Factors influencing survival after recurrence in osteosarcoma: A report from the Children's Oncology Group

Barkauskas, Donald A.; Krailo, Mark; Meyers, Paul A.; Schwartz, Cindy L.; Doski, John J.; Görlick, Richard; Janeway, Katherine A.; Isakoff, Michael S.

doi:10.1002/pbc.27444

Cited by 40 publications

(43 citation statements)

References 28 publications

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“…Solid tumors contribute disproportionately to the morbidity and mortality of all pediatric patients with cancer despite aggressive management with multimodality therapy. 1 This problem is especially acute in children and young adults with relapsed or refractory disease, 2 , 3 , 4 , 5 , 6 whose poor rates of survival have remained relatively unchanged during the last two decades. 1 Thus, new therapeutic strategies are needed to improve outcomes and reduce treatment-related complications for this group of patients.…”

Section: Introductionmentioning

confidence: 99%

Route of 41BB/41BBL Costimulation Determines Effector Function of B7-H3-CAR.CD28ζ T Cells

Nguyen

Okeke

Clay

et al. 2020

Molecular Therapy - Oncolytics

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B7-H3 is actively being explored as an immunotherapy target for pediatric patients with solid tumors using monoclonal antibodies or T cells expressing chimeric antigen receptors (CARs). B7-H3-CARs containing a 41BB costimulatory domain are currently favored by several groups based on preclinical studies. In this study, we initially performed a detailed analysis of T cells expressing B7-H3-CARs with different hinge/transmembrane (CD8α versus CD28) and CD28 or 41BB costimulatory domains (CD8α/CD28, CD8α/41BB, CD28/CD28, CD28/41BB). Only subtle differences in effector function were observed between CAR T cell populations in vitro . However, CD8α/CD28-CAR T cells consistently outperformed other CAR T cell populations in three animal models, resulting in a significant survival advantage. We next explored whether adding 41BB signaling to CD8α/CD28-CAR T cells would further enhance effector function. Surprisingly, incorporating 41BB signaling into the CAR endodomain had detrimental effects, while expressing 41BBL on the surface of CD8α/CD28-CAR T cells enhanced their ability to kill tumor cells in repeat stimulation assays. Furthermore, 41BBL expression enhanced CD8α/CD28-CAR T cell expansion in vivo and improved antitumor activity in one of four evaluated models. Thus, our study highlights the intricate interplay between CAR hinge/transmembrane and costimulatory domains. Based on our study, we selected CD8α/CD28-CAR T cells expressing 41BBL for early phase clinical testing.

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Section: Introductionmentioning

confidence: 99%

Route of 41BB/41BBL Costimulation Determines Effector Function of B7-H3-CAR.CD28ζ T Cells

Nguyen

Okeke

Clay

et al. 2020

Molecular Therapy - Oncolytics

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“…Early metastatic spread and recurrences after tumor removal are strongly related to poor prognosis in OSA [36]. Considering that tumor cell migration, colony establishment and microtumor outgrowth are all hallmarks of the early stages of metastatic progression, we tested the effect of β-blocker PPN on the establishment and progression of 2D tumor colonies, 3D spheroid growth and OSA cell chemotaxis.…”

Section: Resultsmentioning

confidence: 99%

Drug Repurposing of β-blocker Propranolol in Osteosarcoma: Preclinical Antitumor Efficacy Alone or in Combination with Chemotherapy.

Solernó¹,

Sobol²,

Capobianco³

et al. 2020

Preprint

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Background: Osteosarcoma is still associated with poor response to therapy and alarmingly elevated mortality rates, especially in developing countries, highlighting the urgent need of novel therapeutic strategies. Given that β-adrenergic receptor (β-AR) signaling regulates many cellular processes involved in the initiation and progression of cancer, multiple efforts have been made to repurpose non-selective β-blocker propranolol in oncology. Considering the unsatisfied clinical needs of osteosarcoma, we evaluated the in vitro and in vivo antitumoral activity of propranolol as a monotherapy or in combination with metronomic chemotherapy, in β-AR-expressing human osteosarcoma cells. Methods: In vitro anti-osteosarcoma effects of propranolol were assessed on high-density cell growth, chemotaxis, colony-forming ability and three-dimensional spheroids. Cell cycle phase distribution and apoptosis were evaluated using flow cytometry analysis, and quantification of hypodiploid cell population and TUNEL labelling, respectively. Propranolol addition to chemotherapy was evaluated in vitro and in human osteosarcoma xenografts generated in athymic mice.Results: Propranolol significantly impaired MG-63 and U-2 OS cellular growth in a concentration range of 10-100 µM (IC50 ≈ 45µM) and was capable of blocking in vitro protumoral effects triggered by catecholamines. Cytostatic activity of propranolol was associated to reduced mitosis and G0/G1 cell cycle, but not to apoptosis induction. Moreover, β-blocker drastically reduced colony formation, spheroid progression and migration of osteosarcoma cells. Synergistic effects were observed in vitro after combining propranolol with chemotherapeutic agents methotrexate or cisplatin. In vivo, treatment with propranolol (10 mg/kg i.p.), alone and especially in addition to non-interrupted low-dose cisplatin (2 mg/kg i.p.), markedly abrogated xenograft progression, reducing tumor growth rates by 25 or 70%, respectively. After histological analysis, propranolol and cisplatin combined therapy resulted in low tumor mitotic index and increased tumor necrosis. Conclusions: Considering its robust antitumoral effects, β-AR antagonization using β-blocker propranolol seems to be an achievable and cost-effective therapeutic approach to modulate osteosarcoma aggressiveness, in addition to chemotherapy. Propranolol could be proposed as a co-adjuvant agent for the management of osteosarcoma, especially in low- and middle-income countries where access to treatment resources are limited. Further preclinical and clinical studies of propranolol repurposing in osteosarcoma are warranted.

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“…Different opinions about whether surgical margin and recurrence affect metastasis and survival [22,23]. Some studies suggested safe surgical margin only affects recurrence, and recurrence didn't increase metastasis and reduce survival [24][25][26]. However, more studies suggested the risk of local recurrence was leading to metastasis and reducing survival [6,27,28].…”

Section: Discussionmentioning

confidence: 99%

What Are the Results of Limb Salvage Surgery for Primary Malignant Bone Tumor in the Forearm?

Liu

Yang

Jin

et al. 2020

Preprint

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Background The forearm primary malignant bone tumor is rare and limb salvage is difficult. The purpose of this study was to analyze epidemiological characteristics of forearm primary malignant bone tumors and to explore oncological and functional results of limb salvage surgery in forearm.Methods 369 patients with primary forearm malignant bone tumors were retrospectively analyzed from 2000 to 2017. There were 266 patients with radius tumor and 46 (17.3%) of them were malignancy, while 103 patients with ulna lesion and 22 (21.4%) of them were malignant tumor. The oncological results, prognostic factors and functional results after limb salvage surgery of forearm malignancy were analyzed.Results A total of 60 patients received limb salvage surgery. Fifty-six patients followed more than 12 months or progressions within 12 months were included in final evaluation. Radius resection was performed in 38 patients and distal radius (25 patients) was most frequent. Ulna resection was performed in 18 patients and proximal ulna (13 patients) was most frequent. The surgical margin contained intracapsular resection in 3 patients, marginal resection in 8 patients and wide resection in 45 patients. The follow-up averaged 72.1 (7-192, median 62.5) months. Local recurrence occurred in 11 patients (19.6%) and distant metastasis occurred in 14 patients (25%). The 5-year recurrence free survival rates was 79.8%. Univariate analysis showed history of unplanned resection, tumor located in ulna, tumor located in proximal forearm and inadequate surgical margin were associated with recurrence. The overall 5-year and 10-year survival rates were 83.5% and 71.7%, respectively. Univariate analysis showed inadequate surgical margin, local recurrence and distant metastasis were associated with death. Forty-two patients were evaluated by MSTS score with an average of (93.0 ± 5.1) %.Conclusions The incidence of radius malignant tumor is higher than that of ulna. The distal radius and proximal ulna are most frequency involved sites. Unplanned resection, tumor located in ulna, tumor located in proximal forearm and inadequate surgical margin are risk factors for local recurrence; local recurrence and distant metastasis are independent prognostic factors of death. The oncology control and function result of limb salvage surgery was satisfactory.

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Factors influencing survival after recurrence in osteosarcoma: A report from the Children's Oncology Group

Cited by 40 publications

References 28 publications

Route of 41BB/41BBL Costimulation Determines Effector Function of B7-H3-CAR.CD28ζ T Cells

Route of 41BB/41BBL Costimulation Determines Effector Function of B7-H3-CAR.CD28ζ T Cells

Drug Repurposing of β-blocker Propranolol in Osteosarcoma: Preclinical Antitumor Efficacy Alone or in Combination with Chemotherapy.

What Are the Results of Limb Salvage Surgery for Primary Malignant Bone Tumor in the Forearm?

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