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

Mixed Connective Tissue Disease Presenting as Longitudinal Extensive Transverse Myelitis and Vasculitic Neuropathy

Mixed connective tissue disease (MCTD) is described as an entity with mixed features of systemic lupus erythematosus, systemic sclerosis, polymyositis/ dermatomyositis, and rheumatoid arthritis together with the presence of high-titre anti-U1 small nuclear and anti-ribonucleoprotein (anti-RNP) antibodies. Here, we present a case of an 18-year-old female patient who presented with quadriparesis, sensory loss in all four limbs, and trophic ulcers. Laboratory investigations were strongly positive for ANA, KU, SM/RNP, SM, SSA, and RIBOSOME P protein. MRI brain showed diffuse T2 hyperintensity in the spinal cord extending from cervicomedullary junction to conus with a subtle expansion of cord. A diagnosis of longitudinal extensive transverse myelitis and vasculitic neuropathy in the case of MCTD was made.</jats:p

Mitochondrial functions of RECQL4 are required for the prevention of aerobic glycolysis dependent cell invasion

Germline mutations in RECQL4 helicase are associated with Rothmund-Thomson syndrome (RTS), which is characterized by cancer predisposition. RECQL4 localizes to the mitochondria where it acts as an accessory factor during mtDNA replication. To understand the specific mitochondrial functions of RECQL4, isogenic cell lines were created whereby the mitochondrial localization of the helicase was either retained or abolished. The mitochondrial integrity was affected due to the absence of RECQL4 in mitochondria, leading to a decrease in F1F0-ATP synthase activity. In these cells where RECQL4 does not localize to mitochondria, the membrane potential was decreased while ROS levels increased due to the presence of high levels of catalytically inactive SOD2. Inactive SOD2 accumulated due to diminished SIRT3 activity. Lack of the mitochondrial functions of RECQL4 led to aerobic glycolysis which in turn led to an increased invasive capability in these cells. Altogether this study demonstrates for the first time that owing to its mitochondrial functions, the accessory mitochondrial replication helicase RECQL4 prevents the invasive step in the neoplastic transformation process.</jats:p

miR-210-3p promotes obesity-induced adipose tissue inflammation and insulin resistance by targeting SOCS1 mediated NF-κB pathway

Under the condition of chronic obesity, an increased level of free fatty acids along with low oxygen tension in the adipose tissue creates a pathophysiological adipose tissue microenvironment (ATenv) leading to the impairment of adipocyte function and insulin resistance. Here, we found the synergistic effect of hypoxia and lipid (HL) surge in fostering adipose tissue macrophages(ATMs) inflammation and its polarization. ATenv significantly increased miR-210-3p expression in ATMs which promotes NF-kB activation-dependent proinflammatory cytokines expressions along with the downregulation of anti-inflammatory cytokines expression. Interestingly, delivery of miR-210-3p mimic significantly increased the macrophage inflammation in absence of HL co-stimulation; while miR-210-3p inhibitor notably compromised HL-induced macrophage inflammation through increased production of SOCS1 (suppressor of cytokine signalling 1), a negative regulator of NF-kB inflammatory signalling pathway. Mechanistically, miR-210 directly binds to 3′ UTR of SOCS1 mRNA and silenced its expression and thus preventing proteasomal degradation of NF-kB p65. Direct delivery of anti-miR-210-3p LNA in the ATenv markedly rescued mice from obesity-induced adipose tissue inflammation and insulin resistance. Thus, miR-210-3p inhibition in ATMs could serve as a novel therapeutic strategy for managing obesity-induced type 2 diabetes.</p

Preparation of macro-, micro-, and nano-sized poly(Tannic acid) particles with controllable degradability and multiple biomedical uses

Different size ranges of poly(Tannic acid) (p(TA)) particles, 2000-500 mu m, 500-200 mu m, 200-20 mu m, and 20-0.5 mu m, were successfully synthesized by using lecithin/gasoline microemulsion media. Macro, micro, and nano sized p(TA) particles were crosslinked via poly(ethylene glycol) diglycidyl ether (PEGGE) with 85 +/- 7% gravimetric yield. The hydrolytic degradation of different sizes of p(TA) particles in physiological pH conditions, in pH 5.4, 7.4, and 9.0 buffer solutions at 37.5 degrees C, were investigated. It was found that p(TA) particles with 20-0.5 mu m size distribution are more stable than the other sized particles due to the higher amounts of crosslinker used during synthesis. Furthermore, macro size p(TA) particles (2000-500 mu m) were totally degraded at pH 9 within 12 days, whereas a linear and sustained degradation profile was obtained at pH 7.4 with 75 +/- 4% weight loss for 24 days. The antioxidant capacity of p(TA) particles was also tested and 20-0.5 mu m sized p(TA) particles demonstrated the highest antioxidant capacity with 0.1305 +/- 0.0124 mg gallic acid equivalency and 145 +/- 21 mM trolox equivalent g(-1). It was also further demonstrated that the degraded p(TA) particles showed high antimicrobial activity against a wide spectrum of bacteria and yeast strains such as Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and Candida albicans. In vitro blood compatibility of p(TA) particles was also examined by hemolysis % and blood clotting index and micrometer sized p(TA) particles are more hemocompatible with enhanced blood clotting capability. In addition, WST-1 cytotoxicity test results showed that 200-20 mu m and 20-0.5 mu m sized p(TA) particles were biocompatible up to 50 mu g/mL concentration with 74 +/- 3 and 68 +/- 2% cell viabilities for L929 fibroblast cells. (C) 2016 Elsevier Ltd. All rights reserved