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Current Oncology (Toronto, Ont.) Feb 2022In recent years, modifications of treatment protocols introduced in pediatric oncology have resulted in a significant improvement in treatment outcomes. Unfortunately,...
BACKGROUND
In recent years, modifications of treatment protocols introduced in pediatric oncology have resulted in a significant improvement in treatment outcomes. Unfortunately, the probability of subsequent malignant neoplasm (SMN) in this group of patients is 3 to 6 times higher than the general age-matched population. In this study, we sought to evaluate the treatment options for patients with secondary bone tumors after prior anti-cancer therapy.
MATERIALS AND METHODS
Twenty-four patients (median age 12.9 years) with subsequent malignant bone tumors were treated according to oncological guidelines for bone sarcoma during the period 1991-2020. All patients had a standard tumor imaging and laboratory evaluation. All toxicities were documented.
RESULTS
The median time from the first neoplasm to SMN was 7.6 years (range 2.4 to 16.3 years). All patients received chemotherapy and underwent surgery as a local control procedure. Two patients with Ewing sarcoma had additional radiation on the tumor bed. A complete response was achieved in 20 patients. With a median follow-up of 18.3 years (range 5.7 to 40.3 years), 18 patients (75%) are alive. The estimated 5-year post-subsequent bone malignant neoplasm survival was 74.5% (95% CI 55-95%). Fourteen patients required chemotherapy dose modification, and doxorubicin was discontinued in seven patients. One patient required a renal transplant two years after treatment. There were no other significant toxicities.
CONCLUSIONS
The treatment of bone SMNs can be effective, although in many patients it is necessary to reduce the doses of drugs. Early detection and aggressive treatment can improve the outcome.
Topics: Adolescent; Bone Neoplasms; Child; Combined Modality Therapy; Doxorubicin; Humans; Sarcoma; Sarcoma, Ewing
PubMed: 35200584
DOI: 10.3390/curroncol29020085 -
International Journal of Molecular... Sep 2020Osteosarcoma is the most common primary malignant bone tumour in children and adolescents. Due to micrometastatic spread, radical surgery alone rarely results in cure.... (Review)
Review
Osteosarcoma is the most common primary malignant bone tumour in children and adolescents. Due to micrometastatic spread, radical surgery alone rarely results in cure. Introduction of combination chemotherapy in the 1970s, however, dramatically increased overall survival rates from 20% to approximately 70%. Unfortunately, large clinical trials aiming to intensify treatment in the past decades have failed to achieve higher cure rates. In this review, we revisit how the heterogenous nature of osteosarcoma as well as acquired and intrinsic resistance to chemotherapy can account for stagnation in therapy improvement. We summarise current osteosarcoma treatment strategies focusing on molecular determinants of treatment susceptibility and resistance. Understanding therapy susceptibility and resistance provides a basis for rational therapy betterment for both identifying patients that might be cured with less toxic interventions and targeting resistance mechanisms to sensitise resistant osteosarcoma to conventional therapies.
Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Disease-Free Survival; Drug Resistance, Neoplasm; Humans; Osteosarcoma; Survival Rate
PubMed: 32961800
DOI: 10.3390/ijms21186885 -
The American Journal of Surgical... Apr 2018ACTB-GLI1 fusions have been reported as the pathognomonic genetic abnormality defining an unusual subset of actin-positive, perivascular myoid tumors, known as...
A Distinct Malignant Epithelioid Neoplasm With GLI1 Gene Rearrangements, Frequent S100 Protein Expression, and Metastatic Potential: Expanding the Spectrum of Pathologic Entities With ACTB/MALAT1/PTCH1-GLI1 Fusions.
ACTB-GLI1 fusions have been reported as the pathognomonic genetic abnormality defining an unusual subset of actin-positive, perivascular myoid tumors, known as "pericytoma with the t(7;12) translocation." In addition, GLI1 oncogenic activation through a related MALAT1-GLI1 gene fusion has been recently reported in 2 unrelated gastric tumors, namely plexiform fibromyxoma and gastroblastoma. Triggered by unexpected targeted RNA-sequencing results detecting GLI1-related fusions in a group of malignant neoplasms with round to epithelioid morphology, and frequently strong S100 protein immunoreactivity, we investigated their clinicopathologic features in relation to other known pathologic entities sharing similar genetics. On the basis of a combined approach of targeted RNA sequencing and fluorescence in situ hybridization screening, we identified 6 cases with GLI1 gene fusions, including 4 fused to ACTB, 1 with MALAT1 and 1 with PTCH1 gene. Patients had a mean age of 36 years at diagnosis (range, 16 to 79 y) and slight female predilection all except 1 tumor originated in the soft tissue. Microscopically, the tumors had a monomorphic epithelioid phenotype arranged in a distinctive nested or cord-like architecture, separated by thin septae and delicate capillary network. All except 2 cases were strongly positive for S100 protein, whereas being negative for SOX10, SMA, and EMA. Only 1 tumor showed focal cytokeratin positivity in rare cells. Although the tumors showed some resemblance to pericytic/glomus tumors or myoepithelial tumors, the immunoprofile was not supportive of either lineage. Moreover, in contrast to the benign course of so-called pericytoma with t(7;12), 3 patients in this series developed metastatic disease to either lymph nodes or lung. In fact the only patient with lung metastases showed a novel PTCH1-GLI1 gene fusion. It remains to be determined whether these tumors represent a clinically and immunohistologically distinct subset of pericytoma, or an altogether novel soft tissue sarcoma. Our findings open new opportunities for targeted therapy, as tumors with GLI1 oncogenic activation, and subsequent PTCH1 overexpression, might be sensitive to sonic hedgehog pathway inhibitors.
Topics: Actins; Adolescent; Adult; Aged; Biomarkers, Tumor; Biopsy; Bone Neoplasms; Epithelioid Cells; Female; Gene Fusion; Gene Rearrangement; Genetic Predisposition to Disease; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Male; Middle Aged; Neoplasm Metastasis; Patched-1 Receptor; Phenotype; RNA, Long Noncoding; S100 Proteins; Soft Tissue Neoplasms; Young Adult; Zinc Finger Protein GLI1
PubMed: 29309307
DOI: 10.1097/PAS.0000000000001010 -
Archives of Pathology & Laboratory... Jun 2017Chondroblastoma is a rare primary bone tumor of young people that typically arises in the ends of the long bones. Radiologic investigations show a small, circumscribed,... (Review)
Review
Chondroblastoma is a rare primary bone tumor of young people that typically arises in the ends of the long bones. Radiologic investigations show a small, circumscribed, lytic lesion. The tumor is characterized histologically by the proliferation of chondroblasts along with areas of mature cartilage, giant cells, and occasionally, secondary aneurysmal bone cyst formation. Chondroblastoma, however, may also present with atypical features, such as prominent hemosiderin deposition, numerous giant cells, or the presence of a large aneurysmal bone cyst component. Malignant entities such as clear cell chondrosarcoma and chondroblastic osteosarcoma must also be considered. Recently, immunohistochemical stains such as DOG1 and SOX9 have been described in chondroblastoma, and K36M mutations in either the H3F3A or H3F3B genes have also been identified. While generally regarded as a benign entity, chondroblastoma manifests an intermediate type of behavior, given its ability to recur locally, and rarely, metastasize.
Topics: Amino Acid Substitution; Anoctamin-1; Bone Neoplasms; Bone and Bones; Chloride Channels; Chondroblastoma; Chondrosarcoma; Diagnosis, Differential; Histones; Humans; Mutation; Neoplasm Proteins; Neoplasm Recurrence, Local; Osteosarcoma; SOX9 Transcription Factor
PubMed: 28557595
DOI: 10.5858/arpa.2016-0281-RS -
Bone May 2022Metastasis is responsible for a large majority of death from malignant solid tumors. Bone is one of the most frequently affected organs in cancer metastasis, especially...
Metastasis is responsible for a large majority of death from malignant solid tumors. Bone is one of the most frequently affected organs in cancer metastasis, especially in breast and prostate cancer. Development of bone metastasis requires cancer cells to successfully complete a number of challenging steps, including local invasion and intravasation, survival in circulation, extravasation and initial seeding, and finally, formation of metastatic colonies after a period of dormancy or indolent growth. During this process, cancer cells often undergo a series of cellular and molecular changes to gain cellular plasticity that helps them adapt to various environments they encounter along the journey of metastasis. Understanding the mechanisms behind cellular plasticity and adaptation during the formation of bone metastasis is crucial for the development of novel therapies.
Topics: Bone Neoplasms; Cell Plasticity; Humans; Male; Neoplasm Metastasis; Prostatic Neoplasms
PubMed: 33069922
DOI: 10.1016/j.bone.2020.115693 -
Critical Reviews in Oncology/hematology Feb 2014The mechanisms underlying malignant cell metastasis to secondary sites such as bone are complex and no doubt multifactorial. Members of the small integrin-binding ligand... (Review)
Review
The mechanisms underlying malignant cell metastasis to secondary sites such as bone are complex and no doubt multifactorial. Members of the small integrin-binding ligand N-linked glycoproteins (SIBLINGs) family, particularly bone sialoprotein (BSP) and osteopontin (OPN), exhibit multiple activities known to promote malignant cell proliferation, detachment, invasion, and metastasis of several osteotropic cancers. The expression level of BSP and OPN is elevated in a variety of human cancers, particularly those that metastasize preferentially to the skeleton. Recent studies suggest that the "osteomimicry" of malignant cells is not only conferred by transmembrane receptors bound by BSP and OPN, but includes the "switch" in gene expression repertoire typically expressed in cells of skeletal lineage. Understanding the role of BSP and OPN in tumor progression, altered pathophysiology of bone microenvironment, and tumor metastasis to bone will likely result in development of better diagnostic approaches and therapeutic regimens for osteotropic malignant diseases.
Topics: Animals; Bone Neoplasms; Bone and Bones; Gene Expression Regulation, Neoplastic; Humans; Integrin-Binding Sialoprotein; Neoplasm Metastasis; Osteopontin
PubMed: 24071501
DOI: 10.1016/j.critrevonc.2013.08.013 -
International Journal of Molecular... Oct 2022The most prevalent malignant bone tumor, osteosarcoma, affects the growth plates of long bones in adolescents and young adults. Standard chemotherapeutic methods showed... (Review)
Review
The most prevalent malignant bone tumor, osteosarcoma, affects the growth plates of long bones in adolescents and young adults. Standard chemotherapeutic methods showed poor response rates in patients with recurrent and metastatic phases. Therefore, it is critical to develop novel and efficient targeted therapies to address relapse cases. In this regard, RNA interference technologies are encouraging options in cancer treatment, in which small interfering RNAs regulate the gene expression following RNA interference pathways. The determination of target tissue is as important as the selection of tissue-specific promoters. Moreover, small interfering RNAs should be delivered effectively into the cytoplasm. Lentiviral vectors could encapsulate and deliver the desired gene into the cell and integrate it into the genome, providing long-term regulation of targeted genes. Silencing overexpressed genes promote the tumor cells to lose invasiveness, prevents their proliferation, and triggers their apoptosis. The uniqueness of cancer cells among patients requires novel therapeutic methods that treat patients based on their unique mutations. Several studies showed the effectiveness of different approaches such as microRNA, drug- or chemotherapy-related methods in treating the disease; however, identifying various targets was challenging to understanding disease progression. In this regard, the patient-specific abnormal gene might be targeted using genomics and molecular advancements such as RNA interference approaches. Here, we review potential therapeutic targets for the RNA interference approach, which is applicable as a therapeutic option for osteosarcoma patients, and we point out how the small interfering RNA method becomes a promising approach for the unmet challenge.
Topics: Humans; Adolescent; RNA, Small Interfering; Neoplasm Recurrence, Local; Osteosarcoma; RNA Interference; Bone Neoplasms; MicroRNAs; RNA, Double-Stranded; Cell Line, Tumor
PubMed: 36293439
DOI: 10.3390/ijms232012583 -
The Oncologist 2004Bisphosphonates effectively inhibit osteoclast-mediated bone resorption and are integral in the treatment of benign and malignant bone diseases. The evolution of... (Review)
Review
Bisphosphonates effectively inhibit osteoclast-mediated bone resorption and are integral in the treatment of benign and malignant bone diseases. The evolution of bisphosphonates over the past 30 years has led to the development of nitrogen-containing bisphosphonates (N-BPs), which have a mechanism of action different from that of the nonnitrogen-containing bisphosphonates. Studies conducted over the past decade have elucidated the mechanism of action and pharmacologic properties of the N-BPs. N-BPs exert their effects on osteoclasts and tumor cells by inhibiting a key enzyme in the mevalonate pathway, farnesyl diphosphate synthase, thus preventing protein prenylation and activation of intracellular signaling proteins such as Ras. Recent evidence suggests that N-BPs also induce production of a unique adenosine triphosphate analogue (Apppi) that can directly induce apoptosis. Our increased understanding of the pharmacologic effects of bisphosphonates is shedding light on the mechanisms by which they exert antitumor effects. As a result of their biochemical effects on protein prenylation, N-BPs induce caspase-dependent apoptosis, inhibit matrix metalloproteinase activity, and downregulate alpha(v)beta(3) and alpha(v)beta(5) integrins. In addition, zoledronic acid (Zometa; Novartis Pharmaceuticals Corp.; East Hanover, NJ and Basel, Switzerland) exerts synergistic antitumor activity when combined with other anticancer agents. Zoledronic acid also inhibits tumor cell adhesion to the extracellular matrix and invasion through Matrigel trade mark and has antiangiogenic activity. A growing body of evidence from animal models demonstrates that zoledronic acid and other bisphosphonates can reduce skeletal tumor burden and prevent metastasis to bone. Further studies are needed to fully elucidate these biochemical mechanisms and to determine if the antitumor potential of bisphosphonates translates to the clinical setting.
Topics: Animals; Apoptosis; Bone Neoplasms; Cell Adhesion; Diphosphonates; Disease Models, Animal; Humans; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; Osteoclasts; Signal Transduction
PubMed: 15459425
DOI: 10.1634/theoncologist.9-90004-3 -
Cells Apr 2022Ewing sarcoma (ES) is a rare aggressive cancer of bone and soft tissue that is mainly characterized by a reciprocal chromosomal translocation. As a result, about 90% of... (Review)
Review
Ewing sarcoma (ES) is a rare aggressive cancer of bone and soft tissue that is mainly characterized by a reciprocal chromosomal translocation. As a result, about 90% of cases express the EWS-FLI1 fusion protein that has been shown to function as an aberrant transcription factor driving sarcomagenesis. ES is the second most common malignant bone tumor in children and young adults. Current treatment modalities include dose-intensified chemo- and radiotherapy, as well as surgery. Despite these strategies, patients who present with metastasis or relapse still have dismal prognosis, warranting a better understanding of treatment resistant-disease biology in order to generate better prognostic and therapeutic tools. Since the genomes of ES tumors are relatively quiet and stable, exploring the contributions of epigenetic mechanisms in the initiation and progression of the disease becomes inevitable. The search for novel biomarkers and potential therapeutic targets of cancer metastasis and chemotherapeutic drug resistance is increasingly focusing on long non-coding RNAs (lncRNAs). Recent advances in genome analysis by high throughput sequencing have immensely expanded and advanced our knowledge of lncRNAs. They are non-protein coding RNA species with multiple biological functions that have been shown to be dysregulated in many diseases and are emerging as crucial players in cancer development. Understanding the various roles of lncRNAs in tumorigenesis and metastasis would determine eclectic avenues to establish therapeutic and diagnostic targets. In ES, some lncRNAs have been implicated in cell proliferation, migration and invasion, features that make them suitable as relevant biomarkers and therapeutic targets. In this review, we comprehensively discuss known lncRNAs implicated in ES that could serve as potential biomarkers and therapeutic targets of the disease. Though some current reviews have discussed non-coding RNAs in ES, to our knowledge, this is the first review focusing exclusively on ES-associated lncRNAs.
Topics: Bone Neoplasms; Child; Epigenesis, Genetic; Humans; Neoplasm Recurrence, Local; RNA, Long Noncoding; Sarcoma, Ewing; Young Adult
PubMed: 35455947
DOI: 10.3390/cells11081267 -
Journal of Extracellular Vesicles Jul 2021Distant organ metastasis, often termed as organotropic metastasis or metastatic organotropism, is a fundamental feature of malignant tumours and accounts for most... (Review)
Review
Distant organ metastasis, often termed as organotropic metastasis or metastatic organotropism, is a fundamental feature of malignant tumours and accounts for most cancer-related mortalities. This process is orchestrated by many complex biological interactions and processes that are mediated by a combination of anatomical, genetic, pathophysiological and biochemical factors. Recently, extracellular vesicles (EVs) are increasingly being demonstrated as critical mediators of bi-directional tumour-host cell interactions, controlling organ-specific infiltration, adaptation and colonization at the secondary site. EVs govern organotropic metastasis by modulating the pre-metastatic microenvironment through upregulation of pro-inflammatory gene expression and immunosuppressive cytokine secretion, induction of phenotype-specific differentiation and recruitment of specific stromal cell types. This review discusses EV-mediated metastatic organotropism in visceral (brain, lung, liver, and lymph node) and skeletal (bone) metastasis, and discusses how the pre-metastatic education by EVs transforms the organ into a hospitable, tumour cell-friendly milieu that supports the growth of metastatic cells. Decoding the organ-specific traits of EVs and their functions in organotropic metastasis is essential in accelerating the clinical application of EVs in cancer management.
Topics: Animals; Bone Neoplasms; Brain Neoplasms; Extracellular Vesicles; Humans; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Neoplasm Metastasis
PubMed: 34295457
DOI: 10.1002/jev2.12125