PCN94 - Cost-effectiveness and preference for follow-up scenarios following breast cancer

OBJECTIVES: About one in every eight women in The Netherlands develops breast cancer. Every year, 11,000 new cases are registered and about 3500 women die of breast cancer. Prognosis after primary treatment for patients with breast cancer is improving. This leads to an increased number of patients in follow-up, which leads to increased workload. One of the main goals of follow-up is to improve the survival of patients. This study aims to determine a more individualized follow-up by modelling costeffectiveness of various follow-up scenarios and by determining individual preferences by using a discrete choice experiment (DCE). METHODS: A discrete-event state-transition model was developed to estimate the cost-effectiveness of all scenarios for all patient groups. In addition, a discrete choice experiment (DCE) was designed to establish patient preferences. The DCE incorporated three process attributes (duration of follow-up, frequency and type of consult) and data were collected in a sample of 125 breast cancer patients. Patients had to complete all 18 choice sets that were generated from the three attributes. RESULTS: The modelling study revealed recommendations for follow-up in different age categories. Patients younger than 40 and patients with unfavorable tumor characteristics (>3 lymph nodes, tumor size >2 cm) can benefit from a more intensive follow-up of five or possibly ten years. Patients older than 40 but younger than 70 years old sometimes benefit from a more intensive follow-up; e.g. when younger than 50 and tumor size >2 cm. The DCE, however, showed that patients chose maximum levels of follow-up independent from age and their individual clinical risk profile. Duration of follow-up and type of consult (either hospital visit or telephone) weighted approximately 0.43 and 0.50 respectively. The frequency of follow-up (either once or twice a year) was least important (0.07). CONCLUSIONS: The model showed that follow-up may be individualized according to risk profile and age. However, patients preferred long and intensive follow-up strategies after breast cancer treatment. Taking into account individual patient preferences it may be recommended to reduce the frequency of follow-up to once a year. The service delivery by nurse practioners is well appreciated and another means for improving cost-effective follow-up

Design of a freeform two-reflector system to collimate and shape a point source distribution

In this paper we propose a method to compute a freeform reflector system for collimating and shaping a beam from a point source. We construct these reflectors such that the radiant intensity of the source is converted into a desired target. An important generalization in our approach compared to previous research is that the output beam can be in an arbitrary direction. The design problem is approached by using a generalized Monge-Amp\`ere equation. This equation is solved using a least-squares algorithm for non-quadratic cost functions. This algorithm calculates the optical map, from which we can then compute the surfaces. We test our algorithm on two cases. First we consider a uniform source and target distribution. Next, we use the model of a laser diode light source and a ring-shaped target distribution

An Iterative Least-Squares Method for the Hyperbolic Monge-Amp\`ere Equation with Transport Boundary Condition

A least-squares method for solving the hyperbolic Monge-Amp\`ere equation with transport boundary condition is introduced. The method relies on an iterative procedure for the gradient of the solution, the so-called mapping. By formulating error functionals for the interior domain, the boundary, both separately and as linear combination, three minimization problems are solved iteratively to compute the mapping. After convergence, a fourth minimization problem, to compute the solution of the Monge-Amp\`ere equation, is solved. The approach is based on a least-squares method for the elliptic Monge-Amp\`ere equation by Prins et al., and is improved upon by the addition of analytical solutions for the minimization on the interior domain and by the introduction of two new boundary methods. Lastly, the iterative method is tested on a variety of examples. It is shown that, when the iterative method converges, second-order global convergence as function of the spatial discretization is obtained.Comment: 30 pages, 24 figure

Detection of osteomyelitis in the diabetic foot by imaging techniques. A systematic review and meta-analysis comparing mri, white blood cell scintigraphy, and FDG-PET

OBJECTIVE Diagnosing bone infection in the diabetic foot is challenging and often requires several diagnostic procedures, including advanced imaging. We compared the diagnostic performances of MRI, radiolabeled white blood cell (WBC) scintigraphy (either with 99mTc-hexamethylpropyleneamineoxime [HMPAO] or 111In-oxine), and [18F]fluorodeoxyglucose positron emission tomography (18F-FDG-PET)/ computed tomography. RESEARCH DESIGN AND METHODS We searchedMedline andEmbase as of August 2016 for studies of diagnostic tests on patients known or suspected to have diabetes and a foot infection. We performed a systematic review using criteria recommended by the Cochrane Review of a database that included prospective and retrospective diagnostic studies performed on patients with diabetes in whom there was a clinical suspicion of osteomyelitis of the foot. The preferred reference standard was bone biopsy and subsequent pathological (or microbiological) examination. RESULTS Our review found 6,649 articles; 3,894 in Medline and 2,755 in Embase. A total of 27 full articles and 2 posters was selected for inclusion in the analysis. The performance characteristics for the 18F-FDG-PET were: sensitivity, 89%; specificity, 92%; diagnostic odds ratio (DOR), 95; positive likelihood ratio (LR), 11; and negative LR, 0.11. For WBC scan with 111In-oxine, the values were: sensitivity, 92%; specificity, 75%; DOR, 34; positive LR, 3.6; and negative LR, 0.1. For WBC scan with 99mTc-HMPAO, the values were: sensitivity, 91%; specificity, 92%; DOR, 118; positive LR, 12; and negative LR, 0.1. Finally, forMRI, the valueswere: sensitivity, 93%; specificity, 75%; DOR, 37; positive LR, 3.66, and negative LR, 0.10. CONCLUSIONS The various modalities have similar sensitivity, but 18F-FDG-PET and 99mTc-HMPAO-labeled WBC scintigraphy offer the highest specificity. Larger prospective studies with a direct comparison among the different imaging techniques are required

Cancer-related somatic mutations in transmembrane helices alter adenosine A1 receptor pharmacology

Overexpression of the adenosine A1 receptor (A1AR) has been detected in various cancer cell lines. However, the role of A1AR in tumor development is still unclear. Thirteen A1AR mutations were identified in the Cancer Genome Atlas from cancer patient samples. We have investigated the pharmacology of the mutations located at the 7-transmembrane domain using a yeast system. Concentration-growth curves were obtained with the full agonist CPA and compared to the wild type hA1AR. H78L3.23 and S246T6.47 showed increased constitutive activity, while only the constitutive activity of S246T6.47 could be reduced to wild type levels by the inverse agonist DPCPX. Decreased constitutive activity was observed on five mutant receptors, among which A52V2.47 and W188C5.46 showed a diminished potency for CPA. Lastly, a complete loss of activation was observed in five mutant receptors. A selection of mutations was also investigated in a mammalian system, showing comparable effects on receptor activation as in the yeast system, except for residues pointing toward the membrane. Taken together, this study will enrich the view of the receptor structure and function of A1AR, enlightening the consequences of these mutations in cancer. Ultimately, this may provide an opportunity for precision medicine for cancer patients with pathological phenotypes involving these mutations.Medicinal Chemistr

Physical and Cognitive Functioning After 3 Years Can Be Predicted Using Information From the Diagnostic Process in Recently Diagnosed Multiple Sclerosis

Objective\ud To predict functioning after 3 years in patients with recently diagnosed multiple sclerosis (MS).\ud \ud Design\ud Inception cohort with 3 years of follow-up. At baseline, predictors were obtained from medical history taking, neurologic examination, and magnetic resonance imaging (MRI).\ud \ud Setting\ud Neurology outpatient clinic.\ud \ud Participants\ud Patients with MS (N=156); 146 with complete follow-up.\ud \ud Interventions\ud Not applicable.\ud \ud Main Outcome Measures\ud Inability to walk at least 500m, impaired dexterity, cognitive impairments, incontinence, inability to drive a car or use public transportation, social dysfunction, and reliance on a disability pension.\ud \ud Results\ud Clinical prediction rules were constructed for the models that were well calibrated (sufficient agreement between predicted and observed outcomes, based on visual inspection of calibration curves) and that showed sufficient discrimination (area under the receiver operation characteristic curve >.70) after internal bootstrap validation. The models for the inability to walk at least 500m, impaired dexterity, and cognitive impairments were well calibrated. Discrimination was sufficient for all 7 models, except the one predicting social dysfunction (.67). The inability to walk at least 500m was predicted by the perceived ability to walk, impairment of the cerebellar tract, and the number of MRI lesions in the spinal cord. Impaired dexterity was predicted by the perceived ability to use the hands, impairments of the pyramidal, cerebellar, and sensory tracts, and the T2-weighted infratentorial lesion load. Cognitive impairment was predicted by age, gender, the perceived ability to concentrate, and the T2-weighted supratentorial lesion load.\ud \ud Conclusions\ud Inability to walk at least 500m, impaired dexterity, and cognitive impairments can be predicted with predictors that are derived from medical history taking, neurologic examination, and MRI shortly after a definite diagnosis of MS has been made.\ud \u

Which Compound to Select in Lead Optimization? Prospectively Validated Proteochemometric Models Guide Preclinical Development

In quite a few diseases, drug resistance due to target variability poses a serious problem in pharmacotherapy. This is certainly true for HIV, and hence, it is often unknown which drug is best to use or to develop against an individual HIV strain. In this work we applied ‘proteochemometric’ modeling of HIV Non-Nucleoside Reverse Transcriptase (NNRTI) inhibitors to support preclinical development by predicting compound performance on multiple mutants in the lead selection stage. Proteochemometric models are based on both small molecule and target properties and can thus capture multi-target activity relationships simultaneously, the targets in this case being a set of 14 HIV Reverse Transcriptase (RT) mutants. We validated our model by experimentally confirming model predictions for 317 untested compound – mutant pairs, with a prediction error comparable with assay variability (RMSE 0.62). Furthermore, dependent on the similarity of a new mutant to the training set, we could predict with high accuracy which compound will be most effective on a sequence with a previously unknown genotype. Hence, our models allow the evaluation of compound performance on untested sequences and the selection of the most promising leads for further preclinical research. The modeling concept is likely to be applicable also to other target families with genetic variability like other viruses or bacteria, or with similar orthologs like GPCRs

Patient preference regarding assessment of clinical follow-up after percutaneous coronary intervention: the PAPAYA study

Aims: To keep patients in long-term clinical follow-up programmes after percutaneous coronary intervention (PCI), knowledge of the patient-preferred mode for follow-up assessment is crucial. We systematically assessed patient preference, and explored potential relationships with age and gender.Methods and results: In the prospective, observational PAPAYA study (ClinicalTrials.gov: NCT02189070), 2,566 patients, treated by PCI between June 2008 and May 2012, were invited to participate in a postal survey on the patient-preferred mode (postal questionnaire, telephone or e-mail consultation) and frequency of follow-up assessment. A total of 1,797 (70.0%) patients responded. The vast majority preferred completing postal questionnaires (1,248 [69.9%]) as compared to telephone (240 [13.4%]) or e-mail-based approaches (227 [12.7%]) (p<0.001). With increasing age, there was a gradual decline in preference for e-mail (p<0.001); the youngest patients (≤60 years) preferred e-mail-based follow-up more often than the oldest (21.1% vs. 3.1%). Nevertheless, 79.9% of the youngest preferred to be approached in ways other than by e-mail. Women more often preferred approaches other than e-mail (94.1% vs. 87.3%, p<0.001).Conclusions: Patients showed a distinct preference for completing postal questionnaires rather than being approached by telephone or e-mail. Younger patients accepted e-mail-based follow-up more often, but the majority of the youngest patients still preferred approaches other than by e-mail - See more at: http://www.pcronline.com/eurointervention/ahead-of-print/201510-06/patient-preference-regarding-assessment-of-clinical-follow-up-after-percutaneous-coronary-intervention-the-papaya-study