Lee N.A.,Divisions of Hematology Oncology
Clinical and Experimental Allergy
Summary: The 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. © 2014 John Wiley & Sons Ltd. Source
Jacobsen E.A.,Mayo Medical School |
LeSuer W.E.,Mayo Medical School |
Willetts L.,Mayo Medical School |
Willetts L.,University of Alberta |
And 12 more authors.
Allergy: European Journal of Allergy and Clinical Immunology
Background: The importance and specific role(s) of eosinophils in modulating the immune/inflammatory phenotype of allergic pulmonary disease remain to be defined. Established animal models assessing the role(s) of eosinophils as contributors and/or causative agents of disease have relied on congenitally deficient mice where the developmental consequences of eosinophil depletion are unknown. Methods: We developed a novel conditional eosinophil-deficient strain of mice (iPHIL) through a gene knock-in strategy inserting the human diphtheria toxin (DT) receptor (DTR) into the endogenous eosinophil peroxidase genomic locus. Results: Expression of DTR rendered resistant mouse eosinophil progenitors sensitive to DT without affecting any other cell types. The presence of eosinophils was shown to be unnecessary during the sensitization phase of either ovalbumin (OVA) or house dust mite (HDM) acute asthma models. However, eosinophil ablation during airway challenge led to a predominantly neutrophilic phenotype (>15% neutrophils) accompanied by allergen-induced histopathologies and airway hyper-responsiveness in response to methacholine indistinguishable from eosinophilic wild-type mice. Moreover, the iPHIL neutrophilic airway phenotype was shown to be a steroid-resistant allergic respiratory variant that was reversible upon the restoration of peripheral eosinophils. Conclusions: Eosinophil contributions to allergic immune/inflammatory responses appear to be limited to the airway challenge and not to the sensitization phase of allergen provocation models. The reversible steroid-resistant character of the iPHIL neutrophilic airway variant suggests underappreciated mechanisms by which eosinophils shape the character of allergic respiratory responses. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Source
Hyperthermic intraperitoneal chemotherapy following cytoreductive surgery improves outcome in patients with primary appendiceal mucinous adenocarcinoma: A pooled analysis from three tertiary care centers
Shaib W.L.,Winship Cancer Institute |
Martin L.K.,Divisions of Hematology Oncology |
Choi M.,Wayne State University |
Chen Z.,Emory University |
And 9 more authors.
Purpose. Appendiceal mucinous neoplasms (AMN) are a rare heterogeneous group of diseases. In the absence of randomized trials, AMN management is controversial.The goal of this study was to evaluate the impact of hyperthermic intraperitoneal chemotherapy (HIPEC) after cytoreductive surgery on survival in AMN patients. Patients and Methods. Patient data including demographics, pathology, type of therapy, and outcomes were collected from Emory University, the Ohio State University, and Wayne State University databases. One of the three centers did not use HIPEC. Statistical analysis evaluating overall survival (OS) of AMN patients was performed. Results. Between 1990 and 2010, 163 AMN patients were identified. Histology showed 60 patients had diffuse peritoneal adenomucinosis, 88 had peritoneal mucinous carcinomatosis (PMCA), and 15 had PMCA with indeterminate or discordant features. Complete surgical resection was achieved in 76 patients. HIPEC was used in 79 patients. The median OS was 77 months for patients who received HIPEC comparedwith25months forpatientswhodidnot (p,.001). Inmultivariable analysis, histopathologic subtype (p,.001), complete surgical resection (p,.001), and HIPEC (p,.001) were independent predictors for improved OS. A survival advantage for AMN patients treated at HIPEC-treating centers was observed (p 5 .0026). After adjusting for HIPEC therapy, no significant survival difference was observed between the non-HIPEC-treating center and the HIPEC-treating centers (p 5.094). Conclusion. The addition of HIPEC to cytoreductive surgery likely provides a survival advantage and should be considered in the treatment strategy for AMN. © AlphaMed Press. Source
Gupta S.,Divisions of Hematology Oncology |
Parsa V.,Divisions of Hematology Oncology |
Heilbrun L.K.,Barbara Ann Karmanos Cancer Institute |
Smith D.W.,Barbara Ann Karmanos Cancer Institute |
And 3 more authors.
Multiple molecularly targeted agents (MTAs) have been approved for the management of metastatic renal cell carcinoma (mRCC). Sunitinib and mammalian target of rapamycin inhibitors (temsirolimus, everolimus) are primarily metabolized in the liver, whereas the metabolism of bevacizumab is unclear. There are limited data on the toxicity profile and the efficacy of these agents in patients with renal insufficiency (RI). This is clinically relevant, especially as about one-third of patients with mRCC have renal dysfunction. The primary objective was to assess the safety and efficacy of targeted agents in patients with mRCC with RI. Medical records of patients with mRCC at Wayne State University, started on sunitinib, temsirolimus, everolimus, or bevacizumab, were reviewed. Patients with a calculated creatinine clearance of less than or equal to 60 ml/min were deemed to have RI. Data on safety and efficacy of MTA therapy were collected and analyzed with respect to renal function. RI was observed in 33% of our patients with mRCC. The incidence of toxicities, responses, time to progression, and overall survival were not significantly different in patients with RI compared with patients with normal renal function. Patients with RI had larger median increases in blood pressure with sunitinib and bevacizumab, increased incidence of thyroid dysfunction with sunitinib, and increased incidence of rash and dose interruptions with mammalian target of rapamycin inhibitors, than did patients with normal renal function. In conclusion, RI was commonly observed in our patients with mRCC. Molecularly targeted agents are well tolerated, and efficacy seems to be maintained in patients with RI. Vigilant monitoring of hypertension would be recommended for patients receiving sunitinib and bevacizumab. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source