Publications by authors named "David M Loeb"

76 Publications

A multicenter report on the safety and efficacy of plerixafor based stem cell mobilization in children with malignant disorders.

Transfusion 2021 Jan 21. Epub 2021 Jan 21.

Division of Hematology, Oncology, Blood and Bone Marrow Transplant, Nationwide Children's Hospital, Columbus, Ohio, USA.

Background: Pleraxifor for peripheral blood stem cell (PBSC) mobilization in children with malignancies is often given following failure of standard mobilization (SM) rather than as a primary mobilizing agent.

Study Design And Methods: In this retrospective multicenter study, we report the safety of plerixafor-based PBSC mobilization in children with malignancies and compare outcomes between patients who received plerixafor upfront with SM (Group A) with those who received plerixafor following failure of SM (Group B). In the latter pleraxifor was given either following a low peripheral blood (PB) CD34 (<20 cells/cu.mm) (Group B1) or as a second collection process due to an unsuccessful yield (CD34 + < 2 × 10 /kg) (Group B2) following failed SM and first apheresis attempts.

Results: The study cohort (n = 47) with a median age of 8 (range 0.6-21) year, comprised 19 (40%) Group A and 28 (60%) Group B patients (B1 = 12 and B2 = 16). Pleraxifor mobilization was successful in 87.2% of patients, similar between Groups A and B (84.2% vs 89.2%) and resulted in a median 4-fold increase in PB CD34. Median number of apheresis attempts was 2 in Groups A and B1 but 4 in Group B2. In Group B2, median total CD34+ yield post-plerixafor was 9-fold higher than after SM (P = .0013). Mild to moderate transient adverse events affected 8.5% of patients. Among patients who proceeded to autologous transplant (n = 39), all but one engrafted.

Conclusion: Plerixafor-based PBSC collection was safe and effective in our cohort and supports consideration as a primary mobilizing agent in children with malignancies.
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http://dx.doi.org/10.1111/trf.16260DOI Listing
January 2021

Respiratory Failure in a Child With Pulmonary Metastatic Osteosarcoma and COVID-19.

J Pediatr Hematol Oncol 2020 Aug 26. Epub 2020 Aug 26.

*Department of Pediatrics, Albert Einstein College of Medicine †Division of Pediatric Hematology, Oncology and Marrow & Blood Cell Transplantation, Children's Hospital at Montefiore, Bronx, NY.

The novel coronavirus, SARS-CoV-2, causes much more severe disease in adults than in children. Although it is anticipated that immune compromised children and children with cancer may be at higher risk of developing severe or fatal COVID-19, there are no currently published reports of fatal disease in a child with cancer. Because of the discrepancy in disease severity between adult and pediatric patients, we report the case of an adolescent with pulmonary metastatic osteosarcoma who died of COVID-19 early in the course of the pandemic in New York City in the hope that heightening awareness that pulmonary metastatic disease may predispose to a more severe outcome will increase surveillance in this vulnerable population.
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http://dx.doi.org/10.1097/MPH.0000000000001897DOI Listing
August 2020

Wnt Signaling in Osteosarcoma.

Adv Exp Med Biol 2020 ;1258:125-139

Department of Orthopedic Surgery, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA.

Wnt molecules are a class of cysteine-rich secreted glycoproteins that participate in various developmental events during embryogenesis and adult tissue homeostasis. Since its discovery in 1982, the roles of Wnt signaling have been established in various key regulatory systems in biology. Wnt signals exert pleiotropic effects, including mitogenic stimulation, cell fate specification, and differentiation. The Wnt signaling pathway in humans has been shown to be involved in a wide variety of disorders including colon cancer, sarcoma, coronary artery disease, tetra-amelia, Mullerian duct regression, eye vascular defects, and abnormal bone mass. The canonical Wnt pathway functions by regulating the function of the transcriptional coactivator β-catenin, whereas noncanonical pathways function independent of β-catenin. Although the role of Wnt signaling is well established in epithelial malignancies, its role in mesenchymal tumors is more controversial. Some studies have suggested that Wnt signaling plays a pro-oncogenic role in various sarcomas by driving cell proliferation and motility; however, others have reported that Wnt signaling acts as a tumor suppressor by committing tumor cells to differentiate into a mature lineage. Wnt signaling pathway also plays an important role in regulating cancer stem cell function. In this review, we will discuss Wnt signaling pathway and its role in osteosarcoma.
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http://dx.doi.org/10.1007/978-3-030-43085-6_8DOI Listing
December 2020

Delayed presentations of pediatric solid tumors at a tertiary care hospital in the Bronx due to COVID-19.

Pediatr Blood Cancer 2021 02 29;68(2):e28615. Epub 2020 Jul 29.

Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York.

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http://dx.doi.org/10.1002/pbc.28615DOI Listing
February 2021

Skp2 depletion reduces tumor-initiating properties and promotes apoptosis in synovial sarcoma.

Transl Oncol 2020 Oct 2;13(10):100809. Epub 2020 Jul 2.

Department of Orthopedic Surgery, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY. Electronic address:

Synovial sarcoma (SS) is an aggressive soft-tissue cancer with a poor prognosis and a propensity for local recurrence and distant metastasis. In this study, we investigated whether S phase kinase-associated protein (Skp2) plays an oncogenic role in tumor initiation, progression, and metastasis of SS. Our study revealed that Skp2 is frequently overexpressed in SS specimens and SS18-SSX transgenic mouse tumors, as well as correlated with clinical stages. Next, we identified that genetic depletion of Skp2 reduced mesenchymal and stemness markers, and inhibited the invasive and proliferative capacities of SS cell lines. Furthermore, Skp2 depletion markedly suppressed the growth of SS xenografts tumors. Treatment of SS cell lines with the skp2 inhibitor flavokawain A (FKA) reduced Skp2 expression in a dose-dependent manner and resulted in cell cycle arrest and apoptosis. FKA also suppressed the invasion and tumor-initiating properties in SS, similar to the effects of Skp2 knockdown. In addition, a combination of FKA and conventional chemotherapy showed a synergistic therapeutic efficacy. Taken together, our results suggest that Skp2 plays an essential role in the biology of SS by promoting the mesenchymal state and cancer stemness. Given that chemotherapy resistance is often associated with cancer stemness, strategies of combining Skp2 inhibitors with conventional chemotherapy in SS may be desirable.
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http://dx.doi.org/10.1016/j.tranon.2020.100809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334610PMC
October 2020

A clinically and genomically annotated nerve sheath tumor biospecimen repository.

Sci Data 2020 06 19;7(1):184. Epub 2020 Jun 19.

Sidney Kimmel Comprehensive Cancer Center and Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, USA.

Nerve sheath tumors occur as a heterogeneous group of neoplasms in patients with neurofibromatosis type 1 (NF1). The malignant form represents the most common cause of death in people with NF1, and even when benign, these tumors can result in significant disfigurement, neurologic dysfunction, and a range of profound symptoms. Lack of human tissue across the peripheral nerve tumors common in NF1 has been a major limitation in the development of new therapies. To address this unmet need, we have created an annotated collection of patient tumor samples, patient-derived cell lines, and patient-derived xenografts, and carried out high-throughput genomic and transcriptomic characterization to serve as a resource for further biologic and preclinical therapeutic studies. In this work, we release genomic and transcriptomic datasets comprised of 55 tumor samples derived from 23 individuals, complete with clinical annotation. All data are publicly available through the NF Data Portal and at http://synapse.org/jhubiobank.
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http://dx.doi.org/10.1038/s41597-020-0508-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305302PMC
June 2020

Results of a Randomized, Double-Blinded, Placebo-Controlled, Phase 2.5 Study of Saracatinib (AZD0530), in Patients with Recurrent Osteosarcoma Localized to the Lung.

Sarcoma 2020 30;2020:7935475. Epub 2020 Apr 30.

Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California Children's Hospital Los Angeles, 4650 Sunset Blvd Mail Stop 57, Los Angeles, CA 90027, USA.

Purpose: Osteosarcoma is a rare cancer and a third of patients who have completed primary treatment will develop osteosarcoma recurrence. The Src pathway has been implicated in the metastatic behavior of osteosarcoma; about 95% of samples examined express Src or have evidence of downstream activation of this pathway. Saracatinib (AZD0530) is a potent and selective Src kinase inhibitor that was evaluated in adults in Phase 1 studies. The primary goal of this study was to determine if treatment with saracatinib could increase progression-free survival (PFS) for patients who have undergone complete resection of osteosarcoma lung metastases in a double-blinded, placebo-controlled trial. . Subjects with recurrent osteosarcoma localized to lung and who had complete surgical removal of all lung nodules were randomized within six weeks after complete surgical resection. Saracatinib, or placebo, was administered at a dose of 175 mg orally, once daily, for up to thirteen 28-day cycles.

Results: Thirty-seven subjects were included in the analyses; 18 subjects were randomized to receive saracatinib and 19 to receive placebo. Intent-to-treat analysis demonstrated a median PFS of 19.4 months in the saracatinib treatment group and 8.6 months in the placebo treatment group (=0.47). Median OS was not reached in either arm.

Conclusions: Although saracatinib was well tolerated in this patient population, there was no apparent impact of the drug in this double-blinded, placebo-controlled trial on OS, and Src inhibition alone may not be sufficient to suppress metastatic progression in osteosarcoma. There is a suggestion of potential clinical benefit as evidenced by longer PFS in patients randomized to saracatinib based on limited numbers of patients treated.
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http://dx.doi.org/10.1155/2020/7935475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211262PMC
April 2020

Phase II trial of gemcitabine and nab-paclitaxel in patients with recurrent Ewing sarcoma: A report from the National Pediatric Cancer Foundation.

Pediatr Blood Cancer 2020 07 9;67(7):e28370. Epub 2020 May 9.

Division of Pediatric Hematology-Oncology, Duke Children's Hospital and Health Center, Durham, North Carolina.

Background: The combination of gemcitabine and docetaxel is often used to treat patients with recurrent sarcoma. Nab-paclitaxel is a taxane modified to improve drug exposure and increase intratumoral accumulation and, in combination with gemcitabine, is standard therapy for pancreatic cancer. Applying the dosages and schedule used for pancreatic cancer, we performed a phase II trial to assess the response rate of gemcitabine and nab-paclitaxel in patients with relapsed Ewing sarcoma.

Procedure: Using a Simon's two-stage design to identify a response rate of ≥ 35%, patients received nab-paclitaxel 125 mg/m followed by gemcitabine 1000 mg/m i.v. on days 1, 8, and 15 of four-week cycles. Immunohistochemical analysis of archival tissue was performed to identify possible biomarkers of response.

Results: Eleven patients from four institutions enrolled, with a median age of 22 years (range, 14-27). Patients were heavily pretreated (median 3 prior regimens, range, 1-7). Thirty-five cycles were administered (median 2, range, 1-8). Accrual was stopped after 11 patients, due to only one confirmed partial response. Two other patients had partial responses after two cycles, but withdrew because of adverse effects or progression before confirmation of continued response. The predominant toxicity was myelosuppression, and four (36%) patients were removed due to hematologic toxicity despite pegfilgrastim and dose reductions. Expression of secreted protein, acidic and rich in cysteine (SPARC) and CAV-1 in archival tumors was not predictive of clinical benefit in this small cohort of patients.

Conclusions: In patients with heavily pretreated Ewing sarcoma, the confirmed response rate of 9% was similar to multi-institutional studies of gemcitabine and docetaxel.
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http://dx.doi.org/10.1002/pbc.28370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771264PMC
July 2020

An evolutionary framework for treating pediatric sarcomas.

Cancer 2020 06 16;126(11):2577-2587. Epub 2020 Mar 16.

Cancer Biology and Evolution Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.

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http://dx.doi.org/10.1002/cncr.32777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318114PMC
June 2020

Enolate-forming compounds provide protection from platinum neurotoxicity.

Chem Biol Interact 2020 Feb 21;317:108961. Epub 2020 Jan 21.

Department of Anesthesiology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, 10467, USA.

Cisplatin (CisPt) and other platinum (Pt)-based antineoplastic drugs (e.g., carboplatin, oxaliplatin) are highly effective and widely used in the treatment of solid tumors in both pediatric and adult patients. Although considered to be life-saving as a cancer treatment, Pt-based drugs frequently result in dose-limiting toxicities such as chemotherapy-induced peripheral neuropathies (CIPN). Specifically, irreversible damage to outer hair cells and injury of sensory neurons are linked to profound sensorineural hearing loss (ototoxicity), which complicates tumor management and can lead to a poor clinical prognosis. Given the severity of CIPN, substantial effort has been devoted to the development of neuroprotective compounds, regardless clinical results have been underwhelming. It is noteworthy that Pt is a highly reactive electrophile (electron deficient) that causes toxicity by forming adducts with nucleophilic (electron rich) targets on macromolecules. In this regard, we have discovered a series of carbon-based enol nucleophiles; e.g., N-(4-acetyl-3,5-dihydroxyphenyl)-2-oxocytclopentane-1-carboxamide (Gavinol), that can prevent neurotoxicity by scavenging the platinum ion. The chemistry of enol compounds is well understood and mechanistic research has demonstrated the role of this chemistry in cytoprotection. Our cell-derived data were corroborated by calculations of hard and soft, acids and bases (HSAB) parameters that describe the electronic character of interacting electrophiles and nucleophiles. Together, these observations indicate that the respective mechanisms of Pt neurotoxicity and antitumor activity are separable and can therefore be affected independently.
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http://dx.doi.org/10.1016/j.cbi.2020.108961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069230PMC
February 2020

Three-dimensional in vitro modeling of malignant bone disease recapitulates experimentally accessible mechanisms of osteoinhibition.

Cell Death Dis 2018 11 26;9(12):1161. Epub 2018 Nov 26.

Department of Molecular and Cellular Medicine, Institute for Regenerative Medicine, Texas A&M Health Science Center, College Station, TX, 77845, USA.

Malignant bone disease (MBD) occurs when tumors establish in bone, causing catastrophic tissue damage as a result of accelerated bone destruction and inhibition of repair. The resultant so-called osteolytic lesions (OL) take the form of tumor-filled cavities in bone that cause pain, fractures, and associated morbidity. Furthermore, the OL microenvironment can support survival of tumor cells and resistance to chemotherapy. Therefore, a deeper understanding of OL formation and MBD progression is imperative for the development of future therapeutic strategies. Herein, we describe a novel in vitro platform to study bone-tumor interactions based on three-dimensional co-culture of osteogenically enhanced human mesenchymal stem cells (OEhMSCs) in a rotating wall vessel bioreactor (RWV) while attached to micro-carrier beads coated with extracellular matrix (ECM) composed of factors found in anabolic bone tissue. Osteoinhibition was recapitulated in this model by co-culturing the OEhMSCs with a bone-tumor cell line (MOSJ-Dkk1) that secretes the canonical Wnt (cWnt) inhibitor Dkk-1, a tumor-borne osteoinhibitory factor widely associated with several forms of MBD, or intact tumor fragments from Dkk-1 positive patient-derived xenografts (PDX). Using the model, we observed that depending on the conditions of growth, tumor cells can biochemically inhibit osteogenesis by disrupting cWnt activity in OEhMSCs, while simultaneously co-engrafting with OEhMSCs, displacing them from the niche, perturbing their activity, and promoting cell death. In the absence of detectable co-engraftment with OEhMSCs, Dkk-1 positive PDX fragments had the capacity to enhance OEhMSC proliferation while inhibiting their osteogenic differentiation. The model described has the capacity to provide new and quantifiable insights into the multiple pathological mechanisms of MBD that are not readily measured using monolayer culture or animal models.
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http://dx.doi.org/10.1038/s41419-018-1203-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6255770PMC
November 2018

Knock-in of the R394W mutation causes MDS and cooperates with to drive aggressive myeloid neoplasms in mice.

Oncotarget 2018 Oct 19;9(82):35313-35326. Epub 2018 Oct 19.

The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Wilms tumor 1 (WT1) is a zinc finger transcriptional regulator, and has been implicated as both a tumor suppressor and oncogene in various malignancies. Mutations in the DNA-binding domain of the gene are described in 10-15% of normal-karyotype AML (NK-AML) in pediatric and adult patients. Similar mutations have been reported in adult patients with myelodysplastic syndrome (MDS). mutations have been independently associated with treatment failure and poor prognosis in NK-AML. Internal tandem duplication (ITD) mutations of FMS-like tyrosine kinase 3 () commonly co-occur with -mutant AML, suggesting a cooperative role in leukemogenesis. The functional role of mutations in hematologic malignancies appears to be complex and is not yet fully elucidated. Here, we describe the hematologic phenotype of a knock-in mouse model of a mutation (R394W), described in cases of human leukemia. We show that mice develop MDS which becomes 100% penetrant in a transplant model, exhibit an aberrant expansion of myeloid progenitor cells, and demonstrate enhanced self-renewal of hematopoietic progenitor cells . We crossbred mice with knock-in mice, and show that mice with both mutations (/) develop a transplantable MDS/MPN, with more aggressive features compared to either single mutant mouse model.
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http://dx.doi.org/10.18632/oncotarget.26238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6219680PMC
October 2018

A phase II study of temsirolimus and liposomal doxorubicin for patients with recurrent and refractory bone and soft tissue sarcomas.

Clin Sarcoma Res 2018 5;8:21. Epub 2018 Nov 5.

1Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD USA.

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/m weekly) with the chemotherapeutic agent liposomal doxorubicin (30 mg/m 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. The trial was registered on clinicaltrials.gov (NCT00949325) on 30 July 2009. http://www.editorialmanager.com/csrj/default.aspx.
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http://dx.doi.org/10.1186/s13569-018-0107-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6217787PMC
November 2018

Outcomes of Measurable Residual Disease in Pediatric Acute Myeloid Leukemia before and after Hematopoietic Stem Cell Transplant: Validation of Difference from Normal Flow Cytometry with Chimerism Studies and Wilms Tumor 1 Gene Expression.

Biol Blood Marrow Transplant 2018 10 19;24(10):2040-2046. Epub 2018 Jun 19.

Division of Hematology, Oncology, and Blood and Marrow Transplantation, Children's Hospital Los Angeles, USC Keck School of Medicine, Los Angeles, CA, USA.

We enrolled 150 patients in a prospective multicenter study of children with acute myeloid leukemia undergoing hematopoietic stem cell transplantation (HSCT) to compare the detection of measurable residual disease (MRD) by a "difference from normal" flow cytometry (ΔN) approach with assessment of Wilms tumor 1 (WT1) gene expression without access to the diagnostic specimen. Prospective analysis of the specimens using this approach showed that 23% of patients screened for HSCT had detectable residual disease by ΔN (.04% to 53%). Of those patients who proceeded to transplant as being in morphologic remission, 10 had detectable disease (.04% to 14%) by ΔN. The disease-free survival of this group was 10% (0 to 35%) compared with 55% (46% to 64%, P < .001) for those without disease. The ΔN assay was validated using the post-HSCT specimen by sorting abnormal or suspicious cells to confirm recipient or donor origin by chimerism studies. All 15 patients who had confirmation of tumor detection relapsed, whereas the 2 patients with suspicious phenotype cells lacking this confirmation did not. The phenotype of the relapse specimen was then used retrospectively to assess the pre-HSCT specimen, allowing identification of additional samples with low levels of MRD involvement that were previously undetected. Quantitative assessment of WT1 gene expression was not predictive of relapse or other outcomes in either pre- or post-transplant specimens. MRD detected by ΔN was highly specific, but did not identify most relapsing patients. The application of the assay was limited by poor quality among one-third of the specimens and lack of a diagnostic phenotype for comparison.
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http://dx.doi.org/10.1016/j.bbmt.2018.06.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6239928PMC
October 2018

Association of Dasatinib With Progression-Free Survival Among Patients With Advanced Gastrointestinal Stromal Tumors Resistant to Imatinib.

JAMA Oncol 2018 06;4(6):814-820

Department of Internal Medicine, University of Michigan, Ann Arbor.

Importance: Gastrointestinal stromal tumors (GISTs) are life-threatening when metastatic or not amenable to surgical removal. In a few patients with advanced GISTs refractory to imatinib mesylate, treatment with sunitinib malate followed by regorafenib provides tumor control; however, additional active treatments are needed for most patients.

Objective: To evaluate the 6-month progression-free survival (PFS), tumor objective response, and overall survival rates in patients with GISTs treated with dasatinib.

Design, Setting, And Participants: This single-arm clinical trial used a Bayesian design to enroll patients 13 years or older with measurable imatinib-refractory metastatic GISTs treated at 14 sarcoma referral centers from June 1, 2008, through December 31, 2009. A control group was not included. Patients were followed up for survival for a minimum of 5 years from date of enrollment. Tumor imaging using computed tomography or magnetic resonance imaging was performed every 8 weeks for the first 24 weeks and every 12 weeks thereafter. Tumor response was assessed by local site using the Choi criteria. Treatment was continued until tumor progression, unacceptable toxic effects after reduction in drug dose, or patient or physician decision. Archival tumor tissue was evaluated for expression of the proto-oncogene tyrosine-protein kinase Src (SRC), phosphorylated SRC (pSRC), and succinate dehydrogenase complex iron sulfur subunit B (SDHB) proteins and for mutation in the V-Kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) and platelet-derived growth factor receptor α (PDGFRA) genes. Data analysis was performed from May 19, 2017, through December 20, 2017.

Interventions: Dasatinib, 70 mg orally twice daily.

Main Outcomes And Measures: The primary end point was the 6-month PFS estimate using greater than 30% as evidence of an active drug and less than 10% as evidence of inactive treatment.

Results: In this study, 50 patients were enrolled (median age, 60 years; age range, 19-78 years; 31 [62%] male and 19 [38%] female; 41 [82%] white), and 48 were evaluable for response. The estimated 6-month PFS rate was 29% in the overall population and 50% in a subset of 14 patients with pSRC in GISTs. Objective tumor response was observed in 25%, including 1 patient with an imatinib-resistant mutation in PDGFRA exon 18.

Conclusions And Relevance: Dasatinib may have activity in a subset of patients with imatinib-resistant GISTs. Further study is needed to determine whether pSRC is a prognostic biomarker.
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http://dx.doi.org/10.1001/jamaoncol.2018.0601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6145709PMC
June 2018

Size-based detection of sarcoma circulating tumor cells and cell clusters.

Oncotarget 2017 Oct 24;8(45):78965-78977. Epub 2017 Aug 24.

Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.

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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http://dx.doi.org/10.18632/oncotarget.20697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5668012PMC
October 2017

Inhibition of porcupine prolongs metastasis free survival in a mouse xenograft model of Ewing sarcoma.

Oncotarget 2017 Oct 21;8(45):78265-78276. Epub 2017 Jul 21.

Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.

The most pressing unmet clinical need for patients with Ewing sarcoma (ES) is the prevention and treatment of metastasis. The Wnt signaling pathway regulates a number of cellular functions associated with metastasis, including proliferation, motility, and stem cell self-renewal. Functional interaction between Wnt ligands and their receptors requires palmitoylation by Porcupine (Porcn), making this an ideal therapeutic target. We studied the effect of WNT974, a potent, selective Porcn inhibitor, on ES metastasis. , WNT974 does not affect ES proliferation or sarcosphere formation, but suppresses multiple transcriptional regulators of metastasis and inhibits cell migration. , in an orthotopic implantation/amputation model of spontaneous distant metastasis, single agent WNT974 treatment leads to a significant delay in formation of lung metastasis and a substantial improvement in post-amputation survival without a major effect on primary tumor growth. The drug produces no survival benefit in a tail vein injection model, supporting the hypothesis that WNT974 inhibits early steps in the metastatic cascade, such as migration and invasion. Our findings strongly implicate Wnt signaling in the early steps of ES metastasis and demonstrate that WNT974 has the potential to significantly improve the survival of ES patients through the specific inhibition of metastasis.
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http://dx.doi.org/10.18632/oncotarget.19432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5667961PMC
October 2017

Metabolic modulation of Ewing sarcoma cells inhibits tumor growth and stem cell properties.

Oncotarget 2017 Sep 24;8(44):77292-77308. Epub 2017 Aug 24.

The Faris D. Virani Ewing Sarcoma Center at The Texas Children's Cancer and Hematology Centers, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.

Ewing sarcoma (EWS) is a highly aggressive and metabolically active malignant tumor. Metabolic activity can broadly be characterized by features of glycolytic activity and oxidative phosphorylation. We have further characterized metabolic features of EWS cells to identify potential therapeutic targets. EWS cells had significantly more glycolytic activity compared to their non-malignant counterparts. Thus, metabolic inhibitors of glycolysis such as 2-deoxy-D-glucose (2DG) and of the mitochondrial respiratory pathway, such as metformin, were evaluated as potential therapeutic agents against a panel of EWS cell lines . Results indicate that 2DG alone or in combination with metformin was effective at inducing cell death in EWS cell lines. The predominant mechanism of cell death appears to be through stimulating apoptosis leading into necrosis with concomitant activation of AMPK-α. Furthermore, we demonstrate that the use of metabolic modulators can target putative EWS stem cells, both and , and potentially overcome chemotherapeutic resistance in EWS. Based on these data, clinical strategies using drugs targeting tumor cell metabolism present a viable therapeutic modality against EWS.
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http://dx.doi.org/10.18632/oncotarget.20467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5652780PMC
September 2017

Consensus and controversies regarding the treatment of rhabdomyosarcoma.

Pediatr Blood Cancer 2018 Feb 14;65(2). Epub 2017 Sep 14.

Division of Pediatric Hematology/Oncology, University of Kentucky, Lexington, Kentucky.

Optimal treatment of rhabdomyosarcoma (RMS) requires multidisciplinary approach, incorporating chemotherapy with local control. Although current therapies are built on cooperative group trials, a comprehensive standard of care to guide clinical decision making has been lacking, especially for relapsed patients. Therefore, we assembled a panel of pediatric and adolescent and young adult sarcoma experts to develop treatment guidelines for managing RMS and to identify areas in which further research is needed. We created algorithms incorporating evidence-based care for patients with RMS, emphasizing the importance of clinical trials and close integration of all specialties involved in the care of these patients.
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http://dx.doi.org/10.1002/pbc.26809DOI Listing
February 2018

Reduced-Intensity Haploidentical Bone Marrow Transplantation with Post-Transplant Cyclophosphamide for Solid Tumors in Pediatric and Young Adult Patients.

Biol Blood Marrow Transplant 2017 Dec 12;23(12):2127-2136. Epub 2017 Aug 12.

Blood and Marrow Transplantation Program, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Hospital, Baltimore, Maryland.

High-risk, recurrent, or refractory solid tumors in pediatric, adolescent, and young adult (AYA) patients have an extremely poor prognosis despite current intensive treatment regimens. We piloted an allogeneic bone marrow transplant platform using reduced-intensity conditioning (RIC) and partially HLA-mismatched (haploidentical) related donors for this population of pediatric and AYA solid tumor patients. Sixteen patients received fludarabine, cyclophosphamide, melphalan, and low-dose total body irradiation RIC haploidentical BMT (haploBMT) followed by post-transplantation cyclophosphamide (PTCy), mycophenolate mofetil, and sirolimus. All assessable patients were full donor chimeras on day 30 with a median neutrophil recovery of 19 days and platelet recovery of 21 days. One patient (7%) exhibited secondary graft failure associated with concomitant infection. The median follow-up time was 15 months. Overall survival was 88%, 56%, and 21% at 6, 12, and 24 months, respectively. Median survival from transplant date was 14 months with a median progression-free survival 7 months. We observed limited graft-versus-host disease in 3 patients and nonrelapse mortality in 1 patient. We demonstrated that RIC haploBMT with PTCy is feasible and has acceptable toxicities in patients with incurable pediatric and AYA solid tumors; thus, this approach serves as a platform for post-transplant strategies to prevent relapse and optimize progression-free survival.
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http://dx.doi.org/10.1016/j.bbmt.2017.08.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5986177PMC
December 2017

A phase II trial evaluating the feasibility of adding bevacizumab to standard osteosarcoma therapy.

Int J Cancer 2017 10 3;141(7):1469-1477. Epub 2017 Jul 3.

Division of Pediatrics, MD Anderson Cancer Center, Houston, TX.

Increased vascular endothelial growth factor (VEGF) expression in osteosarcoma correlates with a poor outcome. We conducted a phase II trial to evaluate the feasibility and efficacy of combining bevacizumab, a monoclonal antibody against VEGF, with methotrexate, doxorubicin and cisplatin (MAP) in patients with localized osteosarcoma. Eligible patients received two courses of MAP chemotherapy before definitive surgery at week 10. Bevacizumab (15 mg/kg) was administered 3 days before starting chemotherapy then on day 1 of weeks 3 and 5 of chemotherapy. After surgery, patients received MAP for a total of 29 weeks; bevacizumab was added every 2 or 3 weeks on day 1 of chemotherapy at least 5 weeks after surgery. Group sequential monitoring rules were used to monitor for unacceptable bevacizumab-related targeted toxicity (grade 4 hypertension, proteinuria or bleeding, grade 3 or 4 thrombosis/embolism, and grade 2-4 major wound complications). Thirty-one patients (median age 12.8 years) with localized osteosarcoma were enrolled. No unacceptable targeted toxicities were observed except for wound complications (9 minor and 6 major), which occurred in 15 patients; none required removal of prosthetic hardware or amputation. The estimated 4-year event-free survival (EFS) rate and overall survival rate were 57.5 ± 10.0% and 83.4 ± 7.8%, respectively. Eight (28%) of 29 evaluable patients had good histologic response (<5% viable tumor) to preoperative chemotherapy. The addition of bevacizumab to MAP for localized osteosarcoma is feasible but frequent wound complications are encountered. The observed histologic response and EFS do not support further evaluation of bevacizumab in osteosarcoma.
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http://dx.doi.org/10.1002/ijc.30841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5812455PMC
October 2017

Targeted therapy for soft tissue sarcomas in adolescents and young adults.

Adolesc Health Med Ther 2017 30;8:41-55. Epub 2017 Mar 30.

Division of Pediatric Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Soft tissue sarcomas (STSs) are a heterogeneous group of tumors originating from the mesenchyme. Even though they affect individuals in all age groups, the prevalence of subtypes of STSs changes significantly from childhood through adolescence into adulthood. The mainstay of therapy is surgery, with or without the addition of chemotherapy and/or radiation therapy. These treatment modalities are associated, in many cases, with significant morbidity and, given the heterogeneity of tumor histologies encompassed by the term "STS", have not uniformly improved outcomes. Moreover, some subgroups of STSs appear to be more, and others less, responsive to conventional chemotherapy agents. Over the last two decades, our understanding of the biology of STSs is slowly increasing, allowing for the development of more targeted therapies. We review the new treatment modalities that have been tested on patients with STSs, with a special focus on adolescents and young adults, a group of patients that is often underrepresented in clinical trials and has not received the dedicated attention it deserves, given the significant differences in biology and treatment response in comparison to children and adults.
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http://dx.doi.org/10.2147/AHMT.S70377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5384699PMC
March 2017

Treatment pathway of bone sarcoma in children, adolescents, and young adults.

Cancer 2017 Jun 21;123(12):2206-2218. Epub 2017 Mar 21.

Center for Cancer and Blood Disorders, Connecticut Children's Medical Center, Hartford, Connecticut.

When pediatric, adolescent, and young adult patients present with a bone sarcoma, treatment decisions, especially after relapse, are complex and require a multidisciplinary approach. This review presents scenarios commonly encountered in the therapy of bone sarcomas with the goal of objectively presenting a consensus, multidisciplinary management approach. Little variation was found in the authors' group with respect to local control or systemic therapy. Clinical trials were universally prioritized in all settings. Decisions regarding relapse therapies in the absence of a clinical trial had very minor variations initially, but a consensus was reached after a literature review and discussion. This review presents a concise document and figures as a starting point for evidence-based care for patients with these rare diseases. This framework allows prospective decision making and prioritization of clinical trials. It is hoped that this framework will inspire and focus future clinical research and thus lead to new trials to improve efficacy and reduce toxicity. Cancer 2017;123:2206-2218. © 2017 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.30589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5485018PMC
June 2017

Personalized Medicine in the Oncology Clinic: Implementation and Outcomes of the Johns Hopkins Molecular Tumor Board.

JCO Precis Oncol 2017 31;2017. Epub 2017 May 31.

The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD.

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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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6039131PMC
http://dx.doi.org/10.1200/PO.16.00046DOI Listing
May 2017

High-dose Cyclophosphamide is Effective Therapy for Pediatric Severe Aplastic Anemia.

J Pediatr Hematol Oncol 2016 11;38(8):627-635

Departments of *Oncology, Division of Pediatric Oncology †Pediatrics, The Division of Hematology ‡Medicine, The Division of Hematology §Pathology, The Division of Transfusion Medicine ¶The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD ∥Department of Pathology and Lab Medicine, The Division of Transfusion Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA.

Objective: Use of high-dose cyclophosphamide without hematopoietic stem cell transplant to treat severe aplastic anemia (SAA) has been controversial due to concern for increased infectious toxicity as compared with antithymocyte globulin and cyclosporine A. As children often tolerate dose-intensive therapy better than adults, we sought to perform a detailed retrospective analysis of both treatment response and toxicity in 28 patients younger than 22 years of age treated with 29 courses of high-dose cyclophosphamide as the sole form of immunosuppression.

Study Design: Children and adolescents with SAA who lacked an human leukocyte antigen-matched sibling donor were treated with cyclophosphamide 50 mg/kg/d for 4 consecutive days then received daily granulocyte colony stimulating factor until neutrophil recovery, transfusion support, and antimicrobial prophylaxis.

Results: Overall survival was 85%, with hematologic response of 79% and complete response of 66%. Cumulative incidences of bacterial infection (86%) and fungal infection (62%) were high but deaths due to infection were rare, as were clonal evolution (1/28), clinically relevant paroxysmal nocturnal (1/28), and relapse (2/28).

Conclusions: Response rates and survival following high-dose cyclophosphamide in pediatric patients with SAA exceed those seen in adults and compare favorably to antithymocyte globulin/cyclosporine A with manageable infectious toxicity.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5074865PMC
http://dx.doi.org/10.1097/MPH.0000000000000647DOI Listing
November 2016

Phase 2 study of dasatinib in patients with alveolar soft part sarcoma, chondrosarcoma, chordoma, epithelioid sarcoma, or solitary fibrous tumor.

Cancer 2017 Jan 3;123(1):90-97. Epub 2016 Oct 3.

University of Michigan, Ann Arbor, Michigan.

Background: Alveolar soft part sarcoma (ASPS), chondrosarcoma (CS), chordoma, epithelioid sarcoma, and solitary fibrous tumor (SFT) are malignant tumors that are relatively resistant to chemotherapy and for which more effective drug therapy is needed.

Methods: The 5 listed subtypes were enrolled into a single indolent sarcoma cohort in a phase 2 study of dasatinib using a Bayesian continuous monitoring rule for enrollment. The primary objective was to estimate the 6-month progression-free survival (PFS) rate according to the Choi criteria with a target of ≥50%. Cross-sectional imaging was performed before the start of treatment, every 2 months for 6 months, and then every 3 months during treatment. The 2- and 5-year survival rates were determined.

Results: One hundred sixteen patients were enrolled within 45 months, and 109 began treatment with dasatinib. The 6-month PFS rate and the median PFS were 48% and 5.8 months, respectively. The PFS rate at 6 months was highest with ASPS (62%) and lowest with SFT (30%). More than 10% of the patients with ASPS, CS, or chordoma had stable disease for more than 1 year. Collectively, for all 5 subtypes, the 2- and 5-year overall survival rates were 44% and 13%, respectively. An objective response was observed in 18% of the patients with CS or chordoma.

Conclusions: Dasatinib failed to achieve control of sarcoma growth for at least 6 months in more than 50% of the patients in this trial according to the Choi tumor response criteria. An objective tumor response and prolonged stable disease was observed in >10% of patients with CS or chordoma. Cancer 2017;90-97. © 2016 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.30379DOI Listing
January 2017

Induction of Immune Response after Allogeneic Wilms' Tumor 1 Dendritic Cell Vaccination and Donor Lymphocyte Infusion in Patients with Hematologic Malignancies and Post-Transplantation Relapse.

Biol Blood Marrow Transplant 2016 12 12;22(12):2149-2154. Epub 2016 Sep 12.

Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.

Relapse of hematologic malignancies is the primary cause of treatment failure after allogeneic hematopoietic stem cell transplantation (HCT). Treatment for post-HCT relapse using donor lymphocyte infusion (DLI) has limited utility, particularly in the setting of acute leukemia, and can result in the development of graft-versus-host disease (GVHD). The Wilms' tumor 1 (WT1) gene product is a tumor-associated antigen that is expressed in acute leukemia and other hematologic malignancies, with limited expression in normal tissues. In this pilot trial, we assessed safety and feasibility of a WT1 peptide-loaded donor-derived dendritic cell (DC) vaccine given with DLI designed to enhance and direct the graft-versus-leukemia effect. Secondary objectives were to evaluate immunologic and clinical responses. A total of 5 subjects, median age 17 years (range, 9 to 19 years), with post-HCT relapse were enrolled. Disease subtypes included acute lymphoblastic leukemia (n = 3), acute myelogenous leukemia (n = 1), and Hodgkin lymphoma (n = 1). Successful vaccine production was feasible from all donors. DC vaccination and DLI were well tolerated. One recipient developed grade 1 skin GVHD not requiring systemic therapy. The most common adverse events included grade 1 reversible pain and pruritus at the vaccine injection and delayed-type hypersensitivity (DTH) skin testing sites. There were no grade 3 or higher adverse events related to the research. Immune responses consisted of ELISpot response in 3 recipients and positive DTH tests to WT1 peptide cocktail in 2 subjects. Our study provides 1 of the first attempts to apply tumor-specific vaccine therapy to the allogeneic setting. Preliminary results show the DC-based vaccination is safe and feasible after allogeneic HCT, with a suggestion that this approach can be used to sensitize the repopulated allogeneic-donor immune system to WT1. Future directions may include testing of vaccination strategies in the early post-transplantation setting for relapse prevention.
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http://dx.doi.org/10.1016/j.bbmt.2016.08.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499897PMC
December 2016

Desmoplastic small round cell tumor: postoperative retroperitoneal mass.

Radiol Case Rep 2016 Sep 17;11(3):248-50. Epub 2016 Jun 17.

Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 401 North Broadway St., Suite 1440, Baltimore, MD, 21287, USA.

We describe the case of a 14-year-old boy who presented with a large, 17.6-cm retroperitoneal mass, along with multiple metastases, and was diagnosed with desmoplastic small round cell tumor. After initial chemotherapy, he underwent gross total resection with a positive margin. On postoperative radiation planning computed tomography, a 6.8-cm heterogeneous mass was noted in the surgical bed. Given the tumor's aggressive nature and positive surgical margins, there was real concern for recurrent disease. Further evaluation with magnetic resonance imaging elucidated that the mass consisted of simple fluid and fat, without contrast enhancement, suggesting a postoperative fluid collection. He was able to continue with adjuvant treatment as planned. This case example illustrates that even large postoperative heterogeneous masses may still be related to postoperative fluid collection in patients with aggressive tumor. However, it is important to rule out recurrent disease before starting adjuvant therapy given improved outcomes with gross total resection in desmoplastic small round cell tumor.
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http://dx.doi.org/10.1016/j.radcr.2016.05.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4996917PMC
September 2016

Highly personalized detection of minimal Ewing sarcoma disease burden from plasma tumor DNA.

Cancer 2016 10 28;122(19):3015-23. Epub 2016 Jun 28.

Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.

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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http://dx.doi.org/10.1002/cncr.30144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5102400PMC
October 2016

A monoclonal antibody against the Wnt signaling inhibitor dickkopf-1 inhibits osteosarcoma metastasis in a preclinical model.

Oncotarget 2016 Apr;7(16):21114-23

Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.

The outcome of patients with metastatic osteosarcoma has not improved since the introduction of chemotherapy in the 1970s. Development of therapies targeting the metastatic cascade is a tremendous unmet medical need. The Wnt signaling pathway has been the focus of intense investigation in osteosarcoma because of its role in normal bone development. Although the role of Wnt signaling in the pathogenesis of osteosarcoma is controversial, there are several reports of dickkopf-1 (DKK-1), a Wnt signaling antagonist, possibly playing a pro-tumorigenic role. In this work we investigated the effect of anti-DKK-1 antibodies on the growth and metastasis of patient-derived osteosarcoma xenografts. We were able to detect human DKK-1 in the blood of tumor-bearing mice and found a correlation between DKK-1 level and tumor proliferation. Treatment with the anti-DKK-1 antibody, BHQ880, slowed the growth of orthotopically implanted patient-derived osteosarcoma xenografts and inhibited metastasis. This effect was correlated with increased nuclear beta-catenin staining and increased expression of the bone differentiation marker osteopontin. These findings suggest that Wnt signaling is anti-tumorigenic in osteosarcoma, and support the targeting of DKK-1 as an anti-metastatic strategy for patients with osteosarcoma.
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http://dx.doi.org/10.18632/oncotarget.8522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5008272PMC
April 2016