Response-adapted omission of radiotherapy and comparison of consolidation chemotherapy in intermediate- and advanced-stage children and adolescents with classic Hodgkin lymphoma: a titration study with an embedded non-inferiority randomised controlled trial

BACKGROUND: Children and adolescents with intermediate-stage and advanced-stage classical Hodgkin lymphoma achieve an event-free survival at 5 years of about 90% after treatment with vincristine, etoposide, prednisone, and doxorubicin (OEPA) followed by cyclophosphamide, vincristine, prednisone, and procarbazine (COPP) and radiotherapy, but long-term treatment effects affect survival and quality of life. We aimed to investigate whether radiotherapy can be omitted in patients with morphological and metabolic adequate response to OEPA and whether modified consolidation chemotherapy reduces gonadotoxicity. METHODS: Our study was designed as a titration study with an open-label, embedded, multinational, non-inferiority, randomised controlled trial, and was carried out at 186 hospital sites across 16 European countries. Children and adolescents with newly diagnosed intermediate-stage (treatment group 2) and advanced-stage (treatment group 3) classical Hodgkin lymphoma who were younger than 18 years and stratified according to risk using Ann Arbor disease stages IIAE, IIB, IIBE, IIIA, IIIAE, IIIB, IIIBE, and all stages IV (A, B, AE, and BE) were included in the study. Patients with early disease (treatment group 1) were excluded from this analysis. All patients were treated with two cycles of OEPA (1·5 mg/m(2) vincristine taken intravenously capped at 2 mg, on days 1, 8, and 15; 125 mg/m(2) etoposide taken intravenously on days 1–5; 60 mg/m(2) prednisone taken orally on days 1–15; and 40 mg/m(2) doxorubicin taken intravenously on days 1 and 15). Patients were randomly assigned to two (treatment group 2) or four (treatment group 3) cycles of COPP (500 mg/m(2) cyclophosphamide taken intravenously on days 1 and 8; 1·5 mg/m(2) vincristine taken intravenously capped at 2 mg, on days 1 and 8; 40 mg/m(2) prednisone taken orally on days 1 to 15; and 100 mg/m(2) procarbazine taken orally on days 1 to 15) or COPDAC, which was identical to COPP except that 250 mg/m(2) dacarbazine administered intravenously on days 1 to 3 replaced procarbazine. The method of randomisation (1:1) was minimisation with stochastic component and was centrally stratified by treatment group, country, trial sites, and sex. The primary endpoint was event-free survival, defined as time from treatment start until the first of the following events: death from any cause, progression or relapse of classical Hodgkin lymphoma, or occurrence of secondary malignancy. The primary objectives were maintaining 90% event-free survival at 5 years in patients with adequate response to OEPA treated without radiotherapy and to exclude a decrease of 8% in event-free survival at 5 years in the embedded COPDAC versus COPP randomisation to show non-inferiority of COPDAC. Efficacy analyses are reported per protocol and safety in the intention-to-treat population. The trial is registered with ClinicalTrials.gov (trial number NCT00433459) and EUDRACT (trial number 2006-000995-33), and is closed to recruitment. FINDINGS: Between Jan 31, 2007, and Jan 30, 2013, 2102 patients were recruited. 737 (35%) of the 2102 recruited patients were in treatment group 1 (early-stage disease) and were not included in our analysis. 1365 (65%) of the 2102 patients were in treatment group 2 (intermediate-stage disease; n=455) and treatment group 3 (advanced-stage disease; n=910). Of these 1365, 1287 (94%) patients (435 [34%] of 1287 in treatment group 2 and 852 [66%] of 1287 in treatment group 3) were included in the titration trial per-protocol analysis. 937 (69%) of 1365 patients were randomly assigned to COPP (n=471) or COPDAC (n=466) in the embedded trial. Median follow-up was 66·5 months (IQR 62·7–71·7). Of 1287 patients in the per-protocol group, 514 (40%) had an adequate response to treatment and were not treated with radiotherapy (215 [49%] of 435 in treatment group 2 and 299 [35%] of 852 in treatment group 3). 773 (60%) of 1287 patients with inadequate response were scheduled for radiotherapy (220 [51%] of 435 in the treatment group 2 and 553 [65%] of 852 in treatment group 3. In patients who responded adequately, event-free survival rates at 5 years were 90·1% (95% CI 87·5–92·7). event-free survival rates at 5 years in 892 patients who were randomly assigned to treatment and analysed per protocol were 89·9% (95% CI 87·1–92·8) for COPP (n=444) versus 86·1% (82·9–89·4) for COPDAC (n=448). The COPDAC minus COPP difference in event-free survival at 5 years was −3·7% (−8·0 to 0·6). The most common grade 3–4 adverse events (intention-to-treat population) were decreased haemoglobin (205 [15%] of 1365 patients during OEPA vs 37 [7%] of 528 treated with COPP vs 20 [2%] of 819 treated with COPDAC), decreased white blood cells (815 [60%] vs 231 [44%] vs 84 [10%]), and decreased neutrophils (1160 [85%] vs 223 [42%] vs 174 [21%]). One patient in treatment group 2 died of sepsis after the first cycle of OEPA; no other treatment-related deaths occurred. INTERPRETATION: Our results show that radiotherapy can be omitted in patients who adequately respond to treatment, when consolidated with COPP or COPDAC. COPDAC might be less effective, but is substantially less gonadotoxic than COPP. A high proportion of patients could therefore be spared radiotherapy, eventually reducing the late effects of treatment. With more refined criteria for response assessment, the number of patients who receive radiotherapy will be further decreased. FUNDING: Deutsche Krebshilfe, Elternverein für Krebs-und leukämiekranke Kinder Gießen, Kinderkrebsstiftung Mainz, Tour der Hoffnung, Menschen für Kinder, Programme Hospitalier de Recherche Clinique, and Cancer Research UK

Elitfotbollsspelares självbedömning

Syfte: Uppsatsens syfte är att belysa huruvida svenska elitfotbollsspelares bild av sina matchprestationer är rimliga och därmed utgör en god grund för ett självreglerat lärande. Teori: Uppsatsen grundar sig på socialkognitiv teori om självreglerat lärande. Här tas främst Banduras begrepp upplevelse av den egna förmågan och Zimmermans socialkognitiva modell för självreglering upp. Dessutom presenteras teori om inre feedback och självinstruktion. Slutligen tas begreppen självbedömning och självutvärdering, och deras förhållande till det självreglerade lärandet, upp. Metod: 22 svenska elitfotbollsspelare bedömde sina prestationer i 1-5 matcher per spelare. Spelarens tränare bedömde spelarens prestation i samma matcher. Bedömningarna gjordes på en 7-gradig ordinalskala i webbenkät med fyra frågor som stod för varsin del av prestationen. Korrelation (Pearsons r), andel överensstämmelse och andel över- och underskattade prestationer uppmättes och analyserades. Måtten jämfördes mellan manliga och kvinnliga spelare, utifrån tre åldersnivåer, och utifrån tre prestationsnivåer. Dessutom mättes separat överensstämmelse mellan spelar- och tränarbedömningar för de fyra delarna av prestationen. Resultat: Svenska elitfotbollsspelares förmåga att bedöma sina matchprestationer är, i korrelationsmått, något lägre än vad tidigare forskning visar om samma förmåga hos skolelever. Det är vanligare att svenska elitfotbollsspelares självbedömningar avviker än överensstämmer med deras tränares bedömningar. Kvinnliga elitfotbollsspelare tenderar att underskatta sina matchprestationer. Sett till hela urvalet visas högst förmåga att bedöma sina prestationer när prestationerna är låga. Höga prestationer tenderar att underskattas mer än medelhöga och låga prestationer

Learning with Digital Tools on Public Knowledge Institutions A Literature Review based on Grounded Theory

Syftet med uppsatsen är att ge en översikt över hur de senaste årens forskning beskriver hur lärande med digitala verktyg på publika kunskapsinstitutioner ser ut. Den övergripande fråge-ställningen är: Hur beskrivs lärande med digitala verktyg på publika kunskapsinstitutioner av aktuell forskning? Studien förhåller sig till en bakgrund inom områdena lärande, lärande på publika kunskapsinstitutioner, lärande med digitala verktyg och lärande med digitala verktyg på publika kunskapsinstitutioner. Studien kan, utifrån metodval, beskrivas som en induktiv systematisk litteraturstudie med kva-litativ ansats, genomförd enligt Grounded Theory Literature Review Method (Wolfswinkel, Furtmueller &Wilderom, 2013). Materialet omfattas av 43 vetenskapliga artiklar som kodades och kategoriserades. De mest framträdande koncepten presenteras och analyseras som studiens resultat. Resultatet består dels av en översiktlig kategorisering av de studerade lärandesituationernas förutsättningar, och vilka grundantaganden artiklarna utgår ifrån, och dels av en analys av artiklarnas beskrivningar av lärande. Analysen mynnar ut i en början till ett sammanfattande ramverk, bestående av fyra beskrivningar av lärande med digitala verktyg på publika kunskapsinstitutioner och ett konstaterande om att detta lärande beskrivs ha starka kopplingar till begreppen individuell interaktivitet och social interaktion. Förhållandet mellan dessa begrepp beskrivs emellertid både som uppmuntrande och motverkande. Som förslag på vidare forskning tar uppsatsen upp olika uppslag som ytterligare och mer ingående undersöker den individuella interaktivitetens och den sociala interaktionens roller i lärande med digitala verktyg på publika kunskapsinstitutioner.The purpose of the thesis is to provide an overview of how recent years of research describe learning with digital tools in public knowledge institutions. The overall research question is: How is learning with digital tools at public knowledge institutions described in current re-search? The study relates to a background in the fields of learning, learning in public knowledge institutions, learning with digital tools and learning with digital tools in public knowledge institutions. The study can, based on its methodology, be described as an inductive systematic literature review with a qualitative approach, conducted according to the Grounded Theory Literature Review Method (Wolfswinkel, Furtmueller & Wilderom, 2013). The material is covered by 43 journal articles which were coded and categorized. The most prominent concepts are presented and analyzed as the result of the study. The result consists partly of an overall categorization of the conditions of the studied learning situations, and the basic assumptions the articles are based on, and partly by an analysis of the articles’ descriptions of the learning situations. The analysis develops into a summarizing framework consisting of four descriptions of learning with digital tools at public knowledge institutions and a conclusion that this learning is described has as having strong links with the concepts of individual interactivity and social interaction. The relationship between these concepts is, however, described as both encouraging and opposing. As a proposal for further research, the thesis brings up different suggestions that further and more in depth investigates the roles of individual interactivity and social interaction in learning with digital tools in public knowledge institutions

The role of tumour-infiltrating eosinophils, mast cells and macrophages in Classical and Nodular Lymphocyte Predominant Hodgkin Lymphoma in children

OBJECTIVES: To study Hodgkin lymphoma (HL) microenvironment in a Swedish paediatric population and its relation to clinical parameters. METHODS: Tumour tissue from classical HL (cHL) (n=87) and nodular lymphocyte predominant HL (NLPHL) (n=11) was investigated for Epstein-Barr Virus (EBV) and analysed for eosinophils, mast cells and macrophages. RESULTS: In cHL, EBV positivity was more common in low age (p&lt;0.001) and in mixed cellularity (MC) (p&lt;0.001). Higher mast cell infiltration was seen in stage III-IV (p&lt;0.001), and with presence of B-symptoms (p=0.01). Cases with high mast cell counts displayed higher erythrocyte sedimentation rate (ESR), lower haemoglobin and albumin levels. Higher macrophage infiltration was seen in stage III-IV (p=0.02) and there was elevated ESR and neutrophil count. All NLPHL cases were EBV negative, had lower rates of inflammatory cells and lower degree of inflammatory reaction in laboratory parameters. There was no difference in survival estimates with regard to infiltration of inflammatory cells. CONCLUSIONS: Higher levels of mast cells and macrophages in cHL tumours reflected the clinical presentation in laboratory parameters, B-symptoms and more advanced stages. NLPHL differs from cHL in numbers of inflammatory cells in the tumour, and in laboratory parameters. This article is protected by copyright. All rights reserved.Both last authors contributed equally.</p

MEMS-based VCSEL beam steering using replicated polymer diffractive lens

Abstract. This paper describes a fully integrated micro-optical system, in which dynamic angular control of the beam from a VCSEL (vertical cavity surface emitting laser) is realized by laterally moving a collimat¬ing diffractive lens in the light path. The lens is mounted on a translatable silicon stage, which consists of a frame with an opening for the light to traverse the lens and electro-statically driven comb actuators, by which the lateral movement is achieved. Devices implementing both 1D and 2D scanning have been fabricated and evaluated. Integration of the lens onto the translatable silicon stage is done using a newly developed fabrication process based on hot embossing of an amorphous fluorocarbon polymer. This fabrication process relies on a reversed-order protocol, where the structuring of the optical element precedes the silicon microstructuring. Assembly and packaging of the VCSEL-MOEMS system, using LTCC (low temperature cofired ceramic) technique, is also demonstrated. Optical evaluation of the system and beam steering function shows significant beam deflection for a relatively low driving voltage (~70 V)

Long-term effectiveness of vedolizumab in inflammatory bowel disease : a national study based on the Swedish National Quality Registry for Inflammatory Bowel Disease (SWIBREG)

Objectives: Clinical trials have demonstrated the efficacy of vedolizumab in inflammatory bowel disease (IBD). However, these findings may not reflect the clinical practice. Therefore, we aimed to describe a vedolizumab-treated patient population and assess long-term effectiveness. Materials and methods: Patients initiating vedolizumab between 1 June 2014 and 30 May 2015 were identified through the Swedish National Quality Registry for IBD. Prospectively collected data on treatment and disease activity were extracted. Clinical remission was defined as Patient Harvey Bradshaw index <5 in Crohn’s disease (CD) and Patient Simple Clinical Colitis Activity index <3 in ulcerative colitis (UC). Results: Two-hundred forty-six patients (147 CD, 92 UC and 7 IBD-Unclassified) were included. On study entry, 86% had failed TNF-antagonist and 48% of the CD patients had undergone ≥1 surgical resection. After a median follow-up of 17 (IQR: 14–20) months, 142 (58%) patients remained on vedolizumab. In total, 54% of the CD- and 64% of the UC patients were in clinical remission at the end of follow-up, with the clinical activity decreasing (p < .0001 in both groups). Faecal-calprotectin decreased in CD (p < .0001) and in UC (p = .001), whereas CRP decreased in CD (p = .002) but not in UC (p = .11). Previous anti-TNF exposure (adjusted HR: 4.03; 95% CI: 0.96–16.75) and elevated CRP at baseline (adjusted HR: 2.22; 95% CI: 1.10–4.35) seemed to be associated with discontinuation because of lack of response. Female sex was associated with termination because of intolerance (adjusted HR: 2.75; 95% CI: 1.16–6.48). Conclusion: Vedolizumab-treated patients represent a treatment-refractory group. A long-term effect can be achieved, even beyond 1 year of treatment

SOX5/6/21 prevent oncogene-driven transformation of brain stem cells

Molecular mechanisms preventing self-renewing brain stem cells from oncogenic transformation are poorly defined. We show that the expression levels of SOX5, SOX6, and SOX21 (SOX5/6/21) transcription factors increase in stem cells of the subventricular zone (SVZ) upon oncogenic stress, whereas their expression in human glioma decreases during malignant progression. Elevated levels of SOX5/6/21 promoted SVZ cells to exit the cell cycle, whereas genetic ablation of SOX5/6/21 dramatically increased the capacity of these cells to form glioma-like tumors in an oncogene-driven mouse brain tumor model. Loss-of-function experiments revealed that SOX5/6/21 prevent detrimental hyperproliferation of oncogene expressing SVZ cells by facilitating an antiproliferative expression profile. Consistently, restoring high levels of SOX5/6/21 in human primary glioblastoma cells enabled expression of CDK inhibitors and decreased p53 protein turnover, which blocked their tumorigenic capacity through cellular senescence and apoptosis. Altogether, these results provide evidence that SOX5/6/21 play a central role in driving a tumor suppressor response in brain stem cells upon oncogenic insult

Clinical effectiveness of golimumab in ulcerative colitis : a prospective multicentre study based on the Swedish IBD Quality Register, SWIBREG

Objectives Clinical trials demonstrated that golimumab is effective in anti-TNF naive patients with ulcerative colitis. We aimed to assess the clinical effectiveness of golimumab in a real-world setting. Materials and methods This was a prospective cohort study, conducted at 16 Swedish hospitals. Data were collected using an electronic case report form. Patients with active ulcerative colitis, defined as Mayo endoscopic subscore &amp;gt;= 2 were eligible for inclusion. The primary outcomes were clinical effectiveness at 12 weeks and 52 weeks, i.e. response (defined as a decrease in Mayo score by &amp;gt;= 3 points or 30% from baseline) and remission (defined as a Mayo score of &amp;lt;= 2 with no individual subscores &amp;gt;1). Results Fifty patients were included. At study entry, 70% were previously exposed to anti-TNF, 16% to vedolizumab, and 96% to immunomodulators. The 12 and 52-week drug continuation rates were 37/50 (74%) and 23/50 (46%), respectively. The 12-week response rate was 14/50 (28%), the remission rate, 8/50 (16%) and the corresponding figures at week 52 were 13/50 (26%) and 10/50 (20%). Among patients who continued golimumab, the median Mayo score decreased from 7 (6-9) at baseline to 1 (0-5) at 52 weeks (p &amp;lt; .01) and the faecal calprotectin decreased from 862 (335-1759) mu g/g to 90 (34-169) mu g/g (p &amp;lt; .01). Clinical response at week 12 was highly predictive of clinical remission at week 52 (adjusted OR: 73.1; 95% CI: 4.5-1188.9). Conclusions The majority of golimumab treated patients represented a treatment refractory patient-group. Despite this, our results confirm that golimumab is an effective therapy in ulcerative colitis.Funding Agencies|MSD; Swedish governments agreement on medical training and research [OLL-836791, OLL-929900]</p