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Objective: To examine the association between surgical waiting times (SWTs) and all-cause mortality (ACM) in non-metastatic patients with RCC, in relation to tumour stage. Patients and methods: This nation-wide population-based cohort study included 9,918 M0 RCC patients registered in the National Swedish Kidney Cancer Register, between 2009 and 2021, followed-up for ACM until 9 December 2021, and having measured SWTs. The associations between primarily SWTs from date of radiological diagnosis to date of surgery (WRS) and secondarily SWTs from date of radiological diagnosis to date of treatment decision (WRT) and date of treatment decision to date of surgery (WTS), in relation to ACM, were analysed using Cox regression analysis, adjusted for clinical and demographic characteristics, stratified and unstratified according to T-stage. Results: During a mean follow-up time of 5 years (49,873 person-years), 23% (n = 2291) of the patients died. The adjusted hazard ratio (AHR) for WRS (months) for all patients was 1.03 (95% confidence interval [CI] = 1.02–1.04; p < 0.001). When subdividing WRS on T-stage, the AHRs were 1.03 (95% CI = 1.01–1.04; p < 0.001) and 1.05 (95% CI = 1.02–1.08; p = 0.003) for stages T1 and T3, respectively, while non-significant for T2 (p = 0.079) and T4 (p = 0.807). Similar results were obtained for WRT and WTS. Conclusions: Prolonged SWTs significantly increased the risk of early overall death among patients with RCC. The increased risk of early death from any cause show the importance of shortening SWTs in clinical work of patients with this malignant disease.

Distant spreading of tumor cells to the central nervous system in non-small cell lung cancer (NSCLC) occurs frequently and poses major clinical issues due to limited treatment options. RNAs displaying differential expression in brain metastasis versus primary NSCLC may explain distant tumor growth and may potentially be used as therapeutic targets. In this study, we conducted systematic microRNA expression profiling from tissue biopsies of primary NSCLC and brain metastases from 25 patients. RNA analysis was performed using the nCounter Human v3 miRNA Expression Assay, NanoString technologies, followed by differential expression analysis and in silico target gene pathway analysis. We uncovered a panel of 11 microRNAs with differential expression and excellent diagnostic performance in brain metastasis versus primary NSCLC. Five microRNAs were upregulated in brain metastasis (miR-129-2-3p, miR-124-3p, miR-219a-2-3p, miR-219a-5p, and miR-9-5p) and six microRNAs were downregulated in brain metastasis (miR-142-3p, miR-150-5p, miR-199b-5p, miR-199a-3p, miR-199b-5p, and miR-199a-5p). The differentially expressed microRNAs were predicted to converge on distinct target gene networks originating from five to twelve core target genes. In conclusion, we uncovered a unique microRNA profile linked to two target gene networks. Our results highlight the potential of specific microRNAs as biomarkers for brain metastasis in NSCLC and indicate plausible mechanistic connections.

Distant spreading of tumor cells to the central nervous system in non-small cell lung cancer (NSCLC) occurs frequently and poses major clinical issues due to limited treatment options. RNAs displaying differential expression in brain metastasis versus primary NSCLC may explain distant tumor growth and may potentially be used as therapeutic targets. In this study, we conducted systematic microRNA expression profiling from tissue biopsies of primary NSCLC and brain metastases from 25 patients. RNA analysis was performed using the nCounter Human v3 miRNA Expression Assay, NanoString technologies, followed by differential expression analysis and in silico target gene pathway analysis. We uncovered a panel of 11 microRNAs with differential expression and excellent diagnostic performance in brain metastasis versus primary NSCLC. Five microRNAs were upregulated in brain metastasis (miR-129-2-3p, miR-124-3p, miR-219a-2-3p, miR-219a-5p, and miR-9-5p) and six microRNAs were downregulated in brain metastasis (miR-142-3p, miR-150-5p, miR-199b-5p, miR-199a-3p, miR-199b-5p, and miR-199a-5p). The differentially expressed microRNAs were predicted to converge on distinct target gene networks originating from five to twelve core target genes. In conclusion, we uncovered a unique microRNA profile linked to two target gene networks. Our results highlight the potential of specific microRNAs as biomarkers for brain metastasis in NSCLC and indicate plausible mechanistic connections.

The impact of using wind observations from the Aeolus satellite in a limited-area numerical weather prediction (NWP) system is being investigated using the limited-area NWP model Harmonie–Arome over the Nordic region. We assimilate the horizontal line-of-sight (HLOS) winds observed by Aeolus using 3D-Var data assimilation for two different periods, one in September–October 2018 when the satellite was recently launched and a later period in April–May 2020 to investigate the updated data processing of the HLOS winds. We find that the quality of the Aeolus observations has degraded between the first and second experiment period over our domain. However, observations from Aeolus, in particular the Mie winds, have a clear impact on the analysis of the NWP model for both periods, whereas the forecast impact is neutral when compared against radiosondes. Results from evaluation of observation minus background and observation minus analysis departures based on Desroziers diagnostics show that the observation error should be increased for Aeolus data in our experiments, but the impact of doing so is small. We also see that there is potential improvement in using 4D-Var data assimilation, which generates flow-dependent analysis increments, with the Aeolus data.

Winds measured by lidar from the Aeolus satellite are compared with winds measured by two ground-based radars – MARA in Antarctica (70.77∘ S, 11.73∘ E) and ESRAD (67.88∘ N, 21.10∘ E) in Arctic Sweden – for the period 1 July–31 December 2019. Aeolus is a demonstrator mission to test whether winds measured by Doppler lidar from space can have sufficient accuracy to contribute to improved weather forecasting. A comprehensive programme of calibration and validation has been undertaken following the satellite launch in 2018, but, so far, direct comparison with independent measurements from the Arctic or Antarctic regions have not been made. The comparison covers heights from the low troposphere to just above the tropopause. Results for each radar site are presented separately for Rayleigh (clear) winds, Mie (cloudy) winds, sunlit (“summer”) and non-sunlit (“winter”) seasons, and ascending and descending satellite tracks. Horizontally projected line-of-sight (HLOS) winds from Aeolus, reprocessed using baseline 2B10, for passes within 100 km of the radar sites, are compared with HLOS winds calculated from 1 h averaged radar horizontal wind components. The agreement in most data subsets is very good, with no evidence of significant biases ( m s−1). Possible biases are identified for two subsets (about −2 m s−1 for the Rayleigh winds for the descending passes at MARA and about 2 m s−1 for the Mie winds for the ascending passes at ESRAD, both in winter), but these are only marginally significant. A robust significant bias of about 7 m s−1 is found for the Mie winds for the ascending tracks at MARA in summer. There is also some evidence for increased random error (by about 1 m s−1) for the Aeolus Mie winds at MARA in summer compared to winter. This might be related to the presence of sunlight scatter over the whole of Antarctica as Aeolus transits across it during summer.

Introduction The effects of single-fraction gamma knife radiosurgery (sf-GKRS) on patients with renal cell carcinoma (RCC) brain metastases (BM) in the era of targeted agents (TA) and immune checkpoint inhibitors (ICI) are insufficiently studied. Methods and materials Clear cell metastatic RCC patients treated with sf-GKRS due to BM in 2005-2014 at three European centres were retrospectively analysed (n= 43). Median follow-up was 56 months. Ninety-five percent had prior nephrectomy, 53% synchronous metastasis and 86% extracranial disease at first sf-GKRS. Karnofsky performance status (KPS) ranged from 60 to 100%. Outcome measures were overall survival (OS), local control (LC) and adverse radiation effects (ARE). Results One hundred and ninety-four targets were irradiated. The median number of targets at first sf-GKRS was two. The median prescription dose was 22.0 Gy. Thirty-seven percent had repeated sf-GKRS. Eighty-eight percent received TA. LC rates at 12 and 18 months were 97% and 90%. Median OS from the first sf-GKRS was 15.7 months. Low serum albumin (HR for death 5.3), corticosteroid use pre-sf-GKRS (HR for death 5.8) and KPS < 80 (HR for death 9.1) were independently associated with worse OS. No further prognostic information was gleaned from MSKCC risk group, synchronous metastasis, age, number of BM or extracranial metastases. Other prognostic scores for BM radiosurgery, including DS-GPA, renal-GPA, LLV-SIR and CITV-SIR, again, did not add further prognostic value. ARE were seldom symptomatic and were associated with tumour volume, 10-Gy volume and pre-treatment perifocal oedema. ARE were less common among patients treated with TA within 1 month of sf-GKRS. Conclusions We identified albumin, corticosteroid use and KPS as independent prognostic factors for sf-GKRS of clear cell RCC BM. Studies focusing on the prognostic significance of albumin in sf-GKRS are rare. Further studies with a larger number of patients are warranted to confirm the above analytical outcome. Also, in keeping with previous studies, our data showed optimal rates of local tumour control and limited toxicity post radiosurgery, rendering GKRS the tool of choice in the management of RCC BM.

ImportanceDisulfiram has demonstrated broad antitumoral effect in several preclinical studies. One of the proposed indications is for the treatment of glioblastoma.ObjectiveTo evaluate the efficacy and safety of disulfiram and copper as add-on to alkylating chemotherapy in patients with recurrent glioblastoma.Design, Setting, and ParticipantsThis was a multicenter, open-label, randomized phase II/III clinical trial with parallel group design. Patients were recruited at 7 study sites in Sweden and 2 sites in Norway between January 2017 and November 2020. Eligible patients were 18 years or older, had a first recurrence of glioblastoma, and indication for treatment with alkylating chemotherapy. Patients were followed up until death or a maximum of 24 months. The date of final follow-up was January 15, 2021. Data analysis was performed from February to September 2022.InterventionsPatients were randomized 1:1 to receive either standard-of-care (SOC) alkylating chemotherapy alone, or SOC with the addition of disulfiram (400 mg daily) and copper (2.5 mg daily).Main Outcomes and MeasuresThe primary end point was survival at 6 months. Secondary end points included overall survival, progression-free survival, adverse events, and patient-reported quality of life.ResultsAmong the 88 patients randomized to either SOC (n = 45) or SOC plus disulfiram and copper (n = 43), 63 (72%) were male; the mean (SD) age was 55.4 (11.5) years. There was no significant difference between the study groups (SOC vs SOC plus disulfiram and copper) in 6 months survival (62% [26 of 42] vs 44% [19 of 43]; P = .10). Median overall survival was 8.2 months (95% CI, 5.4-10.2 months) with SOC and 5.5 months (95% CI, 3.9-9.3 months) with SOC plus disulfiram and copper, and median progression-free survival was 2.6 months (95% CI, 2.4-4.6 months) vs 2.3 months (95% CI, 1.7-2.6 months), respectively. More patients in the SOC plus disulfiram and copper group had adverse events grade 3 or higher (34% [14 of 41] vs 11% [5 of 44]; P = .02) and serious adverse events (41% [17 of 41] vs 16% [7 of 44]; P = .02), and 10 patients (24%) discontinued disulfiram treatment because of adverse effects.Conclusions and RelevanceThis randomized clinical trial found that among patients with recurrent glioblastoma, the addition of disulfiram and copper to chemotherapy, compared with chemotherapy alone, resulted in significantly increased toxic effects, but no significant difference in survival. These findings suggest that disulfiram and copper is without benefit in patients with recurrent glioblastoma.Trial RegistrationClinicalTrials.gov Identifier: NCT02678975; EUDRACT Identifier: 2016-000167-16

The impact of combined direct normal irradiation nowcasts on revenues of two different concentrating solar power plant technologies under a time-of-delivery tariff is investigated. The applied tariff scheme offers considerably increased remuneration during evening hours with maximum energy demand and is similar to that used in South Africa for some concentrating solar power (CSP) plants already. The ideal forecast derived from ground-based observations was used to quantify the maximum economic advantage of using any forecasting scheme - and is estimated around 4 % for parabolic trough power plants and as around 8 % for solar tower power plants. This implies a maximum impact of up to 2.2 Mio and 5.3 Mio EUR of additional revenues per year for a typical 110 MW solar trough or solar tower power plant, respectively. The investigated nowcast strategy merges several satellite and numerical weather prediction based nowcasts together with a smart persistence approach in order to generate a best-of nowcast for now- and forecast time horizons up to 9 hours and in the 15 min temporal resolution required for the electricity market participation. The results for the combined nowcast are evaluated with respect to daily power plant operating principles and focusing on a power plant specific forecast verification strategy. The combined nowcast is therefore compared with ECMWF IFS based forecasts and with an optimized ground observation driven persistence approach in two representative locations around the Mediterranean area. The study investigates the impact both with respect to annual energy yield and economic annual revenues of CSP plants. It is found that in our study period 2010 and 2013 to 2015 the merged nowcast strategy adds 0.8 to 4.4 % in additional revenues per year compared to the ECMWF IFS day ahead forecast, which is a typical example of nowadays routinely available forecasts in the power plant's control room. This implies additional revenues of about 450 to 2900 kEUR per year when adding a nowcasting scheme to the solar production forecast tool already in operation at some power plants.

The impact of using wind speed data from the Aeolus satellite in a limited area Numerical Weather Prediction (NWP) system is being investigated using the limited area NWP model Harmonie-Arome over the Nordic region. We assimilate the Horizontal Line of Sight (HLOS) winds observed by Aeolus using a 3D-Var data assimilation for two different periods, one in Sept-Oct 2018 when the satellite was recently launched, and a later period in Apr-May 2020 to investigate the updated data processing of the HLOS winds. We find that the quality of the Aeolus observations have degraded between the first and second experiment period over our domain. However observations from Aeolus, in particular the Mie winds, have a clear impact on the analysis of the NWP model for both periods whereas the forecast impact is neutral when compared against radiosondes. Results from evaluation of observation minus background and observation minus analysis departures based on Desroziers diagnostics show that the observation error should be increased for Aeolus data in our experiments, but the impact of doing so is small. We also see that there is potential improvement in using 4D-Var data assimilation with the Aeolus data.

The impact of using wind speed data from the Aeolus satellite in a limited area Numerical Weather Prediction (NWP) system is being investigated using the limited area NWP model Harmonie-Arome over the Nordic region. We assimilate the Horizontal Line of Sight (HLOS) winds observed by Aeolus using 3D-Var data assimilation for two different periods, one in Sept–Oct 2018 when the satellite was recently launched, and a later period in Apr–May 2020 to investigate the updated data processing of the HLOS winds. We find that the quality of the Aeolus observations have degraded between the first and second experiment period over our domain. However observations from Aeolus, in particular the Mie winds, have a clear impact on the analysis of the NWP model for both periods whereas the forecast impact is neutral when compared against radiosondes. Results from evaluation of observation minus background and observation minus analysis departures based on Desroziers diagnostics show that the observation error should be increased for Aeolus data in our experiments, but the impact of doing so is small. We also see that there is potential improvement in using 4D-Var data assimilation, which generate flow-dependent analysis increments, with the Aeolus data.

Two atmospheric VHF radars: ESRAD (Esrange MST radar) located near Kiruna in the Swedish Arctic and MARA (Moveable Atmospheric Radar for Antarctica) at the Indian research station Maitri in Antarctica perform wind measurements in the troposphere and lower stratosphere on a regular basis. We compared horizontal winds at altitudes between about 0.5 and 14 km derived from the radar data using the full correlation analysis (FCA) technique with radiosonde observations and models. The comparison with 28 radiosondes launched from January 2017 to August 2019 showed that ESRAD underestimates the zonal and meridional winds by about 8 % and 25 %, respectively. This is likely caused by the receiver group arrangement used for the FCA together with a high level of non-white noise. A similar result was found when comparing with the regional numerical weather prediction model HARMONIE-AROME (Bengtsson et al., 2017) for the period September 2018–May 2019. The MARA winds were compared with winds from radiosondes for the period February–October 2014 (291 occasions). In contrast to ESRAD, there is no indication that MARA underestimates the winds compared to the sondes. The mean difference between the radar and radiosonde winds is close to zero for both zonal and meridional components. The comparison of MARA with the ECMWF ERA5 reanalysis for January–December 2019 reveals good agreement with the mean difference between 0.1 and −0.5 m/s depending on the component and season. The random errors in the wind components (standard deviations over all estimates in 1 h averages) are typically 2–3 m/s for both radars. Standard deviation of the differences between radars and sondes are 3–5 m/s.

MetCoOp is a Nordic collaboration on operational Numerical Weather Prediction based on a common limited-area km-scale ensemble system. The initial states are produced using a 3-dimensional variational data assimilation scheme utilizing a large amount of observations from conventional in-situ measurements, weather radars, global navigation satellite system, advanced scatterometer data and satellite radiances from various satellite platforms. A version of the forecasting system which is aimed for future operations has been prepared for an enhanced assimilation of microwave radiances. This enhanced data assimilation system will use radiances from the Microwave Humidity Sounder, the Advanced Microwave Sounding Unit-A and the Micro-Wave Humidity Sounder-2 instruments on-board the Metop-C and Fengyun-3 C/D polar orbiting satellites. The implementation process includes channel selection, set-up of an adaptive bias correction procedure, and careful monitoring of data usage and quality control of observations. The benefit of the additional microwave observations in terms of data coverage and impact on analyses, as derived using the degree of freedom of signal approach, is demonstrated. A positive impact on forecast quality is shown, and the effect on the precipitation for a case study is examined. Finally, the role of enhanced data assimilation techniques and adaptions towards nowcasting are discussed.

Two atmospheric VHF radars: ESRAD located near Kiruna in the Swedish Artic and MARA at Indian research station Maitri in Antarctica perform wind measurements in the troposphere and lower stratosphere on a regular basis. We compared horizontal winds at altitudes between about 0.5 km and 14 km derived from the radar data using the full correlation analysis technique with radiosonde observations and models. The comparison with 28 radiosondes launched from January 2017 to August 2019 showed that ESRAD underestimates the zonal and meridional winds by about 8 % and 25 %, respectively. The mean differences between the radar and radiosonde winds are −1.4 m/s and 0.4 m/s. A similar result was found when comparing with the regional NWP model HARMONIE-AROME for the period September 2018–May 2019. The ESRAD random error was estimated to be 2.8 m/s (2.4 m/s) for the zonal (meridional) component. The comparison of MARA with the ECMWF ERA5 reanalysis for January–December 2019 reveals good agreement between them with the mean difference between 0.1 m/s and −0.5 m/s depending on the component and season. The MARA random errors are 2.6 m/s and 2.3 m/s for the zonal and meridional winds, respectively.

Objective: To explore cost-effectiveness of targeted therapies (TTs) in the treatment of metastatic renal cell carcinoma (mRCC) in a real-world context using a nationwide population-based approach. ...

In this article the performance for short-range solar radiation forecasts by the global deterministic and ensemble models from the European Centre for Medium-Range Weather Forecasts (ECMWF) is compared with an ensemble of the regional mesoscale model HARMONIE-AROME used by the national meteorological services in Sweden, Norway and Finland. Note however that only the control members and the ensemble means are included in the comparison. The models resolution differs considerably with 18 km for the ECMWF ensemble, 9 km for the ECMWF deterministic model, and 2.5 km for the HARMONIE-AROME ensemble. The models share the same radiation code. It turns out that they all underestimate systematically the Direct Normal Irradiance (DNI) for clear-sky conditions. Except for this shortcoming, the HARMONIE-AROME ensemble model shows the best agreement with the distribution of observed Global Horizontal Irradiance (GHI) and DNI values. During mid-day the HARMONIE-AROME ensemble mean performs best. The control member of the HARMONIE-AROME ensemble also scores better than the global deterministic ECMWF model. This is an interesting result since mesoscale models have so far not shown good results when compared to the ECMWF models. Three days with clear, mixed and cloudy skies are used to illustrate the possible added value of a probabilistic forecast. It is shown that in these cases the mesoscale ensemble could provide decision support to a grid operator in terms of forecasts of both the amount of solar power and its probabilities.

ESRAD and MARA, , respectivelyThe Aeolus HLOS wind component (L2B) is also compared to the corresponding component of winds derived from the HARMONIE model for the ESRAD collocations and from the ECMWF ERA5 re-analysis for the MARA collocations. We estimate bias, root-mean-squared error and correlation for the Aeolus winds the radar and model data.

Background:The long-term benefits of local therapy in metastatic renal cell carcinoma (mRCC) have been widely documented. In this context, single fraction gamma knife radiosurgery (SF-GKRS) is routinely used in the management of brain metastases. However, SF-GKRS is not always feasible due to volumetric and regional constraints. We intend to illustrate how a dose-volume adaptive hypofractionated GKRS technique based on two concurrent dose prescriptions termed rapid rescue radiosurgery (RRR) can be utilized in this particular scenario.Case Description:A 56-year-old man presented with left-sided hemiparesis; the imaging showed a 13.1 cc brain metastasis in the right central sulcus (Met 1). Further investigation confirmed the histology to be a metastatic clear cell RCC. Met 1 was treated with upfront RRR. Follow-up magnetic resonance imaging (MRI) at 10 months showed further volume regression of Met 1; however, concurrently, a new 17.3 cc lesion was reported in the boundaries of the left frontotemporal region (Met 2) as well as a small metastasis (Results:Gradual and sustained tumor ablation of Met 1 and Met 2 was demonstrated on a 20 months long follow- up. The patient succumbed to extracranial disease 21 months after the treatment of Met 1 without evidence of neurological impairment post-RRR.Conclusion:Despite poor prognosis and precluding clinical factors (failing systemic treatment, eloquent location, and radioresistant histology), RRR provided optimal tumor ablation and salvage of neurofunction with limited toxicity throughout follow-up.

For more than a decade, GNSS-meteorology has been increasingly used operationally in Europe particularly for data assimilation in Numerical Weather Prediction (NWP) models, mainly thanks to the EIG EUMETNET GNSS Water Vapour Program (E-GVAP, 2005-today). As such, GNSS has become a well-established, mature observing technique for data assimilation applications. Over this period however, scientists and specialists in GNSS-meteorology noted the clear potential for enhancements and novelties in the domain. The work carried out by the COST Action ES1206 Working Group 2 members addressed these potential enhancements and novelties from the meteorological point of view, in collaboration with WG1. This included the establishment of discussion channels with forecasters in order to determine which GNSS products would be best suited for their day-to-day operational requirements. Particular areas of interest include engaging more operational forecasters (e.g. use of meteorological case studies), especially for non-numerical nowcasting of severe weather, and getting more meteorological agencies to assimilate GNSS products in regions of Europe where they were not yet/well exploited. It also included the development of the techniques and tools necessary to benefit from the brand new products developed by the Action WG1 and WG2 members, namely real-time GNSS tropospheric products for rapid-cycle NWP and non-numerical nowcasting, data assimilation of horizontal tropospheric gradients and tropospheric slant delays as well as tomographic products. Finally, the work carried out by the WG2 members brought operational improvements through dialog, transfer of knowledge, and standardisation (e.g. the new standardized tropo-SINEX format or the development of assimilation operators). The major WG2 outcomes are discussed in this Chapter.

In this section a summary of the national progress reports is given. GNSS4SWEC Management Committee (MC) members provided outline of the work conducted in their countries combining input from different partners involved. In the COST Action paticipated member from 32 COST countries, 1 Near Neighbour Country and 8 Intrantional Partners from Australia, Canada, Hong Kong and USA. The text reflects the state as of 1 January 2018.

Since October 2013 a convective-scale weather prediction model has been used operationally to provide short-term forecasts covering large parts of the Nordic region. The model is now operated by a bilateral cooperative effort [Meteorological Cooperation on Operational Numerical Weather Prediction (MetCoOp)] between the Norwegian Meteorological Institute and the Swedish Meteorological and Hydrological Institute. The core of the model is based on the convection-permitting Applications of Research to Operations at Mesoscale (AROME) model developed by Météo-France. In this paper the specific modifications and updates that have been made to suit advanced high-resolution weather forecasts over the Nordic regions are described. This includes modifications in the surface drag description, microphysics, snow assimilation, as well as an update of the ecosystem and surface parameter description. Novel observation types are introduced in the operational runs, including ground-based Global Navigation Satellite System (GNSS) observations and radar reflectivity data from the Norwegian and Swedish radar networks. After almost two years’ worth of experience with the AROME-MetCoOp model, the model’s sensitivities to the use of specific parameterization settings are characterized and the forecast skills demonstrating the benefit as compared with the global European Centre for Medium-Range Weather Forecasts’ Integrated Forecasting System (ECMWF-IFS) are evaluated. Furthermore, case studies are provided to demonstrate the ability of the model to capture extreme precipitation and wind events.

Objective To explore cost-effectiveness of targeted therapies (TTs) in the treatment of metastatic renal cell carcinoma (mRCC) in a real-world context using a nationwide population-based approach. Methods Data on patients diagnosed with mRCC between 2002 and 2012 were extracted from Swedish national health data registers. To facilitate comparisons of patients diagnosed before and after TT introduction to the market, three cohorts were derived: pre-TT introduction (preTT), patients diagnosed 2002–2005; early TT introduction (TTi), patients diagnosed 2006–2008; and late TT introduction (TTii), which was limited to patients diagnosed 2009–2010 to ensure availability of total health care resource utilization (HCRU) data. Patients were followed until end of 2012. The value of TTs across cohorts was estimated using mean HCRU costs per life-year (LY) gained. Data on HCRU were obtained through national health registers for dispensed medication and inpatient and outpatient care, and the associated costs were estimated using the Lin method to account for censoring. LYs gained were defined as the difference in mean survival over the study period. Results The preTT, TTi, and TTii cohorts consisted of 1,366, 1,158, and 806 patients, respectively. Mean survival in years from mRCC diagnosis was 1.45 in the preTT cohort, 1.62 in the TTi cohort, and 1.83 in the TTii cohort. The respective mean total HCRU cost per patient over the study period was US$16,894, US$29,922, and US$30,037. The cost per LY gained per cohort was US$78,656 for TTi vs preTT, US$34,132 for TTii vs preTT, and US$523 for TTii vs TTi. Conclusion Given common willingness-to-pay per LY gained thresholds, this study in a real-world population suggests the use of TTs in the Swedish mRCC population is increasingly cost-effective over time.

Background: One-quarter of all cancer deaths in Sweden occur in hospitals. If the place of death affects the quality of end-of-life (EOL) is largely unknown. Methods: This population-based, retrospective study included all adults cancer deaths reported to the Swedish Register of Palliative Care in 2011–2013 (N = 41,729). Hospital deaths were compared to deaths occurring in general or specialised palliative care, or in nursing homes with respect to care quality indicators in the last week of life. Odds ratios (OR) with 95% confidence intervals (CI) were calculated with specialised palliative home care as reference. Results: Preferred place of death was unknown for 63% of hospitalised patients and consistent with the actual place of death in 25% compared to 97% in palliative home care. Hospitalised patients were less likely to be informed when death was imminent (OR: 0.3; CI: 0.28–0.33) as were their families (OR: 0.51; CI: 0.46–0.57). Validated screening tools were less often used in hospitals for assessment of pain (OR: 0.32; CI: 0.30–0.34) or other symptoms (OR: 0.31; CI: 0.28–0.34) despite similar levels of EOL symptoms. Prescriptions of as needed drugs against anxiety (OR: 0.27; CI: 0.24–0.30), nausea (OR: 0.19; CI: 0.17–0.21), or pulmonary secretions (OR: 0.29; CI: 0.26–0.32) were less prevalent in hospitals. Bereavement support was offered after 57% of hospital deaths compared to 87–97% in palliative care units and 72% in nursing homes. Conclusions: Dying in hospital was associated with inferior end-of-life care quality among cancer patients in Sweden.

Background: Metastatic papillary renal cell carcinoma (mPRCC) is understudied. The disease is often aggressive and specific treatment options are lacking. Patients and methods: mPRCC patients (n = 86) referred to three academic centres in Sweden and Germany in the years 2005–2015 were retrospectively identified from medical records. Statistical analyses included Kaplan–Meier curves and calculation of Cox proportional hazards, generating hazard ratios with 95% confidence intervals. The aim of the study was to evaluate overall survival (OS) of mPRCC patients treated outside of clinical trials in the era of targeted agents (TA) and to identify clinically useful prognostic factors. Results: Median OS of all mPRCC patients was 11.2 months. TA were used in 77% of the patients and associated with younger age and better Eastern Cooperative Oncology Group performance status (PS). Brain metastases were common (28%). Patients with synchronous or metachronous metastases had similar OS. Variables independently associated with risk of death included age ≥60 years, worse PS and ≥3 metastatic sites. The MSKCC criteria did not provide additional prognostic information. A subgroup analysis of TA-treated patients revealed an association of lymph node metastasis with risk of death in addition to the other prognostic factors. Conclusion: OS in mPRCC remained short in the era of targeted agents. Age, PS, and number of metastatic sites provided independent prognostic information.

Background and purpose Investigate effects of stereotactic radiotherapy (SRT) or surgical metastasectomy (SM) on overall survival (OS) in metastatic renal cell carcinoma (mRCC) in the era of targeted agents (TA). Material and methods mRCC patients ( n = 117) treated with SRT ( n = 57), SM ( n = 30) or both modalities sequentially ( n = 30) at two oncological centres in Sweden in 2005–2014 were retrospectively included. Median follow-up (mFU) was 63 months. Results A majority had clear cell histology, 1–3 metastases, and ECOG performance status of 0 or 1. Two thirds had intermediate or poor risk and 44% synchronous metastases. 65% received TA. SRT patients were more likely to have adverse risk profiles. Median OS was 51 months without significant differences between SRT and SM. ECOG 1 vs 0 (HR 2.9; CI 1.6–5.2; p p = 0.03) and watchful waiting >18 months prior to treatment (HR 0.3; CI 0.2–0.6; p = 0.001) were independently associated with OS. 15% of curatively treated patients ( n = 60) were relapse-free with mFU of 87 months. Conclusions OS after SRT was comparable to SM and longer than expected considering patients with adverse risk profiles were common. Fit patients with non-brain metastases treated after an initial period of watchful waiting had the best prognosis.

Data assimilation methods for convective-scale numerical weather prediction at operational centres are surveyed in this paper. The operational methods include variational methods (3D-Var and 4D-Var), ensemble methods (LETKF) and hybrids between variational and ensemble methods (3DEnVar and 4DEnVar). At several of the operational centres, other assimilation algorithms, like latent heat nudging, are additionally applied to improve the model initial state, with emphasis on convective scales. It is demonstrated that the quality of forecasts based on initial data from convective-scale data assimilation is significantly better than the quality of forecasts from simple downscaling of larger-scale initial data. The duration of positive impact depends however on the weather situation, the size of the computational domain and the data that are assimilated. It is furthermore shown that more-advanced methods applied at convective scales provide improvements compared to simpler methods. This motivates continued research and development in convective-scale data assimilation. Challenges in research and development for improvements of convective-scale data assimilation are also reviewed and discussed in this paper. The difficulty of handling the wide range of spatial and temporal scales makes development of multi-scale assimilation methods and space-time covariance localization techniques important. Improved utilization of observations is also important. In order to extract more information from existing observing systems of convective-scale phenomena, for example weather radar data and satellite image data, it is necessary to provide improved statistical descriptions of the observation errors associated with these observations.

Background: Disulfiram (DSF) is a well-tolerated, inexpensive, generic drug that has been in use to treat alcoholism since the 1950s. There is now independent preclinical data that supports DSF as an anticancer agent, and experimental data suggest that copper may increase its anti-neoplastic properties. There is also some clinical evidence that DSF is a promising anticancer agent in extracranial cancers. In glioblastoma, DSF induced O6-methylguanine methyltransferase (MGMT) inhibition may increase response to alkylating chemotherapy. A recent phase I study demonstrated the safety of DSF in glioblastoma patients when DSF was administered at doses below 500 mg/day together with chemotherapy. We plan to assess the effects of DSF combined with nutritional copper supplement (DSF-Cu) as an adjuvant to alkylating chemotherapy in glioblastoma treatment. Methods: In an academic, industry independent, multicenter, open label randomized controlled phase II/III trial with parallel group design (1:1) we will assess the efficacy and safety of DSF-Cu in glioblastoma treatment. The study will include 142 patients at the time of first recurrence of glioblastoma where salvage therapy with alkylating chemotherapy is planned. Patients will be randomized to treatment with or without DSF-Cu. Primary end-point is survival at 6 months. Secondary end-points are overall survival, progression free survival, quality of life, contrast enhancing tumor volume and safety. Discussion: There is a need to improve the treatment of recurrent glioblastoma. Results from this randomized controlled trial with DSF-Cu in glioblastoma will serve as preliminary evidence of the future role of DSF-Cu in glioblastoma treatment and a basis for design and power estimations of future studies. In this publication we provide rationale for our choices and discuss methodological issues. Trial registration: The study underwent registration in EudraCT 2016-000167-16 (Date: 30.03.2016,) and Clinicaltrials.gov NCT02678975 (Date: 31.01.2016) before initiating the study.

11 Background: Ilixadencel is a cell-based allogeneic off-the-shelf product aimed to prime anti-cancer immune response when injected intratumorally. The present randomized Phase II multicenter trial (MERECA; NCT02432846) evaluated intratumoral ilixadencel administration (2 doses 2 weeks apart) pre-nephrectomy followed by sunitinib post-nephrectomy compared with sunitinib monotherapy post-nephrectomy as first-line systemic therapy in patients with newly diagnosed synchronous metastatic renal cell carcinoma (mRCC). Methods: Patients were randomly assigned at two-to-one ratio to the combination (COMBO) or sunitinib (SUN) arm. Overall survival (OS) was assessed from enrollment while progression free survival (PFS) and tumor response was assessed per RECIST 1.1 (independent blinded central review) from start of sunitinib. Results: From April 2014 to January 2017, 88 patients (58 COMBO, 30 SUN) were randomized. In the COMBO arm, 2 patients did not receive ilixadencel, 10 did not receive sunitinib, and 1 did not have any follow up CT-scan. Five patients in the SUN arm never received sunitinib. Five patients (11%) in the COMBO arm had a complete response as best response versus one patient (4%) in the SUN arm. Confirmed ORR was 42.2 % (19/45) versus 24.0% (6/25). Median Duration of Response was 7.1 months versus 2.9 months. Median PFS was 11.8 months versus 11.0 months. Median OS has still not been reached in either group. As of July 2019, 57% and 43% were alive in the COMBO and SUN arms, respectively. Treatment with ilixadencel did not add any treatment-related Grade 3-4 Adverse Events. Conclusions: Compared to sunitinib monotherapy, combined treatment with ilixadencel followed by sunitinib demonstrated higher confirmed ORR, including several complete responses and longer duration of response, in patients with newly diagnosed synchronous mRCC. Clinical trial information: 02432846.

This retrospective study investigated overall survival (OS) and factors influencing OS in Swedish patients with metastatic renal cell carcinoma (mRCC) during the pre- (2002-2005), early (2006-2008), and late (2009-2012) targeted therapy (TT) era.Three national Swedish registries identified patients with mRCC. Median OS was estimated using the Kaplan-Meier method. Multivariate analysis was performed using Cox proportional hazards regression. Subgroup analysis was conducted for patients with synchronous metastases (M1) and the elderly (aged≥75y).A total of 4,217 patients with mRCC were identified, including 1,533 patients with M1 and 1,275 elderly patients. For patients with mRCC diagnosed in 2002 to 2005, 2006 to 2008, and 2009 to 2012, median OS was 10.0, 13.0, and 18.0 months. Similarly, median OS improved in the M1 and elderly populations. Elderly patients were less likely to be prescribed TT (≥75 vs.75y): 18.3 vs. 63.5% (in 2006-2008) and 28.6% vs. 55.9% (in 2009-2012). Diagnosis of mRCC in 2009 to 2012, nephrectomy and TT prescription were associated with improved OS in the total mRCC, M1, and elderly populations.This real-world study showed continued significant improvement in mRCC OS during the late TT era, including in M1 and elderly populations. TT should be considered for all patients with mRCC based on tolerability, regardless of age.

Atmospheric moisture-related information obtained from Global Navigation Satellite System (GNSS) observations from ground-based receiver stations of the Nordic GNSS Analysis Centre (NGAA) have been used within a state-of-the-art km-scale numerical weather prediction system. Different processing techniques have been implemented to derive the the moisture-related GNSS information in the form of Zenith Total Delays (ZTD) and these are described and compared. In addition full scale data assimilation and modelling experiments have been carried out to investigate the impact of utilizing moisture related GNSS data from the NGAA processing centre on a numerical weather prediction (NWP) model initial state and on the following forecast quality. The sensitivity of results to aspects of the data processing, observation density, bias-correction and data assimilation have been investigated. Results show a benefit on forecast quality of using GNSS ZTD as an additional observation type. The results also show a sensitivity to thinning distance applied for GNSS ZTD observations but not to modifications to the number of predictors used in the variational bias correction applied. In addition it is demonstrated that the assimilation of GNSS ZTD can benefit from more general data assimilation enhancements and that there is an interaction of GNSS ZTD with other types of observations used in the data assimilation. Future plans include further investigation of optimal thinning distances and application of more advanced data assimilation techniques.

The impact of cloud-affected satellite radiances on numerical weather prediction (NWP) accuracy is investigated. The NWP model used is the HIgh Resolution Limited Area Model (HIRLAM). Its four-dime ...

Background We have examined healthcare staff attitudes of toward a blogging cancer patient who publishes critical posts about her treatment and their possible effect on patient-staff relationships and treatment decisions. Methods We used two versions of a questionnaire containing a vignette based on a modified real case involving a 39-year-old cancer patient who complained on her blog about how she was encountered and the treatment she received. Initially she was not offered a new, and expensive treatment, which might have influenced her perception of further encounters. In one version of the vignette, the team decides to put extra effort into both encounters and offers the expensive new cancer treatment. In the other version, the team decides to follow the clinic’s routine to the letter. Subsequently, blog postings became either positive or negative in tone. We also divided participants into value-neutral and value-influenced groups (regarding personal values) by asking how their trust in healthcare would be affected if the team’s suggestion were followed. Results A total of 56 % (95 % CI: 51–61) of the respondents faced with a team decision to ‘do something-extra’ in encounters would act in accordance with this ambition. Concerning treatment, 32 % (95 % CI: 28–38) would follow the team’s decision to offer a new and expensive treatment. A large majority of those who received the “follow-routine” version agreed to do so in encountering [94 % (95 % CI: 91–97)]. Similar proportions were found regarding treatment [86 % (95 % CI: 82–90)]. A total of 83 % (95 % CI: 76–91) of the value-neutral participants who received the “do-something-extra” version stated that they would act as the team suggested regarding encounters, while 57 % (95 % CI: 47–67) would do so in regard to treatment. Among the value-influenced participants who received the “do-something-extra” version, 45 % (95 % CI: 38–51) stated that they would make an extra effort to accommodate the patient and her needs, while the proportion for treatment was 22 % (95 % CI: 16–27). Among those who had received the “follow-routine” version, a large majority agreed, and no difference was indicated between the value-neutral and the value-influenced participants. Conclusion The present study indicates that healthcare staff is indeed influenced by reading a patient’s critical blog entries, largely regarding encounters, but also concerning treatment is concerned. Value-neutral healthcare personnel seem to exhibit a pragmatic attitude and be more inclined to heed and respond to a patient whose criticism may well be warranted. The study also indicates that healthcare staff is partly positive or negative to future blogging patients depending on how the issue has been framed. For future research we suggest as a bold hypothesis that the phrase “clinical routine” might conceal power aspects masquerading as adopted ethical principles. Electronic supplementary material The online version of this article (doi:10.1186/s12910-016-0115-3) contains supplementary material, which is available to authorized users.

A 4-dimensional variational data assimilation (4D-Var) scheme for the HIgh Resolution Limited Area Model (HIRLAM) forecasting system is described in this article. The innovative approaches to the multi-incremental formulation, the weak digital filter constraint and the semi-Lagrangian time integration are highlighted with some details. The implicit dynamical structure functions are discussed using single observation experiments, and the sensitivity to various parameters of the 4D-Var formulation is illustrated. To assess the meteorological impact of HIRLAM 4D-Var, data assimilation experiments for five periods of 1 month each were performed, using HIRLAM 3D-Var as a reference. It is shown that the HIRLAM 4D-Var consistently out-performs the HIRLAM 3D-Var, in particular for cases with strong mesoscale storm developments. The computational performance of the HIRLAM 4D-Var is also discussed. Keywords: data assimilation; analysis; numerical weather prediction (Published: 17 February 2012) Citation: Tellus A 2012, 64 , 14985, DOI: 10.3402/tellusa.v64i0.14985

A nowcasting system for generation of short-range precipitation forecasts has been developed at the Swedish Meteorological and Hydrological Institute (SMHI). The methodology consists of utilising a time-series of radar reflectivity composites for deriving an advection field, which will give a better representation of the motion of the precipitation pattern compared to a model wind field. The advection field is derived applying a 4-dimensional variational data assimilation technique. The resulting field is then used for a semi-Lagrangian advection of the latest available reflectivity field forward in time. During the forecast, the advected field is gradually replaced by a numerical weather prediction forecast in order to include the onset of convection and advection into the radar coverage area. In an idealised example with simulated observations the functionality of the method is demonstrated. For a case study of a full scale example the resulting precipitation forecast shows large improvements compared to the operational numerical weather prediction model used at SMHI, especially for forecasts up to three hours, where the largest influence from the radar advection occurs. In an objective validation of the structure, amplitude and location of modelled precipitation, where the forecasts are compared to radar observations, these findings are confirmed. The same validation of model runs over a longer time period also clearly indicates that the amplitude, structure and location of the precipitation patterns are significantly improved as compared to a short-range forecast from the operational forecast model used at SMHI.

When biomass is used to produce fuels and green products by thermochemical conversion, the ability to handle or remove the fine particle phase in the product gas is crucial. The product gas from biomass gasification contains relatively volatile organic compounds (“tar”) condensed on nonvolatile cores of, for example, aggregated soot particles and char. The problems are, for example, that particles will poison catalysts used for upgrading of the gas and loss of thermal energy occurs when carbonaceous particles are being formed. The aim of the work is to design and use novel methodologies to characterize the particles in the product gas stream. A methodology has been developed to sample and characterize fine particles by a sampling probe connected to either a denuder or a packed bed device. The system was designed to avoid condensation of organic compounds when diluting the sample and decreasing the temperature. A flame soot generator connected to a condensation−evaporation unit was used to produce internally mixed model particles, i.e., particles consisting of a core of soot with an outer layer of condensed volatile compounds. A scanning mobility particle sizer (SMPS) and a differential mobility analyzer followed by an aerosol particle mass analyzer (APM) were used to characterize the particles. Because of the agglomerated structure of soot, the SMPS system was not adequate to fully characterize the mass of volatiles condensed onto the soot core, and therefore the DMA-heater-APM technique was used to determine the mass fraction of the condensed phase on the soot particles. The two different configurations were studied, and the sampling system was shown to work at a high load of organic mass. In both cases, the organic removal efficiency was >99.5%. Minor condensation of organics on the sampled soot was found for the denuder but not the packed bed. On the other hand, the particle losses were substantially higher for the packed bed compared to the denuder. The results showed that the tested sampling methodology can be used to get sufficient characterization of particles in the product gas and to evaluate the performance of biomass product gas cleaning systems at high temperature. (Less)

The objective was to investigate the effects of omega-3 fatty acids, known for their anti-inflammatory effects, on time to lymphoma progression and survival in the TLL mouse, a strain genetically prone to developing aggressive T-cell lymphoma. Compared to mice fed a standard diet, TLL mice fed omega-3 (menhaden fish oil) experienced a significant delay in disease progression and were more likely to remain alive and symptom free during the first 8 months of the study. In contrast, omega-6 supplementation (corn oil) did not significantly affect lymphoma progression. Irrespective of diet, all mice eventually progressed, and 1-year survival was not different between the groups. Immunological analysis demonstrated a significantly altered B-cell compartment and fewer NK cells in healthy C57Black6 mice fed omega-3, compared to controls. In conclusion, a diet rich in omega-3 fatty acids delays lymphoma development in the TLL mouse possibly by mechanisms that include complex effects on immune function.

An extended observation operator for the direct assimilation of cloud-affected infrared satellite radiances in the High Resolution Limited Area Model (HIRLAM) is examined. The operator includes a s ...