Summary Background Until now, only imatinib and sunitinib have proven clinical benefit in patients with gastrointestinal stromal tumours (GIST), but almost all metastatic GIST eventually develop ...resistance to these agents, resulting in fatal disease progression. We aimed to assess efficacy and safety of regorafenib in patients with metastatic or unresectable GIST progressing after failure of at least imatinib and sunitinib. Methods We did this phase 3 trial at 57 hospitals in 17 countries. Patients with histologically confirmed, metastatic or unresectable GIST, with failure of at least previous imatinib and sunitinib were randomised in a 2:1 ratio (by computer-generated randomisation list and interactive voice response system; preallocated block design (block size 12); stratified by treatment line and geographical region) to receive either oral regorafenib 160 mg daily or placebo, plus best supportive care in both groups, for the first 3 weeks of each 4 week cycle. The study sponsor, participants, and investigators were masked to treatment assignment. The primary endpoint was progression-free survival (PFS). At disease progression, patients assigned placebo could crossover to open-label regorafenib. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT01271712. Results From Jan 4, to Aug 18, 2011, 240 patients were screened and 199 were randomised to receive regorafenib (n=133) or matching placebo (n=66). Data cutoff was Jan 26, 2012. Median PFS per independent blinded central review was 4·8 months (IQR 1·4–9·2) for regorafenib and 0·9 months (0·9–1·8) for placebo (hazard ratio HR 0·27, 95% CI 0·19–0·39; p<0·0001). After progression, 56 patients (85%) assigned placebo crossed over to regorafenib. Drug-related adverse events were reported in 130 (98%) patients assigned regorafenib and 45 (68%) patients assigned placebo. The most common regorafenib-related adverse events of grade 3 or higher were hypertension (31 of 132, 23%), hand-foot skin reaction (26 of 132, 20%), and diarrhoea (seven of 132, 5%). Interpretation The results of this study show that oral regorafenib can provide a significant improvement in progression-free survival compared with placebo in patients with metastatic GIST after progression on standard treatments. As far as we are aware, this is the first clinical trial to show benefit from a kinase inhibitor in this highly refractory population of patients. Funding Bayer HealthCare Pharmaceuticals.
Summary Background Pazopanib, a multitargeted tyrosine kinase inhibitor, has single-agent activity in patients with advanced non-adipocytic soft-tissue sarcoma. We investigated the effect of ...pazopanib on progression-free survival in patients with metastatic non-adipocytic soft-tissue sarcoma after failure of standard chemotherapy. Methods This phase 3 study was done in 72 institutions, across 13 countries. Patients with angiogenesis inhibitor-naive, metastatic soft-tissue sarcoma, progressing despite previous standard chemotherapy, were randomly assigned by an interactive voice randomisation system in a 2:1 ratio in permuted blocks (with block sizes of six) to receive either pazopanib 800 mg once daily or placebo, with no subsequent cross-over. Patients, investigators who gave the treatment, those assessing outcomes, and those who did the analysis were masked to the allocation. The primary endpoint was progression-free survival. Efficacy analysis was by intention to treat. The trial is registered with ClinicalTrials.gov , number NCT00753688. Findings 372 patients were registered and 369 were randomly assigned to receive pazopanib (n=246) or placebo (n=123). Median progression-free survival was 4·6 months (95% CI 3·7–4·8) for pazopanib compared with 1·6 months (0·9–1·8) for placebo (hazard ratio HR 0·31, 95% CI 0·24–0·40; p<0·0001). Overall survival was 12·5 months (10·6–14·8) with pazopanib versus 10·7 months (8·7–12·8) with placebo (HR 0·86, 0·67–1·11; p=0·25). The most common adverse events were fatigue (60 in the placebo group 49% vs 155 in the pazopanib group 65%), diarrhoea (20 16% vs 138 58%), nausea (34 28% vs 129 54%), weight loss (25 20% vs 115 48%), and hypertension (8 7% vs 99 41%). The median relative dose intensity was 100% for placebo and 96% for pazopanib. Interpretation Pazopanib is a new treatment option for patients with metastatic non-adipocytic soft-tissue sarcoma after previous chemotherapy. Funding GlaxoSmithKline.
Summary Background We report a proof-of-mechanism study of RG7112, a small-molecule MDM2 antagonist, in patients with chemotherapy-naive primary or relapsed well-differentiated or dedifferentiated ...MDM2 -amplified liposarcoma who were eligible for resection. Methods Patients with well-differentiated or dedifferentiated liposarcoma were enrolled at four centres in France. Patients received up to three 28-day neoadjuvant treatment cycles of RG7112 1440 mg/m2 per day for 10 days. If a patient progressed at any point after the first cycle, the lesion was resected or, if unresectable, an end-of-study biopsy was done. The primary endpoint was to assess markers of RG7112-dependent MDM2 inhibition and P53 pathway activation (P53, P21, MDM2, Ki-67, macrophage inhibitory cytokine-1 MIC-1, and apoptosis). All analyses were per protocol. This trial is registered with EudraCT, number 2009-015522-10. Results Between June 3, and Dec 14, 2010, 20 patients were enrolled and completed pretreatment and day 8 biopsies. 18 of 20 patients had TP53 wild-type tumours and two carried missense TP53 mutations. 14 of 17 assessed patients had MDM2 gene amplification. Compared with baseline, P53 and P21 concentrations, assessed by immunohistochemistry, had increased by a median of 4·86 times (IQR 4·38–7·97; p=0·0001) and 3·48 times (2·05–4·09; p=0·0001), respectively, at day 8 (give or take 2 days). At the same timepoint, relative MDM2 mRNA expression had increased by a median of 3·03 times (1·23–4·93; p=0·003) that at baseline. The median change from baseline for Ki-67-positive tumour cells was −5·05% (IQR −12·55 to 0·05; p=0·01). Drug exposure correlated with blood concentrations of MIC-1 (p<0·0001) and haematological toxicity. One patient had a confirmed partial response and 14 had stable disease. All patients experienced at least one adverse event, mostly nausea (14 patients), vomiting (11 patients), asthenia (nine patients), diarrhoea (nine patients), and thrombocytopenia (eight patients). There were 12 serious adverse events in eight patients, the most common of which were neutropenia (six patients) and thrombocytopenia (three patients). Discussion MDM2 inhibition activates the P53 pathway and decreases cell proliferation in MDM2 -amplified liposarcoma. This study suggests that it is feasible to undertake neoadjuvant biopsy-driven biomarker studies in liposarcoma. Funding F Hoffmann-La Roche.
Summary Background The effect of imatinib discontinuation on progression-free survival and overall survival in long-lasting responders with advanced gastrointestinal stromal tumours (GIST) is ...unknown. We assessed treatment interruption in patients with non-progressive disease according to the Response Evaluation Criteria In Solid Tumors criteria after 3 years of imatinib in a randomised trial. Methods In this open-label national multicentre phase 3 study in France, patients with GIST free of progression after 3 years of imatinib 400 mg/day were randomly assigned to continue or interrupt imatinib. Randomisation was done centrally and independently from other study procedures with computer-generated permuted blocks of two and four patients stratified by participating centre and presence or absence of residual disease on CT scan. The primary endpoint was progression-free survival. An interim analysis was planned after the first 50 randomly assigned patients. Analysis was done according to the intention-to-treat principle—ie, all patients randomly assigned to a study group were included. This study is registered with ClinicalTrial.gov , number NCT00367861. Findings 434 patients were enrolled in this trial between May 27, 2002, and May 5, 2009. Between June 13, 2005, and May 30, 2007, 50 patients with non-progressive disease who had received 3 years of treatment with imatinib were randomly assigned to continue or interrupt their treatment, 25 patients in each group. By Dec 7, 2009, after a median follow-up of 35 months (95% CI 33–38) after random assignment, 2-year progression-free survival was 80% (95% CI 58–91) in the continuation group and 16% (5–33) in the interruption group (p<0·0001). There was no difference in adverse events grade 3 or greater (oedema and asthenia) between the two groups. Interpretation Imatinib interruption after 3 years in responders results in a high risk of rapid progression in patients with advanced GIST. Discontinuation of imatinib is not recommended outside clinical trials unless patients experience significant toxic effects. Funding Conticanet, the Ligue Contre Le Cancer du Rhone, and Novartis.
Peanut (Arachis hypogaea) is mainly grown for oil extraction and the remaining oil-free seed referred as peanut meal (PM) leaves with high protein content which can be a possible substitute for ...fishmeal in aqua-diets. This study evaluates the suitability of three types of processed peanut seeds, namely untreated PM (UPM), fermented PM (FPM), and germinated PM (GPM) from peanut seeds to replace fishmeal in barramundi (Lates calcarifer) diets cultured under a commercial production environment. Nine formulated diets having 3 inclusion levels from the 3 different peanuts (15%, 30% and 60% fishmeal replacement) were evaluated against a control without PM. The performance of various types and levels of PMs was assessed by examining the growth, gut and liver condition and survival of fish after eight weeks of feeding the test diets. The immunological responses of juvenile barramundi were assessed by exposing the fish to the hypoxic conditions for 4 hours. The results showed that fermentation and germination significantly (P<0.05) reduced the tannins and alkaloid contents in the PMs. The fish fed 15% GPM diet grew faster and had higher survival than fish fed control diet, while fish fed diet including 60% GPM showed a significant reduction in growth and survival, and an increase in food conversion rate (FCR). FPM and UPM at any inclusion levels did not alter the growth, survival and FCR. Histology analysis revealed that fish fed 60% GPM and UPM showed higher amount of lipid droplets in liver, myodigeneration in fish muscle and a decrease number of acidic mucins in distal gut compare to all other test diets. Stress caused by reduced dissolved oxygen did not change the sodium, potassium, chlorides and alanine aminotransferase concentrations of plasma of fish fed any diet. However, the stress did increase plasma cortisol significantly (P<0.05) in fish fed 60% GPM, 30% and 60% UPM diets. These results suggest that the PMs can partly replace the fishmeal in juvenile barramundi diet and the processing further improves the PMs quality by reducing its antinutritional factors which in turn can increase either its inclusion level in the barramundi diets or improved growth and health status of the species.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
There have been many scales to predict pneumonia in stroke patients, but they are so complex, making it difficult to apply in practice. Therefore, we conducted this study to assess the role of the ...National Institutes of Health Stroke Scale (NIHSS) and the Gugging Swallowing Screen (GUSS) in predicting stroke-associated pneumonia (SAP). These scales are routinely used in stroke patients. Therefore, their application in predicting SAP risk will be of high value in clinical practice. There has been no previous study evaluating the effectiveness of SAP risk prediction for each of these scales.
This study aimed to compare the value of NIHSS and GUSS in SAP prediction and their convenience in clinical practice.
It was a cohort study. The receiver operating characteristics (ROC) curves were constructed to assess the sensitivity (Se) and specificity (Sp) of the scales. Area under the curves (AUC) were calculated, and we compared them.
NIHSS had a medium value of predictor of SAP with AUC 0.764 (95% CI 0.735-0.792), 65.4% Se, 76.5% Sp. GUSS had good value in predicting SAP with AUC 0.858 (95% CI 0.833-0.880), 80.5% Se, 80.1% Sp. Pairwise comparison of ROCs curves demonstrated that the difference between two AUCs was significant (p < 0.01). Performing GUSS required 24.5 ± 6.7 minutes, 2.5 times longer than NIHSS (9.9 ± 2.0 minutes).
GUSS had a better predictive value of SAP than NIHSS. But NIHSS was more convenient in clinical practice because of its simple instrument and quick performance.
We evaluated whether sex affects the steady-state pharmacokinetics of the antimalarial drugs, primaquine and doxycycline, in healthy subjects. Seventeen male and 17 female healthy Vietnamese subjects ...were administered 30 mg (base) of primaquine daily for 14 days. After a 2-week washout period, 14 male and 14 female subjects were administered 100 mg (base) of doxycycline daily for 14 days. Women had significantly higher median values of C(max) (212 versus 122 ng/mL, P< 0.001) and AUC(0-24) (1,909 versus 917 ng . h/mL, P < 0.001) of primaquine compared with men. Other than a longer t(max) in women, no sex-related differences were seen in the pharmacokinetics of doxycycline. The primaquine pharmacokinetic data suggest that women have increased exposure to primaquine, which may put them at increased risk for toxicity when administered the same maintenance dose as men. The similar pharmacokinetics of doxycycline between the two sexes justifies the same maintenance dose.
The planar Hall effect (PHE) sensor based on a simple giant magneto resistance (GMR) trilayer structure NiFe/Cu/NiFe has been designed and fabricated successfully using conventional clean room ...fabrication methods. The PHE sensor is integrated by 24 sensor patterns with dimensions of 50 × 50 μm. Influence of individual layer thickness to sensitivity of sensor has been investigated. Sensitivity and planar Hall voltage increases with the decrease of Cu-layer thickness. The results are discussed in terms of the reinforcement of the antiferromagnetic interaction between NiFe layers and shunting current through the layer Cu. The optimum configuration has been found in the structure with the Cu-layer of 1 nm. In this case a single planar Hall effect sensor exhibits a high sensitivity of about 8 μV Oe−1 and a maximal of the signal change as large as V ∼ 55 μV. These values are comparable to those of the typical PHE sensor based on complex GMR spin-valve structure. With a high sensitivity and simple structure, this sensor is very promising for practical detection of magnetic beads and identifying multiple biological agents in the environment.
This paper deals with the magnetization, magnetoresistance and planar Hall effect (PHE) of NiFe(10) Cu(1.2) NiFe(tp) IrMn(15) (nm) and NiFe(10) Cu(1.2) CoFe(tp) IrMn(15) (nm) spin-valve structures ...with various thicknesses of pinned layer tp = 2, 6, 9, 12 nm and a fixed free layer NiFe of tf = 10 nm. Experimental investigations are performed for 50 × 50 μm junctions fabricated using lithography technique. The results show that the thinner the pinned layers, the higher is the PHE sensitivity obtained in both systems. In addition, in the spin-valve structures with the same pinned layer thickness, the CoFe-based system exhibits higher magnetoresistive ratio, but lower PHE sensitivity with respect to those of the FeNi-based system. The results are discussed in terms of the spin twist as well as the coherent rotation of the magnetization in the individual ferromagnetic layers. The highest PHE sensitivity S of 110 μV (kA m−1)−1 has been obtained in the FeNi-based spin-valve structure with tp = 2 nm. This result is rather promising for the spintronic biochip developments.
Food has been reported to increase the bioavailability of mefloquine in healthy volunteers, but its role in increasing blood mefloquine concentrations in malaria patients treated with mefloquine is ...unclear. In this study, we compared blood mefloquine concentrations after the administration of artesunate (8
mg/kg) and mefloquine (15
mg/kg) over 12
h with either a low-fat (∼3
g of fat) or high-fat (∼30
g of fat) meal for the treatment of
Plasmodium falciparum malaria in 12 Vietnamese patients. No statistical differences were detected in the following kinetic parameters between the low-fat (
n
=
6) and high-fat (
n
=
6) groups, respectively: maximum blood mefloquine concentrations (2838
±
531
ng/ml and 2556
±
657
ng/ml, 95% CI −486 to 1050
ng/ml,
P
=
0.43) and the area under the blood mefloquine concentration versus time curves (246.8
±
58.3
μg.h/ml and 238.3
±
28.4
μg.h/ml, 95% CI −50.5 to 67.5
μg.h/ml,
P
=
0.75). A fatty meal does not appear to increase the bioavailability of mefloquine in malaria patients and should not affect the response of malaria infections to treatment.
PDF
