Health Behaviors Predict Higher Interleukin-6 Levels among Patients Newly Diagnosed with Head and Neck Squamous Cell Carcinoma

Duffy, Sonia A.; Teknos, Theodoros N.; Taylor, Jeremy M. G.; Fowler, Karen E.; Islam, Mohammad Mahmudul; Wolf, Gregory T.; McLean, Scott A.; Ghanem, Tamer; Terrell, Jeffrey E.

doi:10.1158/1055-9965.epi-12-0987

Cited by 36 publications

(41 citation statements)

References 70 publications

(78 reference statements)

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“…Recently, Duffy and colleagues found that smoking was independently associated with a higher serum interleukin-6 (IL-6) level among patients with head and neck cancer (27), and a higher IL-6 level was predictive of an increased risk of recurrence and poorer OS (28). In nasopharyngeal carcinoma, IL-6 facilitates tumor carcinogenesis and malignancy enhancement via activation of the STAT3, and a higher IL-6 level is associated with advanced stage nasopharyngeal carcinoma (29).…”

Section: Discussionmentioning

confidence: 99%

Prognostic Impact of Cigarette Smoking on the Survival of Patients with Established Nasopharyngeal Carcinoma

OuYang

Mao

et al. 2013

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background: Cigarette smoking is associated with the etiology of nasopharyngeal carcinoma; however, the influence of smoking on survival in patients with established nasopharyngeal carcinoma remains unknown.Methods: We retrospectively analyzed 1,849 patients with nasopharyngeal carcinoma who were categorized as never, former, and current smokers. Cumulative effect of smoking was defined in terms of pack-years. Associations between cigarette exposure and survival were estimated by Cox proportional hazards model.Results: The risks of death, progression, locoregional relapse, and distant metastasis were significantly higher for former and current smokers (all P 0.002) than never smokers. Heavy smokers with high pack-years had HRs for death of 3.31 [95% confidence interval (CI), 2.58-4.26; P < 0.001], for progression of 2.53 (95% CI, 2.03-3.16; P < 0.001), and for distant metastasis of 2.65 (95% CI, 1.89-3.70; P < 0.001). Specifically, in the cohort of 495 patients treated with intensity-modulated radiotherapy/three-dimensional conformal radiotherapy, we obtained similarly significant results. All of the survival outcomes remained significant in multivariate analyses.Conclusions: Pretreatment cigarette smoking is an independent, poor prognostic factor for patients with nasopharyngeal carcinoma, which is associated with increased risk of death, progression, locoregional relapse, and distant metastasis, with the risk increasing with pack-years.Impact: It is clear that cigarette smoking not only promotes carcinogenesis in the normal nasopharyngeal epithelium, but also affects the survival of patients with nasopharyngeal carcinoma. Cancer Epidemiol Biomarkers Prev; 22(12); 2285-94. Ó2013 AACR.

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Section: Discussionmentioning

confidence: 99%

Prognostic Impact of Cigarette Smoking on the Survival of Patients with Established Nasopharyngeal Carcinoma

OuYang

Mao

et al. 2013

Cancer Epidemiology, Biomarkers &Amp; Prevention

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“…Squamous cell head and neck carcinomas are highly inflammatory in nature and express a number of cytokines and growth factors involved in inflammation (47). Specifically, pretreatment serum IL6 levels have been found to predict recurrence and poor survival in head and neck cancer (48); smoking is associated with high IL6 levels, and this may result from the adverse effects of smoking on sleep patterns (49). Beyond this, the consequences of smoking-induced inflammation and immune dysregulation are not well understood (50).…”

Section: Other Potential Mechanismsmentioning

confidence: 99%

Smoking at Diagnosis Is an Independent Prognostic Factor for Cancer-Specific Survival in Head and Neck Cancer: Findings from a Large, Population-Based Study

Sharp

McDevitt

Carsin

et al. 2014

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background: Some studies suggest smoking may result in poorer clinical outcomes in head and neck cancer, but the evidence is heterogeneous and some of it is poor quality. In a large, population-based, study we investigated: (i) whether smoking at diagnosis is an independent prognostic factor for cancer-specific survival in head and neck cancer; and (ii) whether the association varies by site and treatment.Methods: Head and neck cancers (ICD10 C01-C14, and C30-32) diagnosed from 1994 to 2009 were abstracted from the National Cancer Registry Ireland, and classified by smoking status at diagnosis. Follow-up was for 5 years or until December 31, 2010. Multivariate Cox proportional hazards models were used to compare cancerspecific death rates in current, ex-, and never smokers. Subgroup analyses by site and treatment were conducted.Results: In total, 5,652 head and neck cancers were included. At diagnosis, 24% were never smokers, 20% exsmokers, and 56% current smokers. Compared with never smokers, current smokers had a significantly raised death rate from cancer [multivariate HR, 1.36; 95% confidence interval (CI), 1.21-1.53]. The association was similar after restriction to squamous cell tumors. A significantly increased cancer-related death rate was seen for current smokers with oral cavity, pharyngeal, and laryngeal cancers. The association was stronger in surgically treated patients [HR, 1.49; 95% CI, 1.25-1.79; P(interaction) ¼ 0.01]. Neither radiotherapy nor chemotherapy modified the effect of smoking.Conclusions: Patients with head and neck cancer who smoke at diagnosis have a significantly increased cancer death rate.Impact: Greater efforts are needed to encourage and support smoking cessation in those at risk of, and diagnosed with, head and neck cancer. Cancer Epidemiol Biomarkers Prev; 23(11); 2579-90. Ó2014 AACR.

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“…26,27,31,32,36,[54][55][56][57][58][59][60] Elevated concentrations of IL-6 were found in the saliva of patients with premalignant HNSCC lesions. 26 Higher pretreatment serum IL-6 levels were associated with lower HNSCC overall survival, higher tumor recurrence, and increased development of second primary tumors.…”

Section: Discussionmentioning

confidence: 99%

“…26 Higher pretreatment serum IL-6 levels were associated with lower HNSCC overall survival, higher tumor recurrence, and increased development of second primary tumors. 26,31,36,59 In patient HNSCC tumor tissue specimens, IL-6 levels correlated with the HNSCC tumor grade and were reduced after effective radio-or chemotherapies. 55,57 IL-6Ra mRNA levels were higher in oral cancer cells relative to normal mucosa, and increased IL-6Ra expression was associated with larger tumors of advanced histological stage.…”

Section: Discussionmentioning

confidence: 99%

“…26,[28][29][30][31][32][33][34][35] IL-6 was identified as a valuable biomarker for predicting recurrence and overall HNSCC patient survival. 26,31,36 Tocilizumab, a humanized anti-IL-6Ra mAb that blocks IL-6 binding and neutralizes IL-6-induced activities, 37,38 was approved by the FDA for the treatment of inflammatory diseases such as rheumatoid arthritis, juvenile idiopathic arthritis, Castleman's disease, and Crohn's disease. Tocilizumab and siltuximab, an IL-6 neutralizing antibody, are in clinical trials for multiple myeloma, prostate cancer, and metastatic kidney cancer.…”

Section: Introductionmentioning

confidence: 99%

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HCS Campaign to Identify Selective Inhibitors of IL-6-Induced STAT3 Pathway Activation in Head and Neck Cancer Cell Lines

Johnston

Sen

Hua

et al. 2015

ASSAY and Drug Development Technologies

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Signal transducer and activator of transcription factor 3 (STAT3) is hyperactivated in head and neck squamous cell carcinomas (HNSCC). Cumulative evidence indicates that IL-6 production by HNSCC cells and/or stromal cells in the tumor microenvironment activates STAT3 and contributes to tumor progression and drug resistance. A library of 94,491 compounds from the Molecular Library Screening Center Network (MLSCN) was screened for the ability to inhibit interleukin-6 (IL-6)-induced pSTAT3 activation. For contractual reasons, the primary high-content screening (HCS) campaign was conducted over several months in 3 distinct phases; 1,068 (1.1%) primary HCS actives remained after cytotoxic or fluorescent outliers were eliminated. One thousand one hundred eighty-seven compounds were cherry-picked for confirmation; actives identified in the primary HCS and compounds selected by a structural similarity search of the remaining MLSCN library using hits identified in phases I and II of the screen. Actives were confirmed in pSTAT3 IC 50 assays, and an IFNc-induced pSTAT1 activation assay was used to prioritize selective inhibitors of STAT3 activation that would not inhibit STAT1 tumor suppressor functions. Two hundred three concentration-dependent inhibitors of IL-6-induced pSTAT3 activation were identified and 89 of these also produced IC 50 s against IFN-c-induced pSTAT1 activation. Forty-nine compounds met our hit criteria: they reproducibly inhibited IL-6-induced pSTAT3 activation by ‡70% at 20 lM; their pSTAT3 activation IC 50 s were £25 lM; they were ‡2-fold selective for pSTAT3 inhibition over pSTAT1 inhibition; a cross target query of PubChem indicated that they were not biologically promiscuous; and they were ‡90% pure. Twenty-six chemically tractable hits that passed filters for nuisance compounds and had acceptable drug-like and ADME-Tox properties by computational evaluation were purchased for characterization. The hit structures were distributed among 5 clusters and 8 singletons. Twenty-four compounds inhibited IL-6-induced pSTAT3 activation with IC 50 s £20 lM and 13 were ‡3-fold selective versus inhibition of pSTAT1 activation. Eighteen hits inhibited the growth of HNSCC cell lines with average IC 50 s £ 20 lM. Four chemical series were progressed into lead optimization: the guanidinoquinazolines, the triazolothiadiazines, the amino alcohols, and an oxazole-piperazine singleton.

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Health Behaviors Predict Higher Interleukin-6 Levels among Patients Newly Diagnosed with Head and Neck Squamous Cell Carcinoma

Cited by 36 publications

References 70 publications

Prognostic Impact of Cigarette Smoking on the Survival of Patients with Established Nasopharyngeal Carcinoma

Prognostic Impact of Cigarette Smoking on the Survival of Patients with Established Nasopharyngeal Carcinoma

Smoking at Diagnosis Is an Independent Prognostic Factor for Cancer-Specific Survival in Head and Neck Cancer: Findings from a Large, Population-Based Study

HCS Campaign to Identify Selective Inhibitors of IL-6-Induced STAT3 Pathway Activation in Head and Neck Cancer Cell Lines

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