Plastic lengthening amputation with vascularized bone grafts in children with bone sarcoma: a preliminary report.

BACKGROUND: At present, amputation was widely adopted for young patients when limb salvage was deemed risky with several surgical strategy such as rotationplasty. However, leg length discrepancies and unfavorable cosmetic results were indispensable complication of this strategy. The purpose of this study was to propose a novel reconstruction strategy and evaluate the early clinical and functional outcomes of the strategy. METHODS: Plastic lengthening amputation (PLA) has been developed by lengthening the stump to preserve one additional distal joint for fixing the artificial limb well. The surgical technique and postoperative management were documented, and the functional outcomes were compared with those of traditional amputation (TA). Six pairs of patients matched for age, sex, location, pathological type, and final prosthesis underwent individually designed plastic lengthening amputation with vascularized autografts or traditional amputation between January 2005 and December 2007. All patients were followed, and the locomotor index and the musculoskeletal tumor society score (MSTS) were used to describe and quantitatively grade limb functional outcomes after amputation. The complications and functional outcomes of the patients taken two kinds of procedures were compared. RESULTS: Twelve patients with osteosarcoma or Ewing's sarcoma of either the femur or tibia were included in the study. Six patients underwent plastic lengthening amputations, three of whom also underwent vascular anastomosis. Patients were followed for an average of 48.17 months; bone healing required an average of 3.3 months. No local recurrence was found. The average postoperative locomotor index functional score of the affected limb was 32.67 ± 5.89 in the plastic lengthening amputation group while was 19.50 ± 7.87 in the traditional amputation group. The MSTS functional scores were 22.67 ± 1.33 and 24.17 ± 1.45 at 6 and 12 months for patients in PLA group while 17.00 ± 1.549 and 17.83 ± 1.64 at 6 and 12 months for patients in TA group. CONCLUSIONS: Plastic lengthening amputations with vascularized autografts could preserve the knee joint to improve the function of the amputated limb in selected bone sarcoma patients.

Intra-Articular Viscosupplementation for Patients with Hip Osteoarthritis: A Meta-Analysis and Systematic Review.

BACKGROUND The aim of this study was to review the efficacy and safety of intra-articular (IA) viscosupplementation (VS) for hip osteoarthritis (OA). MATERIAL AND METHODS We searched Medline, Clinical Trial Register Center, EMBASE, and Cochrane databases for randomized controlled trials (RCTs) comparing VS with placebo injection for hip OA. We included suitable studies, assessed the quality of studies, and extracted data on pain reduction, function improvement at different time points, and safety profiles. The comparisons of pain and function outcome were performed by meta-analysis. RESULTS Five high-quality randomized controlled studies trials (RCTs) with 591 patients with hip OA were identified. Although several trials demonstrated a significant decline in pain in VS groups during follow-up compared to baseline, without severe adverse events, the pooled analysis did not show VS was superior to placebo at any time windows [7-14 days: standardized mean difference (SMD): -0.18; 95% CI, -0.47 to 0.10, p=0.21; 28-30 days: 0.02 (-0.15, 0.19), p=0.82; or at final visit: -0.14 (-0.46, 0.18), p=0.38]. Similar results were also observed in the combined data of functional results. CONCLUSIONS IA VS does not reduce pain or improve function significantly better than placebo in a short-term follow-up. The benefits and safety of VS should be further assessed by sufficiently-sized, methodologically sound studies with validated assessment of more clinically relevant end-points.

iPARTS2: an improved tool for pairwise alignment of RNA tertiary structures, version 2.

Since its first release in 2010, iPARTS has become a valuable tool for globally or locally aligning two RNA 3D structures. It was implemented by a structural alphabet (SA)-based approach, which uses an SA of 23 letters to reduce RNA 3D structures into 1D sequences of SA letters and applies traditional sequence alignment to these SA-encoded sequences for determining their global or local similarity. In this version, we have re-implemented iPARTS into a new web server iPARTS2 by constructing a totally new SA, which consists of 92 elements with each carrying both information of base and backbone geometry for a representative nucleotide. This SA is significantly different from the one used in iPARTS, because the latter consists of only 23 elements with each carrying only the backbone geometry information of a representative nucleotide. Our experimental results have shown that iPARTS2 outperforms its previous version iPARTS and also achieves better accuracy than other popular tools, such as SARA, SETTER and RASS, in RNA alignment quality and function prediction. iPARTS2 takes as input two RNA 3D structures in the PDB format and outputs their global or local alignments with graphical display. iPARTS2 is now available online at http://genome.cs.nthu.edu.tw/iPARTS2/.

Accuracy of intraocular lens power calculation formulas in long eyes: a systematic review and meta-analysis.

IMPORTANCE: Visual outcome after intraocular lens (IOL) implantation in long eyes is considerably affected by IOL power calculation. Various formulas have been designed to achieve an accurate IOL power prediction. However, controversy about the accuracy remains. BACKGROUND: To evaluate the accuracy of IOL power calculation formulas in long eyes. DESIGN: Meta-analysis. PARTICIPANTS: Patients with ocular axial length (AL) over 24.5 mm. METHODS: A comprehensive search in PubMed, EMBASE, Cochrane Data Base of Systematic Reviews and the Cochrane Central Register of Controlled Trials were conducted by September, 2017. The weighted mean differences of mean absolute errors (MAE) and the odds ratio of percentage of eyes within ±0.50D of prediction error among formulas were analysed. MAIN OUTCOMES MEASURES: Between-group differences of MAE among formulas. RESULTS: Eleven observational studies, involving 4047 eyes, were enrolled. Six formulas for IOL power calculation were compared: Barrett Universal II, Haigis, Holladay 2, SRK/T, Hoffer Q and Holladay 1. The MAE of Barrett Universal II was statistically lower than that of Holladay 2 (mean difference, MD = -0.04D, P = 0.0002), SRK/T (MD = -0.05D, P < 0.00001), Hoffer Q (MD = -0.07D, P < 0.00001) and Holladay 1 (MD = -0.07D, P < 0.00001). Barrett Universal II yielded significantly higher percentage of eyes within ±0.50D of the prediction error than the other formulas. The heterogeneity was minimized through dividing eyes into two groups by the AL of 26 mm. CONCLUSIONS AND RELEVANCE: This study demonstrates the superiority of Barrett Universal II over Holladay 2, SRK/T, Hoffer Q and Holladay 1 in predicting IOL power in long eyes.

Meta-analysis of accuracy of intraocular lens power calculation formulas in short eyes.

IMPORTANCE: Intraocular lens (IOL) power selection is a critical factor affecting visual outcome after IOL implantation in short eyes. Many formulas have been developed to achieve a precise prediction of the IOL power. However, controversy regarding the accuracy remains. BACKGROUND: To investigate the accuracy of different IOL power calculation formulas in short eyes. DESIGN: Meta-analysis. PARTICIPANTS: Patients with the axial length of eyes less than 22 mm from previously reported studies. METHODS: A comprehensive search in Pubmed, EMBASE, Cochrane Data Base of Systematic Reviews and the Cochrane Central Register of Controlled Trials was conducted by October 2016. We assessed the methodological quality using a modified QUADAS-2 tool and performed analysis on weighted mean differences of mean absolute errors (MAE) among different formulas. MAIN OUTCOMES MEASURES: The between-group difference of MAE was evaluated with weighted mean difference and 95% confidence intervals. RESULTS: Ten observational studies, involving 1161 eyes, were enrolled to compare six formulas: Haigis, Holladay 2, Hoffer Q, Holladay 1, SRK/T and SRK II. Among them, the Holladay 2 introduced the smallest overall MAE (0.496D) without statistical significance. The difference of MAE is statistically significant between Haigis and Hoffer Q (mean difference = -0.07D, P = 0.003), Haigis and SRK/T (mean difference = -0.07D, P = 0.009), Haigis and SRK II (mean difference = -0.41D, P = 0.01). For publication bias and small-study effect, neither funnel plot nor egger's test detected statistical finding. CONCLUSION AND RELEVANCE: The overall evidence from the studies confirmed the superiority of Haigis over Hoffer Q, SRK/T and SRK II in prediction IOL power in short eyes.

PTH1-34 blocks radiation-induced osteoblast apoptosis by enhancing DNA repair through canonical Wnt pathway.

Focal radiotherapy for cancer patients has detrimental effects on bones within the radiation field and the primary clinical signs of bone damage include the loss of functional osteoblasts. We reported previously that daily injection of parathyroid hormone (PTH, 1-34) alleviates radiation-induced osteopenia in a preclinical radiotherapy model by improving osteoblast survival. To elucidate the molecular mechanisms, we irradiated osteoblastic UMR 106-01 cells and calvarial organ culture and demonstrated an anti-apoptosis effect of PTH1-34 on these cultures. Inhibitor assay indicated that PTH exerts its radioprotective action mainly through protein kinase A/ß-catenin pathway. γ-H2AX foci staining and comet assay revealed that PTH efficiently promotes the repair of DNA double strand breaks (DSBs) in irradiated osteoblasts via activating the ß-catenin pathway. Interestingly, Wnt3a alone also blocked cell death and accelerated DNA repair in primary osteoprogenitors, osteoblastic and osteocytic cells after radiation through the canonical signaling. Further investigations revealed that both Wnt3a and PTH increase the amount of Ku70, a core protein for initiating the assembly of DSB repair machinery, in osteoblasts after radiation. Moreover, down-regulation of Ku70 by siRNA abrogated the prosurvival effect of PTH and Wnt3a on irradiated osteoblasts. In summary, our results identify a novel role of PTH and canonical Wnt signaling in regulating DSB repair machinery and apoptosis in osteoblasts and shed light on using PTH1-34 or Wnt agonist as possible therapy for radiation-induced osteoporosis.

Truncated Escherichia coli thioredoxin induces proliferation of human blood mononuclear cells and production of reactive oxygen species as well as proinflammatory cytokines.

UNLABELLED: Thioredoxin (Trx) is a redox protein characterized by a Trx fold. A naturally occurring truncated human Trx, Trx 80, which lacks the C-terminal strand-helix of the Trx fold, stimulates proliferation of peripheral blood mononuclear cells (PBMCs). It has not been clear how Trx80 gains this function. This study investigates whether a peptide with substantial sequence difference from Trx80, but retaining an abridged Trx fold can elicit PBMC proliferation. We genetically truncated a carboxy-terminal ß-α motif of Escherichia coli Trx to produce a peptide, Trx83, which shares low sequence identity with human Trx80. Addition of reduced-form Trx83 to resting human PBMCs promoted cell proliferation, while oxidized-form Trx83 lacked the function. By contrast, oxidized-form Trx80 exhibited a high activity in promoting PBMC proliferation, indicating the importance of sequence context of an abridged thioredoxin in influencing PBMC proliferation. Trx83 increases cellular reactive oxygen species and proinflammatory cytokines TNF-α and IL-1ß, suggesting that Trx83 modulates inflammatory pathways. This notion is supported by the observation that cystine or cysteine abolishes the Trx83 induced PBMC proliferation. The PBMC stimulatory activity of Trx83 may have potential for pharmacological developments. SIGNIFICANCE OF THE STUDY: Elicitation of primary proliferative responses of PBMCs by a protein is generally difficult. We show that Escherichia coli Trx83 with a truncated Trx fold induces PBMC proliferation, but only in the disulfide-reduced form. In contrast, oxidized-form human Trx80 is a potent stimulator. These results demonstrate that the sequence context of an abridged Trx fold is influential in inducing PBMC proliferation. The stimulatory effect of Trx83 is associated with an increase of inflammatory response. The possibility of eliciting PBMC proliferation and switching this activity on/off by redox control provides a perspective for developing Trx83 as a PBMC stimulatory agent. Copyright © 2016 John Wiley & Sons, Ltd.

Low-intensity pulsed ultrasound enhances bone repair in a rabbit model of steroid-associated osteonecrosis.

BACKGROUND: Steroids are a leading cause of femoral head osteonecrosis. Currently there are no medications available to prevent and/or treat steroid-associated osteonecrosis. Low-intensity pulsed ultrasound (LIPUS) was approved by the FDA for treating delayed union of bone fractures. Some studies have reported that LIPUS can enhance bone formation and local blood flow in an animal model of fracture healing. However, whether the effect of osteogenesis and neovascularization by LIPUS can enhance the repair progress in steroid-associated osteonecrosis is unknown. QUESTIONS/PURPOSES: We hypothesized that LIPUS may facilitate osteogenesis and neovascularization in the reparative processes of steroid-associated osteonecrosis. Using a rabbit animal model, we asked whether LIPUS affects (1) bone strength and trabecular architecture; (2) blood vessel number and diameter; and (3) BMP-2 and VEGF expression. METHODS: Bilateral femoral head necrosis was induced by lipopolysaccharide and methylprednisolone in 24 rabbits. The left femoral heads of rabbits received LIPUS therapy (200 mW/cm(2)) for 20 minutes daily and were classified as the LIPUS group. The right femoral heads of the same rabbits did not receive therapy and were classified as the control group. All rabbits were euthanized 12 weeks after LIPUS therapy. Micro-CT, biomechanical testing, histologic evaluation, immunohistochemistry, quantitative real-time PCR, and Western blot were used for examination of the effects of LIPUS. RESULTS: Twelve weeks after LIPUS treatment, the loading strength in the control group was 355 ± 38 N (95% CI, 315-394 N), which was lower (p = 0.028) than that in the LIPUS group (441 ± 78 N; 95% CI, 359-524 N). The bone tissue volume density (bone volume/total volume) in the LIPUS group (49.29% ± 12.37%; 95 % CI, 36.31%-62.27%) was higher (p = 0.022) than that in the control group (37.93% ± 8.37%; 95 % CI, 29.15%-46.72%). The percentage of empty osteocyte lacunae in the LIPUS group (17% ± 4%; 95% CI, 15%-20%) was lower (p = 0.002) than that in the control group (26% ± 9%; 95% CI, 21%-32%). The mineral apposition rate (µm/day) in the LIPUS group (2.3 ± 0.8 µm/day; 95% CI, 1.8 2.8 µm/day) was higher (p = 0.001) than that in the control group (1.6 ± 0.3 µm/day; 95% CL, 1.4-1.8 µm/day). The number of blood vessels in the LIPUS group (7.8 ± 3.6/mm(2); 95% CI, 5.5-10.1 mm(2)) was greater (p = 0.025) than the number in the control group (5.7 ± 2.6/mm(2); 95% CI, 4.0-7.3 mm(2)). Messenger RNA (mRNA) and protein expression of BMP-2 in the LIPUS group (75 ± 7, 95% CI, 70-79; and 30 ± 3, 95% CI, 28-31) were higher (both p < 0.001) than those in the control groups (46 ± 5, 95% CI, 43-49; and 15 ± 2, 95% CI, 14-16). However, there were no differences (p = 0.114 and 0.124) in mRNA and protein expression of vascular endothelial growth factor between the control (26 ± 3, 95% CI, 24-28; and 22 ± 6, 95% CI, 18-26) and LIPUS groups (28 ± 2, 95% CI, 26-29; and 23 ± 6, 95% CI, 19-27). CONCLUSIONS: The results of this study indicate that LIPUS promotes osteogenesis and neovascularization, thus promoting bone repair in this steroid-associated osteonecrosis model. CLINICAL RELEVANCE: LIPUS may be a promising modality for the treatment of early-stage steroid-associated osteonecrosis. Further research, including clinical trials to determine whether LIPUS has a therapeutic effect on patients with early-onset steroid-associated osteonecrosis may be warranted.

Epidermal growth factor receptor (EGFR) signaling regulates epiphyseal cartilage development through ß-catenin-dependent and -independent pathways.

The epidermal growth factor receptor (EGFR) is an essential player in the development of multiple organs during embryonic and postnatal stages. To understand its role in epiphyseal cartilage development, we generated transgenic mice with conditionally inactivated EGFR in chondrocytes. Postnatally, these mice exhibited a normal initiation of cartilage canals at the perichondrium, but the excavation of these canals into the cartilage was strongly suppressed, resulting in a delay in the formation of the secondary ossification center (SOC). This delay was accompanied by normal chondrocyte hypertrophy but decreased mineralization and apoptosis of hypertrophic chondrocytes and reduced osteoclast number at the border of marrow space. Immunohistochemical analyses demonstrated that inactivation of chondrocyte-specific EGFR signaling reduced the amounts of matrix metalloproteinases (MMP9, -13, and -14) and RANKL (receptor activator of NF-κB ligand) in the hypertrophic chondrocytes close to the marrow space and decreased the cartilage matrix degradation in the SOC. Analyses of EGFR downstream signaling pathways in primary epiphyseal chondrocytes revealed that up-regulation of MMP9 and RANKL by EGFR signaling was partially mediated by the canonical Wnt/ß-catenin pathway, whereas EGFR-enhanced MMP13 expression was not. Further biochemical studies suggested that EGFR signaling stimulates the phosphorylation of LRP6, increases active ß-catenin level, and induces its nuclear translocation. In line with these in vitro studies, deficiency in chondrocyte-specific EGFR activity reduced ß-catenin amount in hypertrophic chondrocytes in vivo. In conclusion, our work demonstrates that chondrocyte-specific EGFR signaling is an important regulator of cartilage matrix degradation during SOC formation and epiphyseal cartilage development and that its actions are partially mediated by activating the ß-catenin pathway.

Evidence for using alendronate to treat adult avascular necrosis of the femoral head: a systematic review.

Osteonecrosis or avascular osteonecrosis (AVN) of the femoral head is a devastating multifactorial disease that affects 20 000 persons each year in the United States. The purpose of this systematic review was to determine the efficacy and safety of alendronate for adult AVN during short- and long-term follow-up. Electronic databases were searched for randomized or nonrandomized clinical trials, cohort, case-control studies, and series of cases in which alendronate was used for treatment of adult AVN of the femoral head. Relevant articles with adequate data on reduction of pain, improvement of articular function, slowing of bone collapse progression, or need for total hip arthroplasty (THA) were included after applying inclusion and exclusion criteria. Eight articles involving 788 hips with evidence level 1b to 3b were included in this systematic review. Most studies suggested a positive short-term efficacy of alendronate treatment in reducing pain, improving articular function, slowing of bone collapse progression, and delaying the need for THA for adult AVN patients. The favorable long-term results were also presented in those treated patients after 10-year follow-up. In addition, there were no severe adverse effects associated with alendronate treatment observed during short- and long-term follow-up, and most of the included studies suggested use of alendronate in early AVN with small necrotic lesion to achieve better outcomes. The findings support consideration of alendronate use for adult AVN, particularly with early stage and small necrotic size. The lack of large-scale, randomized, and double-blind studies justifies new studies to demonstrate the detailed indication and the optimized strategy of alendronate treatment. Level of evidence: Level 3a.

Cartilage oligomeric matrix protein gene multilayers inhibit osteogenic differentiation and promote chondrogenic differentiation of mesenchymal stem cells.

There are still many challenges to acquire the optimal integration of biomedical materials with the surrounding tissues. Gene coatings on the surface of biomaterials may offer an effective approach to solve the problem. In order to investigate the gene multilayers mediated differentiation of mesenchymal stem cells (MSCs), gene functionalized films of hyaluronic acid (HA) and lipid-DNA complex (LDc) encoding cartilage oligomeric matrix protein (COMP) were constructed in this study via the layer-by-layer self-assembly technique. Characterizations of the HA/DNA multilayered films indicated the successful build-up process. Cells could be directly transfected by gene films and a higher expression could be obtained with the increasing bilayer number. The multilayered films were stable for a long period and DNA could be easily released in an enzymatic condition. Real-time polymerase chain reaction (RT-PCR) assay presented significantly higher (p<0.01) COMP expression of MSCs cultured with HA/COMP multilayered films. Compared with control groups, the osteogenic gene expression levels of MSCs with HA/COMP multilayered films were down-regulated while the chondrogenic gene expression levels were up-regulated. Similarly, the alkaline phosphatase (ALP) staining and Alizarin red S staining of MSCs with HA/COMP films were weakened while the alcian blue staining was enhanced. These results demonstrated that HA/COMP multilayered films could inhibit osteogenic differentiation and promote chondrogenic differentiation of MSCs, which might provide new insight for physiological ligament-bone healing.

Comparison of oncological and functional outcomes in Lower-limb osteosarcoma pediatric patients: a large single-center retrospective cohort study.

OBJECTIVE: Treating pediatric osteosarcoma in long bones is challenging due to skeletal immaturity, which restricts the generalizability of insights derived from adult patients. Are there disparities in outcomes? How should surgical protocols be tailored for children of varying ages? What are the specific postoperative complications? A large single-center retrospective cohort study of 345 patients under 14 years old with lower-limb osteosarcoma treated in our department since 2000 was conducted to address these inquiries. METHODS: A retrospective analysis of 345 pediatric patients with lower-limb osteosarcoma admitted to our department between 2000 and 2019 was conducted. Clinical and functional outcomes were compared based on age groups, surgical methods, type of prosthesis, and primary tumor location. Patients were divided into the low-age group (≤10 y old) and the high-age group (>10 y old). Overall survival rate (OS), progressionfree survival rate (PFS), and prosthesis survival rate were assessed using Kaplan-Meier curves, nonparametric survival analysis (log-rank test), and Univariate cox regression were used for comparison. The incidence of complications, local relapse rate (LRR), metastasis rate, final limb-salvage, and amputation rate, and Musculoskeletal Tumor Society (MSTS) score of different independent groups were further evaluated using χ2 test or Fisher's exact test, and t -test was employed to evaluate the measurement data. RESULTS: The average age of the patients was 11.10±2.32 years ranging from 4 to 14 y, with an average follow-up duration of 48.17 months. The 5, 10, and 15-year OS rates were 50.3%, 43.8%, and 37.9%, respectively. The progression-free survival rate was 44.8% at 5 years and 41.1% at 10 years. The final limb salvage rate was 61.45%, while the final amputation rate was 38.55%. The low-age group had a higher amputation rate compared with the high-age group (48.00% vs. 33.18%, P =0.009). The overall LRR was 9.28%, and the incidence of metastasis was 28.99%. The LRR of the limb-salvage group was higher than the amputation group ( P =0.004). The low-age group experienced more prosthesis-related complications than the high-age group ( P =0.001). The most common prosthesis-related complication in the low-age group was soft-tissue failure, while the periprosthetic infection was most frequent in the high-age group. The high-age group had a higher cumulative prosthesis survival compared with the low-age group ( P =0.0097). Modular prosthesis showed better MSTS scores and higher cumulative prosthetic survival than expandable prosthesis in pediatric patients ( P <0.05). CONCLUSION: Limb preservation in pediatric patients becomes increasingly efficacious with advancing age, while consideration of amputation is warranted for younger patients. The prevailing postoperative complications associated with prosthesis encompass soft tissue failure and periprosthetic infection. Younger patients diagnosed with lower limb osteosarcoma exhibit a heightened amputation rate and a greater incidence of prosthesis-related complications.

Age-dependent molecular variations in osteosarcoma: implications for precision oncology across pediatric, adolescent, and adult patients.

Background: Osteosarcoma is a leading subtype of bone tumor affecting adolescents and adults. Comparative molecular characterization among different age groups, especially in pediatric, adolescents and adults, is scarce. Methods: We collected samples from 194 osteosarcoma patients, encompassing pediatric, adolescent, and adult cohorts. Genomic analyses were conducted to reveal prevalent mutations and compare molecular features in pediatric, adolescent, and adult patients. Results: Samples from 194 osteosarcoma patients across pediatric to adult ages were analyzed, revealing key mutations such as TP53, FLCN, NCOR1, and others. Children and adolescents showed more gene amplifications and HRD mutations, while adults had a greater Tumor Mutational Burden (TMB). Mutations in those over 15 were mainly in cell cycle and PI3K/mTOR pathways, while under 15s had more in cell cycle and angiogenesis with higher VEGFA, CCND3, TFEB mutations. CNV patterns varied with age: VEGFA and XPO5 amplifications more in under 25s, and CDKN2A/B deletions in over 25s. Genetic alterations in genes like MCL1 and MYC were associated with poor prognosis, with VEGFA mutations also indicating worse outcomes. 58% of patients had actionable mutations, suggesting opportunities for targeted therapies. Age-specific patterns were observed, with Multi-TKI mutations more common in younger patients and CDK4/6 inhibitor mutations in adults, highlighting the need for personalized treatment approaches in osteosarcoma. In a small group of patients with VEGFR amplification, postoperative treatment with multi-kinase inhibitors resulted in a PR in 3 of 13 cases, especially in patients under 15. A significant case involved a 13-year-old with a notable tumor size reduction achieving PR, even with other genetic alterations present in some patients with PD. Conclusion: This study delineates the molecular differences among pediatric, adolescent, and adult osteosarcoma patients at the genomic level, emphasizing the necessity for precision diagnostics and treatment strategies, and may offer novel prognostic biomarkers for patients with osteosarcoma. These findings provide a significant scientific foundation for the development of individualized treatment approaches tailored to patients of different age groups.

Ten versus five polymorphonuclear leukocytes as threshold in frozen section tests for periprosthetic infection: a meta-analysis.

We objectively appraised available evidence regarding the threshold for the number of polymorphonuclear leukocytes required in frozen section tests used to diagnose periprosthetic infection. Pooled summary estimates for sensitivity, specificity, positive likelihood ratio, negative likelihood ratio and diagnostic odds ratio (OR) were compared for ten and five polymorphonuclear leukocytes per high power field as the threshold. The total cohort included 1011 patients and the rate of infection was 19.2%. Although there was no difference in sensitivity or diagnostic OR, specificity was significantly higher for ten than for five polymorphonuclear leukocytes per high power field (p=0.007) In sum, a threshold of 10 polymorphonuclear leukocytes is better for diagnosing periprosthetic infections.

Autologous menisci-cruciate ligament composite as a flap for soft tissue reconstruction following malignant bone tumor resection around the knee.

BACKGROUND: Despite significant improvements in oncological treatment, the management of soft tissue defects following malignant tumor resection remains challenging. We investigated whether autologous menisci and cruciate ligament, which are traditionally discarded, can be recycled as a supplemental flap in repairing soft tissue defects following malignant bone tumor resection and endoprosthetic reconstruction around the knee. METHODS: Four knee specimens were dissected to provide a basis for the design of the menisci-cruciate ligament composite. Then, 40 patients with bone malignancies around the knee were enrolled and underwent reconstruction with free or vascularized composite following malignant tumor resection. The clinical, radiographic, and functional outcomes of this technique were evaluated in >1-year follow-up in each patient and compared with 87 patients who suffered from bone malignancies around the knee and were treated by limb salvage but without composite at our center over the same period. During the follow-up, a composite from one patient who underwent secondary amputation was retrieved and examined for in vivo remodeling. RESULTS: Fourteen patients were treated with vascularized composite transfer (10 distal femurs and 4 proximal tibias) and 26 patients with free composite transfer (19 distal femurs and 7 proximal tibias). The composite can be used to cover the area of soft tissue defect from 22 to 48.38 cm2 (34.67 ± 6.48 cm2 ). With contrast-enhanced ultrasound, peripheral rim healing and dotted blood flow signal at the side of anastomosis were detected on a patient 16 months after free composite transfer. Gross macroscopic remodeling and histopathologic analysis of a retrieved composite also indicated good healing with surrounding tissues and living cells in the composite. The complications and oncologic outcomes were comparable between study and control cohorts, but better Musculoskeletal Tumor Society (MSTS) score for patients reconstructed with composite (26.68 vs. 25.66, p  = 0.004). Of note, MSTS score was higher for patients reconstructed with composite at distal femur subdivision compared with the same subdivision in the control cohort (26.97 vs. 25.90, p  = 0.009). No statically significant difference was noted in complications, oncologic, and functional outcomes for patients reconstructed with free or vascularized composite. CONCLUSION: Autogenous menisci-cruciate ligament composite is an alternative option for soft tissue reconstruction. Either vascularized or free composite can be applied, depending on the size and localization of the defect.

Preoperative denosumab treatment in patients with giant cell bone tumors in limbs: A retrospective study using propensity score matching.

BACKGROUND AND OBJECTIVES: Denosumab is recommended for advanced giant cell tumor of bone (GCTB) that is unresectable or resectable with unacceptable morbidity. But the effect of preoperative denosumab treatment on the local control GCTB remains controversial. METHODS: We conducted a study of 49 patients with GCTB in the limbs treated with denosumab before surgery and 125 patients without in our hospital from 2010 to 2017. Propensity-score matching (PSM) at a 1:1 ratio between the denosumab and control groups was performed to minimize possible selection bias, and compared the recurrence rate, limb function, and surgical degradation between the two groups. RESULTS: The 3-year recurrence rates in the denosumab group and the control group were 20.4% and 22.9% after PSM, respectively (p = 0.702). In the denosumab group, 75.5% (n = 37/49) of patients experienced surgical downgrading. Limb joint preservation rates were 92.1% (35) for 38 patients treated with denosumab and 60.2% (71) for 118 control subjects. (p ≺ 0.001). Postoperative MSTS were higher in patients in the denosumab group than in the control group (24.1 vs. 22.6, p = 0.034). CONCLUSIONS: Preoperative denosumab treatment did not result in an increased risk of local recurrence of GCTB. Patients with advanced GCTB may benefit from preoperative denosumab treatment for surgical downgrading and the preservation of the joint.

Is there really no benefit of vertebroplasty for osteoporotic vertebral fractures? A meta-analysis.

BACKGROUND: Osteoporotic vertebral compressed fractures (VCFs) are the most common osteoporotic fractures. Although percutaneous vertebroplasty (PVP) reportedly relieves pain and improves function, a recent pooled analysis from two multicenter randomized controlled trials concluded the improvement in pain and disability treated with PVP was similar to those with sham surgery. QUESTIONS/PURPOSE: Using meta-analysis we therefore asked whether compared with either nonoperative therapy or a sham injection for patients with VCF, PVP would (1) better relieve pain, (2) provide greater improvement in pain-related disability, and (3) increase the recurrence of vertebral fractures. METHODS: We searched PubMed, EMBASE, Medline, and the Cochrane library using the keywords "vertebroplasty AND osteoporosis OR fracture". We included nine of the 469 articles identified. Using a random effects model, we calculated the weighted mean differences to evaluate the pain reduction at different times as the primary outcome. Pain-related disability was assessed by a quality of life (QOL) measure. Improvement of QOL and recurrence of vertebral fractures were the secondary outcomes. We used subgroup analysis to reinvestigate pain relief and function improvement of PVP based on two different controls: nonoperative therapy and sham injection. The total number of patients was 886. RESULTS: Pain scoring was similar between the PVP group and the sham injection group at 1 to 29 days and 90 days. However, compared with nonoperative therapy, PVP reduced pain at all times studied. QOL in the PVP group was improved or tended to be improved compared with QOL for both control groups. The risk of new fractures was similar between the PVP groups and both control groups. CONCLUSIONS: Different control groups may have accounted for the different conclusions in the literature regarding the ability of PVP to relieve pain and restore function recovery. Compared with nonoperative treatment PVP relieved pain better and improved QOL. PVP did not increase the risk of new fractures. LEVEL OF EVIDENCE: Level II, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.

The hexosamine biosynthesis pathway-related gene signature correlates with immune infiltration and predicts prognosis of patients with osteosarcoma.

Objectives: Osteosarcoma is a malignant bone tumor with poor outcomes affecting the adolescents and elderly. In this study, we comprehensively assessed the metabolic characteristics of osteosarcoma patients and constructed a hexosamine biosynthesis pathway (HBP)-based risk score model to predict the prognosis and tumor immune infiltration in patients with osteosarcoma. Methods: Gene expression matrices of osteosarcoma were downloaded from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) and Gene Expression Omnibus (GEO) databases. GSVA and univariate Cox regression analysis were performed to screen the metabolic features associated with prognoses. LASSO regression analysis was conducted to construct the metabolism-related risk model. Differentially expressed genes (DEGs) were identified and enrichment analysis was performed based on the risk model. CIBERSORT and ESTIMATE algorithms were executed to evaluate the characteristics of tumor immune infiltration. Comparative analyses for immune checkpoints were performed and the Tumor Immune Dysfunction and Exclusion (TIDE) algorithm was used to predict immunotherapeutic response. Finally, hub genes with good prognostic value were comprehensive analyzed including drug sensitivity screening and immunohistochemistry (IHC) experiments. Results: Through GSVA and survival analysis, the HBP pathway was identified as the significant prognostic related metabolism feature. Five genes in the HBP pathway including GPI, PGM3, UAP1, OGT and MGEA5 were used to construct the HBP-related risk model. Subsequent DEGs and enrichment analyses showed a strong correlation with immunity. Further, CIBERSORT and ESTIMATE algorithms showed differential immune infiltration characteristics correlated with the HBP-related risk model. TIDE algorithms and immune checkpoint analyses suggested poor immunotherapeutic responses with low expression of immune checkpoints in the high-risk group. Further analysis revealed that the UAP1 gene can predict metastasis. IHC experiments suggested that UAP1 expression correlated significantly with the prognosis and metastasis of osteosarcoma patients. When screening for drug sensitivity, high UAP1 expression was suggestive of great sensitivity to antineoplastic drugs including cobimetinib and selumetinib. Conclusion: We constructed an HBP-related gene signature containing five key genes (GPI, PGM3, UAP1, OGT, MGEA5) which showed a remarkable prognostic value for predicting prognosis and can guide immunotherapy and targeted therapy for osteosarcoma.

Experience with periprosthetic infection after limb salvage surgery for patients with osteosarcoma.

BACKGROUND: The rate of postoperative infection developing is higher after limb salvage surgery (LSS) following sarcoma resection compared with conventional arthroplasty. The goal of this study is to summarize our experience in management of periprosthetic joint infection (PJI) and the risk factors of early PJI after LSS. METHODS: Between January 2010 and July 2019, 53 patients with osteosarcoma in the lower extremities who encountered periprosthetic infection after segmental tumor endoprosthetic replacement in our center were analyzed. Detailed patient characteristics and therapeutic information were collected from database of our institution or follow-up data and we divided patients according to the interval time between infection and tumor resection (surgery-infection interval) and investigate potential risk factors. RESULTS: A total of 53 (5.08%) patients were suffered postoperative infection. The average interval between surgery and clinical signs of deep infections are 27.5 days. For the drainage culture, positive results were only presented in 11 patients (20.8%). Almost half of this study's (47.2%) patients underwent a traditional two-stage revision, that was, after the removal of the infected prosthesis, we applied antibiotic-loaded bone cements as a spacer. The mean blood loss during initial implantation surgery and operation time both correlated with interval period between PJI and initial implantation significantly (P = 0.028, P = 0.046). For several patients which infection marker was hardly back to normal after spacer implantation, we conservatively introduced an improved combination of bone cement and prosthesis for the second-stage surgery (5.6%). There were six patients needing re-operation, of which three were due to the aseptic loosening of the prosthesis, one developed periprosthetic infection again, and two patients encountered local recurrence and underwent amputation. Two patients were dead from distal metastasis. CONCLUSIONS: A two-stage revision strategy remains effective and standardized methods for PJI patients. Total operation time and blood loss during LSS of osteosarcoma are the main risk factors of early PJI. For the patients without confirmed eradiation of microorganisms, an improved combination of bone cement and prosthesis applied in the second-stage surgery could achieve satisfied functional and oncologic results.

Establishment and characterization of a highly metastatic human osteosarcoma cell line from osteosarcoma lung metastases.

OS (Osteosarcoma) is the most common malignant tumor in adolescents, and lung metastasis limits its therapeutic outcome. The present study aimed to establish a highly metastatic human OS cell line directly from lung metastases and characterize its biological functions. In this study, epithelioid tumor cells with large nucleo-cytoplasmic ratio and abundant organelles were obtained by the tissue mass adherent and repeated digestion adherent method and named ZOSL-1 cells. ZOSL-1 cells had the potential to proliferate in vitro with a doubling time of 39.28 ± 3.04 h and migrate with or without a matrix. ZOSL-1 cells were tumorigenic in vivo, and had the ability to develop lung metastasis after intratibial injection. ZOSL-1 cells expressed the osteogenic-related genes osteocalcin and osteopontin. In addition, the expression of ZOSL-1 in Fas cell surface death receptor (FAS), CD44 molecule (CD44), GNAS complex locus (GNAS), scavenger receptor class B member 1 (SCARB1), C-X-C motif chemokine receptor 4 (CXCR4), cadherin 11 (CDH11), neurofibromin 2 (NF2) and ezrin (EZR) genes may be related to its transfer efficiency. Taken together, these results indicated the high metastatic capability and important biological functions of ZOSL-1 cells. ZOSL-1 establishment provided a relevant model for the study of osteosarcoma lung metastasis.