Publications by authors named "Jonathan Gill"

69 Publications

Case Discussion and Literature Review: Cancer Immunotherapy, Severe Immune-Related Adverse Events, Multi-Inflammatory Syndrome, and Severe Acute Respiratory Syndrome Coronavirus 2.

Front Oncol 2021 4;11:625707. Epub 2021 Feb 4.

Pediatric Stem Cell Transplantation and Cellular Therapy, CARTOX Program, University of Texas at MD Anderson Cancer Center, Houston, TX, United States.

Pediatric, adolescent and young adult (AYA) patients receiving novel cancer immunotherapies may develop associated toxicities with overlapping signs and symptoms that are not always easily distinguished from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection/clinical sequelae. We describe 2 diagnostically challenging cases of SARS-CoV-2 and Multi-Inflammatory Syndrome-Adult (MIS-A), in patients with a history of acute lymphoblastic leukemia following cellular therapy administration and review evolving characterization of both the natural course of SARS-CoV-2 infection and toxicities experienced in younger cancer immunotherapy patients. Vigilant monitoring for unique presentations and epidemiologic surveillance to promptly detect changes in incidence of either condition may be warranted.
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http://dx.doi.org/10.3389/fonc.2021.625707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891040PMC
February 2021

Diagnosis, grading and management of toxicities from immunotherapies in children, adolescents and young adults with cancer.

Nat Rev Clin Oncol 2021 Feb 19. Epub 2021 Feb 19.

Department of Pediatrics, CARTOX Program, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Cancer immunotherapies are associated with remarkable therapeutic response rates but also with unique and severe toxicities, which potentially result in rapid deterioration in health. The number of clinical applications for novel immune effector-cell therapies, including chimeric antigen receptor (CAR)-expressing cells, and other immunotherapies, such as immune-checkpoint inhibitors, is increasing. In this Consensus Statement, members of the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network Hematopoietic Cell Transplantation-Cancer Immunotherapy (HCT-CI) Subgroup, Paediatric Diseases Working Party (PDWP) of the European Society of Blood and Marrow Transplantation (EBMT), Supportive Care Committee of the Pediatric Transplantation and Cellular Therapy Consortium (PTCTC) and MD Anderson Cancer Center CAR T Cell Therapy-Associated Toxicity (CARTOX) Program collaborated to provide updated comprehensive recommendations for the care of children, adolescents and young adults receiving cancer immunotherapies. With these recommendations, we address emerging toxicity mitigation strategies, we advocate for the characterization of baseline organ function according to age and discipline-specific criteria, we recommend early critical care assessment when indicated, with consideration of reversibility of underlying pathology (instead of organ failure scores) to guide critical care interventions, and we call for researchers, regulatory agencies and sponsors to support and facilitate early inclusion of young patients with cancer in well-designed clinical trials.
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http://dx.doi.org/10.1038/s41571-021-00474-4DOI Listing
February 2021

Prognostic and Therapeutic Utility of Variably Expressed Cell Surface Receptors in Osteosarcoma.

Sarcoma 2021 2;2021:8324348. Epub 2021 Feb 2.

Department of Orthopaedic Surgery, Montefiore Medical Center, The Children's Hospital at Montefiore, Bronx, NY, USA.

Background: Six cell surface receptors, human epidermal growth factor receptor-2 (Her-2), platelet-derived growth factor receptor- (PDGFR-), insulin-like growth factor-1 receptor (IGF-1R), insulin receptor (IR), c-Met, and vascular endothelial growth factor receptor-3 (VEGFR-3), previously demonstrated variable expression across varying patient-derived and standard osteosarcoma (OS) cell lines. The current study sought to validate previous expression patterns and evaluate whether these receptors offer prognostic and/or therapeutic value.

Methods: Patient-derived OS cell lines ( = 52) were labeled with antibodies to Her-2, PDGFR-, IGF-1R, IR, c-Met, and VEGFR-3. Expression was characterized using flow cytometry. The difference in geometric mean fluorescent intensity (geoMFI = geoMFI - geoMFI) was calculated for each receptor across all cell lines. Receptor expression was categorized as low (Q1), intermediate (Q2, Q3), or high (Q4). The event-free survival (EFS) and overall survival for the six cell surface receptors were estimated by the Kaplan-Meier method. Differences in hazard for EFS event and overall survival event for patients in each of the three expression levels in each of the six cell surface receptors were assessed using the log-rank test.

Results: All 6 receptors were variably expressed in the majority of cell lines. IR and PDGFR- expressions were found to be significant predictors for EFS amongst patients with nonmetastatic disease (=0.02 and 0.01, respectively). The hazard ratio for EFS was significantly higher between high IR and intermediate IR expression (HR = 2.66, =0.02), as well as between high PDGFR- and intermediate PDGFR- expression (HR = 5.68, =0.002). Her-2, c-Met, IGF-1R, and VEGFR-3 were not found to be significant predictors for either EFS or overall survival.

Conclusion: The six cell surface receptors demonstrated variable expression across the majority of patient-derived OS cell lines tested. Limited prognostic value was offered by IR and PDGFR- expression within nonmetastatic patients. The remaining receptors do not provide clear prognostic utility. Nevertheless, their consistent, albeit variable, surface expression across a large panel of patient-derived OS cell lines maintains their potential use as future therapeutic targets.
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http://dx.doi.org/10.1155/2021/8324348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872755PMC
February 2021

Survey of Paediatric Oncologists and Pathologists regarding Their Views and Experiences with Variant Translocations in Ewing and Ewing-Like Sarcoma: A Report of the Children's Oncology Group.

Sarcoma 2020 5;2020:3498549. Epub 2020 Dec 5.

Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Advances in molecular diagnostics have identified subsets of Ewing and Ewing-like sarcomas driven by variant translocations with unique biology. It is likely that patients with these tumours will have different clinical features and therapeutic outcomes. Nevertheless, the management of these patients both locally and within cooperative group trials depends on the local pathological diagnosis. It is not known what molecular diagnostic approaches are employed by local pathologists or if the exact translocation is commonly determined. In addition, it is not known what therapeutic approaches are employed for these patients or what cooperative trials are deemed appropriate for these patients by expert consensus. To answer these questions, we performed an international survey of oncologists and pathologists to better understand the diagnostic approaches used to identify variant translocations and the influence the findings have on therapy and clinical trial eligibility. An online survey was distributed to oncologists and pathologists primarily in North America. A total of 141 surveys were completed, representing a 28% response rate. The majority of respondents considered EWSR1-ETS gene family translocations (range 61-96%) to be Ewing sarcoma and would include them on the primary arm of a Ewing sarcoma clinical trial. There was a lack of consensus on how to classify and stratify BCOR-CCNB3, CIC-DUX4, and EWSR1+ with non-ETS partner fusions. Most respondents were either unsure how their institution tested, or their institution did not perform the test. In cases with atypical Ewing morphology, most respondents favoured additional fusion transcript testing. There is a lack of consensus regarding the classification and stratification of rare molecular subtypes in Ewing sarcoma. It is not clear how these alternative translocations have impacted outcomes for past clinical studies. This suggests a need for molecular confirmation of diagnoses and centralized or minimum standardization of testing for future trial enrolment.
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http://dx.doi.org/10.1155/2020/3498549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787769PMC
December 2020

ABBV-085, Antibody-Drug Conjugate Targeting LRRC15, Is Effective in Osteosarcoma: A Report by the Pediatric Preclinical Testing Consortium.

Mol Cancer Ther 2021 03 9;20(3):535-540. Epub 2020 Dec 9.

Division of Pediatrics, University of Texas MD Anderson Cancer Center, Houston, Texas.

Membrane protein leucine-rich repeat containing 15 (LRRC15) is known to be expressed in several solid tumors including osteosarcoma. ABBV-085, an antibody-drug conjugate against LRRC15, conjugated to monomethyl auristatin E (MMAE), was studied in osteosarcoma patient-derived xenografts (PDXs) by the Pediatric Preclinical Testing Consortium (PPTC). expression data were obtained from PPTC RNA-sequencing data for the PDX models. The TARGET database was mined for expression in human osteosarcoma. Protein expression was confirmed via IHC in three PDX models. Seven osteosarcoma PDX models (OS1, OS9, OS33, OS34, OS42, OS55, and OS60) with varying gene expression were studied. ABBV-085 was administered at 3 mg/kg (OS33), 6 mg/kg (all seven PDXs), and 12 mg/kg (OS60) weekly for 4 consecutive weeks via intraperitoneal injection. Control cohorts included vehicle and an isotype MMAE-linked antibody. Tumor volumes and responses were reported using PPTC statistical analysis. OS1, OS33, OS42, OS55, and OS60 had high expression while OS9 and OS34 had low expression. ABBV-085 inhibited tumor growth in six of seven PDX models as compared with vehicle control and significantly improved event-free survival in five of seven models as compared with isotype controls. Two models showed maintained complete responses while all others showed progressive disease. Response correlated with LRRC15 expression. ABBV-085's antitumor activity against osteosarcoma PDX suggests LRRC15 may be a rational target for pursuing clinical trials in patients with this disease.
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http://dx.doi.org/10.1158/1535-7163.MCT-20-0406DOI Listing
March 2021

PGC-1β-expressing POMC neurons mediate the effect of leptin on thermoregulation in the mouse.

Sci Rep 2020 10 15;10(1):16888. Epub 2020 Oct 15.

Biozentrum, University of Basel, Klingelbergstrasse 50/70, 4056, Basel, Switzerland.

The arcuate nucleus (ARC) of the hypothalamus is a key regulator of food intake, brown adipose tissue (BAT) thermogenesis, and locomotor activity. Whole-body deficiency of the transcriptional coactivator peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1β (PGC-1β) disrupts mouse circadian locomotor activity and BAT-regulated thermogenesis, in association with altered gene expression at the central level. We examined whether PGC-1β expression in the ARC is required for proper energy balance and locomotor behavior by generating mice lacking the PGC-1β gene specifically in pro-opiomelanocortin (POMC) neurons. POMC neuron-specific deletion of PGC-1β did not impact locomotor behavior, food intake, body composition, energy fuel utilization and metabolic rate in fed, 24-h fasted and 24-h refed conditions. In contrast, in the fed state, deletion of PGC-1β in POMC cells elevated core body temperature during the nighttime period. Importantly, this higher body temperature is not associated with changes in BAT function and gene expression. Conversely, we provide evidence that mice lacking PGC-1β in POMC neurons are more sensitive to the effect of leptin on heat dissipation. Our data indicate that PGC-1β-expressing POMC neurons are part of a circuit controlling body temperature homeostasis and that PGC-1β function in these neurons is involved in the thermoregulatory effect of leptin.
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http://dx.doi.org/10.1038/s41598-020-73794-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567876PMC
October 2020

Precise Holographic Manipulation of Olfactory Circuits Reveals Coding Features Determining Perceptual Detection.

Neuron 2020 10 24;108(2):382-393.e5. Epub 2020 Aug 24.

Neuroscience Institute, New York University Langone Health, New York, NY 10016, USA; Tech4Health Institute, New York University Langone Health, New York, NY 10016, USA; Department of Ophthalmology, New York University Langone Health, New York, NY 10016, USA. Electronic address:

Sensory systems transform the external world into time-varying spike trains. What features of spiking activity are used to guide behavior? In the mouse olfactory bulb, inhalation of different odors leads to changes in the set of neurons activated, as well as when neurons are activated relative to each other (synchrony) and the onset of inhalation (latency). To explore the relevance of each mode of information transmission, we probed the sensitivity of mice to perturbations across each stimulus dimension (i.e., rate, synchrony, and latency) using holographic two-photon optogenetic stimulation of olfactory bulb neurons with cellular and single-action-potential resolution. We found that mice can detect single action potentials evoked synchronously across <20 olfactory bulb neurons. Further, we discovered that detection depends strongly on the synchrony of activation across neurons, but not the latency relative to inhalation.
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http://dx.doi.org/10.1016/j.neuron.2020.07.034DOI Listing
October 2020

Initial testing of TPO-receptor agonist eltrombopag in osteosarcoma patient-derived xenograft models by the pediatric preclinical testing consortium.

Pediatr Hematol Oncol 2021 Feb 17;38(1):8-13. Epub 2020 Aug 17.

Division of Pediatric Oncology, MD Anderson Children's Cancer Hospital, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Eltrombopag is a small molecule, thrombopoietin receptor agonist approved for the treatment of patients with aplastic anemia and chronic immune thrombocytopenia. It is also a polyvalent cation chelator and inhibits leukemia cell proliferation via reduction of intracellular iron. The efficacy of eltrombopag was tested against a panel of six Pediatric Preclinical Testing Consortium osteosarcoma xenografts at doses of 5 mg/kg/day (moderate dose) and 50 mg/kg/day (high dose). Eltrombopag, at moderate doses, failed to significantly improve event-free survival (EFS) in 6/6 models. At high doses, eltrombopag significantly prolonged EFS in 2/2 models, though the effect size was small. All models tested demonstrated progressive disease. While eltrombopag did not meaningfully inhibit osteosarcoma growth, it also did not stimulate tumor growth, suggesting it may be safely investigated as a supportive care agent to enhance platelet recovery post chemotherapy.
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http://dx.doi.org/10.1080/08880018.2020.1802539DOI Listing
February 2021

Dose-response effect of eribulin in preclinical models of osteosarcoma by the pediatric preclinical testing consortium.

Pediatr Blood Cancer 2020 10 24;67(10):e28606. Epub 2020 Jul 24.

Division of Pediatrics, University of Texas MD Anderson Cancer Center, Houston, Texas.

The pediatric preclinical testing program previously demonstrated activity of eribulin in osteosarcoma patient-derived xenograft (PDX) models. The phase 2 trial in patients with relapsed osteosarcoma failed to meet response endpoints. Eribulin was evaluated in the original and an expanded set of PDX models and tested at multiple dose levels and schedules to evaluate dose-response. Maximal response was observed at the highest dose, consistent with prior results. The alternative schedule generated similar responses. We demonstrate steep dose-response for eribulin in osteosarcoma PDX models, implying that any deviation from achievement of effective concentrations may have a significant impact on activity.
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http://dx.doi.org/10.1002/pbc.28606DOI Listing
October 2020

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

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

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

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

Cell surface vimentin-positive circulating tumor cell-based relapse prediction in a long-term longitudinal study of postremission neuroblastoma patients.

Int J Cancer 2020 12 23;147(12):3550-3559. Epub 2020 Jun 23.

Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Neuroblastoma (NB) is a deadly childhood disease that carries a 50% chance of relapse for anyone in remission and similar level of 5-year survival. We investigated the value of our proprietary approach-cell surface vimentin (CSV) positive circulating tumor cells (CTC) to monitor treatment response and predict relapse in NB patients under remission in a Phase II long-term preventative clinical trial. We longitudinally analyzed peripheral blood samples from 93 patients for 27 cycles (~25 months) and discovered that the presence of CSV CTCs in the first two sequential samples (baseline, cycle 4 [month 3-4]) was a significant indicator of earlier relapse. We observed strong correlation between relapse-free survival (RFS) and lack of CSV CTCs in first 4 cycles of therapy (95%). There was sensitivity reaching 100% in predicting RFS in patients who had neither CSV CTCs nor MycN amplification. Of note, the low number of CSV CTCs seems equivalent to low tumor load because the prevention therapy difluoromethylornithine yields faster reduction of relapse risk when none or only 1-2 CSV CTCs (every 6 mL) are present in the blood samples compared to >3 CSV CTCs. To the best of our knowledge, this is the first study that directly observes CTCs in under remission NB patients for relapse prediction and the first to gather sequential CSV CTC data in any study in a long-term longitudinal manner.
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http://dx.doi.org/10.1002/ijc.33140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839076PMC
December 2020

HER2-Targeted Therapy in Osteosarcoma.

Adv Exp Med Biol 2020 ;1257:55-66

Division of Pediatrics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

In this chapter, we will review studies of HER2 in osteosarcoma and discuss the controversies that have existed in this field. Our present understanding of HER2 in the context of osteosarcoma is that it is expressed on a subset of patient samples, but that expression is not prognostic. We will review the two trials that have been conducted in osteosarcoma which have targeted HER2. Use of an antibody, trastuzumab, did not suggest activity, but a smaller study using HER2-targeted CAR T cells suggested activity may be present. A trial of an antibody-drug conjugate targeting HER2 for recurrent osteosarcoma is under consideration. Trials targeting other surface proteins for the treatment of osteosarcoma have occurred or are in development. Indeed, this leads us to discuss in a broader fashion therapeutic approaches to targeting surface proteins. It is hoped that some of these approaches will lead to new effective therapies for patients with osteosarcoma.
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http://dx.doi.org/10.1007/978-3-030-43032-0_5DOI Listing
August 2020

Initial in vivo testing of a multitarget kinase inhibitor, regorafenib, by the Pediatric Preclinical Testing Consortium.

Pediatr Blood Cancer 2020 06 24;67(6):e28222. Epub 2020 Mar 24.

Division of Pediatrics, University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: Regorafenib is a small molecule multikinase inhibitor that inhibits multiple kinases including BRAF, KIT, PDGFRB, RAF, RET, and VEGFR1-3.

Procedures: The in vivo anticancer effects of regorafenib were assessed in a panel of six osteosarcoma models, three rhabdomyosarcoma models, and one Ewing sarcoma model.

Results: Regorafenib induced modest inhibition of tumor growth in the models evaluated.

Conclusion: The overall pattern of response to regorafenib appears similar to that of the kinase inhibitor sorafenib, with pronounced slowing of tumor growth in some models, limited to the period of agent administration, being the primary treatment effect.
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http://dx.doi.org/10.1002/pbc.28222DOI Listing
June 2020

Association of T and N Categories of the American Joint Commission on Cancer, 8th Edition, With Metastasis and Survival in Patients With Orbital Sarcoma.

JAMA Ophthalmol 2020 04;138(4):374-381

Orbital Oncology and Ophthalmic Plastic Surgery, Department of Plastic Surgery, The University of Texas MD Anderson Cancer Center, Houston.

Importance: No previous studies to date have validated the American Joint Committee on Cancer (AJCC) 8th edition of the TNM classification for orbital sarcoma.

Objectives: To determine the prognostic performance of the most recent TNM classification for orbital sarcoma and to identify other prognostic factors for local recurrence, lymph node metastasis, distant metastasis, and death due to disease.

Design, Setting, And Participants: This single-center retrospective cohort study included 73 consecutive patients treated for orbital sarcoma from March 1, 2003, through June 30, 2018. Data were analyzed from November 1 to December 31, 2018.

Main Outcomes And Measures: T and N categories at presentation and disease-related outcomes, including local recurrence, lymph node metastasis, distant metastasis (DM), and death due to disease (DD).

Results: The 73 participants included 43 men (59%), and the median age was 21 (range, 0-77) years. The common histologic types were rhabdomyosarcoma (RMS) (35 [48%]), solitary fibrous tumor/hemangiopericytoma (10 [14%]), and Ewing sarcoma (8 [11%]). The most common TNM designations were T2 N0 M0 (26 [36%]) and T4 N0 M0 (24 [33%]). T category was associated with the risk of all disease-related outcomes, including local recurrence (hazard ratio [HR] for T2 vs T4, 0.22 [95% CI, 0.06-0.81]; HR for T3 vs T4, 0.59 [95% CI, 0.13-2.65]; P = .03), lymph node metastasis by the last follow-up (T1, 1 [14%]; T2, 0; T3, 0; T4, 12 [35%]; P = .001), DM (HR for T2 vs T4, 0.29 [95% CI, 0.08-1.07]; P = .04), and DD (HR of T2 vs T4, 0.16 [95% CI, 0.04-0.73]; HR of T3 vs T4, 0.30 [95% CI, 0.04-2.34]; P = .02). Higher risk of DM and higher risk of DD were associated with disease category of at least T3 (HR for DM, 3.24 [95% CI, 0.89-11.72; P = .06]; HR for DD, 6.32 [95% CI, 1.43-27.95; P = .005]), N1 disease (HR for DM, 13.33 [95% CI, 4.07-43.65; P < .001]; HR for DD, 7.07 [95% CI, 2.45-20.44; P < .001]), tumor size larger than 3 cm (HR for DM, 2.72 [95% CI, 0.92-8.05; P = .06]; HR for DD, 5.79 [95% CI, 1.85-18.14; P < .001]), and age of patient with RMS younger than 1 year or 10 years or older (HR for DM, 6.85 [95% CI, 0.83-56.53; P = .04]; HR for DD, 7.03 [95% CI, 0.85-57.83; P = .04]). Higher risk of local recurrence was associated with disease category of at least T3 (HR for3 cm, 0.27 [95% CI, 0.09-0.77]; P = .009). Higher risk of lymph node metastasis was associated with disease category of at least T3 (odds ratio [OR], 13.33 [95% CI, 1.77-602.30]; P = .004), alveolar RMS (OR, 9.98 [95% CI, 2.13-51.55]; P = .001), and age of patient with RMS younger than 1 year or 10 years or older (OR, 9.20 [95% CI, 1.01-458.29] P = .03).

Conclusions And Relevance: In patients with orbital sarcoma, T and N categories at presentation (defined by the AJCC 8th edition classification) correlate with metastasis and survival. These findings appear to support consideration of strict surveillance testing for regional nodal and systemic metastases in patients with orbital sarcoma with disease category of at least T3 and/or N1 disease.
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http://dx.doi.org/10.1001/jamaophthalmol.2020.0039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7047857PMC
April 2020

BDNF is a mediator of glycolytic fiber-type specification in mouse skeletal muscle.

Proc Natl Acad Sci U S A 2019 08 18;116(32):16111-16120. Epub 2019 Jul 18.

Biozentrum, University of Basel, CH-4056 Basel, Switzerland;

Brain-derived neurotrophic factor (BDNF) influences the differentiation, plasticity, and survival of central neurons and likewise, affects the development of the neuromuscular system. Besides its neuronal origin, BDNF is also a member of the myokine family. However, the role of skeletal muscle-derived BDNF in regulating neuromuscular physiology in vivo remains unclear. Using gain- and loss-of-function animal models, we show that muscle-specific ablation of BDNF shifts the proportion of muscle fibers from type IIB to IIX, concomitant with elevated slow muscle-type gene expression. Furthermore, BDNF deletion reduces motor end plate volume without affecting neuromuscular junction (NMJ) integrity. These morphological changes are associated with slow muscle function and a greater resistance to contraction-induced fatigue. Conversely, BDNF overexpression promotes a fast muscle-type gene program and elevates glycolytic fiber number. These findings indicate that BDNF is required for fiber-type specification and provide insights into its potential modulation as a therapeutic target in muscle diseases.
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http://dx.doi.org/10.1073/pnas.1900544116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6690026PMC
August 2019

Peroxisome proliferator-activated receptor γ coactivator 1α regulates mitochondrial calcium homeostasis, sarcoplasmic reticulum stress, and cell death to mitigate skeletal muscle aging.

Aging Cell 2019 10 10;18(5):e12993. Epub 2019 Jul 10.

Biozentrum, Division of Pharmacology/Neurobiology, University of Basel, Basel, Switzerland.

Age-related impairment of muscle function severely affects the health of an increasing elderly population. While causality and the underlying mechanisms remain poorly understood, exercise is an efficient intervention to blunt these aging effects. We thus investigated the role of the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a potent regulator of mitochondrial function and exercise adaptation, in skeletal muscle during aging. We demonstrate that PGC-1α overexpression improves mitochondrial dynamics and calcium buffering in an estrogen-related receptor α-dependent manner. Moreover, we show that sarcoplasmic reticulum stress is attenuated by PGC-1α. As a result, PGC-1α prevents tubular aggregate formation and cell death pathway activation in old muscle. Similarly, the pro-apoptotic effects of ceramide and thapsigargin were blunted by PGC-1α in muscle cells. Accordingly, mice with muscle-specific gain-of-function and loss-of-function of PGC-1α exhibit a delayed and premature aging phenotype, respectively. Together, our data reveal a key protective effect of PGC-1α on muscle function and overall health span in aging.
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http://dx.doi.org/10.1111/acel.12993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6718523PMC
October 2019

LigaSure Use Decreases Intraoperative Blood Loss Volume and Blood Transfusion Volume in Sarcoma Surgery.

J Am Acad Orthop Surg 2019 Nov;27(22):841-847

From the Albert Einstein College of Medicine (Ms. Levine), Musculoskeletal Tumor Center, Beijing Key Laboratory for Musculoskeletal Tumors, Peking University People's Hospital (Dr. Zhang), the Department of Orthopaedic Surgery, Montefiore Medical Center, (Dr. Hoang, Dr. Yang, Dr. Bekarev, and Dr. Geller), the Tulane University School of Medicine (Mr. Jurkowski), Division of Pediatrics, University of Texas, MD Anderson Cancer Center (Dr. Roth, Dr. Gill, and Dr. Gorlick), and the Department of Epidemiology & Population Health, Albert Einstein College of Medicine, (Dr. Lo and Ms. Eisenberg).

Introduction: The LigaSure system has been successfully used in thoracic and abdominal surgery. However, to date, its use in the resection of sarcomas has not been systematically studied. We aimed to determine whether the use of the LigaSure system reduces blood loss and blood transfusion volumes in sarcoma surgery.

Methods: One hundred forty-two consecutive patients who underwent sarcoma surgeries between July 2010 and October 2016 were included. Conventional electrocautery alone (n = 91) and with LigaSure (n = 51) were compared. Case-matched samples (n = 46) from each group were additionally compared.

Results: The use of the LigaSure system resulted in a significant decrease in mean intraoperative blood loss (P = 0.02) and blood transfusion volume (P = 0.04). Likewise, a significant decrease in both mean and median intraoperative blood loss (P = 0.003; P < 0.0001) was seen with LigaSure in the case-matched analysis. In the soft-tissue sarcoma subgroup, a significant decrease was observed in mean hemoglobin reduction (P = 0.03) and mean intraoperative blood loss with LigaSure (P = 0.04). No adverse perioperative complications attributed to the LigaSure system were identified.

Conclusions: The LigaSure vessel sealing and dividing system is a safe and effective hemostatic tool for deep dissection in bone and soft-tissue sarcoma surgery.

Level Of Evidence: Level III, therapeutic study.
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http://dx.doi.org/10.5435/JAAOS-D-18-00144DOI Listing
November 2019

Challenges of Clinical Management of Adolescent and Young Adults With Bone and Soft Tissue Sarcoma.

Cancer J 2018 Nov/Dec;24(6):301-306

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

Clinical management of adolescents and young adults with bone and soft tissue sarcomas is quite challenging, mainly because of different chemotherapy approaches adopted by pediatric and adult oncologists and tumor-associated factors related to this peculiar age group. Overcoming these barriers is essential for adolescent and young adult patients, whose survival and long-term physical effects are worse than their pediatric counterparts. Nowadays, constant efforts from international collaborations between pediatric and adult oncologists of sarcoma groups have optioned in converging toward a common therapeutic strategy, while improving quality of treatment, as well as research advances dedicated to this at-risk age group of patients with sarcomas.
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http://dx.doi.org/10.1097/PPO.0000000000000337DOI Listing
September 2019

Down-regulation of Skp2 expression inhibits invasion and lung metastasis in osteosarcoma.

Sci Rep 2018 09 24;8(1):14294. Epub 2018 Sep 24.

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

Osteosarcoma (OS), the most common primary cancer of bone, exhibits a high propensity for local invasion and distant metastasis. This study sought to elucidate the role of S phase kinase-associated protein (Skp2) in osteosarcoma invasion and metastasis and to explore flavokawain A (FKA), a natural chalcone from kava extract, as a potential Skp2 targeting agent for preventing osteosarcoma progression. Skp2 was found to be overexpressed in multiple osteosarcoma cell lines, including 5 standard and 8 primary patient-derived cell lines. Patients whose tumors expressed high levels of Skp2 sustained a significantly worse metastasis-free (p = 0.0095) and overall survival (p = 0.0013) than those with low Skp2. Skp2 knockdown markedly reduced in vitro cellular invasion and in vivo lung metastasis in an orthotopic mouse model of osteosarcoma. Similar to Skp2 knockdown, treatment with FKA also reduced Skp2 expression in osteosarcoma cell lines and blocked the invasion of osteosarcoma cells in vitro and lung metastasis in vivo. Together, our findings suggest that Skp2 is a promising therapeutic target in osteosarcoma, and that FKA may be an effective Skp2-targeted therapy to reduce osteosarcoma metastasis.
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http://dx.doi.org/10.1038/s41598-018-32428-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6155331PMC
September 2018

A phase I window, dose escalating and safety trial of metformin in combination with induction chemotherapy in relapsed refractory acute lymphoblastic leukemia: Metformin with induction chemotherapy of vincristine, dexamethasone, PEG-asparaginase, and doxorubicin.

Pediatr Blood Cancer 2018 09 1;65(9):e27224. Epub 2018 Jun 1.

Johns Hopkins All Children's Hospital, St. Petersburg, FL.

Background: Acute lymphoblastic leukemia (ALL) remains a major cause of death in children. AMP-activated protein kinase (AMPK) affects the unfolded protein response (UPR), leading to increased vulnerability to endoplasmic reticulum (ER) stress in ALL cells. In vitro, metformin causes ALL cell death via AMPK-mediated inhibition of the UPR. It was evaluated whether ER stress could be induced in relapsed ALL through a phase I study investigating the safety and feasibility of metformin in combination with relapse induction chemotherapy.

Procedure: Metformin was administered twice daily for 28 days in addition to vincristine, dexamethasone, PEG-asparaginase and doxorubicin (VXLD). Dose escalation of metformin was evaluated using a 3+3 design. Pharmacokinetics (PK), pharmacodynamic (PD) evaluation of the AMPK and ER stress/UPR pathways, and treatment response were assessed.

Results: Fourteen patients were enrolled; all were evaluable for toxicity. The recommended phase 2 dose (RP2D) was Dose level 2, 1,000 mg/m /day. A single dose-limiting toxicity (DLT), hypoglycemia with acidosis, was observed at the RP2D and two DLTs, diarrhea and acidosis, were observed at Dose Level 3. Nine patients were evaluable for response as defined by the protocol, receiving at least 85% of planned metformin doses. Five complete remissions, one partial response, and one stable disease were observed. PD evaluation showed induction of ER stress, activation of AMPK, and inhibition of the UPR.

Conclusions: The VXLD with metformin was tolerable with a RP2D for metformin of 1,000 mg/m /day and yielded responses in a heavily pretreated population. ER stress was induced and toxicities attributable to metformin occurred in all dose levels.
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http://dx.doi.org/10.1002/pbc.27224DOI Listing
September 2018

High-Dose Chemotherapy with Stem Cell Rescue in Desmoplastic Small Round Cell Tumor: A Single-Institution Experience and Review of the Literature.

Sarcoma 2018 6;2018:1948093. Epub 2018 May 6.

Division of Pediatrics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Purpose: Desmoplastic small round cell tumor (DSRCT) is a rare cancer that predominantly affects males averaging 21 years of age at the time of diagnosis. We describe four cases from our institution and place them within the context of a comprehensive review of the literature.

Patients And Methods: Study population included any patient who received treatment at Children's Hospital at Montefiore (CHAM) with histologic diagnosis of DSRCT. A search of the electronic databases PubMed, Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE for the terms "desmoplastic" AND "small" AND "round" AND "cell" AND "tumor" was performed.

Results: One CHAM patient died of disease at 39 months, one patient has relapsed disease at 40 months, and two patients have no evidence of disease at 60 and 91 months. In the literature review, the 3-year OS was 36% and 5-year OS was 13%. There was a statistically significant difference in OS between no transplant and SCT in remission (=0.004); however, there was no difference between no transplant and SCT not in remission (=0.23).

Conclusion: Given the poor prognosis in DSRCT, this study supports further prospective research into the possible benefit of consolidation of autologous SCT in patients with DSRCT who are in remission, with the alternative inference that these patients in remission may fare well without SCT. Our retrospective review of the literature does not support SCT for patients who are not in remission.
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http://dx.doi.org/10.1155/2018/1948093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5960572PMC
May 2018

Malignant Peripheral Nerve Sheath Tumors in Neurofibromatosis: Impact of Family History.

J Pediatr Hematol Oncol 2018 08;40(6):e359-e363

Pediatric Hematology/Oncology and Marrow and Blood Cell Transplantation.

Objective: The main objective of this study was to determine if family history of malignant peripheral nerve sheath tumor (MPNST) increases risk of developing an MPNST in patients with neurofibromatosis-1 (NF-1).

Materials And Methods: Individuals with NF-1 registered with the Children's Tumor Foundation's Neurofibromatosis Registry were emailed an anonymous 15-minute survey with regard to personal and family history of NF-1, MPNST, ages of onset, and symptomatology. Participation was voluntary and information was self-reported.

Results: The survey was sent to 4801 registrants, 878 responded. Presence of a family history of MPNST was found to be a risk factor for the development of MPNST; 19.4% of respondents confirming a family history of MPNST developed MPNST compared with 7.5% of respondents with no family history (odds ratio, 2.975; 95% confidence interval, 1.232-7.187; P=0.021). NF-1 patients with a positive family history developed MPNST at a younger age than those with no family history (8.3% vs. 0.5% P=0.003 and 13.9% vs. 2.4% P=0.003, for onset before 10 and 20, respectively). In the MPNST population with a known family history, onset prior to age 10 was significantly more prevalent (42.9% vs. 7% P=0.029).

Conclusions: These results suggest a positive family history of MPNST represents a risk factor for the development and early onset of MPNST in individuals with NF-1.
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http://dx.doi.org/10.1097/MPH.0000000000001156DOI Listing
August 2018

Moderate Modulation of Cardiac PGC-1α Expression Partially Affects Age-Associated Transcriptional Remodeling of the Heart.

Front Physiol 2018 21;9:242. Epub 2018 Mar 21.

Biozentrum, University of Basel, Basel, Switzerland.

Aging is associated with a decline in cardiac function due to a decreased myocardial reserve. This adverse cardiac remodeling comprises of a variety of changes, including a reduction in mitochondrial function and a decline in the expression of the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a central regulator of mitochondrial biogenesis and metabolic adaptation in the myocardium. To study the etiological involvement of PGC-1α in cardiac aging, we used mouse models mimicking the modest down- and upregulation of this coactivator in the old and the exercised heart, respectively. Young mice with reduced cardiac expression of PGC-1α recapitulated part of the age-related impairment in mitochondrial gene expression, but otherwise did not aggravate the aging process. Inversely however, moderate overexpression of PGC-1α counteracts numerous key age-related remodeling changes, e.g., by improving blood pressure, age-associated apoptosis, and collagen accumulation, as well as in the expression of many, but not all cardiac genes involved in mitochondrial biogenesis, dynamics, metabolism, calcium handling and contractility. Thus, while the reduction of PGC-1α in the heart is insufficient to cause an aging phenotype, moderate overexpression reduces pathological remodeling of older hearts and could thereby contribute to the beneficial effects of exercise on cardiac function in aging.
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http://dx.doi.org/10.3389/fphys.2018.00242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5871735PMC
March 2018

Detection of circulating tumor DNA in patients with osteosarcoma.

Oncotarget 2018 Feb 18;9(16):12695-12704. Epub 2018 Jan 18.

Division of Hematology/Oncology, Children's Hospital at Montefiore, Bronx, NY, USA.

Identification and quantification of somatic alterations in plasma-derived, circulating tumor DNA (ctDNA) is gaining traction as a non-invasive and cost effective method of disease monitoring in cancer patients, particularly to evaluate response to treatment and monitor for disease recurrence. To our knowledge, genetic analysis of ctDNA in osteosarcoma has not yet been studied. To determine whether somatic alterations can be detected in ctDNA and perhaps applied to patient management in this disease, we collected germline, tumor, and serial plasma samples from pediatric, adolescent, and young adult patients with osteosarcoma and used targeted Next Generation Sequencing (NGS) to identify somatic single nucleotide variants (SNV), insertions and deletions (INDELS), and structural variants (SV) in 7 genes commonly mutated in osteosarcoma. We demonstrate that patient-specific somatic alterations identified through comparison of tumor-germline pairs can be detected and quantified in cell-free DNA of osteosarcoma patients.
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http://dx.doi.org/10.18632/oncotarget.24268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5849166PMC
February 2018

Pediatric oncologist willingness to offer germline TP53 testing in osteosarcoma.

Cancer 2018 03 3;124(6):1242-1250. Epub 2018 Jan 3.

Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome caused by mutations in the tumor-suppressor gene TP53. Osteosarcoma is a sentinel cancer in LFS. Prior studies using Sanger sequencing platforms have demonstrated that 3% of individuals with osteosarcoma harbor a mutation in TP53. New data from next-generation sequencing have demonstrated that 3.8% of patients with osteosarcoma have a known pathogenic variant, and an additional 5.7% carry exonic variants of unknown significance in TP53.

Methods: Pediatric oncologists were e-mailed an anonymous 18-question survey assessing their willingness to offer TP53 germline testing to a child with osteosarcoma with or without a family history, and they were evaluated for changes in their choices with the prior data and the new data.

Results: One hundred seventy-seven pediatric oncologists (22%) responded to the survey. Respondents were more likely to offer TP53 testing to a patient with a positive family history (77.4% vs 12.4%; P < .0001). Significantly more providers responded that they would offer TP53 testing once they were provided with the new data (25.4% vs 12.4%; P = .0038). The proportion of providers who responded that they were unsure increased significantly when they were presented with the new data (25.4% vs 10.2%; P = .0002). Potential implications for other family members and the possibility that surveillance imaging would detect new malignancies at an earlier stage were important factors influencing a provider's decision to offer TP53 testing.

Conclusions: Recent data increase the proportion of providers willing to offer testing, and this suggests concern on the part of pediatric oncologists that variants of unknown significance may be disease-defining in rare cancers. Cancer 2018;124:1242-50. © 2018 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.31212DOI Listing
March 2018

Allogeneic hematopoietic stem cell transplantation is associated with cure and durable remission of late-onset primary isolated central nervous system hemophagocytic lymphohistiocytosis.

Pediatr Transplant 2018 02 13;22(1). Epub 2017 Dec 13.

Pediatric Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Children's Cancer Hospital, Houston, TX, USA.

Primary isolated CNS presentation of HLH is exceedingly rare and typically associated with significant morbidity and mortality. We describe an adolescent patient with late-onset, primary isolated CNS HLH and a compound heterozygous PRF1 mutation (c50delT (p.L17 fs); c.1229G>C (p.R410P)), not previously reported with this phenotype. He was successfully treated with allogeneic HSCT following a reduced-intensity conditioning regimen, despite a high pre-HSCT comorbidity index. Two years after transplant, he is alive and in disease remission. While patients with systemic HLH and active CNS disease have relatively poorer outcomes, a high index of suspicion may aid with early diagnosis of primary isolated CNS HLH; prompt treatment with HSCT may be associated with improved cure and durable remission of this rare disease.
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http://dx.doi.org/10.1111/petr.13101DOI Listing
February 2018

Current and future therapeutic approaches for osteosarcoma.

Expert Rev Anticancer Ther 2018 01 14;18(1):39-50. Epub 2017 Dec 14.

a Department of Pediatrics , The University of Texas MD Anderson Cancer Center , Houston , TX , USA.

Introduction: Current treatment of osteosarcoma includes surgical resection of all gross disease in conjunction with systemic chemotherapy to control micro-metastatic disease. This yields a 5-year event free survival (EFS) of approximately 70% for patients with localized osteosarcoma while patients with metastatic or recurrent disease fare poorly with overall survival rates of less than 20%. Areas covered: This review outlines the current and future approach towards the treatment of osteosarcoma. A literature search was performed utilizing PubMed. Several recent clinical trials are reviewed in detail, as is innovative research evaluating novel agents and surgical techniques which hold promise. Expert commentary: The outcome for patients with osteosarcoma has not changed in several decades. This plateau in survival rates highlights the need for a novel approach towards research. There remains a great deal of interest in utilizing the very high risk population of recurrent osteosarcoma patients to rapidly and sequentially evaluate novel agents to determine if any of these agents hold promise. Several phase II studies are ongoing or in development that offer hope based on intriguing preclinical data. Furthermore, initiatives in obtaining specimens to further explore the genetic and immunological profile behind osteosarcoma will be essential towards identifying novel pathways and targets to exploit.
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http://dx.doi.org/10.1080/14737140.2018.1413939DOI Listing
January 2018

PGC-1α affects aging-related changes in muscle and motor function by modulating specific exercise-mediated changes in old mice.

Aging Cell 2018 02 25;17(1). Epub 2017 Oct 25.

Biozentrum, University of Basel, Basel, Switzerland.

The age-related impairment in muscle function results in a drastic decline in motor coordination and mobility in elderly individuals. Regular physical activity is the only efficient intervention to prevent and treat this age-associated degeneration. However, the mechanisms that underlie the therapeutic effect of exercise in this context remain unclear. We assessed whether endurance exercise training in old age is sufficient to affect muscle and motor function. Moreover, as muscle peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is a key regulatory hub in endurance exercise adaptation with decreased expression in old muscle, we studied the involvement of PGC-1α in the therapeutic effect of exercise in aging. Intriguingly, PGC-1α muscle-specific knockout and overexpression, respectively, precipitated and alleviated specific aspects of aging-related deterioration of muscle function in old mice, while other muscle dysfunctions remained unchanged upon PGC-1α modulation. Surprisingly, we discovered that muscle PGC-1α was not only involved in improving muscle endurance and mitochondrial remodeling, but also phenocopied endurance exercise training in advanced age by contributing to maintaining balance and motor coordination in old animals. Our data therefore suggest that the benefits of exercise, even when performed at old age, extend beyond skeletal muscle and are at least in part mediated by PGC-1α.
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http://dx.doi.org/10.1111/acel.12697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5770876PMC
February 2018