Targeted inhibition of SCFSKP2 confers anti-tumor activities resulting in a survival benefit in osteosarcoma.

Osteosarcoma(OS) is a highly aggressive bone cancer for which treatment has remained essentially unchanged for decades. Although OS is characterized by extensive genomic heterogeneity and instability, RB1 and TP53 have been shown to be the most commonly inactivated tumor suppressors in OS. We previously generated a mouse model with a double knockout (DKO) of Rb1 and Trp53 within cells of the osteoblastic lineage, which largely recapitulates human OS with nearly complete penetrance. SKP2 is a repression target of pRb and serves as a substrate recruiting subunit of the SCFSKP2 complex. In addition, SKP2 plays a central role in regulating the cell cycle by ubiquitinating and promoting the degradation of p27. We previously reported the DKOAA transgenic model, which harbored a knock-in mutation in p27 that impaired its binding to SKP2. Here, we generated a novel p53-Rb1-SKP2 triple-knockout model (TKO) to examine SKP2 function and its potential as a therapeutic target in OS. First, we observed that OS tumorigenesis was significantly delayed in TKO mice and their overall survival was markedly improved. In addition, the loss of SKP2 also promoted an apoptotic microenvironment and reduced the stemness of DKO tumors. Furthermore, we found that small-molecule inhibitors of SKP2 exhibited anti-tumor activities in vivo and in OS organoids as well as synergistic effects when combined with a standard chemotherapeutic agent. Taken together, our results suggest that SKP2 inhibitors may reduce the stemness plasticity of OS and should be leveraged as next-generation adjuvants in this cancer.

Stand-Alone Anchored Spacer vs Anterior Plate Construct in the Management of Adjacent Segment Disease after Anterior Cervical Discectomy and Fusion: A Systematic Review and Meta-Analysis of Comparative Studies.

STUDY DESIGN: Systematic Review and Meta-Analysis. OBJECTIVES: This study aimed to evaluate the clinical and radiological outcomes of surgically treated adjacent segment disease (ASDis) following ACDF with either anterior plate construct (APC) or stand-alone anchored spacers (SAAS). METHOD: Multiple databases were searched until December 2022 for pertinent studies. The primary outcome was health-related quality of life outcomes [JOA, NDI, and VAS], whereas, the secondary outcomes included operative characteristics [estimated blood loss (EBL) and operative time (OT)], radiological outcomes [C2-C7 Cobb angle, disc height index (DHI) changes, fusion rate], and complications. RESULTS: A total of 5 studies were included, comprising 210 patients who had been surgically treated for cervical ASDis. Among them, 113 received APC, and 97 received SAAS. Postoperative dysphagia was significantly higher in the APC group [47% vs 11%, OR = 7.7, 95% CI = 3.1-18.9, P < .05]. Similarly, operative time and blood loss were higher in the APC group compared to the SAAS group; [MD = 16.96, 95% CI = 7.87-26.06, P < .05] and [MD = 5.22, 95% CI = .35 - 10.09, P < .05], respectively. However, there was no difference in the rate of prolonged dysphagia and clinical outcomes in terms of JOA, NDI, and VAS. Furthermore, there was no difference in the radiological parameters including the C2-7 Cobb angle and DHI as well as the fusion rate. CONCLUSION: Our meta-analysis demonstrated that both surgical techniques (APC and SAAS) are effective in treating ASDis. However, with low certainty of the evidence, considering patients are at high risk of dysphagia following revision cervical spine surgery SAAS may be the preferred choice.

Open and closed reduction methods for intramedullary nailing of femoral shaft fractures: A systematic review and meta-analysis of comparative studies.

Introduction: Closed reduction and intramedullary nailing is the preferred surgical intervention for femoral shaft fractures. Open reduction involves opening the fracture site and is performed in various circumstances. Comparative studies of the approaches have conflicting results. We sought to compare the outcomes and complications of open and closed reduction for intramedullary nailing of femoral shaft fractures. Materials and methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines, a systematic review of comparative studies included the databases and registers PubMed (Medline), Embase, Scopus, and Cochrane Central (PROSPERO registration ID: CRD42022325382). Additional studies were identified through hand and citation searching. Two reviewers independently extracted data. The standardized mean difference and 95% confidence intervals were determined for continuous variables, whereas odds ratios and 95% confidence intervals were assessed for dichotomous variables. Results: Closed reduction had a higher pooled union rate (93.93%, 92.02%), an increased odds ratio for union (OR = 1.624 [95% CI: 1.004, 2.624]; p = .048), and a faster time to union (SMD = -0.292 [95% CI: -0.549, -0.0.035]; p = .026). There were no differences in operative time (SMD = 0.128 [95% CI: -0.700, 0.956] p = .762) or overall complication rate (OR = 1.314 [95% CI: 0.966, 1.787] p = .082). Conclusions: Closed reduction has the advantage of higher union rates, quicker time to union, and lower overall infection compared to open reduction for intramedullary nailing of femoral shaft fractures. Open reduction remains a reasonable alternative with acceptable union rates when closed reduction is not feasible.

Unexpected intraoperative positive culture (UIPC) in presumed aseptic revision spine surgery: a systematic review and meta-analysis.

BACKGROUND CONTEXT: Unexpected intraoperative positive culture (UIPC) has recently become increasingly common in revision spine surgery, being implicated as an etiological factor in revision spine surgery indications such as implant failure or pseudoarthrosis. PURPOSE: Utilizing the available literature, this study aimed to investigate the prevalence of UIPC, and its clinical importance in patients following presumed aseptic revision spine surgery. STUDY DESIGN: Meta-analysis and systematic review. METHODS: Multiple databases and reference articles were searched until May 2022. The primary outcome was the pooled rate of UIPC, and the secondary outcomes were the microbiological profile of UIPC, the risk factors of UIPC, and the clinical fate of UIPC. RESULTS: Twelve studies were eligible for meta-analysis, with a total of 1,108 patients. The pooled rate of UIPC was 24.3% (95% CI=15.8%-35.5%) in adult patients, and 43.2% (95% CI=32.9%-54.2%) in pediatric patients. The UIPC rate was higher when both conventional wound culture and sonication were used together compared to sonication alone or conventional wound culture alone. The rates were 28.9%, 23.6%, and 15.5 %, respectively. In adult and pediatric patients, the most commonly cultured organism was Cutibacterium acnes (42.5% vs 57.7%), followed by coagulase-negative Staphylococcus (39.9% vs 30.5%). Male patients had a higher rate of UIPC (OR= 2.6, 95% CI=1.84-3.72, p<.001), as did patients with a longer fusion construct (MD=0.76, 95% CI=0.27-1.25, p<.001). CONCLUSIONS: The pooled rate of UIPC in aseptic spine revision surgery was 24.3% and 43.2% in adult and pediatric patients respectively. The most common organisms were C. acnes and coagulase-negative Staphylococcus. The impact of UIPC on patients` clinical outcomes is not fully understood. We are not able to recommend routine culture in revision spine surgery, however, adding sonication may aid in the diagnosis of UIPC. There is not enough evidence to recommend specific treatment strategies at this time, and further studies are warranted.

The interaction of SKP2 with p27 enhances the progression and stemness of osteosarcoma.

Osteosarcoma is a highly aggressive malignancy for which treatment has remained essentially unchanged for years. Our previous studies found that the F-box protein SKP2 is overexpressed in osteosarcoma, acting as a proto-oncogene; p27Kip1 (p27) is an inhibitor of cyclin-dependent kinases and a downstream substrate of SKP2-mediated ubiquitination. Overexpression of SKP2 and underexpression of p27 are common characteristics of cancer cells. The SCFSKP2 E3 ligase ubiquitinates Thr187-phosphorylated p27 for proteasome degradation, which can be abolished by a Thr187Ala knock-in (p27T187A KI) mutation. RB1 and TP53 are two major tumor suppressors commonly coinactivated in osteosarcoma. We generated a mouse model with a double knockout (DKO) of Rb1 and Trp53 within cells of the osteoblastic lineage, which developed osteosarcoma with full penetrance. When p27T187A KI mice were crossed on to the DKO background, p27T187A protein was found to accumulate in osteosarcoma tumor tissues. Furthermore, p27T187A promoted apoptosis in DKO tumors, slowed disease progression, and significantly prolonged overall survival. RNA sequencing analysis also linked the SCFSKP2 -p27T187A axis to potentially reduced cancer stemness. Given that RB1 and TP53 loss or coinactivation is common in human osteosarcoma, our study suggests that inhibiting the SKP2-p27 axis may represent a desirable therapeutic strategy for this cancer.

A Case Report Describing Pre-operative Contouring of an Orthopedic Implant using a 3D-Printed Patient-specific Model.

Introduction: Paget's disease is a metabolic bone disorder characterized by abnormal patterns in bone remodeling, resulting in variable degrees of chronic bone pain, deformation of the long bones and rarely, and pathologic fracture. These issues can pose difficult surgical challenges, particularly in the elderly frail population, where the benefits of orthopedic intervention must be balanced with minimizing inherent surgical risks. Such considerations often include reducing operative time and blood loss, allowing for early mobilization, stabilizing an impending fracture, and providing symptom relief. Case Report: A 77-year-old female with a 10-year history of Paget's disease presented to an outside orthopedic clinic with progressive right leg pain and worsening anterior bowing following minor trauma to the extremity. Ultimately, the patient was offered in situ prophylactic intramedullary (IM) nail fixation, intended to augment her bone's native strength and prevent further microfractures and subsequent deformation. A three-dimensional (3D) printed patient specific model was developed to permit for pre-contouring of an off-the-shelf implant and subsequent sterilization and use at a future point in time. She underwent uneventful IM nailing of her tibia with the pre-contoured implant and proceeded to progress clinically postoperatively. Conclusion: In this report, we present an innovative use of a 3D printed patient-specific tibia model to pre-contour an IM nail. This surgical approach was undertaken to treat an elderly patient with a symptomatic and progressive deformity of the tibia secondary to Paget's disease of bone.

Skp2 depletion reduces tumor-initiating properties and promotes apoptosis in synovial sarcoma.

Synovial sarcoma (SS) is an aggressive soft-tissue cancer with a poor prognosis and a propensity for local recurrence and distant metastasis. In this study, we investigated whether S phase kinase-associated protein (Skp2) plays an oncogenic role in tumor initiation, progression, and metastasis of SS. Our study revealed that Skp2 is frequently overexpressed in SS specimens and SS18-SSX transgenic mouse tumors, as well as correlated with clinical stages. Next, we identified that genetic depletion of Skp2 reduced mesenchymal and stemness markers, and inhibited the invasive and proliferative capacities of SS cell lines. Furthermore, Skp2 depletion markedly suppressed the growth of SS xenografts tumors. Treatment of SS cell lines with the skp2 inhibitor flavokawain A (FKA) reduced Skp2 expression in a dose-dependent manner and resulted in cell cycle arrest and apoptosis. FKA also suppressed the invasion and tumor-initiating properties in SS, similar to the effects of Skp2 knockdown. In addition, a combination of FKA and conventional chemotherapy showed a synergistic therapeutic efficacy. Taken together, our results suggest that Skp2 plays an essential role in the biology of SS by promoting the mesenchymal state and cancer stemness. Given that chemotherapy resistance is often associated with cancer stemness, strategies of combining Skp2 inhibitors with conventional chemotherapy in SS may be desirable.

Minimally Invasive Spine Lumbar Surgery in Obese Patients: A Systematic Review and Meta-Analysis.

BACKGROUND: Transforaminal lumbar interbody fusion (TLIF) is the treatment of choice for lumbar spinal stenosis and spondylolisthesis. The procedure can be performed through a traditional open approach (O-TLIF) or through minimally invasive techniques (MI-TLIF). Spinal surgeries in obese patients can pose risks, including increased rates of infection and thromboembolic events. QUESTIONS/PURPOSES: We sought to systematically review the literature on the differences between MI-TLIF and O-TLIF in the obese patient in terms of complication rate, functional outcomes, blood loss, and length of hospital stay. METHODS: We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to systematically search PubMed, Embase, Web of Science, and the Cochrane Library for studies published through February 2019 and identified those comparing the outcomes of O-TLIF and MI-TLIF in obese patients. The primary outcome was complication rate (total, infections, dural tears); secondary outcomes were blood loss, length of hospital stay, and functional scores. Two authors independently reviewed the studies using the Newcastle-Ottawa Scale, and data were pooled using the Mantel-Haenszel random-effects model. RESULTS: In the sample of 430 patients, the average age was 53.5 years, there were 153 men and 203 women, and the average body mass index was 33.6. Complications were significantly higher in O-TLIF than in MI-TLIF (OR = 0.420 [95% CI: 0.199, 0.887]; I 2 = 45.20%). No difference was detected between the two groups for visual analog scale back pain scores and Oswestry Disability Index scores between the pre-operative and last follow-up visits (SMD = -0.034 [95% CI -0.695, 0.627]; I 2 = 62.14% and SMD = 0.617 [95% CI: -1.082, 2.316]; I 2 = 25%, respectively). Blood loss was significantly lower in MI-TLIF compared to O-TLIF (SMD = -426.736 [95% CI: -490.720, -362.752]; I 2 = 70.53%), as was the duration of hospital stay (SMD = -1.079 [95% CI: -1.591, -0.208]; I 2 = 84.3%). CONCLUSION: MI-TLIF has equivalent efficacy to O-TLIF in obese patients at long-term follow-up. In addition, complication rate, blood loss, and length of hospital stay were lower in MI-TLIF than in O-TLIF.

Peroneal tendon dislocation in talus fracture and diagnostic value of fleck sign.

INTRODUCTION: Talus fractures are not uncommon and one of the serious fractures in the foot and ankle. Peroneal tendon dislocation is one of the commonly missed soft tissue injuries which may have significant impact on the outcomes including persistent pain and swelling. They have been reported to be associated with calcaneum as well as talus fractures. AIM: To report the incidence of peroneal tendon dislocation in talus fracture and the significance of fleck sign in the diagnosis of peroneal tendon dislocation. METHODS: We retrospectively reviewed 93 consecutive talus fractures in the period between 1/1/2011 to 1/11/2018. Inclusion criteria were: The patient underwent open reduction and internal fixation, had pre-operative CT scan that is available for review and three view ankle plain radiographs. Two independent authors review the radiographs for peroneal tendon dislocation, fleck sign and fracture classification, if any. Any dispute was resolved by the senior author.Patient records were reviewed for laterality, age, sex,mode of injury, associated injuries and operative interventions. 50 ankles met the inclusion criteria. 49 were males, mean age was 32.5 year and the predominant mode of injury was a fall from height. RESULTS: Peroneal tendon dislocation was found in ten patients out of 50 (20%). Risk of dislocation increased with severity of the fracture and neck fractures. Most of the dislocations were missed by surgeons and radiologist, and no additional procedures were done to address such an injury. The Fleck sign had a statistically significant correlation with peroneal tendons dislocations (p=.005) CONCLUSION: Peroneal tendons dislocation is associated with as high as 20% of talus fractures. The authors recommend carefully reviewing CT scans by surgeons and radiologists alike to avoid missing such injury and allow for appropriate surgical approach utilization. The Fleck sign is a highly specific radiographic sign that has a statistically significant correlation with PT dislocation and hence we recommend intra-operative assessment of peroneal tendons in patients with the fleck sign.

Meta-Analysis of the Diagnostic Accuracy of Primary Bone and Soft Tissue Sarcomas by 18F-FDG-PET.

OBJECTIVES: The goal of this meta-analysis was to assess the use of FDG-PET in the diagnosis of primary bone and soft tissue sarcomas. SUBJECTS AND METHODS: Several databases, including PubMed, Embase, Cochrane Library, and Web of Science, were searched. In addition to sensitivity and specificity, the diagnostic accuracy region for detecting and grading sarcomas were pooled using bivariate and hierarchical summary receiver-operating characteristic (HSROC) models. Subgroup analysis included pooling soft tissue and bone sarcomas separately, and sensitivity analysis included high-quality studies. The quality of eligible studies was assessed using QUADAS-2. RESULTS: Of the 1,258 papers screened, 21 studies satisfied the inclusion criteria. The pooled sensitivity and specificity of FDG-PET combined with CT for the detection of sarcomas were 89.2 and 76.3%, respectively. These diagnostic accuracy measures were higher when combined with CT than those of PDG-PET alone. Diagnostic accuracy for bone and soft tissue lesions were comparable but slightly better for soft tissue tumors. Pooling only the high-quality studies with low risk of bias yielded a sensitivity of 88.5% and specificity reduced to 65.6%. There was no evidence for publication bias, but significant heterogeneity among the studies was apparent. This study also showed that FDG-PET can efficiently differentiate between benign and malignant tumors, with a mean standard uptake value of maximally 2.52 units in benign and 6.81 units in malignant tumors (89.2% sensitivity and 75.1% specificity). CONCLUSION: Our findings indicate FDG-PET can efficiently differentiate between benign and malignant bone and soft tissue tumors. We also found that FDG-PET improves accuracy in diagnosing soft tissue sarcomas when combined with CT.

Functional and Radiological Outcomes of Combined Anterior-Posterior Approach Versus Posterior Alone in Management of Isthmic Spondylolisthesis. A Systematic Review and Meta-Analysis.

BACKGROUND: Lumbar isthmic spondylolisthesis (IS) in adults is defined as the forward slippage of a vertebra onto the top of the vertebra, resulting from a defect in the pars intraarticular, and can be low grade or high grade. Persistent back pain or neurological deficit are indications for surgical intervention. Surgery can be done from back, front, or both, with or without fusion, instrumentation, or decompression, and short or long segment. METHODS: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, several databases were searched through August 2017 for any observational or experimental studies that evaluated combined anterior-posterior approach versus posterior alone in management of IS. Primary outcome was fusion rate, whereas secondary outcomes included functional outcomes (Visual Analogue Scale [VAS] and Oswestry Disability Index [ODI] score), complication rate (infection, neurological), and reoperation rate. Descriptive, quantitative, and qualitative data were extracted. Most of the cases were low-grade IS. RESULTS: Of the 645 articles identified, 6 studies were eligible for the meta-analysis, with a total of 397 patients with IS, 198 in the combined (anterior interbody fusion [ALIF] + postero-lateral fusion [PLF]) group and 199 in the posterior (transformational interbody fusion [TLIF]/ postero-lateral interbody fusion [PLIF] + PLF) group, average age of 47.2 years, and 185:212 male : female ratio. Although the fusion rate reached 100% in some studies, the pooled odds ratio (OR) of fusion rate (OR = 1.02, 95% confidence interval [CI]: 0.294, 3.552, P = .972) did not reach statistical significance between (ALIF + PLF) versus (TLIF/PLIF + PLF). The estimated pooled standardized mean difference (SMD) showed less blood loss in the anterior approach compared to the posterior approach (SMD = -0.528, 95% CI: -0.777, -0.278, P < .001), with no difference in operative time and length of hospital stay. Despite both groups showing significant improvement in pain and functional scores at final follow up, ODI and VAS were not significantly different between groups with ODI (SMD = -0.644, 95% CI: -1.948, 0.621, P = .311) and VAS (SMD = 0.113, 95% CI: -0.173, 0.400, P = .439). The complication rate for the anterior approach was higher than the posterior, whereas reoperation rate was higher in the posterior approach than the anterior. CONCLUSIONS: No significant difference between anterior and posterior approaches was found in the global assessment of fusion rate and clinical outcomes, despite a higher rate of complications using the anterior approach. LEVEL OF EVIDENCE: 3. CLINICAL RELEVANCE: Both anterior and posterior approach are a valid option for treatment of isthemic spondylolisthesis.

Arthroscopic Bankart repair for the acute anterior shoulder dislocation: systematic review and meta-analysis.

BACKGROUND: The ideal treatment of acute anterior shoulder dislocation remains one of the topics that spark debate over the value of primary repair for the first-time anterior shoulder dislocation. The high rate of complications especially in young adults, such as recurrent instability, residual pain, and inability to return to sports, has led to the quest for an ideal management of such injuries. OBJECTIVE: In this meta-analysis, we compare between the immediate arthroscopic repair and conservative treatment of primary anterior shoulder dislocation as well as arthroscopic reconstruction of recurrent anterior shoulder dislocation. Outcome measures were failure rate (dislocation, subluxation, and instability) and revision rates. METHODS: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we searched several database including PubMed, MEDLINE, EMBASE, Web of Science, Cochrane Library, and ClinicalTrials.gov through August 2017 to identify observational and experimental randomized controlled trials comparing the outcomes of immediate arthroscopic repair and conservative treatment of primary shoulder dislocations as well as arthroscopic reconstruction of recurrent dislocation. The primary outcome was failure rate, whereas, secondary outcomes were revision rate and functional outcomes. RESULTS: Out of the 710 studies identified, 12 were eligible for meta-analysis. The estimated pooled failure rate was 13.7% (7.7%-19.6%), whereas, the pooled revision rate was 7.1% (3.8%-10.4%) in immediate arthroscopic repair of primary shoulder dislocation. The odd ratio (OR) of failure and revision rates were significantly lower in arthroscopic repair of primary shoulder dislocation compared to conservative treatment (OR 0.103, 95% CI [0.052, 0.201]), (OR 0.217, 95% CI [0.078, 0.607]), respectively. The odd ratio (OD) of failure and revision rates were lower in arthroscopic repair of primary shoulder dislocation compared to arthroscopic reconstruction of the recurrent shoulder dislocation; however, the difference was statistically insignificant (OR 0.423, 95% CI [0.117, 1.522]) and (OR 0.358, 95% CI [0.044, 2.920]) respectively. CONCLUSION: The outcome of immediate arthroscopic repair of primary anterior shoulder dislocation is superior and encouraging with significant reduction in failure and revision rates compared to conservative treatment. Nevertheless, the failure and revision rates are statistically insignificant compared to arthroscopic reconstruction of recurrent dislocation. Hence, there is evidence to support immediate arthroscopic repair option for primary anterior shoulder dislocations over conservative treatment in young active patients, in order to reduce the risk of failure and revision rates. However, the evidence is inconclusive compared to arthroscopic reconstruction of recurrent dislocation.

Applicability of the AAOS appropriate-use criteria for distal radius fractures in surgical practice.

PURPOSE: The appropriate-use criteria (AUC) for distal radius fracture (DRF) was developed by the American Academy of Orthopedic Surgeons (AAOS) to aid surgeons in making evidence-based treatment decisions for DRFs. The aim of our study was to cross-reference the management of operatively treated DRFs with the web-based AAOS published AUC recommendations. METHODS: The AUC for DRF evaluates the appropriateness of ten treatment options for each of 240 mutually exclusive patient scenarios based on the combination of five factors. For every scenario, each treatment is classified as appropriate, maybe appropriate or rarely appropriate. We retrospectively reviewed the medical charts and radiographs of all adult patients ≥19 years who underwent surgery for DRFs between 1 January and 31 December 2014 and determined the rate of appropriateness of treatment in this consecutive series of patients. RESULTS: Over the study period, 108 patients (83.3% men; mean age 39.8 years) with 113 DRFs (five bilateral) were treated surgically. The most frequent scenario was represented by a type C fracture, high-energy mechanism, normal functional demand, American Society Anesthesiologists (ASA) status 1-3 and no associated injuries. The most frequently used treatment was volar locking plate (54.0%). Based on the AUC, treatment was appropriate for 96 cases (85.0%), maybe appropriate for 15 (13.2%), and rarely appropriate for two (1.8%). CONCLUSIONS: A web-based electronic AUC application can be an attractive and easy decision-making aid for orthopaedic surgeons. Application of the AUC to clinical data was relatively simple, and most operatively treated DRFs were managed appropriately. LEVEL OF EVIDENCE: IV.