The eye lens dose of the interventionalist:Measurement in practice

Objective: Early 2018, the new eye lens dose limit of 20 mSv per year for occupational exposure to ionising radiation was implemented in the European Union. Dutch guidelines state that monitoring is compulsory above an expected eye lens dose of 15 mSv/year. In this study we propose a method to investigate whether the eye lens dose of interventionalists would exceed 15 mSv/year and to determine if the eye lens dose can be derived from the regular personal dosimeter measurements. Methods: The eye lens dose, Hp(3), of interventional radiologists (n = 2), cardiologists (n = 2) and vascular surgeons (n = 3) in the Máxima Medical Centre, The Netherlands, was measured during six months, using thermoluminescence dosimeters on the forehead. Simultaneously, the surface dose, Hp(0,07), and whole body dose, Hp(10), were measured using regular dosimeters outside the lead skirt at chest level. The dosimeters were simultaneously refreshed every four weeks. The eye lens dose was compared to both the body-worn dosimeter values. Measurements were performed in the angiography suite, Cath lab and hybrid OR. Results: A clear relation was observed between the two dosimeters: Hp(3) ≈ 0,25 Hp(0,07). The extrapolated year dose for the eye lens did not exceed 15 mSv for any of the interventionalists (average 3 to 10 studies/month). Conclusions: The eye lens dose can be monitored indirectly through the regular dosimeter at chest level. Additionally, based on the measurements we conclude that all monitored interventionalists remain below the dose limit and compulsory monitoring limit for the eye lens dose.</p

Topotecan lacks third space sequestration

The objective of this study was to determine the influence of pleural and ascitic fluid on the pharmacokinetics of the antitumor camptothecin derivative topotecan. Four patients with histological proof of malignant solid tumor received topotecan (0.45 or 1.5 mg/m2) p.o. on several occasions in both the presence and absence of third space volumes. Serial plasma and pleural or ascitic fluid samples were collected during each dosing and analyzed by high-performance liquid chromatography for both the intact lactone form of topotecan and its ring-opened carboxylate form. The apparent topotecan clearance demonstrated substantial interpatient variability but remained unchanged within the same patient in the presence [110 +/- 55.6 liters/ h/m2 (mean +/- SD of eight courses)] or absence of pleural and ascitic fluid [118 +/- 31.1 liters/h/m2 (mean +/- SD of seven courses)]. Similarly, terminal half-lives and area under the concentration-time curve ratios of lactone:total drug in plasma were similar between courses within each patient. Topotecan penetration into pleural and ascitic fluid demonstrated a mean lag time of 1.61 h (range, 1.37-1.86 h), and ratios with plasma concentration increased with time after dosing in all patients. The mean ratio of third space topotecan total drug area under the concentration-time curve to that in plasma was 0.55 (range, 0.26-0.87). These data indicate that topotecan can be safely administered to patients with pleural effusions or ascites and that there is substantial penetration of topotecan into these third spaces, which may prove beneficial for local antitumor effects

Inter- and intrapatient variability in oral topotecan pharmacokinetics: implications for body-surface area dosage regimens

Anticancer drugs still are dosed based on the body-surface area (BSA) of the individual patient, although the BSA is not the main predictor of the clearance for the majority of drugs. The relevance of BSA-based dosing has not been evaluated for topotecan yet. A retrospective pharmacological analysis was performed of kinetic data from four clinical Phase I studies in which topotecan was administered p.o. as a single agent combined with data from a combination study of topotecan and cisplatin. A strong correlation (r = 0.91) was found between the area under the plasma concentration time curve of the lactone and carboxylate forms of topotecan by plotting 326 data sets obtained from 112 patients receiving oral topotecan at dose levels ranging from 0.15-2.70 mg/m2. The intrapatient variability, studied in 47 patients sampled for 3 or more days, for the apparent lactone clearance, ranged from 7.4-69% (mean, 24 +/- 13%; median, 20%). The interpatient variabilities in the lactone clearance, calculated with the data of all studied patients, expressed in liter/h/m2 and in liter/h were 38% and 42%, respectively. In view of the relatively high inter- and intrapatient variabilities in topotecan clearance, in contrast to a variability of only 12% in the BSA of the studied patients, no advantage of BSA-based dosing was found over fixed dose regimens

Identification of Srp9 as a febrile seizure susceptibility gene

Objective: Febrile seizures (FS) are the most common seizure type in young children. Complex FS are a risk factor for mesial temporal lobe epilepsy (mTLE). To identify new FS susceptibility genes we used a forward genetic strategy in mice and subsequently analyzed candidate genes in humans. Methods: We mapped a quantitative trait locus (QTL1) for hyperthermia-induced FS on mouse chromosome 1, containing the signal recognition particle 9 (Srp9) gene. Effects of differential Srp9 expression were assessed in vivo and in vitro. Hippocampal SRP9 expression and genetic association were analyzed in FS and mTLE patients. Results: Srp9 was differentially expressed between parental strains C57BL/6J and A/J. Chromosome substitution strain 1 (CSS1) mice exhibited lower FS susceptibility and Srp9 expression than C57BL/6J mice. In vivo knockdown of brain Srp9 reduced FS susceptibility. Mice with reduced Srp9 expression and FS susceptibility, exhibited reduced hippocampal AMPA and NMDA currents. Downregulation of neuronal Srp9 reduced surface expression of AMPA receptor subunit GluA1. mTLE patients with antecedent FS had higher SRP9 expression than patients without. SRP9 promoter SNP rs12403575(G/A) was genetically associated with FS and mTLE. Interpretation: Our findings identify SRP9 as a novel FS susceptibility gene and indicate that SRP9 conveys its effects through endoplasmic reticulum (ER)-dependent synthesis and trafficking of membrane proteins, such as glutamate receptors. Discovery of this new FS gene and mechanism may provide new leads for early diagnosis and treatment of children with complex FS at risk for mTLE

Prediction of the systemic exposure to oral 9-amino-20(S)-camptothecin using single-samples analysis.

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Short- and long-term outcomes after endarterectomy with autologous patching in endurance athletes with iliac artery endofibrosis

Objective: Endurance athletes such as cyclists may develop intermittent claudication owing to iliac artery endofibrosis after long-lasting extreme hemodynamic challenges. This study investigated short-term (&lt;1.5 years) and long-term (&gt;5 years) satisfaction and safety after a surgical endarterectomy and autologous patching. Methods: Data of endurance athletes who underwent an endarterectomy for flow limitation of the iliac artery owing to endofibrosis between 1997 and 2015 in one center were studied. Maximal cycling exercise tests, ankle-brachial index with flexed hips, echo-Doppler examination (peak systolic velocity), and contrast-enhanced magnetic resonance angiography were performed before and 6 to 18 months after surgery. Short-term and long-term satisfaction were evaluated using questionnaires. Potential patch dilatation was assessed using echo-Doppler. Results: Analysis of 68 patients (79 legs; 55.7% males, median age at the time of surgery, 34 years; interquartile range, 26-41 years) demonstrated that cycling workload at symptom onset improved from 226 ± 97 to 333 ± 101 (P &lt;.001) Watts. Peak workload increased from 326 ± 111 to 352 ± 93 Watts (P &lt;.001). Ankle-brachial index with flexed hips increased from 0.34 (interquartile range [IQR], 0.00-0.47) to 0.59 (IQR, 0.51-0.69; P &lt;.001). Peak systolic velocity with extended and flexed hip decreased from 2.04 m·sec-1 (IQR, 1.52-2.56 m·3sec-1) to 1.25 m·sec-1 (IQR, 0.92-1.62 m·sec-1; P &lt;.001) and 2.40 m·sec-1 (IQR, 1.81-2.81 m·sec-1) to 1.15 m·sec-1 (IQR, 0.97-1.60 m·sec-1; P &lt;.001), respectively. Thirty-day major complication rate was 5.1% (hematoma requiring evacuation nLegs = 2, septic bleeding from deep infection nLegs = 1, and iliac occlusion requiring thrombectomy nLegs = 1). In the short term, 91.2% of patients reported symptom reduction with a 93.7% overall satisfaction rate. After a median of 11.1 years (IQR, 7.8-17.6 years), the overall satisfaction was 91.7%; 94.5% of patients reported persistent symptom reduction. Patch dilatation of &gt;20 mm was observed in two patients. Linear mixed model analysis revealed no alarming patch dilatation in the long term. Conclusions: Endarterectomy with an autologous patch for intermittent claudication owing to iliac artery endofibrosis in endurance athletes shows high rates of patient satisfaction and symptom reduction in both the short and long term. The risk of surgical complications or patch dilatation is mild. A surgical intervention for flow limitation of the iliac artery owing to endofibrosis is safe and successful

Early cessation of the clinical development of LiPlaCis, a liposomal cisplatin formulation

Purpose To evaluate the safety and tolerability of LiPlaCis a liposomal formulated platinum compound in patients with solid tumours and to determine the maximum tolerated dose (MTD) of intravenous v) LiPlaCis and to assess plasma and urine pharmacokinetics and plasma biomarkers Patients and methods Patients with solid tumours without standard therapeutic options were enrolled to receive LiPlaCis administered as a 1 h infusion without additional hydration every 3 weeks until RECIST progression or unacceptable toxicity Cohorts of 3-6 patients were treated at each dose level until MTD was reached Results Eighteen patients were enrolled and 64 cycles were delivered At the first dose level 3 patients experienced an infusion reaction Despite prophylactic pre medication and prolongation of the infusion to 2 h in further patients three other patients had mild acute infusion reactions Toxicity at the fifth dose level of 120 mg consisted of grade 2 renal toxicity reversible after hydration in 2 patients and grade 4 thrombocytopaenia in one of these patients Peak plasma concentrations and AUC were dose proportional The interpatient variability in the clearance of total LiPlaCis derived platinum was 41% Platinum was excreted via the urine mainly during the first 24 h after administration Investigated plasma biomarkers sPLA(2) and SC5b 9 were related to but not predictive for acute infusion reactions Conclusion The observed safety profile suggests no benefit over standard cisplatin formulations and LiPlaCis will require reformulation to enable further development (C) 2010 Elsevier Ltd All rights reserve