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Background Maintenance of functioning and well-being during the progression-free survival (PFS) period is important for glioma patients. This study aimed to determine whether health-related quality of life (HRQoL) can be maintained during progression-free time, and factors associated with HRQoL deterioration in this period. Methods We included longitudinal HRQoL data from previously published clinical trials in glioma. The percentage of patients with stable HRQoL until progression was determined per scale and at the individual patient level (i.e. considering all scales simultaneously). We assessed time to a clinically relevant deterioration in HRQoL, expressed in deterioration-free survival and time-to-deterioration (the first including progression as an event). We also determined the association between sociodemographic and clinical factors and HRQoL deterioration in the progression-free period. Results Five thousand five hundred and thirty-nine patients with at least baseline HRQoL scores had a median time from randomization to progression of 7.6 months. Between 9–29% of the patients deteriorated before disease progression on the evaluated HRQoL scales. When considering all scales simultaneously, 47% of patients deteriorated on ≥1 scale. Median deterioration-free survival period ranged between 3.8–5.4 months, and median time-to-deterioration between 8.2–11.9 months. For most scales, only poor performance status was independently associated with clinically relevant HRQoL deterioration in the progression-free period. Conclusions HRQoL was maintained in only 53% of patients in their progression-free period, and treatment was not independently associated with this deterioration in HRQoL. Routine monitoring of the patients’ functioning and well-being during the entire disease course is therefore important, so that interventions can be initiated when problems are signaled.

OBJECTIVE: The My Baby's Movements (MBM) trial aimed to evaluate the impact on stillbirth rates of a multifaceted awareness package (the MBM intervention). DESIGN: Stepped-wedge cluster-randomised controlled trial. SETTING: Twenty-seven maternity hospitals in Australia and New Zealand. POPULATION: Women with a singleton pregnancy without major fetal anomaly at ≥28 weeks of gestation from August 2016 to May 2019. METHODS: The MBM intervention was implemented at randomly assigned time points, with the sequential introduction of eight groups of between three and five hospitals at 4-monthly intervals. Using generalised linear mixed models, the stillbirth rate was compared in the control and the intervention periods, adjusting for calendar time, study population characteristics and hospital effects. MAIN OUTCOME MEASURES: Stillbirth at ≥28 weeks of gestation. RESULTS: There were 304 850 births with 290 105 births meeting the inclusion criteria: 150 053 in the control and 140 052 in the intervention periods. The stillbirth rate was lower (although not statistically significantly so) during the intervention compared with the control period (2.2/1000 versus 2.4/1000 births; aOR 1.18, 95% CI 0.93-1.50; P = 0.18). The decrease in stillbirth rate was greater across calendar time: 2.7/1000 in the first versus 2.0/1000 in the last 18 months. No increase in secondary outcomes, including obstetric intervention or adverse neonatal outcome, was evident. CONCLUSIONS: The MBM intervention did not reduce stillbirths beyond the downward trend over time. As a result of low uptake, the role of the intervention remains unclear, although the downward trend across time suggests some benefit in lowering the stillbirth rate. In this study setting, an awareness of the importance of fetal movements may have reached pregnant women and clinicians prior to the implementation of the intervention. TWEETABLE ABSTRACT: The My Baby's Movements intervention to raise awareness of decreased fetal movement did not significantly reduce stillbirth rates.

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PURPOSE: Meningiomas are the most frequent primary intracranial tumors. Patient outcome varies widely from benign to highly aggressive, ultimately fatal courses. Reliable identification of risk of progression for individual patients is of pivotal importance. However, only biomarkers for highly aggressive tumors are established (CDKN2A/B and TERT), whereas no molecularly based stratification exists for the broad spectrum of patients with low- and intermediate-risk meningioma. METHODS: DNA methylation data and copy-number information were generated for 3,031 meningiomas (2,868 patients), and mutation data for 858 samples. DNA methylation subgroups, copy-number variations (CNVs), mutations, and WHO grading were analyzed. Prediction power for outcome was assessed in a retrospective cohort of 514 patients, validated on a retrospective cohort of 184, and on a prospective cohort of 287 multicenter cases. RESULTS: Both CNV- and methylation family-based subgrouping independently resulted in increased prediction accuracy of risk of recurrence compared with the WHO classification (c-indexes WHO 2016, CNV, and methylation family 0.699, 0.706, and 0.721, respectively). Merging all risk stratification approaches into an integrated molecular-morphologic score resulted in further substantial increase in accuracy (c-index 0.744). This integrated score consistently provided superior accuracy in all three cohorts, significantly outperforming WHO grading (c-index difference P = .005). Besides the overall stratification advantage, the integrated score separates more precisely for risk of progression at the diagnostically challenging interface of WHO grade 1 and grade 2 tumors (hazard ratio 4.34 [2.48-7.57] and 3.34 [1.28-8.72] retrospective and prospective validation cohorts, respectively). CONCLUSION: Merging these layers of histologic and molecular data into an integrated, three-tiered score significantly improves the precision in meningioma stratification. Implementation into diagnostic routine informs clinical decision making for patients with meningioma on the basis of robust outcome prediction.

PURPOSE Malignant optic glioma of adulthood is a rare, invasive neoplasm of the anterior visual pathway with 66 cases reported in the literature. It presents as anaplastic astrocytoma (WHO grade III) or glioblastoma (WHO grade IV). The present case series covers the spectrum of disease manifestations, discusses neuroradiological findings, and reviews the current literature. METHODS Retrospective case series of five patients from three tertiary referral centers and literature review. RESULTS Visual loss with or without pain was the presenting symptom in all patients (two women, three men). Two patients were initially misdiagnosed as optic neuritis, and one patient as atypical non-arteritic anterior ischemic optic neuropathy (NAION). A neoplastic disease was suspected in the two remaining patients. MRI features were iso- to hypointensity on T1-weighted native images, contrast enhancement, and hyperintensity on T2-weighted images. Biopsy was generally diagnostic; however, one patient required two biopsies for diagnosis. The series includes an exceptional case of intraocular tumor extension and vitreous spread. The disease was lethal within one to two years in all patients. CONCLUSIONS Malignant optic glioma is a diagnostic challenge and remains a devastating and lethal disease. Advances in the understanding of tumor biology have yet failed to translate into effective treatment regimens.

Background \ud Pain is a frequent symptom of atopic dermatitis (AD).\ud \ud Objectives \ud The aims of the study were to evaluate the effects of dupilumab on pain/discomfort in AD and to determine whether pain correlates with other outcomes.\ud \ud Methods \ud This was a post hoc analysis of 5 randomized, placebo-controlled clinical trials in which adults with chronic AD received placebo or dupilumab 300 mg every 2 weeks or once weekly with and without topical corticosteroids. Proportions of patients with no pain/discomfort on this dimension of the 5-dimension EuroQoL (EQ-5D) at week 16 (all trials) and week 52 (CHRONOS) were compared between placebo and dupilumab. Correlations were evaluated between pain/discomfort and signs and symptoms of AD.\ud \ud Results \ud Among 2632 evaluated patients, 72.9% to 83.1% reported at least moderate pain/discomfort at baseline. Higher proportions treated with dupilumab reported no pain/discomfort at week 16 relative to placebo; risk differences ranged from 22.3% (95% confidence interval = 11.5%–33.1%) to 42.2% (95% confidence interval = 26.6%–57.8%, all P ≤ 0.0001), with similar effects observed at week 52. Correlations at baseline of pain/discomfort with signs and symptoms of AD were low to moderate.\ud \ud Conclusions \ud Pain/discomfort, present in a substantial proportion of patients with moderate-to-severe AD, was significantly reduced by dupilumab treatment. Given the low-to-moderate correlations with other AD symptoms at baseline, pain likely represents a distinct AD symptom.\ud \ud Trial Registration: ClinicalTrials.gov identifiers NCT01859988, NCT02277743, NCT02277769, NCT02260986, and NCT02755649.

Background Variability in standard-of-care classifications precludes accurate predictions of early tumor recurrence for individual patients with meningioma, limiting the appropriate selection of patients who would benefit from adjuvant radiotherapy to delay recurrence. We aimed to develop an individualized prediction model of early recurrence risk combining clinical and molecular factors in meningioma. Methods DNA methylation profiles of clinically annotated tumor samples across multiple institutions were used to develop a methylome model of 5-year recurrence-free survival (RFS). Subsequently, a 5-year meningioma recurrence score was generated using a nomogram that integrated the methylome model with established prognostic clinical factors. Performance of both models was evaluated and compared with standard-of-care models using multiple independent cohorts. Results The methylome-based predictor of 5-year RFS performed favorably compared with a grade-based predictor when tested using the 3 validation cohorts (ΔAUC = 0.10, 95% CI: 0.03–0.018) and was independently associated with RFS after adjusting for histopathologic grade, extent of resection, and burden of copy number alterations (hazard ratio 3.6, 95% CI: 1.8–7.2, P < 0.001). A nomogram combining the methylome predictor with clinical factors demonstrated greater discrimination than a nomogram using clinical factors alone in 2 independent validation cohorts (ΔAUC = 0.25, 95% CI: 0.22–0.27) and resulted in 2 groups with distinct recurrence patterns (hazard ratio 7.7, 95% CI: 5.3–11.1, P < 0.001) with clinical implications. Conclusions The models developed and validated in this study provide important prognostic information not captured by previously established clinical and molecular factors which could be used to individualize decisions regarding postoperative therapeutic interventions, in particular whether to treat patients with adjuvant radiotherapy versus observation alone.

Currently no treat-to-target framework to guide systemic treatment in adults with moderate-to-severe atopic dermatitis exists. We sought to reach international consensus through an eDelphi process on a core set of recommendations for such an approach. Recommendations were developed by an international Steerng Committee, spanning 3 areas (Guiding Principles, Decision Making, and Outcome Thresholds) and 2 specific time-points; an initial acceptable target at 3 months and an optimal target at 6 months, each based on improvements in patient global assessment plus at least one specific outcome domain. These treat-to-target-orientated recommendations were evaluated by an extended international panel of physicians, nurses and patients. Proposed recommendations were rated using a 9-point Likert scale; for each recommendation, consensus agreement was reached if >= 75% of all respondents rated agreement as >= 7. Consensus on 16 core recommendations was reached over 2 eDelphi rounds. These provide a framework for shared decision-making on systemic treatment continuation, modification, or discontinuation.

Atopic dermatitis is a heterogeneous disease and resists classification. In this review, we discuss atopic dermatitis nomenclature and identify morphologic phenotypes, which will facilitate correct diagnoses and development of treatment strategies. We support using the term 'atopic dermatitis' rather than eczema, because it describes the allergic background and inflammation ('itis') as drivers of the disease. Atopic dermatitis has many morphologic manifestations that vary by topographic area affected, age, or race and require consideration in differential diagnosis. Different phenotypes based on morphology and topographic location, ethnicity, and age are discussed. A better-defined phenotype identification for atopic dermatitis will facilitate earlier and correct diagnosis of this complex condition and inform selection of the most appropriate treatment choice in an era in which targeted therapies may generate more individualized patient care.

We investigate the differential ionization probability of chiral molecules in the strong field regime as a function of the helicity of the incident light. To this end, we analyze the fourfold ionization of bromochlorofluoromethane (CHBrClF) with subsequent fragmentation into four charged fragments and different dissociation channels of the singly ionized methyloxirane. We observe a variation of the differential ionization probability in a range of several percent. Accordingly, we conclude that the helicity of light is a quantity that should be considered for the theoretical description of the strong field ionization rate of chiral molecules., 12 pages, 6 figures, submitted

Introduction: Atopic dermatitis (AD), a predominantly type 2 inflammatory skin disease, affects approximately 2-5% of adults, with a high burden of disease. In moderate-to-severe AD, lesions can be extensive and pruritus intense with patients experiencing skin pain, sleep and mental health disturbances, and diminished quality of life (QoL). Methods: The objective of this study was to evaluate the efficacy of dupilumab for the treatment of AD from the patients' perspective using patient-reported outcome data from four clinical trials (CHRONOS, SOLO 1&2, and CAFE) in patients (N = 1553) receiving either the approved 300 mg q2w dupilumab with/without topical corticosteroids (TCS) dose or control (placebo or placebo + TCS). Patient Global Assessment of Disease Status (PGADS) was used to measure patients' well-being and Patient Global Assessment of Treatment Effect (PGATE) was used to measure treatment efficacy. Patients were asked "Considering all the ways in which your eczema affects you, indicate how well you are doing" to assess their perception of well-being and "How would you rate the way your eczema responded to the study medication?" to assess their perception of treatment effect. Possible responses for both metrics included poor, fair, good, very good, and excellent. Results: In all four studies, a significantly higher proportion of dupilumab-treated patients reported "Good"/"Very Good"/"Excellent" disease status from week 2 through study end versus control (CHRONOS, 52 weeks: 69.8% vs. 25.1%; SOLO 1&2, 16 weeks: 59.5% vs. 24.6%; CAFE, 16 weeks: 84.1% vs. 45.4%; all P < 0.0001), and significantly more dupilumab-treated patients reported "Good"/"Very Good"/"Excellent" treatment efficacy versus control (CHRONOS: 72.6% vs. 24.8%; SOLO 1&2: 65.0% vs. 21.1%; CAFE, 16 weeks: 85.0% vs. 36.1%; all P < 0.0001). Conclusion: Adult patients with AD perceived that dupilumab with/without concomitant TCS was highly efficacious and improved overall disease status and well-being as early as week 2 and throughout treatment periods up to 1 year.

Background Different analytical methods may lead to different conclusions about the impact of treatment on health-related quality of life (HRQoL). This study aimed to examine 3 different methods to evaluate change in HRQoL and to study whether these methods result in different conclusions. Methods HRQoL data from 15 randomized clinical trials were combined (CODAGLIO project). Change in HRQoL scores, measured with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and BN20 questionnaires, was analyzed in 3 ways: (1) at the group level, comparing mean changes in scale/item scores between treatment arms, (2) at the patient level per scale/item, calculating the percentage of patients that deteriorated, improved, or remained stable per scale/item, and (3) at the individual patient level, combining all scales/items. Results Baseline and first follow-up HRQoL data were available for 3727 patients. At the group scale/item level, only the item “hair loss” showed a significant and clinically relevant change (ie, ≥10 points) over time, whereas change scores on the other scales/items were statistically significant only (all P Conclusions Different analytical methods of changes in HRQoL result in distinct conclusions of treatment effects, all of which may be relevant for informing clinical decision making.

© 2020 Australian College of Midwives The rate of late gestation stillbirth in Australia is unacceptably high. Up to one third of stillbirths are preventable, particularly beyond 28 weeks’ gestation. The aim of this second paper in the Stillbirth in Australia series is to highlight one key national initiative, the Safer Baby Bundle (SBB), which has been led by the Centre of Research Excellence in Stillbirth in partnership with state health departments. Addressing commonly identified evidence practice gaps, the SBB contains five elements that, when implemented together, should result in better outcomes than if performed individually. This paper describes the development of the SBB, what the initiative aims to achieve, and progress to date. By collaborating with Departments of Health and other partners to amplify uptake of the SBB, we anticipate a reduction of at least 20% in Australia's stillbirth rate after 28 weeks’ gestation is achievable.

The paper’s starting point is the United Nations Human Rights Council working group’s revised draft of a Legally Binding Instrument to Regulate, in International Human Rights Law, the Activities of Transnational Corporations and other Business Enterprises of July 2019. The paper examines the draft treaty’s potential to activate and operationalize public law, private law, and criminal law for enforcing human rights. It conceptualizes a complementary approach of these three branches of law in which private and criminal legal enforcement mechanisms stand in the foreground. It argues for linking civil (tort) and criminal liability for harm caused by hands-off corporate policies, complemented by the obligation to interpret managerial duties in conformity with the human rights standards of public international law. The combination of public, private, and criminal law allows effective enforcement of human rights vis-à-vis global corporations.

Objective: We report the case of a 65-year old woman with refractory epilepsy with bilateral tonic-clonic seizures caused by progressive severe leukoencephalopathy who was treated with deep brain stimulation (DBS) for status epilepticus. The patient was admitted to our institution under treatment[for full text, please go to the a.m. URL], 70. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), Joint Meeting mit der Skandinavischen Gesellschaft für Neurochirurgie

We have conducted an experimental study on the photo double ionization (PDI) of carbon-dioxide dimers at photon energies of 37 and 55 eV and oxygen dimers at photon energies of 38, 41.5, and 46 eV, while focusing on the dissociation dynamics upon single-photon absorption. The investigation was performed by applying the cold-target recoil-ion momentum spectroscopy method in order to collect and record the three-dimensional momenta of the ionic fragments and emitted electrons from the dissociating dimer in coincidence. The kinetic-energy release upon fragmentation and the electron angular distributions in the laboratory and body-fixed frames, as well as the relative electron-electron emission angle, show unambiguous experimental evidence of intermolecular Coulombic decay (ICD) in carbon-dioxide dimers upon photoionization below and above the double-ionization threshold of CO2 monomers. The PDI of oxygen dimers is less conclusive and shows contributions from ICD and knock-off ionization mechanisms. As for atomic dimers, the present results reveal that ICD in CO2 dimers after valence PDI can also serve as a source for low-energy electrons, known to be very relevant in biological systems, cells, and tissues.

The effectiveness and safety of dupilumab for the treatment of moderate to severe atopic dermatitis (AD) has been demonstrated in phase III clinical trials. At this moment, daily practice data on dupilumab treatment with respect to clinical effectiveness and safety are scarce. The objective of this study was to study the clinical effectiveness of 16 weeks treatment with dupilumab in adult patients with moderate to severe AD in daily practice. Data were extracted from the BioDay registry, a prospective multicenter registry. Sixteen-weeks clinical effectiveness of dupilumab was expressed as number of patients achieving EASI-50, EASI-75 as well as patient reported outcome measures (POEM, DLQI, NRS-pruritus). A clinically relevant response was defined based on thresholds in one or more outcomes of the 3 major AD domains (EASI, NRS-pruritus, DLQI). In total, 138 patients treated with dupilumab in daily practice were included. This cohort included patients with very difficult- to-treat AD with 84 patients (61%) who failed treatment on ≥2 immunosuppressive drugs. At week 16, the mean percent change in EASI score was 73%. The EASI-50 and EASI-75 was achieved by 114 (86%) and 82 (62%) patients after 16 weeks of treatment. Also patient-reported outcomes including sleep, itch and quality of life significantly improved during dupilumab treatment. A clinically relevant response was achieved by 89% of the patients after 16 weeks of treatment. The most reported side effects were conjunctivitis in 47 (34%) and eosinophilia in 78 (57%) patients. In conclusion, treatment with dupilumab significantly improved signs and symptoms of AD in patients with very difficult-to-treat AD in a daily practice setting with the majority of patients achieving a clinically relevant response after 16 weeks of treatment.

Lead halide perovskites are causing a change of paradigm in photovoltaics. Among other peculiarities, these perovskites exhibit an atypical temperature dependence of the fundamental optical gap: It decreases in energy with decreasing temperature. So far reports ascribe such a behavior to a particularly strong electron-phonon renormalization of the band gap, neglecting completely contributions from thermal expansion effects. However, high pressure experiments performed, for instance, on the archetypal perovskite MAPbI$_3$, where MA stands for methylammonium, yield a negative pressure coefficient for the gap of the tetragonal room-temperature phase, which speaks against the assumption of a negligible gap shift due to thermal expansion. On the basis of the high pressure results, we show here that for MAPbI$_3$ the temperature-induced gap renormalization due to electron-phonon interaction can only account for about 40\% of the total energy shift, thus implying thermal expansion to be the dominant term. Furthermore, this result possesses general validity, holding also for the tetragonal or cubic phase, stable at ambient conditions, of other halide perovskite counterparts., 24 pages (manuscript 17 pages + supplementary information 7 pages), 5 figures (manuscript 4 figures + supplementary information 1 figure), submitted to J. Phys. Chem. Lett

Introduction: Dupilumab has shown promising results in phase III trials and has recently been approved for the treatment of moderate to severe atopic dermatitis (AD) in adults. At this moment, daily practice data on dupilumab treatment are lacking. Objective: To study the effect of 16 weeks treatment with dupilumab on clinical efficacy, serum biomarkers (and peripheral blood T-cell skewing) in adult patients with moderate-severe AD in daily practice. Methods: Data were extracted from the Bioday registry. 16-weeks clinical effectiveness of dupilumab was expressed as number of patients achieving EASI-50, EASI-75) as well as patient reported outcomes measures (POEM, DLQI, NRS-itch). 29 biomarkers representing different disease pathways were measured in 35 patients treated with dupilumab without concomitant use of oral immunosuppressive drugs at 5 different time points (baseline, 4, 8, 12 and 16 weeks). We performed a pilot study on T cell skewing within the total, but also “skin-homing” (CLA+CCR4+) CD4 T cell population. Results: In total, 105 patients treated with dupilumab in daily practice were included. At week 16, the mean percent change in EASI score was 72%. The EASI-50 and EASI-75 were achieved by 87 (85%) and 59 (58%) patients after 16 weeks of treatment. The most reported side effect were conjunctivitis in 39 (37%) and eosinophilia in 67 (65%) patients. Dupilumab significantly decreased type 2 and severity serum biomarkers including, CCL17 (TARC), CCL18 (PARC), periostin and IL-22. No change in overall T-cell skewing based on cytokine expressions was observed. However there was a decrease in the percentage of IL-13, and IL-22 expressing CLA+CCR4+ CD4 T cells and an increase in IFN-g expressing CLA+CCR4+ CD4 T cells. Conclusion: Treatment with dupilumab improved disease severity and significantly suppressed Th2 and severity related serum biomarkers in patients with very difficult-to-treat AD in a daily practice setting. In addition, dupilumab seems to affect the functional skewing of especially skin-homing T cells.

© 2018 American Physical Society. We demonstrate the use of cold target recoil ion momentum spectroscopy to perform state-selective measurements of the dissociative channels following single-photon double-ionization of H2O. The two dominant dissociation channels observed lead to two-body (OH++H++2e-) and three-body (2H++O+2e-) ionic fragmentation channels. In the two-body case we observe the presence of an autoionization process with a double-differential cross section that is similar to the single-photon double-ionization of helium well above threshold. In the three-body case, momentum and energy correlation maps in conjunction with new classical trajectory calculations in the companion theory paper by Z. L. Streeter et al. [Phys. Rev. A 98, 053429 (2018)10.1103/PhysRevA.98.053429] lead to the determination of the eight populated dication states and their associated fragmentation geometry. For the latter case, state-specific relative cross sections, median kinetic energy releases, and median angles between asymptotic proton momenta are presented. This benchmark-level experiment demonstrates that, in principle, state-selective fixed-frame triple-differential cross sections can be measured for some dication states of the water molecule.

We present a combined experimental and theoretical investigation of the electron dynamics and body-frame angular dependence of valence photo-single ionization of CF4 and subsequent dissociation into CF3+ and F. Ionization from a valence t2 orbital shows overlapping shape resonances close to threshold that couple to the same total symmetry, leading to striking changes in the photoelectron angular distributions when viewed in the body-frame.

Glioblastomas are highly malignant primary brain tumors with one of the worst survival rates among all human cancers. With a more profound understanding of the cellular and molecular mechanisms of tumor initiation and acquired resistance to conventional radio- and chemotherapy, novel therapeutic targets might be discovered to optimize therapeutic approaches. In this regard, the identification of a small cellular subpopulation, called glioblastoma stem cell or stem-like cells or glioma-initiating cells or brain tumor propagating cells, has gained attention. In this article, we briefly summarize the current state of knowledge about this tumor cell population and discuss future directions for basic and clinical research

BACKGROUND The impact of treatment on both the quality and the quantity of life, i.e. the ‘net clinical benefit’, should be considered to inform glioma patients and facilitate shared decision making. We applied two methods (i.e. Quality Adjusted Effect Sizes (QASES) and Joint Modelling (JM)) that combine survival and health-related quality of life (HRQoL) data into one outcome, to gain insight in the net clinical benefit of a treatment strategy. In addition, we assessed if both methods result in similar interpretations. MATERIAL AND METHODS We calculated the net clinical benefit in one randomized controlled trial, EORTC 26951 comparing radiotherapy (RT) + PCV chemotherapy versus RT alone, as a proof of concept for other trials. With the QASES method, effect sizes for differences in survival and HRQoL between treatment arms were calculated. Next, the combined effect size can be determined by weighing the emphasis put on survival or HRQoL (e.g. survival more important). JM allows simultaneous modeling of a longitudinal outcome (HRQoL), and a time-to event outcome (survival). HRQoL scales/items that were selected for primary analysis in the main study were also selected for this analysis: fatigue, global health, social functioning, communication deficit, seizures, physical functioning, and nausea/vomiting. RESULTS 288/386 patients completed baseline HRQoL forms and were included in the analysis. Overall survival (OS) was significantly longer with combined treatment (difference of 10.8 months). In contrast, the percentage of patients who experienced a clinically relevant deterioration (≥10 points) in nausea/vomiting, fatigue, social functioning and global health up to one year after treatment compared to baseline was larger in the RT+PCV arm. The QASES corresponded to a reduction in the median OS difference from 10.8 months to 6.8 months when adjusted for the HRQoL scales/items, when given equal weights to OS and HRQoL. JM analyses resulted in a theoretical loss of treatment effect in OS of 2–6% when adjusting for HRQoL. CONCLUSION Both methods showed that adjusting for the impact of treatment on a relevant HRQoL parameter reduced the survival benefit in the experimental treatment arm compared to standard treatment arm. Applying these methods may facilitate communicating the impact of treatment to patients in clinical practice.

BACKGROUND Precision medicine trials targeting the epidermal growth factor receptor (EGFR) in glioblastoma patients require selection for EGFR-amplified tumors. However, there is currently no golden standard in determining the amplification status of EGFR or EGFRvIII expression. Here, we aimed to determine which technique and which cut-offs are suitable to determine EGFR amplification status. MATERIAL AND METHODS We compared fluorescent in-situ hybridization (FISH) and RT-qPCR data from patients screened for trial inclusion into the Intellance 2 clinical trial, with data from a panel-based next generation sequencing (NGS) platform (both DNA and RNA). RESULTS By using data from >1000 samples, we show which cut-offs are optimal to determine EGFR gene amplification by FISH. Our data also show that gene amplification (as determined by FISH) correlates with EGFR expression levels (as determined by RT-qPCR) with ROC analysis showing an under the curve area of up to 0.902. EGFR expression as assessed by RT-qPCR therefore may function as a surrogate marker for EGFR amplification. Our NGS data shows that EGFR copy numbers can strongly vary between tumors with levels ranging from 2 to more than 100 copies per cell. Levels exceeding 5 gene copies can be used to define EGFR-amplification by NGS; below this level FISH detects very few (if any) EGFR amplified nuclei and none of the samples express EGFRvIII. CONCLUSION Our data from central laboratories and diagnostic sequencing facilities, using material from patients eligible for clinical trial inclusion, help defining the optimal cut-off for various techniques to determine EGFR amplification for diagnostic purposes.

© 2018 the Owner Societies. We present a combined experimental and theoretical investigation of the electron dynamics and body-frame angular dependence of valence photo-single ionization of CF4and subsequent dissociation into CF3+and F. Ionization from a valence t2orbital shows overlapping shape resonances close to threshold that couple to the same total symmetry, leading to striking changes in the photoelectron angular distributions when viewed in the body-frame.

© 2017 Elsevier Ltd Background Rindopepimut (also known as CDX-110), a vaccine targeting the EGFR deletion mutation EGFRvIII, consists of an EGFRvIII-specific peptide conjugated to keyhole limpet haemocyanin. In the ACT IV study, we aimed to assess whether or not the addition of rindopepimut to standard chemotherapy is able to improve survival in patients with EGFRvIII-positive glioblastoma. Methods In this randomised, double-blind, phase 3 trial, we recruited patients aged 18 years and older with glioblastoma from 165 hospitals in 22 countries. Eligible patients had newly diagnosed glioblastoma confirmed to express EGFRvIII by central analysis, and had undergone maximal surgical resection and completion of standard chemoradiation without progression. Patients were stratified by European Organisation for Research and Treatment of Cancer recursive partitioning analysis class, MGMT promoter methylation, and geographical region, and randomly assigned (1:1) with a prespecified randomisation sequence (block size of four) to receive rindopepimut (500 μg admixed with 150 μg GM-CSF) or control (100 μg keyhole limpet haemocyanin) via monthly intradermal injection until progression or intolerance, concurrent with standard oral temozolomide (150–200 mg/m2for 5 of 28 days) for 6–12 cycles or longer. Patients, investigators, and the trial funder were masked to treatment allocation. The primary endpoint was overall survival in patients with minimal residual disease (MRD; enhancing tumour

Despite maximal surgical and medical therapy, the treatment of glioblastoma remains a seriously vexing problem, with median survival well under 2 years and few long-term survivors. Targeted therapy has yet to produce significant advances in treatment of these lesions in spite of advanced molecular characterization of glioblastoma and glioblastoma cancer stem cells. Recently, immunotherapy has emerged as a promising mode for some of the hardest to treat tumors, including metastatic melanoma. Although immunotherapy has been evaluated in glioblastoma in the past with limited success, better understanding of the failures of these therapies could lead to more successful treatments in the future. Furthermore, there is a persistent challenge for the use of immune therapy to treat glioblastoma secondary to the existence of redundant mechanisms of tumor-mediated immune suppression. Here we will address these mechanisms of immunosuppression in glioblastoma and therapeutic approaches