Mayo Clinic - AuthorCitation

PRELIMINARY RESULTS FROM AN OPEN‐LABEL, PHASE II STUDY OF TIPIFARNIB IN RELAPSED OR REFRACTORY PERIPHERAL T‐CELL LYMPHOMA

Sokol, Lubomir , Jacobsen, Eric D. , Burrows, Francis , Melvin, C., Mishra, Vishnu S. , Scholz, Catherine, Witzig, Thomas E. , Sokol, Lubomir , Advani, Ranjana H. , Mondejar, Rufino , Piris, Miguel Á. , Gualberto, Antonio

Hematological Oncology | June 7, 2017 | Volume: 35 | Issue: S2 | Pages: 251-252

Frontline Science: Eosinophil-deficient MBP-1 and EPX double-knockout mice link pulmonary remodeling and airway dysfunction with type 2 inflammation

Ochkur, Sergei I. , Doyle, Alfred D. , Jacobsen, Elizabeth A. , LeSuer, William E., Li, Wen , Protheroe, Cheryl, Zellner, Katie R. , Colbert, Dana, Shen, Hua-Hao, Irvin, C. G., Lee, James J. , Lee, Nancy A., Protheroe, Cheryl A, Jacobsen, Elizabeth A

Journal of Leukocyte Biology | May 18, 2017 | Volume: 102 | Issue: 3 | Pages: 589-599

10.1189/jlb.3hi1116-488rr | PMID 28515227

Abstract Eosinophils and the release of cationic granule proteins have long been implicated in the development of the type 2–induced pathologies linked with respiratory inflammation. Paradoxically, the ablation of the two genes encoding the most abundant of these granule proteins, major basic protein-1 (MBP-1) and eosinophil peroxidase (EPX), results in a near collapse of eosinophilopoiesis. The specificity of this lineage ablation and the magnitude of the induced eosinopenia provide a unique opportunity to clarify the importance of eosinophils in acute and chronic inflammatory settings, as well as to identify potential mechanism(s) of action linked with pulmonary eosinophils in those settings. Specifically, we examined these issues by assessing the induced immune responses and pathologies occurring in MBP-1−/−/EPX−/− mice after 1) ovalbumin sensitization/provocation in an acute allergen-challenge protocol, and 2) crossing MBP-1−/−/EPX−/− mice with a double-transgenic model of chronic type 2 inflammation (i.e., I5/hE2). Acute allergen challenge and constitutive cytokine/chemokine expression each induced the accumulation of pulmonary eosinophils in wild-type controls that was abolished in the absence of MBP-1 and EPX (i.e., MBP-1−/−/EPX−/− mice). The expression of MBP-1 and EPX was also required for induced lung expression of IL-4/IL-13 in each setting and, in turn, the induced pulmonary remodeling events and lung dysfunction. In summary, MBP-1−/−/EPX−/− mice provide yet another definitive example of the immunoregulatory role of pulmonary eosinophils. These results highlight the utility of this unique strain of eosinophil-deficient mice as part of in vivo model studies investigating the roles of eosinophils in health and disease settings.

HA, Guess, CJ, Girman, SJ, Jacobsen, MM, Lieber, Ha, Guess, Girman, Cynthia J. , Jacobsen, S. J.

The Japanese Journal of Urology | April 6, 2017 | Volume: 88 | Issue: 2 | Pages: 316

10.5980/jpnjurol.88.316_4

Lung Pathologies in a Chronic Inflammation Mouse Model Are Independent of Eosinophil Degranulation

Jacobsen, Elizabeth A. , Ochkur, Sergei I. , Doyle, Alfred D. , LeSuer, William E., Li, Wen , Protheroe, Cheryl, Colbert, Dana, Zellner, Katie R. , Shen, Huahao , Irvin, Charles G. , Lee, James J. , Lee, Nancy A., Protheroe, Cheryl A, Jacobsen, Elizabeth A

American Journal of Respiratory and Critical Care Medicine | March 6, 2017 | Volume: 195 | Issue: 10 | Pages: 1321-1332

10.1164/rccm.201606-1129oc | PMID 27922744

Abstract Rationale The release of eosinophil granule proteins in the lungs of patients with asthma has been dogmatically linked with lung remodeling and airway hyperresponsiveness. However, the demonstrated inability of established mouse models to display the eosinophil degranulation occurring in human subjects has prevented a definitive in vivo test of this hypothesis. Objectives To demonstrate in vivo causative links between induced pulmonary histopathologies/lung dysfunction and eosinophil degranulation. Methods A transgenic mouse model of chronic T-helper cell type 2–driven inflammation overexpressing IL-5 from T cells and human eotaxin 2 in the lung (I5/hE2) was used to test the hypothesis that chronic histopathologies and the development of airway hyperresponsiveness occur as a consequence of extensive eosinophil degranulation in the lung parenchyma. Measurement and Main Results Studies targeting specific inflammatory pathways in I5/hE2 mice surprisingly showed that eosinophil-dependent immunoregulative events and not the release of individual secondary granule proteins are the central contributors to T-helper cell type 2–induced pulmonary remodeling and lung dysfunction. Specifically, our studies highlighted a significant role for eosinophil-dependent IL-13 expression. In contrast, extensive degranulation leading to the release of major basic protein-1 or eosinophil peroxidase was not causatively linked to many of the induced pulmonary histopathologies. However, these studies did define a previously unappreciated link between the release of eosinophil peroxidase (but not major basic protein-1) and observed levels of induced airway mucin. Conclusions These data suggest that improvements observed in patients with asthma responding to therapeutic strategies ablating eosinophils may occur as a consequence of targeting immunoregulatory mechanisms and not by simply eliminating the destructive activities of these purportedly end-stage effector cells.

A phase IIa study of afuresertib, an oral pan‐AKT inhibitor, in patients with Langerhans cell histiocytosis

Arceci, R.J., Allen, Carl E. , Jacobsen, Eric D. , Whitlock, James A. , Vassallo, Robert , Morris, Shannon R., Portnoy, Alison, Reedy, Beth Ann, Smith, Deborah A. , Noble, Robert, Murnane, Amy A., Cornfeld, Mark, Heaney, Mark , McClain, Kenneth L. , Vaiselbuh, Sarah R., Dunkel, Ira J. , Rodríguez‐Galindo, Carlos , Vassallo, Robert , McClain, Kenneth L , Allen, Carl E

Pediatric Blood & Cancer | November 2, 2016 | Volume: 64 | Issue: 5 | Pages: No page available

10.1002/pbc.26325 | PMID 27804235

AbstractBackgroundLangerhans cell histiocytosis (LCH) is a clonal neoplasm characterized by widely varied clinical presentations, including multisystem involvement and systemic inflammatory symptoms. The AKT pathway is relevant to survival and proliferation of dendritic cells, and is also often upregulated in hematopoietic malignancies. A clinical response in an adult patient with LCH participating in the first‐in‐human trial of afuresertib prompted this prospective trial.ProcedureThe population in the current study included treatment‐naïve (n = 7) and recurrent/refractory patients with LCH (n = 10), who received oral afuresertib (125 mg). The majority of patients were treated for > 24 weeks, with four patients receiving treatment for > 48 weeks.ResultsPharmacokinetic analysis showed similar exposures in previously reported patients with other hematologic malignancies. Primary drug‐related toxicities included Grade 1/2 nausea, diarrhea, dyspepsia, and vomiting. Grade 3 toxicities included fatigue, diarrhea, and pain (one of each). Another severe adverse event involved soft tissue necrosis. The overall response rate in evaluable subjects was 33% in treatment‐naïve patients and 28% in patients with recurrent/refractory disease, which did not meet the predefined Bayesian criteria for efficacy.ConclusionAfuresertib has clinical activity in some patients with newly diagnosed and advanced LCH.

Use of Adjuvant Cisplatin-Based Versus Carboplatin-Based Chemotherapy in Non–Small-Cell Lung Cancer: Findings From the Florida Initiative for Quality Cancer Care

Lee, Ji‐Hyun , Fulp, William J. , Schreiber, Fred, Brown, R. H. , Levine, Richard M., Cartwright, Thomas H. , Abesada‐Terk, Guillermo, Kim, George P., Alemany, Carlos, Faig, Douglas, Sharp, Philip, Markham, Merry Jennifer , Malafa, Mokenge P. , Jacobsen, Paul B. , Tanvetyanon, Tawee , Brown, Richard H, Abesada-Terk, Guillermo, Sharp, Philip V, Malafa, Mokenge, Brown, Richard H., Markham, Merry J

Journal of Oncology Practice | July 17, 2015 | Volume: 11 | Issue: 4 | Pages: 332-337

10.1200/jop.2014.001750 | PMID 25991639

In this study, academic practice status and treatment year predicted use of adjuvant cisplatin-based chemotherapy.

Differential activation of airway eosinophils inducesIL‐13‐mediated allergic Th2 pulmonary responses in mice

Jacobsen, Elizabeth A. , Doyle, Alfred D. , Colbert, Dana, Zellner, Katie R. , Protheroe, Cheryl, LeSuer, William E., Lee, N. A., Lee, J. J., Lee, N.A., Jacobsen, Elizabeth A

Allergy | May 23, 2015 | Volume: 70 | Issue: 9 | Pages: 1148-1159

10.1111/all.12655 | PMID 26009788

AbstractBackgroundEosinophils are hallmark cells of allergic Th2 respiratory inflammation. However, the relative importance of eosinophil activation and the induction of effector functions such as the expression ofIL‐13 to allergic Th2 pulmonary disease remain to be defined.MethodsWild‐type or cytokine‐deficient (IL‐13−/−orIL‐4−/−) eosinophils treated with cytokines (GM‐CSF,IL‐4,IL‐33) were adoptively transferred into eosinophil‐deficient recipient mice subjected to allergen provocation using established models of respiratory inflammation. Allergen‐induced pulmonary changes were assessed.ResultsIn contrast to the transfer of untreated blood eosinophils to the lungs of recipient eosinophil deficient mice, which induced no immune/inflammatory changes either in the lung or in the lung draining lymph nodes (LDLN), pretreatment of blood eosinophils withGM‐CSFprior to transfer elicited trafficking of these eosinophils toLDLN. In turn, theseLDLNeosinophils elicited the accumulation of dendritic cells andCD4+T cells to these sameLDLNs without inducing pulmonary inflammation. However, exposure of eosinophils toGM‐CSF,IL‐4, andIL‐33 prior to transfer induced not only immune events in theLDLN, but also allergen‐mediated increases in airway Th2 cytokine/chemokine levels, the subsequent accumulation ofCD4+T cells as well as alternatively activated (M2) macrophages, and the induction of pulmonary histopathologies. Significantly, this allergic respiratory inflammation was dependent on eosinophil‐derivedIL‐13, whereasIL‐4 expression by eosinophils had no significant role.ConclusionThe data demonstrate the differential activation of eosinophils as a function of cytokine exposure and suggest that eosinophil‐specificIL‐13 expression by activated cells is a necessary component of the subsequent allergic Th2 pulmonary pathologies.

Florida Initiative for Quality Cancer Care: Changes in Psychosocial Quality of Care Indicators Over a 3-Year Interval

Jacobsen, Paul B. , Lee, Ji‐Hyun , Fulp, William J. , Siegel, Erin M. , Shibata, David , Laronga, Christine , Gray, Jhanelle E. , Schreiber, Fred, Brown, R. H. , Levine, Richard M., Cartwright, Thomas H. , Abesada‐Terk, Guillermo, Kim, George , Alemany, Carlos, Faig, Douglas, Sharp, Philip, Markham, Merry Jennifer , Malafa, Mokenge P. , Fulp, William, Gray, Jhanelle, Tanvetyanon, Tawee , BROWN, RICHARD, Levine, Richard, Cartwright, Thomas, Abesada-Terk, Guillermo, Malafa, Mokenge, Markham, Merry J

Journal of Oncology Practice | February 26, 2015 | Volume: 11 | Issue: 1 | Pages: e103-e109

10.1200/jop.2014.001525 | PMID 25352389

Findings suggest that more intensive efforts than audit and feedback will be required to improve the quality of psychosocial care, and that greater recognition of problems with emotional well-being may tax the ability of practices to link patients with appropriate services.

Changes in the Care of Non–Small-Cell Lung Cancer After Audit and Feedback: The Florida Initiative for Quality Cancer Care

Lee, Ji‐Hyun , Fulp, William J. , Schreiber, Fred, Brown, R. H. , Levine, Richard M., Cartwright, Thomas H. , Abesada‐Terk, Guillermo, Kim, George P., Alemany, Carlos, Faig, Douglas, Sharp, Philip, Markham, Merry Jennifer , Malafa, Mokenge P. , Jacobsen, Paul B. , Tanvetyanon, Tawee , Brown, Richard H, Abesada-Terk, Guillermo, Sharp, Philip V, Malafa, Mokenge, Markham, Merry J

Journal of Oncology Practice | July 18, 2014 | Volume: 10 | Issue: 4 | Pages: e247-e254

10.1200/jop.2013.001275 | PMID 24737876

This study is among the first to report on the use of audit and feedback to improve medical oncology practices specifically for the processes of care in NSCLC. A modest but important improvement was observed between 2006 and 2009.

Re‐defining the unique roles for eosinophils in allergic respiratory inflammation

Jacobsen, Elizabeth A. , Lee, N. A., Lee, J. J., Lee, N.A., Jacobsen, Elizabeth A

Clinical & Experimental Allergy | June 24, 2014 | Volume: 44 | Issue: 9 | Pages: 1119-1136

10.1111/cea.12358 | PMID 24961290

SummaryThe role of eosinophils in the progression and resolution of allergic respiratory inflammation is poorly defined despite the commonality of their presence and in some cases their use as a biomarker for disease severity and/or symptom control. However, this ambiguity belies the wealth of insights that have recently been gained through the use of eosinophil‐deficient/attenuated strains of mice that have demonstrated novel immunoregulatory and remodelling/repair functions for these cells in the lung following allergen provocation. Specifically, studies of eosinophil‐deficient mice suggest that eosinophils contribute to events occurring in the lungs following allergen provocation at several key moments: (i) the initiating phase of events leading to Th2‐polarized pulmonary inflammation, (ii) the suppression Th1/Th17 pathways in lung‐draining lymph nodes, (iii) the recruitment of effector Th2 T cells to the lung, and finally, (iv) mechanisms of inflammatory resolution that re‐establish pulmonary homoeostasis. These suggested functions have recently been confirmed and expanded upon using allergen provocation of an inducible eosinophil‐deficient strain of mice (iPHIL) that demonstrated an eosinophil‐dependent mechanism(s) leading to Th2 dominated immune responses in the presence of eosinophils in contrast to neutrophilic as well as mixed Th1/Th17/Th2 variant phenotypes in the absence of eosinophils. These findings highlighted that eosinophils are not exclusively downstream mediators controlled by T cells, dendritic cells (DC) and/or innate lymphocytic cells (ILC2). Instead, eosinophils appear to be more aptly described as significant contributors in complex interrelated pathways that lead to pulmonary inflammation and subsequently promote resolution and the re‐establishment of homoeostatic baseline. In this review, we summarize and put into the context the evolving hypotheses that are now expanding our understanding of the roles eosinophils likely have in the lung following allergen provocation.

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