Expanded HILUS Trial: A Pooled Analysis of Risk Factors for Toxicity From Stereotactic Body Radiation Therapy of Central and Ultracentral Lung Tumors.

PURPOSE: Stereotactic body radiation therapy for tumors near the central airways implies high-grade toxic effects, as concluded from the HILUS trial. However, the small sample size and relatively few events limited the statistical power of the study. We therefore pooled data from the prospective HILUS trial with retrospective data from patients in the Nordic countries treated outside the prospective study to evaluate toxicity and risk factors for high-grade toxic effects. METHODS AND MATERIALS: All patients were treated with 56 Gy in 8 fractions. Tumors within 2 cm of the trachea, the mainstem bronchi, the intermediate bronchus, or the lobar bronchi were included. The primary endpoint was toxicity, and the secondary endpoints were local control and overall survival. Clinical and dosimetric risk factors were analyzed for treatment-related fatal toxicity in univariable and multivariable Cox regression analyses. RESULTS: Of 230 patients evaluated, grade 5 toxicity developed in 30 patients (13%), of whom 20 patients had fatal bronchopulmonary bleeding. The multivariable analysis revealed tumor compression of the tracheobronchial tree and maximum dose to the mainstem or intermediate bronchus as significant risk factors for grade 5 bleeding and grade 5 toxicity. The 3-year local control and overall survival rates were 84% (95% CI, 80%-90%) and 40% (95% CI, 34%-47%), respectively. CONCLUSIONS: Tumor compression of the tracheobronchial tree and high maximum dose to the mainstem or intermediate bronchus increase the risk of fatal toxicity after stereotactic body radiation therapy in 8 fractions for central lung tumors. Similar dose constraints should be applied to the intermediate bronchus as to the mainstem bronchi.

Investigating survival, quality of life and cognition in PROton versus photon therapy for IDH-mutated diffuse grade 2 and 3 GLIOmas (PRO-GLIO): a randomised controlled trial in Norway and Sweden.

INTRODUCTION: The use of proton therapy increases globally despite a lack of randomised controlled trials demonstrating its efficacy and safety. Proton therapy enables sparing of non-neoplastic tissue from radiation. This is principally beneficial and holds promise of reduced long-term side effects. However, the sparing of seemingly non-cancerous tissue is not necessarily positive for isocitrate dehydrogenase (IDH)-mutated diffuse gliomas grade 2-3, which have a diffuse growth pattern. With their relatively good prognosis, yet incurable nature, therapy needs to be delicately balanced to achieve a maximal survival benefit combined with an optimised quality of life. METHODS AND ANALYSIS: PRO-GLIO (PROton versus photon therapy in IDH-mutated diffuse grade 2 and 3 GLIOmas) is an open-label, multicentre, randomised phase III non-inferiority study. 224 patients aged 18-65 years with IDH-mutated diffuse gliomas grade 2-3 from Norway and Sweden will be randomised 1:1 to radiotherapy delivered with protons (experimental arm) or photons (standard arm). First intervention-free survival at 2 years is the primary endpoint. Key secondary endpoints are fatigue and cognitive impairment, both at 2 years. Additional secondary outcomes include several survival measures, health-related quality of life parameters and health economy endpoints. ETHICS AND DISSEMINATION: To implement proton therapy as part of standard of care for patients with IDH-mutated diffuse gliomas grade 2-3, it should be deemed safe. With its randomised controlled design testing proton versus photon therapy, PRO-GLIO will provide important information for this patient population concerning safety, cognition, fatigue and other quality of life parameters. As proton therapy is considerably more costly than its photon counterpart, cost-effectiveness will also be evaluated. PRO-GLIO is approved by ethical committees in Norway (Regional Committee for Medical & Health Research Ethics) and Sweden (The Swedish Ethical Review Authority) and patient inclusion has commenced. Trial results will be published in international peer-reviewed journals, relevant conferences, national and international meetings and expert forums. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT05190172).

Assessing the potential for sea-based macroalgae cultivation and its application for nutrient removal in the Baltic Sea.

Marine eutrophication is a pervasive and growing threat to global sustainability. Macroalgal cultivation is a promising circular economy solution to achieve nutrient reduction and food security. However, the location of production hotspots is not well known. In this paper the production potential of macroalgae of high commercial value was predicted across the Baltic Sea region. In addition, the nutrient limitation within and adjacent to macroalgal farms was investigated to suggest optimal site-specific configuration of farms. The production potential of Saccharina latissima was largely driven by salinity and the highest production yields are expected in the westernmost Baltic Sea areas where salinity is >23. The direct and interactive effects of light availability, temperature, salinity and nutrient concentrations regulated the predicted changes in the production of Ulva intestinalis and Fucus vesiculosus. The western and southern Baltic Sea exhibited the highest farming potential for these species, with promising areas also in the eastern Baltic Sea. Macroalgal farming did not induce significant nutrient limitation. The expected spatial propagation of nutrient limitation caused by macroalgal farming was less than 100-250 m. Higher propagation distances were found in areas of low nutrient and low water exchange (e.g. offshore areas in the Baltic Proper) and smaller distances in areas of high nutrient and high water exchange (e.g. western Baltic Sea and Gulf of Riga). The generated maps provide the most sought-after input to support blue growth initiatives that foster the sustainable development of macroalgal cultivation and reduction of in situ nutrient loads in the Baltic Sea.

Recent change in spatial distribution of the European flat oyster (Ostrea edulis) inferred from field data and empirical models of living oysters and empty shells.

Marine coastal areas are increasingly affected by human activities resulting in changes in species and habitat distributions. Understanding these patterns and its causes and consequences is important for conservation and restoration of such changing habitats. One habitat that has been heavily affected by human use are the North Sea oyster beds which once were abundant but have lost large parts of its coastal distribution due to overexploitation. Based on data of living and dead assemblages of Ostrea edulis collected using video transects, we used an ensemble modeling technique to model and predict current and recent distribution of O. edulis along the Swedish west coast where its distribution is, in relative terms, still rather unaffected. We could detect a recent change in the distribution of O. edulis along the coast which to a large extent could be attributed to a change in depth distribution, suggesting that the population of O. edulis have a slightly shallower distribution today than in the past. Although a potential mismatch between living and dead assemblages, caused by a complex combination of biological and environmental conditions, needs to be considered in the interpretations drawn, it may be a way around the lack of suitable background data in management decisions. This provides important information for management and conservation of the native oyster beds. Furthermore, this study illustrates a method for identifying recent changes in species distribution using dead assemblages of bivalves.

Identifying high-density areas of oysters using species distribution modeling: Lessons for conservation of the native Ostrea edulis and management of the invasive Magallana (Crassostrea) gigas in Sweden.

AIM: Understanding spatial patterns of the distribution of adult native oyster, Ostrea edulis, and the invasive Magallana (Crassostrea) gigas is important for management of these populations. The aim of this study was to use ensemble SDM's to (a) identify and predict conservation hotspots, (b) assess the current level of protection for O. edulis, and (c) quantify the amount of overlap between the two species where interactions with M. gigas are most likely. LOCATION: Skagerrak, Sweden. METHODS: We used data collected by video at depths from 0.5 to 10 m in 436 sites. Models of occurrence and densities >1 m-2 were fitted and assessed using ensemble methods ("biomod2" package). Models of high-density hotspots were used to predict, map, and quantify areal extent of the species in order to assess the degree of overlap with protected areas and the potential for interactions between the two species. RESULTS: Both species were widely distributed in the region. Observations of high-density habitats, mainly occurring at depths of ≈3 and 0.5 m for O. edulis and M. gigas, respectively, were found in 4% and 2% of the sites. Models provided useful predictions for both species (AUC = 0.85-0.99; sensitivity = 0.74-1.0; specificity = 0.72-0.97). High-density areas occupy roughly 15 km2 each with substantial overlap between species. 50% of these are protected only by fisheries regulations, 44% are found in Natura 2000 reserves and 6% of the predicted O. edulis enjoys protection in a national park. MAIN CONCLUSIONS: Data collection by video in combination with SDM's provides a realistic approach for large-scale quantification of spatial patterns of marine population and habitats. O. edulis and M. gigas are common in the area, but a large proportion of the most valuable O. edulis habitats are not found in protected areas. The overlap between species suggests that efforts to manage the invasive M. gigas need to be integrated with management actions to conserve the native O. edulis.

In situ characterization of benthic fluxes and denitrification efficiency in a newly re-established mussel farm.

Mussel farming has been proposed as a mechanism to mitigate eutrophication in coastal waters. However, localizing the intensive filtration of organic matter by mussels can cause a concomitant enrichment of organic matter in sediments below farms, which may influence biogeochemical processes and fates of nutrients in the system. In the context of mitigating eutrophication, it is important to quantify sedimentary changes induced at early life stages of mussel farms. Accordingly, this study investigated how a newly re-established mussel farm affected sedimentation rates, sediment characteristics, sediment-water solute fluxes and nitrate (NO3-) reduction rates (measured in situ) during the first year of production. Sedimentation rates were enhanced at the farm relative to a reference station, and both organic and inorganic carbon accumulated in the sediment with time. Increased organic matter input likely drove the slightly elevated sedimentary effluxes of ammonium (NH4+) and dissolved inorganic phosphorus (DIP) in the farm. Denitrification was the main NO3- reduction process, however, there was a relative increase in the remobilization of bioavailable nitrogen underneath the farm as dissimilatory nitrate reduction to ammonium (DNRA) rates were enhanced by >200% and the denitrification efficiency was 49% lower compared to the reference station. The sedimentary methane (CH4) release tended to be higher at the farm, but fluxes were not significantly different from reference conditions. Low sedimentary pigment concentrations indicated a reduced presence of benthic microalgae at the farm, which likely influenced sediment-water solute fluxes. Over the production cycle, the release of dissolved inorganic nitrogen (DIN) and DIP underneath the farm were respectively 426% and 510% relative to reference conditions. Impacts of the mussel farm were thus measurable already during the first year of establishment. These immediate changes to the sediment biogeochemistry, as well as long-term effects, should be considered when estimating the environmental impact of mussel aquaculture.

The HILUS-Trial-a Prospective Nordic Multicenter Phase 2 Study of Ultracentral Lung Tumors Treated With Stereotactic Body Radiotherapy.

INTRODUCTION: Stereotactic body radiation therapy of thoracic tumors close to the central airways implies risk of severe toxicity. We report a prospective multicenter phase 2 trial for tumors located less than or equal to 1 cm from the proximal bronchial tree with primary end point of local control and secondary end point of toxicity. METHODS: Stereotactic body radiation therapy with 7 Gy × 8 was prescribed to the 67% isodose encompassing the planning target volume. The patients were stratified to group A (tumors ≤ 1 cm from the main bronchi and trachea) or group B (all other tumors). Risk factors for treatment-related death were tested in univariate analysis, and a logistic regression model was developed for fatal bronchopulmonary bleeding versus dose to the main bronchi and trachea. RESULTS: A total of 65 patients (group A/group B, n = 39/26) were evaluated. The median distance between the tumor and the proximal bronchial tree was 0 mm (0-10 mm). The 2-year local control was 83%. Grade 3 to 5 toxicity was noted in 22 patients, including 10 cases of treatment-related death (bronchopulmonary hemorrhage, n = 8; pneumonitis, n = 1; fistula, n = 1). Dose to the combined structure main bronchi and trachea and tumor distance to the main bronchi were important risk factors. Dose modeling revealed minimum dose to the "hottest" 0.2 cc to the structure main bronchi and trachea as the strongest predictor for lethal bronchopulmonary hemorrhage. CONCLUSIONS: On the basis of the presented data, 7 Gy × 8, prescribed to the planning target volume-encompassing isodose, should not be used for tumors located within 1 cm from the main bronchi and trachea. Group B-type tumors may be considered for the treatment on the basis of an individual risk-benefit assessment and a maximum dose to the main bronchi and trachea in the order of 70 to 80 Gy (equivalent dose in 2 Gy fractions).

An open-source, citizen science and machine learning approach to analyse subsea movies.

BACKGROUND: The increasing access to autonomously-operated technologies offer vast opportunities to sample large volumes of biological data. However, these technologies also impose novel demands on ecologists who need to apply tools for data management and processing that are efficient, publicly available and easy to use. Such tools are starting to be developed for a wider community and here we present an approach to combine essential analytical functions for analysing large volumes of image data in marine ecological research. NEW INFORMATION: This paper describes the Koster Seafloor Observatory, an open-source approach to analysing large amounts of subsea movie data for marine ecological research. The approach incorporates three distinct modules to: manage and archive the subsea movies, involve citizen scientists to accurately classify the footage and, finally, train and test machine learning algorithms for detection of biological objects. This modular approach is based on open-source code and allows researchers to customise and further develop the presented functionalities to various types of data and questions related to analysis of marine imagery. We tested our approach for monitoring cold water corals in a Marine Protected Area in Sweden using videos from remotely-operated vehicles (ROVs). Our study resulted in a machine learning model with an adequate performance, which was entirely trained with classifications provided by citizen scientists. We illustrate the application of machine learning models for automated inventories and monitoring of cold water corals. Our approach shows how citizen science can be used to effectively extract occurrence and abundance data for key ecological species and habitats from underwater footage. We conclude that the combination of open-source tools, citizen science systems, machine learning and high performance computational resources are key to successfully analyse large amounts of underwater imagery in the future.

Intratumoral retrograde microdialysis treatment of high-grade glioma with cisplatin.

PURPOSE: This study evaluates the application of a microdialysis technique for interstitial chemotherapy using cisplatin in high-grade glioma. METHOD: An in vitro study demonstrated that cisplatin can be administered through retrograde microdialysis and defined the recovery for cisplatin. In a subsequent phase I study, 1-4 microdialysis catheters were implanted in tumor tissue, brain adjacent to tumor (BAT) tissue, and subcutaneous tissue in 10 patients with recurrent high-grade glioma. Cisplatin was administered continuously in daily doses between 0.3 and 3.9 mg for 4 to12 days. Microdialysis samples were continuously collected and analyzed for glucose metabolites, glutamate, glycerol, and cisplatin concentrations. Treatment tolerability was evaluated through clinical monitoring. Quality of life was assessed using the EORTC-QLQ-C30 questionnaire for up to 3 months after treatment. RESULTS: This in vitro study showed that cisplatin could be administrated with a recovery of 41-97%, depending on flowrate, type of catheter, and cisplatin concentration. During the treatment, patients were exposed to a total dose of 1.2-36.8 mg cisplatin. The concentration of cisplatin in BAT, serum, and subcutaneous tissue was close to detection level in all but two patients. A transient neurologic deterioration due to edema was commonly observed, but no systemic side effects were recorded. After onset of treatment, concentrations of glutamate and glycerol were significantly increased in tumor tissue but not in BAT, with a peak after 3 days, and consistent for the rest of the treatment. Five of the patients survived between 153 and 492 days after treatment. CONCLUSION: This phase I study demonstrates that retrograde microdialysis can be used to administer cisplatin interstitially into high-grade glioma tissue. A high cytotoxicity was detected in tumor tissue, but not in the surrounding brain. Retrograde microdialysis appears to be a clinically useful method for intratumoral drug administration in high-grade glioma.

Cleaning up seas using blue growth initiatives: Mussel farming for eutrophication control in the Baltic Sea.

Eutrophication is a serious threat to aquatic ecosystems globally with pronounced negative effects in the Baltic and other semi-enclosed estuaries and regional seas, where algal growth associated with excess nutrients causes widespread oxygen free "dead zones" and other threats to sustainability. Decades of policy initiatives to reduce external (land-based and atmospheric) nutrient loads have so far failed to control Baltic Sea eutrophication, which is compounded by significant internal release of legacy phosphorus (P) and biological nitrogen (N) fixation. Farming and harvesting of the native mussel species (Mytilus edulis/trossulus) is a promising internal measure for eutrophication control in the brackish Baltic Sea. Mussels from the more saline outer Baltic had higher N and P content than those from either the inner or central Baltic. Despite their relatively low nutrient content, harvesting farmed mussels from the central Baltic can be a cost-effective complement to land-based measures needed to reach eutrophication status targets and is an important contributor to circularity. Cost effectiveness of nutrient removal is more dependent on farm type than mussel nutrient content, suggesting the need for additional development of farm technology. Furthermore, current regulations are not sufficiently conducive to implementation of internal measures, and may constitute a bottleneck for reaching eutrophication status targets in the Baltic Sea and elsewhere.

Metabolic response patterns in brain microdialysis fluids and serum during interstitial cisplatin treatment of high-grade glioma.

BACKGROUND: High-grade gliomas are associated with poor prognosis. Tumour heterogeneity and invasiveness create challenges for effective treatment and use of systemically administrated drugs. Furthermore, lack of functional predictive response-assays based on drug efficacy complicates evaluation of early treatment responses. METHODS: We used microdialysis to deliver cisplatin into the tumour and to monitor levels of metabolic compounds present in the tumour and non-malignant brain tissue adjacent to tumour, before and during treatment. In parallel, we collected serum samples and used multivariate statistics to analyse the metabolic effects. RESULTS: We found distinct metabolic patterns in the extracellular fluids from tumour compared to non-malignant brain tissue, including high concentrations of a wide range of amino acids, amino acid derivatives and reduced levels of monosaccharides and purine nucleosides. We found that locoregional cisplatin delivery had a strong metabolic effect at the tumour site, resulting in substantial release of glutamic acid, phosphate, and spermidine and a reduction of cysteine levels. In addition, patients with long-time survival displayed different treatment response patterns in both tumour and serum. Longer survival was associated with low tumour levels of lactic acid, glyceric acid, ketoses, creatinine and cysteine. Patients with longer survival displayed lower serum levels of ketohexoses, fatty acid methyl esters, glycerol-3-phosphate and alpha-tocopherol, while elevated phosphate levels were seen in both tumour and serum during treatment. CONCLUSION: We highlight distinct metabolic patterns associated with high-grade tumour metabolism, and responses to cytotoxic cisplatin treatment.

Assessment of the population of Ostrea edulis in Sweden: A marginal population of significance?

The European flat oyster Ostrea edulis is an economically and ecologically important species subjected to extensive protection and restoration efforts, due to sharp population declines in Europe. In Sweden, O. edulis occurs at the northern fringe of its range. Knowledge of the distribution and abundance of the species is limited, and the size of the population has never been estimated. Oyster fishery sustainability has never been assessed.Using a random sampling approach and towed video, we collected data on oyster occurrence at 435 sites to estimate abundance and distribution of O. edulis in the Swedish Skagerrak region. Furthermore, the size of the population was assessed and the current management and legislation strategy of the species was analyzed.Living O. edulis was found in 27% of all sampled sites above 6 m, and the size of the population was estimated to 36.6 ± 16.3 million individuals (total population ± SE). The distribution was patchy, and approximately 60% of the population was found in oyster bed densities (≥5 oysters/m2), which corresponds to around 1% of the sampled sites.The nondestructive sampling method and representative design provided useful estimates of population size and error, which indicate that the marginal population of O. edulis in Sweden constitutes a significant part of the remaining European population. We argue that the relatively good status of the Swedish population can be explained by (a) private ownership of fishing rights, (b) a small-scale fishery that exploits <0.5% of the estimated population annually, conducted using nondestructive methods, and (c) parasite-free waters, potentially due to effective prevention of spread of infection. OPEN RESEARCH BADGES: This article has earned an Open Data Badge for making publicly available the digitally-shareable data necessary to reproduce the reported results. The data is available at https://osf.io/jgpxw/?view_only=d070b45802a4426da028efffde3d0f76.

Radiotherapy induces an immediate inflammatory reaction in malignant glioma: a clinical microdialysis study.

The knowledge of response to radiation in the immuno-microenvironment of high grade gliomas is sparse. In vitro results have indicated an inflammatory response of myeloid cells after irradiation. Therefore, microdialysis was used to verify whether this is operative in tumor tissue and brain adjacent to tumor (BAT) after clinical radiotherapy of patients with high grade glioma. Stereotactic biopsies and implantation of microdialysis catheters in tumor tissue and BAT were performed in eleven patients with high-grade glioma. The patients were given daily radiation fractions of 2-3.4 Gy. Microdialysis samples were collected before radiotherapy and during the first five days of radiation. Cytokines, glucose metabolites, glutamate and glycerol were analyzed. Immunohistochemistry was performed to detect macrophages (CD68) and monocytes (CD163) as well as IL-6, IL-8 and MCP-1. A significant increase of IL-8, MCP-1 and MIP-1a were detected in tumor tissue already after the first dose of radiation and increased further during 5 days of radiation. IL-6 did also increase but after five fractions of radiation. In BAT, the cytokine response was modest with significant increase of IL-8 after third dose of radiation. We found a positive correlation between baseline IL-8 and IL-6 microdialysis levels in tumor tissue and survival. Glucose metabolites or glycerol and glutamate did not change during radiation. In all tumors staining for macrophages was demonstrated. IL-6 was found in viable tumor cells while MCP-1 was demonstrated in macrophages or tumor matrix. Our findings suggest that radiation induces a rapid enhancement of the prevailing inflammation in high-grade glioma tissue. The microdialysis technique is feasible for this type of study and could be used to monitor metabolic changes after different interventions.

SPACE - A randomized study of SBRT vs conventional fractionated radiotherapy in medically inoperable stage I NSCLC.

BACKGROUND: Stereotactic body radiotherapy (SBRT) has been introduced for small lung tumors due to excellent local control and few side effects, even though there are no comparative studies. SPACE (Stereotactic Precision And Conventional radiotherapy Evaluation) is the first randomized phase II trial comparing SBRT and conventional fractionated radiotherapy (3DCRT). METHODS: Patients with stage I medically inoperable NSCLC were randomized to receive SBRT to 66Gy in 3 fractions (one week) or 3DCRT to 70Gy (7weeks). Patients were followed to assess efficacy, toxicity and HRQL. FINDINGS: Between 2007 and 2011, 102 patients were randomized. Mean age 74 (57-86), 60% women, the vast majority (92%) had COPD or cardiovascular comorbidity. The SBRT arm included more patients with T2-tumors (p=0.02) and male gender (p=0.35). The median follow-up was 37months with a 1-, 2- and 3-year PFS of: SBRT: 76%, 53%, 42% and 3DCRT: 87%, 54% 42%, HR=0.85 (95% CI 0.52-1.36) with no difference between the groups and no difference in OS (HR=0.75, 95% CI 0.43-1.30). At the end of the study 70% of SBRT patients had not progressed compared to 59% (3DCRT, p=0.26). Toxicity was low with no grade 5 events. Pneumonitis of any grade was observed in 19% (SBRT) and 34% (3DCRT, p=0.26), and esophagitis in 8% and 30% respectively (p=0.006). HRQL was evaluated with the EORTC QLQ 30 and LC14 module and patients treated with 3DCRT experienced worse dyspnea (p=0.01), chest pain (p=0.02) and cough (>10 points difference). INTERPRETATION: There was no difference in PFS and OS between SBRT and conventionally treated patients despite an imbalance of prognostic factors. We observed a tendency of an improved disease control rate in the SBRT group and they experienced better HRQL and less toxicity. SBRT is convenient for patients and should be considered standard treatment for patients with inoperable stage I NSCLC.

Computational high-throughput screening of fluid permeability in heterogeneous fiber materials.

We explore computational high-throughput screening as a design strategy for heterogeneous, isotropic fiber materials. Fluid permeability, a key property in the design of soft porous materials, is systematically studied using a multi-scale lattice Boltzmann framework. After characterizing microscopic permeability as a function of solid volume fraction in the microstructure, we perform high-throughput computational screening of in excess of 35 000 macrostructures consisting of a continuous bulk interrupted by spherical/elliptical domains with either lower or higher microscopic permeability (hence with two distinct microscopic solid volume fractions and therefore two distinct microscopic permeabilities) to assess which parameters determine macroscopic permeability for a fixed average solid volume fraction. We conclude that the fractions of bulk and domains and the distribution of solid volume fraction between them are the primary determinants of macroscopic permeability, and that a substantial increase in permeability compared to the corresponding homogenous material is attainable.

Characterization of the serum metabolome following radiation treatment in patients with high-grade gliomas.

BACKGROUND: Glioblastomas progress rapidly making response evaluation using MRI insufficient since treatment effects are not detectable until months after initiation of treatment. Thus, there is a strong need for supplementary biomarkers that could provide reliable and early assessment of treatment efficacy. Analysis of alterations in the metabolome may be a source for identification of new biomarker patterns harboring predictive information. Ideally, the biomarkers should be found within an easily accessible compartment such as the blood. METHOD: Using gas-chromatographic- time-of-flight-mass spectroscopy we have analyzed serum samples from 11 patients with glioblastoma during the initial phase of radiotherapy. Fasting serum samples were collected at admittance, on the same day as, but before first treatment and in the morning after the second and fifth dose of radiation. The acquired data was analyzed and evaluated by chemometrics based bioinformatics methods. Our findings were compared and discussed in relation to previous data from microdialysis in tumor tissue, i.e. the extracellular compartment, from the same patients. RESULTS: We found a significant change in metabolite pattern in serum comparing samples taken before radiotherapy to samples taken during early radiotherapy. In all, 68 metabolites were lowered in concentration following treatment while 16 metabolites were elevated in concentration. All detected and identified amino acids and fatty acids together with myo-inositol, creatinine, and urea were among the metabolites that decreased in concentration during treatment, while citric acid was among the metabolites that increased in concentration. Furthermore, when comparing results from the serum analysis with findings in tumor extracellular fluid we found a common change in metabolite patterns in both compartments on an individual patient level. On an individual metabolite level similar changes in ornithine, tyrosine and urea were detected. However, in serum, glutamine and glutamate were lowered after treatment while being elevated in the tumor extracellular fluid. CONCLUSION: Cross-validated multivariate statistical models verified that the serum metabolome was significantly changed in relation to radiation in a similar pattern to earlier findings in tumor tissue. However, all individual changes in tissue did not translate into changes in serum. Our study indicates that serum metabolomics could be of value to investigate as a potential marker for assessing early response to radiotherapy in malignant glioma.

Fast and robust automatic calibration for single-shot dual-wavelength digital holography based on speckle displacements.

The objective of this paper is to describe a fast and robust automatic single-shot dual-wavelength holographic calibration method that can be used for online shape measurement applications. We present a model of the correction in two terms for each lobe, one to compensate the systematic errors caused by off-axis angles and the other for the curvature of the reference waves, respectively. Each hologram is calibrated independently without a need for an iterative procedure or information of the experimental set-up. The calibration parameters are extracted directly from speckle displacements between different reconstruction planes. The parameters can be defined as any fraction of a pixel to avoid the effect of quantization. Using the speckle displacements, problems associated with phase wrapping is avoided. The procedure is shown to give a shape accuracy of 34 µm using a synthetic wavelength of 1.1 mm for a measurement on a cylindrical test object with a trace over a field of view of 18 mm×18 mm.

Hypofractionated stereotactic radiotherapy in medium-sized to large arteriovenous malformations.

We have reviewed treatment results in terms of obliteration and complications in 24 patients with medium to large sized cerebral arteriovenous malformations (AVMs) (mean volume 18.5±8.9cm(3); range: 10-42) treated with hypofractionated stereotactic radiotherapy (HSRT). AVMs are congenital lesions associated with a high morbidity and mortality. Radiosurgery is one option for treatment. However, in larger AVMs with volumes exceeding 10cm(3) obliteration rates are less favourable and radiation induced complications more frequent. For larger AVMs, volume-staged radiosurgery is one option while another option may be the use of HSRT. Patients were treated with 6-7Gy in five fractions to a total dose of 30-35Gy (mean total dose 32.9±1.6Gy [standard error of the mean]). Sixteen patients (69.6%) showed obliteration after a mean time of 35.2±14.8 months (range: 24-60). Only one patient (4.2%) experienced symptomatic radionecrosis. Our treatment with HSRT seems safe and efficient for treatment of medium to large sized AVMs. Treatment results seem to be in line with volume-staged radiosurgery and may be an alternative for AVMs not suitable for single fraction radiosurgery.

Modeling and predicting the growth of the mussel, Mytilus edulis: implications for planning of aquaculture and eutrophication mitigation.

The increased pressure on the marine ecosystems highlights the need for policies and integrated approaches for sustainable management of coastal areas. Spatial planning based on geographic information of human activities, ecological structures and functions, and their associated goods and services is a fundamental component in this context. Here, we evaluate the potential of predictive modeling to provide spatial data on one ecosystem function, mussel growth for use in such processes. We developed a methodology based on statistical modeling, spatial prediction, and mapping for the relative growth of the blue mussel, Mytilus edulis. We evaluated the performance of different modeling techniques and classification schemes using empirical measurements of growth from 144 sampling sites and data on biological, chemical, and physical predictors. Following comparisons of the different techniques and schemes, we developed random forest models to predict growth along the Swedish west coast. Implemented into GIS the best model produced in this study predicts that low, intermediate, and high growth rates can be expected in 53%, 32%, and 15% of modeled area, respectively. The results of this study also suggest that the nature and quality of predictor data hold the key to improving the predictive power of models. On a more general note, this study exemplifies a feasible approach based on measuring, modeling, and mapping for obtaining scientifically based spatial information on ecosystem functions and services affected by a complex set of factors. Such information is fundamental for maritime spatial planning and ecosystem-based management and its importance is likely to increase in the future. Because of its close link to nutrient assimilation and production yield, site-specific information of soft tissue growth such as the map of predicted growth rate developed in this study can be used as a tool for optimizing actions aimed at mitigating eutrophication and aquaculture operations and in maritime spatial planning processes of coastal areas.