scholarly journals Systematic Review of Recurrent Osteosarcoma Systemic Therapy

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1757
Author(s):  
Ioanna Gazouli ◽  
Anastasios Kyriazoglou ◽  
Ioannis Kotsantis ◽  
Maria Anastasiou ◽  
Anastasios Pantazopoulos ◽  
...  
Keyword(s):  
Clinical Evidence ◽  
Treatment Effectiveness ◽  
Treatment Strategies ◽  
Bone Cancer ◽  
Predictive Biomarkers ◽  
Mtor Inhibitors ◽  
Cytotoxic Chemotherapy ◽  
Driver Mutations ◽  
Preclinical Research ◽  
Primary Bone

Osteosarcoma is the most frequent primary bone cancer, mainly affecting those of young ages. Although surgery combined with cytotoxic chemotherapy has significantly increased the chances of cure, recurrent and refractory disease still impose a tough therapeutic challenge. We performed a systematic literature review of the available clinical evidence, regarding treatment of recurrent and/or refractory osteosarcoma over the last two decades. Among the 72 eligible studies, there were 56 prospective clinical trials, primarily multicentric, single arm, phase I or II and non-randomized. Evaluated treatment strategies included cytotoxic chemotherapy, tyrosine kinase and mTOR inhibitors and other targeted agents, as well as immunotherapy and combinatorial approaches. Unfortunately, most treatments have failed to induce objective responses, albeit some of them may sustain disease control. No driver mutations have been recognized, to serve as effective treatment targets, and predictive biomarkers of potential treatment effectiveness are lacking. Hopefully, ongoing and future clinical and preclinical research will unlock the underlying biologic mechanisms of recurrent and refractory osteosarcoma, expanding the therapeutic choices available to pre-treated osteosarcoma patients.

scholarly journals Molecular Biology of Osteosarcoma

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2130 ◽  
Author(s):  
Anna M. Czarnecka ◽  
Kamil Synoradzki ◽  
Wiktoria Firlej ◽  
Ewa Bartnik ◽  
Pawel Sobczuk ◽  
...  
Keyword(s):  
Werner Syndrome ◽  
Bone Cancer ◽  
Driver Mutations ◽  
Tumor Initiating Cells ◽  
Li Fraumeni Syndrome ◽  
Bifunctional Molecules ◽  
Diamond Blackfan Anemia ◽  
Genomic Studies ◽  
Primary Bone ◽  
Altered Gene

Osteosarcoma (OS) is the most frequent primary bone cancer in children and adolescents and the third most frequent in adults. Many inherited germline mutations are responsible for syndromes that predispose to osteosarcomas including Li Fraumeni syndrome, retinoblastoma syndrome, Werner syndrome, Bloom syndrome or Diamond–Blackfan anemia. TP53 is the most frequently altered gene in osteosarcoma. Among other genes mutated in more than 10% of OS cases, c-Myc plays a role in OS development and promotes cell invasion by activating MEK–ERK pathways. Several genomic studies showed frequent alterations in the RB gene in pediatric OS patients. Osteosarcoma driver mutations have been reported in NOTCH1, FOS, NF2, WIF1, BRCA2, APC, PTCH1 and PRKAR1A genes. Some miRNAs such as miR-21, -34a, -143, -148a, -195a, -199a-3p and -382 regulate the pathogenic activity of MAPK and PI3K/Akt-signaling pathways in osteosarcoma. CD133+ osteosarcoma cells have been shown to exhibit stem-like gene expression and can be tumor-initiating cells and play a role in metastasis and development of drug resistance. Although currently osteosarcoma treatment is based on adriamycin chemoregimens and surgery, there are several potential targeted therapies in development. First of all, activity and safety of cabozantinib in osteosarcoma were studied, as well as sorafenib and pazopanib. Finally, novel bifunctional molecules, of potential imaging and osteosarcoma targeting applications may be used in the future.

scholarly journals Parosteal Osteosarcoma with Pancreatic Metastasis and Multiple Relapses: A Case Report and Review of the Literature

2021 ◽  
pp. 983-988
Author(s):  
Daniel Cirotski ◽  
Jyoti Panicker
Keyword(s):  
Age Groups ◽  
Bone Cancer ◽  
Pancreatic Metastasis ◽  
Low Grade ◽  
Parosteal Osteosarcoma ◽  
Disease Course ◽  
Review Of The Literature ◽  
Histologic Subtype ◽  
Primary Bone ◽  
Multiple Relapses

Osteosarcoma is the most common primary bone cancer in all age groups. Metastasis mostly occurs with high-grade tumors disseminating to the lungs and other bones. Spread to the pancreas is rare and undocumented in the low-grade subtypes. Additionally, it is uncommon for the disease course of low-grade subtypes to involve multiple relapses. We present a 35-year-old woman with parosteal osteosarcoma who has experienced an atypical metastasis to the pancreas as well as multiple local and pulmonary relapses. The lesion was identified incidentally on routine imaging, and the patient underwent resection. We compare our case to the other reports of pancreatic metastasis in the literature. Despite being especially rare, clinicians ought to be aware of pancreatic metastasis of osteosarcoma. Furthermore, despite parosteal osteosarcoma’s less aggressive disease course, it can uncommonly lead to multiple relapses. We present a rare case exemplifying these phenomena in the prognostically favorable histologic subtype of parosteal osteosarcoma.

scholarly journals Gene expression-based biomarkers designating glioblastomas resistant to multiple treatment strategies

2021 ◽  
Author(s):  
Otília Menyhárt ◽  
János Tibor Fekete ◽  
Balázs Győrffy
Keyword(s):  
Gene Expression ◽  
Treatment Strategies ◽  
Area Under The Curve ◽  
Predictive Biomarkers ◽  
Subsequent Treatment ◽  
Survival Status ◽  
Multiple Treatment ◽  
Post Surgery ◽  
Potential Biomarker ◽  
Elevated Expression

Abstract Despite advances in molecular characterization of glioblastoma multiforme (GBM), only a handful of predictive biomarkers exist with limited clinical relevance. We aimed to identify differentially expressed genes in tumor samples collected at surgery associated with response to subsequent treatment, including temozolomide (TMZ) and nitrosoureas. Gene expression was collected from multiple independent datasets. Patients were categorized as responders/nonresponders based on their survival status at 16 months post-surgery. For each gene, the expression was compared between responders and nonresponders with a Mann-Whitney U test and receiver operating characteristic. The package "roc" was used to calculate the area under the curve (AUC). The integrated database comprises 454 GBM patients from three independent datasets and 10,103 genes. The highest proportion of responders (68%) were among patients treated with TMZ combined with nitrosoureas, where FCGR2B upregulation provided the strongest predictive value (AUC=0.72, p < 0.001). Elevated expression of CSTA and MRPS17 was associated with a lack of response to multiple treatment strategies. DLL3 upregulation was present in subsequent responders to any treatment combination containing TMZ. Three genes (PLSCR1, MX1, and MDM2) upregulated both in the younger cohort and in patients expressing low MGMT delineate a subset of patients with worse prognosis within a population generally associated with a favorable outcome. The identified transcriptomic changes provide biomarkers of responsiveness, offer avenues for preclinical studies, and may enhance future GBM patient stratifications. The described methodology provides a reliable pipeline for the initial testing of potential biomarker candidates for future validation studies.

scholarly journals Metabolic Interplay between the Immune System and Melanoma Cells: Therapeutic Implications

Biomedicines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 607
Author(s):  
Alice Indini ◽  
Francesco Grossi ◽  
Mario Mandalà ◽  
Daniela Taverna ◽  
Valentina Audrito
Keyword(s):  
Metabolic Pathways ◽  
Cancer Metabolism ◽  
Acquired Resistance ◽  
Treatment Strategies ◽  
Predictive Biomarkers ◽  
Treatment Resistance ◽  
Metastatic Potential ◽  
Biological Behavior ◽  
Therapeutic Implications ◽  
Systemic Treatments

Malignant melanoma represents the most fatal skin cancer due to its aggressive biological behavior and high metastatic potential. Treatment strategies for advanced disease have dramatically changed over the last years due to the introduction of BRAF/MEK inhibitors and immunotherapy. However, many patients either display primary (i.e., innate) or eventually develop secondary (i.e., acquired) resistance to systemic treatments. Treatment resistance depends on multiple mechanisms driven by a set of rewiring processes, which involve cancer metabolism, epigenetic, gene expression, and interactions within the tumor microenvironment. Prognostic and predictive biomarkers are needed to guide patients’ selection and treatment decisions. Indeed, there are no recognized clinical or biological characteristics that identify which patients will benefit more from available treatments, but several biomarkers have been studied with promising preliminary results. In this review, we will summarize novel tumor metabolic pathways and tumor-host metabolic crosstalk mechanisms leading to melanoma progression and drug resistance, with an overview on their translational potential as novel therapeutic targets.

scholarly journals Osteosarcoma and Metastasis Associated Bone Degradation—A Tale of Osteoclast and Malignant Cell Cooperativity

2021 ◽  
Vol 22 (13) ◽  
pp. 6865
Author(s):  
Kirstine Sandal Nørregaard ◽  
Henrik Jessen Jürgensen ◽  
Henrik Gårdsvoll ◽  
Lars Henning Engelholm ◽  
Niels Behrendt ◽  
...  
Keyword(s):  
Bone Metastasis ◽  
Cancer Cells ◽  
Bone Cancer ◽  
Degradation Process ◽  
Cell Types ◽  
Malignant Cell ◽  
Pathological Process ◽  
Course Of Disease ◽  
Bone Degradation ◽  
Primary Bone

Cancer-induced bone degradation is part of the pathological process associated with both primary bone cancers, such as osteosarcoma, and bone metastases originating from, e.g., breast, prostate, and colon carcinomas. Typically, this includes a cancer-dependent hijacking of processes also occurring during physiological bone remodeling, including osteoclast-mediated disruption of the inorganic bone component and collagenolysis. Extensive research has revealed the significance of osteoclast-mediated bone resorption throughout the course of disease for both primary and secondary bone cancer. Nevertheless, cancer cells representing both primary bone cancer and bone metastasis have also been implicated directly in bone degradation. We will present and discuss observations on the contribution of osteoclasts and cancer cells in cancer-associated bone degradation and reciprocal modulatory actions between these cells. The focus of this review is osteosarcoma, but we will also include relevant observations from studies of bone metastasis. Additionally, we propose a model for cancer-associated bone degradation that involves a collaboration between osteoclasts and cancer cells and in which both cell types may directly participate in the degradation process.

Genomic immunotherapy (IO) biomarkers detected on comprehensive genomic profiling (CGP) of tissue and circulating tumor DNA (ctDNA).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2541-2541
Author(s):  
Takayuki Yoshino ◽  
Hanna Tukachinsky ◽  
Jessica Kim Lee ◽  
Ethan Sokol ◽  
Dean C. Pavlick ◽  
...  
Keyword(s):  
Limit Of Detection ◽  
Predictive Biomarkers ◽  
Principal Component ◽  
Pathogenic Mutation ◽  
Circulating Tumor Dna ◽  
Driver Mutations ◽  
Cancer Type ◽  
Liquid Biopsies ◽  
Mutational Burden ◽  
Relative Prevalence

2541 Background: The dramatic impact of IO on treatment outcomes has heightened interest in predictive biomarkers, including genomic markers such as tumor mutational burden (TMB) and microsatellite instability (MSI). The recent FDA approval of pembrolizumab for previously treated advanced solid tumors with elevated TMB (≥10 mut/Mb on FoundationOne CDx, F1CDx) now requires a better understanding of the prevalence of this and other IO biomarkers detected on CGP, including differences between TMB detected in tissue and mutational burden detected in blood (bTMB). Methods: Tissue and plasma biopsies were profiled with two CGP panels of 324 genes with 0.8 Mb genome coverage (F1CDx and FoundationOne LiquidCDx). Mutational burden was calculated by counting somatic variants (single nucleotide and indels, including synonymous variants, excluding germline and driver mutations) with variant allele frequency (VAF) ≥5% in tissue (TMB) or ≥0.5% in ctDNA (bTMB). MSI score was assessed using 95 repetitive loci and principal component analysis (tissue) or >1,800 repetitive loci (plasma). ctDNA levels were estimated using composite tumor fraction (cTF), a metric based on aneuploidy and VAF. Results: Pan-cancer, TMB ≥10 was detected in 19% of tissue cases (29,238/156,294) and was common in melanoma (53%), small cell (41%), NSCLC (40%), bladder (39%), and endometrial (24%). bTMB ≥10 was detected in 13% of liquid biopsies (806/6,295); prevalence by cancer type was correlated with prevalence of elevated TMB (r = 0.81). Samples with bTMB ≥10 had an elevated cTF (median 13%, IQR 5 - 31%) as compared to samples with bTMB <10 (median 1.8%, IQR 0.6 - 7%, p < 0.001). Among 353 cases with both tissue and liquid CGP results (median 11 months apart), the relative prevalence of TMB ≥10 (12%) and bTMB ≥10 (13%) were similar, with concordant detection in 303 cases (86%). MSI-high (MSI-H) was seen in 2.2% of tissue CGP (3,461/156,294), most often in endometrial (19%), stomach (6.0%), and colorectal (5.3%) cancers, while MSI-H was detected in 0.68% of ctDNA specimens (43/6,295), which were also those with elevated cTF (median 11%, IQR 7 - 23%). Of 3,504 cases with MSI-H signature on tissue or liquid CGP, 1,619 (46%) had a pathogenic mutation detected in MLH1/MSH2/MSH6/PMS2 (15% predicted germline). CD274 amplification was detected in 1,207 cases (0.77%) of tissue CGP and 11 cases (0.17%) in ctDNA. Conclusions: Elevated bTMB is overall less prevalent than elevated tissue TMB, though these biomarkers are detected in similar cancer types. Detection of bTMB ≥10 and MSI-H in liquid biopsy was associated with elevated ctDNA levels, suggesting a limit of detection, and potentially indicating a more aggressive biology in samples positive for these biomarkers. Further investigation is needed to understand the utility of bTMB for identifying high TMB tumors that may benefit from IO.

Translational Research in Cutaneous Melanoma: New Therapeutic Perspectives

2018 ◽  
Vol 18 (2) ◽  
pp. 166-181 ◽  
Author(s):  
Antonio Marra ◽  
Cristina R. Ferrone ◽  
Celeste Fusciello ◽  
Giosue Scognamiglio ◽  
Soldano Ferrone ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Poor Prognosis ◽  
Immune Escape ◽  
Checkpoint Inhibitor ◽  
Predictive Biomarkers ◽  
Driver Mutations ◽  
Targeted Agents ◽  
Therapeutic Approaches ◽  
Aggressive Form ◽  
Immune Escape Mechanisms

Melanoma is an aggressive form of skin cancer characterized by poor prognosis and high mortality. The development of targeted agents based on the discovery of driver mutations as well as the implementation of checkpoint inhibitor-based immunotherapy represents a major breakthrough in the treatment of metastatic melanoma. However, in both cases the development of drug resistance and immune escape mechanisms as well as the lack of predictive biomarkers limits their extraordinary clinical efficacy. In this article, we summarize the available therapeutic options for patients with metastatic melanoma, outline the mechanisms implicated in the resistance to both targeted agents and immunotherapy, discuss potential predictive biomarkers and outline future therapeutic approaches under investigation.

scholarly journals From CPAP to tailored therapy for obstructive sleep apnoea

2018 ◽  
Vol 13 ◽  
Author(s):  
Peter A. Cistulli ◽  
Kate Sutherland ◽  
Kristina Kairaitis ◽  
Brendon J. Yee
Keyword(s):  
Obstructive Sleep Apnoea ◽  
Treatment Effectiveness ◽  
Treatment Strategies ◽  
Current Treatment ◽  
Sleep Apnoea ◽  
Patient Acceptance ◽  
Cpap Therapy ◽  
Individual Level ◽  
Obstructive Sleep ◽  
The Individual

Obstructive Sleep Apnoea (OSA) is a common sleep disorder that is associated with daytime symptoms and a range of comorbidity and mortality. Continuous Positive Airway Pressure (CPAP) therapy is highly efficacious at preventing OSA when in use and has long been the standard treatment for newly diagnosed patients. However, CPAP therapy has well recognised limitations in real world effectiveness due to issues with patient acceptance and suboptimal usage. There is a clear need to enhance OSA treatment strategies and options. Although there are a range of alternative treatments (e.g. weight loss, oral appliances, positional devices, surgery, and emerging therapies such as sedatives and oxygen), generally there are individual differences in efficacy and often OSA will not be completely eliminated. There is increasing recognition that OSA is a heterogeneous disorder in terms of risk factors, clinical presentation, pathophysiology and comorbidity. Better characterisation of OSA heterogeneity will enable tailored approaches to therapy to ensure treatment effectiveness. Tools to elucidate individual anatomical and pathophysiological phenotypes in clinical practice are receiving attention. Additionally, recognising patient preferences, treatment enhancement strategies and broader assessment of treatment effectiveness are part of tailoring therapy at the individual level. This review provides a narrative of current treatment approaches and limitations and the future potential for individual tailoring to enhance treatment effectiveness.

scholarly journals Osteosarcoma of the hard palate in a dog ˗ case report

2021 ◽  
Vol 73 (1) ◽  
pp. 207-213
Author(s):  
B.L. Silveira ◽  
G.D. Cassali ◽  
T.C.M. Lopes
Keyword(s):  
Computed Tomography ◽  
Hard Palate ◽  
Bone Cancer ◽  
Metronomic Chemotherapy ◽  
Surgical Excision ◽  
Well Being ◽  
Conventional Chemotherapy ◽  
Primary Bone ◽  
Firm Mass

ABSTRACT The osteosarcoma (OSA) is the most diagnosed primary bone cancer in canine patients. This work reports a case of a canine, six years old, mongrel, female, intact, with an OSA in the hard palate. Physical examination detected a firm mass in the palate. Thoracic radiographs, hematological and biochemical exams, histopathological exams and computed tomography were requested. A chondroblastic OSA was diagnosed and the tumor was characterized by immunohistochemistry. There was never evidence of metastasis in this case. The treatment consisted of the combination of conventional chemotherapy, metronomic chemotherapy, and palliative care, aiming at greater survival and well-being of the patient since surgical excision was not possible due to the location and extension of the tumor. Osteogenic sarcomas of the hard palate are rarely seen and described in the literature. In this article we present a characterization of the osteosarcoma with uncommon localization in the hard palate.

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