Recognition is increasing for the effect of AKI on patients, and the resulting societal burden from its long-term effects, including development of chronic kidney disease and end-stage renal disease ...needing dialysis or transplantation.2 Few systematic efforts to manage (prevent, diagnose, and treat) AKI have been put in place and few resources have been allocated to inform health-care professionals and the public of the importance of AKI as a preventable and treatable disease.
Summary Background Regorafenib is a multikinase inhibitor with proven activity in refractory gastrointestinal stromal tumours and chemotherapy-refractory advanced colorectal cancers. We assessed this ...agent's efficacy and safety in patients with metastatic soft tissue sarcomas previously treated with anthracycline. Methods In this randomised, double-blind, phase 2 trial undertaken in France and Austria, we enrolled patients aged 18 years and older with advanced soft tissue sarcomas who had received previous doxorubicin or other anthracycline treatment. These patients were randomly assigned (1:1) into one of the following four cohorts: liposarcoma, leiomyosarcoma, synovial sarcoma, and other sarcomas. Participants were treated with oral regorafenib (160 mg per day 3 weeks on and 1 week off) or matched placebo. Patients receiving placebo were offered optional crossover in case of centrally confirmed disease progression. The random allocation schedule was computer-generated with permuted blocks of four patients, with two stratification factors: country (France or Austria) and previous exposure to pazopanib (yes or no). Eligibility criteria included patients with histologically proven advanced and inoperable soft tissue sarcomas with intolerance or failure to doxorubicin or other anthracycline-based chemotherapy and at least one unidimensionally or bidimensionally measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1). The primary endpoint was RECIST-based progression-free survival after central radiological review in the intention-to-treat population. Patients, physicians, and radiologists of the panel were masked to treatment allocation. This study is still open for recruitment for an additional stratum (patients previously treated with pazopanib) and registered with ClinicalTrials.gov , NCT01900743. Findings From Aug 5, 2013, to Nov 26, 2014, 182 patients were randomly assigned to one of four cohorts and included in the final analysis. At the cutoff date (Jan 7, 2016), the number of required events was reached for the four cohorts. In the liposarcoma cohort, progression-free survival was 1·1 months (95% CI 0·9–2·3) with regorafenib versus 1·7 months (0·9–1·8) with placebo (HR 0·89 95% CI 0·48–1·64 p=0·70). In the leiomyosarcoma cohort, progression-free survival was 3·7 months (95% CI 2·5–5·0) with regorafenib versus 1·8 (1·0–2·8) months with placebo (HR 0·46 95% CI 0·46–0·80 p=0·0045). In the synovial sarcoma cohort, progression-free survival was 5·6 months (95% CI 1·4–11·6) with regorafenib versus 1·0 (0·8–1·4) with placebo (HR 0·10 95% CI 0·03–0·35 p<0·0001). In the other sarcoma cohort, progression-free survival was 2·9 months (95% CI 1·0–7·8) with regorafenib versus 1·0 (0·9–1·9) with placebo (HR 0·46 95% CI 0·25–0·81 p=0·0061). Before crossover, the most common clinically significant grade 3 or higher adverse events were arterial hypertension (17 19% events in the 89 patients in the regorafenib group vs two 2% events in the 92 patients in the placebo group), hand and foot skin reaction (14 15% vs no events) and asthenia (12 13% vs six 6%). One treatment-related death occurred in the regorafenib group due to liver failure. Interpretation Regorafenib has an important clinical antitumour effect in non-adipocytic soft tissue sarcomas, improving progression-free survival. Regorafenib should be further evaluated in this setting, and its therapeutic role has to be defined in the context of the growing therapeutic armamentarium, already including one approved multikinase inhibitor, pazopanib. Funding Bayer HealthCare.
Summary Background We designed the EURAMOS-1 trial to investigate whether intensified postoperative chemotherapy for patients whose tumour showed a poor response to preoperative chemotherapy (≥10% ...viable tumour) improved event-free survival in patients with high-grade osteosarcoma. Methods EURAMOS-1 was an open-label, international, phase 3 randomised, controlled trial. Consenting patients with newly diagnosed, resectable, high-grade osteosarcoma aged 40 years or younger were eligible for randomisation. Patients were randomly assigned (1:1) to receive either postoperative cisplatin, doxorubicin, and methotrexate (MAP) or MAP plus ifosfamide and etoposide (MAPIE) using concealed permuted blocks with three stratification factors: trial group; location of tumour (proximal femur or proximal humerus vs other limb vs axial skeleton); and presence of metastases (no vs yes or possible). The MAP regimen consisted of cisplatin 120 mg/m2 , doxorubicin 37·5 mg/m2 per day on days 1 and 2 (on weeks 1 and 6) followed 3 weeks later by high-dose methotrexate 12 g/m2 over 4 h. The MAPIE regimen consisted of MAP as a base regimen, with the addition of high-dose ifosfamide (14 g/m2 ) at 2·8 g/m2 per day with equidose mesna uroprotection, followed by etoposide 100 mg/m2 per day over 1 h on days 1–5. The primary outcome measure was event-free survival measured in the intention-to-treat population. This trial is registered with ClinicalTrials.gov , number NCT00134030. Findings Between April 14, 2005, and June 30, 2011, 2260 patients were registered from 325 sites in 17 countries. 618 patients with poor response were randomly assigned; 310 to receive MAP and 308 to receive MAPIE. Median follow-up was 62·1 months (IQR 46·6–76·6); 62·3 months (IQR 46·9–77·1) for the MAP group and 61·1 months (IQR 46·5–75·3) for the MAPIE group. 307 event-free survival events were reported (153 in the MAP group vs 154 in the MAPIE group). 193 deaths were reported (101 in the MAP group vs 92 in the MAPIE group). Event-free survival did not differ between treatment groups (hazard ratio HR 0·98 95% CI 0·78–1·23); hazards were non-proportional (p=0·0003). The most common grade 3–4 adverse events were neutropenia (268 89% patients in MAP vs 268 90% in MAPIE), thrombocytopenia (231 78% in MAP vs 248 83% in MAPIE), and febrile neutropenia without documented infection (149 50% in MAP vs 217 73% in MAPIE). MAPIE was associated with more frequent grade 4 non-haematological toxicity than MAP (35 12% of 301 in the MAP group vs 71 24% of 298 in the MAPIE group). Two patients died during postoperative therapy, one from infection (although their absolute neutrophil count was normal), which was definitely related to their MAP treatment (specifically doxorubicin and cisplatin), and one from left ventricular systolic dysfunction, which was probably related to MAPIE treatment (specifically doxorubicin). One suspected unexpected serious adverse reaction was reported in the MAP group: bone marrow infarction due to methotrexate. Interpretation EURAMOS-1 results do not support the addition of ifosfamide and etoposide to postoperative chemotherapy in patients with poorly responding osteosarcoma because its administration was associated with increased toxicity without improving event-free survival. The results define standard of care for this population. New strategies are required to improve outcomes in this setting. Funding UK Medical Research Council, National Cancer Institute, European Science Foundation, St Anna Kinderkrebsforschung, Fonds National de la Recherche Scientifique, Fonds voor Wetenschappelijk Onderzoek-Vlaanderen, Parents Organization, Danish Medical Research Council, Academy of Finland, Deutsche Forschungsgemeinschaft, Deutsche Krebshilfe, Federal Ministry of Education and Research, Semmelweis Foundation, ZonMw (Council for Medical Research), Research Council of Norway, Scandinavian Sarcoma Group, Swiss Paediatric Oncology Group, Cancer Research UK, National Institute for Health Research, University College London Hospitals, and Biomedical Research Centre.
Background Radiofrequency ablation of saphenous veins has proven efficacy with an excellent side effect profile but has the disadvantage of a lengthy pullback procedure. This article reports a new ...endovenous catheter for radiofrequency-powered segmental thermal ablation (RSTA) of incompetent great saphenous veins (GSVs). Methods A prospective, nonrandomized, multicenter study was conducted to evaluate the safety, feasibility, and early clinical outcomes of RSTA of the GSV. Results A total of 194 patients with 252 GSVs with an average diameter of 5.7 ± 2.2 mm (range, 2.0 to 18.0 mm) received RSTA under tumescent local anesthesia. In 58 patients (29.9%), bilateral treatment (average length treated, 36.7 ± 10.8 cm) was done. The average total endovenous procedure time was 16.4 ± 8.2 minutes, and the average total energy delivery time was 2.2 ± 0.6 minutes. The corresponding endovenous fluence equivalent delivered to the proximal 7-cm vein segment was 82 ± 25 J/cm2 (range, 38 to 192). Follow-up at 3 days, 3 months, and 6 months was obtained from 250, 164, and 62 limbs, respectively. Occlusion rates were 99.6% for all three follow-up dates according to life-table analysis. The average Venous Clinical Severity Score was 3.4 ± 1.2 at 3 days, 0.9 ± 1.6 at 3 months, and 1.5 ± 1.8 at 6 months compared with 3.9 ± 2.0 at baseline. Conclusion Radiofrequency segmental thermal ablation is feasible, safe, and well tolerated.
Summary To date, chemosensitivity to neoadjuvant chemotherapy of patients with high-grade osteosarcoma is evaluated on surgical resection by evaluation of the percentage of necrotic cells. As yet, no ...predictive profile of response to chemotherapy has been used in clinical practice. Because we have previously shown that the integrin pathway controls genotoxic-induced cell death and hypoxia, we hypothesized that in primary biopsies, expression of proteins involved in this pathway could be associated with sensitivity to neoadjuvant chemotherapy in high-grade osteosarcoma. We studied β 1, β 3, and β 5 integrin expression and integrin-linked kinase, focal adhesion kinase (FAK), glycogen synthase kinase 3 β (GSK3 β ), Rho B, angiopoietin-2, β -catenin, and ezrin expression by immunohistochemistry in 36 biopsies of osteosarcomas obtained before treatment. All patients received a chemotherapy regimen in the neoadjuvant setting. An immunoreactive score was assessed, combining the percentage of positive tumor cells and staining intensity. We evaluated the correlation of the biomarkers with response to chemotherapy, metastasis-free survival, and overall survival. A combination of 3 biomarkers ( β 5 integrin, FAK, and GSK3 β ) discriminated good and poor responders to chemotherapy, with the highest area under the curve (89.9%; 95% confidence interval, 77.4-1.00) and a diagnostic accuracy of 90.3%. Moreover, high expression of ezrin was associated with an increased risk of metastasis (hazard ratio, 3.93; 95% confidence interval, 1.19-12.9; P = .024). We report a protein expression profile in high-grade osteosarcoma associating β 5 integrin, FAK, and GSK3 β that significantly correlates with poor response to neoadjuvant chemotherapy. This biomarker profile could help select patients for whom an alternative protocol using inhibitors of this pathway can be proposed.
Background T-cell interferon-γ release assays (IGRAs) are used in the diagnosis of Mycobacterium tuberculosis infection and could be useful biomarkers of response to treatment of latent TB infection ...for clinical trials, infection control units, and TB programs. Methods This investigation was a prospective, controlled substudy of IGRA responses in 82 healthy South African adults with HIV seronegative and positive tuberculin skin test results randomly assigned to treatment with 6 months of daily isoniazid preventive therapy (IPT) or observation before Bacillus Calmette-Guérin revaccination in a clinical trial. QuantiFERON-TB Gold In-Tube (QFT-GIT) assay was used to measure interferon-γ (IFN-γ) response to mycobacterial antigens at baseline and after IPT or observation. Results IFN-γ levels declined between baseline and the end of IPT (signed rank test P ≤ .0001) and between baseline and a similar period of observation without IPT (signed rank test P = .03). The rate of decrease in IFN-γ responses over time did not differ between the groups (Mann-Whitney-Wilcoxon test P = .31). QFT-GIT test results in two subjects (5%) in the IPT group and two subjects (5%) in the observation group reverted from positive to negative during follow-up. No significant difference was found between the groups with respect to baseline positivity or the proportion of patients whose tests reverted to negative. Conclusions IPT had no effect on changes in QFT-GIT readouts during short-term follow-up of adults with positive tuberculin skin tests in a high TB incidence setting. QFT-GIT is unlikely to be a useful biomarker of response to treatment of latent TB infection. Trial registry ClinicalTrials.gov ; No.: NCT01119521; URL: www.clinicaltrials.gov
Abstract Objective Superficial vein thrombosis (SVT) is a common disease in clinical practice. In terms of pathophysiology and outcomes, the condition is related to venous thromboembolism, bearing a ...potential for severe thromboembolic complications if it is not treated adequately. A wide range of treatment approaches (including oral and injectable anticoagulants, pain medication, nondrug therapy including compression therapy, and no treatment at all) are applied in clinical practice, but there is sparse information about selection of patients for therapies, current treatment pathways, and drug use as well as outcomes. The INvestigating SIGnificant Health TrendS in the management of Superficial Vein Thrombosis (INSIGHTS-SVT) study aims to close this gap by collecting representative data on the current treatment of SVT. Methods The observational prospective study of about 1200 patients is carried out by up to 120 clinical and office-based physicians who regularly treat patients with SVT and are capable of conducting appropriate compression ultrasound diagnostics, such as vascular physicians, phlebologists, internists, vascular surgeons, and general practitioners. Patients are eligible for inclusion if they have ultrasound-confirmed acute, isolated SVT of the lower extremities. Documentation about the characteristics of the patients, diagnostics, comorbidities, and medical and nonmedical treatment is collected at baseline, at 10 ± 3 days or at approximately 45 days (depending on treatment), at approximately 3 months, and at approximately 12 months. Patients are requested to fill in quality of life questionnaires (on pain, Venous Insufficiency Epidemiological and Economic Study on Quality of Life/Symptoms VEINES-QOL/Sym, EuroQol-5 Dimension 5-Level EQ-5D-5L) at baseline and at approximately 3 months. Interventions are not stipulated by the trial protocol. Results The primary efficacy outcome is the incidence of venous thromboembolism at 3 months; the primary safety outcome is the combined incidence of major and clinically relevant bleeding events at 3 months. As quality measures, plausibility checks at data entry, queries based on statistical analyses that focus on outliers and distribution of values, monitoring visits, and adjudication procedures will be applied. Conclusions This large study is expected to provide a comprehensive picture of patients with SVT under clinical practice conditions in Germany.
Abstract Objective A comparison of length of stay in an emergency department (ED) after loading patients at risk for seizures with either intravenous (IV) phenytoin or intramuscular (IM) fosphenytoin ...was studied. Methods This was a retrospective observational cohort study that was conducted over a 24-month period in an academic teaching hospital (693 beds). Patients included were 18 years or older, discharged from the ED without hospital admission, and loaded with either IV phenytoin or IM fosphenytoin. The primary end point was the comparison of length of stay in the ED until discharge after loading. Characterization of seizure etiology, cardiac risk factors, and adverse drug events were also observed. Results A total of 51 patients were evaluated who received IV phenytoin compared with 59 for IM fosphenytoin. The median time-to-discharge difference between IV phenytoin vs IM fosphenytoin was 1:49 hours (95% confidence interval, 1:24-2:24 hours; P < .001). There was no statistical difference in cardiac risk factors and occurrence of adverse drug events between groups. Conclusions This study found that patients were discharged from the ED earlier with the loading of IM fosphenytoin compared to IV phenytoin.
To assess community pharmacists' knowledge of human immunodeficiency virus (HIV), antiretroviral therapy, and new in-home oral fluid HIV test.
A cross-sectional questionnaire administered to ...pharmacists, student pharmacists, and technicians before an education program at the New Mexico Pharmacists Association 2013 Mid-Winter Meeting in Albuquerque, NM. The main outcome measure was community pharmacists' correct response rate of 75% or more.
Overall survey response rate of attendees was 89% (173/194 attendees). Among them 87 participants were community pharmacists; 87% of community pharmacists responded correctly when asked how HIV antiretroviral medications work and 84.3% correctly identified known sources of HIV infection. The 75% predefined adequate knowledge threshold was not met on any HIV screening or in-home HIV test knowledge items. Only 65.1% of community pharmacists correctly identified the minimum number of antiretroviral drugs that should be included in an ideal HIV treatment regimen. The only variable that positively influenced pharmacists' knowledge was age. An inverse relationship between pharmacist age and HIV knowledge was observed among study participants.
Community pharmacists from urban and rural areas in New Mexico possessed adequate basic HIV knowledge, but did not demonstrate adequate HIV screening or in-home HIV test knowledge. Future educational interventions aimed at improving pharmacist knowledge in this area are warranted.
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