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To present a clear and comprehensive summary of the published data on unicompartmental knee replacement (UKA) or total knee replacement (TKA), comparing domains of outcome that have been shown to be important to patients and clinicians to allow informed decision making. Systematic review using data from randomised controlled trials, nationwide databases or joint registries, and large cohort studies. Medline, Embase, Cochrane Controlled Register of Trials (CENTRAL), and Clinical Trials.gov, searched between 1 January 1997 and 31 December 2018. Studies published in the past 20 years, comparing outcomes of primary UKA with TKA in adult patients. Studies were excluded if they involved fewer than 50 participants, or if translation into English was not available. 60 eligible studies were separated into three methodological groups: seven publications from six randomised controlled trials, 17 national joint registries and national database studies, and 36 cohort studies. Results for each domain of outcome varied depending on the level of data, and findings were not always significant. Analysis of the three groups of studies showed significantly shorter hospital stays after UKA than after TKA (-1.20 days (95% confidence interval -1.67 to -0.73), -1.43 (-1.53 to -1.33), and -1.73 (-2.30 to -1.16), respectively). There was no significant difference in pain, based on patient reported outcome measures (PROMs), but significantly better functional PROM scores for UKA than for TKA in both non-trial groups (mean difference -0.58 (-0.88 to -0.27) and -0.32 (-0.48 to -0.15), respectively). Regarding major complications, trials and cohort studies had non-significant results, but mortality after TKA was significantly higher in registry and large database studies (risk ratio 0.27 (0.16 to 0.45)), as were venous thromboembolic events (0.39 (0.27 to 0.57)) and major cardiac events (0.22 (0.06 to 0.86)). Early reoperation for any reason was higher after TKA than after UKA, but revision rates at five years remained higher for UKA in all three study groups (risk ratio 5.95 (1.29 to 27.59), 2.50 (1.77 to 3.54), and 3.13 (1.89 to 5.17), respectively). TKA and UKA are both viable options for the treatment of isolated unicompartmental osteoarthritis. By directly comparing the two treatments, this study demonstrates better results for UKA in several outcome domains. However, the risk of revision surgery was lower for TKA. This information should be available to patients as part of the shared decision making process in choosing treatment options. PROSPERO number CRD42018089972.

Background Isolated lateral compartment knee arthritis is less prevalent than medial. While the reported results of medial unicompartmental knee replacement (UKR) have been good and comparable to total knee replacement, the results of lateral UKR have been mixed. We present the short-term results and survivorship of a fixed-bearing UKR designed specifically for the lateral compartment. Methods We report the result of 130 primary fixed-bearing lateral Oxford (FLO) UKRs (123 patients) performed between 2015 and 2019 with a minimum follow-up of 1 year. The indications for lateral UKR were: isolated lateral osteoarthritis ( n  = 122), post-trauma ( n  = 5) and osteonecrosis ( n  = 3). The mean age was 69.1 (± 11.6), mean BMI 28.4 (± 4.9), 66.9% female, 60% right-sided, and mean follow-up 3 (range 1–4.8 years, standard deviation ± 1) years. The primary outcome measure was the Oxford knee score (OKS). Survival analysis was performed with “revision for any reason”, “reoperation”, and “implant failure” as the endpoints. Results Six patients died from unrelated reasons. None of the implants failed. One required the addition of a medial UKR for medial arthritis. There were no other reoperations. At 4 years, the survival for implant failure was 100% and for both revision and all reoperations was 99.5% (95% CI 96.7–99.9%). At the last review, at a mean of 3 years, the mean Oxford knee score was 41. Conclusion The good survivorship and outcome scores suggest that UKR designed for the lateral compartment is an excellent alternative to total knee replacement in selected patients with isolated lateral tibiofemoral arthritis at short-term follow-up.

Anterior cruciate ligament (ACL) rupture is a common debilitating injury that can cause instability of the knee. We aimed to investigate the best management strategy between reconstructive surgery and non-surgical treatment for patients with a non-acute ACL injury and persistent symptoms of instability. We did a pragmatic, multicentre, superiority, randomised controlled trial in 29 secondary care National Health Service orthopaedic units in the UK. Patients with symptomatic knee problems (instability) consistent with an ACL injury were eligible. We excluded patients with meniscal pathology with characteristics that indicate immediate surgery. Patients were randomly assigned (1:1) by computer to either surgery (reconstruction) or rehabilitation (physiotherapy but with subsequent reconstruction permitted if instability persisted after treatment), stratified by site and baseline Knee Injury and Osteoarthritis Outcome Score—4 domain version (KOOS4). This management design represented normal practice. The primary outcome was KOOS4 at 18 months after randomisation. The principal analyses were intention-to-treat based, with KOOS4 results analysed using linear regression. This trial is registered with ISRCTN, ISRCTN10110685, and ClinicalTrials.gov, NCT02980367. Between Feb 1, 2017, and April 12, 2020, we recruited 316 patients. 156 (49%) participants were randomly assigned to the surgical reconstruction group and 160 (51%) to the rehabilitation group. Mean KOOS4 at 18 months was 73·0 (SD 18·3) in the surgical group and 64·6 (21·6) in the rehabilitation group. The adjusted mean difference was 7·9 (95% CI 2·5–13·2; p=0·0053) in favour of surgical management. 65 (41%) of 160 patients allocated to rehabilitation underwent subsequent surgery according to protocol within 18 months. 43 (28%) of 156 patients allocated to surgery did not receive their allocated treatment. We found no differences between groups in the proportion of intervention-related complications. Surgical reconstruction as a management strategy for patients with non-acute ACL injury with persistent symptoms of instability was clinically superior and more cost-effective in comparison with rehabilitation management. The UK National Institute for Health Research Health Technology Assessment Programme.

Introduction Magnetic resonance imaging (MRI) scans are increasingly used for knee osteoarthritis evaluation and preoperative planning before unicompartmental knee arthroplasty (UKA), and often patients already have MRI scans before their initial surgeon consultation. This highlights the need for surgeons to understand anteromedial osteoarthritis (AMOA) patterns on MRI. Hence, we aim to describe MRI findings in patients with AMOA meeting current indications for medial UKA. Materials and methods We analysed MRI scans from 100 knees evaluated for UKA between 2006 and 2013. Inclusion criteria comprised full-thickness medial compartment loss and intact lateral compartment joint space on preoperative radiographs. Assessment included cartilage lesions, osteophytes, meniscal damage, and anterior-cruciate ligament (ACL) status on tibial and femoral surfaces. Final decision to proceed with UKA relied on intraoperative findings, independent of MRI. Results Complete anteromedial tibial and femoral cartilage loss preserved posterior cartilage rims was evident in all cases. Cartilage thinning occurred in the lateral compartment in 34% of cases. While 62% displayed lateral osteophytes, only 6 exhibited small areas of full-thickness cartilage loss. ACL abnormalities varied: 27% normal, 3% ruptured, and 70% had intrasubstance high signal. Larger osteophytes in the medial (p = 0.012) and lateral (p = 0.002) intercondylar notch correlated significantly with ACL damage. All underwent medial UKA, with no evidence of areas with full lateral compartment cartilage loss intraoperatively. Conclusions The MRI findings confirmed the radiographic diagnosis of bone-on-bone medial disease but highlights a range of findings in the ACL, lateral compartment, and patellofemoral joint compartment for patients who met the current x-ray and intraoperative indication for UKA. Further research is required to understand if these MRI changes will affect long-term outcomes.

Isolated lateral compartment knee arthritis is less prevalent than medial. While the reported results of medial unicompartmental knee replacement (UKR) have been good and comparable to total knee replacement, the results of lateral UKR have been mixed. We present the short-term results and survivorship of a fixed-bearing UKR designed specifically for the lateral compartment. We report the result of 130 primary fixed-bearing lateral Oxford (FLO) UKRs (123 patients) performed between 2015 and 2019 with a minimum follow-up of 1 year. The indications for lateral UKR were: isolated lateral osteoarthritis (n = 122), post-trauma (n = 5) and osteonecrosis (n = 3). The mean age was 69.1 ([+ or -] 11.6), mean BMI 28.4 ([+ or -] 4.9), 66.9% female, 60% right-sided, and mean follow-up 3 (range 1-4.8 years, standard deviation [+ or -] 1) years. The primary outcome measure was the Oxford knee score (OKS). Survival analysis was performed with \"revision for any reason\", \"reoperation\", and \"implant failure\" as the endpoints. Six patients died from unrelated reasons. None of the implants failed. One required the addition of a medial UKR for medial arthritis. There were no other reoperations. At 4 years, the survival for implant failure was 100% and for both revision and all reoperations was 99.5% (95% CI 96.7-99.9%). At the last review, at a mean of 3 years, the mean Oxford knee score was 41. The good survivorship and outcome scores suggest that UKR designed for the lateral compartment is an excellent alternative to total knee replacement in selected patients with isolated lateral tibiofemoral arthritis at short-term follow-up.

Anteromedial osteoarthritis of the knee (AMOA) has been defined anatomically, histologically and radiologically and yet little is known about the epidemiology of the disease or the risk factors involved in the development of the disease. The broad aim of this thesis was to combine clinical insight with the utilisation of modern, large epidemiological datasets to provide information to inform better the clinical management of patients with AMOA. Specifically, the prevalence and incidence of AMOA, the time taken to progress from early disease to severe disease that may require surgical intervention, the radiological characterisation of disease and the assessment of mechanical risk factors implicit in the development of this pattern of disease are investigated. A cross-sectional study of the radiological prevalence of AMOA in a symptomatic cohort in a specialist secondary care knee clinic showed that AMOA was the commonest pattern of knee OA, present in more than 60% of symptomatic subjects. Less than 25% of subjects with AMOA presented with advanced or 'bone-on-bone' disease, emphasising the clinical importance of understanding the progression from earlier stages of disease to this advanced stage. A 20-year longitudinal radiographic study was performed on 1000 women to describe the prevalence, incidence and progression of AMOA. The prevalence of AMOA was 43% and the incidence over 20-years was 0.4. Life table analysis showed that the risk of developing advanced AMOA in a previously normal knee was 2.6%. Of those subjects with early radiological AMOA, 11% progressed to advanced 'bone-on-bone' disease within 10 years and 37% within 20 years. The role of mechanical risk factors in the development of AMOA showed that both anatomical limb and proximal tibial alignment were significantly more varus aligned in those that developed AMOA at 20-years. Assessment of the shape of the medial tibial plateau in a longitudinal MRI study showed that the angle of the upslope at the anterior aspect of the plateau was significantly increased in the group that subsequently developed AMOA. To enable AMOA to be studies in future MRI studies, the MRI description of the disease was defined. In summary, AMOA was shown to be the most common pattern of knee OA both in symptomatic surgical cohorts and in the community. The progression of the disease from an early stage to an advanced stage, which may require surgical intervention, was described for the first time. To enable better the recognition of AMOA in modern epidemiological studies, the MRI description of AMOA was defined and the clinical relevance of modern MRI was discussed. The anatomical alignment of the limb, the alignment of the proximal tibia and the morphology of the tibial plateau were all shown to have a role in the development of AMOA. Addressing these mechanical factors may provide a therapeutic surgical target for the management of patients with AMOA.

Primary results from the phase 3 ALSYMPCA trial showed that radium-223 dichloride (radium-223), a targeted α-emitter, improved overall survival compared with placebo and was well tolerated in patients with castration-resistant prostate cancer and symptomatic bone metastases. We did a prespecified subgroup analysis from ALSYMPCA to assess the effect of previous docetaxel use on the efficacy and safety of radium-223. In the phase 3, randomised, double-blind ALSYMPCA trial, patients with symptomatic castration-resistant prostate cancer, at least two symptomatic bone metastases, no known visceral metastases, and who were receiving best standard of care were randomly assigned (2:1) via an interactive voice response system to receive six injections of radium-223 (50 kBq/kg intravenously) or matching placebo, with one injection given every 4 weeks. Patients had either received previous docetaxel treatment or were unsuitable for or declined docetaxel; previous docetaxel use (yes or no) was a trial stratification factor. We investigated the effect of previous docetaxel use on radium-223 treatment for the primary endpoint of overall survival, the main secondary efficacy endpoints, and safety. Efficacy analyses were done for the intention-to-treat population; safety analyses were done for the safety population. The trial has been completed and is registered with ClinicalTrials.gov, number NCT00699751. Randomisation took place between June 12, 2008, and Feb 1, 2011. 526 (57%) of 921 randomly assigned patients had received previous docetaxel treatment (352 in the radium-223 group and 174 in the placebo group) and 395 (43%) had not (262 in the radium-223 group and 133 in the placebo group). Radium-223 prolonged median overall survival compared with placebo, irrespective of previous docetaxel use (previous docetaxel use, hazard ratio [HR] 0·70, 95% CI 0·56–0·88; p=0·002; no previous docetaxel use, HR 0·69, 0·52–0·92; p=0·01). The benefit of radium-223 compared with placebo was seen in both docetaxel subgroups for most main secondary efficacy endpoints; risk for time to time to first symptomatic skeletal event was reduced with radium-223 versus placebo in patients with previous docetaxel use, but the difference was not significant in those with no previous docetaxel use. 322 (62%) of 518 patients previously treated with docetaxel had grade 3–4 adverse events, compared with 205 (54%) of 383 patients without docetaxel. Patients who had previously been treated with docetaxel had a higher incidence of grade 3–4 thrombocytopenia with radium-223 than with placebo (31 [9%] of 347 patients vs five [3%] of 171 patients), whereas the incidence was similar between treatment groups among patients with no previous docetaxel use (seven [3%] of 253 patients vs one [1%] of 130 patients). The incidences of grade 3–4 anaemia and neutropenia were similar between the radium-223 and placebo groups within both docetaxel subgroups. Radium-223 is effective and well tolerated in patients with castration-resistant prostate cancer and symptomatic bone metastases, irrespective of previous docetaxel use. Algeta ASA and Bayer HealthCare Pharmaceuticals.

The optimal timing of radiotherapy after radical prostatectomy for prostate cancer is uncertain. We aimed to compare the efficacy and safety of adjuvant radiotherapy versus an observation policy with salvage radiotherapy for prostate-specific antigen (PSA) biochemical progression. We did a randomised controlled trial enrolling patients with at least one risk factor (pathological T-stage 3 or 4, Gleason score of 7–10, positive margins, or preoperative PSA ≥10 ng/mL) for biochemical progression after radical prostatectomy (RADICALS-RT). The study took place in trial-accredited centres in Canada, Denmark, Ireland, and the UK. Patients were randomly assigned in a 1:1 ratio to adjuvant radiotherapy or an observation policy with salvage radiotherapy for PSA biochemical progression (PSA ≥0·1 ng/mL or three consecutive rises). Masking was not deemed feasible. Stratification factors were Gleason score, margin status, planned radiotherapy schedule (52·5 Gy in 20 fractions or 66 Gy in 33 fractions), and centre. The primary outcome measure was freedom from distant metastases, designed with 80% power to detect an improvement from 90% with salvage radiotherapy (control) to 95% at 10 years with adjuvant radiotherapy. We report on biochemical progression-free survival, freedom from non-protocol hormone therapy, safety, and patient-reported outcomes. Standard survival analysis methods were used. A hazard ratio (HR) of less than 1 favoured adjuvant radiotherapy. This study is registered with ClinicalTrials.gov, NCT00541047. Between Nov 22, 2007, and Dec 30, 2016, 1396 patients were randomly assigned, 699 (50%) to salvage radiotherapy and 697 (50%) to adjuvant radiotherapy. Allocated groups were balanced with a median age of 65 years (IQR 60–68). Median follow-up was 4·9 years (IQR 3·0–6·1). 649 (93%) of 697 participants in the adjuvant radiotherapy group reported radiotherapy within 6 months; 228 (33%) of 699 in the salvage radiotherapy group reported radiotherapy within 8 years after randomisation. With 169 events, 5-year biochemical progression-free survival was 85% for those in the adjuvant radiotherapy group and 88% for those in the salvage radiotherapy group (HR 1·10, 95% CI 0·81–1·49; p=0·56). Freedom from non-protocol hormone therapy at 5 years was 93% for those in the adjuvant radiotherapy group versus 92% for those in the salvage radiotherapy group (HR 0·88, 95% CI 0·58–1·33; p=0·53). Self-reported urinary incontinence was worse at 1 year for those in the adjuvant radiotherapy group (mean score 4·8 vs 4·0; p=0·0023). Grade 3–4 urethral stricture within 2 years was reported in 6% of individuals in the adjuvant radiotherapy group versus 4% in the salvage radiotherapy group (p=0·020). These initial results do not support routine administration of adjuvant radiotherapy after radical prostatectomy. Adjuvant radiotherapy increases the risk of urinary morbidity. An observation policy with salvage radiotherapy for PSA biochemical progression should be the current standard after radical prostatectomy. Cancer Research UK, MRC Clinical Trials Unit, and Canadian Cancer Society.

Background p63, a member of the p53 gene family, is an important regulator for epithelial tissue growth and development. ∆Np63α is the main isoform of p63 and highly expressed in Non-melanoma skin cancer (NMSC). Extracellular signal-regulated kinase 3 (ERK3) is an atypical mitogen-activated protein kinase (MAPK) whose biochemical features and cellular regulation are distinct from those of conventional MAPKs such as ERK1/2. While ERK3 has been shown to be upregulated in lung cancers and head and neck cancers, in which it promotes cancer cell migration and invasion, little is known about the implication of ERK3 in NMSCs. Methods Fluorescent immunohistochemistry was performed to evaluate the expression levels of ΔNp63α and ERK3 in normal and NMSC specimens. Dunnett’s test was performed to compare mean fluorescence intensity (MFI, indicator of expression levels) of p63 or ERK3 between normal cutaneous samples and NMSC samples. A mixed effects (ANOVA) test was used to determine the correlation between ΔNp63α and ERK3 expression levels (MFI). The regulation of ERK3 by ΔNp63α was studied by qRT-PCR, Western blot and luciferase assay. The effect of ERK3 regulation by ΔNp63α on cell migration was measured by performing trans-well migration assay. Results The expression level of ∆Np63α is upregulated in NMSCs compared to normal tissue. ERK3 level is significantly upregulated in AK and SCC in comparison to normal tissue and there is a strong positive correlation between ∆Np63α and ERK3 expression in normal skin and skin specimens of patients with AK, SCC or BCC. Further, we found that ∆Np63α positively regulates ERK3 transcript and protein levels in A431 and HaCaT skin cells, underlying the upregulation of ERK3 expression and its positive correlation with ∆Np63α in NMSCs. Moreover, similar to the effect of ∆Np63α depletion, silencing ERK3 greatly enhanced A431 cell migration. Restoration of ERK3 expression under the condition of silencing ∆Np63α counteracted the increase in cell migration induced by the depletion of ∆Np63α. Mechanistically, ERK3 inhibits the phosphorylation of Rac1 G-protein and the formation of filopodia of A431 skin SCC cells. Conclusions ERK3 is positively regulated by ∆Np63α and mediates the role of ∆Np63α in suppressing cell migration in NMSC.