Pazopanib in Patients with Osteosarcoma Metastatic to the Lung: Phase 2 Study Results and the Lessons for Tumor Measurement

Background. This single-arm, multicenter, phase 2 study evaluated the safety and antitumor activity of pazopanib in patients with unresectable, pulmonary metastatic osteosarcoma. Patients and Methods. Patients with pulmonary metastatic osteosarcoma unresponsive to chemotherapy were eligible. Patients who received prior tyrosine kinase inhibitor therapy were excluded. Pazopanib at 800 mg once daily was administered for 28-day cycles. Tumor responses were evaluated by local radiology assessment 1 month prior to and after initiation of treatment to calculate tumor doubling time and after every even numbered cycle. The primary endpoints were progression-free survival at 4 months, concomitant with a demonstrated 30% increase in tumor doubling time relative to the pretreatment growth rate. Results. 12 patients (7 female) were enrolled. The study was terminated prematurely due to withdrawal of financial support by the sponsor. 8 subjects were eligible for the primary analysis, whereas 4 patients were in a predefined exploratory “slow-growing” cohort. In the “fast-growing” cohort, 3 of the 8 patients (37.5%) eligible for first-stage analysis were deemed “success” by the preplanned criteria, adequate to proceed to second-stage accrual. In addition, 1 of the 4 patients in the “slow-growing” cohort experienced a partial remission. Grade 1-2 diarrhea was the most common adverse event, and grade 3 events were infrequent. Conclusion. This study illustrates a novel method of demonstrating positive drug activity in osteosarcoma by increasing tumor doubling time, and this is further supported by a partial response in a patient with “slow-growing” disease. This trial is registered with NCT01759303.

Osteosarcoma and Metastasis

Osteosarcoma is the most common primary bone malignancy in adolescents. Its high propensity to metastasize is the leading cause for treatment failure and poor prognosis. Although the research of osteosarcoma has greatly expanded in the past decades, the knowledge and new therapy strategies targeting metastatic progression remain sparse. The prognosis of patients with metastasis is still unsatisfactory. There is resonating urgency for a thorough and deeper understanding of molecular mechanisms underlying osteosarcoma to develop innovative therapies targeting metastasis. Toward the goal of elaborating the characteristics and biological behavior of metastatic osteosarcoma, it is essential to combine the diverse investigations that are performed at molecular, cellular, and animal levels from basic research to clinical translation spanning chemical, physical sciences, and biology. This review focuses on the metastatic process, regulatory networks involving key molecules and signaling pathways, the role of microenvironment, osteoclast, angiogenesis, metabolism, immunity, and noncoding RNAs in osteosarcoma metastasis. The aim of this review is to provide an overview of current research advances, with the hope to discovery druggable targets and promising therapy strategies for osteosarcoma metastasis and thus to overcome this clinical impasse.

CCL4 Stimulates Cell Migration in Human Osteosarcoma via the mir-3927-3p/Integrin αvβ3 Axis

Osteosarcoma is the most common type of primary malignant bone cancer, and it is associated with high rates of pulmonary metastasis. Integrin αvβ3 is critical for osteosarcoma cell migratory and invasive abilities. Chemokine (C-C motif) ligand 4 (CCL4) has diverse effects on different cancer cells through its interaction with its specific receptor, C-C chemokine receptor type 5 (CCR5). Analysis of mRNA expression in human osteosarcoma tissue identified upregulated levels of CCL4, integrin αv and β3 expression. Similarly, an analysis of records from the Gene Expression Omnibus (GEO) dataset showed that CCL4 was upregulated in human osteosarcoma tissue. Importantly, the expression of both CCL4 and integrin αvβ3 correlated positively with osteosarcoma clinical stages and lung metastasis. Analysis of osteosarcoma cell lines identified that CCL4 promotes integrin αvβ3 expression and cell migration by activating the focal adhesion kinase (FAK), protein kinase B (AKT), and hypoxia inducible factor 1 subunit alpha (HIF-1α) signaling pathways, which can downregulate microRNA-3927-3p expression. Pharmacological inhibition of CCR5 by maraviroc (MVC) prevented increases in integrin αvβ3 expression and cell migration. This study is the first to implicate CCL4 as a potential target in the treatment of metastatic osteosarcoma.

Low GNG12 Expression Predicts Adverse Outcomes: A Potential Therapeutic Target for Osteosarcoma

BackgroundG protein subunit gamma 12 (GNG12) is observed in some types of cancer, but its role in osteosarcoma is unknown. This study hypothesized that GNG12 may be a potential biomarker and therapeutic target. We aimed to identify an association between GNG12 and osteosarcoma based on the Gene Expression Omnibus and the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) databases.MethodsOsteosarcoma samples in GSE42352 and TARGET database were selected as the test cohorts. As the external validation cohort, 78 osteosarcoma specimens from The Second Affiliated Hospital of Nanchang University were collected. Patients with osteosarcoma were divided into high and low GNG12 mRNA-expression groups; differentially expressed genes were identified as GNG12-related genes. The biological function of GNG12 was annotated using Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, gene set enrichment analysis, and immune infiltration analysis. Gene expression correlation analysis and competing endogenous RNA regulatory network construction were used to determine potential biological regulatory relationships of GNG12. Overall survival, Kaplan–Meier analysis, and log-rank tests were calculated to determine GNG12 reliability in predicting survival prognosis.ResultsGNG12 expression decreased in osteosarcoma samples. GNG12 was a highly effective biomarker for osteosarcoma [area under the receiver operating characteristic (ROC) curve (AUC) = 0.920], and the results of our Kaplan–Meier analysis indicated that overall survival and progression-free survival differed significantly between low and high GNG-expression group (p < 0.05). Functional analyses indicated that GNG12 may promote osteosarcoma through regulating the endoplasmic reticulum. Expression correlation analysis and competing endogenous RNA network construction showed that HOTTIP/miR-27a-3p may regulate GNG12 expression. Furthermore, the subunit suppresses adaptive immunity via inhibiting M1 and M2 macrophage infiltration. GNG12 was inhibited in metastatic osteosarcoma compared with non-metastatic osteosarcoma, and its expression predicted survival of patients (1, 3, and 5-year AUCs were 0.961, 0.826, and 0.808, respectively).ConclusionThis study identified GNG12 as a potential biomarker for osteosarcoma prognosis, highlighting its potential as an immunotherapy target.

Cutaneous metastatic osteosarcoma – A rare case report

Introduction/Objective Osteosarcoma is an aggressive malignant primary bone tumor with common metastases to lungs via hematogenous spread. Other common sites of metastasis include bone and kidneys. Metastasis (excluding extraskeletal) to the skin is extremely rare. To date, roughly 12 cases of cutaneous metastasis have been reported in the literature. Methods/Case Report We report a 44-year-old female patient with a history of osteosarcoma of proximal tibia who underwent wide local excision in 2018 and subsequent chemotherapy. Approximately 2 years after her initial diagnosis, she presented with a painful mass in the left mid-thigh. Imaging studies revealed a 1.7 cm calcified nodule suspicious for metastatic osteosarcoma or a partially calcified granuloma. Fat necrosis and old hematoma were also considered in the radiographic differential, although less likely. An excisional biopsy was performed, which showed a high grade osteoid-producing tumor involving the deep dermis and subcutaneous adipose tissue confirming a metastasis of osteosarcoma. A new skin nodule developed at the same site six months later; though radiographic imaging studies were suggestive of subcutaneous fat stranding in the setting of cellulitis or vascular insufficiency. Given her prior history, another excisional biopsy was performed, which showed recurrent metastatic osteosarcoma. Results (if a Case Study enter NA) NA Conclusion Metastatic osteosarcoma to the skin is a rarely reported event in the literature. The prior clinical history and high index of clinical suspicion are essential in rendering the correct diagnosis. As the skin may be the first site of metastases it is important to include metastatic osteosarcoma in the differential in patients with a prior history of osteosarcoma who develops new skin or subcutaneous lesions. This case highlights the importance of providing history to the pathologist, as other tumors and non-neoplastic lesions can mimic osteosarcoma, particularly in small biopsy specimens. The easier access to the skin/ subcutis could also aid in obtaining tissue for molecular testing.

A Typical Perplexing Life-sustaining Therapy Decision at the End of life: A Case Report from Sri Lanka with Attributes Potentially worth Adopting from the UK Legislature

In many developing parts of the world, evidence on advance care planning (ACP) is either lacking or fragmented. Lack of streamlined means for ACP is known to lead to inconveniences for the clinicians as well as the patients and their families. This case report focuses on a young male diagnosed with metastatic osteosarcoma, who explicitly verbalised his wishes to be managed conservatively without involving invasive life-sustaining measures. However, the patient faced cardiopulmonary resuscitation before his demise against his wishes, which also contradicted with the medical point of view. Sri Lankan doctors face moral, ethical and legal dilemmas as they deal with terminally ill patients at the verge of their death due to the deficiencies in the medical and legislative frameworks in the country.