Early Variations of Circulating Interleukin-6 and Interleukin-10 Levels During Thoracic Radiotherapy Are Predictive for Radiation Pneumonitis

Arpin, D.; Pérol, David; Blay, Jean‐Yves; Falchero, L.; Claude, L.; Vuillermoz-Blas, Sylvie; Martel-Lafay, Isabelle; Ginestet, C.; Alberti, Laurent; Nosov, Dimitri; Étienne-Mastroïanni, B.; Cottin, Vincent; Pérol, Maurice; Guérin, Jean-Claude; Cordier, Jean-François; Carrié, C.

doi:10.1200/jco.2005.01.7145

Cited by 135 publications

(108 citation statements)

References 40 publications

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“…The second fibrosis risk factor identified by Giotopoulos et al (34) was to have inherited the transforming growth factor-h1 (TGF-h À509T) single-nucleotide polymorphism (and having undergone radiotherapy), a gene which maps to one of our putative fibrosis linkage intervals. Finally, studies of cancer patients undergoing radiation therapy have revealed bronchoalveolar lavage (35) and serum (8,36,37) levels of TGF-h and IL-6 to be associated with the development of a radiation response, which supports the concept that the mouse pathology correlates with the clinical side effects seen with therapeutic radiation in the cancer patients.…”

Section: Discussionmentioning

confidence: 64%

Distinct Loci Influence Radiation-Induced Alveolitis from Fibrosing Alveolitis in the Mouse

et al. 2007

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Thoracic radiotherapy may produce the morbidity-associated lung responses of alveolitis or fibrosing alveolitis in treated cancer patients. The genetic factors that influence a patient's likelihood of developing alveolitis and the relationship of this inflammatory response to the development of fibrosis are largely unknown. Herein we use genetic mapping to identify radiation-induced lung response susceptibility loci in reciprocal backcross mice bred from C3H/HeJ (alveolitis response) and C57BL/6J ( fibrosing alveolitis/fibrosis response) strains. Mice were treated with 18-Gy whole thorax irradiation and their survival, lung histopathology, and bronchoalveolar lavage cell types were recorded. A genome-wide scan was completed using 139 markers. The C3H/HeJ alveolitis response included mast cell infiltration and increased neutrophil numbers in the lavage compared with the level in the C57BL/6J strain, which developed fibrosis. In backcross mice, posttreatment survival was dictated by the development of an alveolitis response with increased mast cell, bronchoalveolar lavage total cell, and neutrophil numbers. Fibrosis was measured only in a subset of mice developing alveolitis and, in these mice, was associated with neutrophil count. Genotyping revealed coinheritance of C3H alleles (chromosomes 2, 4, 19, and X) and C57BL/6J alleles (chromosomes 1, 7, 9, and 17) to result in higher fibrosis scores in backcross mice. Mice that inherited C57BL/6J alleles at the putative alveolitis susceptibility loci were spared this response and lived to the end of the experiment. In this animal model, independent loci control the development of alveolitis from fibrosis, whereas fibrosing alveolitis occurs with the coinheritance of these factors.

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Section: Discussionmentioning

confidence: 64%

Distinct Loci Influence Radiation-Induced Alveolitis from Fibrosing Alveolitis in the Mouse

et al. 2007

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“…Though, the functional relevance of lipid droplet formation for radiation-induced pneumopathy remains to be defined. We speculate that as biomarkers for radiation-induced pneumopathy in patients [18,19]. Moreover, a time-dependent increase in tissue levels of TGF-ß, tumor necrosis factor-α, IL-1ß, and IL-6 mRNA as well as of MCP-1 and 3 and MIP-1γ proteins levels has been described in irradiated mice [13,17,20].…”

Section: Discussionmentioning

confidence: 99%

New insights into the molecular pathology of radiation-induced pneumopathy

Cappuccini¹,

Eldh

Bruder

et al. 2011

Radiotherapy and Oncology

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“…13 Interferon-g is reported to be a central mediator of pneumonitis, and 2 independent reports have demonstrated a significant correlation with serum IL-6 and pneumonitis in patients receiving pulmonary radiation. [14][15][16] Although the pathogenesis of PI3K-and mTOR-inhibitor-related pneumonitis has yet to be elucidated, pleiotropic effects on cytokine production have been demonstrated, consistent with a proinflammatory response. 17,18 Further, bronchoalveolar lavage findings of a predominance of CD8 1 T cells may suggest a T-cell-mediated autoimmune response.…”

Section: Org Frommentioning

confidence: 99%

Phase 2 study of idelalisib and entospletinib: pneumonitis limits combination therapy in relapsed refractory CLL and NHL

Barr

Saylors

Spurgeon

et al. 2016

Blood

132

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and 9 Gilead Sciences Inc., Foster City, CA Key Points• Concomitant PI3Kd and SYK inhibition resulted in treatment-emergent pneumonitis, necessitating early study termination.• Initial trials of novel combinations should use conservative designs that are focused on safety.Although agents targeting B-cell receptor signaling have provided practice-changing results in relapsed chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL), they require prolonged administration and provide incomplete responses. Given synergistic preclinical activity with phosphatidylinositol 3-kinase d and spleen tyrosine kinase inhibition, this phase 2 study evaluated the safety and efficacy of the combination of idelalisib and entospletinib. Eligible patients with relapsed or refractory CLL or NHL underwent intrapatient dose escalation with each agent. With a median treatment exposure of 10 weeks, 60% and 36% of patients with CLL or follicular lymphoma, respectively, achieved objective responses. However, the study was terminated early because of treatmentemergent pneumonitis in 18% of patients (severe in 11 of 12 cases). Although most patients recovered with supportive measures and systemic steroids, 2 fatalities occurred and were attributed to treatment-emergent pneumonitis. Increases of interferon-g and interleukins 6, 7, and 8 occurred over time in patients who developed pneumonitis. Future studies of novel combinations should employ conservative designs that incorporate pharmacodynamics/biomarker monitoring. These investigations should also prospectively evaluate plasma cytokine/chemokine levels in an attempt to validate biomarkers predictive of response and toxicity.

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Early Variations of Circulating Interleukin-6 and Interleukin-10 Levels During Thoracic Radiotherapy Are Predictive for Radiation Pneumonitis

Abstract: Early variations of circulating IL-6 and IL-10 levels during 3D-CRT are significantly associated with the risk of radiation pneumonitis. Variations of circulating IL-6 and IL-10 levels during 3D-CRT may serve as independent predictive factors for this complication.

Cited by 135 publications

References 40 publications

Distinct Loci Influence Radiation-Induced Alveolitis from Fibrosing Alveolitis in the Mouse

Distinct Loci Influence Radiation-Induced Alveolitis from Fibrosing Alveolitis in the Mouse

New insights into the molecular pathology of radiation-induced pneumopathy

Phase 2 study of idelalisib and entospletinib: pneumonitis limits combination therapy in relapsed refractory CLL and NHL

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