Management of giant cell tumors of the distal radius: a systematic review and meta-analysis.

PURPOSE: The treatment of giant cell tumors (GCT) of the distal radius remains challenging, with no consensus on the optimal surgical management. Surgical management remains the mainstay of treatment with options including intralesional curettage and en-bloc resection with reconstruction. The objective of this systematic review and meta-analysis was to evaluate and compare the outcomes of these two procedures. METHODS: Using OVID-Medline and Embase databases, a systematic literature search was performed. Comparative studies, assessing intralesional curettage and en-bloc resection in patients with GCTs of the distal radius, were included. Data regarding rates of local recurrence, metastasis, overall complications, and functional outcomes, were collected and analyzed. The ROBINS-I tool was utilized for risk of bias appraisal within each study outcome. RESULTS: Thirteen studies (n = 373 patients) reporting on 191 intralesional curettage procedures and 182 en-bloc resections were included in the analysis. The average age of participants was 31.9 (SD ± 2.4) years and average follow-up was 7.1 (SD ± 3.6) years. Patients that underwent intralesional curettage were more likely to develop local recurrence (Risk Ratio (RR) 3.3, 95% CI, [2.1, 5.4], p < 0.00001) when compared to patients that underwent en-bloc resection. In Campanacci grade 3 lesions, the risk for local recurrence was 5.9 (95% CI, [2.2, 16.3], p = 0.0006) times higher in patients that received intralesional curettage. Patients that underwent intralesional curettage showed an 84% reduction in the relative risk of developing overall complications compared to en-bloc resection (95% CI, [0.1, 0.4], p < 0.00001), and a larger decrease in Visual Analog Scale and lower Disabilities of the Arm, Shoulder, and Hand (DASH) scores (p < 0.00001). Risk ratio for developing a local recurrence, with PMMA versus bone graft following an intralesional procedure was not significant (RR 1.2, 95% CI, [0.6, 2.6], p = 0.62). CONCLUSIONS: In the surgical management of GCT of the distal radius, intralesional curettage increased local recurrence compared to en-bloc resection with reconstruction, particularly in grade 3 tumors. However, it led to significantly fewer operative complications, lower pain scores, and improved functional outcomes compared to en-bloc resection. Both treatment options remain relevant in the contemporary management of GCTs of the distal radius. Surgical decision making should include both patient and tumor factors when determining the optimal treatment strategy for these patients. LEVEL 3 EVIDENCE: Meta-analysis of Level 3 studies.

Giant cell tumour of bone.

Giant cell tumour of bone (GCTB) is a locally aggressive lesion that is difficult to treat as salvaging the joint can be associated with a high rate of local recurrence (LR). We evaluated the risk factors for tumour relapse after treatment of a GCTB of the limbs. A total of 354 consecutive patients with a GCTB underwent joint salvage by curettage and reconstruction with bone graft and/or cement or en bloc resection. Patient, tumour, and treatment factors were analyzed for their impact on LR. Patients treated with denosumab were excluded. There were 53 LRs (15%) at a mean 30.5 months (5 to 116). LR was higher after curettage (18.4%) than after resection (4.6%; p = 0.008). Neither pathological fracture (p = 0.240), Campanacci grade (p = 0.734), soft-tissue extension (p = 0.297), or tumour size (p = 0.872) affected the risk of recurrence. Joint salvage was possible in 74% of patients overall (262/354), and 98% after curettage alone (262/267). Of 49 patients with LR after curettage, 44 (90%) underwent repeated curettage and joint salvage. For patients treated by curettage, only age less than 30 years (p = 0.042) and location in the distal radius (p = 0.043) predicted higher LR. The rate of LR did not differ whether cement or bone graft was used (p = 0.753), but may have been reduced by the use of hydrogen peroxide (p = 0.069). Complications occurred in 15.3% of cases (54/354) and did not differ by treatment. Most patients with a GCTB can undergo successful joint salvage by aggressive curettage, even in the presence of a soft-tissue mass, pathological fracture, or a large lesion, with an 18.4% risk of local recurrence. However, 90% of local relapses after curettage can be treated by repeat joint salvage. Maximizing joint salvage is important to optimize long-term function since most patients with a GCTB are young adults. Younger patients and those with distal radius tumours treated with joint-sparing procedures have a higher rate of local relapse and may require more aggressive treatment and closer follow-up.

Intermuscular extremity myxoid liposarcoma can be managed by marginal resection following neoadjuvant radiotherapy.

BACKGROUND: Compared with other soft tissue sarcomas, myxoid liposarcoma (MLS) occurs in younger patients, has a propensity for intermuscular locations and is highly radiosensitive. With pre-operative radiotherapy, intermuscular MLS demonstrates substantial volume reduction and can be easily separated from surrounding tissues during resection. However, it is unclear whether marginal excision of MLS is oncologically safe. This study aimed to assess the association between margins and survival in irradiated, intermuscular MLS. METHODS: The study identified 198 patients from seven sarcoma centres with a first presentation of localized, extremity, intermuscular MLS that received pre-operative radiotherapy and was diagnosed between 1990 and 2017. Patient and treatment characteristics, radiological and histological responses to neoadjuvant treatment and clinical surveillance were recorded. RESULTS: Margins were microscopically positive in 11% (n = 22), <1.0 mm in 15% (n = 29) and ≥1.0 mm in 72% (n = 143). There was no association between margin status and local recurrence-free, metastasis-free or overall survival. This finding held true even in patients at higher risk of worse overall survival based on multivariable analysis (% round cell≥5%, percentage ellipsoid tumour volume change ≤ -60.1%). CONCLUSION: Irradiated, extremity, intermuscular myxoid liposarcoma can safely undergo marginal resection without compromising oncologic control.

Emerging point-of-care autologous cellular therapy using adipose-derived stromal vascular fraction for neurodegenerative diseases.

Neurodegenerative disorders are characterized by the gradual decline and irreversible loss of cognitive functions and CNS structures. As therapeutic recourse stagnates, neurodegenerative diseases will cost over a trillion dollars by 2050. A dearth of preventive and regenerative measures to hinder regression and enhance recovery has forced patients to settle for traditional therapeutics designed to manage symptoms, leaving little hope for a cure. In the last decade, pre-clinical animal models and clinical investigations in humans have demonstrated the safety and promise of an emerging cellular product from subcutaneous fat. The adipose-derived stromal vascular fraction (SVF) is an early intervention and late-stage novel 'at point' of care cellular treatment, demonstrating improvements in clinical applications for Multiple Sclerosis, Alzheimer's disease, and Parkinson's disease. SVF is a heterogeneous fraction of cells forming a robust cellular ecosystem and serving as a novel and valuable source of point-of-care autologous cell therapy, providing an easy-to-access population that we hypothesize can mediate repair through 'bi-directional' communication in response to pathological cues. We provide the first comprehensive review of all pre-clinical and clinical findings available to date and highlight major challenges and future directions. There is a greater medical and economic urgency to innovate and develop novel cellular therapy solutions that enable the repair and regeneration of neuronal tissue that has undergone irreversible and permanent damage.

Neuronal CaMKK2 promotes immunosuppression and checkpoint blockade resistance in glioblastoma.

Glioblastoma (GBM) is notorious for its immunosuppressive tumor microenvironment (TME) and is refractory to immune checkpoint blockade (ICB). Here, we identify calmodulin-dependent kinase kinase 2 (CaMKK2) as a driver of ICB resistance. CaMKK2 is highly expressed in pro-tumor cells and is associated with worsened survival in patients with GBM. Host CaMKK2, specifically, reduces survival and promotes ICB resistance. Multimodal profiling of the TME reveals that CaMKK2 is associated with several ICB resistance-associated immune phenotypes. CaMKK2 promotes exhaustion in CD8+ T cells and reduces the expansion of effector CD4+ T cells, additionally limiting their tumor penetrance. CaMKK2 also maintains myeloid cells in a disease-associated microglia-like phenotype. Lastly, neuronal CaMKK2 is required for maintaining the ICB resistance-associated myeloid phenotype, is deleterious to survival, and promotes ICB resistance. Our findings reveal CaMKK2 as a contributor to ICB resistance and identify neurons as a driver of immunotherapeutic resistance in GBM.

Assessment of Risk of Bias in Osteosarcoma and Ewing's Sarcoma Randomized Controlled Trials: A Systematic Review.

AIM: The aim of this study was to systematically assess the risk of bias in osteosarcoma and Ewing's sarcoma (ES) randomized controlled trials (RCT) and to examine the relationships between bias and conflict of interest/industry sponsorship. METHODS: An OVID-MEDLINE search was performed (1976-2019). Using the Cochrane Collaboration guidelines, two reviewers independently assessed the prevalence of risk of bias in different RCT design domains. The relationship between conflicts of interest and industry funding with the frequency of bias was examined. RESULTS: 73 RCTs met inclusion criteria. Prevalence of low-risk bias domains was 47.3%, unclear-risk domains 47.8%, and 4.9% of the domains had a high-risk of bias. Domains with the highest risk of bias were blinding of participants/personnel and outcome assessors, followed by randomization and allocation concealment. Overtime, frequency of unclear-risk of bias domains decreased (χ2 = 5.32, p = 0.02), whilst low and high-risk domains increased (χ2 = 8.13, p = 0.004). Studies with conflicts of interest and industry sponsorships were 4.2 and 3.1 times more likely to have design domains with a high-risk of bias (p < 0.05). CONCLUSION: This study demonstrates that sources of potential bias are prevalent in both osteosarcoma and ES RCTs. Studies with financial conflicts of interest and industry sponsors were significantly more likely to have domains with a high-risk of bias. Improvements in reporting and adherence to proper methodology will reduce the risk of bias and improve the validity of the results of RCTs in osteosarcoma and ES.

Effectiveness of a tailored neck training program on neck strength, movement, and fatigue in under-19 male rugby players: a randomized controlled pilot study.

PURPOSE: To investigate the effect of a tailored neck muscle conditioning program on neck muscle strength, neck muscle fatigue, and range of neck movement in 16-18-year-old male rugby players. MATERIALS AND METHODS: Thirty-four male rugby players were divided into forward and back playing positions and randomized within these groups. Seventeen players were randomly assigned to each group. The test group was given a tailored 6-week exercise regime based on their baseline measurements to be performed three times a week in addition to their normal training and playing. The control group trained and played as normal. The outcome measures used were cervical spine range of movement, neck strength, and neck muscle fatigability. RESULTS: There were no clinically relevant statistically significant differences between the two groups. Trends identified between the two groups suggest that a tailored neck exercise program increases neck strength, particularly neck extension, and increases resistance to fatigue, as well as influencing right- and left-sided neck muscle balance. A reduction in range of movement was also demonstrated in the test group. There was a great deal of variability in range of movement and strength within this age group. No previously undiagnosed neck conditions were detected, and there were no adverse events reported. CONCLUSION: This study has shown that neck strength, range of movement, and susceptibility of the neck muscles to fatigue can be influenced using a focused neck training regime. It forms an important basis for a larger, multicenter study to ensure the neck is given due attention in rugby training and receives the same focus of conditioning as other parts of the body.

The potential therapeutic use of stem cells in cartilage repair.

As our population demographics change, osteoarthritis and cartilage defects are becoming more prevalent. The discovery of stems cells and their ability for indefinite regeneration has revolutionised the way cartilage problems are viewed. Tissue engineering has been shown to be the ideal way of repairing articular cartilage lesions, i.e. back to native tissue. Cartilage is an ideal tissue engineering target as it is avascular, aneural and alymphatic. The two main types of stem cells being investigated in chondrogenesis are embryological and mesenchymal stem cells. Research into embryological stem cells has been surrounded by controversy because of ethical, religious and social concerns. We discuss the use of embryological and mesenchymal stem cells in cartilage repair and the various factors involved in the differentiation into chondrocytes. We also discuss commonly used mesenchymal stem cell markers and their limitations.

Embryonic versus mesenchymal stem cells in cartilage repair.

As our population changes osteoarthritis and cartilage defects are becoming more prevalent. The discovery of stems cells and their ability for indefinite regeneration has revolutionised the way cartilage problems are viewed. Tissue engineering has been shown to be the ideal way of repairing articular cartilage lesions, i.e. back to native tissue. The two main types of stem cells being investigated in chondrogenesis are embryological and mesenchymal stem cells. Research into embryological stem cells has been surrounded by controversy because of tumour formation and damaging embryos during the harvest of cells. We discuss the use of embryological and mesenchymal stem cells in cartilage repair and the various factors involved in the differentiation into chondrocytes.

Treating stiffness after total knee arthroplasty: a technical note and preliminary results.

Total Knee Replacement is used to treat pain, stiffness and reduced range of movement. It has been estimated that a minimum of 90 degrees of range of motion in the knee is required for normal activities of daily living. In this article we demonstrate a technical note with a small patient series about the methods of treating knee stiffness after Total Knee Replacement.

Pre-operative Embolization of Primary and Secondary Bone Tumours is Safe and Effective: a Retrospective Study.

BACKGROUND: The surgical treatment of bone tumours can result in large peri-operative blood loss, due to their large sizes and hypervascularity. Pre-operative embolisation has been successfully used to downgrade vascularity, thus reducing peri-operative blood loss and its associated complications. METHODS: Pre-operative embolisation was successfully undertaken on twenty-six patients with a variety of primary and secondary bone tumours. RESULTS: Mean blood loss was 796 mL and we experienced no complications. CONCLUSION: Pre-operative arterial embolisation of large, richly vascular bone tumours in anatomically difficult positions, is a safe and effective method of downstaging vascularity and reducing blood loss.