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Nature Reviews. Disease Primers Dec 2022Osteosarcoma is the most common primary malignant tumour of the bone. Osteosarcoma incidence is bimodal, peaking at 18 and 60 years of age, and is slightly more common... (Review)
Review
Osteosarcoma is the most common primary malignant tumour of the bone. Osteosarcoma incidence is bimodal, peaking at 18 and 60 years of age, and is slightly more common in males. The key pathophysiological mechanism involves several possible genetic drivers of disease linked to bone formation, causing malignant progression and metastasis. While there have been significant improvements in the outcome of patients with localized disease, with event-free survival outcomes exceeding 60%, in patients with metastatic disease, event-free survival outcomes remain poor at less than 30%. The suspicion of osteosarcoma based on radiographs still requires pathological evaluation of a bone biopsy specimen for definitive diagnosis and CT imaging of the chest should be performed to identify lung nodules. So far, population-based screening and surveillance strategies have not been implemented due to the rarity of osteosarcoma and the lack of reliable markers. Current screening focuses only on groups at high risk such as patients with genetic cancer predisposition syndromes. Management of osteosarcoma requires a multidisciplinary team of paediatric and medical oncologists, orthopaedic and general surgeons, pathologists, radiologists and specialist nurses. Survivors of osteosarcoma require specialized medical follow-up, as curative treatment consisting of chemotherapy and surgery has long-term adverse effects, which also affect the quality of life of patients. The development of osteosarcoma model systems and related research as well as the evaluation of new treatment approaches are ongoing to improve disease outcomes, especially for patients with metastases.
Topics: Child; Humans; Quality of Life; Osteosarcoma; Bone Neoplasms
PubMed: 36481668
DOI: 10.1038/s41572-022-00409-y -
The Oncologist Jun 2006Methotrexate (MTX) is one of the most widely used anti-cancer agents, and administration of high-dose methotrexate (HDMTX) followed by leucovorin (LV) rescue is an... (Review)
Review
Methotrexate (MTX) is one of the most widely used anti-cancer agents, and administration of high-dose methotrexate (HDMTX) followed by leucovorin (LV) rescue is an important component in the treatment of a variety of childhood and adult cancers. HDMTX can be safely administered to patients with normal renal function by the use of alkalinization, hydration, and pharmacokinetically guided LV rescue. Despite these measures, HDMTX-induced renal dysfunction continues to occur in approximately 1.8% of patients with osteosarcoma treated on clinical trials. Prompt recognition and treatment of MTX-induced renal dysfunction are essential to prevent potentially life-threatening MTX-associated toxicities, especially myelosuppression, mucositis, and dermatitis. In addition to conventional treatment approaches, dialysis-based methods have been used to remove MTX with limited effectiveness. More recently carboxypeptidase-G(2) (CPDG(2)), a recombinant bacterial enzyme that rapidly hydrolyzes MTX to inactive metabolites, has become available for the treatment of HDMTX-induced renal dysfunction. CPDG(2) administration has been well tolerated and resulted in consistent and rapid reductions in plasma MTX concentrations by a median of 98.7% (range, 84%-99.5%). The early administration of CPDG(2) in addition to LV may be beneficial for patients with MTX-induced renal dysfunction and significantly elevated plasma MTX concentrations.
Topics: Antimetabolites, Antineoplastic; Humans; Leucovorin; Methotrexate; Neoplasms; Renal Insufficiency; gamma-Glutamyl Hydrolase
PubMed: 16794248
DOI: 10.1634/theoncologist.11-6-694 -
Journal of Clinical Oncology : Official... Apr 2023For survivors of childhood cancer treated with doxorubicin, dexrazoxane is cardioprotective for at least 5 years. However, longer-term data are lacking.
PURPOSE
For survivors of childhood cancer treated with doxorubicin, dexrazoxane is cardioprotective for at least 5 years. However, longer-term data are lacking.
METHODS
Within the Children's Oncology Group and the Dana Farber Cancer Institute's Childhood Acute Lymphoblastic Leukemia Consortium, we evaluated four randomized trials of children with acute lymphoblastic leukemia or Hodgkin lymphoma, who received doxorubicin with or without dexrazoxane, and a nonrandomized trial of patients with osteosarcoma who all received doxorubicin with dexrazoxane. Cumulative doxorubicin doses ranged from 100 to 600 mg/m across these five trials, and dexrazoxane was administered uniformly (10:1 mg/m ratio) as an intravenous bolus before doxorubicin. Cardiac function was prospectively assessed in survivors from these trials, plus a matched group of survivors of osteosarcoma treated with doxorubicin without dexrazoxane. Two-dimensional echocardiograms and blood biomarkers were analyzed centrally in blinded fashion. Multivariate analyses adjusted for demographic characteristics, cumulative doxorubicin dose, and chest radiotherapy determined the differences and associations by dexrazoxane status.
RESULTS
From 49 participating institutions, 195 participants were assessed at 18.1 ± 2.7 years since cancer diagnosis (51% dexrazoxane-exposed; cumulative doxorubicin dose 297 ± 91 mg/m). Dexrazoxane administration was associated with superior left ventricular fractional shortening (absolute difference, +1.4% [95% CI, 0.3 to 2.5]) and ejection fraction (absolute difference, +1.6% [95% CI, 0.0 to 3.2]), and lower myocardial stress per B-type natriuretic peptide (-6.7 pg/mL [95% CI, -10.6 to -2.8]). Dexrazoxane was associated with a reduced risk of having lower left ventricular function (fractional shortening < 30% or ejection fraction < 50%; odds ratio, 0.24 [95% CI, 0.07 to 0.81]). This protective association was primarily seen in those treated with cumulative doxorubicin doses ≥ 250 mg/m.
CONCLUSION
Among young adult-aged survivors of childhood cancer, dexrazoxane was associated with a cardioprotective effect nearly 20 years after initial anthracycline exposure.
Topics: Young Adult; Child; Humans; Aged; Dexrazoxane; Cancer Survivors; Doxorubicin; Antibiotics, Antineoplastic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Osteosarcoma; Bone Neoplasms
PubMed: 36669148
DOI: 10.1200/JCO.22.02423 -
Annals of Oncology : Official Journal... Jun 2022Compared with adult cancers, pediatric cancers are uniquely characterized by a genomically stable landscape and lower tumor mutational burden. Alternative splicing,... (Review)
Review
BACKGROUND
Compared with adult cancers, pediatric cancers are uniquely characterized by a genomically stable landscape and lower tumor mutational burden. Alternative splicing, however, a global cellular process that produces different messenger RNA/protein isoforms from a single messenger RNA transcript, has been increasingly implicated in the development of pediatric cancers.
DESIGN
We review the current literature on the role of alternative splicing in adult cancer, cancer predisposition syndromes, and pediatric cancers. We also describe multiple splice variants identified in adult cancers and confirmed through comprehensive genomic profiling in our institutional cohort of rare, refractory, and relapsed pediatric and adolescent young adult cancer patients. Finally, we summarize the contributions of alternative splicing events to neoantigens and chemoresistance and prospects for splicing-based therapies.
RESULTS
Published dysregulated splicing events can be categorized as exon inclusion, exon exclusion, splicing factor up-regulation, or splice site alterations. We observe these phenomena in cancer predisposition syndromes (Lynch syndrome, Li-Fraumeni syndrome, CHEK2) and pediatric leukemia (B-cell acute lymphoblastic leukemia), sarcomas (Ewing sarcoma, rhabdomyosarcoma, osteosarcoma), retinoblastoma, Wilms' tumor, and neuroblastoma. Within our institutional cohort, we demonstrate splice variants in key regulatory genes (CHEK2, TP53, PIK3R1, MDM2, KDM6A, NF1) that resulted in exon exclusion or splice site alterations, which were predicted to impact functional protein expression and promote tumorigenesis. Differentially spliced isoforms and splicing proteins also impact neoantigen creation and treatment resistance, such as imatinib or glucocorticoid regimens. Additionally, splice-altering strategies with the potential to change the therapeutic landscape of pediatric cancers include antisense oligonucleotides, adeno-associated virus gene transfers, and small molecule inhibitors.
CONCLUSIONS
Alternative splicing plays a critical role in the formation and growth of pediatric cancers, and our institutional cohort confirms and highlights the broad spectrum of affected genes in a variety of cancers. Further studies that elucidate the mechanisms of disease-inducing splicing events will contribute toward the development of novel therapeutics.
Topics: Adolescent; Alternative Splicing; Carcinogenesis; Cell Transformation, Neoplastic; Child; Humans; Neoplasms; RNA, Messenger; Syndrome; Young Adult
PubMed: 35339647
DOI: 10.1016/j.annonc.2022.03.011 -
Frontiers in Public Health 2022Osteosarcoma (OSC) and Ewing's sarcoma (EWS) are children's most common primary bone tumors. The purpose of the study is to develop and validate a new nomogram to... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Osteosarcoma (OSC) and Ewing's sarcoma (EWS) are children's most common primary bone tumors. The purpose of the study is to develop and validate a new nomogram to predict the cancer-specific survival (CSS) of childhood OSC and EWS.
METHODS
The clinicopathological information of all children with OSC and EWS from 2004 to 2018 was downloaded from the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate Cox regression analyses were used to screen children's independent risk factors for CSS. These risk factors were used to construct a nomogram to predict the CSS of children with OSC and EWS. A series of validation methods, including calibration plots, consistency index (C-index), and area under the receiver operating characteristic curve (AUC), were used to validate the accuracy and reliability of the prediction model. Decision curve analysis (DCA) was used to validate the clinical application efficacy of predictive models. All patients were divided into low- and high-risk groups based on the nomogram score. Kaplan-Meier curve and log-rank test were used to compare survival differences between the two groups.
RESULTS
A total of 2059 children with OSC and EWS were included. All patients were randomly divided into training cohort 60% ( = 1215) and validation cohort 40% ( = 844). Univariate and multivariate analysis suggested that age, surgery, stage, primary site, tumor size, and histological type were independent risk factors. Nomograms were established based on these factors to predict 3-, 5-, and 8-years CSS of children with OSC and EWS. The calibration plots showed that the predicted value was highly consistent with the actual value. In the training cohort and validation cohort, the C-index was 0.729 (0.702-0.756) and 0.735 (0.702-0.768), respectively. The AUC of the training cohort and the validation cohort also showed similar results. The DCA showed that the nomogram had good clinical value.
CONCLUSION
We constructed a new nomogram to predict the CSS of OSC and EWS in children. This predictive model has good accuracy and reliability and can help doctors and patients develop clinical strategies.
Topics: Bone Neoplasms; Child; Humans; Nomograms; Osteosarcoma; Reproducibility of Results; Sarcoma, Ewing
PubMed: 35178367
DOI: 10.3389/fpubh.2022.837506 -
Archives of Pathology & Laboratory... Jan 2020Chondroblastoma-like osteosarcoma is an exceedingly rare variant of osteosarcoma, with 22 cases reported in the English-language literature. The tumor is slightly more... (Review)
Review
CONTEXT.—
Chondroblastoma-like osteosarcoma is an exceedingly rare variant of osteosarcoma, with 22 cases reported in the English-language literature. The tumor is slightly more common in males, with a broad age range (from childhood to elderly). The most commonly involved bones are the metatarsus and tibia, followed by the femur. Most tumors have malignant or worrisome radiographic findings. Prognosis is variable, depending on the presence or absence of lung metastases, local recurrence, and probably tumor location. Histologically, chondroblastoma-like osteosarcoma is characterized by monotonous, minimally to moderately atypical rounded cells with ovoid nuclei resembling chondroblastoma, and abnormal osteoid deposition with destruction of the bone.
OBJECTIVE.—
To review the clinical, radiographic, and histopathologic features of chondroblastoma-like osteosarcoma.
DATA SOURCES.—
PubMed-published chondroblastoma-like osteosarcoma cases in the English-language literature.
CONCLUSIONS.—
Although exceedingly rare, chondroblastoma-like osteosarcoma should be considered in the differential diagnosis of chondroblastoma, especially in the presence of radiologic findings suggestive of an aggressive lesion.
Topics: Bone Neoplasms; Chondroblastoma; Diagnosis, Differential; Humans; Osteosarcoma
PubMed: 31389716
DOI: 10.5858/arpa.2019-0191-RA -
Oncology Letters Feb 2018Sarcomas arise from primitive mesenchymal cells, which are classified, into two main groups: Bone and soft tissue sarcomas. We have searched all-important electronic...
Sarcomas arise from primitive mesenchymal cells, which are classified, into two main groups: Bone and soft tissue sarcomas. We have searched all-important electronic databases including Google scholar and PubMed for the collection of latest literature pertaining to pediatric sarcomas. Latest literature confirmed that these tumors are relatively rare and represent only 1% of all malignancies but they have higher incidence in children. Pediatric sarcomas comprise about 13% of all pediatric malignancies and are ranked third in childhood cancers. The highest incidence rates are reported among rhabdomyosarcoma, osteosarcoma and Ewing's sarcomas in children. All of these neoplasms often display highly aggressive behavior with tendency to form metastases. Important globally used management avenues include surgery with systemic chemotherapy and have success rate of 70% at 5-years. Furthermore, in the cases of advanced stages, the prognosis is poor, chances of treatment failure and recurrence are quite high. Utilization of cancer stem cells is the latest approach with great potential in management of above pathological state. The present review article discuss all-important aspects of commonly found pediatric sarcomas throughout the world.
PubMed: 29434830
DOI: 10.3892/ol.2017.7467