: We conducted a retrospective analysis of 41 patients with localized rectal or pararectal GISTs treated between 1991 and 2011 in 13 French Sarcoma Group centers. RESULTS: Of 12 patients who received preoperative imatinib therapy for a median duration of 7 (2-12) months, 8 experienced a partial response, 3 had stable disease, and 1 had a complete response. Thirty and 11 patients underwent function-sparing conservative surgery and abdominoperineal resection, respectively. Tumor resections were mostly R0 and R1 in 35 patients. Tumor rupture occurred in 12 patients. Eleven patients received postoperative imatinib with a median follow-up of 59 (2.4-186) months. The median time to disease relapse was 36 (9.8-62) months. The 5-year overall survival rate was 86.5%. Twenty patients developed local recurrence after surgery alone, two developed recurrence after resection combined with preoperative and/or postoperative imatinib, and eight developed metastases. In univariate analysis, the mitotic index (≤5) and tumor size (≤5 cm) were associated with a significantly decreased risk of local relapse. Perioperative imatinib was associated with a significantly reduced risk of overall relapse and local relapse. CONCLUSIONS: Perioperative imatinib therapy was associated with improved disease-free survival. Preoperative imatinib was effective. Tumor shrinkage has a clear benefit for local excision in terms of feasibility and function preservation. Given the complexity of rectal GISTs, referral of patients with this rare disease to expert centers to undergo a multidisciplinary approach is recommended.

Which subgroup of patients with rheumatoid arthritis benefits from switching to rituximab versus alternative anti-tumour necrosis factor (TNF) agents after previous failure of an anti-TNF agent?

BACKGROUND: Patients with rheumatoid arthritis (RA) with an inadequate response to TNF antagonists (aTNFs) may switch to an alternative aTNF or start treatment from a different class of drugs, such as rituximab (RTX). It remains unclear in which clinical settings these therapeutic strategies offer most benefit. OBJECTIVE: To analyse the effectiveness of RTX versus alternative aTNFs on RA disease activity in different subgroups of patients. METHODS: A prospective cohort study of patients with RA who discontinued at least one aTNF and subsequently received either RTX or an alternative aTNF, nested within the Swiss RA registry (SCQM-RA) was carried out. The primary outcome, longitudinal improvement in 28-joint count Disease Activity Score (DAS28), was analysed using multivariate regression models for longitudinal data and adjusted for potential confounders. RESULTS: Of the 318 patients with RA included; 155 received RTX and 163 received an alternative aTNF. The relative benefit of RTX varied with the type of prior aTNF failure: when the motive for switching was ineffectiveness to previous aTNFs, the longitudinal improvement in DAS28 was significantly better with RTX than with an alternative aTNF (p = 0.03; at 6 months, -1.34 (95% CI -1.54 to -1.15) vs -0.93 (95% CI -1.28 to -0.59), respectively). When the motive for switching was other causes, the longitudinal improvement in DAS28 was similar for RTX and alternative aTNFs (p = 0.40). These results were not significantly modified by the number of previous aTNF failures, the type of aTNF switches, or the presence of co-treatment with a disease-modifying antirheumatic drug. CONCLUSION: This observational study suggests that in patients with RA who have stopped a previous aTNF treatment because of ineffectiveness changing to RTX is more effective than switching to an alternative aTNF.

Outcome of Patients with Platelet-Derived Growth Factor Receptor Alpha-Mutated Gastrointestinal Stromal Tumors in the Tyrosine Kinase Inhibitor Era.

PURPOSE: Platelet-derived growth factor receptor-alpha (PDGFRA) mutations are found in approximately 5% to 7% of advanced gastrointestinal stromal tumors (GIST). We sought to extensively assess the activity of imatinib in this subgroup. EXPERIMENTAL DESIGN: We conducted an international survey among GIST referral centers to collect clinical data on patients with advanced PDGFRA-mutant GISTs treated with imatinib for advanced disease. RESULTS: Fifty-eight patients were included, 34 were male (59%), and median age at treatment initiation was 61 (range, 19-83) years. The primary tumor was gastric in 40 cases (69%). Thirty-two patients (55%) had PDGFRA-D842V substitutions whereas 17 (29%) had mutations affecting other codons of exon 18, and nine patients (16%) had mutation in other exons. Fifty-seven patients were evaluable for response, two (4%) had a complete response, eight (14%) had a partial response, and 23 (40%) had stable disease. None of 31 evaluable patients with D842V substitution had a response, whereas 21 of 31 (68%) had progression as their best response. Median progression-free survival was 2.8 [95% confidence interval (CI), 2.6-3.2] months for patients with D842V substitution and 28.5 months (95% CI, 5.4-51.6) for patients with other PDGFRA mutations. With 46 months of follow-up, median overall survival was 14.7 months for patients with D842V substitutions and was not reached for patients with non-D842V mutations. CONCLUSIONS: This study is the largest reported to date on patients with advanced PDGFRA-mutant GISTs treated with imatinib. Our data confirm that imatinib has little efficacy in the subgroup of patients with D842V substitution in exon 18, whereas other mutations appear to be sensitive to imatinib. Clin Cancer Res; 18(16); 4458-64. ©2012 AACR.

Seizures after single-agent overdose with pharmaceutical drugs: Analysis of cases reported to a poison center.

Abstract Context. Seizures during intoxications with pharmaceuticals are a well-known complication. However, only a few studies report on drugs commonly involved and calculate the seizure potential of these drugs. Objectives. To identify the pharmaceutical drugs most commonly associated with seizures after single-agent overdose, the seizure potential of these pharmaceuticals, the age-distribution of the cases with seizures and the ingested doses. Methods. A retrospective review of acute single-agent exposures to pharmaceuticals reported to the Swiss Toxicological Information Centre (STIC) between January 1997 and December 2010 was conducted. Exposures which resulted in at least one seizure were identified. The seizure potential of a pharmaceutical was calculated by dividing the number of cases with seizures by the number of all cases recorded with that pharmaceutical. Data were analyzed using descriptive statistics. Results. We identified 15,441 single-agent exposures. Seizures occurred in 313 cases. The most prevalent pharmaceuticals were mefenamic acid (51 of the 313 cases), citalopram (34), trimipramine (27), venlafaxine (23), tramadol (15), diphenhydramine (14), amitriptyline (12), carbamazepine (11), maprotiline (10), and quetiapine (10). Antidepressants were involved in 136 cases. Drugs with a high seizure potential were bupropion (31.6%, seizures in 6 of 19 cases, 95% CI: 15.4-50.0%), maprotiline (17.5%, 10/57, 95% CI: 9.8-29.4%), venlafaxine (13.7%, 23/168, 95% CI: 9.3-19.7%), citalopram (13.1%, 34/259, 95% CI: 9.5-17.8%), and mefenamic acid (10.9%, 51/470, 95% CI: 8.4-14.0%). In adolescents (15-19y/o) 23.9% (95% CI: 17.6-31.7%) of the cases involving mefenamic acid resulted in seizures, but only 5.7% (95% CI: 3.3-9.7%) in adults (≥ 20y/o; p < 0.001). For citalopram these numbers were 22.0% (95% CI: 12.8-35.2%) and 10.9% (95% CI: 7.1-16.4%), respectively (p = 0.058). The probability of seizures with mefenamic acid, citalopram, trimipramine, and venlafaxine increased as the ingested dose increased. Conclusions. Antidepressants were frequently associated with seizures in overdose, but other pharmaceuticals, as mefenamic acid, were also associated with seizures in a considerable number of cases. Bupropion was the pharmaceutical with the highest seizure potential even if overdose with bupropion was uncommon in our sample. Adolescents might be more susceptible to seizures after mefenamic acid overdose than adults. "Part of this work is already published as a conference abstract for the XXXIV International Congress of the European Association of Poisons Centres and Clinical Toxicologists (EAPCCT) 27-30 May 2014, Brussels, Belgium." Abstract 8, Clin Toxicol 2014;52(4):298.

Oral insecticidal activity of root colonizing Pseudomonas fluorescens CHA0: a biocontrol agent with potential to control plant pests and diseases

The application of microbial biocontrol agents for the control of fungal plant diseases and plant insect pests is a promising approach in the development of environmentally benign pest management strategies. The ideal biocontrol organism would be a bacterium or a fungus with activity against both, insect pests and fungal pathogens. Here we demonstrate the oral insecticidal activity of the root colonizing Pseudomonas fluorescens CHA0, which is so far known for its capacity to efficiently suppress fungal plant pathogens. Feeding assays with CHA0-sprayed leaves showed that this strain displays oral insecticidal activity and is able to efficiently kill larvae of three important insect pests. We further show data indicating that the Fit insect toxin produced by CHA0 and also metabolites controlled by the global regulator GacA contribute to oral insect toxicity.

Circulating microRNAs as long-term biomarkers for the detection of erythropoiesis-stimulating agent abuse.

MicroRNAs (miRNAs) are small, non-protein coding transcripts involved in many cellular and physiological mechanisms. Recently, a new class of miRNA called 'circulating miRNAs' was found in cell-free body fluids such as plasma and urine. Circulating miRNAs have been shown to be very stable, specific, and sensitive biomarkers. In this paper, we investigate whether circulating miRNAs can serve as biomarkers for erythropoiesis-stimulating agent abuse. To this end, we analyzed miRNA levels in plasma by miRNA microarrays and quantitative real-time polymerase chain reaction (PCR). Plasma samples are derived from a clinical study with healthy subjects injected with erythropoiesis-stimulating agent (C.E.R.A.). Based on microarray results, we observed a significant difference in the levels of miRNAs in plasma after C.E.R.A. injection. We demonstrated that a specific miRNA, miR-144, exhibit a high increase that lasts 27 days after C.E.R.A. stimulation. Considering the fact that miR-144 is an essential erythropoiesis agent in different organisms, these findings suggest the possibility of using miR-144 as a sensitive and informative biomarker to detect C.E.R.A. abuse. Copyright © 2011 John Wiley & Sons, Ltd.

Patients' preferences on information and involvement in decision-making for gastrointestinal surgery

Objective: The relationship between physicians and patients has undergone¦important changes, and the current emancipation of patients has led to¦a real partnership in medical decision-making. This study aimed to assess¦patients' preferences on different aspects of decision-making during treatment¦and potential complications, as well as the amount and type of preoperative¦information before visceral surgery.¦Methods: Prospective non-randomized study based on a questionnaire given¦to 253 consecutive patients scheduled for elective GI surgery.¦Results: Concerning surgical complications or treatment in the intensive care¦unit, 64% of patients wished to take actively part in any medical decisions.¦The respective figures for cardiac resuscitation and treatment limitations were¦89% and 60%. About information, 73%, 77% and 47% of patients wish¦detailed information, information on a potential ICUhospitalization and cardiac¦resuscitation, respectively. Elderly and low-educated patients were significantly¦less interested in shared medical decision-making (p = 0·003 and 0·015) and in¦information receiving (p = 0·03 and 0·05). Similarly, involvement of the family¦in decision-making was significantly less important in elderly and male patients¦(p = 0·05 and 0·03 respectively). Neither the type of operation (minor or major)¦nor the severity of disease (malignancies vs. non-malignancies) was a significant¦factor for shared decision-making, information or family involvement.¦Conclusion: The vast majority of surgical patients clearly want to get adequate¦preoperative information about their disease and the planned treatment. They¦also consider it as crucial to be involved in any kind of decision-making for¦treatment and complications. The family's role is limited to support the treating¦physicians if the patient is unable to participate in taking decisions.

Artificial Snow Optimization in Winter Sport Destinations Using a Multi-agent Simulation

This paper presents the Juste-Neige system for predicting the snow height on the ski runs of a resort using a multi-agent simulation software. Its aim is to facilitate snow cover management in order to i) reduce the production cost of artificial snow and to improve the profit margin for the companies managing the ski resorts; and ii) to reduce the water and energy consumption, and thus to reduce the environmental impact, by producing only the snow needed for a good skiing experience. The software provides maps with the predicted snow heights for up to 13 days. On these maps, the areas most exposed to snow erosion are highlighted. The software proceeds in three steps: i) interpolation of snow height measurements with a neural network; ii) local meteorological forecasts for every ski resort; iii) simulation of the impact caused by skiers using a multi-agent system. The software has been evaluated in the Swiss ski resort of Verbier and provides useful predictions.

Female-biased infection and transmission of the gastrointestinal nematode Trichuris arvicolae infecting the common vole, Microtus arvalis.

Previous studies addressing the importance of host gender in parasite transmission have shed light on males as the more important hosts, with the higher transmission potential of males being explained by the fact that they often harbour higher parasite loads than females. However, in some systems females are more heavily infected than males and may be responsible for driving infection under such circumstances. Using a wild population of common voles (Microtus arvalis), we showed that females were more frequently infected by the intestinal nematode Trichuris arvicolae than males (i.e. prevalence based on the presence of eggs in the faeces) and that females were shedding greater numbers of parasite eggs per gram of faeces (EPG) than males. By applying an anthelmintic treatment to either male or female voles, we demonstrated that treating females significantly reduced parasite burdens (i.e. prevalence and EPG) of both male and female hosts, while treating males only reduced parasite burden in males. These findings indicate that in this female-biased infection system females play a more important role than males in driving the dynamics of parasite transmission.

Treatment of gastrointestinal stromal tumor after imatinib and sunitinib.

Purpose of review Tyrosine kinase inhibitors (TKIs), such as imatinib and sunitinib, have changed the outcome of patients with gastrointestinal stromal tumor (GIST) and prolonged survival by many-fold. Unfortunately, treatment failure and tumor progression seem inevitable over time and constitute an unresolved clinical challenge. This article reviews current efforts to overcome drug resistance and progression. Recent findings The major mechanism of resistance toward imatinib and sunitinib is the development of secondary resistance mutations in the kinase domain of KIT. Recent efforts aim at inhibitors with increased activity against resistance mutations or a broader spectrum of activity. Other strategies include indirect KIT inhibition by modulating KIT chaperone proteins or inhibition of KIT-dependent and independent signaling pathways. Summary dThe rapid improvement of our understanding of GIST biology as well as resistance mechanisms towards imatinib and sunitinib will greatly facilitate the development of novel treatment strategies. This article summarizes the results of recently reported third and fourth-line clinical trials in patients with resistant GIST and reviews data of important proof-of-concept studies.