Comparison of oncological and functional outcomes in Lower-limb osteosarcoma pediatric patient : 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), Progression-Free Survival rate (PFS), and prosthesis survival rate were assessed using Kaplan-Meier curves, Non-parametric 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 to 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 to 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.

Network pharmacology and experimental verification-based strategy for exploring the mechanisms of luteolin in the treatment of osteosarcoma.

BACKGROUND: Luteolin is an active ingredient in various traditional Chinese medicines for the treatment of multiple tumors. However, the mechanisms of its inhibitory effect on osteosarcoma proliferation and metastasis remain unclear. PURPOSE: To elucidate the anti-osteosarcoma mechanisms of luteolin based on network pharmacology and experimental verification. STUDY DESIGN: Integrate network pharmacology predictions, scRNA-seq analysis, molecular docking, and experimental validation. METHODS: Luteolin-related targets and osteosarcoma-associated targets were collected from several public databases. The luteolin against osteosarcoma targets were screened and a PPI network was constructed to identify the hub targets. The GO and KEGG enrichment of osteosarcoma-associated targets and luteolin against osteosarcoma targets were performed. And scRNA-seq analysis was performed to determine the distribution of the core target expression in OS tissues. Molecular docking, cell biological assays, and osteosarcoma orthotopic mouse model was performed to validate the inhibitory effect and mechanisms of luteolin on osteosarcoma proliferation and metastasis. RESULTS: Network pharmacology showed that 251 luteolin against osteosarcoma targets and 8 hub targets including AKT1, ALB, CASP3, IL6, JUN, STAT3, TNF, and VEGFA, and the PI3K-AKT signaling pathway might play an important role in anti-osteosarcoma of luteolin. Analysis of public data revealed that AKT1, IL6, JUN, STAT3, TNF, and VEGFA expression in OS tissue was significantly higher than that in normal bones, and the diagnostic value of VEGFA for overall survival and metastasis was increased over time. scRNA-seq analysis revealed significantly higher expression of AKT1, STAT3, and VEGFA in MYC+ osteoblastic OS cells, especially in primary samples. Moreover, the docking activity between luteolin and the hub targets was excellent, as verified by molecular docking. Experimental results showed that luteolin could inhibit cell viability and significantly decrease the expression of AKT1, STAT3, IL6, TNF, and VEGFA, and luteolin could also inhibit osteosarcoma proliferation and metastasis in osteosarcoma orthotopic mouse model. CONCLUSION: This study shows that luteolin may regulate multiple signaling pathways by targeting various genes like AKT1, STAT3, IL6, TNF, and VEGFA to inhibit osteosarcoma proliferation and metastasis.

Super-enhancer-driven MLX mediates redox balance maintenance via SLC7A11 in osteosarcoma.

Osteosarcoma (OS) is a common type of bone tumor for which there has been limited therapeutic progress over the past three decades. The prevalence of transcriptional addiction in cancer cells emphasizes the biological significance and clinical relevance of super-enhancers. In this study, we found that Max-like protein X (MLX), a member of the Myc-MLX network, is driven by super-enhancers. Upregulation of MLX predicts a poor prognosis in osteosarcoma. Knockdown of MLX impairs growth and metastasis of osteosarcoma in vivo and in vitro. Transcriptomic sequencing has revealed that MLX is involved in various metabolic pathways (e.g., lipid metabolism) and can induce metabolic reprogramming. Furthermore, knockdown of MLX results in disturbed transport and storage of ferrous iron, leading to an increase in the level of cellular ferrous iron and subsequent induction of ferroptosis. Mechanistically, MLX regulates the glutamate/cystine antiporter SLC7A11 to promote extracellular cysteine uptake required for the biosynthesis of the essential antioxidant GSH, thereby detoxifying reactive oxygen species (ROS) and maintaining the redox balance of osteosarcoma cells. Importantly, sulfasalazine, an FDA-approved anti-inflammatory drug, can inhibit SLC7A11, disrupt redox balance, and induce massive ferroptosis, leading to impaired tumor growth in vivo. Taken together, this study reveals a novel mechanism in which super-enhancer-driven MLX positively regulates SLC7A11 to meet the alleviated demand for cystine and maintain the redox balance, highlighting the feasibility and clinical promise of targeting SLC7A11 in osteosarcoma.

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.

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.

Single-cell transcriptome analysis reveals T-cell exhaustion in denosumab-treated giant cell tumor of bone.

Denosumab (DMAB), a human monoclonal antibody against the receptor activator of the nuclear factor-kappa B ligand, is used for the treatment for unresectable giant cell tumor of bone (GCTB). However, little is known about the molecular and functional characteristics of GCTB-infiltrating lymphocytes after DMAB treatment. Here, we performed single-cell RNA sequencing and immunostaining assays to delineate the immune landscape of GCTB in the presence and absence of DMAB. We found that exhausted CD8+ T cells were preferentially enriched in DMAB-treated GCTB. A distinct M2-skewed type of tumor-associated macrophages (TAMs) comprises the majority of GCTB TAMs. We identified cytokines, including interleukin-10, and inhibitory receptors of M2 TAMs as important mediators of CD8+ T cell exhaustion. We further revealed that DMAB treatment notably increased the expression levels of periostin (POSTN) in GCTB cells. Furthermore, POSTN expression was transcriptionally regulated by c-FOS signaling and correlated with GCTB recurrence in patients after DMAB treatment. Collectively, our findings reveal that CD8+ T-cells undergo unappreciated exhaustion during DMAB therapy and that GCTB cell-derived POSTN educates TAMs and establishes a microenvironmental niche that facilitates GCTB recurrence.

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.

Anticancer Activity of Sweroside Nanoparticles in Prostate Cancer Bone Metastasis in PC-3 Cells Involved in Wnt/ß-Catenin Signaling Pathway.

Bone metastasis is a significant cause of morbidity and mortality in patients with prostate cancer (PCa). This study is aimed at illustrating the mechanism of sweroside-mediated regulation in bone metastasis in PCa cells. Owing to the limitations of antitumor drugs in terms of their physical and chemical properties, making them into nanomaterials can effectively improve drug stability and bioavailability. Apoptosis was assessed with flow cytometry using the annexin V/propidium iodide binding assay; proteins, including p53, P21, Bcl-2, and Bax; and induction of intracellular reactive oxygen species (ROS). Using colony formation assay, sphere formation assay, and the expression changes in CD133 and CD44, stem cell characteristics were assessed. Epithelial-mesenchymal transition (EMT) activity was accessed by levels of the expression changes of EMT-related markers, vimentin and E-cadherin. Wnt/ß-catenin signaling pathway was examined to detect the levels of the expression changes of snail and ß-catenin. PC-3 cells were treated with lithium chloride (LiCl), which is an agonist of Wnt/ß-catenin signaling, and the levels of CD133, CD44, vimentin, E-cadherin, snail, and ß-catenin were detected. T-cell factor/lymphocyte enhancer factor (TCF/LEF) activity in cells overexpressing ß-catenin was used to detect the effects on ß-catenin transcription, and the expression of c-myc, Cyclin D1, Survivin, and MMP-7 were used to detect Wnt downstream target genes. Our results suggest that sweroside induces apoptosis and intracellular ROS; upregulates apoptotic proteins; and suppresses proliferation, invasion, and migration, preventing stem cell characteristics, including sphere formation, colony formation, and CD133 and CD44 expressions. Furthermore, sweroside nanoparticles exerts inhibitory effects on ß-catenin transcription by suppressing TTCF/LEF activity in cells overexpressing ß-catenin and downregulation of the expression of Wnt downstream target genes, including c-myc, Cyclin D1, Survivin, and MMP-7. The potential therapeutic effect of sweroside nanoparticles on bone metastatis of PCa was suggested, by these findings.

Pharmacological Inhibition of Core Regulatory Circuitry Liquid-liquid Phase Separation Suppresses Metastasis and Chemoresistance in Osteosarcoma.

Liquid-liquid phase-separated (LLPS) transcriptional factor assemblies at super-enhancers (SEs) provide a conceptual framework for underlying transcriptional control in mammal cells. However, the mechanistic understanding of LLPS in aberrant transcription driven by dysregulation of SEs in human malignancies is still elusive. By integrating SE profiling and core regulatory circuitry (CRC) calling algorithm, the CRC of metastatic and chemo-resistant osteosarcoma is delineated. CRC components, HOXB8 and FOSL1, produce dense and dynamic phase-separated droplets in vitro and liquid-like puncta in cell nuclei. Disruption of CRC phase separation decreases the chromatin accessibility in SE regions and inhibits the release of RNA polymerase II from the promoter of SE-driven genes. Importantly, absence of CRC key component causes a reduction in osteosarcoma tumor growth and metastasis. Moreover, it is shown that CRC condensates can be specifically attenuated by the H3K27 demethylase inhibitor, GSK-J4. Pharmacological inhibition of the CRC phase separation results in metastasis suppression and re-sensitivity to chemotherapy drugs in patient-derived xenograft model. Taken together, this study reveals a previously unknown mechanism that CRC factors formed LLPS condensates, and provides a phase separation-based pharmacological strategy to target undruggable CRC components for the treatment of metastatic and chemo-resistant osteosarcoma.

A Novel Method to Treat Progressive Desmoid Tumors Involving Neurovascular Bundles: A Retrospective Cohort Study.

BACKGROUND: More effective therapies are needed to treat progressive desmoid tumors when active surveillance and systemic therapy fail. OBJECTIVE: To assess the efficacy and safety of sandwich isolation surgery on the local control of progressive desmoid tumors involving neurovascular bundles. METHODS: A total of 27 patients with progressive desmoid tumors at extremities involving neurovascular bundles who received surgery at our hospital between August 2014 and August 2018 were identified. A total of 13 patients received sandwich isolation surgery, in which R2 resection was performed in neurovasculature-involving regions, and a biomaterial patch was used to envelop involved neurovascular structures and isolate residual tumors. In non-neurovasculature-involving regions, wide resection was performed without isolation. A total of 14 patients received traditional surgery, which included tumor resection without isolation procedure. RESULTS: In sandwich isolation group, tumor progressions and local recurrences occurred in 3 patients outside the isolated neurovasculature-involving regions. However, no progressions or recurrences occurred in any patients in the isolated neurovasculature-involving regions where R2 resection was performed. Sandwich isolation surgery group and traditional surgery group shared similar baseline clinical characteristics. The estimated 3-yr event-free survival rate was 76.9% after sandwich isolation surgery, and 32.7% after traditional surgery (P = .025). Patients who received sandwich isolation surgery were less likely to have local recurrence (hazard ratio: 0.257, P = .040). No complications were noted except intermittent mild pain in operative regions (2 cases). CONCLUSION: Sandwich isolation surgery is effective and safe for local control of desmoid tumors involving neurovascular bundles.

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.

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.

Discontinuous polyostotic fibrous dysplasia with multiple systemic disorders and unique genetic mutations: A case report.

BACKGROUND: Polyostotic fibrous dysplasia (PFD) is an uncommon developmental bone disease in which normal bone and marrow are replaced by pseudotumoral tissue. The etiology of PFD is unclear, but it is generally thought to be caused by sporadic, post-zygotic mutations in the GNAS gene. Herein, we report the case of a young female with bone pain and lesions consistent with PFD, unique physical findings, and gene mutations. CASE SUMMARY: A 27-year-old female presented with unbearable bone pain in her left foot for 4 years. Multiple bone lesions were detected by radiographic examinations, and a diagnosis of PFD was made after a biopsy of her left calcaneus with symptoms including pre-axial polydactyly on her left hand and severe ophthalmological problems such as high myopia, vitreous opacity, and choroidal atrophy. Her serum cortisol level was high, consistent with Cushing syndrome. Due to consanguineous marriage of her grandparents, boosted whole exome screening was performed to identify gene mutations. The results revealed mutations in HSPG2 and RIMS1, which may be contributing factors to her unique findings. CONCLUSION: The unique findings in this patient with PFD may be related to mutations in the HSPG2 and RIMS1 genes.

Overcoming therapeutic failure in osteosarcoma via Apatinib-encapsulated hydrophobic poly(ester amide) nanoparticles.

Anti-angiogenic tyrosine kinase inhibitors (TKIs) have been proved to be effective in prolonging progression-free survival in advanced osteosarcoma. However, osteosarcoma stem-like cells persist for a long time and ultimately cause disease recurrence and therapy resistance. Here, we reveal that inefficient accumulation of Apatinib, an anti-angiogenic TKI, induces the expression of ribosome-associated genes in osteosarcoma, and confers apoptosis resistance. An engineered nanoscale delivery system based on hydrophobic poly(ester amide) has been established to effectively deliver Apatinib to improve the treatment. Notably, the considerable uptake by osteosarcoma cells enables this nanodrug to distribute increasingly inside the tumor. Furthermore, the delivered nano-Apatinib can suppress osteosarcoma stemness and enhance osteosarcoma stem-like cell apoptosis, and overcomes the crucial bottleneck of the unfavorable stem-like cell residue for TKI therapy. Importantly, nano-Apatinib significantly inhibits the osteosarcoma stem-like cell-derived tumor growth in contrast with free Apatinib, with minimal side effects. These results suggest that this Apatinib-loaded nano delivery system may serve as a promising strategy to solve the issue of TKI therapeutic resistance existing in advanced osteosarcoma.

Nanoparticle enhanced combination therapy for stem-like progenitors defined by single-cell transcriptomics in chemotherapy-resistant osteosarcoma.

The adaptation of osteosarcoma cells to therapeutic pressure impedes the efficacy of chemotherapy for osteosarcoma. However, the characteristics and cellular organization of therapy-resistant cells in osteosarcoma tumors remain elusive. Here, we utilized single-cell transcriptomics to systematically map the cell-type-specific gene expression in a chemotherapy-resistant osteosarcoma tumor. Our data demonstrated the VEGFR2-JMJD3-abundant subsets as quiescent stem-like cells, thereby establishing the hierarchy of therapy-resistant actively cycling progenitor pools (JMJD3-abundant) in osteosarcoma. VEGFR2 inhibitor and JMJD3 inhibitor synergistically impeded osteosarcoma cell propagation and tumor growth. Although osteosarcoma cells are predisposed to apoptosis induced by the synergistic therapy through activation of the CHOP pro-apoptotic factor via the endoplasmic reticulum (ER) stress, the stem-like/progenitor cells exhibit an adaptive response, leading to their survival. Reduction in cellular glutathione levels in stem-like/progenitor cells caused by the treatment with a glutathione synthesis inhibitor increases ER stress-induced apoptosis. Importantly, the marked therapeutic improvement of synergistic therapy against stem-like/progenitor cells was achieved by using glutathione-scavenging nanoparticles, which can load and release the drug pair effectively. Overall, our study provides a framework for understanding glutathione signaling as one of the therapeutic vulnerabilities of stem-like/progenitor cells. Broadly, these findings revealed a promising arsenal by encapsulating glutathione-scavenging nanoparticles with co-targeting VEGFR2 and JMJD3 to eradicate chemotherapy-resistant osteosarcoma.

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.

CB-5083, an inhibitor of P97, suppresses osteosarcoma growth and stem cell properties by altering protein homeostasis.

Osteosarcoma is the most common primary malignant bone tumor in children and adolescents, and its treatment still needs to be improved. Here, we assessed the antitumor ability of CB-5083, an oral inhibitor of P97, in osteosarcoma. MTT, colony formation, sphere formation, cell cycle and apoptosis assays and animal studies showed that CB-5083 significantly inhibited osteosarcoma cell growth in vitro and in vivo. The inhibition of P97 also led to suppression of endoplasmic reticulum-associated degradation (ERAD), thereby resulted in activation of the apoptosis function of the unfolded protein response (UPR), and ultimately induced the death of osteosarcoma cells. Furthermore, an analysis of clinical patient samples confirmed that P97 can predict the outcomes of patients with osteosarcoma. Our studies showed that CB-5083 inhibited the growth and stem cell abilities of osteosarcoma cells both in vitro and in vivo and might be a promising drug for osteosarcoma treatment.

Ectopic Expression of miR-532-3p Suppresses Bone Metastasis of Prostate Cancer Cells via Inactivating NF-κB Signaling.

miR-532-3p is a widely documented microRNA (miRNA) involved in multifaceted processes of cancer tumorigenesis and metastasis. However, the clinical significance and biological functions of miR-532-3p in bone metastasis of prostate cancer (PCa) remain largely unknown. Herein, we report that miR-532-3p was downregulated in PCa tissues with bone metastasis, and downexpression of miR-532-3p was significantly associated with Gleason grade and serum prostate-specific antigen (PSA) levels and predicted poor bone metastasis-free survival in PCa patients. Upregulating miR-532-3p inhibited invasion and migration abilities of PCa cells in vitro, while silencing miR-532-3p yielded an opposite effect on invasion and migration abilities of PCa cells. Importantly, upregulating miR-532-3p repressed bone metastasis of PCa cells in vivo. Our results further demonstrated that overexpression of miR-532-3p inhibited activation of nuclear facto κB (NF-κB) signaling via simultaneously targeting tumor necrosis factor receptor-associated factor 1 (TRAF1), TRAF2, and TRAF4, which further promoted invasion, migration, and bone metastasis of PCa cells. Therefore, our findings reveal a novel mechanism contributing to the sustained activity of NF-κB signaling underlying the bone metastasis of PCa.

Clinical Significance of the Radiological Relationship between the Tumor and the main blood vessels in Enneking IIB Osteosarcoma of the extremities.

Aim: Osteosarcoma is one of the most prevalent primary bone malignancies in children and adolescents. Magnetic resonance imaging (MRI) has been considered a very critical tool to provide anatomical information of tumor and surrounding main blood vessels. To evaluate the prognostic significance of the radiological vascular involvement according to the pre-treatment MRI in patients with Enneking IIB osteosarcoma. Methods: In this retrospective study, we included 482 patients younger than 50 years old with Enneking IIB primary osteosarcoma of the extremities with complete clinical records from 2005 to 2015.Univariate and multivariable analyses were conducted to identify the risk factors for OS (Overall survival) and EFS (Event-free survival). The correlations between the risk factors was performed using Spearman analysis. The Kaplan-Meier method was used to calculate survival curves. Based on the radiological relationship between the tumor lesion and the surrounding reactive area with the main blood vessels as shown on pretreatment MRI findings. Results: Radiological vascular involvement assessed via pretreatment MRI is an important risk factor for Enneking IIB primary patients with osteosarcoma (HROS=2.32/HREFS=1.81 P<0.01) according to the univariate and multivariable analyses. Enneking IIB patients with osteosarcoma were assigned to three subtypes based on the radiological relationship between the main blood vessels and the lesion or reactive area. The 5-year cumulative OS of patients classified by the three types were 81.6% (type I), 67.1% (type II) and 44.8% (type III)(P<0.01). The 5-year cumulative EFS of the three types were 60.2% (type I), 46.7% (type II) and 30.2% (type III)(P<0.05). The total 5-year cumulative OS and EFS for all patients were 68.3% and 48.3%, respectively. Conclusion: Vascular involvement according to radiological findings from pretreatment MRI is an independent risk factor for cumulative OS and EFS in patients with Enneking IIB primary osteosarcoma of the extremities. The new subtyping based on the relationship between the tumors and surrounding reactive area with the main blood vessels based on pretreatment MRI can predict the prognosis of patients with osteosarcoma and provide certain directive information for selecting the appropriate surgical procedure for individual patients.