Interpretation of ambiguous situations: evidence for a dissociation between social and physical threat in Williams syndrome

There is increasing evidence that Williams syndrome (WS) is associated with elevated anxiety that is non-social in nature, including generalised anxiety and fears. To date very little research has examined the cognitive processes associated with this anxiety. In the present research, attentional bias for non-social threatening images in WS was examined using a dot-probe paradigm. Participants were 16 individuals with WS aged between 13 and 34 years and two groups of typically developing controls matched to the WS group on chronological age and attentional control ability respectively. The WS group exhibited a significant attention bias towards threatening images. In contrast, no bias was found for group matched on attentional control and a slight bias away from threat was found in the chronological age matched group. The results are contrasted with recent findings suggesting that individuals with WS do not show an attention bias for threatening faces and discussed in relation to neuroimaging research showing elevated amygdala activation in response to threatening non-social scenes in WS

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Cost-utility analysis on robot-assisted and laparoscopic prostatectomy based on long-term functional outcomes

Robot-Assisted Radical Prostatectomy (RARP) is one of the standard treatment options for prostate cancer. However, controversy still exists on its added value. Based on a recent large-sample retrospective cluster study from the Netherlands showing significantly improved long-term urinary functioning after RARP compared to Laparoscopic RP (LRP), we evaluated the cost-effectiveness of RARP compared to LRP. A decision tree was constructed to measure the costs and effects from a Dutch societal perspective over a ~ 7 year time-horizon. The input was based on the aforementioned study, including patient-reported consumption of addition care and consumed care for ergonomic issues reported by surgeons. Intervention costs were calculated using a bottom-up costing analysis in 5 hospitals. Finally, a probabilistic-, one-way sensitivity- and scenario analyses were performed to show possible decision uncertainty. The intervention costs were €9964 for RARP and €7253 for LRP. Total trajectory costs were €12,078 for RARP and €10,049 for LRP. RARP showed higher QALYs compared to LRP (6.17 vs 6.11). The incremental cost-utility ratio (ICUR) was €34,206 per QALY gained, in favour of RARP. As a best-case scenario, when RARP is being centralized (> 150 cases/year), total trajectory costs decreased to €10,377 having a higher utilization, and a shorter procedure time and length of stay resulting in an ICUR of €3495 per QALY gained. RARP showed to be cost-effective compared to LRP based on data from a population-based, large scale study with 7 years of follow-up. This is a clear incentive to fully reimburse RARP, especially when hospitals provide RARP centralized

Cost-utility analysis on robot-assisted and laparoscopic prostatectomy based on long-term functional outcomes

Robot-Assisted Radical Prostatectomy (RARP) is one of the standard treatment options for prostate cancer. However, controversy still exists on its added value. Based on a recent large-sample retrospective cluster study from the Netherlands showing significantly improved long-term urinary functioning after RARP compared to Laparoscopic RP (LRP), we evaluated the cost-effectiveness of RARP compared to LRP. A decision tree was constructed to measure the costs and effects from a Dutch societal perspective over a ~ 7 year time-horizon. The input was based on the aforementioned study, including patient-reported consumption of addition care and consumed care for ergonomic issues reported by surgeons. Intervention costs were calculated using a bottom-up costing analysis in 5 hospitals. Finally, a probabilistic-, one-way sensitivity- and scenario analyses were performed to show possible decision uncertainty. The intervention costs were €9964 for RARP and €7253 for LRP. Total trajectory costs were €12,078 for RARP and €10,049 for LRP. RARP showed higher QALYs compared to LRP (6.17 vs 6.11). The incremental cost-utility ratio (ICUR) was €34,206 per QALY gained, in favour of RARP. As a best-case scenario, when RARP is being centralized (> 150 cases/year), total trajectory costs decreased to €10,377 having a higher utilization, and a shorter procedure time and length of stay resulting in an ICUR of €3495 per QALY gained. RARP showed to be cost-effective compared to LRP based on data from a population-based, large scale study with 7 years of follow-up. This is a clear incentive to fully reimburse RARP, especially when hospitals provide RARP centralized

Imaging performance in guiding response to neoadjuvant therapy according to breast cancer subtypes: A systematic literature review

Monitoring therapeutic response to neoadjuvant chemotherapy(NAC) is likely to improve NAC effectiveness in breast cancer(BC). Imaging performance seems to vary per tumour subtype(by ER and HER2 status), therefore we performed a systematic review on subtype specific imaging performance in monitoring NAC in BC. Studies examining imaging performance in predicting pathologic complete response(pCR) during NAC in BC subtypes were selected. Per study, negative- and positive predictive value, sensitivity(se) and specificity(sp), AUC and accuracy were derived. Fifteen/106 articles were included. Inter-study variability was revealed in: monitoring interval, response and pCR definitions. In ER-positive/HER2-negative BC, 181F FDG-PET/CT showed se/sp of 38%–89%/74%–100%, MRI showed se/sp of 35%–37%/87%–89%. In triple negative BC, 181F FDG-PET/CT showed se/sp of 0%–79%/95%–100%. 181F FDG-PET/CT showed in ER-positive/HER2-positive BC se/sp of 59%/80% and in ER-negative/HER2-positive 27%/88%. Evidence on imaging performance in monitoring NAC according BC subtypes is lacking. Consensus should be reached in: definitions of pCR, response and monitoring interval before starting well-designed studies

Long-term functional outcomes after robot-assisted prostatectomy compared to laparoscopic prostatectomy: Results from a national retrospective cluster study

Background Despite multiple studies evaluating the effectiveness of Robot-Assisted Radical Prostatectomy (RARP), there is no definitive conclusion about the added value of RARP. A retrospective cluster study was conducted to evaluate long-term sexual and urinary functioning after RARP and Laparoscopic Radical Prostatectomy (LRP) based on real-world data from 12 Dutch hospitals. Methods Data was collected from patients who underwent surgery between 2010 and 2012. A mixed effect model was used to evaluate differences between groups on urinary and sexual functioning (EPIC-26). Additionally, a regression analysis was conducted to evaluate the relationship between these functional outcomes and, among others, hospital volume. Results 1370 (65.1%) patients participated, 907 underwent RARP and 463 LRP, with a median follow-up time of 7.08 years (SD = 0.98). The RARP group showed a statistically and clinically significant better urinary functioning compared to the LRP group (p = 0.002). RARP showed also a shorter procedure time (p=<0.001), reduced blood loss (p=<0.001), and a higher chance of neurovascular bundle preservation (39.8% vs 29.1%; p=<0.01). Conclusion RARP resulted in better long-term urinary function compared to LRP. Based on the results from this study, guidelines concerning the preferred surgery type and the position on reimbursement may change, especially when RARP proves to be cost-effective

Treatment with Tumor-infiltrating Lymphocytes in Advanced Melanoma Evaluation of Early Clinical Implementation of an Advanced Therapy Medicinal Product

Tumor-infiltrating lymphocytes (TIL)-therapy in advanced melanoma is an advanced therapy medicinal product (ATMP) which, despite promising results, has not been implemented widely. In a European setting, TIL-therapy has been in use since 2011 and is currently being evaluated in a randomized controlled trial. As clinical implementation of ATMPs is challenging, this study aims to evaluate early application of TIL-therapy, through the application of a constructive technology assessment (CTA). First the literature on ATMP barriers and facilitators in clinical translation was summarized. Subsequently, application of TILtherapy was evaluated through semistructured interviews with 26 stakeholders according to 6 CTA domains: clinical, economic, patient-related, organizational, technical, and future. In addition, treatment costs were estimated. A number of barriers to clinical translation were identified in the literature, including: inadequate financial support, lack of regulatory knowledge, risks in using live tissues, and the complex path to market approval. Innovative reimbursement procedures could particularly facilitate translation. The CTA survey of TIL-therapy acknowledged these barriers, and revealed the following facilitators: the expected effectiveness resulting in institutional support for an internal pilot, the results of which led to the inclusion of TIL-therapy in a national coverag

Early cost-effectiveness of tumor infiltrating lymphocytes (TIL) for second line treatment in advanced melanoma: A model-based economic evaluation

Background: An emerging immunotherapy is infusion of tumor infiltrating Lymphocytes (TIL), with objective response rates of around 50% versus 19% for ipilimumab. As an Advanced Therapeutic Medicinal Products (ATMP), TIL is highly personalized and complex therapy. It requests substantial upfront investments from the hospital in: expensive lab-equipment, staff expertise and training, as well as extremely tight hospital logistics. Therefore, an early health economic modelling study, as part of a Coverage with Evidence Development (CED) program, was performed. Methods: We used a Markov decision model to estimate the expected costs and outcomes (quality-adjusted life years; QALYs) for TIL versus ipilimumab for second line treatment in metastatic melanoma patients from a Dutch health care perspective over a life long time horizon. Three mutually exclusive health states (stable disease (responders)), progressive disease and death) were modelled. To inform further research prioritization, Value of Information (VOI) analysis was performed. Results: TIL is expected to generate more QALYs compared to ipilimumab (0.45 versus 0.38 respectively) at lower incremental cost (presently €81,140 versus €94,705 respectively) resulting in a dominant ICER (less costly and more effective). Based on current information TIL is dominating ipilimumab and has a probability of 86% for being cost effective at a cost/QALY threshold of €80,000. The Expected Value of Perfect Information (EVPI) amounted to €3 M. Conclusions: TIL is expected to have the highest probability of being cost-effective in second line treatment for advanced melanoma compared to ipilimumab. To reduce decision uncertainty, a clinical trial investigating e.g. costs and survival seems most valuable. This is currently being undertaken as part of a CED program in the Netherlands Cancer Institute, Amsterdam, the Netherlands, in collaboration with Denmark