55 results on '"Christian F Meyer"'
Search Results
2. Molecular Tumor Board Guides Successful Treatment of a Rare, Locally Aggressive, Uterine Mesenchymal Neoplasm
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Christian F. Meyer, Amanda N. Fader, Elaine M. Walsh, Stephanie L. Wethington, Stephanie Gaillard, Deyin Xing, and Melissa H. Lippitt
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Cancer Research ,business.industry ,MEDLINE ,Mesenchymal Neoplasm ,Middle Aged ,Rare Diseases ,Treatment Outcome ,Text mining ,Oncology ,Uterine Neoplasms ,Cancer research ,Humans ,MOLECULAR TUMOR BOARD ,Tumor board ,Medicine ,Female ,business ,Neoplasms, Connective and Soft Tissue - Published
- 2021
3. Melanoma metastatic to the hyoid bone
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Christine G. Gourin, Peter S. Vosler, Deborah X. Xie, Evan J. Lipson, Danielle F. Eytan, Christian F. Meyer, Rajarsi Mandal, John F. Ryan, and Edward F. McCarthy
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medicine.medical_specialty ,Medicine (General) ,head and neck neoplasm ,Metastatic melanoma ,Case Report ,Case Reports ,030204 cardiovascular system & hematology ,Metastasis ,Resection ,03 medical and health sciences ,0302 clinical medicine ,R5-920 ,stomatognathic system ,nose and throat ,melanoma ,Medicine ,metastasis ,In patient ,business.industry ,hyoid bone ,Melanoma ,Hyoid bone ,Ear ,General Medicine ,medicine.disease ,030220 oncology & carcinogenesis ,oncology ,cutaneous malignancy ,Radiology ,Differential diagnosis ,business ,Cutaneous malignancy - Abstract
Metastatic melanoma may be included in the differential diagnosis of hyoid masses in patients with a history of melanoma. Hyoid resection is well tolerated and of diagnostic and therapeutic benefit in patients with tumors metastatic to the hyoid bone., Metastatic melanoma may be included in the differential diagnosis of hyoid massess in patients with a history of melanoma. Hyoid resection is well tolerated and of diagnostic and therapeutic benefit in patients with tumors metastatic to the hyoid bone.
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- 2021
4. A randomized, open‐label, phase 2, multicenter trial of gemcitabine with pazopanib or gemcitabine with docetaxel in patients with advanced soft‐tissue sarcoma
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Scott M. Schuetze, Elizabeth G. Hill, Daniel Y. Reuben, Brian A. Van Tine, Andrew S. Kraft, Elizabeth Garrett-Mayer, Neeta Somaiah, Anthony D. Elias, Kent Armeson, Christian F. Meyer, William L. Read, Amy E. Wahlquist, Sant P. Chawla, and Mohammed M. Milhem
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Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Indazoles ,Phases of clinical research ,Soft Tissue Neoplasms ,Docetaxel ,Neutropenia ,Deoxycytidine ,Gastroenterology ,Pazopanib ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Multicenter trial ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,030212 general & internal medicine ,Adverse effect ,Aged ,Aged, 80 and over ,Sulfonamides ,Cross-Over Studies ,business.industry ,Common Terminology Criteria for Adverse Events ,Middle Aged ,medicine.disease ,Gemcitabine ,Pyrimidines ,Oncology ,030220 oncology & carcinogenesis ,Female ,business ,medicine.drug - Abstract
Background Therapeutic options for patients with advanced soft-tissue sarcoma (STS) are limited. The goal of the current phase 2 study was to examine the clinical activity and safety of the combination of gemcitabine plus pazopanib, a multityrosine kinase inhibitor with activity in STS. Methods The current randomized, phase 2 trial enrolled patients with advanced nonadipocytic STS who had received prior anthracycline-based therapy. Patients were assigned 1:1 to receive gemcitabine at a dose of 1000 mg/m2 on days 1 and 8 with pazopanib at a dose of 800 mg daily (G+P) or gemcitabine at a dose of 900 mg/m2 on days 1 and 8 and docetaxel at a dose of 100 mg/m2 on day 8 (G+T) every 3 weeks. Crossover was allowed at the time of disease progression. The study used a noncomparative statistical design based on the precision of 95% confidence intervals for reporting the primary endpoints of median progression-free survival (PFS) and rate of grade ≥3 adverse events (AEs) for these 2 regimens based on the intent-to-treat patient population (AEs were graded using version 4.0 of the National Cancer Institute Common Terminology Criteria for Adverse Events). Results A total of 90 patients were enrolled: 45 patients on each treatment arm. The median PFS was 4.1 months for each arm (P = .3, log-rank test). The best overall response of stable disease or better (complete response + partial response + stable disease) was the same for both treatment arms (64% for both the G+T and G+P arms). The rate of related grade ≥3 AEs was 82% for the G+T arm and 78% for the G+P arm. Related grade ≥3 AEs occurring in ≥10% of patients in the G+T and G+P arms were anemia (36% and 20%, respectively), fatigue (29% and 13%, respectively), thrombocytopenia (53% and 49%, respectively), neutropenia (20% and 49%, respectively), lymphopenia (13% and 11%, respectively), and hypertension (2% and 20%, respectively). Conclusions The data from the current study have demonstrated the safety and efficacy of G+P as an alternative to G+T for patients with nonadipocytic STS.
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- 2020
5. Neoadjuvant Chemoradiation Compared With Neoadjuvant Radiation Alone in the Management of High-Grade Soft Tissue Extremity Sarcomas
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Sara R. Alcorn, Chen Hu, Carol D. Morris, Sarah Z. Hazell, Kingsley O. Asiedu, Stephanie A. Terezakis, Deborah A. Frassica, Gillian Pulido, Christian F. Meyer, and Adam S. Levin
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Oncology ,lcsh:Medical physics. Medical radiology. Nuclear medicine ,medicine.medical_specialty ,medicine.medical_treatment ,lcsh:R895-920 ,lcsh:RC254-282 ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Medicine ,Radiology, Nuclear Medicine and imaging ,Chemotherapy ,business.industry ,Soft tissue ,Sarcoma ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Trunk ,Radiation therapy ,Standardized mortality ratio ,030220 oncology & carcinogenesis ,Toxicity ,Disease characteristics ,Radiology ,Acute dermatitis ,business - Abstract
Purpose: Patients with large, high-grade soft tissue sarcomas are commonly treated with aggressive limb preservation regimens. This study aimed to assess cancer control outcomes of patients treated with neoadjuvant chemoradiation (CRT) compared with radiation therapy (RT) alone. Methods: We reviewed records of patients with high-grade extremity or trunk soft tissue sarcomas ≥5 cm who were treated with neoadjuvant radiation with or without chemotherapy. Patient and disease characteristics were compared using t test and χ2 tests. Standardized mortality ratio weighted method was used to compare overall survival (OS), local control, and disease-free (DFS) survival. Acute radiation and surgical toxicity were reported. Results: In the study, 64 patients (34 CRT and 30 RT) treated between 1997 and 2015 were analyzed. In the RT group compared with the CRT group, the patient population was older, with a median age of 65 versus 50 years (P < .001), and more likely to have cardiovascular disease (CVD; 30% vs 0%, P < .001). At a median follow-up of 41 months, after adjusting for propensity score of receiving RT, the 3-year LC was 87.3% versus 86.1%, DFS was 58.5% versus 56.6%, and OS was 75.6% versus 69.0% for the CRT and RT groups, respectively (P > .05). Acute dermatitis occurred in 18% versus 3% and surgical complications occurred in 32% versus 17% of CRT and RT patients, respectively. Conclusions: In this study, patients receiving RT alone were more likely to be older and have comorbid cardiovascular disease. When controlling for baseline differences, neoadjuvant CRT and RT provided similar rates of LC, DFS, and OS.
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- 2020
6. Pathways of immune exclusion in metastatic osteosarcoma are associated with inferior patient outcomes
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Gady Cojocaru, Ada J. Tam, Nicolas J. Llosa, Elizabeth D. Thompson, Drew M. Pardoll, Nicholas Siegel, Carol D. Morris, Daniel S. Rhee, Robert A. Anders, John A. Ligon, Teniola Oke, Brian H. Ladle, Aditya Suru, Christine A. Pratilas, Adam S. Levin, Emily Han-Chung Hsiue, Richard L. Blosser, Christian F. Meyer, Franck Housseau, Wei Fu, Woonyoung Choi, Megan H. Fong, and David J. McConkey
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0301 basic medicine ,Cancer Research ,Lung Neoplasms ,sarcoma ,medicine.medical_treatment ,Lymphocyte Activation ,0302 clinical medicine ,Tumor-Associated Macrophages ,Immunotherapy Biomarkers ,Tumor Microenvironment ,Immunology and Allergy ,Medicine ,Cytotoxic T cell ,Electronic Health Records ,RC254-282 ,Osteosarcoma ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Progression-Free Survival ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,translational medical research ,Molecular Medicine ,Cytokines ,Immunotherapy ,pediatrics ,T cell ,Immunology ,Bone Neoplasms ,03 medical and health sciences ,Immune system ,Lymphocytes, Tumor-Infiltrating ,Antigen ,Biomarkers, Tumor ,Humans ,Retrospective Studies ,Pharmacology ,Tumor microenvironment ,business.industry ,Myeloid-Derived Suppressor Cells ,Macrophage Activation ,Immune Checkpoint Proteins ,Immune checkpoint ,030104 developmental biology ,Cancer research ,business ,Transcriptome ,CD8 - Abstract
BackgroundCurrent therapy for osteosarcoma pulmonary metastases (PMs) is ineffective. The mechanisms that prevent successful immunotherapy in osteosarcoma are incompletely understood. We investigated the tumor microenvironment of metastatic osteosarcoma with the goal of harnessing the immune system as a therapeutic strategy.Methods66 osteosarcoma tissue specimens were analyzed by immunohistochemistry (IHC) and immune markers were digitally quantified. Tumor-infiltrating lymphocytes (TILs) from 25 specimens were profiled by functional cytometry. Comparative transcriptomic studies of distinct tumor-normal lung ‘PM interface’ and ‘PM interior’ regions from 16 PMs were performed. Clinical follow-up (median 24 months) was available from resection.ResultsIHC revealed a statistically significantly higher concentration of TILs expressing immune checkpoint and immunoregulatory molecules in PMs compared with primary bone tumors (including programmed cell death 1 (PD-1), programmed death ligand 1 (PD-L1), lymphocyte-activation gene 3 (LAG-3), T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), and indoleamine 2,3-dioxygenase (IDO1). Remarkably, these lymphocytes are excluded at the PM interface compared with PM interior. TILs from PMs exhibited significantly higher amounts of PD-1 and LAG-3 and functional cytokines including interferon-γ (IFNγ) by flow cytometry. Gene expression profiling further confirmed the presence of CD8 and CD4 lymphocytes concentrated at the PM interface, along with upregulation of immunoregulatory molecules and IFNγ-driven genes in the same region. We further discovered a strong alternatively activated macrophage signature throughout the entire PMs along with a polymorphonuclear myeloid-derived suppressor cell signature focused at the PM interface. Expression of PD-L1, LAG-3, and colony-stimulating factor 1 receptor (CSF1R) at the PM interface was associated with significantly worse progression-free survival (PFS), while gene sets indicative of productive T cell immune responses (CD8 T cells, T cell survival, and major histocompatibility complex class 1 expression) were associated with significantly improved PFS.ConclusionsOsteosarcoma PMs exhibit immune exclusion characterized by the accumulation of TILs at the PM interface. These TILs produce effector cytokines, suggesting their capability of activation and recognition of tumor antigens. Our findings suggest cooperative immunosuppressive mechanisms in osteosarcoma PMs including immune checkpoint molecule expression and the presence of immunosuppressive myeloid cells. We identify cellular and molecular signatures that are associated with patient outcomes, which could be exploited for successful immunotherapy.
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- 2021
7. A national analysis of patterns of care and outcomes for adults diagnosed with desmoplastic small round cell tumors in the United States
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Utkarsh Goel, Christian F. Meyer, Faiz Gani, Fabian M. Johnston, and Joseph K. Canner
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Adult ,Male ,medicine.medical_specialty ,medicine.medical_treatment ,Kaplan-Meier Estimate ,Desmoplastic Small Round Cell Tumor ,Medical Oncology ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Interquartile range ,Internal medicine ,medicine ,Round cell ,Humans ,Neoplasm Staging ,Retrospective Studies ,Patterns of care ,Chemotherapy ,business.industry ,Cancer ,General Medicine ,medicine.disease ,Combined Modality Therapy ,Primary tumor ,United States ,Clinical trial ,Radiation therapy ,Oncology ,030220 oncology & carcinogenesis ,Female ,030211 gastroenterology & hepatology ,Surgery ,business - Abstract
Background Because of the rarity of desmoplastic small round cell tumors (DSRCT), there is a lack of data describing patterns of care and survival for these patients. Using a national tumor registry, the current study sought to describe patterns of care and clinical outcomes for patients with DSCRT. Methods Data from the National Cancer Database were used to identify 491 patients aged 18 years or older diagnosed with DSRCT between 2004 and 2014. Multivariable Cox proportional hazards regression analysis was used to identify factors associated with overall survival (OS). Results Among all patients, 41.2% (n = 200), underwent surgical resection of their primary tumor, chemotherapy was administered to 86.5% (n = 415) of patients, while radiation therapy was administered to 13.0% (n = 63) of patients. Over the study, 69.7% of patients died with a median OS of 25.9 months (interquartile range [IQR]: 22.7-27.5); 1-, 3-, and 5-year OS were 78.6%, 32.3%, and 18.4%, respectively. On multivariable analysis, stage IV disease (Hazard Ratio [HR] = 2.12, 95% CI: 1.41-3.18), receipt of surgery (HR = 0.68, 95% CI: 0.50-0.91), chemotherapy (HR = 0.52, 95% CI: 0.35-0.78), or radiation therapy (HR = 0.55, 95% CI: 0.33-0.92) were independently associated with OS. Conclusions Although receipt of multimodality treatment may lead to improved survival, further research and clinical trials are required to establish best practices for the care of DSRCT.
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- 2019
8. Characterization and predictive value of volume changes of extremity and pelvis soft tissue sarcomas during radiation therapy prior to definitive wide excision
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Adam S. Levin, Chengcheng Gui, Carol D. Morris, Deborah A. Frassica, Curtiland Deville, Stephanie A. Terezakis, and Christian F. Meyer
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medicine.medical_specialty ,Radiographic progression ,medicine.medical_treatment ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,0302 clinical medicine ,Medicine ,Tumor control ,Radiology, Nuclear Medicine and imaging ,Clinical significance ,Pelvis ,Myxoid liposarcoma ,Soft tissue sarcoma ,business.industry ,Proportional hazards model ,Soft tissue ,medicine.disease ,Radiation therapy ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Resection margin ,Original Article ,Radiology ,business ,Response to radiation - Abstract
Purpose The purpose of this study was to characterize and evaluate the clinical significance of volume changes of soft tissue sarcomas during radiation therapy (RT), prior to definitive surgical resection. Materials and methods Patients with extremity or pelvis soft tissue sarcomas treated at our institution from 2013 to 2016 with RT prior to resection were identified retrospectively. Tumor volumes were measured using cone-beam computed tomography obtained daily during RT. Linear regression evaluated the linearity of volume changes. Kruskal-Wallis tests, Mann-Whitney U tests, and linear regression evaluated predictors of volume change. Logistic and Cox regression evaluated volume change as a predictor of resection margin status, histologic treatment response, and tumor recurrence. Results Thirty-three patients were evaluated. Twenty-nine tumors were high grade. Prior to RT, median tumor volume was 189 mL (range, 7.2 to 4,885 mL). Sixteen tumors demonstrated significant linear volume changes during RT. Of these, 5 tumors increased and 11 decreased in volume. Myxoid liposarcoma (n = 5, 15%) predicted decreasing tumor volume (p = 0.0002). Sequential chemoradiation (n = 4, 12%) predicted increasing tumor volume (p = 0.008) and corresponded to longer times from diagnosis to RT (p = 0.01). Resection margins were positive in three cases. Five patients experienced local recurrence, and 7 experienced distant recurrence, at median 8.9 and 6.9 months post-resection, respectively. Volume changes did not predict resection margin status, local recurrence, or distant recurrence. Conclusion Volume changes of pelvis and extremity soft tissue sarcomas followed linear trends during RT. Volume changes reflected histologic subtype and treatment characteristics but did not predict margin status or recurrence after resection.
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- 2019
9. Call for improved design and reporting in soft tissue sarcoma studies: A systematic review and meta‐analysis of chemotherapy and survival outcomes in resectable STS
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Christian F. Meyer, Jessica M. Ruck, Adam S. Levin, Fabian M. Johnston, Carol D. Morris, and Alexandra C. Istl
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Oncology ,medicine.medical_specialty ,medicine.medical_treatment ,03 medical and health sciences ,0302 clinical medicine ,Outcome reporting ,Internal medicine ,medicine ,Humans ,Randomized Controlled Trials as Topic ,Chemotherapy ,business.industry ,Soft tissue sarcoma ,Distant recurrence ,Sarcoma ,General Medicine ,medicine.disease ,Neoadjuvant Therapy ,Progression-Free Survival ,Survival Rate ,Pooled analysis ,Chemotherapy, Adjuvant ,030220 oncology & carcinogenesis ,Meta-analysis ,030211 gastroenterology & hepatology ,Surgery ,business - Abstract
New evidence and systemic therapies demand an updated analysis of chemotherapy for soft tissue sarcoma. We completed a meta-analysis of chemotherapy in localized STS, assessing OS, PFS, and local and distant recurrence (local recurrence-free survival [LRFS] and distant recurrence-free survival [DRFS]). Ten studies, totaling 3157 patients, were included. A pooled analysis for 5-year OS, progression-free survival, LRFS, and DRFS showed no benefit of chemotherapy over locoregional therapy alone for all-comers or site-specific STS. We make recommendations to improve outcome reporting and quality indices.
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- 2019
10. BRCA1/2 Functional Loss Defines a Targetable Subset in Leiomyosarcoma
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Sherri Z. Millis, Amanda E. Toland, John L. Hays, Christian F. Meyer, James L. Chen, Nathan D. Seligson, Esko A. Kautto, Colin W. Stets, and Edward N. Passen
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0301 basic medicine ,Leiomyosarcoma ,Oncology ,Subset Analysis ,Cancer Research ,medicine.medical_specialty ,DNA repair ,business.industry ,Somatic cell ,education ,Sarcomas ,DNA Repair Pathway ,medicine.disease ,Poly (ADP-Ribose) Polymerase Inhibitor ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Population study ,Sarcoma ,business - Abstract
Background Soft-tissue sarcomas (STS) describe a heterogeneous group of mesenchymal tumors with limited treatment options. Targeted therapies exist for BRCA1/2 gene alterations, but their prevalence and role have not been fully described in STS. Here, we present the largest effort to characterize the frequency of homologous recombination (HR) DNA repair pathway alterations in STS subtypes and highlight the unique nature of leiomyosarcoma (LMS). Materials and Methods DNA sequencing data were analyzed for HR pathway alterations for 1,236 patients with STS. DNA sequencing data from an additional 1,312 patients were used to confirm the prevalence of HR pathway alterations in LMS. Four uterine LMS (uLMS) patients with functional BRCA2 loss were evaluated for response to poly (ADP-ribose) polymerase (PARP) inhibition. Results In an unselected STS study population, BRCA2 alterations were identified in 15 (1%) patients, and homozygous BRCA2 loss was detected in 9 ( Conclusion HR pathway alterations are rare in most STS. However, we identify uLMS to be enriched for BRCA2 loss and report the positive outcomes of a series of patients treated with PARP inhibitors. Our data suggest that patients with uLMS should be considered for somatic BRCA2 profiling. Prospective trials are necessary to confirm the efficacy of PARP inhibition in uLMS.
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- 2018
11. A phase II study of temsirolimus and liposomal doxorubicin for patients with recurrent and refractory bone and soft tissue sarcomas
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Christian F. Meyer, Breelyn A. Wilky, Jonathan D. Powell, Lillian C. Boyer, Preeti Shah, Allen R. Chen, Margaret F. Ferreira, David M. Loeb, Maria A. Carrera-Haro, Katherine Thornton, Umber Shafique, and Matteo Trucco
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,medicine.medical_treatment ,Population ,Phases of clinical research ,lcsh:RC254-282 ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Chemotherapy ,Doxorubicin ,Progression-free survival ,education ,PI3K/AKT/mTOR pathway ,education.field_of_study ,business.industry ,Research ,Cancer stem cell ,Sarcoma ,Aldehyde dehydrogenase ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Temsirolimus ,030104 developmental biology ,030220 oncology & carcinogenesis ,Liposomes ,mTOR ,business ,Chemoresistance ,medicine.drug - Abstract
Background Relapsed and refractory sarcomas continue to have poor survival rates. The cancer stem cell (CSC) theory provides a tractable explanation for the observation that recurrences occur despite dramatic responses to upfront chemotherapy. Preclinical studies demonstrated that inhibition of the mechanistic target of rapamycin (mTOR) sensitizes the CSC population to chemotherapy. Methods Here we present the results of the Phase II portion of a Phase I/II clinical trial that aimed to overcome the chemoresistance of sarcoma CSC by combining the mTOR inhibitor temsirolimus (20 mg/m2 weekly) with the chemotherapeutic agent liposomal doxorubicin (30 mg/m2 monthly). Results Fifteen patients with relapsed/refractory sarcoma were evaluable at this recommended Phase 2 dose level. The median progression free survival was 315 days (range 27–799). Response rate, defined as stable disease or better for 60 days, was 53%. Nine of the patients had been previously treated with doxorubicin. Therapy was well tolerated. In a small number of patients, pre- and post- treatment tumor biopsies were available for assessment of ALDH expression as a marker of CSCs and showed a correlation between response and decreased ALDH expression. We also found a correlation between biopsy-proven inhibition of mTOR and response. Conclusions Our study adds to the literature supporting the addition of mTOR inhibition to chemotherapy agents for the treatment of sarcomas, and proposes that a mechanism by which mTOR inhibition enhances the efficacy of chemotherapy may be through sensitizing the chemoresistant CSC population. Further study, ideally with pre- and post-therapy assessment of ALDH expression in tumor cells, is warranted. Trial registration The trial was registered on clinicaltrials.gov (NCT00949325) on 30 July 2009. http://www.editorialmanager.com/csrj/default.aspx
- Published
- 2018
12. Anti-PD-1 elicits regression of undifferentiated pleomorphic sarcomas with UV-mutation signatures
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Teniola Oke, Thomas B. Schaffer, Evan J. Lipson, Dung T. Le, Christian F. Meyer, Lingling Chen, John Mc Mahon Gross, Laurene S. Cheung, Jillian T. Ngo, Nicolas J. Llosa, Janis M. Taube, Holly Kemberling, Karim Boudadi, John-William Sidhom, Robert A. Anders, Drew M. Pardoll, and Luis A. Diaz
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0301 basic medicine ,Male ,Cancer Research ,sarcoma ,medicine.medical_treatment ,Immunology ,Programmed Cell Death 1 Receptor ,Case Report ,medicine.disease_cause ,Undifferentiated Pleomorphic Sarcoma ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Biomarkers, Tumor ,Immunology and Allergy ,Humans ,RC254-282 ,Pharmacology ,Mutation ,Tumor microenvironment ,business.industry ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Cell Differentiation ,Immunotherapy ,Middle Aged ,medicine.disease ,Blockade ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Scalp ,tumor biomarkers ,Cancer research ,Molecular Medicine ,Sarcoma ,business ,CD8 - Abstract
Undifferentiated pleomorphic sarcoma (UPS), an aggressive soft-tissue sarcoma of adults, has been characterized by low tumor mutational burden (TMB) and high copy number alterations. Clinical trials of programmed death-1 (PD-1) blockade in UPS have reported widely varying efficacy. We describe two patients with recurrent scalp UPS that experienced clinical benefit from PD-1 blockade. These tumors had high TMB with a UV-induced mutational pattern. Analysis of additional head and neck UPS cases identified five out of seven tumors with high TMB and an ultraviolet (UV) mutational signature. Head and neck UPS tumors also had increased programmed death-ligand 1 (PD-L1) expression and CD8+ T cell infiltration as compared with UPS tumors arising from other sites. In summary, we found that UPS tumors of the head and neck, but not elsewhere, have a PD-L1+, T-cell-inflamed tumor microenvironment and high TMB, suggesting that these tumors represent a distinct genetic subgroup of UPS for which immune checkpoint inhibitor therapy might be effective.
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- 2021
13. Predictors of Recurrence and Patterns of Initial Failure in Localized Ewing Sarcoma: A Contemporary 20-Year Experience
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Christine A. Pratilas, Stephanie A. Terezakis, Christian F. Meyer, Brian H. Ladle, Adam S. Levin, Carol D. Morris, Nicolas J. Llosa, John A. Ligon, Gregory C. Stachelek, Matthew M. Ladra, and Jennifer Vogel
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,Article Subject ,medicine.medical_treatment ,Disease ,Systemic therapy ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Radiology, Nuclear Medicine and imaging ,RC254-282 ,Chemotherapy ,business.industry ,Medical record ,Hazard ratio ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Radiation therapy ,030104 developmental biology ,030220 oncology & carcinogenesis ,Localized disease ,Sarcoma ,business ,Research Article - Abstract
Background. The majority of patients with localized Ewing sarcoma will remain disease-free long term, but for those who suffer recurrence, successful treatment remains a challenge. Identification of clinicopathologic factors predictive of recurrence could suggest areas for treatment optimization. We sought to describe our experience regarding predictors of recurrence and patterns of first failure in patients receiving modern systemic therapy for nonmetastatic Ewing sarcoma. Methods. The medical records of pediatric and adult patients treated for localized Ewing sarcoma between 1999 and 2019 at Johns Hopkins Hospital were retrospectively analyzed. Local control was surgery, radiotherapy, or both. Recurrence-free survival (RFS) was calculated using the Kaplan–Meier method. Univariable and multivariable Cox proportional-hazards modeling was performed to obtain hazard ratios (HR) for recurrence. Results. In 94 patients with initially localized disease, there were 21 recurrences: 4 local, 14 distant, and 3 combined. 5-year and 10-year RFS were 75.6% and 70.5%, respectively. On multivariable analysis including age at diagnosis and tumor size
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- 2021
14. Desmoid tumor mimics local recurrence of extremity sarcoma on MRI
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Shivani Ahlawat, Carol D. Morris, Eugene Brooks, Adam S. Levin, John A. Ligon, Samir Sabharwal, and Christian F. Meyer
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Male ,medicine.medical_specialty ,Adolescent ,Radiography ,Tumor resection ,Bone Neoplasms ,Soft Tissue Neoplasms ,Diagnosis, Differential ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,Child ,Retrospective Studies ,Aged, 80 and over ,medicine.diagnostic_test ,business.industry ,Fibromatosis ,Magnetic resonance imaging ,Extremities ,Sarcoma ,General Medicine ,Middle Aged ,medicine.disease ,Primary tumor ,Magnetic Resonance Imaging ,body regions ,Fibromatosis, Aggressive ,Oncology ,030220 oncology & carcinogenesis ,Orthopedic surgery ,030211 gastroenterology & hepatology ,Surgery ,Female ,Radiology ,Differential diagnosis ,Neoplasm Recurrence, Local ,business - Abstract
Background and objectives The development of desmoid fibromatosis after tumor resection may mimic local recurrence. To our knowledge, this phenomenon has not been reported after extremity sarcoma resection. We report four cases of desmoid-type fibromatosis ("desmoid tumors") mimicking local recurrence after extremity sarcoma resection. Methods We retrospectively reviewed the records of patients treated for extremity sarcoma by our orthopedic oncology service from 2014 to 2019 and identified four patients with biopsy-proven desmoid tumors. We extracted clinical, pathologic, radiographic, and operative data for the primary neoplasms and desmoid tumors. Results Four patients with postresection surveillance magnetic resonance imaging suspicious for local recurrence underwent further analysis showing desmoid tumors. Patients underwent image-guided needle biopsy, with specimens demonstrating fibromatosis-type histologic characteristics. Two cases were β-catenin positive. Desmoid tumors were managed with observation. No patient had experienced local or distant recurrence of the primary tumor at a mean follow-up of 30 months after resection (range, 23-34 months); none underwent surgery for symptoms of desmoid tumors. Conclusions Desmoid tumors should be considered part of the differential diagnosis when assessing patients with radiographic concern for postresection local recurrence of extremity bone and soft-tissue sarcoma. An image-guided needle biopsy can inform diagnosis and management.
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- 2019
15. Minimally Invasive Versus Open Primary Resection for Retroperitoneal Soft Tissue Sarcoma: A Propensity-Matched Study From the National Cancer Database
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Heidi N. Overton, Jasvinder Singh, Nita Ahuja, Timothy M. Pawlik, Joseph K. Canner, Christian F. Meyer, Alex B. Blair, Fabian M. Johnston, Faiz Gani, and Utkarsh Goel
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Database ,business.industry ,Proportional hazards model ,Soft tissue sarcoma ,MEDLINE ,Cancer ,030230 surgery ,computer.software_genre ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,Oncology ,Interquartile range ,Surgical oncology ,030220 oncology & carcinogenesis ,Propensity score matching ,Medicine ,Surgery ,business ,Survival rate ,computer - Abstract
Although well described for gastrointestinal and pelvic cancers, use of minimally invasive surgery (MIS) for the management of retroperitoneal soft tissue sarcoma (RPS) remains unknown. The current study aimed to describe patterns of MIS use and assess the association between MIS and clinical outcomes among patients undergoing surgery for RPS. Patients undergoing a primary resection for RPS between 2010 and 2014 were identified using the National Cancer Database. Multivariable logistic and Cox proportional hazards models were used to assess the association between use of MIS and clinical outcomes. Sensitivity analysis was performed using propensity score-matching (PSM). This study identified 3844 patients who met the inclusion criteria. Of these patients, 89.3% (n = 3432) underwent an open surgery, whereas 10.7% (n = 412) underwent MIS. The patients undergoing MIS were more likely to present with smaller tumors (open vs MIS: median tumor size, 17 cm; interquartile range [IQR, 9.8–26.0] vs 10.5 cm [IQR, 6.5–18.0]) and to undergo surgery at community hospitals (26.8% vs 36.1%; both P 0.05). These findings were confirmed using PSM. MIS was associated with a shorter LOS, however, postoperative mortality and overall survival were comparable by operative approach. Future research is required to evaluate the use of MIS for the management of RPS. Policies are required to ensure that patients receive care in accordance with best practices and recommended guidelines.
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- 2018
16. 536 Intratumoral INT230–6 shows a favorable safety profile and early signs of efficacy in advanced soft tissue sarcoma with monotherapy and in combination with ipilimumab [Intensity IT-01; BMS#CA184–592]
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Giles F. Whalen, Lewis H. Bender, Christian F. Meyer, Anthony B. El-Khoueiry, Nilofer S. Azad, Ian Walters, Albiruni Ryan Abdul Razak, L.L. Siu, Jacob Stephen Thomas, Anthony J. Olszanski, Diana L. Hanna, James C. Hu, Matthew Ingham, and Syed S. Mahmood
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Pharmacology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Early signs ,Soft tissue sarcoma ,Immunology ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Ipilimumab ,medicine.disease ,Intensity (physics) ,Safety profile ,Oncology ,Molecular Medicine ,Immunology and Allergy ,Medicine ,Radiology ,business ,RC254-282 ,medicine.drug - Abstract
BackgroundStudy IT-01 evaluates INT230-6, a novel formulation of cisplatin (CIS) and vinblastine (VIN) with an amphiphilic cell penetration enhancer designed for intratumoral (IT) administration, as monotherapy or in combination with ipilimumab (IPI). In preclinical studies, INT230-6 increases drug dispersion throughout the tumor, allows drug diffusion into cancer cells and recruits dendritic, CD4 and CD8 T-cells. Further, the addition of IPI has shown to improve INT230-6 responses in preclinical models.1MethodsIT-01 is an open-label phase 1/2 study, currently enrolling adult subjects with locally advanced, unresectable or metastatic solid tumors, including soft tissue sarcoma (STS). The study assesses the safety and efficacy of INT230-6 administered IT Q2W up to 5 treatment sessions as monotherapy or with IPI 3mg/kg IV Q3W for 4 doses. Biopsies from injected tumor are taken pretreatment and Day 28 for immunohistochemistry (IHC) analysis.Results22 subjects with STS (14 INT230-6 monotherapy, 8 IPI combination) have been enrolled with a median age was 65, having a median of 4 (2,10) prior therapies. INT230-6 doses of up to 175 mL (87.5 mg of CIS, 17.5 mg VIN) were injected in one or more tumors at a single dosing session, which contains doses exceeding the typical IV doses of the cytotoxic drugs.2 PK analysis estimates that 95% of INT230-6 active agents remain in the tumor. The most common (>25%) related adverse events (AEs) in evaluable monotherapy subjects (n=13) were localized pain (77%), fatigue (39%), decreased appetite (31%), and nausea (31%). The most common (>25%) related AEs in evaluable IPI subjects (n=4) were anemia (50%), fatigue (50%), pruritus (50%), and rash maculo-papular (50%). There were no related grade 4 or 5 AEs in either cohort.The median overall survival (OS) estimate for the monotherapy population (n=14) has not been reached with a median follow-up of 425 days, which compares favorably to results seen in basket studies of patients with similar prognostic factors (ECOG, LDH, # of metastatic sites).3 4 IHC results indicate influx of CD4 and CD8 T-cells without meaningful changes in circulating inflammatory cytokines. Abscopal effects in the monotherapy arm were observed in multiple lesions in 4 subjects. OS data for the 8 IPI combination subjects is immature.ConclusionsIT INT230-6 is well tolerated when administered as monotherapy and combined with IPI in STS subjects. INT230-6 monotherapy survival compares favorably to published basket studies in STS with similar prognostic factors. IHC and abscopal effects indicate dosing may activate a T-cell mediated immune response.Trial RegistrationNCT # 03058289ReferencesBloom AC, et al. Intratumorally delivered formulation, INT230-6, containingpotent anticancer agents induces protective T cell immunity and memory. OncoImmunology 2019.Owelien. Historical PK data from IV administration. J Cancer Res 1977; 8.Livingston J, et al. Validation of prognostic scoring and assessment of clinical benefit for patients with bone sarcomas enrolled in phase I clinical trials. Oncotarget 2016;7: 64421–64430. https://www.oncotarget.com/article/10910/Abstract M, et al. Validation of the Royal Marsden Hospital (RMH) prognostic score in 100 patients with advanced sarcoma enrolled in early phase clinical trials at a major cancer center. JCO 2015. https://ascopubs.org/doi/abs/10.1200/jco.2015.33.15_suppl.10558WagnerEthics ApprovalThe protocol was approved by an institutional review board, independent ethics committee, or research ethics board at each institution. All subjects or their legally acceptable representative provided written informed consent before screening. The study was designed, undertaken, and reported in accordance with the Declaration of Helsinki, and is registered with clinicaltrial.gov with registration no NCT03058289.
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- 2021
17. Early results of intratumoral INT230-6 alone or in combination with ipilimumab in subjects with advanced sarcomas
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Lillian L. Siu, Ian B. Walters, Giles F. Whalen, James S. Hu, Matthew Ingham, Nilofer S. Azad, Albiruni Ryan Abdul Razak, Jacob Stephen Thomas, Christian F. Meyer, Diana L. Hanna, Lewis H. Bender, Anthony B. El-Khoueiry, Syed Mahmood, and Anthony J. Olszanski
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Cisplatin ,Oncology ,Cancer Research ,medicine.medical_specialty ,Chemotherapy ,business.industry ,medicine.medical_treatment ,Cell ,Treatment options ,Ipilimumab ,Vinblastine ,medicine.anatomical_structure ,Early results ,Internal medicine ,medicine ,business ,medicine.drug - Abstract
11557 Background: Patients have limited treatment options following initial chemotherapy failure. INT230-6, a novel formulation of cisplatin (CIS) and vinblastine (VIN) with an amphiphilic cell penetration enhancer, is designed for intratumoral (IT) administration. Study IT-01 (BMS # CA184-592, NCT 03058289) evaluates INT230-6 alone or in combination with ipilimumab (IPI), an antibody to CTLA-4. INT230-6 dosing is set by a % of the volume of the tumor to be injected. The product has been shown to disperse throughout an injected tumor and diffuse into cancer cells. Cell death leads to recruitment of dendritic and T cells, the effect of which may be augmented by CTLA-4 inhibition as evidenced by increased efficacy of the combination in preclinical models. Historically, checkpoint inhibitors have limited activity in sarcoma. Considering the large volume of drug injected and retained in the tumor, coupled with immune infiltration on biopsies, RECIST response methodology may not capture the benefits of INT230-6 treatment. Methods: IT-01 is an open-label phase 1/2 study that is enrolling adult subjects with locally advanced, unresectable or metastatic sarcoma. INT230-6 was administered IT Q2W for 5 doses alone or with IPI 3mg/kg IV Q3W for 4 doses. The study objectives are to assess the safety and efficacy of IT INT230-6 alone and in combination with IPI. Results: 16 heterogenous sarcoma subjects (13 monotherapy, 3 IPI combination) having a median of 3 prior therapies (0, 8) were enrolled to date. The INT230-6 dose was up to 145 mL (72.5 mg of CIS, 14.5 mg VIN) in a single session (an amount of each agent in excess of standard IV doses). The most common ( > 20%) related TEAEs in sarcoma subjects (n = 16) were localized pain (63%), fatigue (38%), decreased appetite (31%), nausea (31%), and vomiting (25%) most of which were low grade; with only grade 3 TEAE above 5% being anemia (13%). There were no related grade 4 or 5 TEAEs. In 11 evaluable monotherapy subjects, the disease control rate (DCR = CR+PD+SD) was 82%. Basket studies of sarcomas, including chordoma, with Royal Marsden Hospital index (RMHI) scores of 2 or higher report median overall survival (mOS) of 4 months. In this study 75% of monotherapy subjects had a RMHI score of 2 and preliminary estimates of mOS was 21.3 (4.67, NA) months. Pilot immunohistochemistry analysis of 5 paired (pre- and 28 days post-dose) biopsy samples showed substantial tumor necrosis, reduction of viable cancer, a decreased cancer proliferation as measured by Ki67, and increased TILs. Conclusions: Preliminary data shows that INT230-6 administered intratumorally alone or in combination with ipilimumab is well-tolerated in this small, heterogenous sarcoma population. The preclinical cancer cell death and immune infiltration mechanism of action appears to translate to sarcoma subjects. There are early signs of efficacy, DCR and potentially OS, that need to be confirmed in randomized studies. Clinical trial information: 03058289.
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- 2021
18. Size-based detection of sarcoma circulating tumor cells and cell clusters
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Christian F. Meyer, Kyle W. Jackson, Carol D. Morris, Catherine M. Albert, Gregory McCarty, Peixuan Zhu, Cha Mei Tang, Christine A. Pratilas, Masanori Hayashi, David M. Loeb, and Adam S. Levin
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0301 basic medicine ,Pathology ,medicine.medical_specialty ,Disease Response ,Cell ,Disease ,Metastasis ,neoplastic cells ,03 medical and health sciences ,0302 clinical medicine ,Circulating tumor cell ,medicine ,xenograft ,circulating ,business.industry ,medicine.disease ,animal models ,3. Good health ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Alveolar rhabdomyosarcoma ,Biomarker (medicine) ,biomarker ,Sarcoma ,business ,Research Paper - Abstract
Metastatic disease is the most important factor in determining the survival of sarcoma patients. Since sarcoma metastasis is predominantly hematogenous, we hypothesized that detection and quantification of circulating tumor cells (CTCs) could reflect response to therapy and risk of metastatic relapse. We evaluated the presence of CTCs using a novel animal model and in the blood of patients with high grade sarcomas utilizing the CellSieve™ size-based low pressure microfiltration system. Sarcoma CTCs were identified based on antibody staining patterns and nuclear morphology. Additionally, RNA was extracted from the CTCs for molecular analysis including demonstration of an EWS-FLI1 translocation, identification of a previously unrecognized p53 mutation in a patient with Ewing sarcoma, and single cell RNA sequencing of CTC from a child with alveolar rhabdomyosarcoma. In mouse xenograft models, the presence of CTC correlates with disease burden and with clinically silent metastases. In human patients, CTCs were readily detected at diagnosis, decreased with successful treatment, and were detectable in the blood of patients with no radiographic evidence of disease prior to the development of overt metastasis. Although evaluation of CTC is established in the care of patients with carcinomas, this technology has yet to be effectively applied to the evaluation and treatment of sarcoma patients. Our work demonstrates that the CellSieve™ microfiltration system can be used to study the biology of CTC in both mouse models and human sarcoma patients, with the potential for application to the monitoring of disease response and prediction of metastatic relapse.
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- 2017
19. Evaluating the Role of Interdigitated Neoadjuvant Chemotherapy and Radiation in the Management of High-Grade Soft-Tissue Sarcoma
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Raju R. Raval, Frank J. Frassica, Christian F. Meyer, Katherine Thornton, Kristin L Weber, Stephanie A. Terezakis, Deborah A. Frassica, and David S. Ettinger
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Adult ,Male ,0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,Poor prognosis ,medicine.medical_treatment ,Treatment outcome ,Soft Tissue Neoplasms ,Disease-Free Survival ,Article ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,Young adult ,Neoadjuvant therapy ,Aged ,Retrospective Studies ,Chemotherapy ,business.industry ,Soft tissue sarcoma ,Sarcoma ,Retrospective cohort study ,Middle Aged ,medicine.disease ,Neoadjuvant Therapy ,Surgery ,Treatment Outcome ,030104 developmental biology ,Oncology ,Chemotherapy, Adjuvant ,030220 oncology & carcinogenesis ,Female ,Neoplasm Grading ,business - Abstract
Objectives High-grade soft-tissue sarcoma (STS) has a poor prognosis. The goal of this study was to review treatment outcomes of patients with high-grade STS treated with interdigitated neoadjuvant chemotherapy (CT) and radiation at our institution. Materials and methods Patients with high-grade STS (1997 to 2010) were planned for treatment with 3 cycles of neoadjuvant CT, interdigitated preoperative radiation therapy (44 Gy administered in split courses with a potential 16 Gy postoperative boost), and 3 cycles of postoperative CT. Cancer control outcomes at 3 years were analyzed. Results Sixteen patients with high-grade STS were evaluated. Median age was 53 years, the median longest tumor diameter was 14.6 cm, and median follow-up was 33 months. All 16 patients received 2 or 3 cycles of neoadjuvant CT and all patients completed neoadjuvant RT. The estimated 3-year rate for local control was 100%, disease-free survival 62.5%, and overall survival 73.4%. Conclusions Patients with high-grade STS treated with interdigitated neoadjuvant CT and radiation before surgical resection had excellent rates of local control, along with disease-free survival and overall survival similar to previously published reports. This combined-modality approach continues to have a role in the treatment of patients with high-grade STS.
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- 2017
20. Combined modality therapy improves overall survival for angiosarcoma
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Mehran Habibi, Stephanie A. Terezakis, Megan N. Kummerlowe, Christian F. Meyer, Adam S. Levin, Katherine Thornton, Carol D. Morris, Deborah A. Frassica, Aaron S. Parzuchowski, and Colette J. Shen
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Adult ,Male ,0301 basic medicine ,Oncology ,medicine.medical_specialty ,Hemangiosarcoma ,MEDLINE ,Antineoplastic Agents ,Soft Tissue Neoplasms ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Overall survival ,Humans ,Medicine ,Combined Modality Therapy ,Radiology, Nuclear Medicine and imaging ,Angiosarcoma ,Young adult ,Survival rate ,Survival analysis ,Aged ,Retrospective Studies ,Aged, 80 and over ,Radiotherapy ,business.industry ,Sarcoma ,Retrospective cohort study ,Hematology ,General Medicine ,Middle Aged ,Survival Analysis ,Survival Rate ,Treatment Outcome ,030104 developmental biology ,Surgical Procedures, Operative ,030220 oncology & carcinogenesis ,Female ,business ,Follow-Up Studies - Published
- 2017
21. Gastric and small intestine gastrointestinal stromal tumors: Do outcomes differ?
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Christopher L. Wolfgang, Nita Ahuja, Anne Marie Lennon, Neeraja Nagarajan, Alireza Najafian, Eric C. Schneider, Joseph K. Canner, Katherine Giuliano, Christian F. Meyer, and Fabian M. Johnston
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Gastrointestinal tract ,medicine.medical_specialty ,Stromal cell ,GiST ,business.industry ,Seer database ,Histology ,Imatinib ,General Medicine ,Gastroenterology ,digestive system diseases ,Small intestine ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,030211 gastroenterology & hepatology ,Surgery ,business ,neoplasms ,Survival analysis ,medicine.drug - Abstract
Background and Objectives Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Previous literature has suggested that small intestine GISTs are more aggressive than gastric GISTs. Our primary objective was to compare the outcomes of gastric and small intestine GISTs in the decade after approval of imatinib for treatment. Methods The SEER database was queried for cases of gastric and small intestine GIST between the years 2002 and 2012, using the ICD-O-3 histology code 8936. Survival analysis was performed using generalized gamma models for time to cause-specific mortality (CSM). Results CSM was 14.0% for the 3,759 gastric GIST patients and 14.3% for the 1,848 small intestine GIST patients. Five-year survival was 82.2% and 83.3% for gastric and small intestine patients, respectively. The number of diagnosed cases of GIST increased over the course of this study, especially for tumors
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- 2016
22. The Immunosuppressive Niche of Soft-Tissue Sarcomas is Sustained by Tumor-Associated Macrophages and Characterized by Intratumoral Tertiary Lymphoid Structures
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Robert A. Anders, Richard L. Blosser, Fabian M. Johnston, Elizabeth D. Thompson, Nicolas J. Llosa, Drew M. Pardoll, Ada J. Tam, Jessica Swailes, David J. McConkey, Jonathan B. Greer, John A. Ligon, Elizabeth A. Montgomery, Gady Cojocaru, Nicholas Siegel, Andriana Lebid, Carol D. Morris, Lingling Chen, Teniola Oke, Christian F. Meyer, Woonyoung Choi, Daniel S. Rhee, Brian H. Ladle, and Adam S. Levin
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0301 basic medicine ,Adult ,Male ,Cancer Research ,Adolescent ,Biology ,CD8-Positive T-Lymphocytes ,Article ,Flow cytometry ,Transcriptome ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Immune system ,Lymphocytes, Tumor-Infiltrating ,Rhabdomyosarcoma ,Tumor-Associated Macrophages ,medicine ,Tumor Microenvironment ,Humans ,Child ,Immune Checkpoint Inhibitors ,Aged ,Aged, 80 and over ,Tumor microenvironment ,B-Lymphocytes ,medicine.diagnostic_test ,Middle Aged ,medicine.disease ,Neoplasms, Complex and Mixed ,Immune checkpoint ,030104 developmental biology ,Tertiary Lymphoid Structures ,Oncology ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Child, Preschool ,Cancer research ,Immunohistochemistry ,Female ,Tumor Escape ,Infiltration (medical) ,CD8 - Abstract
Purpose: Clinical trials with immune checkpoint inhibition in sarcomas have demonstrated minimal response. Here, we interrogated the tumor microenvironment (TME) of two contrasting soft-tissue sarcomas (STS), rhabdomyosarcomas and undifferentiated pleomorphic sarcomas (UPS), with differing genetic underpinnings and responses to immune checkpoint inhibition to understand the mechanisms that lead to response. Experimental Design: Utilizing fresh and formalin-fixed, paraffin-embedded tissue from patients diagnosed with UPS and rhabdomyosarcomas, we dissected the TME by using IHC, flow cytometry, and comparative transcriptomic studies. Results: Our results demonstrated both STS subtypes to be dominated by tumor-associated macrophages and infiltrated with immune cells that localized near the tumor vasculature. Both subtypes had similar T-cell densities, however, their in situ distribution diverged. UPS specimens demonstrated diffuse intratumoral infiltration of T cells, while rhabdomyosarcomas samples revealed intratumoral T cells that clustered with B cells near perivascular beds, forming tertiary lymphoid structures (TLS). T cells in UPS specimens were comprised of abundant CD8+ T cells exhibiting high PD-1 expression, which might represent the tumor reactive repertoire. In rhabdomyosarcomas, T cells were limited to TLS, but expressed immune checkpoints and immunomodulatory molecules which, if appropriately targeted, could help unleash T cells into the rest of the tumor tissue. Conclusions: Our work in STS revealed an immunosuppressive TME dominated by myeloid cells, which may be overcome with activation of T cells that traffic into the tumor. In rhabdomyosarcomas, targeting T cells found within TLS may be key to achieve antitumor response.
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- 2019
23. Targeting Sporadic and Neurofibromatosis Type 1 (NF1) Related Refractory Malignant Peripheral Nerve Sheath Tumors (MPNST) in a Phase II Study of Everolimus in Combination with Bevacizumab (SARC016)
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Christian F. Meyer, Karen Cichowski, Brian Turpin, Denise K. Reinke, Nalini Jayaprakash, Lee J. Helman, Joseph G. Pressey, AeRang Kim, Scott H. Okuno, Yao Lu, Brigitte C. Widemann, Angela C. Hirbe, Ndidi Onwudiwe, Mohammed M. Milhem, John P. Perentesis, Gregory M. Cote, Rashmi Chugh, and Eva Dombi
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Oncology ,medicine.medical_specialty ,Chemotherapy ,Everolimus ,Bevacizumab ,Article Subject ,business.industry ,medicine.medical_treatment ,Phases of clinical research ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,lcsh:RC254-282 ,Refractory ,Internal medicine ,Clinical Study ,medicine ,Radiology, Nuclear Medicine and imaging ,Neurofibromatosis ,Stage (cooking) ,business ,Adverse effect ,medicine.drug - Abstract
Purpose. There are no known effective medical treatments for refractory MPNST. Inactivation of the NF1 tumor suppressor in MPNST results in upregulation of mTOR (mammalian target of rapamycin) signaling and angiogenesis, which contributes to disease progression. We conducted a phase II study for patients (pts) with refractory MPNST combining everolimus (10 mg PO once daily) with bevacizumab (10 mg/kg IV every 2 weeks) to determine the clinical benefit rate (CBR) (complete response, partial response (PR), or stable disease (SD) ≥ 4 months). Patients and Methods. Patients ≥18 years old with chemotherapy refractory sporadic or NF1 MPNST were eligible. Tumor response was assessed after every 2 cycles (the WHO criteria). A two-stage design targeting a 25% CBR was used: if ≥ 1/15 pts in stage 1 responded, enrollment would be expanded by 10 pts, and if ≥ 4/25 patients had clinical benefit, the combination would be considered active. Results. Twenty-five pts, 17 with NF1 and 8 with sporadic MPNST, enrolled. One of 15 pts in stage 1 had clinical benefit. Of 10 additional pts enrolled, 2 had clinical benefit. The median number of completed cycles was 3 (range 1–16). Adverse events were similar to those known for this combination. Conclusion. With a CBR of 12% (3/25), the combination of everolimus and bevacizumab did not reach the study’s target response rate and is not considered active in refractory MPNST.
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- 2019
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24. Highly personalized detection of minimal Ewing sarcoma disease burden from plasma tumor DNA
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Gregory McCarty, Diana Steppan, Catherine M. Albert, Ben Ho Park, Nicolas J. Llosa, Jean Paul Wolinsky, Carol D. Morris, Masanori Hayashi, David Chu, Christian F. Meyer, Adam S. Levin, and David M. Loeb
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0301 basic medicine ,Cancer Research ,Pathology ,medicine.medical_specialty ,business.industry ,Breakpoint ,Cancer ,medicine.disease ,Primary tumor ,Metastasis ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,Multiplex polymerase chain reaction ,medicine ,Cancer research ,Biomarker (medicine) ,Digital polymerase chain reaction ,Sarcoma ,business - Abstract
Background Even though virtually all patients with Ewing sarcoma achieve a radiographic complete response, up to 30% of patients who present with localized disease and up to 90% of those who present with metastases experience a metastatic disease recurrence, highlighting the inability to identify patients with residual disease at the end of therapy. Up to 95% of Ewing sarcomas carry a driving EWS-ETS translocation that has an intronic breakpoint that is specific to each tumor, and the authors developed a system to quantitatively detect the specific breakpoint DNA fragment in patient plasma. Methods The authors used a long-range multiplex polymerase chain reaction (PCR) technique to identify tumor-specific EWS-ETS breakpoints in Ewing sarcoma cell lines, patient-derived xenografts, and patient tumors, and this sequence was used to design tumor-specific primer sets to detect plasma tumor DNA (ptDNA) by droplet digital PCR in xenograft-bearing mice and patients. Results Tumor-specific breakpoint DNA fragments were detected in the plasma of xenograft-bearing mice, and the signal correlated with tumor burden during primary tumor growth, after surgical resection, and at the time of metastatic disease recurrence. Furthermore, the authors were able to detect the specific breakpoint in plasma DNA obtained from 3 patients with Ewing sarcoma and in 2 patients the authors were able to detect ptDNA when there was radiographically undetectable disease present. Conclusions The use of droplet digital PCR to detect tumor-specific EWS-ETS fusion gene breakpoint ptDNA fragments can be developed into a highly personalized biomarker of disease recurrence that can be optimized in animal studies for ultimate use in patients. Cancer 2016;122:3015-3023. © 2016 American Cancer Society.
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- 2016
25. Long-term outcomes in treatment of retroperitoneal sarcomas: A 15 year single-institution evaluation of prognostic features
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Timothy M. Pawlik, Michael A. Choti, Stephanie A. Terezakis, Elizabeth A. Montgomery, Neeraja Nagarajan, Christian F. Meyer, Richard D. Schulick, Deborah A. Frassica, Katherine Thornton, Nita Ahuja, Christopher L. Wolfgang, Joseph M. Herman, Eihab Abdelfatah, and Angela A. Guzzetta
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Leiomyosarcoma ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Retrospective cohort study ,General Medicine ,030230 surgery ,Liposarcoma ,medicine.disease ,Retroperitoneal Neoplasm ,Surgery ,Radiation therapy ,03 medical and health sciences ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,medicine ,Sarcoma ,business ,Grading (tumors) ,Survival analysis - Abstract
Background Retroperitoneal sarcomas are connective tissue tumors arising in the retroperitoneum. Surgical resection is the mainstay of treatment. Debate has arisen over extent of resection, changes in histological classification/grading, and interest in incorporating radiotherapy. Therefore, we reviewed our institution's experience to evaluate prognostic factors. Methods Retrospective chart review of all primary RPS patients at Johns Hopkins Hospital from 1994 to 2010. Histologic diagnosis and grading were re-evaluated with current criteria. Prognostic factors for survival, and recurrence were assessed. Results One hundred thirty-one primary RPS patients met inclusion criteria. Median survival for patients who undergo en-bloc resection to negative margins (R0/R1) is 81.7 months. Surgical margins and grade were the most important factors for survival along with age, gender, presence of metastases and resection of ≥5 organs. Five-year survival for R0/R1 resection was 60%, similar to compartmental resection. Radiotherapy significantly decreased local recurrence (P = 0.026) on multivariate analysis. Grade in leiomyosarcomas and dedifferentiation in liposarcomas dictated patterns of local versus distal recurrence. Conclusions En bloc surgical resection to R0/R1 margins remains the cornerstone of therapy and provides comparable outcomes to compartmental resections. Grade remains important for prognosis, and histology dictates recurrence patterns. Radiotherapy appears promising for local control and warrants further investigation. J. Surg. Oncol. 2016;114:56–64. © 2016 Wiley Periodicals, Inc.
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- 2016
26. Extraskeletal versus Skeletal Ewing Sarcoma in the adult population: Controversies in care
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Carol D. Morris, Andrew D. Lynch, Christian F. Meyer, Faiz Gani, Nita Ahuja, and Fabian M. Johnston
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0301 basic medicine ,Adult ,Male ,medicine.medical_specialty ,Combination therapy ,medicine.medical_treatment ,Adult population ,Bone Neoplasms ,Sarcoma, Ewing ,03 medical and health sciences ,0302 clinical medicine ,Surgical oncology ,Internal medicine ,Medicine ,Humans ,Muscle, Skeletal ,Retrospective Studies ,Chemotherapy ,Adult patients ,business.industry ,Soft tissue sarcoma ,medicine.disease ,Prognosis ,Treatment characteristics ,Combined Modality Therapy ,Survival Rate ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Surgery ,Female ,Sarcoma ,business ,Follow-Up Studies - Abstract
A lack of consensus exists on the prognosis of extraskeletal Ewing sarcoma (EES) relative to its skeletal (ES) counterpart in adults. This study sought to characterize outcome differences between the two diagnoses.From 2004 to 2014, the NCDB identified 2,660 Ewing Sarcoma patients. Cox proportional hazards regression analysis was used to identify risk factors for overall survival (OS).EES patients were older, more likely to be female, and have smaller tumors. Among patients with ES, 4.0% received no treatment, 2.5% received local therapy only (surgery and/or radiation), 16.8% received chemotherapy only, while 52.2% received combination therapy (local and chemotherapy), and 17.0% recieived triple therapy (surgery, radiation and chemotherapy). Among patients with EES, 4.3% recived no treatment, 5.6% received local therapy only, 15.6% received chemotherapy only, while 47.0% received combination therapy, and 21.6% received triple therapy. No difference in OS was observed between the two groups (P = 0.816). Factors independently associated with OS for ES included age (HR = 1.26, P = 0.01), Charlson-Deyo Score (CDS) ≥2 (HR = 3.66, P 0.001), combination therapy (HR = 0.39, P 0.001) and triple therapy (HR = 0.34, P 0.001). For EES, factors for OS were age (HR = 1.52, P 0.001), CDS ≥2 (HR = 1.90, P = 0.02), combination therapy (HR = 0.44, P 0.001), triple therapy (HR = 0.34, P 0.001) and PNET histology (HR = 1.33, P = 0.02).Demographic, histological, and treatment characteristics differ between adult patients diagnosed with ES and ESS. However, survival and independent predictors of survival are consistent between the two diagnoses.
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- 2018
27. High dose-rate Intra-Operative Radiation Therapy During High Risk Genitourinary Surgery: Initial Observations and a Proposal for its Study in Bladder Cancer
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Bashar Safar, Stephanie A. Terezakis, Phuoc T. Tran, Joseph M. Herman, Nikolai A. Sopko, Trinity J. Bivalacqua, Aaron Brant, Max Kates, Meera Chappidi, Jonathan E. Efron, Phillip M. Pierorazio, Niv Milbar, Nita Ahuja, and Christian F. Meyer
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0106 biological sciences ,Research Report ,medicine.medical_specialty ,Surgical margin ,Urology ,medicine.medical_treatment ,030232 urology & nephrology ,01 natural sciences ,radiation therapy ,Cystectomy ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Bladder cancer ,Genitourinary system ,business.industry ,Cancer ,medicine.disease ,Surgery ,Radiation therapy ,Oncology ,Cohort ,Positive Surgical Margin ,business ,010606 plant biology & botany - Abstract
Background: High dose-rate Intra-Operative Radiation Therapy (HD-IORT) is used to provide effective local control for patients with high-risk locally advanced or recurrent tumors. However, the utility of HD-IORT for patients with bladder cancer has not been studied. Objective: To characterize our institutional experience with HD-IORT in patients with cancer requiring genitourinary surgery, in an effort to identify patients with bladder cancer that may benefit from HD-IORT. Methods: We performed a retrospective review of all patients who have undergone HD-IORT during genitourinary surgery at our institution. Patients were stratified by surgical margin status, and primary outcomes assessed were overall survival, recurrence free survival and 90-day complications. Patients undergoing cystectomy and HD-IORT with sarcomatoid urothelial cancer were compared to a similar cohort undergoing cystectomy alone. A sample case of one such patient is discussed in detail. Results: 84 patients at our institution have undergone HD-IORT with genitourinary surgery. Positive surgical margin status was the greatest predictor of both OS (HR = 3.42) and RFS (HR = 2.61). The overall 90-day complication rate was 61%, with wound infections (43%) and GI complications (21%) being most common. 4 of these patients had sarcomatoid urothelial histology, and all are still alive with >2 yrs follow up. This compares to a 52% 1 yr survival in our sarcomatoid urothelial cohort (25 pts) that did not undergo HD-IORT. Conclusions: Our institutional experience with HD-IORT has been promising, particularly among patients with locally advanced disease and sarcomatoid histology. We are currently enrolling patients in a multi-institutional registry to assess the utility of HD-IORT in high risk bladder cancer.
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- 2017
28. Phase Ib/II Study of the Safety and Efficacy of Combination Therapy with Multikinase VEGF Inhibitor Pazopanib and MEK Inhibitor Trametinib In Advanced Soft Tissue Sarcoma
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Ralph Zinner, Funda Meric-Bernstam, Joseph A. Ludwig, Marianna Zahurak, Jason Roszik, Nilofe A. Azad, Vivek Subbiah, Ashley O'Connor, Christian F. Meyer, Kenna R. Mills Shaw, and Razelle Kurzrock
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0301 basic medicine ,Oncology ,Adult ,Male ,Vascular Endothelial Growth Factor A ,Cancer Research ,medicine.medical_specialty ,Indazoles ,Combination therapy ,Drug-Related Side Effects and Adverse Reactions ,medicine.drug_class ,Pyridones ,MAP Kinase Kinase Kinase 1 ,Pyrimidinones ,Tyrosine-kinase inhibitor ,Disease-Free Survival ,Pazopanib ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Protein Kinase Inhibitors ,Aged ,Trametinib ,Sulfonamides ,business.industry ,MEK inhibitor ,Melanoma ,Soft tissue sarcoma ,Cancer ,Sarcoma ,Middle Aged ,medicine.disease ,Surgery ,030104 developmental biology ,Pyrimidines ,030220 oncology & carcinogenesis ,Female ,business ,medicine.drug - Abstract
Purpose: Pazopanib, a multireceptor tyrosine kinase inhibitor targeting primarily VEGFRs1–3, is approved for advanced soft tissue sarcoma (STS) and renal cell cancer. Downstream of VEGFR, trametinib is an FDA-approved MEK inhibitor used for melanoma. We hypothesized that vertical pathway inhibition using trametinib would synergize with pazopanib in advanced STS. Experimental Design: In an open-label, multicenter, investigator-initiated National Comprehensive Cancer Network (NCCN)-sponsored trial, patients with metastatic or advanced STS received pazopanib 800 mg and 2 mg of trametinib continuously for 28-day cycles. The primary endpoint was 4-month progression-free survival (PFS). Secondary endpoints were overall survival, response rate, and disease control rate. Results: Twenty-five patients were enrolled. The median age was 49 years (range, 22–77 years) and 52% were male. Median PFS was 2.27 months [95% confidence interval (CI), 1.9–3.9], and the 4-month PFS rate was 21.1% (95% CI, 9.7–45.9), which was not an improvement over the hypothesized null 4-month PFS rate of 28.3% (P = 0.79). Median overall survival was 9.0 months (95% CI, 5.7–17.7). A partial response occurred in 2 (8%) of the evaluable patients (95% CI, 1.0–26.0), one with PIK3CA E542K-mutant embryonal rhabdomyosarcoma and another with spindle cell sarcoma. The disease control rate was 14/25 (56%; 95% CI, 34.9–75.6). The most common adverse events were diarrhea (84%), nausea (64%), and fatigue (56%). Conclusions: The combination of pazopanib and trametinib was tolerable without indication of added activity of the combination in STS. Further study may be warranted in RAS/RAF aberrant sarcomas. Clin Cancer Res; 23(15); 4027–34. ©2017 AACR.
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- 2017
29. Personalized Medicine in the Oncology Clinic: Implementation and Outcomes of the Johns Hopkins Molecular Tumor Board
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Ben Ho Park, W. Brian Dalton, Christopher D. Gocke, Antonio C. Wolff, Patrick M. Forde, David M. Loeb, Roisin M. Connolly, Vered Stearns, James R. Eshleman, Christian F. Meyer, Cindy Geoghegan, Josh Lauring, Eric S. Christenson, Jennifer E. Axilbund, Jennifer Ensminger, Hyunseok Kang, Shannon Slater, Heather A. Parsons, Dana Petry, and Christine A. Pratilas
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0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,Pathology ,Oncology clinic ,medicine.medical_treatment ,Clinical Trials and Supportive Activities ,MEDLINE ,Alternative medicine ,Article ,Targeted therapy ,03 medical and health sciences ,0302 clinical medicine ,Pharmacotherapy ,Rare Diseases ,Clinical Research ,medicine ,Genetics ,Tumor board ,Medical physics ,Cancer ,business.industry ,Brain Disorders ,Clinical trial ,Brain Cancer ,030104 developmental biology ,Good Health and Well Being ,Oncology ,030220 oncology & carcinogenesis ,Personalized medicine ,Patient Safety ,business - Abstract
Purpose Tumor genomic profiling for personalized oncology therapy is being widely applied in clinical practice even as it is being evaluated more formally in clinical trials. Given the complexities of genomic data and its application to clinical use, molecular tumor boards with diverse expertise can provide guidance to oncologists and patients seeking to implement personalized genetically targeted therapy in practice. Methods A multidisciplinary molecular tumor board reviewed tumor molecular profiling reports from consecutive referrals at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins over a 3-year period. The tumor board weighed evidence for actionability of genomic alterations identified by molecular profiling and provided recommendations including US Food and Drug Administration–approved drug therapy, clinical trials of matched targeted therapy, off-label use of such therapy, and additional tumor or germline genetic testing. Results One hundred fifty-five patients were reviewed. Actionable genomic alterations were identified in 132 patients (85%). Off-label therapies were recommended in 37 patients (24%). Eleven patients were treated off-label, and 13 patients were enrolled onto clinical trials of matched targeted therapies. Median progression-free survival of patients treated with matched therapies was 5 months ( 95% CI, 2.9 months to not reached), and the progression-free survival probability at 6 months was 43% (95% CI, 26% to 71%). Lack of locally available clinical trials was the major limitation on clinical actionability of tumor profiling reports. Conclusion The molecular tumor board recommended off-label targeted therapies for a quarter of all patients reviewed. Outcomes were heterogeneous, although 43% of patients receiving genomically matched therapy derived clinical benefit lasting at least 6 months. Until more data become available from precision oncology trials, molecular tumor boards can help guide appropriate use of tumor molecular testing to direct therapy.
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- 2017
30. Gastrointestinal Stromal Tumors, Version 2.2014
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Thomas F. DeLaney, I. Benjamin Paz, Sarah Boles, Margaret von Mehren, Martin J. Heslin, Suzanne George, Robert S. Benjamin, Karen D. Schupak, John M. Kane, Christian F. Meyer, Joel L. Mayerson, Ephraim S. Casper, Marilyn M. Bui, Richard F. Riedel, John D. Pfeifer, Mary Anne Bergman, Ricardo J. Gonzalez, Jeffrey D. Wayne, Hema Sundar, Ernest U. Conrad, Kristen N. Ganjoo, Brian A. Van Tine, Richard J. O'Donnell, Herbert S. Schwartz, Sean V. McGarry, R. Lor Randall, Scott M. Schuetze, and Alberto S. Pappo
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Oncology ,medicine.medical_specialty ,Pathology ,Indoles ,Receptor, Platelet-Derived Growth Factor alpha ,Stromal cell ,Gastrointestinal Stromal Tumors ,Piperazines ,Internal medicine ,Sunitinib ,medicine ,Humans ,Pyrroles ,neoplasms ,Gastrointestinal tract ,GiST ,business.industry ,Soft tissue sarcoma ,Imatinib ,Guideline ,medicine.disease ,digestive system diseases ,Proto-Oncogene Proteins c-kit ,Pyrimidines ,Imatinib mesylate ,Benzamides ,Mutation ,Imatinib Mesylate ,business ,medicine.drug - Abstract
Gastrointestinal stromal tumors (GIST) are the most common soft tissue sarcoma of the gastrointestinal tract, resulting most commonly from KIT or platelet-derived growth factor receptor α (PDGFRα)-activating mutations. These NCCN Guideline Insights highlight the important updates to the NCCN Guidelines for Soft Tissue Sarcoma specific to the management of patients with GIST experiencing disease progression while on imatinib and/or sunitinib.
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- 2014
31. Soft Tissue Sarcoma, Version 2.2014
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Karen D. Schupak, Martin J. Heslin, I. Benjamin Paz, Ernest U. Conrad, Scott M. Schuetze, Sarah Boles, Jeffrey D. Wayne, Hema Sundar, Brian A. Van Tine, Richard F. Riedel, Richard J. O'Donnell, John M. Kane, R. Lor Randall, Ricardo J. Gonzalez, John D. Pfeifer, Herbert S. Schwartz, Christian F. Meyer, Robert S. Benjamin, Ephraim S. Casper, Joel L. Mayerson, Marilyn M. Bui, Kristen N. Ganjoo, Thomas F. DeLaney, Margaret von Mehren, Alberto S. Pappo, Suzanne George, Sean V. McGarry, and Mary Anne Bergman
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Oncology ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,medicine.medical_treatment ,Soft tissue sarcoma ,MEDLINE ,Sarcoma ,medicine.disease ,Radiation therapy ,Genetic cancer ,Internal medicine ,medicine ,Humans ,Genetic Testing ,Family history ,business ,Genetic testing - Abstract
These NCCN Guidelines Insights highlight the important updates to the NCCN Guidelines for Soft Tissue Sarcoma (STS) specific to the role of radiation therapy in the management of patients with retroperitoneal/intra-abdominal STS. The guidelines have also included recommendations for genetic testing and counseling for patients with a clinical and/or family history of genetic cancer syndromes associated with a predisposition for the development of STS.
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- 2014
32. Prognostic Factors for Advanced GIST
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Christian F. Meyer
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Oncology ,medicine.medical_specialty ,Chemotherapy ,GiST ,business.industry ,medicine.medical_treatment ,Cancer ,Imatinib ,Disease ,Gene mutation ,medicine.disease ,Internal medicine ,medicine ,business ,Clin oncol ,medicine.drug ,Chronic myelogenous leukemia - Abstract
Gastrointestinal stromal tumors (GISTs) heralded the era of molecular targeting in solid tumor oncology as chronic myelogenous leukemia (CML) had in hematologic malignancies. The recognition of GIST as a separate entity from intestinal leiomyosarcomas laid the foundation for treatment of patients with advanced disease. GISTs are mesenchymal tumors of the intestinal tract originating from specialized nerve cells known as the interstitial cells of Cajal (Fletcher et al., Hum Pathol 33(5):459–465, 2002). The identification of activating mutations in the c-KIT gene led to a revolution in the treatment of patients with advanced GIST (Rubin et al., Cancer Res 61(22):8118–8121, 2001; Hirota, Science 279(5350):577–580, 1998). Subsequently, several other gene mutations were identified. Prior to the initial use of imatinib in a metastatic GIST patient (Joensuu et al., N Engl J Med 344(14):1052–1056, 2001), traditional chemotherapy agents failed usually causing stable disease at best without improvement of progression-free or overall survival (OS) (Edmonson et al., Cancer Invest 20(5–6):605–612, 2002; Blay et al., Eur J Cancer 40(9):1327–1331, 2004; Trent et al., Cancer 98(12):2693–2699, 2003; Casper, Curr Treat Options Oncol 1(3):267–273, 2000; Verweij et al., The Lancet 364(9440):1127–1134, 2004). The use of imatinib changed a rapidly fatal disease resistant to many standard chemotherapies with an overall survival (OS) of 12–18 months to an OS of greater than 50 months (Blanke et al., J Clin Oncol 26(4):620–625, 2008; DeMatteo et al., Ann Surg 231(1):51–58, 2000). Our understanding of the nature of this disease both clinically and molecularly has grown exponentially over the past 15 years since the publication of that first case report. This chapter will review prognostic factors identified in the treatment of advanced GIST. These characteristics fall into three broad categories: clinicopathologic factors, treatment factors, and molecular factors.
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- 2016
33. Common Secondary Genomic Variants Associated With Advanced Epithelioid Hemangioendothelioma
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Anne Grand'Maison, James L. Chen, Sherri Z. Millis, Christian F. Meyer, Nathan D. Seligson, David A. Liebner, Brian Turpin, Achal Awasthi, and John L. Hays
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Adult ,Male ,medicine.medical_specialty ,Adolescent ,Cross-sectional study ,Disease ,Hemangioendothelioma ,Young Adult ,Internal medicine ,medicine ,Humans ,Young adult ,Stage (cooking) ,Child ,Epithelioid hemangioendothelioma ,Aged ,Neoplasm Staging ,Original Investigation ,Aged, 80 and over ,business.industry ,Research ,Calcium-Binding Proteins ,High-Throughput Nucleotide Sequencing ,Sarcoma ,Retrospective cohort study ,Genomics ,General Medicine ,Middle Aged ,medicine.disease ,Online Only ,Cross-Sectional Studies ,Oncology ,Transcriptional Coactivator with PDZ-Binding Motif Proteins ,Trans-Activators ,Hemangioendothelioma, Epithelioid ,Female ,business - Abstract
Key Points Question Can next-generation sequencing reveal rationale for the dichotomous biological activity of epithelioid hemangioendothelioma (EHE) while illuminating potentially actionable alterations? Findings In a cross-sectional study of next-generation sequencing results collected from 49 participants diagnosed with EHE, more than half of patients with EHE profiled exhibited pathogenic genomic variants in addition to the WWTR1-CAMTA1 fusion, with 18.4% of participants exhibiting a potentially targetable variant. Participants with stage III/IV EHE were more likely to exhibit a secondary pathogenic variant. Meaning Next-generation sequencing may identify secondary genomic variants that are associated with EHE aggressiveness; additionally, these variants may represent potential therapeutic targets., This cross-sectional study characterizes secondary genomic alterations in patients with epithelioid hemangioendothelioma and their association with clinical outcomes., Importance Epithelioid hemangioendothelioma (EHE) is a rare, malignant vascular sarcoma characterized in most cases by a WWTR1-CAMTA1 fusion. The clinical course of EHE exhibits a dual nature. The condition is often indolent but can rapidly grow and metastasize unpredictably. No biomarkers to date are available to predict this phenotype. The hypothesis of this study was that better defining the genomic landscape of EHE using next-generation sequencing could offer additional therapies and insight into clinical outcomes. Objective To characterize secondary EHE genomic alterations and their association with clinical outcomes. Design, Setting, and Participants Multicenter, cross-sectional, retrospective study of next-generation sequencing results collected from participants diagnosed with EHE. Data were abstracted between May 1, 2013, and May 31, 2019. This analysis was conducted from January through June 2019. Summary genomic data were provided by commercial genomic testing companies. Main Outcomes and Measures Presence or absence of secondary pathogenic genomic variants and their association with disease stage and clinical features. Results A total of 49 participants with EHE were assessed for the presence or absence of secondary genomic variants. Of these, 32 (65.3%) were female; the mean (SD) age at diagnosis was 49.9 (18.3) years (range, 11-81 years). In all, 46 participants (93.9%) had confirmed WWTR1-CAMTA1 fusion; 26 participants (57.1%) exhibited a pathogenic genomic variant secondary to the WWTR1-CAMTA1 fusion; and 9 participants (18.4%) exhibited potentially targetable genomic variants. Commonly altered genes included CDKN2A/B, RB1, APC, and FANCA. Participants older than 45 years at diagnosis had an increased prevalence of secondary genomic variants that was not statistically significant (65.6% vs 38.5%; difference, 27.1%; 95% CI, −3.5% to 58.0%; P = .16) and were more likely to have a clinically targetable variant (28.1% vs 0%; difference, 28.1%; 95% CI, 11.2%-40.2%; P = .03). In 14 participants with clinical data available, those with stage III/IV EHE were more likely to exhibit a secondary pathogenic genomic variant (80% vs 0%; difference, 80%; 95% CI, 55.2%-100%; P = .006). Participants with stage III/IV EHE were diagnosed at an older age (mean [SD] age, 54.6 [14.1] years vs 31.7 [16.0] years; P = .05) and had elevated WWTR1-CAMTA1 fusion expression that was not statistically significant (mean [SD] expression, 677 [706] copies vs 231 [213] copies; P = .20). Conclusions and Relevance Although EHE exhibits few secondary genomic variants, presence of key secondary variants may be prognostic for aggressive EHE. Further research is needed to confirm this finding and determine whether more intensive upfront treatment is necessary for these patients.
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- 2019
34. Abstract 4973: The immunosuppressive tumor microenvironment of metastatic osteosarcoma inhibits the cytotoxic effect of tumor-infiltrating lymphocytes
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Emily H. Hsieu, Christian F. Meyer, David J. McConkey, Adam S. Levin, Carol D. Morris, Daniel S. Rhee, John A. Ligon, Teniola Oke, Nicholas Siegel, Nicolas J. Llosa, Megan H. Fong, Drew M. Pardoll, Robert A. Anders, and Woonyoung Choi
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Cancer Research ,Tumor microenvironment ,biology ,Tumor-infiltrating lymphocytes ,Chemistry ,T cell ,CD3 ,Acquired immune system ,medicine.anatomical_structure ,Immune system ,Oncology ,Granzyme ,Cancer research ,biology.protein ,medicine ,Cytotoxic T cell - Abstract
Background: Patients with metastatic osteosarcoma (OS) have a 5 year overall survival of Methods: Immunohistochemistry (IHC) slides from 66 formalin-fixed paraffin-embedded OS tissue blocks were analyzed. Laser capture microdissection and RNA extraction was performed on 13 OS specimens, and gene expression profiles of the tumor interior vs. tumor interface region were compared utilizing RNA seq. Tumor infiltrating lymphocytes (TILs) were isolated from 25 freshly obtained OS specimens and analyzed by multiparameter flow cytometry (MFC). Results: Digital image analysis of IHC specimens revealed significantly higher immune cell infiltration (CD3+ and CD8+ cells) in the pulmonary metastases compared to primary bone tumors, particularly at the interface between the OS lesion and normal lung tissue. There is increased expression at the interface of the immune checkpoint molecules programmed cell death 1 (PD-1), T cell immunoglobulin mucin-3 (TIM-3) and lymphocyte activation gene 3 (LAG-3). Gene expression profiling showed increased CD8 T cell and resting CD4 memory T cell signature at the interface compared to the tumor interior, and a strong M2 and M0 macrophage signature in both regions. TILs isolated from pulmonary metastases and analyzed by MFC had higher expression of PD-1 and other immune checkpoint molecules, and these TILs were more capable of producing the effector molecules IFN-gamma and granzyme B. Conclusions: Pulmonary metastatic OS lesions are more highly infiltrated with immune cells than primary bone lesions, particularly at the interface. The fact that these immune cells are shown via MFC to be capable of producing cytotoxic cytokines and proteases suggests that these TILs may be tumor-specific lymphocytes capable of acting against the tumor if they were not being inhibited by multiple immune checkpoint molecules. The inability of these immune cells to penetrate further into the tumor interior may represent an adaptive immune response by the tumor through a combination of repellant cytokines and inhibition of TILs via upregulation of PD-1, TIM-3 and LAG-3. Treatment with a combination of anti-PD-1, anti-TIM-3 or anti-LAG-3 directed treatments may unleash these immune cells and allow them to destroy OS tumor cells. Citation Format: John A. Ligon, Teniola F. Oke, Woonyoung Choi, Megan H. Fong, Adam Levin, Daniel S. Rhee, Carol D. Morris, Nicholas Siegel, Emily H. Hsieu, Christian F. Meyer, David J. McConkey, Robert A. Anders, Drew M. Pardoll, Nicolas J. Llosa. The immunosuppressive tumor microenvironment of metastatic osteosarcoma inhibits the cytotoxic effect of tumor-infiltrating lymphocytes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4973.
- Published
- 2019
35. Phase II trial of gemcitabine (G) with pazopanib (P) or gemcitabine with docetaxel (T) in advanced soft tissue sarcoma (STS)
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Amy E. Wahlquist, Sant P. Chawla, Andrew S. Kraft, Brian A. Van Tine, Elizabeth G. Hill, Neeta Somaiah, Daniel Y. Reuben, Anthony D. Elias, Scott M. Schuetze, Elizabeth Garrett-Mayer, Christian F. Meyer, Mohammed M. Milhem, and William L. Read
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Cancer Research ,business.industry ,Soft tissue sarcoma ,medicine.disease ,Gemcitabine ,Pazopanib ,Regimen ,Oncology ,Docetaxel ,Cancer research ,Medicine ,Sarcoma ,business ,medicine.drug - Abstract
11008 Background: P is a multi-tyrosine kinase inhibitor with efficacy in many sarcoma subtypes. We designed a trial to assess the benefit of adding P to G as an alternative regimen to the commonly used combination of G+T in pts with STS (NCT01593748). Methods: We performed an open-label, randomized phase 2 trial enrolling pts with advanced non-adipocytic STS who had received prior anthracycline based therapy. Pts were assigned (1:1 stratified randomization based on leiomyosarcoma and prior pelvic radiation) to receive G 1000 mg/m2 on days 1 and 8 with P 800 mg daily or G 900 mg/m2 on days 1 and 8 and T 100 mg/m2 on day 8, repeated q 3 wks. The primary objectives were estimating median PFS and rate of grade ≥3 adverse events (AEs). Secondary objectives included estimating the hazard ratio (HR) and response rates. Cross-over was allowed for RECIST progression. Sample size of 90 was derived based on the precision of 95% confidence intervals (CI) for reporting toxicity and PFS in each arm. Results: A total of 90 pts enrolled; 45 on each arm. Pt characteristics and results are detailed in Table. Median PFS was 4.1 months for each arm (p= 0.3, based on stratified log-rank test). The clinical benefit rate (PR+SD) was 29% for each arm (p>0.99, based on Fisher’s exact test). The rate of related grade ≥3 AEs were 20.6% with G+T and 19.9% with G+P. Related grade ≥3 AEs (%) occurring in ≥10% of pts (G+T; G+P): anemia (36, 20), fatigue (29; 13), low platelets (56; 51), low neutrophils (20; 49), AST increase (2; 13) and hypertension (2; 20). Conclusions: This study demonstrates comparable efficacy between G+P and G+T, suggesting that G+P can be considered for second-line therapy in advanced non-adipocytic STS. Pt Characteristics and Results. Clinical trial information: NCT01593748. [Table: see text]
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- 2019
36. Extrathoracic Location and 'Borderline' Histology are Associated with Recurrence of Solitary Fibrous Tumors After Surgical Resection
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Nita Ahuja, Breelyn A. Wilky, Angela A. Guzzetta, Christian F. Meyer, and Elizabeth A. Montgomery
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Adult ,Male ,Surgical resection ,Solitary fibrous tumor ,medicine.medical_specialty ,Soft Tissue Neoplasm ,Adolescent ,Soft Tissue Neoplasms ,Complete resection ,Article ,Young Adult ,Postoperative Complications ,Surgical oncology ,Biomarkers, Tumor ,medicine ,Humans ,Survival rate ,Aged ,Neoplasm Staging ,Thoracic Neoplasm ,Aged, 80 and over ,business.industry ,Histology ,Middle Aged ,Thoracic Neoplasms ,Prognosis ,medicine.disease ,Surgery ,Survival Rate ,Oncology ,Solitary Fibrous Tumors ,Female ,Neoplasm Recurrence, Local ,business ,Follow-Up Studies - Abstract
Most solitary fibrous tumors (SFTs) are cured by complete resection, but many recurrent and metastatic SFTs do not respond to treatment and are fatal. Malignant histology, defined by England's pathologic criteria, is strongly associated with recurrence, but some benign SFTs still behave aggressively. Several studies have suggested that extrathoracic SFTs have a worse prognosis. We reviewed thoracic and extrathoracic SFTs from our institution to determine if extrathoracic location is associated with recurrence, independent of malignant histology.With IRB approval, we retrieved patient pathology reports from the Johns Hopkins Surgical Pathology database between 1991 and 2011 and included 83 SFT patients in our analysis. Patient history and outcomes were obtained from the medical record and primary care physicians. Predictors of recurrence were analyzed by univariate and multivariate analysis and survival determined by the Kaplan-Meier method.Of the 83 patients, 59 had extrathoracic SFTs in neurologic (n = 24), extremity or head/neck (n = 13), or visceral/intraabdominal (n = 22) sites. A total of 74 SFTs were classified benign and 9 as malignant. Of the 14 recurrences, 13 occurred in extrathoracic SFTs; only 7 were classified as malignant. Multivariate analysis confirmed that malignant histology had the strongest association with recurrence, but extrathoracic location also independently predicted recurrence. A total of 20 benign SFTs possessed 1 or more of England's criteria but to an insufficient degree for malignant classification. These "borderline" SFTs were more likely to recur than benign SFTs without these features.Extrathoracic and "borderline" SFTs with any of England's criteria have a higher risk of recurrence.
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- 2013
37. Anti-PD-1 Blockade and Stereotactic Radiation Produce Long-Term Survival in Mice With Intracranial Gliomas
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Christopher M. Jackson, Timothy J. Harris, Hans J. Hammers, Eric C. Ford, Nicholas M. Durham, Michael Lim, Phuoc T. Tran, Jillian Phallen, Christian F. Meyer, John Wong, Alfred P. See, Charles G. Drake, Zineb Belcaid, Betty Tyler, Emilia Albesiano, Dimitris Mathios, Drew M. Pardoll, Jacob Ruzevick, Jing Zeng, Gustavo Pradilla, and Henry Brem
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Cancer Research ,Pathology ,medicine.medical_specialty ,Time Factors ,medicine.medical_treatment ,T cell ,Brain tumor ,Radiosurgery ,T-Lymphocytes, Regulatory ,Article ,B7-H1 Antigen ,Mice ,Antigens, Neoplasm ,Cell Line, Tumor ,Animals ,Medicine ,Combined Modality Therapy ,Radiology, Nuclear Medicine and imaging ,Survival analysis ,Tumor microenvironment ,Radiation ,Brain Neoplasms ,business.industry ,Brain ,Immunotherapy ,medicine.disease ,Survival Analysis ,Xenograft Model Antitumor Assays ,Mice, Inbred C57BL ,Radiation therapy ,medicine.anatomical_structure ,Oncology ,Cancer research ,Female ,Lymph Nodes ,Glioblastoma ,business ,Neck ,Spleen ,T-Lymphocytes, Cytotoxic - Abstract
Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults, and radiation is one of the main treatment modalities. However, cure rates remain low despite best available therapies. Immunotherapy is a promising modality that could work synergistically with radiation, which has been shown to increase antigen presentation and promote a proinflammatory tumor microenvironment. Programmed-death-1 (PD-1) is a surface receptor expressed on activated and exhausted T cells, which mediate T cell inhibition upon binding with its ligand PD-L1, expressed on many tumor types including human GBMs. We tested the combination of anti-PD-1 immunotherapy with stereotactic radiosurgery in a mouse orthotopic GBM model.We performed intracranial implantation of mouse glioma cell line GL261 transfected with luciferase into C57BL/6 mice. Mice were stratified into 4 treatment groups: (1) control; (2) radiation only; (3) anti-PD-1 antibody only; and (4) radiation plus anti-PD-1 antibody. Overall survival was quantified. The mice were killed on day 21 after implantation to assess immunologic parameters in the brain/tumor, cervical lymph nodes, and spleen.Improved survival was demonstrated with combination anti-PD-1 therapy plus radiation compared with either modality alone: median survival was 25 days in the control arm, 27 days in the anti-PD-1 antibody arm, 28 days in the radiation arm, and 53 days in the radiation plus anti-PD-1 therapy arm (P.05 by log-rank Mantle-Cox). Long-term survival was seen only in the combined treatment arm, with a fraction (15%-40%) of animals alive at day 180+ after treatment. Immunologic data on day 21 after implantation showed increased tumor infiltration by cytotoxic T cells (CD8+/interferon-γ+/tumor necrosis factor-α+) and decreased regulatory T cells (CD4+/FOXP3) in the combined treatment group compared with the single modality arms.The combination of PD-1 blockade and localized radiation therapy results in long-term survival in mice with orthotopic brain tumors. These studies provide strong preclinical evidence to support combination trials in patients with GBM.
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- 2013
38. A dose-finding study of temsirolimus and liposomal doxorubicin for patients with recurrent and refractory bone and soft tissue sarcoma
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Jonathan D. Powell, Maria A. Carrera-Haro, Umber Shafique, David M. Loeb, M. Fogle Ferreira, Naheed Gul, Christian F. Meyer, Katherine Thornton, Matteo Trucco, Allen R. Chen, Preeti Shah, and Breelyn A. Wilky
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Cancer Research ,Chemotherapy ,business.industry ,Soft tissue sarcoma ,medicine.medical_treatment ,Pharmacology ,medicine.disease ,Temsirolimus ,Oncology ,Pharmacokinetics ,Sirolimus ,Toxicity ,medicine ,Sarcoma ,business ,Active metabolite ,medicine.drug - Abstract
There are few effective therapies for high-risk sarcomas. Initial chemosensitivity is often followed by relapse. In vitro, mammalian target of rapamycin (mTOR) inhibition potentiates the efficacy of chemotherapy on resistant sarcoma cells. Although sarcoma trials using mTOR inhibitors have been disappointing, these drugs were used as maintenance. We conducted a Phase I/II clinical trial to test the ability of temsirolimus to potentiate the cytotoxic effect of liposomal doxorubicin and present here the dose-finding portion of this study. Adult and pediatric patients with recurrent or refractory sarcomas were treated with increasing doses of liposomal doxorubicin and temsirolimus using a continual reassessment method for escalation, targeting a dose-limiting toxicity rate of 20%. Blood samples were drawn before and after the first dose of temsirolimus in Cycles 1 and 2 for pharmacokinetic analysis. The maximally tolerated dose combination was liposomal doxorubicin 30 mg/m(2) monthly with temsirolimus 20 mg/m(2) weekly. Hematologic toxicity was common but manageable. Dose-limiting toxicities were primarily renal. Concurrent administration of liposomal doxorubicin resulted in increased exposure to sirolimus, the active metabolite of temsirolimus. Thus, the combination of liposomal doxorubicin and temsirolimus is safe for heavily pretreated sarcoma patients. Co-administration with liposomal doxorubicin did not alter temsirolimus pharmacokinetics, but increased exposure to its active metabolite.
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- 2013
39. Soft Tissue Sarcoma, Version 2.2012
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Christian F. Meyer, Scott M. Schuetze, Ephraim S. Casper, I. Benjamin Paz, Suzanne George, Joel L. Mayerson, Ricardo J. Gonzalez, Kristen N. Ganjoo, Robert S. Benjamin, Sean V. McGarry, Herbert S. Schwartz, Richard F. Riedel, Thomas F. DeLaney, Martin J. Heslin, Jeffrey D. Wayne, Hema Sundar, Brian A. Van Tine, Raphael E. Pollock, Richard J. O'Donnell, Margaret von Mehren, Karen D. Schupak, R. Lor Randall, Nicole R. McMillian, John D. Pfeifer, John M. Kane, Ernest U. Conrad, Sridhar Shankar, and Marilyn M. Bui
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Sorafenib ,medicine.medical_specialty ,GiST ,business.industry ,Soft tissue sarcoma ,Sarcoma ,Imatinib ,medicine.disease ,Systemic therapy ,Asymptomatic ,digestive system diseases ,Surgery ,Oncology ,Practice Guidelines as Topic ,Aggressive fibromatosis ,medicine ,Humans ,In patient ,medicine.symptom ,business ,neoplasms ,medicine.drug - Abstract
The major changes to the 2012 and 2011 NCCN Guidelines for Soft Tissue Sarcoma pertain to the management of patients with gastrointestinal stromal tumors (GISTs) and desmoid tumors (aggressive fibromatosis). Postoperative imatinib following complete resection for primary GIST with no preoperative imatinib is now included as a category 1 recommendation for patients with intermediate or high risk of recurrence. The panel also reaffirmed the recommendation for preoperative use of imatinib in patients with GISTs that are resectable with negative margins but associated with significant surgical morbidity. Observation was included as an option for patients with resectable desmoid tumors that are small and asymptomatic, not causing morbidity, pain, or functional limitation. Sorafenib is included as an option for systemic therapy for patients with desmoid tumors.
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- 2012
40. Prostate angiosarcoma: is there any association with previous radiation therapy?
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Richard M. Wolf, Ikechukwu Uzoaru, Waseem Khaliq, Emmanuel S. Antonarakis, and Christian F. Meyer
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Oncology ,medicine.medical_specialty ,business.industry ,Urology ,medicine.medical_treatment ,Cancer ,medicine.disease ,Prostate Angiosarcoma ,digestive system diseases ,Radiation therapy ,medicine.anatomical_structure ,Hemangiosarcoma ,Prostate ,Internal medicine ,medicine ,Etiology ,Observational study ,business ,neoplasms ,Pathological - Abstract
For the current review a literature search was carried out using Pubmed, EmBase, and Cochrane databases. All cases of prostate angioscaroma reported to date and observational studies evaluating the radiation associated cancer occurrence were reviewed. Despite the rarity, prostate angiosarcomas display remarkable clinical and pathological heterogeneity, and a treatment challenge. We found the association of prostate angiosarcoma with radiation therapy to be weak based upon the results from observational studies and case reports. Although radiation exposure has been suggested etiology of prostate angiosarcomas, assumption of such association is not supported by the current literature.
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- 2012
41. SU2C-SARC032: A phase II randomized controlled trial of neoadjuvant pembrolizumab with radiotherapy and adjuvant pembrolizumab for high-risk soft tissue sarcoma
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Richard F. Riedel, Lee Hartner, Brian E. Brigman, Steven Attia, Brian A. Van Tine, Andrew J. Wagner, Gabriel Tinoco, Karla V. Ballman, David G. Kirsch, Mohammed M. Milhem, Denise K. Reinke, Melissa Amber Burgess, Christian F. Meyer, Yvonne M. Mowery, Bartosz Chmielowski, Scott M. Schuetze, and Mark A. Dickson
- Subjects
0301 basic medicine ,Surgical resection ,Cancer Research ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Soft tissue sarcoma ,Soft tissue ,Pembrolizumab ,medicine.disease ,Tumor control ,law.invention ,Radiation therapy ,03 medical and health sciences ,030104 developmental biology ,Oncology ,Randomized controlled trial ,law ,medicine ,Radiology ,business ,Adjuvant - Abstract
TPS11588Background: Radiotherapy (RT) and surgical resection achieve local tumor control for most large, high-grade soft tissue sarcomas (STS) of the extremity. However, many patients (pts) subsequ...
- Published
- 2018
42. Multimodal Therapy in the Treatment of Prostate Sarcoma: The Johns Hopkins Experience
- Author
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Jonathan I. Epstein, Trinity J. Bivalacqua, Adam C. Reese, Stephanie A. Terezakis, Christian F. Meyer, Debasish Sundi, Mark P. Schoenberg, Mark W. Ball, Nita Ahuja, and Jonathan E. Efron
- Subjects
Leiomyosarcoma ,Male ,medicine.medical_specialty ,business.industry ,Urology ,Intraoperative radiation ,Prostatic Neoplasms ,Multimodal therapy ,Disease ,Chemoradiotherapy, Adjuvant ,Middle Aged ,medicine.disease ,Survival Analysis ,Disease-Free Survival ,Neoadjuvant Therapy ,Surgery ,Prostate Sarcoma ,medicine.anatomical_structure ,Concurrent chemotherapy ,Oncology ,Prostate ,Cohort ,medicine ,Humans ,business - Abstract
Background The objective of this study was to evaluate the use of neoadjuvant chemoradiation in patients with prostate sarcoma treated at our institution and report oncological outcomes. Materials and methods The records of patients with intermediate- or high-grade prostate sarcoma treated with curative intent at our institution from 1993 to 2013 were reviewed. Patient demographic information, tumor characteristics, and treatment modalities used were assessed. Overall survival (OS), cancer-specific survival (CSS), and recurrence-free survival (RFS) were calculated. Results Eight patients met inclusion criteria. The mean age at presentation was 64 years, and urinary obstruction was the most common presenting symptom. All patients underwent surgical resection and neoadjuvant radiation and 6 had concurrent chemotherapy. Four patients received intraoperative radiation. With a median follow-up of 36 months, there were no local recurrences, 6 metastases, 4 deaths from disease, and no deaths from other causes. The median OS and CSS was 67.8 months, with actuarial OS and CSS rates of 100% at 1 year, 75% at 2 years, 62.5% at 3 years, and 62.5% at 5 years. Median RFS was 14.2 months, with actuarial RFS rate of 75% at 1 year, 37.5% at 2 years, and 25% at 3 years. Conclusion Prostate sarcomas are rarely cured using surgical resection alone. Our cohort treated with a multimodality approach had favorable CSS and RFS compared with historic and contemporary series of surgery alone and no local recurrences. Most patients developed metastatic recurrence, highlighting the aggressive nature of this disease.
- Published
- 2015
43. Favorable Response to Neoadjuvant Chemotherapy and Radiation in a Patient With Prostatic Stromal Sarcoma
- Author
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Jonathan E. Efron, Mark W. Ball, Alex R. Chang, Trinity J. Bivalacqua, Adam C. Reese, and Christian F. Meyer
- Subjects
Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Chemotherapy ,business.industry ,medicine.medical_treatment ,MEDLINE ,Prostatic Neoplasms ,Sarcoma ,Neoadjuvant Therapy ,FAVORABLE RESPONSE ,Stromal sarcoma ,Text mining ,Chemotherapy, Adjuvant ,Internal medicine ,Humans ,Medicine ,Stromal Cells ,business ,Adjuvant ,Neoadjuvant therapy ,Aged - Published
- 2012
44. Prostate angiosarcoma: a case report and literature review
- Author
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Richard M. Wolf, Christian F. Meyer, Waseem Khaliq, Ikechukwu Uzoaru, and Emmanuel S. Antonarakis
- Subjects
Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Hemangiosarcoma ,Article ,Internal medicine ,medicine ,Humans ,Dysuria ,neoplasms ,Pathological ,Aged ,Hematology ,business.industry ,Pelvic pain ,Prostatic Neoplasms ,General Medicine ,medicine.disease ,Prostate Angiosarcoma ,digestive system diseases ,Radiation therapy ,Adenocarcinoma ,Radiology ,medicine.symptom ,business - Abstract
Angiosarcomas are a relatively rare histological subtype of sarcomas and represent
- Published
- 2012
45. (P105) Characterization and Predictive Value of Volume Changes of Extremity and Pelvis Soft-Tissue Sarcomas During Radiotherapy Prior to Surgical Resection
- Author
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Carol D. Morris, Adam S. Levin, Christian F. Meyer, Deborah A. Frassica, Stephanie A. Terezakis, Chengcheng Gui, and Curtiland Deville
- Subjects
Surgical resection ,Cancer Research ,medicine.medical_specialty ,Radiation ,business.industry ,medicine.medical_treatment ,Predictive value ,Radiation therapy ,Oncology ,Pelvis soft tissue ,medicine ,Radiology, Nuclear Medicine and imaging ,Radiology ,business ,Volume (compression) - Published
- 2017
46. Familial GI Stromal Tumor With Loss of Heterozygosity and Amplification of Mutant KIT
- Author
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Anne O. Lidor, Christian F. Meyer, Ross C. Donehower, Sosipatros A. Boikos, Katherine Thornton, Elizabeth A. Montgomery, Daniel J. Zabransky, Rory L. Cochran, Ben Ho Park, Patrick M. Forde, and Julia A. Beaver
- Subjects
0301 basic medicine ,Cancer Research ,Gastrointestinal Stromal Tumors ,Mutant ,Loss of Heterozygosity ,Loss of heterozygosity ,03 medical and health sciences ,0302 clinical medicine ,Gene duplication ,Medicine ,Humans ,Base sequence ,Stromal tumor ,Gastrointestinal Neoplasms ,Genetics ,Base Sequence ,business.industry ,Gene Amplification ,Middle Aged ,Molecular biology ,Pedigree ,Proto-Oncogene Proteins c-kit ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Mutation (genetic algorithm) ,Mutation ,Female ,business - Published
- 2014
47. Pazopanib in sarcomas: expanding the PALETTE
- Author
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Jonathan C. Trent, Breelyn A. Wilky, and Christian F. Meyer
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Indazoles ,medicine.drug_class ,medicine.medical_treatment ,Angiogenesis Inhibitors ,Tyrosine-kinase inhibitor ,Article ,Pazopanib ,Clinical Trials, Phase II as Topic ,Internal medicine ,medicine ,Effective treatment ,Animals ,Humans ,Randomized Controlled Trials as Topic ,Chemotherapy ,Sulfonamides ,Adult patients ,business.industry ,Sarcoma ,medicine.disease ,Surgery ,Clinical trial ,Pyrimidines ,Clinical Trials, Phase III as Topic ,business ,Median survival ,medicine.drug - Abstract
After failure of standard therapy, few effective treatment options exist for adult patients with metastatic sarcomas, and median survival remains dismal at approximately 1 year. Pazopanib, a multitargeted tyrosine kinase inhibitor, has recently been approved for nonadipocytic soft tissue sarcomas refractory to chemotherapy. In this review, we will revisit the efficacy of pazopanib in sarcomas, and present a patient case that illustrates two of many unanswered questions: which sarcoma patients are most likely to benefit from pazopanib therapy, and what criteria are best suited to accurately detect benefit in clinical trials?Pazopanib has been tested in sarcoma patients in a phase II and phase III study, and was shown to prolong progression-free survival by 3 months relative to placebo. Although histology has been the primary stratification variable for subgroup analysis in large sarcoma trials, the PALETTE study did not demonstrate superior response within histologic cohorts. Ongoing trials seek to explore efficacy of pazopanib in previously excluded histologies, as well as include correlative studies to identify histologic and molecular biomarkers to predict patients likely to benefit.Pazopanib has been proven to provide modest benefit overall to nonadipocytic soft tissue sarcoma patients, but we have yet to identify the molecular basis for those patients who derive exceptional benefit.
- Published
- 2013
48. SARC016: Phase II study of everolimus in combination with bevacizumab in sporadic and neurofibromatosis type 1 (NF1) related refractory malignant peripheral nerve sheath tumors (MPNST)
- Author
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Scott H. Okuno, Christian F. Meyer, Gregory M. Cote, Nalini Jayaprakash, Brian A. Van Tine, Brigitte C. Widemann, John P. Perentesis, Ndidi Onwudiwe, AeRang Kim, Rashmi Chugh, Denise K. Reinke, Karen Cichowski, Lee J. Helman, Brian Turpin, Seth M. Steinberg, Eva Dombi, and Mohammed M. Milhem
- Subjects
0301 basic medicine ,congenital, hereditary, and neonatal diseases and abnormalities ,Cancer Research ,Everolimus ,Bevacizumab ,business.industry ,Angiogenesis ,Phases of clinical research ,medicine.disease ,law.invention ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,Refractory ,Downregulation and upregulation ,law ,030220 oncology & carcinogenesis ,mental disorders ,Cancer research ,Medicine ,Suppressor ,Neurofibromatosis ,business ,medicine.drug - Abstract
11053Background: There are no effective medical treatments for MPNST. Inactivation of the NF1 tumor suppressor in MPNST results in upregulation of mTOR signaling and angiogenesis contributes to dis...
- Published
- 2016
49. Programmed death-1 blockade in mismatch repair deficient cancer independent of tumor histology
- Author
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Tim F. Greten, Bert Vogelstein, Bjarne Bartlett, Tianna Dauses, Jennifer N. Uram, Daniel A. Laheru, James J. Lee, Christian F. Meyer, Nilofer S. Azad, Todd S. Crocenzi, George A. Fisher, Hao Wang, Deborah K. Armstrong, Amanda N. Fader, Luis A. Diaz, Dung T. Le, Minori Koshiji, Richard M. Goldberg, Aleksandra Eyring, and Holly Kemberling
- Subjects
0301 basic medicine ,Cancer Research ,biology ,business.industry ,Phases of clinical research ,Cancer ,Pembrolizumab ,medicine.disease ,Blockade ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Immune system ,Oncology ,030220 oncology & carcinogenesis ,Immunology ,Cancer research ,biology.protein ,Medicine ,DNA mismatch repair ,Antibody ,business ,Survival rate - Abstract
3003Background: Mismatch repair deficiency (MRD) is feature of many cancers at a frequency of approximately 1 in 30 patients independent of tumor histology. Tumors with MRD are deficient in the repair of specific DNA replication errors and as a result accumulate hundreds to thousands of mutations per tumor genome. The high number of somatic mutations increase the chances for at least one of these mutations to result in a highly immunogenic neo-antigenic protein that can trigger a potent anti-tumor immune response in the presence of PD-1 blockade. Methods: To further test this hypothesis, we conducted a phase 2 study to evaluate the activity of pembrolizumab (pembro), a programmed death-1 (PD-1) antibody in MRD tumors independent of tumor histology using a basket design. Pembro was administered at 10 mg/kg every 14 days in patients with > 1 prior therapy. The co-primary endpoints were response and progression-free survival rate at 20 weeks. Secondary endpoints included disease control rate (DCR = CR+PR+SD)...
- Published
- 2016
50. Preliminary Results from a Combined 153Sm-EDTMP and External Beam Radiation Therapy for Metastatic Osteosarcoma Patients Using Prospective Absorbed Dose-Based Treatment Planning
- Author
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Stephanie A. Terezakis, Christian F. Meyer, George Sgouros, Anders Josefsson, David M. Loeb, Donika Plyku, Thibault Mauxion, Robert F. Hobbs, and Eric C. Frey
- Subjects
medicine.medical_specialty ,Oncology ,business.industry ,Absorbed dose ,External beam radiation ,Metastatic osteosarcoma ,medicine ,Radiology, Nuclear Medicine and imaging ,Radiology ,business ,Radiation treatment planning ,153sm edtmp - Published
- 2016
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