One-Point Probability Distribution Functions of Supersonic Turbulent Flows in Self-Gravitating Media

Turbulence is essential for understanding the structure and dynamics of molecular clouds and star-forming regions. There is a need for adequate tools to describe and characterize the properties of turbulent flows. One-point probability distribution functions (pdf's) of dynamical variables have been suggested as appropriate statistical measures and applied to several observed molecular clouds. However, the interpretation of these data requires comparison with numerical simulations. To address this issue, SPH simulations of driven and decaying, supersonic, turbulent flows with and without self-gravity are presented. In addition, random Gaussian velocity fields are analyzed to estimate the influence of variance effects. To characterize the flow properties, the pdf's of the density, of the line-of-sight velocity centroids, and of the line centroid increments are studied. This is supplemented by a discussion of the dispersion and the kurtosis of the increment pdf's, as well as the spatial distribution of velocity increments for small spatial lags. From the comparison between different models of interstellar turbulence, it follows that the inclusion of self-gravity leads to better agreement with the observed pdf's in molecular clouds. The increment pdf's for small spatial lags become exponential for all considered velocities. However, all the processes considered here lead to non-Gaussian signatures, differences are only gradual, and the analyzed pdf's are in addition projection dependent. It appears therefore very difficult to distinguish between different physical processes on the basis of pdf's only, which limits their applicability for adequately characterizing interstellar turbulence.Comment: 38 pages (incl. 17 figures), accepted for publication in ApJ, also available with full resolution figures at http://www.strw.leidenuniv.nl/~klessen/Preprint

A phase I clinical and pharmacological study evaluating vinflunine in combination with doxorubicin as first line treatment in metastatic breast cancer

Vinfunine (VFL) is a novel bifluorinated tubulin-targeted agent of the vinca alkaloids class active in advanced stage breast cancer. We conducted a phase I study combining VFL with doxorubicin (DXR) to define the recommended dose (RD), safety, pharmacokinetic (PK) interaction and efficacy. Two schedules (day 1 every 3weeks; days 1 and 8 every 3weeks) were investigated as first line chemotherapy in metastatic breast cancer patients. Thirty-two patients received a total of 162 cycles of the VFL-DXR combination (median 6). The RDs were VFL 250mg/m2/DXR 40mg/m2 every 3weeks for schedule 1 and VFL 120mg/m2/DXR 25mg/m2 days 1 and 8 every 3weeks for schedule 2. The main dose-limiting toxicity was neutropenia. The most frequent non-hematological adverse events were nausea, fatigue, constipation, vomiting, anorexia, stomatitis and dyspnea. Objective response rate was reached in 47.1% of the patients. No PK interaction was observed. VFL-DXR combination is feasible with manageable toxicity. The antitumor activity was promising and supports further evaluatio

A phase I pharmacokinetic and safety study of cabazitaxel in adult cancer patients with normal and impaired renal function

$\textbf{PURPOSE}$ Limited data are available on cabazitaxel pharmacokinetics in patients with renal impairment. This open-label, multicenter study assessed cabazitaxel in patients with advanced solid tumors and normal or impaired renal function. $\textbf{METHODS}$ Cohorts A (normal renal function: creatinine clearance [CrCL] >80 mL/min/1.73 m$^{2}$), B (moderate renal impairment: CrCL 30 to <50 mL/min/1.73 m$^{2}$) and C (severe impairment: CrCL <30 mL/min/1.73 m(2)) received cabazitaxel 25 mg/m$^{2}$ (A, B) or 20 mg/m(2) (C, could be escalated to 25 mg/m$^{2}$), once every 3 weeks. Pharmacokinetic parameters and cabazitaxel unbound fraction (F$_{U}$) were assessed using linear regression and mixed models. Geometric mean (GM) and GM ratios (GMRs) were determined using mean CrCL intervals (moderate and severe renal impairment: 40 and 15 mL/min/1.73 m$^{2}$) versus a control (90 mL/min/1.73 m$^{2}$). $\textbf{RESULTS}$ Overall, 25 patients received cabazitaxel (median cycles: 3 [range 1-20]; Cohort A: 5 [2-13]; Cohort B: 3 [1-15]; and Cohort C: 5 [1-20]), of which 24 were eligible for pharmacokinetic analysis (eight in each cohort). For moderate and severe renal impairment versus normal renal function, GMR estimates were: clearance normalized to body surface area (CL/BSA) 0.95 (90% CI 0.80-1.13) and 0.89 (0.61-1.32); area under the curve normalized to dose (AUC/dose) 1.06 (0.88-1.27) and 1.14 (0.76-1.71); and F U 0.99 (0.94-1.04) and 0.97 (0.87-1.09), respectively. Estimated slopes of linear regression of log parameters versus log CrCL (renal impairment) were: CL/BSA 0.06 (-0.15 to 0.28); AUC/dose -0.07 (-0.30 to 0.16); and F U 0.02 (-0.05 to 0.08). Cabazitaxel safety profile was consistent with previous reports. $\textbf{CONCLUSIONS}$ Renal impairment had no clinically meaningful effect on cabazitaxel pharmacokinetics.This study was supported by Sanofi. Javier Garcia-Corbacho acknowledges clinical fellowship support from SEOM. Experimental Cancer Medicine Centre (ECMC) and NIHR Biomedical Research Centre (BRC) funding is also acknowledged for the Cambridge Cancer Centre

Vaccination with Fendrix of prior nonresponding patients with HIV has a high success rate

Background: Patients with HIV have a poor serological conversion rate with the standard vaccination strategy against hepatitis B virus (HBV) of around 50%. Vaccination with Fendrix confers much better results in these patients. In this study, we tested the effect of revaccination with Fendrix in prior nonresponding patients with HIV and aimed to determine which factors are associated with seroconversion. Methods: Eight Dutch HIV treatment centers participated in this retrospective study. Patients infected with HIV-1 and nonresponding to prior course of vaccination against HBV (anti-HBs <10 IU/ml) and who had Fendrix as a second, third or fourth effort to achieve seroconversion were eligible for inclusion. Primary outcome was the proportion of patients with seroconversion after revaccination with Fendrix. Univariate binary logistic regression analyses were used to determine which factors could be used as predictors for seroconversions. Results: We included 100 patients with HIV. The mean age was 47.3 (11.0) years and 86% were men. Revaccination with Fendrix showed a seroconversion rate of 81% (95% confidence interval 72–88%). Median nadir CD4þ cell count was 300 (20–1040) cells/ ml and median CD4þ cell count at the time at starting vaccination with Fendrix was 605 (210–1190) cells/ml. Regression analyses showed no significant factor associated with seroconversion. Conclusions: Revaccination with Fendrix of patients prior nonresponding to other hepatitis B vaccination strategies has a high success rate. Eighty-one percentage responded with seroconversion, irrespective of CD4þ cell count

Pharmacokinetic (Pk) Activity of Cabazitaxel (Cbz) in Patients (Pts) with Renal Impairment (Ri)

n/

Pigmented villonodular synovitis of the midfoot

A 60-year-old man presented with a longstanding slowly growing swelling at the dorsal aspect of the left midfoot. The lesion was imaged with CT, ultrasound, and MR. On CT bony erosions were evident. On MR the lesions appeared bifocal and one component was hypointense on T2 weighted images suggesting hemosiderin deposits. The other component was hyperintense on T2 which is more unusual for PVNS. Imaging findings, however, suggested PVNS which was pathologically confirmed. A unique finding in this case is the late age of presentation of the disorder. Also the bifocal nature of the lesion is relatively uncommon

Pembrolizumab for recurrent head and neck squamous cell carcinoma (HNSCC): Post hoc analyses of treatment options from the phase III KEYNOTE-040 trial

n/

Outcomes in Patients With Metastatic Renal Cell Carcinoma Who Develop Everolimus-Related Hyperglycemia and Hypercholesterolemia: Combined Subgroup Analyses of the RECORD-1 and REACT Trials

In this study we examined the outcome of metastatic renal cell cancer patients with everolimus treatment-related hyperglycemia and hypercholesterolemia. All patients were treated in 2 large, international prospective trials, RECORD-1 (REnal Cell cancer treatment with Oral RAD001 given Daily) and REACT (RAD001 Expanded Access Clinical Trial in RCC). Patients who experienced these events might have experienced an improved response to everolimus. Background Hyperglycemia and hypercholesterolemia are class effects of mammalian target of rapamycin inhibitors. The purpose of this study was to characterize safety and efficacy of patients with metastatic renal cell carcinoma (mRCC) treated with everolimus in RECORD-1 (REnal Cell cancer treatment with Oral RAD001 given Daily) and REACT (RAD001 Expanded Access Clinical Trial in RCC) who developed these events. Patients and Methods Adults with vascular endothelial growth factor–refractory mRCC received everolimus 10 mg/d in the randomized RECORD-1 (n = 277) and open-label REACT (n = 1367) studies. Outcomes included safety, treatment duration, overall response, and progression-free survival for patients who developed hypercholesterolemia or hyperglycemia. Results In RECORD-1, 12% (33 of 277) and 20% (55 of 277) of patients developed any grade hyperglycemia or hypercholesterolemia, respectively, with only 6% (78 of 1367) and 1% (14 of 1367) of the same events, respectively, in REACT. Median everolimus treatment duration was similar for patients with hyperglycemia or hypercholesterolemia (RECORD-1, 6.2 and 6.2 months, respectively; REACT, 4.4 and 4.5 months, respectively), but longer than the overall populations (RECORD-1, 4.6 months; REACT, 3.2 months). In RECORD-1/REACT, 82%/68% of patients with hyperglycemia and 75%/71% of patients with hypercholesterolemia achieved partial response or stable disease. The incidence of clinically notable Grade 3 or 4 adverse events, other than anemia and lymphopenia, appeared to be similar across trials and subgroups. Although there was a trend for improved progression-free survival with development of hyperglycemia or hypercholesterolemia, the association was not statistically significant. Conclusion Hyperglycemia and hypercholesterolemia were observed in low numbers of patients, and although these events might be associated with improved response to everolimus, the differences were not significant. These findings should be validated with prospective biomarker studies

Netinnovatie Kottervisserij

Als reactie op de aanlandplicht heeft de kottersector via de Coöperatieve Visserij Organisatie (CVO) het initiatief opgepakt om de selectiviteit van de vistuigen te verhogen om zo weinig mogelijk discards te vangen en aan te landen. Na een ontwerpfase met modelonderzoek in de flume tank van SINTEF te Hirtshals, Denemarken, en met ervaringen uit eerdere projecten werden op verscheidene schepen netinnovaties uitgeprobeerd. Er werd onderzoek gedaan op een schip met boomkor, verschillende schepen vissend met pulsvistuigen en op twinriggers. Hierbij werd aanvankelijk gewerkt op ‘trial-and error’ basis met in sommige gevallen zelfmonitoring. Vervolgens werden enkele uitgebreide vangst- en bijvangstvergelijkingen gedaan met medewerkers van IMARES aan boord