Prognostic and predictive value of super-enhancer-derived signatures for survival and lung metastasis in osteosarcoma.

BACKGROUND: Risk stratification and personalized care are crucial in managing osteosarcoma due to its complexity and heterogeneity. However, current prognostic prediction using clinical variables has limited accuracy. Thus, this study aimed to explore potential molecular biomarkers to improve prognostic assessment. METHODS: High-throughput inhibitor screening of 150 compounds with broad targeting properties was performed and indicated a direction towards super-enhancers (SEs). Bulk RNA-seq, scRNA-seq, and immunohistochemistry (IHC) were used to investigate SE-associated gene expression profiles in osteosarcoma cells and patient tissue specimens. Data of 212 osteosarcoma patients who received standard treatment were collected and randomized into training and validation groups for retrospective analysis. Prognostic signatures and nomograms for overall survival (OS) and lung metastasis-free survival (LMFS) were developed using Cox regression analyses. The discriminatory power, calibration, and clinical value of nomograms were evaluated. RESULTS: High-throughput inhibitor screening showed that SEs significantly contribute to the oncogenic transcriptional output in osteosarcoma. Based on this finding, focus was given to 10 SE-associated genes with distinct characteristics and potential oncogenic function. With multi-omics approaches, the hyperexpression of these genes was observed in tumor cell subclusters of patient specimens, which were consistently correlated with poor outcomes and rapid metastasis, and the majority of these identified SE-associated genes were confirmed as independent risk factors for poor outcomes. Two molecular signatures were then developed to predict survival and occurrence of lung metastasis: the SE-derived OS-signature (comprising LACTB, CEP55, SRSF3, TCF7L2, and FOXP1) and the SE-derived LMFS-signature (comprising SRSF3, TCF7L2, FOXP1, and APOLD1). Both signatures significantly improved prognostic accuracy beyond conventional clinical factors. CONCLUSIONS: Oncogenic transcription driven by SEs exhibit strong associations with osteosarcoma outcomes. The SE-derived signatures developed in this study hold promise as prognostic biomarkers for predicting OS and LMFS in patients undergoing standard treatments. Integrative prognostic models that combine conventional clinical factors with these SE-derived signatures demonstrate substantially improved accuracy, and have the potential to facilitate patient counseling and individualized management.

A novel limb-salvage reconstruction strategy with a custom hemipelvic endoprosthesis and preserved femoral head following the resection of periacetabular tumors: A preliminary study.

The treatment of periacetabular malignancy frequently challenges surgeons. To simplify the surgical procedure, we performed a novel reconstruction strategy preserving the femoral head for patients with periacetabular malignancies. We retrospectively reviewed 14 patients who underwent total en bloc resection of a periacetabular tumor and reconstruction of the hip joint with an individualized hemipelvic endoprosthesis and remaining femoral head from July 2015 to January 2019 at our center. Regions of pelvic resection: region II-4 (28.6%), region I + II-5 (35.7%), region II + III-2 (14.3%) and region I + II + III-3 (21.4%). The oncological outcomes were that 13 patients survived without disease and one patient survived with lung metastasis. None of the patients experienced local recurrence (range: 20-62 months; mean: 32 months). The incidence of postoperative complications was 35.7%, including delayed wound healing and deep venous thrombosis. No prosthesis-related complications occurred until the last follow-up in this study (range: 20-62 months; mean: 32 months). The mean Musculoskeletal Tumor Society functional outcome score was 23.2. The mean Toronto Extremity Salvage Score of the patients was 75.7 points, with a mean limb discrepancy of 1.51 cm (range: 0.5-3.2 cm). Reconstruction with preservation of the femoral head showed acceptable early functional and oncological outcomes, and it had an acceptable complication rate.

Minimally invasive direct anterior approach versus standard lateral approach in the management of tumors of the femoral neck.

BACKGROUND: To compare the clinical outcomes of patients with benign or aggressive tumors of the femoral neck who underwent surgical curettage with the use of the direct anterior approach (DAA) and a standard lateral approach. METHODS: Those patients from 2010 to 2017 were retrospectively enrolled. The patients were divided into two groups: group A, consisting of patients who had undergone surgery via the lateral approach; and group B, consisting of patients who had undergone the same procedure via the DAA. RESULTS: Fifty-eight patients were divided into group A (n = 46) and group B (n = 12). The median follow-up was 43 months (15-97 months). There was no significant difference in the 1-year and 3-year recurrence rates (p = 0.74). Group B had comparable operation time and a significantly shorter incision length, less intraoperative blood loss, less postoperative drainage, a shorter hospital stay and less pain on the first postoperative day. Group B also had better hip function as assessed by the Harris Hip Score one month and one year postoperatively. One patient in group B experienced intraoperative incomplete fracture of the femoral neck, which was treated conservatively. CONCLUSIONS: Surgical curettage for patients with benign or aggressive tumors of the femoral neck via the DAA had a comparable local control rate and a better perioperative and functional outcome than via the lateral approach. Certain quality of the femoral neck should be required to avoid pathological fracture, which is difficult to treat by internal fixation in the DAA.

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.

Reconstruction with a novel combined hemipelvic endoprosthesis after resection of periacetabular tumors involving the sacroiliac joint: a report of 25 consecutive cases.

BACKGROUND: Our purpose was to examine the outcomes of patients who underwent extensive resection of periacetabular tumors involving the sacroiliac joint and joint reconstruction with a hemipelvic endoprosthesis. METHODS: The records of 25 consecutive patients diagnosed with Enneking type I/II/IV pelvic tumors from 2010 to 2016 who received resection and hemipelvic endoprosthesis reconstruction were retrospectively reviewed. RESULTS: The median follow-up period was 48 months. At the most recent follow-up, 11 patients were alive, with estimated 3- and 5-year survival rates of 45.6 and 38.0%, respectively. Fourteen patients died, with a mean survival of 20.8 months, and 8 patients had local recurrence at an average of 9.3 months after surgery. Distal metastases were detected in 11 patients at an average of 11.0 months after surgery. The total complication rate was 56.0%, and the most common complications were wound healing disturbances (28.0%) and deep infections (16.0%). The prosthesis-related complication rate was 24.0%; periprosthetic infections and aseptic loosening were most common. The estimated 1- and 3-year prosthesis survival rates were 81.2 and 63.2%, respectively. The mean Musculoskeletal Tumor Society score was 48.0%. Function and prosthesis-related complications did not differ significantly after adding an extra screw fixation to the first sacral vertebra. CONCLUSIONS: Reconstruction with the hemipelvic endoprosthesis described herein provides satisfactory function with a relatively low complication rate. Adding an extra screw fixation to the first sacral vertebra was not associated with any improvement in the clinical results after short-term follow-up. Improvement and further studies of this endoprosthesis are needed.

Comparison of clinical features, management and outcomes of osteosarcoma located in proximal fibula and proximal tibia: a propensity score matching analysis.

BACKGROUND: The aim of this study was to compare proximal fibular and proximal tibial sites regarding osteosarcoma in the proximal crus. Furthermore, we proposed a hypothesis explaining the differences. METHODS: From Jaunary 2000 to February 2015, 28 patients with non-metastatic proximal fibular osteosarcoma and 214 patients with non-metastatic proximal tibial osteosarcoma underwent surgery were identified in our center. All clinical data were analyzed retrospectively. Propensity score matching of patients in a 1:2 ratio was conducted based on age, gender and Enneking stage. To analyze possible factors resulting in amputation, we investigated extraosseous tumor volumes (ETVS), the nearest of the blood vessel to reactive zone (NBR) and the nearest of the blood vessel to tumor (NBT). RESULTS: Amputation rates were higher in the proximal fibula cohort (35.7%) than in the proximal tibia cohort (14.3%; p = 0.046). Comparing possible clinical characteristics related with amputation between two cohorts, the proximal fibula cohort had larger ETVS (p = 0.000). Moreover, the proximal fibula cohort had a smaller NBT for anterior tibial vessels (p = 0.025), a smaller NBR for posterior tibial vessels (p = 0.013) and a smaller NBT for posterior tibial vessels (p = 0.007) than the proximal tibia cohort. Univarite and multivariable analyses showed that NBT for posterior tibial vessels was the only independent factor associated with amputation. The 3-year event-free survival (EFS) and overall survival (OS) rates for the proximal fibula cohort vs. the proximal tibia cohort were 52.6% vs. 78.0% (p = 0.045) and 63.7% vs. 81.2% (p = 0.177), respectively. The MSTS scores for the functional evaluation of limb-salvaging surgery were similar in both groups (p = 0.212). CONCLUSIONS: Amputation rates among patients were higher when osteosarcoma was located in proximal fibula than in proximal tibia. A smaller NBT for posterior tibial vessels was associated with higher amputation rates. Prognosis of the proximal fibula cohort was poorer than that of the proximal tibia cohort of osteosarcoma patients.

Predictive value of dynamic change of haemoglobin levels during therapy on treatment outcomes in patients with Enneking stage IIB extremity osteosarcoma.

BACKGROUND: We aimed to investigate the roles of hemoglobin (Hb) concentrations and dynamic change during treatment on outcomes of patients with extremity osteosarcoma. METHODS: We retrospectively analysed 133 patients with Enneking stage IIB extremity osteosarcoma who underwent standard treatments, including univariate and multivariate analyses of patient charateritics, Hb concentrations and changes during pretreatment, neoadjuvant, adjuvant chemotherapy, and decreased Hb levels (ΔHb) to assess their prognostic value in 5-year overall survival (OS) and lung metastasis-free survival (LMFS). RESULTS: Five-year OS or LMFS were similar between patients who were anaemic and non-anaemic during pretreatment, neoadjuvant or adjuvant chemotherapy. Patients with continuously decreasing Hb had lower 5-year OS (52.3%) than those without continuous Hb decrease (68.5%, P = 0.04). Patients with ΔHb > 7.6 g/L had lower 5-year OS (57.5%) than those with ΔHb ≤7.6 g/L (75.8%, P = 0.04). However, continuous Hb decrease had no prognostic effect on 5-year LMFS. Subgroup analyses showed that patients who were anaemic during pretreatment, neoadjuvant, or adjuvant chemotherapy with ΔHb ≤7.6 g/L had better outcomes than those with ΔHb > 7.6 g/L (P < 0.05, for both). CONCLUSION: Dynamic Hb decrease and ΔHb > 7.6 predicted poor5-year OS in patients with Enneking stage IIB extremity osteosarcoma. Attempts to correct anaemia and their effects on outcomes for osteosarcoma patients should be investigated in future trials.

Robot-assisted sacral tumor resection: a preliminary study.

BACKGROUND: Few studies have been done on robot-assisted sacral surgery. This study aims to evaluate the outcomes of seven patients with benign sacral or presacral tumors treated with a robotic surgical system at a single center. METHODS: All patients with benign sacral or presacral tumors who underwent transperitoneal resection (between June 2015 and June 2016) using the da Vinci Si HD robotic surgical system (Intuitive Surgical Inc.) were included in this retrospective study. RESULTS: Seven patients with a mean age of 43.8 years (range: 22- 62 years) were included in this study. The operation time ranged from 60 to 335 min. Five out of these seven patients with presacral tumor underwent complete tumor resection by the da Vinci robotic surgical system, with a median blood loss of 52 ml. The other patients underwent excision of the presacral tumor by the da Vinci robotic surgical system, followed by a posterior approach, with a median blood loss of 675 ml. The histological diagnosis was schwannoma of the sacral nerve in five cases (71.5%). The other two cases were chordoma and solitary fibroma of the sacrum, respectively. No perioperative or postoperative complications were encountered. The average hospitalization stay was 5.7 days. No recurrences were found at follow-up 24 to 31 months later. CONCLUSION: Robot-assisted minimally invasive sacral surgery can provide precise dissection of the tissue under a perfect view. It is a technically feasible procedure that is associated with minimal blood loss, fewer injuries and short hospitalization. It is particularly suitable for presacral benign tumors.

Microarray Expression Profile and Functional Analysis of Circular RNAs in Osteosarcoma.

BACKGROUND/AIMS: Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents. However, the molecular mechanisms regulating osteosarcoma tumorigenesis and progression are still poorly understood. Circular RNAs (circRNAs) have been identified as microRNA sponges and are involved in many important biological processes. This study aims to investigate the global changes in the expression pattern of circRNAs in osteosarcoma and provide a comprehensive understanding of differentially expressed circRNAs. METHODS: Microarray based circRNA expression was determined in osteosarcoma cell lines and compared with hFOB1.19, which was used as the normal control. We confirmed the microarray data by real time-qPCR in both osteosarcoma cell lines and tissues. The circRNA/microRNA/mRNA interaction network was predicted using bioinformatics. Gene Ontology analysis and 4 annotation tools for pathway analysis (KEGG, Biocarta, PANTHER and Reactome) were used to predict the functions of differentially expressed circRNAs. RESULTS: We revealed a number of differentially expressed circRNAs and 12 of them were confirmed, which suggests a potential role of circRNAs in OS. Among these differentially expressed circRNAs, hsa_circRNA_103801 was up-regulated in both osteosarcoma cell lines and tissues, while hsa_circRNA_104980 was down-regulated. The most likely potential target miRNAs for hsa_circRNA_103801 include hsa-miR-370-3p, hsa-miR-338-3p and hsa-miR-877-3p, while the most potential target miRNAs of hsa_circRNA_104980 consist of hsa-miR-1298-3p and hsa-miR-660-3p. Functional analysis found that hsa_circRNA_103801 was involved in pathways in cancer, such as the HIF-1, VEGF and angiogenesis pathway, the Rap1 signaling pathway and the PI3K-Akt signaling pathway, while hsa_circRNA_104980 was related to some pathways such as the tight junction pathway. CONCLUSIONS: This study has identified the comprehensive expression profile of circRNAs in osteosarcoma for the first time. And the ceRNA network prediction and bioinformatics functional analysis could provide a comprehensive understanding of hsa_circRNA_103801 and hsa_circRNA_104980, which may be involved in the initiation and progression of osteosarcoma. The present study indicates that circRNAs may play important roles in osteosarcoma and thus serve as biomarkers of osteosarcoma diagnosis and treatment.

A proposed classification system for guiding surgical strategy in cases of severe spinal deformity based on spinal cord function.

PURPOSE: Spinal cord function classification systems are not useful for guiding surgery in patients with severe spinal deformities. The aim of this study is to propose a classification system for determining a surgical strategy that minimizes the risk of neurological dysfunction in patients with severe spinal deformities. METHODS: The records of 89 patients with severe spinal deformities treated with vertebral column reconstruction from 2008 to 2013 were retrospectively analyzed. Based on neurophysiological monitoring, magnetic resonance imaging, and neurological symptoms patients were categorized into three groups: group A, normal spinal cord, normal evoked potentials and no neurological symptoms; group B, spinal cord abnormalities and/or abnormal evoked potentials but no neurological symptoms; group C, neurological symptoms with or without spinal cord abnormalities/abnormal evoked potentials. Outcomes and complications were compared between the groups. RESULTS: A total of 89 patients (51 male, 38 female) were included with 47 (52.8 %), 16 (18.0 %), and 26 (29.2 %) patients in groups A, B and C, respectively, and a mean follow-up 34.5 months. There were no differences in age, gender, average preoperative scoliosis, and kyphosis among three groups, but there were differences with respect to the causes of severe spinal deformity and the corrective rate of scoliosis and kyphosis. Changes in intraoperative evoked potentials were different in these three types according to this new classification, and the recovery rates of changes in the three groups were 71.1, 50.0, and 14.1 %, respectively. Postoperative spinal cord injury was positively related to intraoperative changes of evoked potentials. CONCLUSION: The classification system may be useful for guiding surgical decisions in patients with severe spinal deformities to minimize the risk of neurological complications.

Anti-inflammatory and antinociceptive activities of bufalin in rodents.

The aims of this study were to evaluate the anti-inflammatory and analgesic effects of bufalin, a major component of "Chan-su." We used a carrageenan-induced paw edema model to assess the anti-inflammatory activity of this compound, and Western blot analysis detected NF- κ B signaling during this effect. The antinociceptive activities were evaluated by acetic acid-induced writhing, formalin, and hot-plate tests; open-field test investigated effects on the central nervous system. Our data showed that bufalin (0.3 and 0.6 mg/kg, i.p.) potently decreased carrageenan-induced paw edema. Bufalin down regulated the expression levels of nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) during these treatments. Further studies demonstrated that bufalin significantly inhibited the activation of NF-κB signaling. Bufalin also reduced acetic acid-induced writhing and the licking time in the formalin test and increased hot-plate reaction latencies. Naloxone pretreatment (2 mg/kg, i.p.) in the early phases of the formalin test and hot-plate test significantly attenuated the bufalin-induced antinociception effects, which suggests the involvement of the opioid system. A reduction in locomotion was not observed in the open-field test after bufalin administration. Taken together, bufalin treatment resulted in in vivo anti-inflammatory and analgesic effects, and bufalin may be a novel, potential drug for the treatment of inflammatory diseases.

Local control of giant cell tumors of the long bone after aggressive curettage with and without bone cement.

BACKGROUND: Aggressive curettage has been well established for the treatment of giant cell tumors (GCTs) of the bone. The purpose of this study was to review our experience and evaluate the role of different implant materials in patients with GCTs of the extremities after aggressive curettage. METHODS: A total of 119 patients with GCTs of the long bone were treated at the First Affiliated Hospital of Sun Yat-Sen University between 2004 and 2009. We excluded patients presenting metastases, recurrent tumors, and soft tissue involvement and those with Jaffe pathological grade III. The remaining 65 patients were treated with aggressive curettage using a bone graft or bone cement to fill the cavity. The recurrence rates and functional scores associated with the different fillings were analyzed. RESULTS: Aggressive curettage and bone grafting was performed in 34 cases (52.3%), and aggressive curettage with bone cement was performed in 31 cases (47.7%). The overall recurrence rate after the aggressive intralesional procedures was 35.3% with bone grafting and 12.9% when bone cement was used as an adjuvant filling. The recurrence rate following aggressive curettage and bone grafting was higher than that following aggressive curettage with cement (p = 0.038). The Musculoskeletal Tumor Society (MSTS) score for bone graft patients was 91.1%, which was significantly lower than that for patients treated with bone cement (94.7%). CONCLUSIONS: The use of bone cement was associated with a significantly lower recurrence rate than bone grafting following aggressive intralesional curettage to treat benign giant cell tumors of the long bone. Better MSTS functional results were also observed in the bone cement group compared to the bone graft group.

[Proteomics research of bufalin-induced apoptosis in osteosarcoma cell lines].

OBJECTIVE: To study the apoptosis inducing effects of bufalin on various human osteosarcoma cells and the concerning molecular mechanisms. METHOD: MTT assay was used to detect the growth inhibition rates of osteosarcoma cells U-20S, U-20S/MTX300, SaOS-2, IOR/OS9 treated with bufalin in different concentrations and times. The apoptosis of cells was observed flow cytometry 48 h following bufalin treatment. The proteomic techniques were used to separate and compare the treated and control groups 48 h after bufalin-incubation. Then, the proteomic results were validated by western blot. RESULT: Bufalin inhibited the growth of human osteosarcoma cells U20S, U20S/MTX300 (methotrexate resistant cells), SAOS2, IOR/OS9 in a dose- and time-dependent manner. The 72 h IC50 were (37.43 +/- 4.1), (32.24 +/- 5.3) nmol x L(-1) in U20S,U20S/MTX300 cells,respectivly. Flow cytometry showed that the apoptosis cells were increased following bufalin treatment. The protein expression profile showed 24 differentiated expression proteins. Among these proteins, the level of an anti-apoptotic protein, heat shock protein 27 (Hsp27) decreased significantly and the result was then validated by western blot. Ectopic expression of Hsp27 could reduce the bufalin-induced apoptosis remarkably in U20S and U20S/MTX300 cells. CONCLUSION: Bufalin could inhibit the cell growth and induce apoptosis on human osteosarcoma cells. The effect of bufalin may be related to the joint intervention with multiple protein targets. Among them, downregulation of Hsp27 plays a critical role in the bufalin-induced apoptosis in human osteosarcoma cells.

Hybrid gelatin-ascorbyl phosphate scaffolds accelerate diabetic wound healing via ROS scavenging, angiogenesis and collagen remodeling.

Skin wound healing, particularly diabetic wound healing, is challenging in clinical management. Impaired wound healing is associated with persistent oxidative stress, altered inflammatory responses, unsatisfactory angiogenesis and epithelialization. Magnesium ascorbyl phosphate (MAP), which is an ascorbic acid derivative and active ingredient in cosmetics, has been reported to scavenge reactive oxygen species (ROS), and is considered a potential therapeutic agent for diabetic wounds. Herein, we report a hybrid gelatin-MAP scaffolds that can reduces oxidative stress damage, enhances angiogenesis and collagen remodeling to accelerate diabetic wound repair. Preliminary insights based on network pharmacology indicate that MAP may accelerate wound repair through multiple biological pathways, including extracellular matrix remodeling and anti-apoptosis. In vitro studies showed that the hybrid hydrogel scaffold had suitable mechanical properties, excellent biocompatibility and bioactivity. Further animal experiments demonstrated that the hydrogel accelerated full-thickness wound repair in diabetic mice (repair rate MAP vs Control=91.791±3.306 % vs 62.962±6.758 %) through antioxidant, neuroangiogenesis, collagen remodeling, and up-regulated the expression of the related factors COL-1, CD31, VEGF, and CGRP. Overall, we developed a bioactive hybrid hydrogel encapsulating MAP that synergistically promotes diabetic wound repair through multiple biological effects. This potentially integrated therapeutic scaffold may enrich future surgical approaches for treating diabetic wounds.

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.

The survival and complication profiles of the Compress® Endoprosthesis: A systematic review and meta-analysis.

Background/purpose: This study aimed to summarize the survival and complication profiles of the compress® endoprosthesis (CPS) through a systematic review and meta-analysis. Methods: Online databases (PubMed, EMBASE and Web of Science) were searched from inception to November 2023. Trials were included that involved the use of CPS for endoprosthetic replacement in patients with massive segmental bone defects. Patients' clinical characteristics and demographic data were extracted using a standardized form. The methodological quality of included 13 non-comparative studies was assessed on basis of the Methodological Index for Non-Randomized Studies (MINORS). All the available Kaplan-Meier curves in the included studies were digitized and combined using Engauge-Digitizer software and the R Project for Statistical Computing. Results: The meta-analysis of thirteen included studies indicated: the all-cause failure rates of CPS were 26.3 % after surgery, in which the occurrence rates of aseptic loosening were 5.8 %. And the incidences of other complications were as follows: soft tissue failure (1.8 %), structure failure (8.2 %), infection (9.5 %), tumor progression (1.1 %). The 1-, 4-, and 8-year overall survival rates for all-cause failure with 95 % CI were 89 % (86 %-92 %), 75 % (71 %-79 %) and 65 % (60 %-70 %), respectively. The estimated mean survival time of all-cause failure was 145 months (95 % CI, 127-148 months), and the estimated median survival time of all-cause failure was 187 months (95 % CI, 135-198 months). The 1-, 4-, and 8-year overall survival rates of aseptic loosening with 95 % CI were 96 % (94 %-98 %), 91 % (87 %-95 %) and 88 % (83 %-93 %), respectively. The estimated mean survival time of aseptic loosening was 148 months (95 % CI, 137-153 months). Conclusion: CPS's innovative spring system promotes bone ingrowth by providing immediate and high-compression fixation, thereby reducing the risk of aseptic loosening caused by stress shielding and particle-induced osteolysis. CPS requires less residual bone mass for reconstructing massive segmental bone defects and facilitates easier revision due to its non-cemented fixation. In addition, the survival rate, estimated mean survival time, and complication rates of CPS are not inferior to those of common endoprosthesis.

Tumor-informed deep sequencing of ctDNA detects minimal residual disease and predicts relapse in osteosarcoma.

Background: Current surveillance modalities of osteosarcoma relapse exhibit limited sensitivity and specificity. Although circulating tumor DNA (ctDNA) has been established as a biomarker of minimal residual disease (MRD) in many solid tumors, a sensitive ctDNA detection technique has not been thoroughly explored for longitudinal MRD detection in osteosarcoma. Methods: From August 2019 to June 2023, 59 patients diagnosed with osteosarcoma at the First Affiliated Hospital of Sun Yat-sen University were evaluated in this study. Tumor-informed MRD panels were developed through whole exome sequencing (WES) of tumor tissues. Longitudinal blood samples were collected during treatment and subjected to multiplex PCR-based next-generation sequencing (NGS). Kaplan-Meier curves and Log-rank tests were used to compare outcomes, and Cox regression analysis was performed to identify prognostic factors. Findings: WES analysis of 83 patients revealed substantial mutational heterogeneity, with non-recurrent mutated genes accounting for 58.1%. Tumor-informed MRD panels were successfully obtained for 85.5% of patients (71/83). Among 59 patients with successful MRD panel customization and available blood samples, 13 patients exhibited positive ctDNA detection after surgery. Patients with negative post-operative ctDNA had better event-free survival (EFS) compared to those with positive ctDNA, at 1-6 months after surgery, after adjuvant chemotherapy, and more than 6 months after surgery (p < 0.05). In both univariate and multivariate Cox regression analysis, ctDNA results emerged as a significant predictor of EFS (p < 0.05). ctDNA detection preceded positive imaging in 5 patients, with an average lead time of 92.6 days. Thirty-nine patients remained disease-free, with ctDNA results consistently negative or turning negative during follow-up. Interpretation: Our study underscores the applicability of tumor-informed deep sequencing of ctDNA in osteosarcoma MRD surveillance and, to our knowledge, represents the largest cohort to date. ctDNA detection is a significant prognostic factor, enabling the early identification of tumor relapse and progression compared to standard imaging, thus offering valuable insights in guiding osteosarcoma patient management. Funding: The Grants of National Natural Science Foundation of China (No. 82072964, 82072965, 82203798, 82203026), the Natural Science Foundation of Guangdong (No. 2023A1515012659, 2023A1515010302), and the Regional Combination Project of Basic and Applied Basic Research Foundation of Guangdong (No. 2020A1515110010).

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.

Therapeutic Copolymer from Salicylic Acid and l-Phenylalanine as a Nanosized Drug Carrier for Orthotopic Breast Cancer with Lung Metastasis.

Nanoparticle (NP)-mediated drug delivery systems are promising for treating various diseases. However, clinical translation has been delayed by a variety of limitations, such as weak drug loading, nonspecific drug leakage, lack of bioactivity, and short blood circulation. These issues are in part due to the unsatisfactory function of biomaterials for nanocarriers. In addition, the synthesis procedures of drug carrier materials, especially polymers, were usually complicated and led to high cost. In this report, a bioactive copolymer of hydroxy acid and amino acid, poly(salicylic acid-co-phenylalanine) (PSP), was developed for the first time via a one-step rapid and facile synthesis strategy. The PSP could self-assemble into NPs (PSP-NPs) to co-load relatively hydrophilic sphingosine kinase 1 inhibitor (PF543 in HCl salt format) and highly hydrophobic paclitaxel (PTX) to form PF543/PTX@PSP-NPs with efficient dual drug loading. Encouragingly, PF543/PTX@PSP-NPs showed long blood circulation, good stability, and high tumor accumulation, leading to significantly enhanced therapeutic effects on breast cancer. Furthermore, PF543/PTX@PSP-NPs could additionally suppress the lung metastasis of breast cancer, and more importantly, the PSP-NPs themselves as therapeutic nanocarriers also showed an anti-breast cancer effect. With these combined advantages, this new polymer and corresponding NPs will provide valuable insights into the development of new functional polymers and nanomedicines for important diseases.

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.