Publications by authors named "Ellen Spartz"

10 Publications

  • Page 1 of 1

Primary angiosarcoma of the spleen, a rare indication for splenectomy: a case report.

Int J Surg Case Rep 2021 Apr 29;82:105929. Epub 2021 Apr 29.

Department of Surgery, University of Minnesota Medical School, Minneapolis, MN 55414, United States of America.

Introduction And Importance: Primary angiosarcoma of the spleen is a rare condition with a nonspecific clinical presentation and is associated with a poor prognosis. We describe two patients with primary splenic angiosarcoma successfully treated with splenectomy and adjuvant chemotherapy.

Case Presentations: Case 1: A 50-year-old female presented with fatigue and left-sided rib, shoulder, and abdominal pain. A CT scan demonstrated a large splenic mass, and biopsy was diagnostic of angiosarcoma. An open en bloc resection of the spleen was performed, and pathologic examination confirmed high-grade angiosarcoma; the surgical margins were negative. The patient received pegylated liposomal doxorubicin (PLD) and ifosfamide; she demonstrated no evidence of recurrence with four years of follow-up. Case 2: A 70-year-old male presented with acute back pain. A CT scan demonstrated a splenic mass; biopsy was diagnostic of angiosarcoma. The patient underwent open splenectomy, and pathology revealed high-grade angiosarcoma; the surgical margins were positive. The patient received PLD and ifosfamide but presented three years later with metastatic tumor to the spine. The patient had a favorable tumor response to pembrolizumab. The patient's tumor burden remains stable at 5 years following splenectomy.

Clinical Discussion: Angiosarcoma of the spleen is a rare clinical entity and is often challenging to diagnose early. Moratality is high, especially in the case of metastasis or spontaneous rupture.

Conclusion: Due to the rare nature of this tumor, optimal treatment is not known. Here, we show excellent response in two patients to surgery combined with adjuvant therapy.
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http://dx.doi.org/10.1016/j.ijscr.2021.105929DOI Listing
April 2021

CD40 Agonist Overcomes T Cell Exhaustion Induced by Chronic Myeloid Cell IL-27 Production in a Pancreatic Cancer Preclinical Model.

J Immunol 2021 Mar 8;206(6):1372-1384. Epub 2021 Feb 8.

Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, MN 55414;

Pancreatic cancer is a particularly lethal malignancy that resists immunotherapy. In this study, using a preclinical pancreatic cancer murine model, we demonstrate a progressive decrease in IFN-γ and granzyme B and a concomitant increase in Tox and IL-10 in intratumoral tumor-specific T cells. Intratumoral myeloid cells produced elevated IL-27, a cytokine that correlates with poor patient outcome. Abrogating IL-27 signaling significantly decreased intratumoral Tox T cells and delayed tumor growth yet was not curative. Agonistic αCD40 decreased intratumoral IL-27-producing myeloid cells, decreased IL-10-producing intratumoral T cells, and promoted intratumoral Klrg1Gzmb short-lived effector T cells. Combination agonistic αCD40+αPD-L1 cured 63% of tumor-bearing animals, promoted rejection following tumor rechallenge, and correlated with a 2-log increase in pancreas-residing tumor-specific T cells. Interfering with expression in nontumor/host cells abrogated agonistic αCD40+αPD-L1 efficacy. In contrast, interfering with nontumor/host cell led to cure in 100% of animals following agonistic αCD40+αPD-L1 and promoted the formation of circulating central memory T cells rather than long-lived effector T cells. In summary, we identify a mechanistic basis for T cell exhaustion in pancreatic cancer and a feasible clinical strategy to overcome it.
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http://dx.doi.org/10.4049/jimmunol.2000765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7977703PMC
March 2021

Hypoferritinemia and iron deficiency in youth with pediatric acute-onset neuropsychiatric syndrome.

Pediatr Res 2020 Aug 3. Epub 2020 Aug 3.

Division of Allergy, Immunology, & Rheumatology, Department of Pediatrics, Stanford University School of Medicine, Palo Alto, CA, USA.

Background: Pediatric acute-onset neuropsychiatric syndrome (PANS) is an abrupt debilitating psychiatric illness. We anecdotally observed hypoferritinemia and iron deficiency in a subset of patients with PANS, prompting this study.

Methods: In this IRB-approved prospective cohort study, we included patients seen at the Stanford PANS Clinic who met study criteria. The prevalence of hypoferritinemia (using cut-offs of 7 ng/ml in children ≤ 15 years and 18 ng/ml in adolescents > 15 years) and iron deficiency was estimated. Differences in patients with and without hypoferritinemia during PANS flare were explored.

Results: Seventy-nine subjects (mean age of PANS onset of 8.7 years) met study criteria. Hypoferritinemia was observed in 27% and three quarters occurred during a PANS flare. Compared to patients without hypoferritinemia during PANS flare, patients with hypoferritinemia had worse global impairment, more comorbid inflammatory diseases, and exhibited a chronic course of PANS illness. The estimated prevalence of iron deficiency was 3-8% in the PANS cohort, 1.4-2.0-fold higher than in the age- and sex-matched U.S.

Population: More stringent ferritin level cut-offs than the comparison CDC dataset were used.

Conclusion: Hypoferritinemia and iron deficiency appear to be more common in PANS patients. More research is needed to confirm and understand this association.

Impact: Our study suggests hypoferritinemia and iron deficiency are more common in patients with pediatric acute-onset neuropsychiatric syndrome (PANS) than in the sex- and age-matched US population.Hypoferritinemia was commonly observed during a disease flare but not associated with dietary or demographic factors. In patients with PANS and iron deficiency, clinicians should consider possibility of inflammation as the cause especially if iron deficiency cannot be explained by diet and blood loss.Future research should include larger cohorts to corroborate our study findings and consider examining the iron dynamics on MRI brain imaging in order to better understand the pathophysiology of PANS.
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http://dx.doi.org/10.1038/s41390-020-1103-3DOI Listing
August 2020

T Cell Receptor Engineered Lymphocytes for Cancer Therapy.

Curr Protoc Immunol 2020 06;129(1):e97

Department of Microbiology and Immunology, Center for Immunology, University of Minnesota Medical School, Minneapolis, Minnesota.

T lymphocytes are capable of specific recognition and elimination of target cells. Physiological antigen recognition is mediated by the T cell receptor (TCR), which is an alpha beta heterodimer comprising the products of randomly rearranged V, D, and J genes. The exquisite specificity and functionality of T cells can be leveraged for cancer therapy: specifically, the adoptive transfer of T cells that express tumor-reactive TCRs can induce regression of solid tumors in patients with advanced cancer. However, the isolation and expression of a tumor antigen-specific TCRs is a highly involved process that requires identifying an immunogenic epitope, ensuring human cells are of the correct haplotype, performing a laborious T cell expansion process, and carrying out downstream TCR sequencing and cloning. Recent advances in single-cell sequencing have begun to streamline this process. This protocol synthesizes and expands upon methodologies to generate, isolate, and engineer human T cells with tumor-reactive TCRs for adoptive cell therapy. Though this process is perhaps more arduous than the alternative strategy of using chimeric antigen receptors (CARs) for engineering, the ability to target intracellular proteins using TCRs substantially increases the types of antigens that can be safely targeted. © 2020 Wiley Periodicals LLC. Basic Protocol 1: Generation of human autologous dendritic cells from monocytes Basic Protocol 2: In vitro priming and expansion of human antigen-specific T cells Basic Protocol 3: Cloning of antigen-specific T cell receptors based on single-cell VDJ sequencing data Basic Protocol 4: Validation of T cell receptor expression and functionality in vitro Basic Protocol 5: Rapid expansion of T cell receptor-transduced T cells and human T cell clones.
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http://dx.doi.org/10.1002/cpim.97DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054879PMC
June 2020

Patient Complications after Interscalene Block: A Retrospective Comparison of Liposomal Bupivacaine to Nonliposomal Bupivacaine.

Anesthesiol Res Pract 2020 27;2020:6704303. Epub 2020 Mar 27.

Department of Anesthesiology, University of Minnesota, Minneapolis, MN, USA.

Background: The purpose of this study was to investigate if the addition of liposome bupivacaine (LB) to an interscalene block (ISB) had an effect on the number of patients with surgical- or block-related complications.

Methods: This was a single-center retrospective chart view performed by identifying patients who received an ISB from January 1, 2014, through April 26, 2018, at the University of Minnesota. 1,518 patients were identified who received an ISB (LB = 784, nonliposomal bupivacaine = 734). Patients were divided into two groups those who did receive liposome bupivacaine in their ISB and those who did not receive liposome bupivacaine in their ISB. Medical records were individually reviewed for surgical procedure, block medications, complications related to the block or surgical procedure, phone calls to the healthcare system for issues related to opioids or pain within 3 and within 30 days, readmissions within 30 days, and emergency room visits for complications within 3 and 30 days.

Results: There was no significant difference in the number of patients with surgical or anesthetic complications. Only phone calls for pain within 3 days were significantly different. The LB group had 3.2% of patients call compared to 5.6% in the nonliposomal bupivacaine group (aOR = 1.71 (95% CI: 1.04-2.87), =0.036). We found no significant difference in any of the other secondary outcomes.

Conclusions: The use of LB in an ISB demonstrated no significant difference compared to nonliposomal bupivacaine in numbers of complications, emergency room visits, and readmissions.
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http://dx.doi.org/10.1155/2020/6704303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139877PMC
March 2020

Combination PD-1 and PD-L1 Blockade Promotes Durable Neoantigen-Specific T Cell-Mediated Immunity in Pancreatic Ductal Adenocarcinoma.

Cell Rep 2019 08;28(8):2140-2155.e6

Center for Immunology, University of Minnesota Medical School, Minneapolis, MN 55455, USA; Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, MN 55455, USA; Masonic Cancer Center of the University of Minnesota Medical School, Minneapolis, MN 55455, USA. Electronic address:

Pancreatic ductal adenocarcinoma (PDA) is a lethal cancer resistant to immunotherapy. We create a PDA mouse model and show that neoantigen expression is required for intratumoral T cell accumulation and response to immune checkpoint blockade. By generating a peptide:MHC tetramer, we identify that PDA induces rapid intratumoral, and progressive systemic, tumor-specific T cell exhaustion. Monotherapy PD-1 or PD-L1 blockade enhances systemic T cell expansion and induces objective responses that require systemic T cells. However, tumor escape variants defective in IFNγ-inducible Tap1 and MHC class I cell surface expression ultimately emerge. Combination PD-1 + PD-L1 blockade synergizes therapeutically by increasing intratumoral KLRG1+Lag3-TNFα+ tumor-specific T cells and generating memory T cells capable of expanding to spontaneous tumor recurrence, thereby prolonging animal survival. Our studies support that PD-1 and PD-L1 are relevant immune checkpoints in PDA and identify a combination for clinical testing in those patients with neoantigen-specific T cells.
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http://dx.doi.org/10.1016/j.celrep.2019.07.059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7975822PMC
August 2019

Differential Effects of Depleting versus Programming Tumor-Associated Macrophages on Engineered T Cells in Pancreatic Ductal Adenocarcinoma.

Cancer Immunol Res 2019 06 26;7(6):977-989. Epub 2019 Apr 26.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.

Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy resistant to therapies, including immune-checkpoint blockade. We investigated two distinct strategies to modulate tumor-associated macrophages (TAM) to enhance cellular therapy targeting mesothelin in an autochthonous PDA mouse model. Administration of an antibody to colony-stimulating factor (anti-Csf1R) depleted Ly6C protumorigenic TAMs and significantly enhanced endogenous T-cell intratumoral accumulation. Despite increasing the number of endogenous T cells at the tumor site, as previously reported, TAM depletion had only minimal impact on intratumoral accumulation and persistence of T cells engineered to express a murine mesothelin-specific T-cell receptor (TCR). TAM depletion interfered with the antitumor activity of the infused T cells in PDA, evidenced by reduced tumor cell apoptosis. In contrast, TAM programming with agonistic anti-CD40 increased both Ly6C TAMs and the intratumoral accumulation and longevity of TCR-engineered T cells. Anti-CD40 significantly increased the frequency and number of proliferating and granzyme B engineered T cells, and increased tumor cell apoptosis. However, anti-CD40 failed to rescue intratumoral engineered T-cell IFNγ production. Thus, although functional modulation, rather than TAM depletion, enhanced the longevity of engineered T cells and increased tumor cell apoptosis, ultimately, anti-CD40 modulation was insufficient to rescue key effector defects in tumor-reactive T cells. This study highlights critical distinctions between how endogenous T cells that evolve , and engineered T cells with previously acquired effector activity, respond to modifications of the tumor microenvironment.
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http://dx.doi.org/10.1158/2326-6066.CIR-18-0448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6548612PMC
June 2019

Effect of Early and Prophylactic Nonsteroidal Anti-Inflammatory Drugs on Flare Duration in Pediatric Acute-Onset Neuropsychiatric Syndrome: An Observational Study of Patients Followed by an Academic Community-Based Pediatric Acute-Onset Neuropsychiatric Syndrome Clinic.

J Child Adolesc Psychopharmacol 2017 Sep 11;27(7):619-628. Epub 2017 Jul 11.

1 Division of Pediatrics, Department of Allergy, Immunology, & Rheumatology, Stanford University School of Medicine , Palo Alto, California.

Introduction: Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) is characterized by the sudden onset of severe obsessive-compulsive symptoms and/or eating restriction along with at least two coinciding neuropsychiatric symptoms. When associated with group A Streptococcus, the syndrome is labeled Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal infections (PANDAS). An abnormal immune response to infection and subsequent neuroinflammation is postulated to play an etiologic role. We evaluated the impact of nonsteroidal anti-inflammatory drug (NSAID) treatment on flare duration in PANS/PANDAS.

Methods: Patient inclusion criteria: Patients were included if they had at least one neuropsychiatric deterioration ("flare") that met strict PANS/PANDAS research criteria and for which flare duration could be assessed. Flare inclusion criteria: Any flare that started before October 15, 2016 was included and followed until the flare resolved or until the end of our data collection (November 1, 2016). Flare exclusion criteria: Flares were excluded if they were incompletely resolved, treated with aggressive immunomodulation, or treated with NSAIDs late (>30 days of flare onset). Ninety-five patients met study inclusion criteria and collectively experienced 390 flares that met flare criteria. Data were analyzed using multilevel linear models, adjusting for demographics, disease, and treatment covariates.

Results: NSAID use was associated with a significantly shorter flare duration. Flares not treated with NSAIDs had a mean duration of approximately 12.2 weeks (95% CI: 9.3-15.1). Flares that occurred while the child was on NSAID maintenance therapy were approximately 4 weeks shorter than flares not managed with NSAIDs (95% CI: 1.85-6.24; p < 0.0001). Flares treated with NSAIDs within 30 days of flare onset were approximately 2.6 weeks shorter than flares not managed with NSAIDs (95% CI: 0.43-4.68; p = 0.02). Flares treated prophylactically and those treated early with NSAIDs did not differ in duration (p = 0.26). Among the flares that received NSAID treatment within the first 30 days, earlier intervention was modestly associated with shorter flare durations (i.e., for each day that NSAID treatment was delayed, flare duration increased by 0.18 weeks; 95% CI: 0.03-0.33; p = 0.02), though it was not statistically significant after controlling for covariates (p = 0.06).

Conclusion: NSAIDs given prophylactically or within 30 days of flare onset may shorten neuropsychiatric symptom duration in patients with new-onset and relapsing/remitting PANS and PANDAS. A randomized placebo-control clinical trial of NSAIDs in PANS is warranted to formally assess treatment efficacy.
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http://dx.doi.org/10.1089/cap.2016.0193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5749580PMC
September 2017

Course of Neuropsychiatric Symptoms After Introduction and Removal of Nonsteroidal Anti-Inflammatory Drugs: A Pediatric Observational Study.

J Child Adolesc Psychopharmacol 2017 Sep 11;27(7):652-659. Epub 2017 Jul 11.

1 Pediatric Divisions of Allergy, Immunology, & Rheumatology, Stanford University School of Medicine , Stanford, California.

Objective: Accumulating evidence suggests that anti-inflammatory interventions can modulate neuropsychiatric symptoms. Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) is characterized by an abrupt and dramatic onset of obsessive-compulsive (OC) symptoms and/or severely restrictive food intake and at least two coinciding, equally debilitating neuropsychiatric symptoms. When associated with group A Streptococcus, the syndrome is labeled Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal infections (PANDAS). Here, we describe the course of neuropsychiatric symptoms in patients diagnosed with PANS and PANDAS after introduction or removal of nonsteroidal anti-inflammatory drugs (NSAIDs).

Study Design: We reviewed the electronic medical records (EMR) of 218 consecutive patients evaluated in our Stanford PANS Clinic for patients who met strict PANS or PANDAS research criteria and received NSAIDs for arthritis, pain, and/or psychiatric symptoms. We describe neuropsychiatric symptoms that were noted in the EMR before, during, and after NSAIDs were introduced or removed as the sole change in pharmacologic treatment.

Results: Seventy-seven patients were included in the current study. Of the 52 trials in which NSAID addition was the sole change in treatment, 16 (31%) coincided with an improvement in patients' neuropsychiatric symptoms. Of the 57 trials in which removal of NSAID treatment was the sole change in treatment, 20 (35%) coincided with escalation in patients' neuropsychiatric symptoms. Thirty patients (39%) experienced side effects, mainly mild gastrointestinal symptoms, which self-resolved after removal of NSAID, reduction of dose, or change in NSAID.

Conclusions: Improvement in neuropsychiatric symptoms was evident in roughly one-third of NSAID treatment trials. A randomized clinical trial will be necessary to confirm whether NSAIDs are successful in reducing neuropsychiatric symptoms in youth with PANS.
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http://dx.doi.org/10.1089/cap.2016.0179DOI Listing
September 2017

Prion-like transmission of neuronal huntingtin aggregates to phagocytic glia in the Drosophila brain.

Nat Commun 2015 Apr 13;6:6768. Epub 2015 Apr 13.

Department of Biology, Stanford University, Stanford, California 94305, USA.

The brain has a limited capacity to self-protect against protein aggregate-associated pathology, and mounting evidence supports a role for phagocytic glia in this process. We have established a Drosophila model to investigate the role of phagocytic glia in clearance of neuronal mutant huntingtin (Htt) aggregates associated with Huntington disease. We find that glia regulate steady-state numbers of Htt aggregates expressed in neurons through a clearance mechanism that requires the glial scavenger receptor Draper and downstream phagocytic engulfment machinery. Remarkably, some of these engulfed neuronal Htt aggregates effect prion-like conversion of soluble, wild-type Htt in the glial cytoplasm. We provide genetic evidence that this conversion depends strictly on the Draper signalling pathway, unveiling a previously unanticipated role for phagocytosis in transfer of pathogenic protein aggregates in an intact brain. These results suggest a potential mechanism by which phagocytic glia contribute to both protein aggregate-related neuroprotection and pathogenesis in neurodegenerative disease.
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http://dx.doi.org/10.1038/ncomms7768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4515032PMC
April 2015