Genome-wide identification of FoxO-dependent gene networks in skeletal muscle during C26 cancer cachexia

BACKGROUND: Evidence from cachectic cancer patients and animal models of cancer cachexia supports the involvement of Forkhead box O (FoxO) transcription factors in driving cancer-induced skeletal muscle wasting. However, the genome-wide gene networks and associated biological processes regulated by FoxO during cancer cachexia are unknown. We hypothesize that FoxO is a central upstream regulator of diverse gene networks in skeletal muscle during cancer that may act coordinately to promote the wasting phenotype. METHODS: To inhibit endogenous FoxO DNA-binding, we transduced limb and diaphragm muscles of mice with AAV9 containing the cDNA for a dominant negative (d.n.) FoxO protein (or GFP control). The d.n.FoxO construct consists of only the FoxO3a DNA-binding domain that is highly homologous to that of FoxO1 and FoxO4, and which outcompetes and blocks endogenous FoxO DNA binding. Mice were subsequently inoculated with Colon-26 (C26) cells and muscles harvested 26 days later. RESULTS: Blocking FoxO prevented C26-induced muscle fiber atrophy of both locomotor muscles and the diaphragm and significantly spared force deficits. This sparing of muscle size and function was associated with the differential regulation of 543 transcripts (out of 2,093) which changed in response to C26. Bioinformatics analysis of upregulated gene transcripts that required FoxO revealed enrichment of the proteasome, AP-1 and IL-6 pathways, and included several atrophy-related transcription factors, including Stat3, Fos, and Cebpb. FoxO was also necessary for the cancer-induced downregulation of several gene transcripts that were enriched for extracellular matrix and sarcomere protein-encoding genes. We validated these findings in limb muscles and the diaphragm through qRT-PCR, and further demonstrate that FoxO1 and/or FoxO3a are sufficient to increase Stat3, Fos, Cebpb, and the C/EBPβ target gene, Ubr2. Analysis of the Cebpb proximal promoter revealed two bona fide FoxO binding elements, which we further establish are necessary for Cebpb promoter activation in response to IL-6, a predominant cytokine in the C26 cancer model. CONCLUSIONS: These findings provide new evidence that FoxO-dependent transcription is a central node controlling diverse gene networks in skeletal muscle during cancer cachexia, and identifies novel candidate genes and networks for further investigation as causative factors in cancer-induced wasting.R01 AR060217 - NIAMS NIH HHS; R01 AR060209 - NIAMS NIH HHS; T32 HD043730 - NICHD NIH HHS; R00 HL098453 - NHLBI NIH HHS; R00HL098453 - NHLBI NIH HHS; R01AR060209 - NIAMS NIH HHS; R01AR060217 - NIAMS NIH HH

A matched comparison of the patient-reported outcome measures of cemented and cementless total knee replacements, based on the National Joint Registry of England, Wales, Northern Ireland, and Isle of Man and England’s National PROM collection programme

BACKGROUND AND PURPOSE: Total knee replacement (TKR) can be implanted with or without bone cement. It is currently unknown how the functional outcomes compare. Therefore, we compared the patient-reported outcome measures (PROMS) of both fixation methods. PATIENTS AND METHODS: We performed a propensity-matched comparison of 14,404 TKRs (7,202 cemented and 7,202 cementless) enrolled in the National Joint Registry and the English National PROMs collection programme. Subgroup analyses were performed in different age groups (1) < 55 years; (2) 55–64 years; (3) 65–74 years; (4) ≥ 75 years. RESULTS: The 6-month postoperative Oxford Knee Score (OKS) was significantly (p < 0.001) higher for cemented TKR (35, SD 9.7) than cementless TKR (34, SD 9.9). The OKS was also significantly higher for the cemented TKR in all age groups, except the 55–64-year group. A significantly higher proportion of cemented TKRs had an excellent OKS (≥ 41) compared with cementless (32% vs. 28%, p < 0.001) and a lower proportion of poor (< 27) scores (19% vs. 22%, p = 0.001). This was also observed for all age subgroups. There were no significant differences in EQ-5D points gained postoperatively between the groups respectively (0.31 vs. 0.30, p = 0.1). INTERPRETATION: Cemented TKRs had a greater proportion of excellent OKS scores and lower proportion of poor scores both overall and across all age groups. However, the absolute differences are small and below the minimally clinically important difference, making both fixation types acceptable. Currently the vast majority of TKRs are cemented and the results from this study suggest that this is appropriate

A matched comparison of cementless unicompartmental and total knee replacement outcomes based on the National Joint Registry for England, Wales, Northern Ireland and the Isle of Man

BACKGROUND AND PURPOSE: The main treatments for severe medial compartment knee arthritis are unicompartmental (UKR) and total knee replacement (TKR). UKRs have higher revision rates, particularly for aseptic loosening, therefore the cementless version was introduced. We compared the outcomes of matched cementless UKRs and TKRs. PATIENTS AND METHODS: The National Joint Registry was linked to the English Hospital Episode Statistics and Patient Reported Outcome Measures (PROMs) databases. 10,552 cementless UKRs and 10,552 TKRs were propensity matched and regression analysis used to compare revision/reoperation risks. 6-month PROMs were compared. UKR results were stratified by surgeon caseload into low- (< 10 UKRs/year), medium- (10 to < 30 UKRs/year), and high-volume (≥ 30 UKRs/year). RESULTS: 8-year cementless UKR revision survival for the 3 respective caseloads were 90% (95% CI 87–93), 93% (CI 91–95), and 96% (CI 94–97). 8-year reoperation survivals were 76% (CI 71–80), 81% (CI 78–85), and 84% (CI 82–86) respectively. For TKR the 8-year implant survivals for revision and reoperation were 96% (CI 95–97) and 81% (CI 80–83). The HRs for the 3 caseload groups compared with TKR for revision were 2.0 (CI 1.3–2.9), 2.0 (CI 1.6–2.7), and 1.0 (CI 0.8–1.3) and for reoperation were 1.2 (CI 1.0–1.4), 0.9 (CI 0.8–1.0), and 0.6 (CI 0.5–0.7). 6-month Oxford Knee Score (OKS) (39 vs. 37) and EQ-5D (0.80 vs. 0.77) were higher (p < 0.001) for the cementless UKR. INTERPRETATION: Cementless UKRs have higher revision and reoperation rates than TKR for low-volume UKR surgeons, similar reoperation but higher revision rates for mid-volume surgeons, and lower reoperation and similar revision rates for high-volume surgeons. Cementless UKR also had better PROMs

A matched comparison of the patient-reported outcome measures of 38,716 total and unicompartmental knee replacements:an analysis of linked data from the National Joint Registry of England, Northern Ireland and Isle of Man and England’s National PROM collection programme

Background and purpose — The surgical treatment options for severe knee osteoarthritis are unicompartmental (UKR) and total knee replacement (TKR). For patients, functional outcomes are more important than revision rate. We compared the patient-reported outcome measures (PROMs) of both implant types using a large PROMs dataset. Patients and methods — We analysed a propensity-matched comparison of 38,716 knee replacements (19,358 UKRs and 19,358 TKRs) enrolled in the National Joint Registry and the English National PROM collection programme. Subgroup analyses were performed in different age groups. Results — 6-month postoperative Oxford Knee Score (OKS) for UKR and TKR were 38 (SD 9.4) and 36 (SD 9.4) respectively. A higher proportion of UKRs had an excellent OKS (≥ 41) compared with TKR (47% vs 36%) and a lower proportion of poor OKS (< 27) scores (13% vs. 16%). The 6-month OKS was higher in all age groups for UKR compared with TKR, with the difference increasing in older age groups. The mean 6-month EQ-5D score was 0.78 (SD 0.25) and 0.75 (SD 0.25) respectively. The improvement in EQ-5D resulting from surgery was higher for UKR than TKR both overall and in all age groups. All comparisons were statistically significant (p < 0.05). Interpretation — UKR had a greater proportion of excellent OKS scores and lower proportion of poor scores than TKR. Additionally, the quality of life was higher for UKR compared with TKR. These factors should be balanced against the higher revision rate for UKR when choosing which procedure to perform

The effect of surgeon caseload on the relative revision rate of cemented and cementless Unicompartmental Knee Replacements:An analysis from the National Joint Registry for England, Wales, Northern Ireland and the Isle of Man

Background: Unicompartmental knee replacement (UKR) offers substantial benefits compared with total knee replacement (TKR) but is associated with higher revision rates. Data from registries suggest that revision rates for cementless UKR implants are lower than those for cemented implants. It is not known how much of this difference is due to the implant or to other factors, such as a greater proportion of high-volume surgeons using cementless implants. We aimed to determine the effect of surgeon caseload on the revision rate of matched cemented and cementless UKRs. Methods: From a group of 40,522 Oxford (Zimmer Biomet) UKR implants (30,814 cemented, 9,708 cementless) recorded in the National Joint Registry, 14,814 (7,407 cemented, 7,407 cementless) were propensity-score matched. Surgeons were categorized into 3 groups: low volume ( Results: The 10-year survival rates for unmatched cementless and cemented UKR implants were 93.3% (95% confidence interval [CI] = 89.8% to 95.7%) and 89.1% (95% CI = 88.6% to 89.6%), respectively, with the difference being significant (hazard ratio [HR] = 0.59; p Conclusions: Cementless fixation decreased the revision rate by about a quarter, whatever the surgeon caseload. Caseload had a profound effect on implant survival. Low-volume surgeons had a high revision rate with cemented or cementless fixation and therefore should consider either stopping or doing more UKR procedures. High-volume surgeons performing cementless UKR demonstrated a 10-year survival rate of 97.5%, which was similar to that reported in registries for the best-performing TKRs. Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.</p

A matched comparison of revision rates of cemented Oxford Unicompartmental Knee Replacements with Single and Twin Peg femoral components, based on data from the National Joint Registry for England, Wales, Northern Ireland and the Isle of Man

Background and purpose — Registries report high revision rates after unicompartmental knee replacement (UKR) due, in part, to aseptic loosing. In an attempt to improve Oxford UKR femoral component fixation a new design was introduced with a Twin rather than a Single peg. We used the National Joint Registry (NJR) to compare the 5-year outcomes of the Single and Twin Peg cemented Oxford UKRs. Patients and methods — We performed a retrospective observational study using NJR data on propensity score matched Single and Twin Peg UKRs (matched for patient, implant and surgical factors). Data on 2,834 Single Peg and 2,834 Twin Peg were analyzed. Cumulative implant survival was calculated using the Kaplan–Meier method and comparisons between groups performed using Cox regression models. Results — In the matched cohort, the mean follow up for both Single and Twin Peg UKRs was 3.3 (SD 2) and 3.4 years (SD 2) respectively. The 5-year cumulative implant survival rates for Single Peg and Twin Peg were 94.8% (95% CI 93.6–95.8) and 96.2% (CI 95.1–97.1) respectively. Implant revision rates were statistically significantly lower in the Twin Peg (hazard ratio [HR)] = 0.74; p = 0.04). The revision rate for femoral component aseptic loosening decreased significantly (p = 0.03) from 0.4% (n = 11) with the Single Peg to 0.1% (n = 3) with the Twin Peg. The revision rate for pain decreased significantly (p = 0.01) from 0.8% (n = 23) with the Single Peg to 0.3% (n = 9) with the Twin Peg. No other reasons for revision had significant differences in revision rates. Interpretation — The revision rate for the cemented Twin Peg Oxford UKR was 26% less than the Single Peg Oxford UKR. This was mainly because the revision rates for femoral loosening and pain more than halved. This suggests that the Twin Peg component should be used in preference to the Single Peg design.</p

New surgical instrumentation reduces the revision rate of Unicompartmental Knee Replacement:A propensity score matched comparison of 15,906 knees from the National Joint Registry

Background Unicompartmental knee replacement (UKR) offers advantages over total knee replacement but has higher revision rates. New instrumentation known as Microplasty was introduced to address this. The aim was to compare the revision rates of UKRs implanted with Microplasty and traditional instrumentation (Non-Microplasty). Methods National Joint Registry (NJR) data was used to propensity score match 15,906 UKRs (7953 Microplasty and 7953 Non-Microplasty) for important patient, implant and surgical factors. Implant survival rates were determined using the Kaplan–Meier method and compared using Cox regression models in a multilevel model. Results The five-year implant survival for Microplasty and Non-Microplasty UKRs were 96.7% (95% CI: 96.0%–97.2%) and 94.5% (CI: 93.8–95.1%), respectively. The revision rate for Microplasty UKR was significantly lower than that of Non-Microplasty UKRs (hazard ratio [HR] = 0.77, p = 0.008). Compared with Non-Microplasty UKRs, the revision rate of Microplasty UKRs implanted during the year after the introduction of Microplasty was lower, but the difference was not significant (HR: 0.86, CI: 0.67–1.10, p = 0.23), whereas for those implanted more than a year after introduction, the difference was significant (HR: 0.69, CI: 0.54–0.89, p = 0.004). Conclusion The use of Microplasty instrumentation has resulted in an improved five-year UKR survival. Microplasty UKR implanted during the first year after introduction had a small, non-significant decrease in revision rate. As the revision rate did not increase, this suggests that there is no adverse learning curve effect. Microplasty UKRs implanted after this transition period had a revision rate 31% lower than the Non-Microplasty group. Level of evidence II.</p