25 research outputs found
The identification of eosinophilic gastroenteritis in prednisone-dependent eosinophilic bronchitis and asthma
This case reports the unique association of eosinophilic gastrointestinal disease with eosinophilic bronchitis, asthma and chronic rhinosinusitis and some features of lymphocytic hypereosinophilic syndrome, describes a diagnostic protocol for patients with asthma and persistent eosinophilic bronchitis, and suggests that the use of a novel EPX-mAb provides a reliable method to identify eosinophilic inflammation
Pivotal Advance: Eosinophil infiltration of solid tumors is an early and persistent inflammatory host response
Tumor-associated eosinophilia has been observed in numerous human cancers and several tumor models in animals; however, the details surrounding this eosinophilia remain largely undefined and anecdotal. We used a B16-F10 melanoma cell injection model to demonstrate that eosinophil infiltration of tumors occurred from the earliest palpable stages with significant accumulations only in the necrotic and capsule regions. Furthermore, the presence of diffuse extracellular matrix staining for eosinophil major basic protein was restricted to the necrotic areas of tumors, indicating that eosinophil degranulation was limited to this region. Antibody-mediated depletion of CD4+ T cells and adoptive transfer of eosinophils suggested, respectively, that the accumulation of eosinophils is not associated with T helper cell type 2-dependent immune responses and that recruitment is a dynamic, ongoing process, occurring throughout tumor growth. Ex vivo migration studies have identified what appears to be a novel chemotactic factor(s) released by stressed/dying melanoma cells, suggesting that the accumulation of eosinophils in tumors occurs, in part, through a unique mechanism dependent on a signal(s) released from areas of necrosis. Collectively, these studies demonstrate that the infiltration of tumors by eosinophils is an early and persistent response that is spatial-restricted. It is more important that these data also show that the mechanism(s) that elicit this host response occur, independent of immune surveillance, suggesting that eosinophils are part of an early inflammatory reaction at the site of tumorigenesis. © Society for Leukocyte Biology
Defining a link with asthma in mice congenitally deficient in eosinophils
Eosinophils are often dominant inflammatory cells present in the lungs of asthma patients. Nonetheless, the role of these leukocytes remains poorly understood. We have created a transgenic line of mice (PHIL) that are specifically devoid of eosinophils, but otherwise have a full complement of hematopoietically derived cells. Allergen challenge of PHIL mice demonstrated that eosinophils were required for pulmonary mucus accumulation and the airway hyperresponsiveness associated with asthma. The development of an eosinophi-less mouse now permits an unambiguous assessment of a number of human diseases that have been linked to this granulocyte, including allergic diseases, parasite infections, and tumorigenesis
Abiraterone acetate plus prednisolone for metastatic patients starting hormone therapy: 5‐year follow‐up results from the STAMPEDE randomised trial (NCT00268476)
This is an accepted manuscript of a paper published by Wiley in International Journal of Cancer on 12/04/2022, available online: https://doi.org/10.1002/ijc.34018 The accepted manuscript of the publication may differ from the final published versionAbiraterone acetate plus prednisolone (AAP) previously demonstrated improved survival in STAMPEDE, a multi-arm, multi-stage platform trial in men starting long-term hormone therapy for prostate cancer. This long-term analysis in metastatic patients was planned for 3 yrs after the first results. Standard-of-care (SOC) was androgen deprivation therapy. The comparison randomized patients 1:1 to SOC-alone with or without daily abiraterone acetate 1000 mg + prednisolone 5 mg (SOC + AAP), continued until disease progression. The primary outcome measure was overall survival. Metastatic disease risk group was classified retrospectively using baseline CT and bone scans by central radiological review and pathology reports. Analyses used Cox proportional hazards & flexible parametric models, adjusted for baseline stratification factors. 1003 patients were contemporaneously randomized (Nov-2011--Jan-2014): median age 67 yr; 94% newly-diagnosed; metastatic disease risk group: 48% high, 44% low, 8% un-assessable; median PSA 97 ng/mL. At 6.1 yr median follow-up, 329 SOC-alone deaths (118 low-risk, 178 high-risk) and 244 SOC + AAP deaths (75 low-risk, 145 high-risk) were reported. Adjusted HR = 0·60 (95%CI:0·50—0·71; P = 0.31x10−9) favoured SOC + AAP, with 5-yr survival improved from 41% SOC-alone to 60% SOC + AAP. This was similar in low-risk (HR = 0·55; 95%CI:0·41—0·76) and high-risk (HR = 0·54; 95%CI:0·43—0·69) patients. Median and current maximum time on SOC + AAP was 2.4 yr and 8.1 yr. Toxicity at 4 yr post-randomisation was similar, with 16% patients in each group reporting grade 3 or higher toxicity. A sustained and substantial improvement in overall survival of all metastatic prostate cancer patients was achieved with SOC + abiraterone acetate + prednisolone, irrespective of metastatic disease risk group.Cancer Research UK, (CRUK_A12459), Medical Research Council (MRC_MC_UU_12023/25, MC_UU_00004/01), UK Clinical Research Network, and the Swiss Group for Cancer Clinical Research (SAKK).Published onlin
Abiraterone acetate plus prednisolone with or without enzalutamide for patients with metastatic prostate cancer starting androgen deprivation therapy: final results from two randomised phase 3 trials of the STAMPEDE platform protocol
Background:
Abiraterone acetate plus prednisolone (herein referred to as abiraterone) or enzalutamide added at the start of androgen deprivation therapy improves outcomes for patients with metastatic prostate cancer. Here, we aimed to evaluate long-term outcomes and test whether combining enzalutamide with abiraterone and androgen deprivation therapy improves survival.
Methods:
We analysed two open-label, randomised, controlled, phase 3 trials of the STAMPEDE platform protocol, with no overlapping controls, conducted at 117 sites in the UK and Switzerland. Eligible patients (no age restriction) had metastatic, histologically-confirmed prostate adenocarcinoma; a WHO performance status of 0–2; and adequate haematological, renal, and liver function. Patients were randomly assigned (1:1) using a computerised algorithm and a minimisation technique to either standard of care (androgen deprivation therapy; docetaxel 75 mg/m2 intravenously for six cycles with prednisolone 10 mg orally once per day allowed from Dec 17, 2015) or standard of care plus abiraterone acetate 1000 mg and prednisolone 5 mg (in the abiraterone trial) orally or abiraterone acetate and prednisolone plus enzalutamide 160 mg orally once a day (in the abiraterone and enzalutamide trial). Patients were stratified by centre, age, WHO performance status, type of androgen deprivation therapy, use of aspirin or non-steroidal anti-inflammatory drugs, pelvic nodal status, planned radiotherapy, and planned docetaxel use. The primary outcome was overall survival assessed in the intention-to-treat population. Safety was assessed in all patients who started treatment. A fixed-effects meta-analysis of individual patient data was used to compare differences in survival between the two trials. STAMPEDE is registered with ClinicalTrials.gov (NCT00268476) and ISRCTN (ISRCTN78818544).
Findings:
Between Nov 15, 2011, and Jan 17, 2014, 1003 patients were randomly assigned to standard of care (n=502) or standard of care plus abiraterone (n=501) in the abiraterone trial. Between July 29, 2014, and March 31, 2016, 916 patients were randomly assigned to standard of care (n=454) or standard of care plus abiraterone and enzalutamide (n=462) in the abiraterone and enzalutamide trial. Median follow-up was 96 months (IQR 86–107) in the abiraterone trial and 72 months (61–74) in the abiraterone and enzalutamide trial. In the abiraterone trial, median overall survival was 76·6 months (95% CI 67·8–86·9) in the abiraterone group versus 45·7 months (41·6–52·0) in the standard of care group (hazard ratio [HR] 0·62 [95% CI 0·53–0·73]; p<0·0001). In the abiraterone and enzalutamide trial, median overall survival was 73·1 months (61·9–81·3) in the abiraterone and enzalutamide group versus 51·8 months (45·3–59·0) in the standard of care group (HR 0·65 [0·55–0·77]; p<0·0001). We found no difference in the treatment effect between these two trials (interaction HR 1·05 [0·83–1·32]; pinteraction=0·71) or between-trial heterogeneity (I2 p=0·70). In the first 5 years of treatment, grade 3–5 toxic effects were higher when abiraterone was added to standard of care (271 [54%] of 498 vs 192 [38%] of 502 with standard of care) and the highest toxic effects were seen when abiraterone and enzalutamide were added to standard of care (302 [68%] of 445 vs 204 [45%] of 454 with standard of care). Cardiac causes were the most common cause of death due to adverse events (five [1%] with standard of care plus abiraterone and enzalutamide [two attributed to treatment] and one (<1%) with standard of care in the abiraterone trial).
Interpretation:
Enzalutamide and abiraterone should not be combined for patients with prostate cancer starting long-term androgen deprivation therapy. Clinically important improvements in survival from addition of abiraterone to androgen deprivation therapy are maintained for longer than 7 years.
Funding:
Cancer Research UK, UK Medical Research Council, Swiss Group for Clinical Cancer Research, Janssen, and Astellas
Effect of Proton Pump Inhibitor on Esophageal Eosinophilia
Objective: Differentiation between the common etiologies of dense
esophageal eosinophilia such as gastroesophageal reflux disease (GERD)
and eosinophilic esophagitis can be difficult. We hypothesized that histologic features may provide diagnostic clues concerning the etiology of
esophageal eosinophilia.
Methods: We performed a retrospective chart review of 204 children with
the diagnosis of esophagitis characterized by 15 eosinophils (eos) per highpower field (HPF) in at least 1 biopsy. We then restricted our analysis to
subjects who had received at least 8 weeks of only proton pump inhibitors
(PPIs) followed by endoscopy and who had a clinicopathologic response to
this treatment. Symptoms, endoscopic findings, and pathologic descriptions
were reviewed and an eosinophil peroxidase (EPX) index was determined to
assess for degranulation/eosinophil activation.
Results: Of the 204 identified charts, 7 subjects identified met the inclusion
criteria. Five of these 7 patients showed a clinicopathologic response to
PPIs after their follow-up endoscopy, (mean peak eosinophil count: 92 vs
5 eos/HPF, and EPX index: 39.2 vs 14.6, pre- and posttreatment,
respectively). Two patients experienced initial resolution of symptoms and
esophageal eosinophilia with PPI therapy; however, within 17–23 months
they redeveloped symptoms and esophageal eosinophilia while receiving PPI
therapy at the time of a third endoscopy (mean peak eosinophil count: 40 vs
11 vs 36 eos/HPF, and EPX index: 44 vs 21 vs 36.5, pre-, post- and
posttreatment, respectively). No clinicopathologic features or degranulation
patterns differentiated subjects with GERD/PPI responsive esophageal
eosinophilia from those who had transient response to PPI treatment.
Conclusions: No clinicopathologic features differentiated subjects who
responded to PPI treatment. PPI treatment can be helpful to exclude
GERD and PPI responsive esophageal eosinophilia but long-term followup is critical in the management of esophagitis
Local hypersensitivity reaction in transgenic mice with squamous epithelial IL-5 overexpression provides a novel model of eosinophilic oesophagitis
Objective: Eosinophilic oesophagitis (EoE) is a chronic
inflammatory condition of the oesophagus with limited
treatment options. No previous transgenic model has
specifically targeted the oesophageal mucosa to induce
oesophageal eosinophilia.
Design: We developed a mouse model that closely
resembles EoE by utilising oxazolone haptenation in mice
with transgenic overexpression of an eosinophil poietic
and survival factor (interleukin (IL)-5) in resident
squamous oesophageal epithelia.
Results: Overexpression of IL-5 in the healthy
oesophagus was achieved in transgenic mice (L2-IL5)
using the squamous epithelial promoter Epstein–Barr
virus ED-L2. Oxazolone-challenged L2-IL5 mice
developed dose-dependent pan-oesophageal
eosinophilia, including eosinophil microabscess formation
and degranulation as well as basal cell hyperplasia.
Moreover, oesophagi expressed increased IL-13 and the
eosinophil agonist chemokine eotaxin-1. Treatment of
these mice with corticosteroids significantly reduced
eosinophilia and epithelial inflammation.
Conclusions: L2-IL5 mice provide a novel experimental
model that can potentially be used in preclinical testing
of EoE-related therapeutics and mechanistic studies
identifying pathogenetic features associated with
mucosal eosinophilia
Eosinophil-mediated signalling attenuates inflammatory responses in experimental colitis
Objective Eosinophils reside in the colonic mucosa
and increase significantly during disease. Although a
number of studies have suggested that eosinophils
contribute to the pathogenesis of GI inflammation, the
expanding scope of eosinophil-mediated activities
indicate that they also regulate local immune responses
and modulate tissue inflammation. We sought to define
the impact of eosinophils that respond to acute phases
of colitis in mice.
Design Acute colitis was induced in mice by
administration of dextran sulfate sodium, 2,4,6-
trinitrobenzenesulfonic acid or oxazolone to C57BL/6J
(control) or eosinophil deficient (PHIL) mice. Eosinophils
were also depleted from mice using antibodies against
interleukin (IL)-5 or by grafting bone marrow from PHIL
mice into control mice. Colon tissues were collected and
analysed by immunohistochemistry, flow cytometry and
reverse transcription PCR; lipids were analysed by mass
spectroscopy.
Results Eosinophil-deficient mice developed
significantly more severe colitis, and their colon tissues
contained a greater number of neutrophils, than
controls. This compensatory increase in neutrophils was
accompanied by increased levels of the chemokines
CXCL1 and CXCL2, which attract neutrophils. Lipidomic
analyses of colonic tissue from eosinophil-deficient mice
identified a deficiency in the docosahexaenoic acidderived anti-inflammatory mediator 10, 17-
dihydroxydocosahexaenoic acid (diHDoHE), namely
protectin D1 (PD1). Administration of an exogenous
PD1-isomer (10S, 17S-DiHDoHE) reduced the severity of
colitis in eosinophil-deficient mice. The PD1-isomer also
attenuated neutrophil infiltration and reduced levels of
tumour necrosis factor-α, IL-1β, IL-6 and inducible NOsynthase in colons of mice. Finally, in vitro assays
identified a direct inhibitory effect of PD1-isomer on
neutrophil transepithelial migration.
Conclusions Eosinophils exert a protective effect in
acute mouse colitis, via production of anti-inflammatory
lipid mediators