Publications by authors named "John A Livingston"

10 Publications

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Transcriptional activators YAP/TAZ and AXL orchestrate dedifferentiation, cell fate, and metastasis in human osteosarcoma.

Cancer Gene Ther 2021 Jan 6. Epub 2021 Jan 6.

Sarcoma Medical Oncology Department, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Osteosarcoma (OS) is a molecularly heterogeneous, aggressive, poorly differentiated pediatric bone cancer that frequently spreads to the lung. Relatively little is known about phenotypic and epigenetic changes that promote lung metastases. To identify key drivers of metastasis, we studied human CCH-OS-D OS cells within a previously described rat acellular lung (ACL) model that preserves the native lung architecture, extracellular matrix, and capillary network. This system identified a subset of cells-termed derived circulating tumor cells (dCTCs)-that can migrate, intravasate, and spread within a bioreactor-perfused capillary network. Remarkably, dCTCs highly expressed epithelial-to-mesenchymal transition (EMT)-associated transcription factors (EMT-TFs), such as ZEB1, TWIST, and SOX9, which suggests that they undergo cellular reprogramming toward a less differentiated state by coopting the same epigenetic machinery used by carcinomas. Since YAP/TAZ and AXL tightly regulate the fate and plasticity of normal mesenchymal cells in response to microenvironmental cues, we explored whether these proteins contributed to OS metastatic potential using an isogenic pair of human OS cell lines that differ in AXL expression. We show that AXL inhibition significantly reduced the number of MG63.2 pulmonary metastases in murine models. Collectively, we present a laboratory-based method to detect and characterize a pure population of dCTCs, which provides a unique opportunity to study how OS cell fate and differentiation contributes to metastatic potential. Though the important step of clinical validation remains, our identification of AXL, ZEB1, and TWIST upregulation raises the tantalizing prospect that EMT-TF-directed therapies might expand the arsenal of therapies used to combat advanced-stage OS.
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http://dx.doi.org/10.1038/s41417-020-00281-6DOI Listing
January 2021

Evaluating the Soft Tissue Sarcoma Paradigm for the Local Management of Extraskeletal Ewing Sarcoma.

Oncologist 2021 Mar 14;26(3):250-260. Epub 2020 Dec 14.

Departments of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Objectives: We reviewed our experience treating patients with localized extraskeletal Ewing sarcoma (EES) to determine optimal local management strategies for this rare disease.

Methods: Sixty patients with localized EES treated at our institution between 1994 and 2018 were reviewed. The Kaplan-Meier method was used to estimates disease outcomes.

Results: The median follow-up time was 74 months (interquartile range [IQR], 17-121). Half the patients (n = 30) received combined-modality local therapy (CMT) with both surgery and radiation therapy (RT), whereas the other half received single-modality local therapy (SMT) with either surgery or RT. All patients received chemotherapy. The 5-year overall survival was 76%. Twenty-two patients (37%) developed recurrence at a median time of 15 months (IQR, 5-56 months) resulting in 3-year progression-free survival (PFS) of 65%. On univariate analysis, the use of both neoadjuvant and adjuvant chemotherapy was associated with improved 5-year PFS (71% vs. 50%, p = .04) compared with those who received one or the other. Furthermore, 11 patients (18%) developed local recurrences at a median time of 14 months (IQR, 2-19 months), resulting in a 5-year local control (LC) rate of 77%. Use of CMT was not associated with improved LC (83% vs. 72% SMT, p = .41). Also, use of CMT was the only factor associated with poorer disease-specific survival (vs. SMT; hazard ratio, 3.4; p = .047; 95% confidence interval, 1.01-11.4).

Conclusion: For patients with EES, CMT was not associated with a decreased rate of local relapse. These data suggest that SMT alone may be sufficient for LC in select patients. A multi-institutional collaborative effort should be considered to validate these findings.

Implications For Practice: Extraskeletal Ewing sarcoma is a rare chemosensitive sarcoma whose clinical course more closely follows Ewing sarcoma of bone rather than that of other soft tissue sarcomas. Based on this study, combined-modality local therapy did not confer a local control advantage compared with single-modality local therapy. Therefore, single-modality local therapy is likely adequate in select patients with favorable disease features, which has the advantage of ensuring prompt administration of systemic therapy. A multi-institutional collaborative effort is warranted to determine which patients may benefit from de-escalated local therapy.
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http://dx.doi.org/10.1002/onco.13616DOI Listing
March 2021

Impact of Lagtime, Health Insurance Type, and Income Status at Diagnosis on the Long-Term Survival of Adolescent and Young Adult Cancer Patients.

J Adolesc Young Adult Oncol 2020 Jul 14. Epub 2020 Jul 14.

Division of Pediatrics and Patient Care, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Delays in diagnosis can affect the short-term survival outcomes of adolescent and young adult (AYA) cancer patients. We sought to determine the extent to which delayed diagnosis, health insurance type, and income status are associated with the long-term survival of AYA cancer patients. We reviewed an institutional cohort of 268 patients age 15-29 years who were diagnosed with the most common neoplasms of the AYA population between 2001 and 2003. We grouped patients by the time of onset of cancer symptomatology to verified diagnosis (lagtime to diagnosis; short or long), health insurance type at diagnosis (public or private), zip-code-based median household income (≤U.S. $50,000 or >U.S. $50,000), and demographic variables. Overall survival (OS) and late OS (LOS; the time from the 5-year anniversary of cancer diagnosis to death from any cause) were the outcomes of interest. OS and LOS did not differ between those with short or long lagtimes to diagnosis for all cancer and for specific cancer types. Among patients with long lagtimes, those with private insurance had significantly better LOS than those with public insurance ( = 0.03). Compared with those who had public insurance, patients who had private insurance at diagnosis had significantly better LOS ( = 0.008). Patients with household incomes >U.S. $50,000 had better LOS than those with household incomes ≤U.S. $50,000 ( = 0.02). Patients with public insurance and household incomes ≤U.S. $50,000 had the poorest LOS. AYA cancer patients with either public health insurance or a low household income at diagnosis are at risk of an inferior LOS.
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http://dx.doi.org/10.1089/jayao.2020.0041DOI Listing
July 2020

IGF-1R/mTOR Targeted Therapy for Ewing Sarcoma: A Meta-Analysis of Five IGF-1R-Related Trials Matched to Proteomic and Radiologic Predictive Biomarkers.

Cancers (Basel) 2020 Jul 2;12(7). Epub 2020 Jul 2.

Department of Sarcoma Medical Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

: Ten to fourteen percent of Ewing sarcoma (ES) study participants treated nationwide with IGF-1 receptor (IGF-1R)-targeted antibodies achieved tumor regression. Despite this success, low response rates and short response durations (approximately 7-weeks) have slowed the development of this therapy. : We performed a meta-analysis of five phase-1b/2 ES-oriented trials that evaluated the anticancer activity of IGF-1R antibodies +/- mTOR inhibitors (mTORi). Our meta-analysis provided a head-to-head comparison of the clinical benefits of IGF-1R antibodies vs. the IGF-1R/mTOR-targeted combination. Available pretreatment clinical samples were semi-quantitatively scored using immunohistochemistry to detect proteins in the IGF-1R/PI3K/AKT/mTOR pathway linked to clinical response. Early PET/CT imaging, obtained within the first 2 weeks (median 10 days), were examined to determine if reduced FDG avidity was predictive of progression-free survival (PFS). : Among 56 ES patients treated at MD Anderson Cancer Center (MDACC) with IGF-1R antibodies, our analysis revealed a significant ~two-fold improvement in PFS that favored a combination of IGF-1R/mTORi therapy (1.6 vs. 3.3-months, = 0.042). Low pIGF-1R in the pretreatment specimens was associated with treatment response. Reduced total-lesion glycolysis more accurately predicted the IGF-1R response than other previously reported radiological biomarkers. : Synergistic drug combinations, and newly identified proteomic or radiological biomarkers of IGF-1R response, may be incorporated into future IGF-1R-related trials to improve the response rate in ES patients.
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http://dx.doi.org/10.3390/cancers12071768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408058PMC
July 2020

Extraskeletal Myxoid Chondrosarcomas: Combined Modality Therapy With Both Radiation and Surgery Improves Local Control.

Am J Clin Oncol 2019 10;42(10):744-748

Departments of Radiation Oncology.

Objective: We evaluated our experience treating patients with localized extraskeletal myxoid chondrosarcomas (EMCs) to evaluate outcomes and relapse rates in order to better inform treatment decisions for these rare soft tissue sarcomas.

Materials And Methods: We reviewed the records of 41 consecutive patients with localized EMC treated at our institution from 1990 to 2016. Most patients (n=33, 80%) received combined modality therapy with surgery and radiation therapy, whereas only 8 (20%) underwent surgery alone. The Kaplan-Meier method was used to estimate rates of overall survival, disease-specific survival, local control (LC), and distant metastatic-free survival (DMFS).

Results: Median follow-up time was 94 months (range, 8 to 316). The 10-year LC, DMFS, disease-specific survival, and overall survival rates were 90%, 69%, 85%, and 66%, respectively. There were 5 patients (12%) with local relapse at a median time of 75 months (range, 13 to 176). On univariate analysis, the only significant factor associated with poorer LC was the use of surgery alone (10 y LC, 63% vs. 100% for combined modality therapy, P=0.004), which remained the only factor also significant on the multivariable analysis (P=0.02; hazard ratio [HR], 12.7; 95% confidence interval [CI], 1.4-115.3). In total, 13 patients (32%) developed distant metastatic at a median time of 28 months (range, 3 to 154). Interestingly, local recurrence was the only factor associated with poorer DMFS on multivariate analysis (P=0.04; HR, 3.9; 95% CI, 1.1-14.7).

Conclusions: For patients with EMC, surgery alone was associated with a higher risk of local recurrence. Therefore, we recommend optimal local therapeutic strategies upfront with both surgery and radiation therapy to reduce the risk of local and ultimately distant recurrence.
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http://dx.doi.org/10.1097/COC.0000000000000590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771031PMC
October 2019

MAGE-A3 is a Clinically Relevant Target in Undifferentiated Pleomorphic Sarcoma/Myxofibrosarcoma.

Cancers (Basel) 2019 May 15;11(5). Epub 2019 May 15.

Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.

Melanoma-associated antigen 3 (MAGE-A3) expression is generally restricted to the placenta and germline cells of the testis, but it may also be expressed in sarcoma and other cancers and is associated with poor prognosis. Immunotherapy approaches targeting MAGE-A3 in other cancers have shown mixed results in the clinic, however, use of cancer testis antigens such as MAGE-A3 may have therapeutic value in the treatment of soft tissue sarcomas. Based on the recent success of anti-programmed death-1 (PD-1) therapy in undifferentiated pleomorphic sarcoma, we hypothesize that MAGE-A3-based immunotherapies may also provide benefits in this sarcoma type. We analyzed MAGE-A3 expression of sarcoma subtypes available in the Cancer Genome Atlas and Cancer Cell Line Encyclopedia and show that undifferentiated pleomorphic sarcoma/myxofibrosarcoma (UPS/MFS) expresses this potential target gene. We have identified high protein expression by tissue microarray of 106 UPS cores. We also found that high MAGE-A3 mRNA and protein expression is associated with worse overall survival in UPS/MFS. Furthermore, our results show no human leukocyte antigen (HLA) expression loss and relatively high lymphocyte infiltration by lymphocyte specific protein tyrosine kinase (LCK) marker expression. Based on these results, we propose targeting MAGE-A3 in UPS/MFS by immunotherapy techniques.
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http://dx.doi.org/10.3390/cancers11050677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562561PMC
May 2019

Emergency Department Visits by Adolescent and Young Adult Cancer Patients Compared with Pediatric Cancer Patients in the United States.

J Adolesc Young Adult Oncol 2018 10 20;7(5):553-564. Epub 2018 Jun 20.

1 Department of Preventive Medicine and Community Health, University of Texas Medical Branch , Galveston, Texas.

Purpose: Limited information exists on emergency department (ED) visits for adolescent and young adult (AYA) patients with cancer. We examined the clinical reasons for ED visits, and outcomes, for AYAs with cancer compared to pediatric cancer patients.

Methods: The 2013 Nationwide Emergency Department Sample data were used to identify 53,274 AYA (ages 15-39) and 6952 pediatric (ages 0-14) cancer ED visits. We evaluated patient (i.e., demographic and diagnosis) and hospital characteristics, and the ED event outcome (admitted to the same hospital or treated/released). Clinical reasons for visits were identified as procedures, infections, or noninfectious toxicities. Variables were compared between groups using chi-squared tests. Logistic regressions identified characteristics associated with the outcome between and within groups.

Results: AYA cancer visits were more likely to be self-paid (15.8% vs. 1.9%, p < 0.001), and be from low-income households and nonmetro counties than pediatric visits. Toxicity was the most prevalent reason for AYA visits (46.0%) and infections for pediatrics (47.3%, p < 0.001). AYA cancer visits were less likely to be admitted (OR = 0.84, 95% CI = 0.71-0.98; p = 0.03) than pediatric cancer. Among AYAs, self-paid visits were less likely to be admitted compared with privately insured visits (OR = 0.58, 95% CI: 0.52-0.66, p < 0.001). Self-pay did not affect the outcome for pediatric visits.

Conclusions: In the United States, compared with pediatric cancer patients, AYAs with cancer visit EDs more often for toxicity-related problems, and are more often self-paid and from poorer households. These distinctive features impacting health service use should be incorporated into care plans aimed at delineating effective care for these patients.
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http://dx.doi.org/10.1089/jayao.2018.0026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6909771PMC
October 2018

Mesenchymal Chondrosarcoma: a Review with Emphasis on its Fusion-Driven Biology.

Curr Oncol Rep 2018 03 26;20(5):37. Epub 2018 Mar 26.

Department of Sarcoma Medical Oncology, MD Anderson Cancer Center, Houston, TX, 77030, USA.

Mesenchymal chondrosarcoma is a rare but deadly form of chondrosarcoma that typically affects adolescents and young adults. While curative intent is possible for patients with localized disease, few options exist for patients in the unresectable/metastatic setting. Thus, it is imperative to understand the fusion-driven biology of this rare malignant neoplasm so as to lead to the future development of better therapeutics for this disease. This manuscript will briefly review the clinical and pathologic features of mesenchymal chondrosarcoma followed by an appraisal of existing data linked to the fusions, HEY1-NCOA2 and IRF2BP2-CDX1, and the associated downstream pathways.
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http://dx.doi.org/10.1007/s11912-018-0668-zDOI Listing
March 2018

Adolescent and Young Adult Oncology, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology.

J Natl Compr Canc Netw 2018 Jan;16(1):66-97

This selection from the NCCN Guidelines for Adolescent and Young Adult (AYA) Oncology focuses on treatment and management considerations for AYA patients with cancer. Compared with older adults with cancer, AYA patients have unique needs regarding treatment, fertility counseling, psychosocial and behavioral issues, and supportive care services. The complete version of the NCCN Guidelines for AYA Oncology addresses additional aspects of caring for AYA patients, including risk factors, screening, diagnosis, and survivorship.
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http://dx.doi.org/10.6004/jnccn.2018.0001DOI Listing
January 2018

Overexpressed PRAME is a potential immunotherapy target in sarcoma subtypes.

Clin Sarcoma Res 2017 15;7:11. Epub 2017 Jun 15.

Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030 USA.

Background: PRAME (preferentially expressed antigen in melanoma), a member of the cancer-testis antigen family, has been shown to have increased expression in solid tumors, including sarcoma, and PRAME-specific therapies are currently in development for other cancers such as melanoma.

Methods: To map the landscape of PRAME expression in sarcoma, we used publicly available data from The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia (CCLE) projects and determined which sarcoma subtypes and subsets are associated with increased PRAME expression. We also analyzed how PRAME expression correlates with survival and expression of markers related to antigen presentation and T cell function. Furthermore, tumor and normal tissue expression comparisons were performed using data from the genotype-tissue expression (GTEx) project.

Results: We found that uterine carcinosarcoma highly overexpresses the PRAME antigen, and synovial sarcomas and multifocal leiomyosarcomas also show high expressions suggesting that PRAME may be an effective target of immunotherapies of these tumors. However, we also discovered that PRAME expression negatively correlates with genes involved in antigen presentation, and in synovial sarcoma MHC class I antigen presentation deficiencies are also present, potentially limiting the efficacy of immunotherapies of this malignancy.

Conclusions: We determined that uterine carcinosarcoma, synovial sarcoma, and leiomyosarcoma patients would potentially benefit from PRAME-specific immunotherapies. Tumor escape through loss of antigen presentation needs to be further studied.
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http://dx.doi.org/10.1186/s13569-017-0077-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5471883PMC
June 2017