A Pilot Cost-Effectiveness Analysis of Treatments in Newly Diagnosed High-Grade Gliomas: The Example of 5-Aminolevulinic Acid Compared With White-Light Surgery

BACKGROUND: High-grade gliomas are aggressive, incurable tumors characterized by extensive diffuse invasion of the normal brain parenchyma. Novel therapies at best prolong survival; their costs are formidable and benefit is marginal. Economic restrictions thus require knowledge of the cost-effectiveness of treatments. Here, we show the cost-effectiveness of enhanced resections in malignant glioma surgery using a well-characterized tool for intraoperative tumor visualization, 5-aminolevulinic acid (5-ALA). OBJECTIVE: To evaluate the cost-effectiveness of 5-ALA fluorescence-guided neurosurgery compared with white-light surgery in adult patients with newly diagnosed high-grade glioma, adopting the perspective of the Portuguese National Health Service. METHODS: We used a Markov model (cohort simulation). Transition probabilities were estimated with the use of data from 1 randomized clinical trial and 1 noninterventional prospective study. Utility values and resource use were obtained from published literature and expert opinion. Unit costs were taken from official Portuguese reimbursement lists (2012 values). The health outcomes considered were quality-adjusted life-years, lifeyears, and progression-free life-years. Extensive 1-way and probabilistic sensitivity analyses were performed. RESULTS: The incremental cost-effectiveness ratios are below €10 000 in all evaluated outcomes, being around €9100 per quality-adjusted life-year gained, €6700 per life-year gained, and €8800 per progression-free life-year gained. The probability of 5-ALA fluorescence-guided surgery cost-effectiveness at a threshold of €20000 is 96.0% for quality-adjusted life-year, 99.6% for life-year, and 98.8% for progression-free life-year. CONCLUSION: 5-ALA fluorescence-guided surgery appears to be cost-effective in newly diagnosed high-grade gliomas compared with white-light surgery. This example demonstrates cost-effectiveness analyses for malignant glioma surgery to be feasible on the basis of existing data

Evaluation of a Fiber-Optic Based Pulsed Laser System for Fluorescence Spectroscopy

A fiber optic based continous wave laser setup has been developed to record the 5-aminolevulinic (5-ALA) induced Protoporfyrin IX (PpIX) fluorescence signals from cerebral gliomas. To reduce the energy delivered to the tissue as well as suppression of the ambient lamp artifact from the recorded spectra, a pulsed laser setup has been developed and evaluated. This setup has been calibrated and first evaluations were performed on the 5-ALA treated skin showing PpIX fluorescence peaks from the ALA treated skin at 635 and 704 nm wavelengths. The system controls laser pulses through a computer interface and labview software package. Pulses as short as 50 ms over a period time of 500 ms are generated and optimally detected. The results from primary measurements on skin show an effective suppression of room fluorescent lamp artifact from the recorded spectra

Prospective cohort study of radiotherapy with concomitant and adjuvant temozolomide chemotherapy for glioblastoma patients with no or minimal residual enhancing tumor load after surgery

Survival of glioblastoma patients has been linked to the completeness of surgical resection. Available data, however, were generated with adjuvant radiotherapy. Data confirming that extensive cytoreduction remains beneficial to patients treated with the current standard, concomitant temozolomide radiochemotherapy, are limited. We therefore analyzed the efficacy of radiochemotherapy for patients with little or no residual tumor after surgery. In this prospective, non-interventional multicenter cohort study, entry criteria were histological diagnosis of glioblastoma, small enhancing or no residual tumor on post-operative MRI, and intended temozolomide radiochemotherapy. The primary study objective was progression-free survival; secondary study objectives were survival and toxicity. Furthermore, the prognostic value of O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation was investigated in a subgroup of patients. One-hundred and eighty patients were enrolled. Fourteen were excluded by patient request or failure to initiate radiochemotherapy. Twenty-three patients had non-evaluable post-operative imaging. Thus, 143 patients qualified for analysis, with 107 patients having residual tumor diameters ≤1.5 cm. Median follow-up was 24.0 months. Median survival or patients without residual enhancing tumor exceeded the follow-up period. Median survival was 16.9 months for 32 patients with residual tumor diameters >0 to ≤1.5 cm (95% CI: 13.3–20.5, p = 0.039), and 13.9 months (10.3–17.5, overall p < 0.001) for 36 patients with residual tumor diameters >1.5 cm. Patient age at diagnosis and extent of resection were independently associated with survival. Patients with MGMT promoter methylated tumors and complete resection made the best prognosis. Completeness of resection acts synergistically with concomitant and adjuvant radiochemotherapy, especially in patients with MGMT promoter methylation

Evaluation of the third- and fourth-generation GOCE Earth gravity field models with Australian terrestrial gravity data in spherical harmonics

In March 2013 the fourth generation of ESA’s (European Space Agency) global gravity field models, DIR4 (Bruinsma et al, 2010b) and TIM4 (Pail et al, 2010), generated from the GOCE (Gravity field and steady-state Ocean Circulation Explorer) gravity observation satellite were released. We evaluate the models using an independent ground truth data set of gravity anomalies over Australia. Combined with GRACE (Gravity Recovery and Climate Experiment) satellite gravity, a new gravity model is obtained that is used to perform comparisons with GOCE models in spherical harmonics. Over Australia, the new gravity model proves to have significantly higher accuracy in the degrees below 120 as compared to EGM2008 and seems to be at least comparable to the accuracy of this model between degree 150 and degree 260. Comparisons in terms of residual quasi-geoid heights, gravity disturbances, and radial gravity gradients evaluated on the ellipsoid and at approximate GOCE mean satellite altitude (h=250 km) show both fourth generation models to improve significantly w.r.t. their predecessors.Relatively, we find a root-mean-square improvement of 39 % for the DIR4 and 23 % for TIM4 over the respective third release models at a spatial scale of 100 km (degree 200). In terms of absolute errors TIM4 is found to perform slightly better in the bands from degree 120 up to degree 160 and DIR4 is found to perform slightly better than TIM4 from degree 170 up to degree 250. Our analyses cannot confirm the DIR4 formal error of 1 cm geoid height (0.35 mGal in terms of gravity) at degree 200. The formal errors of TIM4, with 3.2 cm geoid height (0.9 mGal in terms of gravity) at degree 200, seem to be realistic. Due to combination with GRACE and SLR data, the DIR models, at satellite altitude, clearly show lower RMS values compared to TIM models in the long wavelength part of the spectrum (below degree and order 120). Our study shows different spectral sensitivity of different functionals at ground level and at GOCE satellite altitude and establishes the link among these findings and the Meissl scheme (Rummel and van Gelderen in Manuscripta Geodaetica 20:379–385, 1995)

The Bregman chord divergence

Distances are fundamental primitives whose choice significantly impacts the performances of algorithms in machine learning and signal processing. However selecting the most appropriate distance for a given task is an endeavor. Instead of testing one by one the entries of an ever-expanding dictionary of {\em ad hoc} distances, one rather prefers to consider parametric classes of distances that are exhaustively characterized by axioms derived from first principles. Bregman divergences are such a class. However fine-tuning a Bregman divergence is delicate since it requires to smoothly adjust a functional generator. In this work, we propose an extension of Bregman divergences called the Bregman chord divergences. This new class of distances does not require gradient calculations, uses two scalar parameters that can be easily tailored in applications, and generalizes asymptotically Bregman divergences.Comment: 10 page

Animal study assessing safety of an acoustic coupling fluid that holds the potential to avoid surgically induced artifacts in 3D ultrasound guided operations

BACKGROUND: Use of ultrasound in brain tumor surgery is common. The difference in attenuation between brain and isotonic saline may cause artifacts that degrade the ultrasound images, potentially affecting resection grades and safety. Our research group has developed an acoustic coupling fluid that attenuates ultrasound energy like the normal brain. We aimed to test in animals if the newly developed acoustic coupling fluid may have harmful effects. METHODS: Eight rats were included for intraparenchymal injection into the brain, and if no adverse reactions were detected, 6 pigs were to be included with injection of the coupling fluid into the subarachnoid space. Animal behavior, EEG registrations, histopathology and immunohistochemistry were used in assessment. RESULTS: In total, 14 animals were included, 8 rats and 6 pigs. We did not detect any clinical adverse effects, seizure activity on EEG or histopathological signs of tissue damage. CONCLUSION: The novel acoustic coupling fluid intended for brain tumor surgery appears safe in rats and pigs under the tested circumstances

Rapid sympathetic cooling to Fermi degeneracy on a chip

Neutral fermions present new opportunities for testing many-body condensed matter systems, realizing precision atom interferometry, producing ultra-cold molecules, and investigating fundamental forces. However, since their first observation, quantum degenerate Fermi gases (DFGs) have continued to be challenging to produce, and have been realized in only a handful of laboratories. In this Letter, we report the production of a DFG using a simple apparatus based on a microfabricated magnetic trap. Similar approaches applied to Bose-Einstein Condensation (BEC) of 87Rb have accelerated evaporative cooling and eliminated the need for multiple vacuum chambers. We demonstrate sympathetic cooling for the first time in a microtrap, and cool 40K to Fermi degeneracy in just six seconds -- faster than has been possible in conventional magnetic traps. To understand our sympathetic cooling trajectory, we measure the temperature dependence of the 40K-87Rb cross-section and observe its Ramsauer-Townsend reduction.Comment: 5 pages, 4 figures (v3: new collision data, improved atom number calibration, revised text, improved figures.

Photothermal treatment of glioma; an in vitro study of macrophage-mediated delivery of gold nanoshells

One of the major factors that limits the treatment effectiveness for gliomas is the presence of the blood–brain barrier (BBB) which protects infiltrating glioma cells from the effects of anti-cancer agents. Circulating monocytes/macrophages (Ma) have a natural ability to traverse the intact and compromised BBB and loaded with anti cancer agents could be used as vectors to target tumors and surrounding tumor infiltrated tissue. Nanoshells (NS) are composed of a dielectric core (silica) coated with an ultrathin gold layer which converts absorbed near-infrared light (NIR) to heat with an extremely high efficacy and stability. We have investigated the effects of exposure to laser NIR on multicell human glioma spheroids infiltrated with empty (containing no nanoshells) or nanoshell loaded macrophages. Our results demonstrated that; (1) macrophages could efficiently take up bare or coated (PEGylated) gold NS: (2) NS loaded macrophages infiltrated into glioma spheroids to the same or, in some cases, to a greater degree than empty Ma; (3) NIR laser irradiation of spheroids incorporating NS loaded macrophages resulted in complete growth inhibition in an irradiance dependent manner, and (4) spheroids infiltrated with empty macrophages had growth curves identical to untreated control cultures. The results of this study provide proof of concept for the use of macrophages as a delivery vector of NS into gliomas for photothermal ablation and open the possibility of developing such regimens for patient treatment

Shifting cancer care towards Multidisciplinarity: the cancer center certification program of the German cancer society

Background: Over the last decades numerous initiatives have been set up that aim at translating the best available medical knowledge and treatment into clinical practice. The inherent complexity of the programs and discrepancies in the terminology used make it difficult to appreciate each of them distinctly and compare their specific strengths and weaknesses. To allow comparison and stimulate dialogue between different programs, we in this paper provide an overview of the German Cancer Society certification program for multidisciplinary cancer centers that was established in 2003. Main body: In the early 2000s the German Cancer Society assessed the available information on quality of cancer care in Germany and concluded that there was a definite need for a comprehensive, transparent and evidence-based system of quality assessment and control. This prompted the development and implementation of a voluntary cancer center certification program that was promoted by scientific societies, health-care providers, and patient advocacy groups and based on guidelines of the highest quality level (S3). The certification system structures the entire process of care from prevention to screening and multidisciplinary treatment of cancer and places multidisciplinary teams at the heart of this program. Within each network of providers, the quality of care is documented using tumor-specific quality indicators. The system started with breast cancer centers in 2003 and colorectal cancer centers in 2006. In 2017, certification systems are established for the majority of cancers. Here we describe the rationale behind the certification program, its history, the development of the certification requirements, the process of data collection, and the certification process as an example for the successful implementation of a voluntary but powerful system to ensure and improve quality of cancer care. Conclusion: Since 2003, over 1 million patients had their primary tumors treated in a certified center. There are now over 1200 sites for different tumor entities in four countries that have been certified in accordance with the program and transparently report their results from multidisciplinary treatment for a substantial proportion of cancers. This led to a fundamental change in the structure of cancer care in Germany and neighboring countries within one decade