22 research outputs found
Targeted antiangiogenic agents in combination with cytotoxic chemotherapy in preclinical and clinical studies in sarcoma.
Sarcomas are a heterogeneous group of mesenchymal malignancies. In recent years, studies have demonstrated that inhibition of angiogenic pathways or disruption of established vasculature can attenuate the growth of sarcomas. However, when used as monotherapy in the clinical setting, these targeted antiangiogenic agents have only provided modest survival benefits in some sarcoma subtypes, and have not been efficacious in others. Preclinical and early clinical data suggest that the addition of conventional chemotherapy to antiangiogenic agents may lead to more effective therapies for patients with these tumors. In the current review, the authors summarize the available evidence and possible mechanisms supporting this approach
Phase 1 study of sirolimus in combination with oral cyclophosphamide and topotecan in children and young adults with relapsed and refractory solid tumors.
PurposeTo determine the maximum tolerated dose (MTD), toxicities, and pharmacodynamics effects of sirolimus combined with oral metronomic topotecan and cyclophosphamide in a pediatric population.Materials and methodsPatients who were 1 to 30 years of age with relapsed/refractory solid tumors (including CNS) were eligible. Patients received daily oral sirolimus and cyclophosphamide (25-50 mg/m2/dose) on days 1-21 and oral topotecan (0.8 mg/m2/dose) on days 1-14 in 28-day cycles. Sirolimus steady-state plasma trough concentrations of 3-7.9 ng/mL and 8-12.0 ng/mL were evaluated, with dose escalation based on a 3+3 phase 1 design. Biomarkers of angiogenesis were also evaluated.ResultsTwenty-one patients were treated (median age 18 years; range 9-30). Dose-limiting toxicities included myelosuppression, ALT elevation, stomatitis, and hypertriglyceridemia. The MTD was sirolimus with trough goal of 8-12.0 ng/mL; cyclophosphamide 25 mg/m2/dose; and topotecan 0.8 mg/m2/dose. No objective responses were observed. Four patients had prolonged stable disease > 4 cycles (range 4-12). Correlative biomarker analyses demonstrated reductions in thrombospondin-1 (p=0.043) and soluble vascular endothelial growth factor receptor-2 plasma concentrations at 21 days compared to baseline.ConclusionsThe combination of oral sirolimus, topotecan, and cyclophosphamide was well tolerated and biomarker studies demonstrated modulation of angiogenic pathways with this regimen
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Detection of circulating tumour DNA is associated with inferior outcomes in Ewing sarcoma and osteosarcoma: a report from the Children's Oncology Group.
BackgroundNew prognostic markers are needed to identify patients with Ewing sarcoma (EWS) and osteosarcoma unlikely to benefit from standard therapy. We describe the incidence and association with outcome of circulating tumour DNA (ctDNA) using next-generation sequencing (NGS) assays.MethodsA NGS hybrid capture assay and an ultra-low-pass whole-genome sequencing assay were used to detect ctDNA in banked plasma from patients with EWS and osteosarcoma, respectively. Patients were coded as positive or negative for ctDNA and tested for association with clinical features and outcome.ResultsThe analytic cohort included 94 patients with EWS (82% from initial diagnosis) and 72 patients with primary localised osteosarcoma (100% from initial diagnosis). ctDNA was detectable in 53% and 57% of newly diagnosed patients with EWS and osteosarcoma, respectively. Among patients with newly diagnosed localised EWS, detectable ctDNA was associated with inferior 3-year event-free survival (48.6% vs. 82.1%; p = 0.006) and overall survival (79.8% vs. 92.6%; p = 0.01). In both EWS and osteosarcoma, risk of event and death increased with ctDNA levels.ConclusionsNGS assays agnostic of primary tumour sequencing results detect ctDNA in half of the plasma samples from patients with newly diagnosed EWS and osteosarcoma. Detectable ctDNA is associated with inferior outcomes
Impact of Two Measures of Micrometastatic Disease on Clinical Outcomes in Patients with Newly Diagnosed Ewing Sarcoma: A Report from the Children's Oncology Group
Targeted antiangiogenic agents in combination with cytotoxic chemotherapy in preclinical and clinical studies in sarcoma.
Phase 1 study of sirolimus in combination with oral cyclophosphamide and topotecan in children and young adults with relapsed and refractory solid tumors.
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Targeted antiangiogenic agents in combination with cytotoxic chemotherapy in preclinical and clinical studies in sarcoma.
Sarcomas are a heterogeneous group of mesenchymal malignancies. In recent years, studies have demonstrated that inhibition of angiogenic pathways or disruption of established vasculature can attenuate the growth of sarcomas. However, when used as monotherapy in the clinical setting, these targeted antiangiogenic agents have only provided modest survival benefits in some sarcoma subtypes, and have not been efficacious in others. Preclinical and early clinical data suggest that the addition of conventional chemotherapy to antiangiogenic agents may lead to more effective therapies for patients with these tumors. In the current review, the authors summarize the available evidence and possible mechanisms supporting this approach
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Precision Medicine in Pediatric Oncology
Improvements in outcome have been seen in children and adolescents with cancer. Nevertheless, challenges remain in trying to improve the outcomes for all children diagnosed with cancer, particularly in patients with metastatic disease or with cancers that are resistant or recur after standard treatment. Precision medicine trials using individualized tumor molecular profiling for selection of targeted therapies are ongoing in adult malignancies. Similar approaches are being applied to children and adolescents with cancer. This article describes how precision medicine is being applied to pediatric oncology and the unique challenges being faced with these efforts
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Incorporating Radiomics into Machine Learning Models to Predict Outcomes of Neuroblastoma
Neuroblastoma is one of the most common pediatric cancers. This study used machine learning (ML) to predict the mortality and a few other investigated intermediate outcomes of neuroblastoma patients non-invasively from CT images. Performances of multiple ML algorithms over retrospective CT images of 65 neuroblastoma patients are analyzed. An artificial neural network (ANN) is used on tumor radiomic features extracted from 3D CT images. A pre-trained 2D convolutional neural network (CNN) is used on slices of the same images. ML models are trained for various pathologically investigated outcomes of these patients. A subspecialty-trained pediatric radiologist independently reviewed the manually segmented primary tumors. Pyradiomics library is used to extract 105 radiomic features. Six ML algorithms are compared to predict the following outcomes: mortality, presence or absence of metastases, neuroblastoma differentiation, mitosis-karyorrhexis index (MKI), presence or absence of MYCN gene amplification, and presence of image-defined risk factors (IDRF). The prediction ranges over multiple experiments are measured using the area under the receiver operating characteristic (ROC-AUC) for comparison. Our results show that the radiomics-based ANN method slightly outperforms the other algorithms in predicting all outcomes except classification of the grade of neuroblastic differentiation, for which the elastic regression model performed the best. Contributions of the article are twofold: (1) noninvasive models for the prognosis from CT images of neuroblastoma, and (2) comparison of relevant ML models on this medical imaging problem
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Risk Factors for Transplant-Associated Thrombotic Microangiopathy after Autologous Hematopoietic Cell Transplant in High-Risk Neuroblastoma
High-risk neuroblastoma has a poor prognosis, and research studies have shown that increasing the intensity of therapy improves outcomes. Autologous hematopoietic cell transplant (aHCT) as consolidation therapy confers a significant survival advantage but is accompanied by significant morbidity. Transplant-associated thrombotic microangiopathy (TA-TMA) is a life-threatening complication caused by endothelial injury that often leads to hemolytic anemia, microthrombotic platelet consumption, and renal injury. Here we investigated the incidence, potential risk factors, and sequelae of TA-TMA in patients with high-risk neuroblastoma. We conducted a retrospective chart review of all patients (n = 141) with neuroblastoma in our institutions who underwent aHCT from 2000 to 2017. Ten patients (7%) developed TA-TMA. The patients in the TA-TMA group were similar to the rest of the subjects in demographics, disease burden, prior therapies, renal function, and timing of transplant. The type of conditioning regimen was the only statistically significant pretransplant variable (P < .001). Six of 15 patients (40%) intended to receive tandem transplants (cyclophosphamide/thiotepa and then carboplatin/etoposide/melphalan (CEM)), 4 of 68 patients (6%) who received conditioning with single CEM, and none of the 56 patients who received busulfan/melphalan were diagnosed with TA-TMA. Patients with TA-TMA were more likely to require intensive care unit transfer, have a longer length of stay in the hospital, and experience a delay or change in their subsequent therapy. In our cohort overall, patients with a delay in therapy after transplant appeared to have a worse overall survival, although the difference was not statistically significant. Because of this high incidence and significant morbidity, we have implemented standardized screening for TA-TMA during and after transplant. We anticipate that screening will lead to earlier intervention and decreased severity of disease