Personalisation of breast cancer follow-up: a time-dependent prognostic nomogram for the estimation of annual risk of locoregional recurrence in early breast cancer patients

The objective of this study was to develop and validate a time-dependent logistic regression model for prediction of locoregional recurrence (LRR) of breast cancer and a web-based nomogram for clinical decision support. Women first diagnosed with early breast cancer between 2003 and 2006 in all Dutch hospitals were selected from the Netherlands Cancer Registry (n = 37,230). In the first 5 years following primary breast cancer treatment, 950 (2.6 %) patients developed a LRR as first event. Risk factors were determined using logistic regression and the risks were calculated per year, conditional on not being diagnosed with recurrence in the previous year. Discrimination and calibration were assessed. Bootstrapping was used for internal validation. Data on primary tumours diagnosed between 2007 and 2008 in 43 Dutch hospitals were used for external validation of the performance of the nomogram (n = 12,308). The final model included the variables grade, size, multifocality, and nodal involvement of the primary tumour, and whether patients were treated with radio-, chemo- or hormone therapy. The index cohort showed an area under the ROC curve of 0.84, 0.77, 0.70, 0.73 and 0.62, respectively, per subsequent year after primary treatment. Model predictions were well calibrated. Estimates in the validation cohort did not differ significantly from the index cohort. The results were incorporated in a web-based nomogram (http://​www.​utwente.​nl/​mira/​influence). This validated nomogram can be used as an instrument to identify patients with a low or high risk of LRR who might benefit from a less or more intensive follow-up after breast cancer and to aid clinical decision making for personalised follow-up

Psychosocial impact of implantable cardioverter defibrillators (ICD) in young adults with Tetralogy of Fallot

Item does not contain fulltextOBJECTIVE: To investigate the psychosocial impact of having an implantable cardioverter defibrillator (ICD) in adults with Tetralogy of Fallot (ToF). METHODS: Included were 26 ToF-patients with an ICD (age 44 +/- 12 years), and two control groups consisting of 28 ToF-patients without an ICD (age 40 +/- 10 years) and a group of 35 ICD-patients of older age without ToF (age 72.0 +/- 8 years). This last control group was chosen to represent the "older general ICD population" with acquired heart disease seen at the out-patient clinic. Psychosocial functioning encompassed daily functioning, subjective health status, quality of life, anxiety, depression, coping and social support. RESULTS: ToF-patients with ICD showed diminished psychosocial functioning in comparison to ToF-patients without ICD. This was reflected by diminished subjectively perceived physical functioning (p = 0.01), general health perception (p < 0.01) and a lower satisfaction with life (p = 0.02). In comparison to older ICD-patients, ToF-patients with ICD showed less satisfaction with life (p = 0.03), experienced more anxiety (p = 0.01) and showed less favourable coping styles, although physical functioning was better for ToF-patients with ICD than for older ICD-patients (p = 0.01). More inappropriate shocks were found in ToF-patients with ICD compared to the older ICD-patients. CONCLUSION: In patients with ToF, ICD implantation had a major impact on psychosocial functioning which should be taken into account when considering ICD implantation in these young patients. To help improve psychosocial functioning, psychological counselling attuned to the specific needs of these patients may be useful.1 juli 201

Non-invasive method to obtain blood curves of 99mTc-mebrofenin

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In vivo visualization and quantification of (disturbed) Oatp-mediated hepatic uptake and Mrp2-mediated biliary excretion of 99mTc-mebrofenin in mice

Hepatic transport of Tc-99m-mebrofenin through organic anion transport protein 1a and 1b (Oatp1a/1b) and multidrug resistance protein 2 (Mrp2) was investigated by small-animal SPECT. On the basis of the results, a noninvasive method to visualize and quantify disturbances in hepatic transport is proposed. Methods: Friend virus B wild-type mice (untreated, bile duct-ligated, vehicle-or rifampicin-treated) and strain-matched knockout mice unable to express the uptake transporters Oatp1a/1b (Slco1a/1b(-/-)/(-/-)) or the efflux transporter Mrp2 (Abcc2(-/-)) were intravenously injected with Tc-99m-mebrofenin (n = 3 per group). After dynamic small-animal SPECT and short CT acquisitions, time-activity curves of the liver and of the gallbladder and intestines were obtained and correlated with direct blood samples. Results: Normal hepatobiliary clearance of Tc-99m-mebrofenin was severely impaired in the bile duct-ligated animal, as evidenced by elevated hepatic tracer levels. In Slco1a/1b2(-/-)/(-/-) mice, a lower area under the curve (AUC) for the liver (P = 0.014) was obtained and no activity was detected in the gallbladder and intestines. Renal rerouting was observed, along with an increase in the blood AUC (P = 0.01). Abcc2(-/-) mice had a higher liver AUC (P = 0.009), a delayed emergence time of Tc-99m-mebrofenin in the gallbladder (P = 0.009), and a lower AUC for the gallbladder and intestines (P = 0.001). The blood curve was similar to that of wild-type mice. Tc-99m-mebrofenin disposition was altered after rifampicin treatments. We observed a dose-dependent delayed time point at which tracer maximized in liver, an increased AUC for liver, and a lower AUC for gallbladder and intestines (P = 0.042, 0.034, and 0.001, respectively, highest dose). Emergence in the gallbladder occurred later (P = 0.009, highest dose), and blood AUC was higher (P = 0.006). Conclusion: The current study visualized and quantified hepatic uptake and biliary efflux of Tc-99m-mebrofenin. Our results demonstrated the possibility of discriminating, on a quantitative level, between lack of functional activity of sinusoidal uptake versus that of biliary efflux transporters

HPLC/ICP-MS in combination with 'reverse' online isotope dilution in drug metabolism studies

During the development of a new drug compound, its metabolism needs to be unraveled. For quantification of the metabolites formed, the drug under investigation is traditionally synthesized with a radiolabel (C-14 or H-3) and the metabolites present in different matrixes (blood, urine, feces) upon drug administration are determined by means of high-performance liquid chromatography (HPLC) coupled to radiodetection. This approach allows for quantification of the metabolites formed and enables a straightforward distinction between exogenous (i.e., drug-related) and endogenous species (as only the radiolabeled species are detected). However, in some cases, the use of a radiolabeled compound in human in vivo studies is not advisible, e.g., for drug compounds or their metabolites showing a long plasma or tissue half-life. In cases where the candidate drug molecule contains an element detectable by means of inductively coupled plasma mass spectrometry (ICP-MS), HPLC/ICP-MS is a promising alternative approach. However, the method lacks specificity when a distinction between drug-related species and endogenous compounds containing the same target element needs to be accomplished. As a result, we have developed an HPLC/ICP-MS-based method combined with "reverse" online isotope dilution ("reverse" online ID) for metabolite quantification. The methodology was evaluated by the analysis of feces samples from rats dosed with a Br-81-labeled drug compound. The method allows for both (i) valid quantification of the drug metabolites and (ii) distinction among endogenous, exogenous, and "mixed" species, based on their isotopic "fingerprint". A good repeatability (relative standard deviation of 4.2%) and limit of detection (0.35 mg of drug compound L-1 of feces extract), of the same order of magnitude as those observed for "normal" online ID HPLC/ICP-MS and HPLC/radiodetection, were achieved