Gastroesophageal and Laryngopharyngeal Reflux Associated With Laryngeal Malignancy: A Systematic Review and Meta-analysis

Parsel, Sean M.; Wu, Eric; Riley, Charles A.; McCoul, Edward D.

doi:10.1016/j.cgh.2018.10.028

Cited by 63 publications

(87 citation statements)

References 59 publications

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“…Tobacco, alcohol, and human papilloma virus have been shown to be associated with head and neck cancers [1]. Recent epidemiologic descriptions have also supported the early oncogenic effects of biliary gastroesophageal reflux on the supra-esophageal mucosa, and with an increasing interest in laryngopharyngeal carcinogenesis [2]. Our prior in vitro and in vivo explorations show the tumorigenic effect of bile at strongly acidic pH on hypopharyngeal cells, enabled through the transcriptional factor NF-κB [3][4][5][6][7].…”

Section: Introductionmentioning

confidence: 90%

The temporal effects of topical NF-κB inhibition, in the in vivo prevention of bile-related oncogenic mRNA and miRNA phenotypes in murine hypopharyngeal mucosa: a preclinical model

Vageli¹,

Kasle²,

Doukas³

et al. 2020

Oncotarget

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Supraesophageal bile reflux at strongly acidic pH can cause hypopharyngeal squamous cell cancer, through activation of the oncogenic NF-κB-related pathway. We hypothesize that topical pre-or post-application of pharmacologic NF-κB inhibitor, BAY 11-7082 (0.25 μmol), on murine (C57BL/6J) HM (twice a day for 10 days) can effectively inhibit acidic bile (10 mmol/l; pH 3.0) induced oncogenic molecular events, similar to prior in vitro findings. We demonstrate that the administration of BAY 11-7082, either before or after acidic bile, eliminates NF-κB activation, prevents overexpression of Bcl2, Rela, Stat3, Egfr, Tnf, Wnt5a, and deregulations of miR-192, miR-504, linked to bile reflux-related hypopharyngeal cancer. Pre-but not post-application of NF-κB inhibitor, significantly blocks overexpression of Il6 and prostaglandin H synthases 2 (Ptgs2), and reverses miR-21, miR-155, miR-99a phenotypes, supporting its early bile-induced pro-inflammatory effect. We thus provide novel evidence that topical administration of a pharmacological NF-κB inhibitor, either before or after acidic bile exposure can successfully prevent its oncogenic mRNA and miRNA phenotypes in HM, supporting the observation that coadministration of NF-κB inhibitor may not be essential in preventing early bile-related oncogenic events and encouraging a capacity for further translational exploration.

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Section: Introductionmentioning

confidence: 90%

The temporal effects of topical NF-κB inhibition, in the in vivo prevention of bile-related oncogenic mRNA and miRNA phenotypes in murine hypopharyngeal mucosa: a preclinical model

Vageli¹,

Kasle²,

Doukas³

et al. 2020

Oncotarget

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“…Recent multinational studies have demonstrated that an increased risk of hypopharyngeal and laryngeal malignancies rarely is attributed to HPV, whereas a well-powered meta-analysis has suggested that gastroesophageal reflux disease and laryngopharyngeal reflux (LPR) are risk factors for laryngeal malignancy regardless of tobacco use or alcohol consumption. 2 Galli et al demonstrated that during gastric reflux, bile-containing fluid frequently reaches the epithelium of the upper aerodigestive tract, making it possible to think that, as in the esophagus, acidic bile reflux could be a significant causative agent in hypopharyngeal carcinoma. 3 However, to our knowledge, evidence of the role of LPR as a pathogenetic factor in the genesis of hypopharyngeal squamous cell carcinoma (HSCC) remains speculative.…”

Section: Introductionmentioning

confidence: 99%

Biliary reflux as a causal factor in hypopharyngeal carcinoma: New clinical evidence and implications

Sasaki¹,

Doukas²,

Costa

et al. 2019

Cancer

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Background Recent preclinical explorations strongly support the tumorigenic potential of bile on laryngopharyngeal mucosa. Herein, the authors describe, in bile‐related human hypopharyngeal squamous cell carcinoma (HSCC), NF‐κB–related messenger RNA (mRNA) and microRNA (miRNA) oncogenic phenotypes similar to those previously identified in acidic bile–exposed premalignant murine hypopharyngeal mucosa. Methods In this pilot study, the authors included human HSCC specimens paired with their adjacent normal tissue (ANT) derived from 3 representative patients with documented biliary laryngopharyngeal reflux (bile[+]) compared with 5 control patients without signs of bile reflux disease (bile[‐]). Immunohistochemical, quantitative polymerase chain reaction, and miRNA analyses were used to detect the levels of activated NF‐κB and expression levels of STAT3, EGFR, BCL2, WNT5A, IL‐6, IL‐1B, ΔNp63, cREL, TNF‐α, TP53, NOTCH1, NOTCH2, NOTCH3, miR‐21, miR‐155, miR‐192, miR‐34a, miR‐375, miR‐451a, miR‐489, miR‐504, and miR‐99a. Results Bile(+) HSCC demonstrated an intense NF‐κB activation accompanied by significant overexpression of RELA(p65), EGFR, STAT3, BCL‐2, cREL, ΔNp63, WNT5A, IL‐6, and IL1B; upregulation of oncomir miR‐21; and downregulation of tumor suppressor miR‐375 compared with their respective ANTs. Bile(+) HSCC demonstrated significantly higher mRNA levels of all the analyzed genes, particularly RELA(p65), IL‐6, EGFR, and TNF‐α compared with bile(‐) tumors. The miR‐21/miR‐375 ratio, which previously has been linked to tumor aggressiveness, was found to be >260‐fold and >30‐fold higher, respectively, in bile(+) HSCCs compared with their ANTs and bile(‐) tumors. Conclusions Although limitations apply to this pilot study due to the small number of patients with HSCC, the novel findings suggest that a history of bile as a component of esophageal reflux disease may represent an independent risk factor for hypopharyngeal carcinogenesis.

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“…GERD is a common digestive system disorder. However, it not only affects the digestive system; evidence suggests that it also results in other organ and tissue diseases, such as respiratory distress, laryngeal malignancy, and dental erosion (Wang et al, 2009;Parsel et al, 2019;Picos et al, 2019). Also, recent research (Dunbar et al, 2016) demonstrated that the earliest pathological changes in GERD were not chemical corrosion of the mucosal surface but inflammation in the epithelium.…”

Section: Discussion Evidence Summary and Interpretationmentioning

confidence: 99%

Efficacy of Chinese Herbal Formula Sini Zuojin Decoction in Treating Gastroesophageal Reflux Disease: Clinical Evidence and Potential Mechanisms

Huang

et al. 2020

Front. Pharmacol.

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Background: Based on 122 cases reported in China, data mining indicated that Sini Powder (SNP) and the Zuojin Pill (ZJP) are both widely used as the basic recipe for treating Gastroesophageal Reflux Disease (GERD). Objectives: To evaluate the intervention effects of Sini Zuojin Decoction (SNZJD) in patients with GERD. Methods: A comprehensive collection of randomized controlled trials (RCTs) using SNZJD in patients with GERD that were published in domestic and foreign journals was made by computer retrieval. RevMan 5.3 software was used for meta-analysis and bias risk assessment, Stata 14.0 software was used for sensitivity analysis, GRADE profiler 3.6 was used to evaluate the level of evidence, and trial sequential analysis (TSA), employed to control for random errors, was performed to assess the main outcomes. Network pharmacology analysis was applied to preliminarily study the mechanisms of action of SNZJD on GERD. Results: Thirteen articles were eventually included, covering a total of 966 patients. Metaanalysis indicated that: ① the SNZJD plus traditional stomach medicines (SPTSM) group was more effective than the traditional stomach medicines (TSM) group (RR = 1.16, 95% CI [1.04, 1.29], P = 0.009); ② the experimental group with SNZJD was significantly better than TSM controls in improving heartburn, substernal chest pain, acid regurgitation, and food regurgitation symptoms (P < 0.0001); ③ SPTSM could significantly decrease total symptom scores with substantial effectiveness (P < 0.00001). The recurrence rate and adverse effects of SNZJD treatment were significantly reduced (P < 0.05). TSA showed that the effective rate of meta-analysis might be reliable, but the recurrence and safety results were still uncertain. According to the evaluation by the GRADE method, the quality

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Gastroesophageal and Laryngopharyngeal Reflux Associated With Laryngeal Malignancy: A Systematic Review and Meta-analysis

Cited by 63 publications

References 59 publications

The temporal effects of topical NF-κB inhibition, in the in vivo prevention of bile-related oncogenic mRNA and miRNA phenotypes in murine hypopharyngeal mucosa: a preclinical model

The temporal effects of topical NF-κB inhibition, in the in vivo prevention of bile-related oncogenic mRNA and miRNA phenotypes in murine hypopharyngeal mucosa: a preclinical model

Biliary reflux as a causal factor in hypopharyngeal carcinoma: New clinical evidence and implications

Efficacy of Chinese Herbal Formula Sini Zuojin Decoction in Treating Gastroesophageal Reflux Disease: Clinical Evidence and Potential Mechanisms

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