Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population

Bee Sugar: a sweet take on the music of soul & Bee Spice: a tale of a single bee

Concert I “Bee Sugar: a sweet take on the music of soul” Set List: Because He Lives (Traditional hymn) Spring Can Really Hang You Up The Most (Tom Wolf/Fran Landsman) Ode to Nikki (Brianna Reed/poem by Nikki Giovanni) When a Woman Loves a Man (Billie Holiday) In the Midst of It All (Yolanda Adams/Kevin Bond) Bee’s Lament (Brianna Reed) Call Me (Aretha Franklin) My first concert, “Bee Sugar, “ is a tribute to my musical history. It explores the humble beginnings of my love affair with music. I chose songs from genres of music I grew up listening to: gospel, jazz and classic soul. My inspiration and muse was my mother. She has been an important factor in my decisions as a musician and has motivated me to continue pursuing a life in music. All of the music I love comes from growing up in a household where there were constant melodies, harmonies, and thoughtful lyrics floating in the air. I originally planned to only sing songs that were by other musicians but I was inspired by my peers and advisor to compose my own songs. I wrote two songs entitled “Ode to Nikki” and “Bee’s Lament.” “Ode to Nikki” developed from my love of poet, Nikki Giovanni’s works. I used her poem A Poem of Friendship as the lyric to the song. I wanted every song to evoke an emotion from each audience member, hoping to welcome them into experiences and the history of my musical journey. Concert II “Bee Spice: a tale of a single bee” Set List: Bee’s Lament Redux (Brianna Reed) So Glad (Joseph Tisdall, Brianna Reed) Notice (Brianna Reed) You Got Me (Brianna Reed) BFF (Brianna Reed, arr. Zachary Seman) Just Sex (Brianna Reed, Zachary Seman) Show &Tell (Joseph Tisdall, Brianna Reed) So Fast (Brianna Reed) When I meet the love of my life I hope I recognize him and he sees me and we both catch the glimmer in each other’s eye and notice the familiarity. That we become friends first and are confident in finding the missing piece of ourselves. That each word we share is truth and loyalty. Support and motivation. Love and forgiveness. I have yet to find this love and if I do know him this just means I do not completely know myself enough to recognize that glimmer in his eyes. Preparing for this senior project could only be done by living life. I had to experience joy, pain, love and heartbreak. I needed to have late nights out with friends and moments in solitude. Spontaneous lyric and poetry were summoned from my sub-conscience begging to be liberated through melodies and rhythms. The majority of my lyric topics stem from personal experiences exploring every emotion felt from either individual or collective memories. They tell the stories, including pain and joy, but always hopeful. I strived to inspire the audience as well as myself. A lot of the inspirational songs were conversations to myself that I knew would be relatable to others as well

ÉMOTIONS POSITIVES ET RÉSILIENCE : EFFETS DES ÉMOTIONS POSITIVES SUR LE BIEN-ÊTRE PHYSIQUE ET PSYCHOLOGIQUE

L’article présente la théorie de Fredrickson sur les émotions positives dite « expansion et construction » (broaden and build) ainsi que des résultats qui la soutiennent. Dans le contexte de cette théorie, nous discutons des bienfaits de l’expansion et de la construction des émotions positives sur la santé physique et psychologique : une résilience aguerrie, des stratégies efficaces face au stress ainsi que la récupération physiologique à la suite d’expériences négatives. Enfin, nous présentons un bref aperçu des approches passées et actuelles pour l’étude des émotions positives et nous proposons de nouvelles techniques pour la mesure de ces émotions en utilisant les nouvelles technologies mobiles.In this paper, we review Fredrickson’s Broaden and Build theory of positive emotions and the empirical work supporting this theory. Within this context we discuss the beneficial psychological and physical health outcomes associated with the broadening and building effects of positive emotions, such as greater resilience and coping in the face of stress as well as physiological recovery after negative experiences. Lastly, this paper will outline past and current approaches to studying positive emotions, and will propose new methods of measuring positive emotion by using modern, mobile technology

Effects of Duloxetine in Rats Trained to Discriminate Between 2- and 22- hr Food Deprivation

Color poster with text and graphs.Duloxetine inhibits serotonin and norepinephrine transporters, and is clinically used to treat depression, pain, and generalized anxiety disorder. Duloxetine has been shown to reduce food intake in several species. The purpose of this study was to examine the effects of duloxetine in non-restricted rats trained to discriminate between 22- and 2-hour food deprivation to gain better understanding of neurochemicals mediating the discriminative stimulus effects of 22-hour food deprivation.University of Wisconsin--Eau Claire Office of Research and Sponsored Programs

Effects of Duloxetine in Rats Trained to Discriminate Between 2 and 22 hr Food Deprivation

Color poster with text, graphs, and tables.Duloxetine inhibits serotonin and norepinephrine transporters, and is clinically used to treat depression, pain, and generalized anxiety disorder. Duloxetine has been shown to reduce food intake in several species. The purpose of this study was to examine the effects of duloxetine in non-restricted rats trained to discriminate between 22- and 2-hour food deprivation to gain better understanding of neurochemicals mediating the discriminative stimulus e ects of 22-hour food deprivation.University of Wisconsin--Eau Claire Office of Research and Sponsored Programs

The human IL-15 superagonist N-803 promotes migration of virus-specific CD8+ T and NK cells to B cell follicles but does not reverse latency in ART-suppressed, SHIV-infected macaques.

Despite the success of antiretroviral therapy (ART) to halt viral replication and slow disease progression, this treatment is not curative and there remains an urgent need to develop approaches to clear the latent HIV reservoir. The human IL-15 superagonist N-803 (formerly ALT-803) is a promising anti-cancer biologic with potent immunostimulatory properties that has been extended into the field of HIV as a potential "shock and kill" therapeutic for HIV cure. However, the ability of N-803 to reactivate latent virus and modulate anti-viral immunity in vivo under the cover of ART remains undefined. Here, we show that in ART-suppressed, simian-human immunodeficiency virus (SHIV)SF162P3-infected rhesus macaques, subcutaneous administration of N-803 activates and mobilizes both NK cells and SHIV-specific CD8+ T cells from the peripheral blood to lymph node B cell follicles, a sanctuary site for latent virus that normally excludes such effector cells. We observed minimal activation of memory CD4+ T cells and no increase in viral RNA content in lymph node resident CD4+ T cells post N-803 administration. Accordingly, we found no difference in the number or magnitude of plasma viremia timepoints between treated and untreated animals during the N-803 administration period, and no difference in the size of the viral DNA cell-associated reservoir post N-803 treatment. These results substantiate N-803 as a potent immunotherapeutic candidate capable of activating and directing effector CD8+ T and NK cells to the B cell follicle during full ART suppression, and suggest N-803 must be paired with a bona fide latency reversing agent in vivo to facilitate immune-mediated modulation of the latent viral reservoir

Application of High-Throughput Next-Generation Sequencing for HLA Typing on Buccal Extracted DNA: Results from over 10,000 Donor Recruitment Samples

<div><p>Background</p><p>Unambiguous HLA typing is important in hematopoietic stem cell transplantation (HSCT), HLA disease association studies, and solid organ transplantation. However, current molecular typing methods only interrogate the antigen recognition site (ARS) of HLA genes, resulting in many <i>cis-trans</i> ambiguities that require additional typing methods to resolve. Here we report high-resolution HLA typing of 10,063 National Marrow Donor Program (NMDP) registry donors using long-range PCR by next generation sequencing (NGS) approach on buccal swab DNA.</p><p>Methods</p><p>Multiplex long-range PCR primers amplified the full-length of HLA class I genes (A, B, C) from promotor to 3’ UTR. Class II genes (DRB1, DQB1) were amplified from exon 2 through part of exon 4. PCR amplicons were pooled and sheared using Covaris fragmentation. Library preparation was performed using the Illumina TruSeq Nano kit on the Beckman FX automated platform. Each sample was tagged with a unique barcode, followed by 2×250 bp paired-end sequencing on the Illumina MiSeq. HLA typing was assigned using Omixon Twin software that combines two independent computational algorithms to ensure high confidence in allele calling. Consensus sequence and typing results were reported in Histoimmunogenetics Markup Language (HML) format. All homozygous alleles were confirmed by Luminex SSO typing and exon novelties were confirmed by Sanger sequencing.</p><p>Results</p><p>Using this automated workflow, over 10,063 NMDP registry donors were successfully typed under high-resolution by NGS. Despite known challenges of nucleic acid degradation and low DNA concentration commonly associated with buccal-based specimens, 97.8% of samples were successfully amplified using long-range PCR. Among these, 98.2% were successfully reported by NGS, with an accuracy rate of 99.84% in an independent blind Quality Control audit performed by the NDMP. In this study, NGS-HLA typing identified 23 null alleles (0.023%), 92 rare alleles (0.091%) and 42 exon novelties (0.042%).</p><p>Conclusion</p><p>Long-range, unambiguous HLA genotyping is achievable on clinical buccal swab-extracted DNA. Importantly, full-length gene sequencing and the ability to curate full sequence data will permit future interrogation of the impact of introns, expanded exons, and other gene regulatory sequences on clinical outcomes in transplantation.</p></div