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1.
Sci Rep ; 14(1): 3412, 2024 02 10.
Article in English | MEDLINE | ID: mdl-38341503

ABSTRACT

To evaluate whether single acetabular column can be reserved and the effect of reconstruction with femoral head plus total hip replacement (THR) for primary malignant peri-acetabulum tumors. From 2007 to 2015, nineteen patients with primary malignant peri-acetabulum tumors were enrolled. All cases underwent single column resection with clear surgical margins. Ten of the 19 tumor's resections were assisted by computer navigation. Femoral heads were applied to reconstruct anterior or posterior column defects; THR was used for joint reconstruction. The surgical safety, oncologic outcome and prosthesis survivorship and function were evaluated by regular follow-up. The average follow-up period was 65.9 months. Surgical margins contained wide resection in 12 cases and marginal resection in 7 cases. One patient with Ewing's sarcoma died 14 months postoperative due to lung metastasis. One case with chondrosarcoma had recurrence. One prosthesis was removed due to infection. The average MusculoSkeletal Tumor Society (MSTS) function score was 83.7%. Due to the relative small number of cases, there was no significant difference in the recurrence rate and prosthesis failure rate between the navigation group and non-navigation group. Single column resection and reconstruction with femoral head autograft plus THR is an effective, safe method with less complication rate and better functional outcome for patients with peri-acetabular tumors.


Subject(s)
Arthroplasty, Replacement, Hip , Bone Neoplasms , Humans , Arthroplasty, Replacement, Hip/adverse effects , Arthroplasty, Replacement, Hip/methods , Acetabulum/surgery , Acetabulum/pathology , Femur Head/surgery , Femur Head/pathology , Bone Neoplasms/pathology , Margins of Excision , Prosthesis Failure , Retrospective Studies , Treatment Outcome
2.
Mol Oncol ; 18(4): 939-955, 2024 Apr.
Article in English | MEDLINE | ID: mdl-37727135

ABSTRACT

Osteosarcoma (OS) is a rare but aggressive malignancy. Despite previous reports, molecular characterization of this disease is not well understood, and little is known regarding OS in Chinese patients. Herein, we analyzed the genomic signatures of 73 Chinese OS cases. TP53, NCOR1, LRP1B, ATRX, RB1, and TFE3 were the most frequently mutated gene in our OS cohort. In addition, the genomic analysis of Western OS patients was performed. Notably, there were remarkable disparities in mutational landscape, base substitution pattern, and tumor mutational burden between the Chinese and Western OS cohorts. Specific molecular mechanisms, including DNA damage repair (DDR) gene mutations, copy number variation (CNV) presence, aneuploidy, and intratumoral heterogeneity, were associated with disease progression. Additionally, 30.1% of OS patients carried clinically actionable alterations, which were mainly enriched in PI3K, MAPK, DDR, and RTK signaling pathways. A specific molecular subtype incorporating DDR alterations and CNVs was significantly correlated with distant metastasis-free survival and event-free survival, and this correlation was observed in all subgroups with different characteristics. These findings comprehensively elucidated the genomic profile and revealed novel prognostic factors in OS, which would contribute to understanding this disease and promoting precision medicine of this population.


Subject(s)
Bone Neoplasms , Osteosarcoma , Humans , DNA Copy Number Variations/genetics , Osteosarcoma/genetics , Genomics , Risk Factors , Mutation/genetics , Bone Neoplasms/genetics
3.
Sci Rep ; 13(1): 20914, 2023 11 27.
Article in English | MEDLINE | ID: mdl-38017005

ABSTRACT

Osteosarcoma is a heterogeneous disease with regard to its chemotherapy response and clinical outcomes. This study aims to investigate the genomic and transcriptomic characteristics related to pre-operative chemotherapy response. Samples from 25 osteosarcoma patients were collected to perform both whole exome and transcriptome sequencing. Osteosarcoma had significant amount of chromosomal copy number variants (CNVs). Chemotherapy responders showed the higher chromosomal CNV burden than non-responders (p = 0.0775), but the difference was not significant. The percentage of COSMIC signature 3, associated with homologous recombination repair deficiency, was higher in responders (56%) than in non-responders (45%). Transcriptomic analysis suggested that 11 genes were significantly up-regulated in responders and 18 genes were up-regulated in non-responders. Both GSEA and KEGG enrichment analysis indicted that four pathways related to cardiomyopathy were up-regulated in responders, while neuroactive ligand - receptor interaction was up-regulated in non-responders. Finally, a previously published chemoresistant model was validated using our dataset, with the area under the curve of 0.796 (95% CI, 0.583-1.000). Osteosarcoma had the heterogeneous mutational profile with frequent occurrence of CNVs. Transcriptomic analysis identified several signaling pathways associated with chemotherapy responsiveness to osteosarcoma. Transcriptomic signatures provides a potential research direction for predicting the chemotherapy response.


Subject(s)
Bone Neoplasms , Osteosarcoma , Humans , Transcriptome , Bone Neoplasms/drug therapy , Bone Neoplasms/genetics , Bone Neoplasms/surgery , Osteosarcoma/drug therapy , Osteosarcoma/genetics , Osteosarcoma/surgery , Gene Expression Profiling , Genomics
4.
Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi ; 37(11): 1319-1325, 2023 Nov 15.
Article in Chinese | MEDLINE | ID: mdl-37987039

ABSTRACT

Objective: To investigate short-term effectiveness and clinical application advantages of orthopedic robot-assisted resection for osteoid osteoma compared with traditional open surgery. Methods: A retrospective analysis was conducted on clinical data of 48 osteoid osteoma patients who met the selection criteria between July 2022 and April 2023. Among them, 23 patients underwent orthopedic robot-assisted resection (robot-assisted surgery group), and 25 patients received traditional open surgery (traditional surgery group). There was no significant difference ( P>0.05) in gender, age, disease duration, lesion location and size, and preoperative visual analogue scale (VAS) score, and musculoskeletal tumor society (MSTS) score between the two groups. The surgical time, intraoperative blood loss, intraoperative lesion localization time, initial localization success rate, infection, and recurrence were recorded and compared. VAS scores before surgery and at 24 hours, 1, 3, 6, and 9 months after surgery and MSTS score before surgery and at 3 months after surgery were assessed. Results: All patients completed the surgery successfully, with no significant difference in surgical time between the two groups ( P>0.05). Compared to the traditional surgery group, the robot-assisted surgery group had less intraoperative blood loss, shorter lesion localization time, and shorter hospitalization time, with significant differences ( P<0.05). The initial localization success rate was higher in the robot-assisted surgery group than in the traditional surgery group, but the difference between the two groups was not significant ( P>0.05). All patients in both groups were followed up, with the follow-up time of 3-12 months in the robot-assisted surgery group (median, 6 months) and 3-14 months in the traditional surgery group (median, 6 months). The postoperative MSTS scores of both groups improved significantly when compared to those before surgery ( P<0.05), but there was no significant difference in the changes in MSTS scores between the two groups ( P>0.05). The postoperative VAS scores of both groups showed a gradually decreasing trend over time ( P<0.05), but there was no significant difference between the two groups after surgery ( P>0.05). During follow-up, except for 1 case of postoperative infection in the traditional surgery group, there was no infections or recurrences in other cases. There was no significant difference in the incidence of postoperative infection between the two groups ( P>0.05). Conclusion: Orthopedic robot-assisted osteoid osteoma resection achieves similar short-term effectiveness when compared to traditional open surgery, with shorter lesion localization time.


Subject(s)
Bone Neoplasms , Osteoma, Osteoid , Robotics , Humans , Blood Loss, Surgical , Osteoma, Osteoid/surgery , Retrospective Studies , Treatment Outcome , Postoperative Complications , Bone Neoplasms/surgery
5.
J Bone Oncol ; 41: 100492, 2023 Aug.
Article in English | MEDLINE | ID: mdl-37546383

ABSTRACT

Background: Analysis of the tumour necrosis rate is an important method to evaluate the effect of neoadjuvant chemotherapy for osteosarcoma. However, at present, there is no specific imaging method to evaluate this effect. The purpose of this study was to evaluate the changes in blood supply after chemotherapy by measuring the CT enhancement rate and to analyse the correlation between the CT enhancement rate and the tumour necrosis rate. Methods: Patients with primary osteosarcoma of the extremities treated in our institute from 2016 to 2017 were analysed retrospectively. In total, 103 eligible patients were enrolled in the study, including 67 males and 36 females, with an average age of 17.7 (6-54) years. Sixty cases had tumour sites in the femur, 25 in the tibia, 10 in the humerus, and eight in other sites. All patients received neoadjuvant chemotherapy including methotrexate, cisplatin + doxorubicin and ifosfamide before surgical treatment. All patients underwent enhanced CT examination of the same tumour site before and after the neoadjuvant chemotherapy protocol. The CT value before and after chemotherapy was measured and the enhancement rate was calculated. The change in the CT enhancement rate after chemotherapy was analysed. Changes in the CT enhancement rate were compared between patients with a tumour necrosis rate greater than 90% and those with one <90%. Results: The average CT enhancement rates before and after chemotherapy were 1.68 (median 1.63, range 1.00-2.51) and 1.39 (median 1.28, range 1.00-2.83), respectively (P < 0.01). The average CT enhancement rate after chemotherapy decreased by 15.0% (median 16.7%, range -27.5-53%): 75 cases exhibited a decrease, three cases remained unchanged, and 25 cases exhibited an increase. The average enhancement rate before chemotherapy was 1.75 (median 1.68, range 1.18-2.51) in the group with a necrosis rate >90% and 1.62 (median 1.52, range 1.00-2.41) in the group with a necrosis rate < 90% (P = 0.068). The average CT enhancement rate after chemotherapy was 1.20 (median 1.21, range 1.00-1.53) in the group with a necrosis rate > 90% and 1.53 (median 1.43, range 1.00-2.83) in the group with a necrosis rate < 90% (P < 0.01). The enhancement rate of the group with a necrosis rate > 90% decreased by 29.0% (median 28%, range -2.3-53%) (P < 0.01); the enhancement rate of the group with a necrosis rate < 90% decreased by 3.8% on average (median 0.7%, range -27.5-44.5%) (P = 0.225). Conclusion: After receiving neoadjuvant chemotherapy, most patients with osteosarcoma of the extremities exhibited reductions in the CT enhancement rate. In cases where the tumour necrosis rate was greater than 90%, the tumour blood supply was significantly reduced. This suggests that imaging evaluations based on the CT enhancement rate can be used as a reference for evaluating the preoperative effect of chemotherapy for osteosarcoma.

6.
Front Oncol ; 13: 1173275, 2023.
Article in English | MEDLINE | ID: mdl-37546405

ABSTRACT

Introduction: Sarcomas are classified into two types, bone sarcoma and soft tissue sarcoma (STS), which account for approximately 1% of adult solid malignancies and 20% of pediatric solid malignancies. There exist more than 50 subtypes within the two types of sarcoma. Each subtype is highly diverse and characterized by significant variations in morphology and phenotypes. Understanding tumor molecular genetics is helpful in improving the diagnostic accuracy of tumors that have been difficult to classify based on morphology alone or that have overlapping morphological features. The different molecular characteristics of bone sarcoma and STS in China remain poorly understood. Therefore, this study aimed to analyze genomic landscapes and actionable genomic alterations (GAs) as well as tumor mutational burden (TMB), microsatellite instability (MSI), and programmed death ligand-1 (PD-L1) expression among Chinese individuals diagnosed with primary bone sarcomas and STS. Methods: This retrospective study included 145 patients with primary bone sarcomas (n = 75) and STS (n = 70), who were categorized based on the 2020 World Health Organization classification system. Results: Patients diagnosed with bone sarcomas were significantly younger than those diagnosed with STS (p < 0.01). The top 10 frequently altered genes in bone sarcoma and STS were TP53, CDKN2A, CDKN2B, MAP3K1, LRP1B, MDM2, RB1, PTEN, MYC, and CDK4.The EWSR1 fusions exhibited statistically significant differences (p < 0.01) between primary bone sarcoma and STS in terms of their altered genes. Based on the actionable genes defined by OncoKB, actionable GAs was found in 30.7% (23/75) of the patients with bone sarcomas and 35.7% (25/70) of those with STS. There were 4.0% (3/75) patients with bone sarcoma and 4.3% (3/70) patients with STS exhibited high tumor mutational burden (TMB-H) (TMB ≥ 10). There was only one patient with STS exhibited MSI-L, while the remaining cases were microsatellite stable. The positive rate of PD-L1 expression was slightly higher in STS (35.2%) than in bone sarcoma (33.3%), however, this difference did not reach statistical significance. The expression of PD-L1 in STS patients was associated with a poorer prognosis (p = 0.007). Patients with STS had a better prognosis than those with bone sarcoma, but the observed difference did not attain statistical significance (p = 0.21). Amplification of MET and MYC genes were negatively correlated with clinical prognosis in bone tumors (p<0.01). Discussion: In conclusion, bone sarcoma and STS have significantly different clinical and molecular characteristics, suggesting that it is vital to diagnose accurately for clinical treatment. Additionally, comprehensive genetic landscape can provide novel treatment perspectives for primary bone sarcoma and STS. Taking TMB, MSI, PD-L1 expression, and OncoKB definition together into consideration, there are still many patients who have the potential to respond to targeted therapy or immunotherapy.

7.
J Cancer Epidemiol ; 2023: 5468291, 2023.
Article in English | MEDLINE | ID: mdl-37153026

ABSTRACT

Aims: Giant cell tumor of the bone (GCTB) is associated with considerable morbidity. As GCTB epidemiological data for China are limited, this study is aimed at describing the disease characteristics of GCTB in China and establishing the historical context for its treatment before recent advances in treatment options. Methods: The disease characteristics, treatment patterns, and local GCTB recurrence rate after primary surgery for GCTB were evaluated in this single-center, retrospective, noninterventional, observational study of patients treated for GCTB at Ji Shui Tan Hospital, Beijing, from 2009 to 2016 based on medical chart review. Patients with unmet need were defined as those whose surgical treatment was difficult or who had to undergo high-morbidity surgery. Results: Among the 668 patients with a primary GCTB diagnosis, 578 (86.5%) of target lesions were in the extremities, and 89 (13.3%) were in the pelvic or axial bone. Of these, 173 (25.9%) were characterized as having an unmet need. Almost all GCTB patients received surgical treatment at both primary diagnosis (666/668 (99.7%)) and last disease recurrence (196/200 (98.0%)). Additionally, about one-third of patients received nonsurgical treatment at primary diagnosis (205/668 (30.7%)) and disease recurrence (67/200 (33.5%)), with neoadjuvant therapy being the most common treatment. The rate of high-morbidity surgery increased for recurrent disease (65/200 (32.5%)) compared with primary diagnosis (111/668 (16.6%)). The 2-year cumulative incidence of postoperative disease recurrence was 29.2%, in line with rates observed in prior studies. Conclusion: As many patients with primary and recurrent disease received high-morbidity surgery, more effective treatments are needed.

8.
Cancer Immunol Immunother ; 72(7): 2331-2346, 2023 Jul.
Article in English | MEDLINE | ID: mdl-36932256

ABSTRACT

BACKGROUND: Acute myeloid leukemia (AML) treatment remains challenging. CD70 was reported as a promising AML-specific antigen. Preclinically, CAR T-cell with single-chain-variable fragment (scFv) or truncated CD27 targeting CD70 has been reported to treat AML. However, various disadvantages including spontaneous exhaustion, proteinase-mediated loss of functional receptors, and high immunogenicity, limited its further application to clinical settings. Alternatively, the single-variable domain on heavy chain (VHH), also known as nanobodies, with comparable binding ability and specificity, provides an optional solution. METHOD: We generated CD70 knocked-out novel nanobody-based anti-CD70-CAR T-cells (nb70CAR-T) with two different VHHs for antigen detection. Next, we detected the CD70 expression on primary AML blasts by flow cytometry and associated the efficacy of nb70CAR-T with the target antigen density. Finally, epigenetic modulators were investigated to regulate the CD70 expression on AML cells to promote the functionality of nb70CAR-T. RESULTS: Our nb70CAR-T exhibited expected tumoricidal functionality against CD70-expressed cell lines and primary AML blasts. However, CD70 expression in primary AML blasts was not consistently high and nb70CAR-T potently respond to an estimated 40.4% of AML patients when the CD70 expression level was over a threshold of 1.6 (MFI ratio). Epigenetic modulators, Decitabine and Chidamide can up-regulate CD70 expression on AML cells, enhancing the treatment efficacy of nb70CAR-T. CONCLUSION: CD70 expression in AML blasts was not fully supportive of its role in AML targeted therapy as reported. The combinational use of Chidamide and Decitabine with nb70CAR-T could provide a new potential for the treatment of AML.


Subject(s)
Leukemia, Myeloid, Acute , Humans , Decitabine/pharmacology , Aminopyridines/metabolism , Immunotherapy, Adoptive , T-Lymphocytes
9.
Mol Biotechnol ; 65(11): 1836-1845, 2023 Nov.
Article in English | MEDLINE | ID: mdl-36807122

ABSTRACT

Osteosarcoma is the most prevalent clinical malignant bone tumor in adolescents. The prognosis of metastatic osteosarcoma is still very poor. The aim of our study was to investigate the clinical diagnosis and prognostic significance of metastasis related genes (MRGs) in patients with osteosarcoma. Clinical information and RNA sequencing data with osteosarcoma patients were obtained and set as the training set from UCSC databases. GSE21257 were downloaded and chosen as the verification cohort. An eight gene metastasis related risk signature including MYC, TAC4, ABCA4, GADD45GIP1, TNFRSF21, HERC5, MAGEA11, and PDE1B was built to predict the overall survival of osteosarcoma patients. Based on risk assessments, patients were classified into high- and low-risk groups. The high-risk patients had higher risk score and shorter survival time. ROC curves revealed that this risk signature can accurately predict survival times of osteosarcoma patients at the 1-, 2-, 3-, 4- and 5- year. GSEA revealed that MYC targets, E2F targets, mTORC1 signaling, Wnt /ß-catenin signaling and cell cycle were upregulated, and cell adhesion molecules, and primary immunodeficiency were decreased in high-risk group. MRGs were highly linked with the tumor immune microenvironment and ICB response. These results identified that MRGs as a novel prognostic and diagnostic biomarker in osteosarcoma.


Subject(s)
Bone Neoplasms , Osteosarcoma , Adolescent , Humans , Osteosarcoma/genetics , Cell Cycle , RNA , ROC Curve , Bone Neoplasms/genetics , Tumor Microenvironment/genetics , ATP-Binding Cassette Transporters
10.
Materials (Basel) ; 15(23)2022 Nov 28.
Article in English | MEDLINE | ID: mdl-36499968

ABSTRACT

The nozzle structure has an important effect on the fluid flow in the mold, which can significantly improve the solidified shell and product quality of alloy steel round bloom. The transient fluid flow, heat transfer, and solidification behavior under different nozzle structures and mold electromagnetic stirring (M-EMS) are investigated using a 3D transient mathematical model. The results show that a third small recirculation zone appears near the meniscus after the application of the swirling flow nozzle (SFN). The impact depth of SFN is shallower than that of the original submerged entry nozzle (SEN) impact, and the lower circulation zone is shifted upward. The horizontal swirling flow generated by SFN can significantly weaken the washing of the initial shell by high-temperature steel and improve the uneven growth phenomenon of the inner and outer curved solidified shell caused by mold curvature. The swirling flow produced by M-EMS in the mold can also improve the washing of the initial shell by the high-temperature jet and the uneven growth of the inner and outer curved shell. M-EMS can expand the high-temperature zone in the upper part of the mold, promote the superheat dissipation of the molten steel, and promote the growth of the solidified shell. In addition, after the application of M-EMS, the tangential velocity of -15° SFN in the meniscus is smaller, and the resulting liquid level fluctuation is lower at 5.07 mm, which is less likely to produce slag entrapment and is conducive to improving the quality of round bloom.

11.
Front Bioeng Biotechnol ; 10: 918126, 2022.
Article in English | MEDLINE | ID: mdl-35935508

ABSTRACT

Surfactants play a vital role in the delignification and saccharification of lignocellulosic biomass. A strategy for coupling surfactant-assisted alkaline pretreatment (SAP) with surfactant-assisted enzymatic hydrolysis (SEH) has been proposed for improving sugar recovery from a potential energy crop, Miscanthus sinensis. Poly (ethylene glycol) 2000 (PEG 2000) was found to be more efficient in SAP than in other tested surfactants. Compositional and structural analysis revealed that the SAP process with 1% of PEG 2000 produced more efficient lignin removal and microstructure disruption of the pretreated sample, thus indicating much higher reducing sugar yields of 544.4-601.2 mg/g compared to the samples that were untreated or pretreated by alkali alone. Moreover, SEH with 1% Tween 80, which could block the lignin-enzyme interactions, produced a substantial reduction of 33.3% in the enzyme loading to achieve a higher sugar recovery from the SAP sample.

12.
Front Oncol ; 12: 822983, 2022.
Article in English | MEDLINE | ID: mdl-35574345

ABSTRACT

Background and Objectives: After diagnosing a primary bone tumor involving the forearm, various excision strategies and reconstruction methods must be considered. This study explored the oncological and functional outcomes of limb salvage surgery for primary malignant bone tumors in the forearm. Methods: Patients with primary forearm bone tumors (n = 369) were retrospectively analyzed between 2000 and 2017. There were 266 patients with radial tumors, and 46 (17.3%) were malignant, whereas 103 patients had ulnar lesions and 22 (21.4%) were malignant tumors. The oncological results, prognostic factors, and functional results after limb salvage surgery of forearm malignancies were analyzed. Results: The follow-up averaged 72.1 (7-192, median 62.5) months. Fifty-six patients who received limb salvage surgery were included in the final evaluation. Radius resection was performed in 38 patients, and distal radius (25 patients) was most frequent. Ulnar resection was performed in 18 patients, and the proximal ulna (13 patients) was most frequent. The surgical margins obtained were intralesional in 3 patients, marginal in 8 patients and wide in 45 patients. Local recurrence occurred in 11 patients (19.6%), and distant metastasis occurred in 14 patients (25%). The 5-year recurrence-free survival rate was 79.8%. Unplanned excision, ulnar involvement, proximal forearm location and inadequate surgical margins were associated with recurrence. The overall 5-year and 10-year survival rates were 83.5 and 71.7%, respectively. Distant metastasis was a poor prognostic factor for the survival rate. Forty-two patients were evaluated by MSTS score with an average of 27.9 ± 1.5. Conclusions: The incidence of radial malignant tumors is higher than that of ulnar lesions. The distal radius and the proximal ulna are the most frequently involved sites. Unplanned excisions, ulnar tumors, proximal forearm tumors, and inadequate surgical margin are the risk factors for local recurrence. Distant metastasis is an independent poor prognostic factor of death. The oncology control and functional results of limb salvage surgery were satisfactory.

13.
J Bone Oncol ; 32: 100410, 2022 Feb.
Article in English | MEDLINE | ID: mdl-35059284

ABSTRACT

BACKGROUND: The changes in the characteristics of the tumor blood supply of giant cell tumor of bone over time after treatment with denosumab remain unclear. The purpose of this study was to evaluate the change in the blood supply imaging characteristics of giant cell tumor of bone after preoperative denosumab treatment and to provide evidence for evaluating the reasonable time for preoperative treatment. METHODS: A total of 59 patients with giant cell tumor of bone who were treated in our hospital from 2014 to 2019 were enrolled in the study. All patients underwent enhanced CT examination of the tumor site before denosumab treatment and every month after treatment. The plain CT value and enhanced CT value of the tumor were measured, and the CT enhancement rate of the tumor was calculated. The change in the CT enhancement rate of the tumor over time after denosumab treatment was analyzed. RESULTS: The average tumor enhancement rates were 2.14 (1.22-4.05), 1.60 (1.12-2.53), 1.38 (1.02-2.24), and 1.25 (1-2.11) before denosumab treatment and one month, three months, and six months after treatment, respectively. After denosumab treatment, the average monthly CT enhancement rate decreased as follows: 0.54 (25.2%) in the first month, 0.11 (5.15%) in the second to third months, and 0.04 (1.87%) in the fourth to sixth months. The tumor enhancement rate was no longer significantly reduced three months post-treatment. There was a significant correlation between the reduction in the CT enhancement rate and the initial CT enhancement rate (P = 0.000). CONCLUSION: The preoperative application of denosumab can reduce tumor blood supply. The decrease in the blood supply is the most significant in the initial stage of treatment. Following treatment, the decrease in the blood supply gradually reduces over time. Therefore, for the purpose of reducing intra-operative bleeding and facilitating surgery, application of denosumab treatment is not recommended more than three months before surgery.

14.
Cancer Genet ; 256-257: 149-157, 2021 08.
Article in English | MEDLINE | ID: mdl-34153775

ABSTRACT

The genomic profiles of osteosarcoma (OS) patients have been extensively investigated; however, the genetic prognostic biomarkers still remain unclear. In the present study, we analyzed the mutational profiles of pre-treatment primary tumor samples from 33 OS patients using whole exome sequencing (WES). These 33 OS patients were divided into two groups according to clinical outcomes: a good prognosis group involving 21 patients with tumor free survival, and a poor prognosis group involving the remaining12 patients who had lung metastases at initial diagnosis. Overall we found that the MAPK signaling pathway may play an important role in determining a good prognosis, while the PI3K-Akt signaling pathway may be an important factor leading to a poor prognosis. Significant differences were observed in the number of somatic copy number alterations, including del (3p), amp (4q), del (7p) and amp (8q), between the two groups. Moreover, significant differences were observed in mutation sites and frequencies between these two groups. The good prognosis group exhibited a significantly higher mutation frequency in somatic JAK-STAT and germline base excision repair pathways than the poor prognosis group. Furthermore, significant difference was also observed in the frequency of potentially actionable alterations between the two groups, suggesting that patients with a poor prognosis potentially have access to a larger number of treatment options. These findings highlight the importance of evaluating genomic disparities in OS, and provide a novel insight into the potential prognostic biomarkers.


Subject(s)
Exome Sequencing , Genetic Heterogeneity , Osteosarcoma/genetics , Adolescent , Adult , Child , Child, Preschool , Clone Cells , Female , Genes, Neoplasm , Genome, Human , Humans , Male , Prognosis , Signal Transduction/genetics , Young Adult
16.
J Cell Physiol ; 236(8): 5832-5847, 2021 08.
Article in English | MEDLINE | ID: mdl-33432627

ABSTRACT

Impressive outcomes have been achieved by chimeric antigen receptor (CAR)-T cell therapy using murine-derived single-chain variable fragment (scFv) FMC63 specific for CD19 in patients with B cell malignancies. However, evidence suggests that human anti-mouse immune responses might be responsible for poor persistence and dysfunction of CAR-T cells, leading to poor outcomes or early tumor recurrence. Substituting a fully human scFv for murine-derived scFv may address this clinically relevant concern. In this study, we discovered two human anti-CD19 scFv candidates through an optimized protein/cell alternative panning strategy and evaluated their function in CAR-T cells and CD19/CD3 bispecific antibody formats. The two clones exhibited excellent cytotoxicity in CAR-T cells and bispecific antibodies in vitro compared with the benchmarks FMC63 CAR-T cells and blinatumomab. Furthermore, Clone 78-BBz CAR-T cells exhibited similar in vivo antitumor activity to FMC63-BBz CAR-T cells. Our results indicate that Clone 78-BBz CAR has excellent efficacy and safety profile and is a good candidate for clinical development.


Subject(s)
Antigens, CD19/immunology , Cell- and Tissue-Based Therapy , Receptors, Antigen, T-Cell/immunology , Receptors, Chimeric Antigen/immunology , Animals , Antibodies, Bispecific/pharmacology , Cell Line, Tumor , Cell- and Tissue-Based Therapy/methods , Humans , Immunotherapy, Adoptive/methods , Mice , Single-Chain Antibodies/immunology , Xenograft Model Antitumor Assays/methods
17.
Sci Rep ; 11(1): 734, 2021 01 12.
Article in English | MEDLINE | ID: mdl-33436664

ABSTRACT

The purpose of this study was to evaluate the functional results, complications and related factors of prosthesis reconstruction after malignant tumor resection of primary proximal humeral, and also evaluate whether soft tissue reconstruction with mesh patch and anchors can improve clinical results. From 2002 to 2016, forty-one patients were enrolled in this study. The pathological diagnosis contained 27 cases of osteosarcoma, 7 cases of chondrosarcoma and other primary malignant bone tumors. Both mesh patch and anchors were used in the reconstruction of joint capsule and the surrounding soft tissues in 27 cases. The mean postoperative follow-up was 60.6 months. The average active abduction angle and passive abduction angle was 33.5 (5-71) degrees and 72.4 (52-104) degrees. The prosthetic humeral head displacement was over 2 cm in 5 cases (12.2%). The average MSTS score was 23.1. The overall 5-year survival rate of prosthesis was 88.2%. The length of osteotomy, whether preserving deltoid muscle, whether applying mesh patch and anchors had significant effects on the abduction angle of shoulder joint; the length of osteotomy, whether applying mesh patch and anchors had significant effects on the degree of upward displacement of prosthesis. The application of both mesh patch and anchors in prosthesis reconstruction achieved more stable result and better function of shoulder joint. To ensure the stability of shoulder joint and the firm wrapping of surrounding soft tissue are key factors affecting the postoperative function.


Subject(s)
Bone Neoplasms/surgery , Chondrosarcoma/surgery , Humerus/surgery , Limb Salvage/methods , Osteosarcoma/surgery , Prosthesis Implantation/methods , Surgical Mesh , Adolescent , Adult , Aged , Bone Neoplasms/pathology , Chondrosarcoma/pathology , Female , Follow-Up Studies , Humans , Humerus/pathology , Male , Middle Aged , Osteosarcoma/pathology , Prognosis , Plastic Surgery Procedures/methods , Retrospective Studies , Young Adult
18.
Blood ; 137(21): 2890-2901, 2021 05 27.
Article in English | MEDLINE | ID: mdl-33512480

ABSTRACT

B-cell maturation antigen (BCMA)-specific chimeric antigen receptor (CAR) T-cell therapies have shown efficacy in relapsed/refractory multiple myeloma (RRMM). Because the non-human originated antigen-targeting domain may limit clinical efficacy, we developed a fully human BCMA-specific CAR, CT103A, and report its safety and efficacy in a phase 1 trial. Eighteen consecutive patients with RRMM, including 4 with prior murine BCMA CAR exposures, were enrolled. CT103A was administered at 1, 3, and 6 × 106 CAR-positive T cells/kg in the dose-escalation phase, and 1 × 106 CAR-positive T cells/kg in the expansion cohort. The overall response rate was 100%, with 72.2% of the patients achieving complete response or stringent complete response. For the 4 murine BCMA CAR-exposed patients, 3 achieved stringent complete response, and 1 achieved a very good partial response. At 1 year, the progression-free survival rate was 58.3% for all cohorts and 79.1% for the patients without extramedullary myeloma. Hematologic toxicities were the most common adverse events; 70.6% of the patients experienced grade 1 or 2 cytokine release syndromes. No immune effector cell-associated neurotoxicity syndrome was observed. To the cutoff date, CAR transgenes were detectable in 77.8% of the patients. The median CAR transgene persistence was 307.5 days. Only 1 patient was positive for the anti-drug antibody. Altogether, CT103A is safe and highly active in patients with RRMM and can be developed as a promising therapy for RRMM. Patients who relapsed from prior murine BCMA CAR T-cell therapy may still benefit from CT103A. This trial was registered at http://www.chictr.org.cn as #ChiCTR1800018137.


Subject(s)
B-Cell Maturation Antigen/antagonists & inhibitors , Immunotherapy, Adoptive , Multiple Myeloma/therapy , Receptors, Chimeric Antigen/therapeutic use , Single-Chain Antibodies/therapeutic use , Adult , Afibrinogenemia/etiology , Aged , Animals , Antibodies, Anti-Idiotypic/biosynthesis , Antineoplastic Agents/therapeutic use , B-Cell Maturation Antigen/immunology , Combined Modality Therapy , Drug Resistance, Neoplasm , Female , Hematologic Diseases/etiology , Humans , Immunity, Humoral , Immunotherapy, Adoptive/adverse effects , Leukemia, Plasma Cell/etiology , Leukemia, Plasma Cell/therapy , Male , Mice , Middle Aged , Multiple Myeloma/drug therapy , Receptors, Chimeric Antigen/administration & dosage , Receptors, Chimeric Antigen/immunology , Remission Induction , Single-Chain Antibodies/immunology , Transgenes
19.
Invest New Drugs ; 39(1): 278-282, 2021 02.
Article in English | MEDLINE | ID: mdl-32915420

ABSTRACT

An inflammatory myofibroblastic tumor (IMT) is a rare invasive soft tissue mass with intramuscular penetration that is primarily treated via a surgical procedure. However, with unclear boundaries and a high rate of relapse, there is no standard treatment for recurrence or unresectable tumors. It is noteworthy that approximately half of IMTs harbor genetic rearrangements of the anaplastic lymphoma kinase (ALK). ALK inhibitors have been used successfully in the treatment of IMTs with a variety of ALK fusions. Here, we present a case of a 15-year-old patient with IMT around the hip. Next-generation sequencing (NGS) revealed an LRRFIP1-ALK fusion, which has not yet been reported in the literature. Crizotinib, an ALK inhibitor, was effective in the treatment of this patient, indicating that ALK inhibitors may be effective for IMT with LRRFIP1-ALK fusions. This report expands the list of gene fusions in IMTs and highlights a new target for treatment.


Subject(s)
Anaplastic Lymphoma Kinase/antagonists & inhibitors , Anaplastic Lymphoma Kinase/genetics , Crizotinib/therapeutic use , Neoplasms, Muscle Tissue/drug therapy , RNA-Binding Proteins/genetics , Adolescent , Gene Fusion , High-Throughput Nucleotide Sequencing , Humans , Male , Neoplasms, Muscle Tissue/genetics
20.
J Bone Oncol ; 26: 100334, 2021 Feb.
Article in English | MEDLINE | ID: mdl-33251099

ABSTRACT

BACKGROUND: Malignancy in giant cell tumor of bone (GCTB) is a rare tumor with relevant literature being sparse. In primary malignant GCTB, distinct areas of benign GCTB are juxtaposed with high-grade sarcoma, while in secondary malignant GCTB sarcoma occurs at the site of previously managed GCTB. This study assesses the distinguishing characteristics of patients with this condition, the time interval for development of secondary malignant GCTB, the outcome of treatment, and explores factors associated with oncologic outcomes. METHODS: This is a retrospective case series of patients from a prospectively collected institutional musculoskeletal oncology database. From January 1998 to December 2016, 1365 patients were managed for extremity GCTBs. 32 (2.3%) patients had malignant GCTB, including 12 with primary malignant GCTB and 20 with secondary malignant GCTB. The study population comprised 18 males and 14 females presenting at a mean age of 33.7 years (±13.0) and followed for a mean of 9.5 years (±7.4). Data were collected on patient and treatment-related factors, and the occurrence of local recurrence, metastasis, and death. The time from the diagnosis of GCTB to the secondary malignant GCTB was defined as the latent period. RESULTS: Malignant GCTB most commonly presents in the distal femur and proximal tibia with pain and swelling. Radiologically, they are aggressive Campanacci Grade III tumors with prominent bony destruction and soft tissue extension. In the 20 patients with secondary malignant GCTB, the tumors were osteosarcoma in 15, undifferentiated pleomorphic sarcoma in 4 patients and fibrosarcoma in one patient. The mean latent period in patients with secondary malignant GCTB was 7.9 year (±7.3). The median recurrence-free survival (RFS) of secondary malignant GCTB (latent period) and benign GCTB were 61.5 and 19 months respectively (p < 0.001), receiver operating curve analysis found 49.5 months to be the critical threshold, with a longer interval to recurrence being seen in malignant recurrence. The 5 and 10-year overall survival rate of malignant GCTB were 45.8% and 36.1% respectively. The 5-year survival rates of primary malignant GCTB and secondary malignant GCTB were 56.2% and 40.0% respectively (p = 0.188). Adequate surgical margins decreased the local recurrence (LR) rate (P = 0.006). Pulmonary metastasis developed in 69% of patients. The median distant metastasis-free survival between malignant GCTB and benign GCTB were 9 and 21 months (p = 0.002). Chemotherapy was associated with a longer pulmonary metastasis free survival (13 months Vs 6 months, P = 0.002), but not with increased overall survival (57.0% Vs 33.3%, P = 0.167). CONCLUSIONS: Malignant GCTB carries a poor prognosis. Accurate diagnosis is critical to avoid inadequate surgical margins when treating primary malignant GCTB. Aggressive tumors and pulmonary metastasis should raise suspicion for malignant GCTB. Secondary malignant transformation should be suspected in patients presenting with recurrence especially after 4 years. Adjuvant chemotherapy use did not benefit survival, but was associated with increased pulmonary progression-free survival.

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