Penetration of topical diclofenac into synovial tissue and fluid of osteoarthritic knees: a multicenter, randomized, placebo-controlled, pharmacokinetic study

Funder: GSK Consumer Healthcare S.A., Nyon, SwitzerlandBackground:: Topical diclofenac, a nonsteroidal anti-inflammatory drug, has proven efficacy and safety in the management of osteoarthritis pain. We investigated penetration of topical diclofenac into knee synovial tissue and fluid (primary objective) and evaluated relative exposure in the knee versus plasma (secondary objective). Methods:: In this phase I, double-blind, multicenter study, patients scheduled for arthroplasty for end-stage knee osteoarthritis were randomly assigned 2:1 to 4 g diclofenac diethylamine 2.32% w/w gel (92.8 mg diclofenac diethylamine, equivalent to 74.4 mg diclofenac, per application) or placebo gel, applied to the affected knee by a trained nurse/designee every 12 h for 7 days before surgery. Diclofenac concentrations were measured in synovial tissue, synovial fluid and plasma from samples obtained during surgery ⩾12 h after last application. Treatment-emergent adverse events (TEAEs) were evaluated. Results:: Evaluable synovial tissue or fluid samples were obtained from 45 (diclofenac n = 29; placebo n = 16) of 47 patients. All diclofenac-treated participants had measurable diclofenac concentrations in synovial tissue [geometric mean 1.57 (95% confidence interval (CI) 1.12, 2.20) ng/g] and fluid [geometric mean 2.27 (95% CI 1.87, 2.76) ng/ml] ⩾12 h after the last dose. Geometric mean (95% CI) ratio of diclofenac in synovial tissue:plasma was 0.32 (0.23, 0.45) and in synovial fluid:plasma was 0.46 (0.40, 0.54). TEAE rates were similar for diclofenac (55.2%) and placebo (58.8%); none were treatment related. Conclusions:: Topical diclofenac diethylamine 2.32% w/w gel penetrated into the osteoarthritic knee after repeated application and remained detectable in synovial tissue and fluid at the end of the final 12 h dosing cycle

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

The 5-Hydroxymethylcytosine Landscape of Prostate Cancer

Analysis of DNA methylation is a valuable tool to understand disease progression and is increasingly being used to create diagnostic and prognostic clinical biomarkers. While conversion of cytosine to 5-methylcytosine (5mC) commonly results in transcriptional repression, further conversion to 5-hydroxymethylcytosine (5hmC) is associated with transcriptional activation. Here we perform the first study integrating whole-genome 5hmC with DNA, 5mC, and transcriptome sequencing in clinical samples of benign, localized, and advanced prostate cancer. 5hmC is shown to mark activation of cancer drivers and downstream targets. Furthermore, 5hmC sequencing revealed profoundly altered cell states throughout the disease course, characterized by increased proliferation, oncogenic signaling, dedifferentiation, and lineage plasticity to neuroendocrine and gastrointestinal lineages. Finally, 5hmC sequencing of cell-free DNA from patients with metastatic disease proved useful as a prognostic biomarker able to identify an aggressive subtype of prostate cancer using the genes TOP2A and EZH2, previously only detectable by transcriptomic analysis of solid tumor biopsies. Overall, these findings reveal that 5hmC marks epigenomic activation in prostate cancer and identify hallmarks of prostate cancer progression with potential as biomarkers of aggressive disease. SIGNIFICANCE: In prostate cancer, 5-hydroxymethylcytosine delineates oncogene activation and stage-specific cell states and can be analyzed in liquid biopsies to detect cancer phenotypes. See related article by Wu and Attard, p. 3880.publishedVersionPeer reviewe

Use of porous stepped meta- physeal sleeves during revision total knee arthroplasty

AbstractIntroduction Revision knee arthroplasty is an increasingly common procedure and can be challenging in the presence of bone defects, ligament instability and soft-tissue deficiencies. Current treatment options in addressing tibial and femoral bone loss in the revision setting include cement, morselised or structural allograft, metal wedges and augments and custom or hinge prosthesis. The aim of this study is to describe our early experience using unique femoral and tibial metaphyseal sleeves as an alternate for dealing with significant tibial and femoral bone loss.Methods Porous stepped metaphyseal sleeves were implanted during twenty revision total knee replacements in eleven men and nine women who had an average age of 73.3 years at the time of the procedure. The indications included aseptic loosening in nineteen cases and second stage reimplantation in one case. Bone defects in tibia and femur were classified intra operatively according to AORI classification. All patients were prospectively followed clinically and radiographically for a mean follow up of sixteen months (range 12-26 months).Results There were no periprosthetic fractures or complications related to the insertion and impaction of the sleeves. The mean length of stay was 9 days (range 5-20 days). Clinical review at the latest follow up revealed no evidence of instability and a good final range of motion (mean 0 to 95 degrees). Radiographs demonstrated reestablishment of joint line, neutral mechanical axis (mean -5 degrees valgus) and signs of stable osteointegration. No cases of progressive osteolysis, loosening or subsidence were noted.Discussion The use of metaphyseal sleeves may facilitate in making revision TKA in the setting of severe bone loss a more reproducible, predictable, and successful option that offers biologic fixation leading to long-term implant stability and surviva

‘2 in 1’ single stage revision of infected Total Knee Arthroplasty using metaphyseal femoral and tibial sleeves: early experience

Introduction: Two-stage revision is a widely accepted and performed intervention for septic total knee arthroplasty (TKA), with an infection eradication rate exceeding 90% in most studies. The ‘2-in-1’ single stage revision has recently been reported to have favourable results. Aim: To evaluate the early clinical results of single-stage reimplantation of infected TKA using stepped metaphyseal femoral and tibial sleeves. Methods: From March 2009 to January 2010, 8 patients with a diagnosis of infected total knee arthroplasty were treated with ‘2 in 1’ single-stage reimplantation in our institution. There were 4 men and 4 women with an average age of 71 years. The revision operation was performed in patients presenting with an infected TKA and who had mild to moderate tibial or femoral bone loss. We used extraction of implants, debridement and lavage in the first stage and re-draped patients prior to the second stage which included the definitive implantation. All the patients received intravenous antibiotics for two weeks and oral antibiotics were continued for further 6–12 weeks until the serum CRP & WBC were normal. None of these patients required intra operative bone allografting. Results: Clinical evaluation at the last follow up showed significant improvement in the knee pain and stiffness score. Radiological evaluation was done using the Knee Society system. None of the knees showed evidence of infection or loosening at the mean follow up of eighteen months. Conclusion: Metaphyseal femoral and tibial sleeves may enable reconstruction of contained and uncontained bone stock, insertion of a stable implant and control of infection in a single operation in revision TKR for infection. The increased morbidity and cost of a two-stage procedure is thus avoided

Reducing Postoperative Blood Loss Following Total Hip Replacement: A New Protocol Using Rivaroxaban And Tranexamic Acid

Blood loss following total hip replacement is a major contributor to increase morbidity and length of stay. Various techniques have been described to reduce its occurrence. We now follow a set protocol, combining rivaroxaban for thrombo-prophylaxis and tranexamic acid to reduce immediate postoperative bleeding. Patients and methods: Using data collected prospectively we looked at 2 groups of consecutive patients undergoing THR. The protocol was the only factor changed during the period studied. Initially we used subcutaneous dalteparin injections and continued use of aspirin in peri-operative period following total hip replacements (Group I–317 patients). A new protocol was introduced involving rivaroxaban for thrombo-prophylaxis with its first dose at least 8 hours from skin closure and stopping aspirin at least 7 days before operation. In addition tranexamic acid was given in a dose of 500 mg (or 1 gm in obese patients) intravenously just prior to incision (Group II–348 patients). We compared these two groups regards Hb drop at 24 hours and blood transfusion requirement. Results: The average Hb drop at 24 hours postop in group I was 3.08 gm/dl compared to 2.31 in group II. (p<0.001). 62 (19.6%) patients in group I required blood transfusion compared to 11 (3.2%) in group II. (p = 0.001) Perioperative blood loss and length of stay reduction was also significantly different. There was no increase in number of DVT/PE, but the sample size was too small to assess this statistically. Conclusion: This protocol drastically reduces requirement of postoperative blood transfusion requirement helping in reducing the length of stay following hip replacement

Jejuno-jejunal intussusception: An unusual initial presentation of metastatic melanoma

Jejuno-jejunal intussusception is a rare mode of metastatic melanoma presentation, with only six cases being reported in the English medical literature to date. We present a case of a 55-year-old female who presented to us with features of obstruction. On exploration, it was discovered that she had jejuno-jejunal intussusception, with enlarged blackened mesenteric lymph nodes. Resection and anastomosis were performed. On further histopathological examination, a lesion was found to be a metastatic malignant melanoma