Drug-interaction and Formulation Aspects of Taxanes in the Treatment of Cancer

__Abstract__ Over forty years ago, samples of the Taxus brevifolia, the pacific yew tree, were screened by the National Cancer Institute (NCI) for anticancer activity. Screening indicated that an extract from the tree possessed activity against tumour cell lines. Paclitaxel the active compound of the extract, was isolated in its pure form in 1969. The mechanism of action was not described until 1979 when Schiff and Horwitz discovered its unique mechanism of cytotoxicity. In contrast to other mitotic agents, paclitaxel and docetaxel promoted the assembly of tubulin and stabilised the resulting microtubules. Clinical studies with paclitaxel started in 1983. At the same time French researchers produced semisynthetic derivatives of baccatin III, an extract from the needles of the European yew Taxus baccata, and modified it with a chemically synthesised side chain. Docetaxel emerged from these efforts and entered clinical trials in 1990. Drug vehicle, drug-interactions, tissue penetration and age are all factors affecting drug pharmacokinetics, and are the focus of this thesis

Overheidsparticipatie in sociale media

Het gebruik van sociale media is in korte tijd sterk gegroeid onder brede lagen van de bevolking. In de afgelopen jaren heeft de overheid al de nodige ervaring opgedaan met sociale media. De vraag die nu voorligt heeft betrekking op een actieve rol van de overheid op sociale media: Wat zijn de mogelijkheden en beperkingen van overheidsparticipatie in sociale media? Om antwoord te geven op deze vraag is het van belang inzicht te krijgen in de technologie achter sociale media, de toepassingen, strategieën en tactieken. Deze inzichten zijn verkregen uit een literatuuronderzoek en een achttal cases waarin sociale media op de een of andere manier in relatie staan tot de overheid

PMD80 Preferences for a New Imaging Technique to Detect Breast Cancer

Objectives Currently, new techniques for the detection of breast cancer are being developed that cause less patient discomfort than X-ray mammography. These techniques might increase screening attendance, and therefore increase the health gains of the population of women in the Netherlands. One of these techniques is photo acoustic mammography (PAM). However, it is still unknown how important attributes such as discomfort, risks and health gains are to its implementation in breast cancer screening. Methods The Analytic Hierarchy Process (AHP), a technique for multi-criteria analysis, was used to estimate patient and health care professionals' preferences for three scenarios of PAM. These scenarios differed in the diagnostic performance that could be achieved by PAM. Preferences for the scenarios of PAM were compared with the preferences for X-ray mammography. Criteria related to the efficiency in applying the technique, diagnostic performance, patient comfort and safety. We elicited preferences of around 30 health care professionals and 300 patients. Results Health care professionals considered the sensitivity of the imaging technique to be the criterion of utmost importance in the selection of a new imaging technique to detect breast cancer. Advantages of less discomfort have relatively less meaning according to the laboratory workers and radiologists involved. However, preferences among patients and health care providers differed. Conclusions New techniques to detect breast cancer in screening programs should at least equal the diagnostic performance of X-ray mammography. Additional advantages could slightly increase screening attendance. X-ray mammography has a relatively lower diagnostic performance for patients with dense breasts. This subpopulation of patients could be the most promising area for new detection techniques with a working principle that differs from X-ray mammograph

Government 2.0: key challenges to its realization

Government 2.0 is often presented as a means to reinforce the relation between state and citizens in an information age. The promise of Government 2.0 is impressive but its potential has not or hardly been realized yet in practice. This paper uses insights from various disciplines to understand Government 2.0 as an institutional transformation. It focuses on three key issues ‑ leadership in government, incentives for citizens and mutual trust ‑ and our analysis shows that Government 2.0 efforts are too often guided by overly optimistic and simplified ideas about these issues. Our discussion suggests that there are no easy, one‑size‑fits‑all ways to address challenges of leadership, citizen incentives and trust: a contextual approach and hard work is needed to tackle these challenges. Realizing Government 2.0 means looking beyond the technology and understanding its potential in a specific situation

Breast imaging using the Twente Photoacoustic Mammoscope (PAM): new clinical measurements

Worldwide, yearly about 450,000 women die from the consequences of breast cancer. Current imaging modalities are not optimal in discriminating benign from malignant tissue. Visualizing the malignancy-associated increased hemoglobin concentration might significantly improve early diagnosis of breast cancer. Since photoacoustic imaging can visualize hemoglobin in tissue with optical contrast and ultrasound-like resolution, it is potentially an ideal method for early breast cancer imaging. The Twente Photoacoustic Mammoscope (PAM) has been developed specifically for breast imaging. Recently, a large clinical study has been started in the Medisch Spectrum Twente in Oldenzaal using PAM. In PAM, the breast is slightly compressed between a window for laser light illumination and a flat array ultrasound detector. The measurements are performed using a Q-switched Nd:YAG laser, pulsed at 1064 nm and a 1 MHz unfocused ultrasound detector array. Three-dimensional data are reconstructed using a delay and sum reconstruction algorithm. Those reconstructed images are compared with conventional imaging and histopathology. In the first phase of the study 12 patients with a malignant lesion and 2 patients with a benign cyst have been measured. The results are used to guide developments in photoacoustic mammography in order to pave the way towards an optimal technique for early diagnosis of breast cancer

First-line palliative HER2-targeted therapy in HER2-positive metastatic breast cancer is less effective after previous adjuvant trastuzumab-based therapy

Background. Survival of patients with human epidermal growth receptor 2 (HER2)-positive metastatic breast cancer (MBC) has improved dramatically since trastuzumab has become available, although the disease eventually progresses in most patients. This study investigates the outcome (overall survival [OS] and time to next treatment [TNT]) in MBC patients pretreated with trastuzumab in the adjuvant setting (TP-group) compared with trastuzumab-näive patients (TN-group) in order to investigate the possibility of trastuzumab resistance. Patients and Methods. Patients treated with first-line HER2-targeted- containing chemotherapy were eligible for the study. A power analysis was performed to estimate the minimum size of the TP-group. OS and TNT were estimated using Kaplan-Meier curves andmultivariable Cox proportional hazards models. Results. Between January 1, 2000, and June 1, 2014, 469 patients were included, of whom 82 were in the TP-group and 387 were in the TN-group. Median OS and TNT were significantly worse in the TP-group compared with the TN-group (17 vs. 30 months, adjusted hazard ratio [HR] 1.84 [1.15-2.96], p5.01 and 7 vs. 13 months, adjusted HR 1.65 [1.06-2.58], p5.03) after adjustment for age, year of diagnosis, diseasefree interval, hormone receptor status, metastatic site, and cytotoxic regimens. Conclusion. First-line trastuzumab-containing treatment regimens are less effective in patients with failure of adjuvant trastuzumab compared with trastuzumab-näive patients and might be due to trastuzumab resistance. The impact of trastuzumab resistance on the response on dual HER2 blockade with trastuzumab and pertuzumab and how resistance mechanisms can be used in the optimization of HER2-targeted treatment lines need further investigation.</p

Phase I and pharmacokinetic study of brostallicin (PNU-166196), a new DNA minor-groove binder, administered intravenously every 3 weeks to adult patients with metastatic cancer

PURPOSE: Brostallicin (PNU-166196) is a cytotoxic agent that binds to the minor groove of DNA with significant antitumor activity in preclinical studies. This trial was designed to determine the maximum tolerated dose, the toxicity profile, and the pharmacokinetics of Brostallicin in cancer patients. Experimental Design: Patients were treated with escalating doses of Brostallicin ranging from 0.85 to 15 mg/m(2) administered as a 10-min i.v. infusion every 3 weeks. Blood samples for pharmacokinetic analysis were collected during the first and second course, and analyzed by liquid-chromatography with tandem-mass spectrometric detection. RESULTS: Twenty-seven evaluable patients received a total of 73 courses. Grade 4 neutropenia was the only dose-limiting toxicity at 12.5 mg/m(2), whereas grade 4 thrombocytopenia (1 patient) and grade 4 neutropenia (2 patients) were the dose-limiting toxicities at 15 mg/m(2). Other side effects, including thrombocytopenia and nausea, were generally mild. The maximum tolerated dose was defined at 10 mg/m(2). The clearance and terminal half-life of Brostallicin were dose-independent, with mean (+/-SD) values of 9.33 +/- 2.38 liters/h/m(2) and 4.69 +/- 1.88 h, respectively. There was no significant accumulation of Brostallicin with repeated administration. Significant relationships were observed between systemic exposure to Brostallicin and neutrophil counts at nadir. One partial response was observed in a patient with a gastrointestinal stromal tumor. CONCLUSION: Brostallicin was found to be well tolerated, with neutropenia being the principal toxicity. The recommended dose for additional evaluation in this schedule is 10 mg/m(2)

Uniform Registration Agreements on Cholesteatoma Care: A Nationwide Consensus Procedure

Background: To coordinate and align the content for registration of cholesteatoma care. Methods: Systematic Delphi consensus procedure, consisting three rounds: two written sessions followed by a face-to-face meeting. Before this procedure, input on important patient outcomes was obtained. Consensus was defined as at least 80% agreement by participants. Hundred-thirty-six adult patients who had undergone cholesteatoma surgery and all ENT surgeons of the Dutch ENT Society were invited. The consensus rounds were att