James D. Wylie

Abiraterone for prostate cancer not previously treated with hormone therapy

Background Abiraterone acetate plus prednisolone improves survival in men with relapsed prostate cancer. We assessed the effect of this combination in men starting long‐term androgen‐deprivation therapy (ADT), using a multigroup, multistage trial design. Methods We randomly assigned patients in a 1:1 ratio to receive ADT alone or ADT plus abiraterone acetate (1000 mg daily) and prednisolone (5 mg daily) (combination therapy). Local radiotherapy was mandated for patients with node‐negative, nonmetastatic disease and encouraged for those with positive nodes. For patients with nonmetastatic disease with no radiotherapy planned and for patients with metastatic disease, treatment continued until radiologic, clinical, or prostate‐specific antigen (PSA) progression; otherwise, treatment was to continue for 2 years or until any type of progression, whichever came first. The primary outcome measure was overall survival. The intermediate primary outcome was failure‐free survival (treatment failure was defined as radiologic, clinical, or PSA progression or death from prostate cancer). Results A total of 1917 patients underwent randomization from November 2011 through January 2014. The median age was 67 years, and the median PSA level was 53 ng per milliliter. A total of 52% of the patients had metastatic disease, 20% had node‐positive or node‐indeterminate nonmetastatic disease, and 28% had node‐negative, nonmetastatic disease; 95% had newly diagnosed disease. The median follow‐up was 40 months. There were 184 deaths in the combination group as compared with 262 in the ADT‐alone group (hazard ratio, 0.63; 95% confidence interval [CI], 0.52 to 0.76; P<0.001); the hazard ratio was 0.75 in patients with nonmetastatic disease and 0.61 in those with metastatic disease. There were 248 treatment‐failure events in the combination group as compared with 535 in the ADT‐alone group (hazard ratio, 0.29; 95% CI, 0.25 to 0.34; P<0.001); the hazard ratio was 0.21 in patients with nonmetastatic disease and 0.31 in those with metastatic disease. Grade 3 to 5 adverse events occurred in 47% of the patients in the combination group (with nine grade 5 events) and in 33% of the patients in the ADT‐alone group (with three grade 5 events). Conclusions Among men with locally advanced or metastatic prostate cancer, ADT plus abiraterone and prednisolone was associated with significantly higher rates of overall and failure‐free survival than ADT alone. (Funded by Cancer Research U.K. and others; STAMPEDE ClinicalTrials.gov number, NCT00268476, and Current Controlled Trials number, ISRCTN78818544.)

ADAMTS metalloproteases generate active versican fragments that regulate interdigital web regression

We show that combinatorial mouse alleles for the secreted metalloproteases Adamts5, Adamts20 (bt), and Adamts9 result in fully penetrant soft-tissue syndactyly. Interdigital webs in Adamts5(-/-);bt/bt mice had reduced apoptosis and decreased cleavage of the proteoglycan versican; however, the BMP-FGF axis, which regulates interdigital apoptosis was unaffected. BMP4 induced apoptosis, but without concomitant versican proteolysis. Haploinsufficiency of either Vcan or Fbln1, a cofactor for versican processing by ADAMTS5, led to highly penetrant syndactyly in bt mice, suggesting that cleaved versican was essential for web regression. The local application of an aminoterminal versican fragment corresponding to ADAMTS-processed versican, induced cell death in Adamts5(-/-);bt/bt webs. Thus, ADAMTS proteases cooperatively maintain versican proteolysis above a required threshold to create a permissive environment for apoptosis. The data highlight the developmental significance of proteolytic action on the ECM, not only as a clearance mechanism, but also as a means to generate bioactive versican fragments.

Pericellular Versican Regulates the Fibroblast-Myofibroblast Transition: A ROLE FOR ADAMTS5 PROTEASE-MEDIATED PROTEOLYSIS*

The cell and its glycosaminoglycan-rich pericellular matrix (PCM) comprise a functional unit. Because modification of PCM influences cell behavior, we investigated molecular mechanisms that regulate PCM volume and composition. In fibroblasts and other cells, aggregates of hyaluronan and versican are found in the PCM. Dermal fibroblasts from Adamts5−/− mice, which lack a versican-degrading protease, ADAMTS5, had reduced versican proteolysis, increased PCM, altered cell shape, enhanced α-smooth muscle actin (SMA) expression and increased contractility within three-dimensional collagen gels. The myofibroblast-like phenotype was associated with activation of TGFβ signaling. We tested the hypothesis that fibroblast-myofibroblast transition in Adamts5−/− cells resulted from versican accumulation in PCM. First, we noted that versican overexpression in human dermal fibroblasts led to increased SMA expression, enhanced contractility, and increased Smad2 phosphorylation. In contrast, dermal fibroblasts from Vcan haploinsufficient (Vcanhdf/+) mice had reduced contractility relative to wild type fibroblasts. Using a genetic approach to directly test if myofibroblast transition in Adamts5−/− cells resulted from increased PCM versican content, we generated Adamts5−/−;Vcanhdf/+ mice and isolated their dermal fibroblasts for comparison with dermal fibroblasts from Adamts5−/− mice. In Adamts5−/− fibroblasts, Vcan haploinsufficiency or exogenous ADAMTS5 restored normal fibroblast contractility. These findings demonstrate that altering PCM versican content through proteolytic activity of ADAMTS5 profoundly influenced the dermal fibroblast phenotype and may regulate a phenotypic continuum between the fibroblast and its alter ego, the myofibroblast. We propose that a physiological function of ADAMTS5 in dermal fibroblasts is to maintain optimal versican content and PCM volume by continually trimming versican in hyaluronan-versican aggregates.

The Effect of NSAID Prophylaxis and Operative Variables on Heterotopic Ossification After Hip Arthroscopy

Background: Heterotopic ossification (HO) is a known complication of hip arthroscopy. Little is known about the factors that lead to HO after hip arthroscopy. Purpose: The aim of this study was to evaluate the effect of nonsteroidal anti-inflammatory drugs (NSAIDs) and other operative variables on the development of HO. Study Design: Cohort study; Level of evidence, 3. Methods: A total of 357 consecutive cases of hip arthroscopy were retrospectively reviewed over a 3-year period. Routine NSAID prophylaxis was not performed for the first 117 cases. Prophylaxis with naproxen for 3 weeks was then routinely prescribed for the remaining 240 cases. Complete follow-up was available for 288 of the original 357 cases. The presence of HO and its characteristics were recorded for each patient, along with baseline demographic and surgical variables. Odds ratios and logistic regression were used to identify causal factors for HO. Results: The incidence of HO in cases in which the patient did not receive NSAID prophylaxis was 25.0% (23/92) versus 5.6% (11/196) of cases in which the patient received NSAIDs. Patients who received no NSAID prophylaxis were 13.6 times more likely to develop HO postoperatively (95% confidence interval, 2.44-75.5; P = .003). Comparing just mixed-type femoroacetabular impingement resections, patients who received no NSAID prophylaxis were 16.6 times more likely to develop HO postoperatively (95% confidence interval, 2.2-126.0; P = .006). Multivariate logistic regression identified the performance of a mixed-type femoroacetabular impingement resection (P = .011) and the absence of NSAID prophylaxis (P = .003) as predictors of HO development. The majority of HO cases (29/34) occurred in patients with mixed-type femoroacetabular impingement who had both osteochondroplasty and acetabuloplasty. Complications of NSAID therapy in this study population included acute renal failure, hematochezia from acute colitis, and gastritis. Conclusion: Routine NSAID prophylaxis reduces but does not eliminate the incidence of HO in patients undergoing hip arthroscopy. Heterotopic ossification was more likely to develop in patients undergoing acetabuloplasty along with osteochondroplasty and in those who did not receive prophylactic postoperative NSAIDs. Side effects from the investigated NSAID regimen can be serious and should be weighed against the potential benefits in preventing the formation of HO.

Psychometric evaluation of the PROMIS Physical Function Computerized Adaptive Test in comparison to the American Shoulder and Elbow Surgeons score and Simple Shoulder Test in patients with rotator cuff disease

BACKGROUND The Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function Computerized Adaptive Test (PF CAT) is a newly developed patient-reported outcome instrument designed by the National Institutes of Health to measure generalized physical function. However, the measurement properties of the PF CAT have not been compared with established shoulder-specific patient-reported outcomes. METHODS Patients with clinical diagnosis of rotator cuff disease completed the American Shoulder and Elbow Surgeons (ASES) score, Simple Shoulder Test (SST), and PF CAT. Responses to each of the 3 instruments were statistically analyzed with a Rasch partial credit model. Associations between instruments, convergent validity, item and person reliability, ceiling and floor effects, dimensionality, and survey length were determined. RESULTS Responses from 187 patients were analyzed. The PF CAT required fewer questions than the ASES or SST (PF CAT, 4.3; ASES, 11; SST, 12). Correlation between all instruments was moderately high. Item reliability was excellent for all instruments, but person reliability of the PF CAT was superior (0.93, excellent) to the SST (0.71, moderate) and ASES (0.48, fair). Ceiling effects were similar among all instruments (PF CAT, 0.53%; SST, 6.1%; ASES, 2.3%). Floor effects were found in 21% of respondents to the SST but in only 3.2% of PF CAT and 2.3% of ASES respondents. CONCLUSION The measurement properties of the PROMIS PF CAT compared favorably with the ASES and SST despite requiring fewer questions to complete. The PROMIS PF CAT had improved person reliability compared with the ASES score and fewer floor effects compared with the SST.

Functional outcomes assessment in shoulder surgery.

The effective evaluation and management of orthopaedic conditions including shoulder disorders relies upon understanding the level of disability created by the disease process. Validated outcome measures are critical to the evaluation process. Traditionally, outcome measures have been physician derived objective evaluations including range of motion and radiologic evaluations. However, these measures can marginalize a patients perception of their disability or outcome. As a result of these limitations, patient self-reported outcomes measures have become popular over the last quarter century and are currently primary tools to evaluate outcomes of treatment. Patient reported outcomes measures can be general health related quality of life measures, health utility measures, region specific health related quality of life measures or condition specific measures. Several patients self-reported outcomes measures have been developed and validated for evaluating patients with shoulder disorders. Computer adaptive testing will likely play an important role in the arsenal of measures used to evaluate shoulder patients in the future. The purpose of this article is to review the general health related quality-of-life measures as well as the joint-specific and condition specific measures utilized in evaluating patients with shoulder conditions. Advances in computer adaptive testing as it relates to assessing dysfunction in shoulder conditions will also be reviewed.

Arthroscopic Capsular Repair for Symptomatic Hip Instability After Previous Hip Arthroscopic Surgery

Background: Management of the hip capsule has been a topic of recent debate in hip arthroscopic surgery. Postoperative instability after hip arthroscopic surgery has been reported and can lead to poor outcomes. Purpose: To determine the outcome of patients diagnosed with symptomatic instability after hip arthroscopic surgery at a minimum of 12 months and 24 months after revision surgery for capsular repair. Study Design: Case series; Level of evidence, 4. Methods: In a cohort of approximately 1100 patients who underwent hip arthroscopic surgery, 33 patients (33 hips) developed symptomatic instability requiring a revision surgery. Two patients suffered anterior dislocations following their initial surgery. Radiographs were reviewed to evaluate for acetabular dysplasia. Three patients were lost to follow-up and 10 patients were excluded as they were <1 year out from the revision surgery. A total of 20 patients (18 female, 2 male) completed a preoperative and postoperative modified Harris Hip Score (mHHS) and Hip Outcome Score (HOS) at a minimum of 12 months. Eleven of these patients had a minimum follow-up of 24 months. All patients filled out a Likert scale of perceived improvement in physical ability at final follow-up. Results: The mean age of the patients was 29.7 years (range, 15.2-55.5 years). The mean lateral center-edge angle was 25°, and the mean acetabular index was 7° before revision. All patients underwent interportal capsulotomy during the index arthroscopic procedure. After their index arthroscopic procedures, patients had minimal improvement at a mean of 19.1 months postoperatively on the mHHS (from 57.1 to 57.6; P = .423), HOS-Activities of Daily Living (ADL) (from 62.7 to 66.4; P = .260), and HOS-Sports (from 42.0 to 39.1; P = .800). For the patients with a minimum 1-year follow-up after revision surgery (n = 20; mean follow-up, 21.3 months), the mean mHHS (from 57.6 preoperatively to 85.8 at final follow-up; P < .001), HOS-ADL (from 66.4 to 85.7; P < .001), and HOS-Sports (from 39.1 to 79.8; P < .001) all improved significantly. The results were similar when looking at only the patients with a minimum 2-year follow-up after revision surgery (n = 11; mean follow-up, 26.1 months); the mean mHHS (from 56.0 preoperatively to 91.5 at final follow-up; P = .001), HOS-ADL (from 68.3 to 89.9; P = .009), and HOS-Sports (from 35.7 to 87.9; P = .001) all improved significantly. When comparing patients with isolated capsular repair to those with additional procedures performed, there were no differences between the groups (all P > .05). At final follow-up, all but 1 patient had improved overall physical ability levels. Conclusion: Revision hip arthroscopic surgery for capsular repair in patients with symptomatic instability after hip arthroscopic surgery provides good functional outcomes at a minimum of 1 and 2 years postoperatively.

Clinical outcomes in patients with castrate-refractory prostate cancer (CRPC) metastatic to bone randomized in the factorial TRAPEZE trial to docetaxel (D) with strontium-89 (Sr89), zoledronic acid (ZA), neither, or both (ISRCTN 12808747).

LBA5000 Background: Bony metastatic CRPC has a poor prognosis and high morbidity. TRAPEZE is a factorial RCT using three agents, D, ZA, and Sr89. All have palliative benefits and are used in bony metastatic CRPC to control bone symptoms and (for D) to prolong survival. ZA was approved on the basis of reducing skeletal related events (SRE). Sr89 was approved to control pain from metastases and to reduce the need for subsequent bone treatments. ZA is commonly combined with D in practice but evidence that the combination is effective is lacking and costs considerable. Sr89 is generally used as a palliative therapy in patients unfit for chemotherapy. Phase II analysis confirmed the safety and feasibility of combining these agents. TRAPEZE aimed to determine clinical and cost-effectiveness scheduling. METHODS Patients were randomised to receive 6 cycles of D plus prednisolone: alone; with ZA; with a single dose of Sr89 after cycle 6 or both. Primary outcomes were clinical progression-free survival (CPFS: pain progression, SRE or death) and cost-effectiveness. Secondary outcomes were SRE free interval (SREFI); total SREs, and overall survival (OS). The log rank test and Cox regression modelling were used to determine clinical effectiveness. RESULTS TRAPEZE randomised 757 patients; median age 68.7 yrs; ECOG 0: 40% 1: 52% 2: 8%; prior RT 45%; median PSA 144 (IQR 51, 354). Provisional stratified log rank analysis of CPFS did not reach statistical significance for either agent (Sr89 p=0.11, ZA p=0.45). Cox regression analysis adjusted for all stratification variables showed benefit of Sr89 on CPFS (HR=0.845; 95%CI 0.72, 0.99, p=0.036) and confirmed no effect of ZA (p=0.46). ZA did show a significant effect on SREFI (HR=0.76; 95%CI 0.63, 0.93, p=0.008). There was no effect of either agent on overall survival (Sr89 p=0.74, ZA p=0.91). CONCLUSIONS Sr89 after six cycles of docetaxel improved CPFS but not OS. ZA did not improve CPFS or OS but did significantly improve median SREFI, mostly post progression, suggesting a role as post chemotherapy maintenance therapy. Further health economic and QoL analyses are pending. CLINICAL TRIAL INFORMATION 12808747.

TRAPEZE: a randomised controlled trial of the clinical effectiveness and cost-effectiveness of chemotherapy with zoledronic acid, strontium-89, or both, in men with bony metastatic castration-refractory prostate cancer

BACKGROUND Bony metastatic castration-refractory prostate cancer is associated with a poor prognosis and high morbidity. TRAPEZE was a two-by-two factorial randomised controlled trial of zoledronic acid (ZA) and strontium-89 (Sr-89), each combined with docetaxel. All have palliative benefits, are used to control bone symptoms and are used with docetaxel to prolong survival. ZA, approved on the basis of reducing skeletal-related events (SREs), is commonly combined with docetaxel in practice, although evidence of efficacy and cost-effectiveness is lacking. Sr-89, approved for controlling metastatic pain and reducing need for subsequent bone treatments, is generally palliatively used in patients unfit for chemotherapy. Phase II analysis confirmed the safety and feasibility of combining these agents. TRAPEZE aimed to determine the clinical effectiveness and cost-effectiveness of each agent. METHODS Patients were randomised to receive six cycles of docetaxel plus prednisolone: alone, with ZA, with a single Sr-89 dose after cycle 6, or with both. Primary outcomes were clinical progression-free survival (CPFS: time to pain progression, SRE or death) and cost-effectiveness. Secondary outcomes were SRE-free interval (SREFI), total SREs, overall survival (OS) and quality of life (QoL). Log-rank test and Cox regression modelling were used to determine clinical effectiveness. Cost-effectiveness was assessed from the NHS perspective and expressed as cost per additional quality-adjusted life-year (QALY). An additional analysis was carried out for ZA to reflect the availability of generic ZA. RESULTS PATIENTS 757 randomised (median age 68.7 years; Eastern Cooperative Oncology Group scale score 0, 40%; 1, 52%; 2, 8%; prior radiotherapy, 45%); median prostate-specific antigen 143.78 ng/ml (interquartile range 50.8-353.9 ng/ml). Stratified log-rank analysis of CPFS was statistically non-significant for either agent (Sr-89, p = 0.11; ZA, p = 0.45). Cox regression analysis adjusted for stratification variables showed CPFS benefit for Sr-89 [hazard ratio (HR) 0.845, 95% confidence interval (CI) 0.72 to 0.99; p = 0.036] and confirmed no effect of ZA (p = 0.46). ZA showed a significant SREFI effect (HR 0.76; 95% CI 0.63 to 0.93; p = 0.008). Neither agent affected OS (Sr-89, p = 0.74; ZA, p = 0.91), but both increased total cost (vs. no ZA and no Sr-89, respectively); decreased post-trial therapies partly offset costs [net difference: Sr-89 £1341; proprietary ZA (Zometa(®), East Hanover, NJ, USA) £1319; generic ZA £251]. QoL was maintained in all trial arms; Sr-89 (0.08 additional QALYs) and ZA (0.03 additional QALYs) showed slight improvements. The resulting incremental cost-effectiveness ratio (ICER) for Sr-89 was £16,590, with £42,047 per QALY for Zometa and £8005 per QALY for generic ZA. CONCLUSION Strontium-89 improved CPFS, but not OS. ZA did not improve CPFS or OS but significantly improved SREFI, mostly post progression, suggesting a role as post-chemotherapy maintenance therapy. QoL was well maintained in all treatment arms, with differing patterns of care resulting from the effects of Sr-89 on time to progression and ZA on SREFI and total SREs. The addition of Sr-89 resulted in additional cost and a small positive increase in QALYs, with an ICER below the £20,000 ceiling per QALY. The additional costs and small positive QALY changes in favour of ZA resulted in ICERs of £42,047 (Zometa) and £8005 for the generic alternative; thus, generic ZA represents a cost-effective option. Additional analyses on the basis of data from the Hospital Episode Statistics data set would allow corroborating the findings of this study. Further research into the use of ZA (and other bone-targeting therapies) with newer prostate cancer therapies would be desirable. STUDY REGISTRATION Current Controlled Trials ISRCTN12808747. FUNDING This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 53. See the NIHR Journals Library website for further project information.

Effect of Naproxen Prophylaxis on Heterotopic Ossification Following Hip Arthroscopy A Double-Blind Randomized Placebo-Controlled Trial

BACKGROUND Heterotopic ossification (HO) is a known complication of hip arthroscopy. Our objective was to determine the effect of postoperative naproxen therapy on the development of HO following arthroscopic surgery for femoroacetabular impingement. METHODS Between August 2011 and April 2013, 108 eligible patients were enrolled and randomized to take naproxen or a placebo for three weeks postoperatively. Radiographs were made at routine follow-up visits for one year following surgery. The primary outcome measure was the development of HO, as classified with the Brooker criteria and two-dimensional measurements on radiographs made at least seventy-five days postoperatively (average, 322 days). The primary analysis, performed with a Fisher exact test, compared the proportion of subjects with HO between the treatment and control groups. A single a priori interim analysis was planned at the midpoint of the study. RESULTS Our data safety and monitoring board stopped this study when the interim analysis showed that the stopping criterion had been met for demonstration of efficacy of the naproxen intervention. The prevalence of HO was 46% (twenty-two of the forty-eight in the final analysis) in the placebo group versus 4% (two of forty-eight) in the naproxen group (p < 0.001). Medication compliance was 69% overall, but it did not differ between the naproxen and placebo groups. Minor adverse reactions to the study medications were reported in 42% of the patients taking naproxen versus 35% of those taking the placebo (p = 0.45). CONCLUSIONS In this trial, prophylaxis with naproxen was effective in reducing the prevalence of HO without medication-related morbidity.