Emulating Randomized Controlled Trials with Hybrid Control Arms in Oncology: A Case Study.

This proof-of-concept study retrospectively assessed the feasibility of applying a hybrid control arm design to a completed phase III randomized controlled trial (RCT; CheckMate-057) in advanced non-small cell lung cancer using a real-world data (RWD) source. The emulated trial consists of an experimental arm (patients from the RCT experimental cohort) and a hybrid control arm (patients from the RCT and RWD control cohorts). For the RWD control cohort, this study used a nationwide electronic health record-derived de-identified database. Three frequentist statistical borrowing methods were evaluated: a two-step Cox model, a fixed Cox model, and propensity score-integrated composite likelihood ("Methods 1-3"). The experimental treatment effect for hybrid control designs were evaluated using hazard ratios (HRs) with 95% confidence interval (CI) estimated from the Cox models accounting for covariate differences. The reduction in study duration compared to the RCT was also evaluated. All three statistical borrowing methods achieved comparable experimental treatment effects to that observed in the CheckMate-057 clinical trial, with HRs of 0.73 (95% CI: 0.59, 0.92), 0.74 (95% CI: 0.61, 0.91), 0.72 (95% CI: 0.59, 0.88) for Methods 1-3, respectively. Reduction in study duration time was 99-115 days when borrowing 30-38 events for Methods 1-3, respectively. This study demonstrated that it is feasible to emulate an RCT using a hybrid control arm design using three frequentist propensity-score based statistical borrowing methods. Selection of an appropriate, fit-for-use RWD cohort is critical to minimizing bias in experimental treatment effect.

Arthroscopic repair of inferior glenoid labrum tears (Down Under lesions) produces similar outcomes to other glenoid tears.

PURPOSE: Inferior glenoid labral tears are an uncommon but distinct shoulder injury. Only a small number of studies have reported outcomes following arthroscopic repair. The aim of the current study was to report minimum 2-year outcomes following inferior labral repair and to compare outcomes and risk factors associated with the injury to non-inferior labral tears. Whether preoperative MRI or MRA identified inferior labral tears was also assessed. METHODS: A prospective study of 162 consecutive patients undergoing arthroscopic glenoid labral repair, excluding isolated superior labral tears, was conducted. Of the 130 patients available for follow-up, 18 (13.7%) had an inferior labral tear ("Down Under lesion"), the remainder had anterior, posterior or mixed anterior/posterior lesions that did not include the inferior pole. Mean follow-up time for the Down Under group was 44 months (SD 10, range 27-57), and 30 months (SD 14, range 4-60) for the non-Down Under group. Postoperative outcomes included the Oxford Shoulder Instability Score and recurrent instability. Associations between Down Under lesions and injury mechanism, instability at presentation, recurrent instability and family history were assessed with multivariable logistic regression. Preoperative MRI or MRA reports by radiologists were examined to determine if Down Under lesions were identified. RESULTS: Oxford Shoulder Instability Scores indicated that most patients in both groups had little pain or shoulder problems postoperatively (average Oxford Score 41; 48 = no symptoms). Oxford Scores were not significantly different between the Down Under and non-Down Under groups. Four patients (22.2%) in the Down Under group had recurring symptoms (pain and instability) compared to 12 (10.6%) in the non-Down Under group; this difference was not statistically significant (adjusted OR 1.09, 95% CI 0.19,4.77). Family history of shoulder instability was positively associated with a Down Under lesion (adjusted OR 5.0, 95%CI 1.51,16.7). MRI or MRA identified 52.9% of Down Under lesions. CONCLUSION: Down Under lesions were an infrequent type of glenoid labral injury, yet postoperative outcomes were similar to other labral tears. Patients with Down Under lesions had a significant risk factor due to family history of shoulder instability. MRI and MRA could not reliably identify Down Under lesions. LEVEL OF EVIDENCE: Level III.

Ten-year safety follow-up and post-explant analysis of an anterior chamber phakic IOL.

PURPOSE: To assess endothelial cell loss (ECL) rate and collect safety data in patients with AcrySof L-series Cachet phakic intraocular lens (pIOL) up to 10 years post-implantation. SETTING: Clinical settings in the United States, European Union, and Canada. DESIGN: Nonrandomized, observational, open-label safety study. METHODS: Central and peripheral endothelial cell density was evaluated and compared with 6-month post-implantation baseline. Nonlinear analysis was performed to identify factors affecting post-explantation ECL. Additional evaluations included uncorrected visual acuity (UCVA), corrected distance visual acuity (CDVA), adverse device effects (ADEs), and serious adverse events (SAEs). RESULTS: The study included 1123 implanted eyes (mean age, 37.5 years). At 10 years, mean central and peripheral ECL was 16% (1.7% annualized). Explantations were performed in 10% of eyes (n = 136/1323). For eyes with pIOL explantation because of ECL (7%), annualized ECL rate post-explantation was numerically lower compared with the overall rate in eyes that underwent explantation for any reason (annualized rate, -1.65% vs -2.03%, respectively; n = 96) and compared with pre-explantation ECL. Mean ± SD CDVA and UCVA were -0.12 ± 0.11 and 0.03 ± 0.22 logarithm of the minimum angle of resolution, respectively. Common ocular ADEs included ECL (10%), pIOL extraction (9%), iris adhesion (7%), and pupillary deformity (2%). Common SAEs included pIOL extraction (11%), ECL (9%), and iris adhesions (8%). CONCLUSIONS: Cachet pIOLs were associated with long-term ECL in some cases. Overall, only 10% of all implanted eyes underwent explantation during 10-year follow-up. In patients requiring explantation because of ECL, the annualized ECL rates decreased post-explantation in some eyes. Continued monitoring of patients regardless of explantation is recommended.

Evaluating Rotational Stability of an Extended Depth of Focus Toric Intraocular Lens Using a Slit Lamp and Image-Based Analysis.

PURPOSE: To evaluate the rotational stability of a toric extended depth of focus (EDOF) intraocular lens (IOL), using either slit lamp evaluation or image-processing software. SETTING: Three clinical practices in the USA. DESIGN: Prospective unmasked randomized clinical trial. METHODS: Subjects presenting for routine cataract surgery that were interested in improved near vision received toric EDOF lenses (TECNIS Symfony® Toric) in both eyes. The measures of interest in the current analysis were the change in orientation of the IOL between 1 day, 1 month and 3 months postoperative. Orientation was measured at the microscope on the day of surgery, and with the slit lamp at all other visits. Day 1, 1-month and 3-month images of the lens orientation were captured with a slit lamp camera. Differences in orientation were recorded and analyzed. RESULTS: A total of 150 eyes had IOL orientation data available. Image analysis showed mean absolute lens orientation changes from 1 day to 1 month and 3 months of less than 2 degrees. The percentage of lenses exhibiting rotation of ≤5 degrees between any measured time points was 97% or higher. Results were similar, but significantly more variable, when IOL orientation was measured at the slit lamp. CONCLUSION: The toric EDOF lens evaluated here demonstrated rotational stability that exceeded the prior ANSI standard. The best method to determine IOL orientation changes was through image analysis. .

Defocus Curve and Patient Satisfaction with a New Extended Depth of Focus Toric Intraocular Lens Targeted for Binocular Emmetropia or Slight Myopia in the Non-Dominant Eye.

PURPOSE: To evaluate the defocus curve and patient satisfaction after implantation of an extended depth of focus (EDOF) toric IOL when both eyes were targeted for emmetropia and when the non-dominant eye was targeted for mini monovision (-0.50D). METHODS: A prospective unmasked randomized clinical trial in three clinical practices in the USA. Subjects presenting for routine cataract surgery were assigned to one of two groups, both receiving bilateral toric EDOF lenses. One group had the non-dominant eye targeted for slight myopia (-0.50D). Measures of interest were the postoperative defocus curve and reported patient satisfaction and visual disturbances. RESULTS: Questionnaire and defocus curve data were available from 37 subjects in the Emmetropia group, while the mini monovision group included questionnaire data from 39 subjects and valid defocus curve data from 14 subjects. Mini monovision subjects had significantly better VA (a half line to a line better, p < 0.05), from a defocus of -1.50 D to -3.00 D. Reported spectacle wear and satisfaction were not significantly different between groups at any distance, but more patients in the mini monovision group reported the ability to function comfortably without glasses at near and overall (near p = 0.02, overall p < 0.01). Halos and starbursts were the two phenomena reported most often for both groups, with reported starbursts slightly more common in the mini monovision group. CONCLUSIONS: A slightly myopic correction in the non-dominant eye improved binocular near vision by 0.5 to 1.0 lines based on defocus curve data. Patients reported better functional vision, but with a slight increase in reported starbursts in the mini monovision group.

Corneal Endothelial Cell Loss and Morphometric Changes 5 Years after Phacoemulsification with or without CyPass Micro-Stent.

PURPOSE: To characterize long-term changes in corneal endothelial cells after phacoemulsification with or without supraciliary Micro-Stent (Alcon) implantation in eyes with open-angle glaucoma (OAG) and visually significant cataract. DESIGN: Three-year safety extension of a 2-year randomized clinical trial. METHODS: Patients from the multicenter Study of an Implantable Device for Lowering Intraocular Pressure in Glaucoma Patients Undergoing Cataract Surgery (COMPASS) trial who underwent Micro-Stent implantation plus phacoemulsification (n = 282) or phacoemulsification alone (n = 67) were analyzed post hoc. Specular microscopy was used to assess endothelial cell loss (ECL), including changes from baseline in endothelial cell density (ECD), coefficient of variation, and percentage of hexagonal cells. RESULTS: Preoperative ECDs in the microstent group (2,432.6 cells/mm2 [95% confidence interval [CI], 2,382.8-2,482.4 cells/mm2]) were similar to those in the control group (2,434.5 cells/mm2 [95% CI, 2,356.5-2,512.4 cells/mm2]) groups. ECL at months 48 and 60 was greater in the Micro-Stent group than in the control group. At month 60, the mean percent of changes in ECD was -20.4% (95% CI, -23.5% to -17.5%) in the Micro-Stent group and -10.1% (95% CI, -13.9% to -6.3%) in the control group. No statistically significant between-group changes from baseline in cellular morphology were observed. Nine adverse events were possibly related to ECL, including 3 eyes with transient focal corneal edema and 4 eyes that required Micro-Stent trimming due to protrusion. CONCLUSIONS: In eyes with OAG, ECL after phacoemulsification is acute and stabilizes after 3 months, whereas ECL after phacoemulsification plus Micro-Stent implantation proceeds for at least 5 years. Clinical findings associated with ECL in these eyes were uncommon (3.3% of implanted eyes), suggesting that ECL is generally a subclinical phenomenon.

Safety and Effectiveness of CyPass Supraciliary Micro-Stent in Primary Open-Angle Glaucoma: 5-Year Results from the COMPASS XT Study.

PURPOSE: To characterize the long-term (up to 5 years) safety and effectiveness of the supraciliary Micro-Stent (Alcon) implanted at the time of phacoemulsification in eyes with coexisting open-angle glaucoma (OAG) and visually significant cataract. DESIGN: Three-year safety extension of a 2-year randomized clinical trial. METHODS: Patients from the multicenter Study of an Implantable Device for Lowering Intraocular Pressure in Glaucoma Patients Undergoing Cataract Surgery (COMPASS) trial who underwent Micro-Stent implantation plus phacoemulsification (n = 215) or phacoemulsification alone (n = 67) were evaluated 36, 48, and 60 months postoperatively. The primary outcome measurement was the occurrence of sight-threatening ocular adverse events. Evaluations at each time point included best-corrected visual acuity (BCVA), anterior and posterior segment examinations, tonometry, gonioscopy, pachymetry, perimetry, specular microscopy, and assessment of adverse events. RESULTS: Three sight-threatening ocular adverse events occurred, 2 in the Micro-Stent group and 1 in the control group, but none of these events was related to the Micro-Stent device. Ocular adverse events were of similar frequencies in both groups, the most common of which were BCVA loss of ≥2 lines compared with best BCVA in COMPASS and worsening of visual field mean defect (VFMD) ≥2.5 dB compared with month 24. Changes in mean BCVA from baseline, clinical examinations, pachymetry, and VFMD were similar in the 2 groups. At 60 months, a higher proportion of subjects in the Micro-Stent group (46%; 95% confidence interval [CI], 38.9%-53.2%) than in the control group (32.1%; 95% CI 19.9%-46.3%) were able to achieve a reduction of ≥20% in intraocular pressure without using hypotensive medication. CONCLUSIONS: Few sight-threatening serious ocular adverse events occurred following Micro-Stent implantation, and clinical evidence of corneal decompensation was minimal.

Extended depth-of-focus toric intraocular lens targeted for binocular emmetropia or slight myopia in the nondominant eye: Visual and refractive clinical outcomes.

PURPOSE: To compare the visual and refractive outcomes with a diffractive toric extended depth-of-focus (EDOF) intraocular lens (IOL) when both eyes are targeted for emmetropia and the nondominant eye is targeted for slight myopia. SETTING: Three clinical practices, United States. DESIGN: Prospective case series. METHODS: Patients having routine cataract surgery with bilateral Tecnis Symfony toric EDOF IOL implantation were assigned to 1 of 2 groups. In 1 group, the nondominant eye was targeted for -0.50 diopter (D) (mini-monovision). Assessments included uncorrected monocular and binocular visual acuities (logarithm of the minimum angle of resolution) at distance (4 m), intermediate (66 cm), and near (40 cm) and the postoperative residual refractive error. RESULTS: Forty patients were enrolled in each group, with 1 dropout. The mean postoperative residual refractive astigmatism was 0.25 D in both groups, with no statistically significant difference. The mean residual refractive astigmatism was 0.50 D or lower in 92% of eyes (72/78) in the mini-monovision group and 95% of eyes (74/78) in the emmetropia group 3 months postoperatively. The mini-monovision group had slightly worse uncorrected visual acuity at 4 m than the emmetropia group (0.16 versus 0.09; P = .002) but better uncorrected acuity at 40 cm (0.25 versus 0.34; P < .001). Binocular uncorrected acuity was not statistically significantly different between groups at 4 m (-0.03 versus -0.01; P = .33) or 66 cm (0.06 versus 0.04; P = .34) but was statistically significant at 40 cm (0.25 versus 0.19; P = .03). CONCLUSIONS: The EDOF toric IOL provided functional distance, intermediate, and near vision. A slight monovision approach appears to improve near visual acuity.

Evaluation of intraocular lens mechanical stability.

PURPOSE: To compare mechanical characteristics and stability of Clareon CNA0T0 intraocular lens (IOL) with 4 currently marketed monofocal IOLs and to evaluate axial displacement and simulated dioptric power shift using a range of compression diameters. SETTING: Alcon Laboratories, Inc., Fort Worth, Texas, USA. DESIGN: Experimental study. METHODS: Clareon CNA0T0, AcrySof SN60WF, enVista MX60, Tecnis ZCB00, and Vivinex iSert XY1 IOLs (10 per group) were assessed using standardized methods for axial displacement, optic decentration, and optic tilt per the International Organization for Standardization ISO11979-3. Axial displacement was also measured over a range of compression diameters (9.0 to 11.0 mm). RESULTS: At 10.0 mm compression, the mean axial displacement for the CNA0T0 IOL (0.02 mm ± 0.01 [SD]) was significantly lower than for the MX60, ZCB00, and XY1 IOLs (P < .005). At all compression diameters, the CNA0T0 and SN60WF IOLs had the lowest levels of axial displacement and corresponding simulated dioptric power shift at the corneal plane versus other IOL models. At 10.0 mm compression, the mean optic decentration was within ±0.06 mm for all models, and there were no significant differences between the CNA0T0 IOL and other IOLs. At 10.0 mm compression, the mean optic tilt was no greater than 1.2 degrees for all IOL models evaluated; however, the mean optic tilt for the CNA0T0 IOL was significantly lower than for the MX60 IOL (P < .005). CONCLUSION: The CNA0T0 and SN60WF IOLs showed the lowest levels of axial displacement and corresponding simulated dioptric power shift over all tested compression diameters, indicating they might provide the most consistent refractive outcomes.

Corneal Endothelial Cell Density and Morphology After Phacoemulsification in Patients With Primary Open-Angle Glaucoma and Cataracts: 2-Year Results of a Randomized Multicenter Trial.

PURPOSE: To evaluate corneal endothelial cell density (ECD) and morphology 2 years after phacoemulsification in subjects from the COMPASS trial (ClinicalTrials.gov, NCT01085357) who had mild-to-moderate primary open-angle glaucoma and visually significant cataracts. METHODS: The central corneal endothelium was evaluated by serial specular microscopy at 0 to 24 months. ECD, coefficient of variation, and percentage of hexagonal cells were evaluated by a central image analysis reading center and central corneal thickness (CCT) was evaluated by ultrasound pachymetry. RESULTS: Of 131 subjects who underwent routine phacoemulsification, analyzable endothelial images at 24 months were available for 126 subjects (96.2%). Mean ± SD central ECD at baseline was 2453 ± 359 cells/mm, decreasing by 10% ± 14% to 2195 ± 517 cells/mm at 3 months (P < 0.001) but stabilizing thereafter with mean endothelial cell loss (ECL) from baseline to 24 months of 9% ± 13% (P < 0.001). Twelve (9.5%) and 10 (7.9%) subjects experienced >30% ECL at 12 and 24 months, respectively. Neither coefficient of variation nor percentage of hexagonal cells changed significantly from baseline at any time point. Mean CCT was similar at baseline (550 ± 35 µm) and at 12 months (551 ± 37 µm) and 24 months (555 ± 35 µm). Age was significantly associated with ECL after cataract surgery (P = 0.02), but baseline intraocular pressure, number of glaucoma medications, and CCT were not. Similar results were observed in patients who underwent CyPass micro-stent implantation accompanying phacoemulsification. CONCLUSIONS: Phacoemulsification in eyes with mild-to-moderate primary open-angle glaucoma results in early ECL, with ECD stabilizing after 3 months and no effect on other endothelial stress markers up to 2 years postoperatively.

Patient-Reported Outcomes/Satisfaction and Spectacle Independence with Blended or Bilateral Multifocal Intraocular Lenses in Cataract Surgery.

PURPOSE: To compare patient-reported outcomes (PROs) and satisfaction results after multifocal intraocular lens (IOL) implantation in three groups: two receiving bilateral implantation of the same IOL and another undergoing blended vision with two different multifocal IOLs. PATIENTS AND METHODS: A questionnaire was administered to patients who had undergone uncomplicated cataract surgery and 2 months of follow-up: the first group underwent bilateral implantation with Alcon's AcrySof ReSTOR 3.0 lens ("3.0/3.0," n=78); the second group underwent implantation with the ReSTOR ActiveFocus 2.5 or the ReSTOR ActiveFocus 2.5 toric lens ("2.5 mini-monovision," n=102); and the third group underwent implantation with the ReSTOR 2.5 lens in the dominant eye and the ReSTOR 3.0 lens in the non-dominant eye ("2.5/3.0," n=89). RESULTS: Overall PROs and satisfaction was similar among the groups. Refractive outcomes and accuracy were similar among the groups, but the 2.5 mini-monovision group reported better intermediate vision. Refractive outcome differences were not meaningful among the groups and were not a differentiating factor in PROs. Substantially fewer patients in the 2.5 mini-monovision group noticed glare and halo compared with the 3.0/3.0 group (P<0.0001, chi-square test). No new safety concerns were reported. CONCLUSION: The 2.5 mini-monovision results in a higher percentage of patients being satisfied with intermediate vision than bilateral ReSTOR 3.0 or blended vision with ReSTOR 2.5/3.0 implants, but overall PRO differences were not statistically significant.

Clinical Outcomes Using a Novel Image-Guided Planning System in Patients With Cataract and IOL Implantation.

PURPOSE: To determine the proportion of eyes with preexisting astigmatism achieving 0.50 diopters (D) or less of residual refractive cylinder 3 months after either implantation of toric intraocular lenses (IOLs) or corneal incisions using the VERION system (Alcon Laboratories, Inc., Fort Worth, TX) measurement module and digital markers for microscope (M) and laser (L). METHODS: Eyes with preexisting astigmatism in the intention-to-treat population were divided into four groups. Eyes in the no laser treatment group underwent toric IOL implantation with the measurement module, vision planner, and digital marker M (n = 102). Eyes in the other three groups underwent implantation of toric (n = 110), monofocal (n = 88), or multifocal (n =100) IOLs using the measurement module, vision planner, and digital marker M, including digital marker L, and LenSx laser (Alcon Laboratories, Inc.). The proportions of eyes achieving 0.50 D or less of relative refractive cylinder and with manifest refraction spherical equivalent (MRSE) deviating 0.50 D or less from the target outcome were evaluated at 3 months. RESULTS: The percentages of eyes achieving 0.50 D or less of relative refractive cylinder in the non-laser-treated, toric, monofocal, and multifocal groups at 3 months were 71.6%, 74.5%, 62.5%, and 71.0%, respectively. The percentages of eyes in these four groups with MRSE accuracies deviating 0.50 D or less from the target at 3 months were 69.6%, 80.0%, 77.3%, and 82.0%, respectively. CONCLUSIONS: The image-guided surgical planning system was effective in accurate correction of preexisting astigmatism in eyes undergoing refractive cataract surgery with IOL implantation, as shown by residual refractive astigmatism and MRSE at 3 months. [J Refract Surg. 2018;34(12):824-831.].

What is the role of bronchial thermoplasty in the management of severe asthma?

Asthma is a common chronic inflammatory condition of the airways. Conventional therapy comprises inhaled corticosteroid and bronchodilators as well as trigger avoidance and management of comorbid conditions. A small group remain symptomatic despite these strategies and novel therapies have been developed. Bronchial thermoplasty is a nonpharmacological therapy which targets airway smooth muscle to improve asthma control. Clinical trials to date have shown the efficacy and safety of bronchial thermoplasty with a persistent effect on extended follow up. Questions remain regarding the exact mechanism of action of bronchial thermoplasty, the cost effectiveness of the procedure and the ideal criteria for patient selection.

Association of body-mass index and outcomes in patients with metastatic melanoma treated with targeted therapy, immunotherapy, or chemotherapy: a retrospective, multicohort analysis.

BACKGROUND: Obesity has been linked to increased mortality in several cancer types; however, the relation between obesity and survival outcomes in metastatic melanoma is unknown. The aim of this study was to examine the association between body-mass index (BMI) and progression-free survival or overall survival in patients with metastatic melanoma who received targeted therapy, immunotherapy, or chemotherapy. METHODS: This retrospective study analysed independent cohorts of patients with metastatic melanoma assigned to treatment with targeted therapy, immunotherapy, or chemotherapy in randomised clinical trials and one retrospective study of patients treated with immunotherapy. Patients were classified according to BMI, following the WHO definitions, as underweight, normal, overweight, or obese. Patients without BMI and underweight patients were excluded. The primary outcomes were the associations between BMI and progression-free survival or overall survival, stratified by treatment type and sex. We did multivariable analyses in the independent cohorts, and combined adjusted hazard ratios in a mixed-effects meta-analysis to provide a precise estimate of the association between BMI and survival outcomes; heterogeneity was assessed with meta-regression analyses. Analyses were done on the predefined intention-to-treat population in the randomised controlled trials and on all patients included in the retrospective study. FINDINGS: The six cohorts consisted of a total of 2046 patients with metastatic melanoma treated with targeted therapy, immunotherapy, or chemotherapy between Aug 8, 2006, and Jan 15, 2016. 1918 patients were included in the analysis. Two cohorts containing patients from randomised controlled trials treated with targeted therapy (dabrafenib plus trametinib [n=599] and vemurafenib plus cobimetinib [n=240]), two cohorts containing patients treated with immunotherapy (one randomised controlled trial of ipilimumab plus dacarbazine [n=207] and a retrospective cohort treated with pembrolizumab, nivolumab, or atezolizumab [n=331]), and two cohorts containing patients treated with chemotherapy (two randomised controlled trials of dacarbazine [n=320 and n=221]) were classified according to BMI as normal (694 [36%] patients), overweight (711 [37%]), or obese (513 [27%]). In the pooled analysis, obesity, compared with normal BMI, was associated with improved survival in patients with metastatic melanoma (average adjusted hazard ratio [HR] 0·77 [95% CI 0·66-0·90] for progression-free survival and 0·74 [0·58-0·95] for overall survival). The survival benefit associated with obesity was restricted to patients treated with targeted therapy (HR 0·72 [0·57-0·91] for progression-free survival and 0·60 [0·45-0·79] for overall survival) and immunotherapy (HR 0·75 [0·56-1·00] and 0·64 [0·47-0·86]). No associations were observed with chemotherapy (HR 0·87 [0·65-1·17, pinteraction=0·61] for progression-free survival and 1·03 [0·80-1·34, pinteraction=0·01] for overall survival). The association of BMI with overall survival for patients treated with targeted and immune therapies differed by sex, with inverse associations in men (HR 0·53 [0·40-0·70]), but no associations observed in women (HR 0·85 [0·61-1·18, pinteraction=0·03]). INTERPRETATION: Our results suggest that in patients with metastatic melanoma, obesity is associated with improved progression-free survival and overall survival compared with those outcomes in patients with normal BMI, and that this association is mainly seen in male patients treated with targeted or immune therapy. These results have implications for the design of future clinical trials for patients with metastatic melanoma and the magnitude of the benefit found supports further investigation of the underlying mechanism of these associations. FUNDING: ASCO/CCF Young Investigator Award, ASCO/CCF Career Development Award, MD Anderson Cancer Center (MDACC) Melanoma Moonshot Program, MDACC Melanoma SPORE, and the Dr Miriam and Sheldon G Adelson Medical Research Foundation.

Acute kidney injury post-major orthopaedic surgery: A single-Centre case-control study.

AIM: To identify risk factors for acute kidney injury following major orthopaedic surgery. METHODS: We included all patients undergoing major orthopaedic surgery at University Hospital Geelong between 2008 and 2014 in the study. Out of 2188 surgeries audited, we identified cases of acute kidney injury using the RIFLE criteria and matched those to controls 2:1 for age, sex, procedure and chronic kidney disease stage. We reviewed their records for risk factors of postoperative acute kidney injury, including medications such as gentamicin, diuretics, non-steroidal anti-inflammatory drugs and angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use. We reviewed the patients' history of cardiovascular disease, chronic liver disease, hypertension and diabetes mellitus along with presence of sepsis and obesity. Associations of hypothetical risk factors were estimated using conditional logistic regression. RESULTS: We identified 164 cases of AKI in an elderly cohort (median age = 73 years). Controlling for baseline comorbidities, both diuretic and angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use were found to be associated with a twofold risk of acute kidney injury (diuretic - OR 2.06 95% CI:1.30-3.26, P < 0.005, angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use OR 2.09 95% CI:1.31-3.32, P < 0.005). A dose-effect model accounting for perioperative nonsteroidal anti-inflammatory drug administration demonstrated a linear relationship between the number of times these drugs were given and postoperative acute kidney injury risk (OR 1.35 95% CI:1.05-1.73, P = 0.02). CONCLUSIONS: We identified perioperative diuretics, non-steroidal anti-inflammatory drugs and angiotensin-converting enzyme inhibitor or angiotensin receptor blocker to be significantly associated with postoperative AKI. Further prospective studies are required to confirm this.

Efficacy and safety of direct switch to indacaterol/glycopyrronium in patients with moderate COPD: the CRYSTAL open-label randomised trial.

BACKGROUND: Dual bronchodilation combining a long-acting ß2-agonist (LABA) and a long-acting muscarinic antagonist (LAMA) is the preferred choice of treatment recommended by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017 guidelines for the management of patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). The once-daily (q.d.) fixed-dose combination (FDC) of LABA, indacaterol 110 µg and LAMA, glycopyrronium 50 µg (IND/GLY 110/50 µg q.d.) demonstrated superior improvements in lung function, dyspnoea and overall health status and better tolerability against LABA or LAMA monotherapies and combination of LABA and inhaled corticosteroid (ICS) in more than 11,000 patients with moderate-to-severe COPD in several randomised controlled clinical trials. METHODS: The CRYSTAL study was the first, 12-week, randomised, open-label trial that evaluated the efficacy and safety of a direct switch from previous treatments to IND/GLY 110/50 µg q.d. on lung function and dyspnoea in patients with moderate COPD and a history of up to one exacerbation in the previous year. Patients were divided into 2 groups according to their background therapy and symptom scores and were randomised (3:1) to IND/GLY or to continue with their previous treatments. RESULTS: The study included 4389 randomised patients, of whom 2160 were in groups switched to IND/GLY (intention-to-treat population). The effect of IND/GLY was superior to LABA + ICS on trough forced expiratory volume in 1 s (FEV1; treatment difference, Δ = +71 mL) and transition dyspnoea index (TDI; [Δ = 1.09 units]), and to LABA or LAMA on trough FEV1 (Δ = +101 mL) and a TDI (Δ = 1.26 units). Improvements in health status and lower rescue medication use were also observed with IND/GLY. The safety profile of the study medication was similar to that observed in previous studies. CONCLUSIONS: IND/GLY demonstrated superior improvements in lung function and dyspnoea after direct switch from previous treatments. TRIAL REGISTRATION: ClinicalTrials.gov number: NCT01985334 .

Protocol for a single-centre, parallel-arm, randomised controlled superiority trial evaluating the effects of transcatheter arterial embolisation of abnormal knee neovasculature on pain, function and quality of life in people with knee osteoarthritis.

INTRODUCTION: Symptomatic knee osteoarthritis (OA) is common. Advanced knee OA is successfully treated with joint replacement surgery, but effectively managing mild to moderate knee OA can be difficult. Angiogenesis increases with OA and might contribute to pain and structural damage. Modifying angiogenesis is a potential treatment pathway for OA. The aim of the current study is to determine whether transcatheter arterial embolisation of abnormal neovasculature arising from the genicular arterial branches improves knee pain, physical function and quality of life in people with mild to moderate symptomatic knee OA. METHODS AND ANALYSIS: The study is a single centre, parallel-arm, double-blinded (participant and assessor), randomised controlled superiority trial with 1:1 random block allocation. Eligible participants have mild to moderate symptomatic knee OA and will be randomly assigned to receive either embolisation of aberrant knee neovasculature of genicular arterial branches or a placebo intervention. Outcome measures will be collected prior to the intervention and again 1, 6 and 12 months postintervention. The primary outcome is change in knee pain between baseline and 12 month assessment as measured by the Knee Injury and Osteoarthritis Outcome Score (KOOS). Secondary outcomes include change in self-reported physical function (KOOS), self-reported quality of life (KOOS, EuroQol: EQ-5D-5L), self-reported knee joint stiffness (KOOS), self-reported global change, 6 min walk test performance, and 30 s chair-stand test performance. Intention-to-treat analysis will be performed including all participants as randomised. To detect a mean between group difference in change pain of 20% at the one year reassessment with a two-sided significance level of α=0.05 and power of 80% using a two-sample t-test, we require 29 participants per arm which allows for 20% of participants to drop out. ETHICS AND DISSEMINATION: Barwon Health Human Research Ethics Committee, 30 May 2016, (ref:15/101). Study results will be disseminated via peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: Universal trial number U1111-1183-8503, Australian New Zealand Clinical Trials Registry, ACTRN12616001184460, approved 29 August 2016.

The effect of N-acetylcysteine (NAC) on human cognition - A systematic review.

Oxidative stress, neuroinflammation and neurogenesis are commonly implicated as cognitive modulators across a range of disorders. N-acetylcysteine (NAC) is a glutathione precursor with potent antioxidant, pro-neurogenesis and anti-inflammatory properties and a favourable safety profile. A systematic review of the literature specifically examining the effect of NAC administration on human cognition revealed twelve suitable articles for inclusion: four examining Alzheimer's disease; three examining healthy participants; two examining physical trauma; one examining bipolar disorder, one examining schizophrenia, and one examining ketamine-induced psychosis. Heterogeneity of studies, insufficiently powered studies, infrequency of cognition as a primary outcome, heterogeneous methodologies, formulations, co-administered treatments, administration regimes, and assessment confounded the drawing of firm conclusions. The available data suggested statistically significant cognitive improvements following NAC treatment, though the paucity of NAC-specific research makes it difficult to determine if this effect is meaningful. While NAC may have a positive cognitive effect in a variety of contexts; larger, targeted studies are warranted, specifically evaluating its role in other clinical disorders with cognitive sequelae resulting from oxidative stress and neuroinflammation.