Immunotherapy for osteosarcoma: Fundamental mechanism, rationale, and recent breakthroughs.

Malignant bone tumors

Ewing sarcoma, a highly aggressive bone and soft-tissue cancer, is considered a prime example of the paradigms of a translocation-positive sarcoma: a genetically rather simple disease with a specific and neomorphic-potential therapeutic target, whose oncogenic role was irrefutably defined decades ago. This is a disease that by definition has micrometastatic disease at diagnosis and a dismal prognosis for patients with macrometastatic or recurrent disease. International collaborations have defined the current standard of care in prospective studies, delivering multiple cycles of systemic therapy combined with local treatment; both are associated with significant morbidity that may result in strong psychological and physical burden for survivors. Nevertheless, the combination of non-directed chemotherapeutics and ever-evolving local modalities nowadays achieve a realistic chance of cure for the majority of patients with Ewing sarcoma. In this review, we focus on the current standard of diagnosis and treatment while attempting to answer some of the most pressing questions in clinical practice. In addition, this review provides scientific answers to clinical phenomena and occasionally defines the resulting translational studies needed to overcome the hurdle of treatment-associated morbidities and, most importantly, non-survival.

https://www.mdpi.com/2077-0383/10/8/1685/pdf

Ewing Sarcoma-Diagnosis, Treatment, Clinical Challenges and Future Perspectives.

Osteosarcoma (OS) is the most common orthopedic neoplasm, with a high metastasis rate and a dismal prognosis despite surgery and chemotherapy. Immunotherapies have offered cancer patients a ray of optimism, but their impact on OS has been disappointing. The objective of this study is to assess the effect of mono, dual, and triple combinations of CTLA‐4, PD‐L1, and TIM3 blockade on OS cell viability, apoptosis, and migration. The MG‐63 and U‐2 OS cell lines were transfected with mono, dual, and triple combinations of siRNAs specific for CTLA‐4, PD‐L1, and TIM3. After evaluation for transfection efficacy by qRT‐PCR, MTT assay and flow cytometry were applied to assess cell viability and apoptosis rate in siRNA‐transfected cells, respectively. Ultimately, the migration of transfected cells was measured by wound‐healing assay. First, the qRT‐PCR analysis revealed that in siRNA‐transfected OS cells, CTLA‐4, PD‐L1, and TIM3 were downregulated. The MTT assay and flow cytometry results confirmed that silencing of these immune checkpoints in dual or triple combinations, but not in the single‐agent blockade, significantly decreases cell viability and increases apoptosis, respectively. These effects were more significant when triple silencing was performed. Finally, the wound‐healing assay revealed that dual and triple silencing of immune checkpoints significantly inhibits cell migration, with triple silencing exhibiting a greater effect. Our findings suggest that triple blockade of CTLA‐4, PD‐L1, and TIM3 is an effective strategy for inhibiting tumor cell progression and migration in OS, which requires large‐scale clinical investigations to be translated into broad therapeutic applicability for OS patients.

Cancer combination therapies by silencing of CTLA‐4, PD‐L1, and TIM3 in osteosarcoma

Chest wall reconstruction in pediatric patients with chest wall tumors: A systematic review.

Intraabdominal metastases in the setting of osteosarcoma are very rare. We describe a case of a 17-year-old boy with high-grade right distal femur osteosarcoma who two years after diagnosis developed extensive intra abdominal metastases involving the omentum, peritoneum, bowel serosa, psoas muscles and abdominal soft tissue. Awareness of and surveillance for unusual patterns of metastasis may allow for earlier detection, intervention, and palliative care decision-making, which may affect survival and quality of life. This report underlines the need for prospective studies evaluating surveillance guidelines for patients after medical and surgical management of osteosarcoma, especially in cases complicated by pulmonary metastases.

Unusual abdominal metastases in osteosarcoma.

Objective We reviewed our experience with pediatric chest wall tumors (CWTs) to identify variables associated with survival, scoliosis development, and need for corrective scoliosis surgery. Background Chest wall neoplasms in children or adolescents are rare. Consequently, there are few large series that detail survival or quality of life indicators, like scoliosis. Methods Medical records were reviewed for all chest wall resections for primary and metastatic CWT performed from October 1, 1986 to September 30, 2016 on patients 21 years or younger at diagnosis. Kaplan-Meier distributions were compared using the log-rank test. Variables correlated with survival, scoliosis development, or need for corrective surgeries were analyzed using competing-risk analysis. Results Seventy-six cases [57 (75%) primary, 19 (25%) metastatic] were identified. Median age at diagnosis was 15.6 years (range: 0.5-21 years). Tumor types were Ewing sarcoma family tumors (54%), other soft tissue sarcomas (21%), osteosarcoma (11%), rhabdomyosarcoma (7%), and other (8%). A median of 3 (range: 1-5) contiguous ribs were resected. Surgical reconstruction included composite Marlex mesh and methyl-methacrylate, Gore-Tex, or primary closure in 57%, 28%, and 14% of procedures, respectively. Overall 5-year survival was 61% (95% confidence interval: 50%-75%). Scoliosis developed in 19 (25%) patients; 6 patients required corrective surgery. Variables associated with overall survival were the presence of metastatic disease at diagnosis, and whether the chest tumor itself was a primary or metastatic lesion. Younger age at chest wall resection was associated with the need for corrective surgery in patients who developed scoliosis. Conclusions Among pediatric and adolescent patients with CWTs, survival depends primarily on the presence of metastases. Age, type of chest wall reconstruction, and tumor size are not associated with scoliosis development. Among patients who develop scoliosis, younger patients are more likely to require corrective surgery.

Survival and Scoliosis Following Resection of Chest Wall Tumors in Children and Adolescents: A Single-center Retrospective Analysis.

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Unusual abdominal metastases in osteosarcoma.

Survival and Scoliosis Following Resection of Chest Wall Tumors in Children and Adolescents: A Single-center Retrospective Analysis.