Role of Deficient DNA Mismatch Repair Status in Patients With Stage III Colon Cancer Treated With FOLFOX Adjuvant Chemotherapy: A Pooled Analysis From 2 Randomized Clinical Trials.

IMPORTANCE: The prognostic impact of DNA mismatch repair (MMR) status in stage III colon cancer patients receiving FOLFOX (folinic acid, fluorouracil, and oxaliplatin) adjuvant chemotherapy remains controversial. OBJECTIVE: To determine the association of MMR status with disease-free survival (DFS) in patients with stage III colon cancer treated with FOLFOX. DESIGN, SETTING, AND PARTICIPANTS: The evaluated biomarkers for MMR status were determined from prospectively collected tumor blocks from patients treated with FOLFOX in 2 open-label, phase 3 randomized clinical trials: NCCTG N0147 and PETACC8. The studies were conducted in general community practices, private practices, and institutional practices in the United States and Europe. All participants had stage III colon adenocarcinoma. They were enrolled in NCCTG N0147 from February 2004 to November 2009 and in PETACC8 from December 2005 to November 2009. INTERVENTIONS: Patients in the clinical trials were randomly assigned to receive 6 months of chemotherapy with FOLFOX or FOLFOX plus cetuximab. Only those patients treated with FOLFOX alone were included in the present study. MAIN OUTCOMES AND MEASURES: Association of MMR status with DFS was analyzed using a stratified Cox proportional hazards model. Multivariable models were adjusted for age, sex, tumor grade, pT/pN stage, tumor location, ECOG (Eastern Cooperative Oncology Group) performance status, and BRAF V600E mutational status. RESULTS: Among 2636 patients with stage III colon cancer treated with FOLFOX, MMR status was available for 2501. Of these, 252 (10.1%) showed deficient MMR status (dMMR; 134 women, 118 men; median age, 59 years), while 2249 (89.9%) showed proficient MMR status (pMMR; 1020 women, 1229 men; median age, 59 years). The 3-year DFS rates in the dMMR and pMMR groups were 75.6% and 74.4%, respectively. By multivariate analysis, patients with dMMR phenotype had significantly longer DFS than those with pMMR (adjusted hazard ratio, 0.73; 95% CI, 0.54-0.97; P = .03). CONCLUSIONS AND RELEVANCE: The deficient MMR phenotype remains a favorable prognostic factor in patients with stage III colon cancer receiving FOLFOX adjuvant chemotherapy. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00079274 for the NCCTG N0147 trial and EudraCT identifier: 2005-003463-23 for the PETACC8 trial.

Comparison of the Non-VKA Oral Anticoagulants Apixaban, Dabigatran, and Rivaroxaban in the Extended Treatment and Prevention of Venous Thromboembolism: Systematic Review and Network Meta-Analysis.

BACKGROUND: Historically, warfarin or aspirin have been the recommended therapeutic options for the extended treatment (>3 months) of VTE. Data from Phase III randomised controlled trials (RCTs) are now available for non-VKA oral anticoagulants (NOACs) in this indication. The current systematic review and network meta-analysis (NMA) were conducted to compare the efficacy and safety of anticoagulants for the extended treatment of VTE. METHODS: Electronic databases (accessed July 2014 and updated April 2016) were systematically searched to identify RCTs evaluating apixaban, aspirin, dabigatran, edoxaban, rivaroxaban, and warfarin for the extended treatment of VTE. Eligible studies included adults with an objectively confirmed deep vein thrombosis, pulmonary embolism or both. A fixed-effect Bayesian NMA was conducted, and results were presented as relative risks (RRs). Sensitivity analyses examining (i) the dataset employed according to the time frame for outcome assessment (ii) the model used for the NMA were conducted. RESULTS: Eleven Phase III RCTs (examining apixaban, aspirin, dabigatran, rivaroxaban, warfarin and placebo) were included. The risk of the composite efficacy outcome (VTE and VTE-related death) was statistically significantly lower with the NOACs and warfarin INR 2.0-3.0 compared with aspirin, with no significant differences between the NOACs. Treatment with apixaban (RR 0.23, 95% CrI 0.10, 0.55) or dabigatran (RR 0.55, 95% Crl 0.43, 0.71) was associated with a statistically significantly reduced risk of 'major or clinically relevant non-major bleed' compared with warfarin INR 2.0-3.0. Apixaban also showed a significantly reduced risk compared with dabigatran (RR 0.42, 95% Crl 0.18, 0.97) and rivaroxaban (RR 0.23, 95% Crl 0.09, 0.59). Sensitivity analyses indicate that results were dependent on the dataset, but not on the type of NMA model employed. CONCLUSIONS: Results from the NMA indicate that NOACs are an effective treatment for prevention of VTE or VTE-related death) in the extended treatment setting. However, bleeding risk differs between potential treatments, with apixaban reporting the most favourable profile compared with other NOACs, warfarin INR 2.0-3.0, and aspirin.

Bivariate evaluation of thromboembolism and bleeding in clinical trials of anticoagulants in patients with atrial fibrillation.

Clinical trials of antithrombotic therapy require a cohesive assessment of benefit and risk. A new graphical method to represent the bivariate relation of benefit and risk in trials of antithrombotic drugs is described and illustrated using published data from the four major registration clinical trials of non-vitamin K oral anticoagulants (NOACs) totalling 71,683 patients for prevention of thromboembolic events (TE) in patients with atrial fibrillation (RE-LY, ROCKET AF, ARISTOTLE, and ENGAGE-AF TIMI48). A curve representing a null hypothesis defines a region of benefit on a two-dimensional plane. Trial results are summarised by a rectangle defined by standard 95 % confidence intervals (CI) for thrombosis and bleeding risks. Benefit is judged by whether the confidence rectangle contains the null curve. The treatment effect is measured by the distance from the null curve to the opposing corners of the confidence rectangle (termed "corner distance (CD)"). Across trials NOACs reduced the absolute risk of TE compared to warfarin by 0.30 % (95 % CI: -0.56 % to -0.05 %) and reduced major bleeding by 0.88 % (95 % CI: -1.26 % to -0.51 %). Bivariate evaluation showed NOAC superiority to warfarin overall and elucidated dose differences; low dose edoxaban increased bivariate TE-bleeding risk 0.08 % (CD = -0.85 % to 0.78 %), whereas high dose edoxaban reduced risk 1.41 % (CD = -2.07 % to -0.70 %). In conclusion, bivariate evaluation facilitates visual assessment of the safety-efficacy profile of antithrombotic drugs. Its application to trials in atrial fibrillation found NOACs superior to warfarin without substantial differences between agents.

[Radically resected pancreatic cancer and adjuvant treatment. A review of the literature]. / Carcinoma del pancreas resecato radicalmente e terapia adiuvante. Revisione della letteratura.

Adjuvant therapy represents the gold standard treatment for radically resected pancreatic cancer. Results from randomized clinical trials confirmed the efficacy of adjuvant therapy for pancreatic cancer but did not define what is the "right choice" in terms of type of antiblastic drug (among gemcitabine, 5-fluorouracil or other drugs), role of polychemotherapy and chemoradiotherapy. The objective of our study was to evaluate the efficacy and toxicity of adjuvant chemotherapy and chemoradiotherapy for radically resected pancreatic cancer through a systematic review of literature data, emphasizing the benefits regarding overall survival, disease-free survival and toxicity.

Model-based drug development in oncology: what's next?

Model-based estimates of tumor growth inhibition (TGI) metrics have the potential to enhance learning in early (phase II) clinical studies. They can be used as end points and biomarkers to predict treatment effect on clinical outcome measures-e.g., overall survival (OS)-and support phase II study design, end-of-phase II decisions, and phase III planning and execution. Efforts should be made to assess models in simulating independent studies with treatments of varying mechanisms of action.

Estimation of renal cell carcinoma treatment effects from disease progression modeling.

To improve future drug development efficiency in renal cell carcinoma (RCC), a disease-progression model was developed with longitudinal tumor size data from a phase III trial of sorafenib in RCC. The best-fit model was externally evaluated on 145 placebo-treated patients in a phase III trial of pazopanib; the model incorporated baseline tumor size, a linear disease-progression component, and an exponential drug effect (DE) parameter. With the model-estimated effect of sorafenib on RCC growth, we calculated the power of randomized phase II trials between sorafenib and hypothetical comparators over a range of effects. A hypothetical comparator with 80% greater DE than sorafenib would have 82% power (one-sided α = 0.1) with 50 patients per arm. Model-based quantitation of treatment effect with computed tomography (CT) imaging offers a scaffold on which to develop new, more efficient, phase II trial end points and analytic strategies for RCC.

Efficacy and safety of deferasirox at low and high iron burdens: results from the EPIC magnetic resonance imaging substudy.

The effect of deferasirox dosing tailored for iron burden and iron loading based on liver iron concentration (LIC) was assessed over 1 year in less versus more heavily iron-overloaded patients in a substudy of the Evaluation of Patients' Iron Chelation with Exjade®. Deferasirox starting dose was 10-30 mg/kg/day, depending on blood transfusion frequency, with recommended dose adjustments every 3 months. Therapeutic goals were LIC maintenance or reduction in patients with baseline LIC <7 or ≥7 mg Fe/g dry weight (dw), respectively. Changes in LIC (R2-magnetic resonance imaging) and serum ferritin after 1 year were assessed. Adverse events (AEs) and laboratory parameters were monitored throughout. Of 374 patients, 71 and 303 had baseline LIC <7 and ≥7 mg Fe/g dw, respectively; mean deferasirox doses were 20.7 and 27.1 mg/kg/day (overall average time to dose increase, 24 weeks). At 1 year, mean LIC and median serum ferritin levels were maintained in the low-iron cohort (-0.02 ± 2.4 mg Fe/g dw, -57 ng/mL; P = not significant) and significantly decreased in the high-iron cohort (-6.1 ± 9.1 mg Fe/g dw, -830 ng/mL; P < 0.0001). Drug-related gastrointestinal AEs, mostly mild to moderate, were more frequently reported in the <7 versus ≥7 mg Fe/g dw cohort (39.4 versus 20.8 %; P = 0.001) and were not confounded by diagnosis, dosing, ethnicity, or hepatitis B and/or C history. Reported serum creatinine increases did not increase in low- versus high-iron cohort patients. Deferasirox doses of 20 mg/kg/day maintained LIC <7 mg Fe/g dw and doses of 30 mg/kg/day were required for net iron reduction in the high-iron cohort, with clinically manageable safety profiles. The higher incidence of gastrointestinal AEs at lower iron burdens requires further investigation.

An indirect comparison of dabigatran, rivaroxaban and apixaban for atrial fibrillation.

New oral anticoagulant drugs are emerging as alternatives to warfarin for the prevention of stroke in patients with non-valvular atrial fibrillation. Two agents are direct factor Xa inhibitors (rivaroxaban and apixaban), and the third is a direct thrombin inhibitor (dabigatran). They have been separately compared to warfarin in large randomised trials. Our objective was to indirectly compare the three agents to each other for major efficacy and safety outcomes. Studies were assessed for comparability and the odds ratios of selected outcomes for each anticoagulant versus one another were estimated indirectly. The three cohorts differed significantly in terms of CHADS(2) score and the number of individuals with a past history of stroke, transient ischemic attack or systemic embolism. The estimated odds ratio of stroke or systemic embolism was 1.35 for rivaroxaban vs dabigatran 150 mg (p=0.04), 0.97 for rivaroxaban versus dabigatran 110 mg (p=0.81), 1.22 for apixaban versus dabigatran 150 mg (p=0.18), 0.88 for apixaban versus dabigatran 110 mg (p=0.34) and 0.90 for apixaban versus rivaroxaban (p=0.43). The estimated odds ratio of major bleeding was 1.10 for rivaroxaban versus dabigatran 150 mg (p=0.36), 1.28 for rivaroxaban versus dabigatran 110 mg (p=0.02), 0.74 for apixaban versus dabigatran 150 mg (p=0.004), 0.87 for apixaban versus dabigatran 110 mg (p=0.17) and 0.68 for apixaban versus rivaroxaban (p<0.001). In conclusion, the available data indicate no significant difference in efficacy between dabigatran 150 mg and apixaban for the prevention of stroke or systemic embolism in patients with non-valvular atrial fibrillation. It appears however that apixaban is associated with less major bleeding than dabigatran 150 mg or rivaroxaban and that rivaroxaban is less effective than dabigatran 150 mg in preventing stroke or systemic embolism. Such an indirect comparison should be used only to generate hypotheses which need to be tested in a dedicated randomised trial comparing the three drugs directly.

Long-term benefits of preventing venous thromboembolic events.

BACKGROUND: Venous thromboembolism (VTE) and its long-term secondary complications are major health problems associated with high rates of morbidity and mortality and considerable costs for healthcare systems. Many patients receive suboptimal therapy, despite the availability of established and effective agents (including low molecular weight heparins, unfractionated heparin, fondaparinux and vitamin K antagonists) and evidence-based, internationally recognised guidelines. Limited knowledge of guidelines, concerns about bleeding risks and the inconvenience of parenteral administration and routine coagulation monitoring contribute to non-adherence to guidelines. Newer oral anticoagulants such as rivaroxaban, dabigatran etexilate, apixaban and edoxaban, which do not have the limitations of established anticoagulants, have been developed. METHOD: Phase III randomised controlled trials for the treatment of acute VTE or for secondary prevention of recurrent VTE were identified in the PubMed and ClinicalTrials.gov databases. The search was limited to phase III studies and performed up to 26 March 2012 with the terms 'rivaroxaban OR Xarelto', 'dabigatran OR Pradaxa', 'apixaban OR Eliquis' and 'edoxaban OR DU-176b OR Lixiana'. FINDINGS: A total of ten phase III studies, four published (three rivaroxaban, one dabigatran), three completed with results presented at recent congresses (dabigatran), and three ongoing (two apixaban, one edoxaban) were identified. Published and completed studies showed that rivaroxaban and dabigatran provided effective and convenient short-term treatment for deep vein thrombosis and VTE, respectively, when compared with standard of care, and showed superiority for long-term prevention of recurrent VTE when compared with placebo. Currently, rivaroxaban is the only newer anticoagulant that has been approved in Europe for the treatment of deep vein thrombosis and prevention of recurrent VTE. CONCLUSIONS: Based on results of completed trials, rivaroxaban and dabigatran both may reduce the incidence of secondary complications of VTE and associated socioeconomic costs. Introduction of these newer anticoagulants is likely to have a substantial impact on clinical practice.

Treatment of seasonal allergic rhinoconjunctivitis with a once-daily SQ-standardized grass allergy immunotherapy tablet.

OBJECTIVES: Specific immunotherapy with the grass allergy immunotherapy tablet (AIT) has been developed as an effective, well tolerated, and convenient treatment for grass pollen induced seasonal allergic rhinoconjunctivitis (ARC). Six phase II/III randomized, placebo-controlled trials with the duration of a single grass pollen season of treatment using the SQ-standardized grass AIT, Grazax (Phleum pratense, 75,000 SQ-T/2,800 BAU, ALK, Denmark), have been published previously. This review compares results from these trials. METHODS: As outcome measures and methods of assessing them were similar across the trials, we have summarized the main efficacy findings (Total Combined Score [TCS], average daily rhinoconjunctivitis symptom and medication scores, percentage of well days, quality of life scores) during a single season of treatment with grass AIT in adults and children with seasonal ARC. RESULTS: The results of the European and North American trials were similar. Compared with the placebo group, who received symptomatic medications only, treatment with grass AIT resulted in fewer rhinoconjunctivitis symptoms, a lower intake of symptomatic medication, better patient self-rated quality of life and a greater percentage of well days during the entire grass pollen season. The data indicate that grass AIT treatment is equally effective in adults and children; the measured effect varies with pollen exposure, but is comparable across regions and continents, with a consistent difference compared with placebo in TCS that was above 20% for all trials. Local adverse events were experienced by the majority of patients. These reactions were generally mild to moderate in severity and transient in duration. Systemic adverse events were rare. CONCLUSIONS: This review confirms SQ-standardized grass AIT as a suitable therapeutic option for seasonal use in patients aged 5 years or older with grass pollen induced ARC.

Worldwide experience with the use of doripenem against extended-spectrum-beta-lactamase-producing and ciprofloxacin-resistant Enterobacteriaceae: analysis of six phase 3 clinical studies.

The worldwide increase in fluoroquinolone-resistant and extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae pathogens has led to doripenem and other carbapenems assuming a greater role in the treatment of serious infections. We analyzed data from 6 phase 3 multinational doripenem clinical trials on ciprofloxacin-resistant Enterobacteriaceae isolates consisting of all genera (CIPRE) and ESBL-producing Enterobacteriaceae isolates consisting of Escherichia coli, Klebsiella spp., and Proteus spp. with ceftazidime MICs of >or=2 microg/ml (ESBLE) for prevalence by geographic region and disease type, in vitro activities of doripenem and comparator agents, and clinical or microbiologic outcomes in doripenem- and comparator-treated patients across disease types (complicated intra-abdominal infection [cIAI], complicated urinary tract infection [cUTI], and nosocomial pneumonia [NP]). Of 1,830 baseline Enterobacteriaceae isolates, 88 (4.8%) were ESBLE and 238 (13.0%) were CIPRE. The incidence of ESBLE was greatest in Europe (7.8%); that of CIPRE was higher in South America (15.9%) and Europe (14.4%). ESBLE incidence was highest in NP (12.9%) cases; that of CIPRE was higher in cUTI (18.3%) and NP (14.9%) cases. Against ESBLE and CIPRE, carbapenems appeared more active than other antibiotic classes. Among carbapenems, doripenem and meropenem were most potent. Doripenem had low MIC(90)s for CIPRE (0.5 microg/ml) and ESBLE (0.25 microg/ml). Doripenem and comparators were highly clinically effective in infections caused by Enterobacteriaceae, irrespective of their ESBL statuses. The overall cure rates were the same for doripenem (82%; 564/685) and the comparators (82%; 535/652) and similar for ESBLE (73% [16/22] versus 72% [21/29]) and CIPRE (68% [47/69] versus 52% [33/64]). These findings indicate that doripenem is an important therapeutic option for treating serious infections caused by ESBLE and CIPRE.

The European contribution to "Sugarbaker's protocol" for the treatment of colorectal peritoneal carcinomatosis.

INTRODUCTION: In 1981, Dr. PH Sugarbaker, challenging oncological orthodoxy, considered carcinomatosis to be a locoregional stage of the disease that was still susceptible to treatment with curative intent. To this end he developed a new therapeutic alternative based on the combined treatment. The macroscopic disease treated by maximum radical oncological cytoreductive surgery (through the peritonectomies described by him), followed by treatment of the residual microscopic disease with the direct intra-abdominal application of intraoperative chemotherapy with locoregional intensification, modulated by hyperthermia and early normothermic postoperative intra-abdominal chemotherapy. Using this new therapeutic regimen, known as "Sugarbaker s Protocol", his group has reported 45% survival rates in carcinomatosis of colorectal origin at 5 years, and, in selected groups of patients, 50% survival rates at 5 years. The scientific community, however, has criticized these results considering that: it is a personal experience, with a not homogenous treatment protocol with developmental modifications over time, that it is a retrospective non-randomized study, and finally that the cytostatics used in his protocol are obsolete. Various European groups have replied to these main criticisms confirming the good results that this new therapeutic alternative offers for patients with carcinomatosis of colorectal origin. The purpose of this article is to present these contributions. MATERIAL AND METHODS: All the articles published in the English language by European groups in the world s medical literature have been reviewed using the Pubmed-MEDLINE database to identify the relevant articles related to the treatment of carcinomatosis of colorectal origin using cytoreduction and intraperitoneal chemotherapy from January 1980 to January 2008. RESULTS: The European contribution during these 25 years in favour of the "Sugarbaker s Protocol" has consisted fundamentally in: a) one multicenter retrospective study; b) two randomized prospective phase III studies; and c) the use of oxaliplatin and irinotecan as new cytostatic agents in the protocols for intraperitoneal chemotherapy. At the same time, two new transcendental European contributions have been made in which the possibility has been considered of combined simultaneous treatment for patients with hepatic metastases and carcinomatosis, and the introduction, as a selection factor, of patients responsive to intravenous induction chemotherapy within the regimen of sandwich treatment (with systemic neoadjuvant and adjuvant chemotherapy) complementary to intraperitoneal chemotherapy. CONCLUSIONS: The results obtained by European groups using "Sugarbaker s protocol" and "Elias protocol" with oxaliplatin compel us to request that these treatments be considered by all professionals involved in the treatment of patients with colorectal carcinomatosis as the best treatment currently available for this condition. Furthermore a randomized, prospective, multicenter study should be carried out to clarify its value and the degree of scientific evidence. A validation of this treatment will change, in the future, the dogmatic consideration of carcinomatosis as an incurable disease stage.

Aportación europea al “protocolo de Sugarbaker” en el tratamiento de la carcinomatosis peritoneal colorrectal / The European contribution to "Sugarbaker's protocol" for the treatment of colorectal peritoneal carcinomatosis

Introducción: el Dr. P. H. Sugarbaker en 1981, desafiando la ortodoxia oncológica, consideró la carcinomatosis como un estadio locorregional de la enfermedad susceptible todavía de tratamiento con intención curativa. Para ello desarrolló una nueva alternativa terapéutica basada en el tratamiento combinado. La enfermedad macroscópica mediante la máxima cirugía citorreductora radical oncológica (merced a las peritonectomías por él descritas), seguido del tratamiento de la enfermedad microscópica residual con la aplicación directa intraabdominal, de quimioterapia de intensificación locorregional, intraoperatoria modulada por hipertermia y de quimioterapia intraabdominal normotérmica postoperatoria precoz. Con este nuevo esquema terapéutico, conocido como "Protocolo de Sugarbaker", su grupo ha publicado supervivencias en carcinomatosis de origen colorrectal de 45% a 5 años y en grupos selectos de pacientes supervivencia de 50% a 5 años. La comunidad científica, sin embargo, ha criticado estos resultados al considerar que: se trata de una experiencia personal, con un protocolo de tratamiento no homogéneo con modificaciones evolutivas en el tiempo, tratarse de un estudio retrospectivo no randomizado, y finalmente considerar que los citostáticos empleados en su protocolo son obsoletos. Diversos grupos europeos han dado respuesta a las principales objeciones, confirmando los buenos resultados que esta nueva alternativa terapéutica ofrece en pacientes con carcinomatosis de origen colorrectal. El objetivo de este trabajo es presentar estas aportaciones. Material y métodos: se han revisado todos los artículos publicados en lengua inglesa por grupos europeos en la literatura médica mundial usando la base de datos Pubmed-MEDLINE para identificar los artículos relevantes relacionados con el tratamiento de la carcinomatosis de origen colorrectal mediante citorreducción y quimioterapia intraperitoneal desde enero de 1980 a enero de 2008...(AU)

Introduction: in 1981, Dr. PH Sugarbaker, challenging oncological orthodoxy, considered carcinomatosis to be a locoregional stage of the disease that was still susceptible to treatment with curative intent. To this end he developed a new therapeutic alternative based on the combined treatment. The macroscopic disease treated by maximum radical oncological cytoreductive surgery (through the peritonectomies described by him), followed by treatment of the residual microscopic disease with the direct intra-abdominal application of intraoperative chemotherapy with locoregional intensification, modulated by hyperthermia and early normothermic postoperative intra-abdominal chemotherapy. Using this new therapeutic regimen, known as "Sugarbaker's Protocol", his group has reported 45% survival rates in carcinomatosis of colorectal origin at 5 years, and, in selected groups of patients, 50% survival rates at 5 years. The scientific community, however, has criticized these results considering that: it is a personal experience, with a not homogenous treatment protocol with developmental modifications over time, that it is a retrospective non-randomized study, and finally that the cytostatics used in his protocol are obsolete. Various European groups have replied to these main criticisms confirming the good results that this new therapeutic alternative offers for patients with carcinomatosis of colorectal origin. The purpose of this article is to present these contributions. Material and methods: all the articles published in the English language by European groups in the world's medical literature have been reviewed using the Pubmed-MEDLINE database to identify the relevant articles related to the treatment of carcinomatosis of colorectal origin using cytoreduction and intraperitoneal chemotherapy from January 1980 to January 2008...(AU)

[Efficacy of raltegravir: from healthy volunteers to phase III trials]. / Eficacia del raltegravir: desde los voluntarios sanos a la fase III.

Raltegravir is the first in a new class of antiretroviral treatments called integrase inhibitors, which work by preventing HIV from inserting its genetic material into the DNA of the human chromosome. Phase I-III studies have shown this drug to have potent antiretroviral action, which is more rapid than that of protease inhibitors. The dose selected in efficacy studies is 400 mg every 12 h. However, due to the favorable pharmacokinetic profile of raltegravir, the possibility of administration of 600 to 800 mg once daily is under study. Given that this drug is not metabolized by the cytochrome P450 system, the potential for pharmacological interactions is low. Moreover, because humans lack a cellular homologue for HIV integrase, raltegravir has a low potential for toxicity. Raltegravir has an intermediate genetic barrier and consequently there may be cross-resistance across the integrase inhibitor class. For all these reasons, raltegravir is an attractive option in treatment-naive and pretreated patients and in those receiving simplification regimens.

[Rivaroxaban (Xarelto): efficacy and safety]. / Rivaroxaban (Xarelto): efficacité et tolérance.

The oral direct Xa inhibitor rivaroxaban (Xarelto) shows great promise for prevention of venous thromboembolic events after major elective orthopedic surgery. Its consistent and predictable pharmacokinetics and pharmacodynamics across a wide range of patient populations allow administration with fixed dosing and with no coagulation monitoring. In 4 orthopaedic surgery clinical trials (12,700 patients), 10mg postoperative (6-10 hours after the end of surgery) dose, once daily, of oral rivaroxaban, achieved superior efficacy and similar safety to enoxaparin, whatever the dose of enoxaparin. Indeed, 40 mg once a day in Europe and 30 mg bid in US of enoxaparin were compared to the same dose of 10mg once daily of rivaroxaban. Furthermore, there is no difference according to liver enzymes elevation and cardio-vascular adverse events. Although the risk of spinal haematoma after neuraxial anaesthesia is rare, it is increased by concomitant use of anticoagulants. In orthopedic surgery trials with rivaroxaban to date, complications such as spinal haematoma have not been reported. The pharmacokinetic profile of rivaroxaban suggests that concurrent use with neuraxial anaesthesia should require no further precautions than currently necessary with low-molecular-weight heparin.

Thalamic lesions in vascular dementia: low sensitivity of fluid-attenuated inversion recovery (FLAIR) imaging.

BACKGROUND AND PURPOSE: The criteria of the National Institute of Neurological Disorders and Stroke (NINDS)-Association Internationale pour la Recherche et l'Enseignement en Neurosciences (AIREN) include thalamic lesions for the diagnosis of vascular dementia (VaD). Although studies concerning VaD and brain aging advocate the use of fluid-attenuated inversion recovery (FLAIR) or T2-weighted images (T2-WI) to detect ischemic lesions, none compared the sensitivity of these sequences to depict thalamic lesions. METHODS: We performed a blinded review of T2-WI and FLAIR images in 73 patients fulfilling the radiological part of the NINDS-AIREN criteria (mean age, 71 years; range, 49 to 83 years). This sample was drawn from a large multicenter trial on VaD and was expected to have a high prevalence of thalamic lesions. In a side-by-side review, including T1-weighted images as well, lesions were classified according to presumed underlying pathology. RESULTS: The total number of thalamic lesions was 214. Two hundred eight (97%) were detected on T2-WI, but only 117 (55%) were detected on FLAIR (chi(2)=5.1; P<0.05). Although the mean size of lesions detected on T2-WI and not on FLAIR (4.4 mm) was significantly lower than the mean size of lesions detected on both sequences (6.7 mm) (P<0.001), 5 of the 29 lesions >10 mm on T2-WI were not visible on FLAIR. FLAIR detected only 81 (51%) of the 158 probable ischemic lesions and 30 (60%) of the 50 probable microbleeds. CONCLUSIONS: FLAIR should not be used as the only T2-weighted sequence to detect thalamic lesions in patients suspected of having VaD.

Elicitation of prior distributions for a phase III randomized controlled trial of adjuvant therapy with surgery for hepatocellular carcinoma.

A randomized, controlled clinical trial of radioactive iodine tagged with lipiodol in patients with resected hepatocellular carcinoma was criticized for its early stopping and resulting small sample size. To clarify its results, a new, larger multicenter trial was therefore proposed. This paper describes the elicitation of the pretrial opinions of the investigators involved in the new trial and the construction of appropriate clinical and skeptical prior distributions based on their responses. The prior distributions provide a useful tool in assessing the state of equipoise before the start of the trial. They can also be used in Bayesian analyses, both at the interim stage(s) as well as at the end of the trial. We illustrate these analyses, assuming that the data resulting from the new trial was the same as that obtained in the earlier trial when it was stopped.