Brachytherapy and non-cancer mortality in patients with oral cavity and oropharynx SCCs.

BACKGROUND: Oral cavity and oropharyngeal squamous cell cancers (OC-OPSCC) display high cancer-specific mortality and increased non-cancer mortality. We examined cause of death in patients treated for OC-OPSCC with brachytherapy, chemotherapy, external beam radiation, surgery, or combination of modalities. We hypothesized that brachytherapy does not increase non-cancer mortality comparably with external beam radiation. METHODS: A database was constructed from institutional tumor registry and electronic medical record data from all patients with first OC-OPSCC diagnosis at our institution between 2000 and 2010, excluding patients with a second primary cancer at diagnosis. The primary outcome was association between treatment modality and non-cancer mortality. RESULTS: Of 693 eligible patients, 460 were deceased; 84 from primary malignancy and 96 from a non-primary cancer cause, including 24 with a second primary cancer. 193 patients received brachytherapy. Cox proportional hazards regression was performed on treatment regimen, stratified by AJCC stage, race, and sex. Age, smoking history, and alcohol had HRs for death of 1.05 (p < 0.005), 1.37 (p = 0.106), and 2.24 (p < 0.005), respectively, while brachytherapy had a 0.53 HR (p < 0.005) for death. Non-smoking OPC patients had an 88% 5-year OS, suggesting these were largely HPV-driven cancers. In smoking OPC patients, 5-year OS was 61%. Non-cancer mortality HR of 0.36 for brachytherapy-treated patients. CONCLUSION: We report non-cancer mortality from a cohort of curatively treated OC-OPSCC and show a significant correlation between brachytherapy and non-cancer survival, independent of remission status. The impact of brachytherapy in OPC was strongest in smokers.

Pepsin Promotes Activation of Epidermal Growth Factor Receptor and Downstream Oncogenic Pathways, at Slightly Acidic and Neutral pH, in Exposed Hypopharyngeal Cells.

Pepsin refluxate is considered a risk factor for laryngopharyngeal carcinogenesis. Non-acidic pepsin was previously linked to an inflammatory and tumorigenic effect on laryngopharyngeal cells in vitro. Yet there is no clear evidence of the pepsin-effect on a specific oncogenic pathway and the importance of pH in this process. We hypothesized that less acidic pepsin triggers the activation of a specific oncogenic factor and related-signalling pathway. To explore the pepsin-effect in vitro, we performed intermittent exposure of 15 min, once per day, for a 5-day period, of human hypopharyngeal primary cells (HCs) to pepsin (1 mg/mL), at a weakly acidic pH of 5.0, a slightly acidic pH of 6.0, and a neutral pH of 7.0. We have documented that the extracellular environment at pH 6.0, and particularly pH 7.0, vs. pH 5.0, promotes the pepsin-effect on HCs, causing increased internalized pepsin and cell viability, a pronounced activation of EGFR accompanied by NF-κB and STAT3 activation, and a significant upregulation of EGFR, AKT1, mTOR, IL1ß, TNF-α, RELA(p65), BCL-2, IL6 and STAT3. We herein provide new evidence of the pepsin-effect on oncogenic EGFR activation and its related-signaling pathway at neutral and slightly acidic pH in HCs, opening a window to further explore the prevention and therapeutic approach of laryngopharyngeal reflux disease.

Weakly Acidic Bile Is a Risk Factor for Hypopharyngeal Carcinogenesis Evidenced by DNA Damage, Antiapoptotic Function, and Premalignant Dysplastic Lesions In Vivo.

BACKGROUND: There is recent in vivo discovery documenting the carcinogenic effect of bile at strongly acidic pH 3.0 in hypopharynx, while in vitro data demonstrate that weakly acidic bile (pH 5.5) has a similar oncogenic effect. Because esophageal refluxate often occurs at pH > 4.0, here we aim to determine whether weakly acidic bile is also carcinogenic in vivo. METHODS: Using 32 wild-type mice C57B16J, we performed topical application of conjugated primary bile acids with or without unconjugated secondary bile acid, deoxycholic acid (DCA), at pH 5.5 and controls, to hypopharyngeal mucosa (HM) twice per day, for 15 weeks. RESULTS: Chronic exposure of HM to weakly acidic bile, promotes premalignant lesions with microinvasion, preceded by significant DNA/RNA oxidative damage, γH2AX (double strand breaks), NF-κB and p53 expression, overexpression of Bcl-2, and elevated Tnf and Il6 mRNAs, compared to controls. Weakly acidic bile, without DCA, upregulates the "oncomirs", miR-21 and miR-155. The presence of DCA promotes Egfr, Wnt5a, and Rela overexpression, and a significant downregulation of "tumor suppressor" miR-451a. CONCLUSION: Weakly acidic pH increases the risk of bile-related hypopharyngeal neoplasia. The oncogenic properties of biliary esophageal reflux on the epithelium of the upper aerodigestive tract may not be fully modified when antacid therapy is applied. We believe that due to bile content, alternative therapeutic strategies using specific inhibitors of relevant molecular pathways or receptors may be considered in patients with refractory GERD.

The role of vitamin D in head and neck cancer.

OBJECTIVE: Head and neck squamous cell carcinoma (HNSCC) describes a set of malignancies of the head and neck that continue to inflict considerable morbidity and mortality. Because HNSCC often presents at an advanced stage, patients frequently undergo intensive multi-modal therapy with an intent to cure. Vitamin D is a precursor to the biologically active hormone calcitriol which governs bone and calcium physiology that is obtained from diet and UV-B exposure. Vitamin D is known to have pleiotropic effects on health and disease. In this review, we examine the role of vitamin D in cancer with emphasis on HNSCC and discuss potential avenues for further research that might better elucidate the role of vitamin D in the management of HNSCC. REVIEW METHODS: A review of MEDLINE database indexed literature concerning the role and biology of vitamin D in HNSCC was conducted, with special consideration of recently published work and research involving immunobiology and HNSCC. CONCLUSIONS: The available evidence suggests that vitamin D may play a role in protecting against HNSCC, particularly in persons who smoke, although conflicting and limited data exists. Promising initial work encourages the pursuit of further study. IMPLICATIONS FOR PRACTICE: The significant morbidity and mortality that HNSCC brings warrants continued research in available and safe interventions that improve patient outcomes. With the rise of immunotherapy as an effective modality for treatment, continued research of vitamin D as an adjunct in the treatment of HNSCC is supported.

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.

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 co-administration of NF-κB inhibitor may not be essential in preventing early bile-related oncogenic events and encouraging a capacity for further translational exploration.

The in vivo preventive and therapeutic properties of curcumin in bile reflux-related oncogenesis of the hypopharynx.

Bile at strongly acidic pH exerts a carcinogenic effect on the hypopharynx, based upon recent pre-clinical studies that support its role as an independent risk factor. We recently demonstrated in vitro that curcumin can prevent oncogenic profile of bile in human hypopharyngeal cells, by inhibiting NF-κB. We hypothesize that topically applied curcumin to the hypopharynx can similarly block early oncogenic molecular events of bile, by inhibiting NF-κB and consequently altering the expression of genes with oncogenic function. Using Mus musculus (C57Bl/6J), we topically applied curcumin (250 µmol/L; three times per day; 10 days) to the hypopharynx, 15 minutes before, 15 minutes after or in combination with bile acids (pH 3.0). Immunohistochemical analysis and qPCR revealed that topically applied curcumin either before, after or in combination with acidic bile exposure significantly suppressed its induced NF-κB activation in regenerating epithelial cells, and overexpression of Rela, Bcl2, Egfr, Stat3, Wnt5a, Tnf, Il6, Ptgs2. Akt1 was particularly inhibited by curcumin when applied simultaneously with bile. We provide novel evidence into the preventive and therapeutic properties of topically applied curcumin in acidic bile-induced early oncogenic molecular events in hypopharyngeal mucosa, by inhibiting NF-κB, and shaping future translational development of effective targeted therapies using topical non-pharmacologic inhibitors of NF-κB.

The Effect of NNK, A Tobacco Smoke Carcinogen, on the miRNA and Mismatch DNA Repair Expression Profiles in Lung and Head and Neck Squamous Cancer Cells.

Tobacco smoking is a common risk factor for lung cancer and head and neck cancer. Molecular changes such as deregulation of miRNA expression have been linked to tobacco smoking in both types of cancer. Dysfunction of the Mismatch DNA repair (MMR) mechanism has also been associated with a poor prognosis of these cancers, while a cross-talk between specific miRNAs and MMR genes has been previously proposed. We hypothesized that exposure of lung and head and neck squamous cancer cells (NCI and FaDu, respectively) to tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is capable of altering the expression of MSH2 and MLH1, key MMR components, by promoting specific miRNA deregulation. We found that either a low (1 µM) or high (2 µM) dose of NNK induced significant upregulation of "oncomirs" miR-21 and miR-155 and downregulation of "tumor suppressor" miR-422a, as well as the reduction of MMR protein and mRNA expression, in NCI and FaDu, compared to controls. Inhibition of miR-21 restored the NNK-induced reduced MSH2 phenotype in both NCI and FaDu, indicating that miR-21 might contribute to MSH2 regulation. Finally, NNK exposure increased NCI and FaDu survival, promoting cancer cell progression. We provide novel findings that deregulated miR-21, miR-155, and miR-422a and MMR gene expression patterns may be valuable biomarkers for lung and head and neck squamous cell cancer progression in smokers.

The Progressive Mutagenic Effects of Acidic Bile Refluxate in Hypopharyngeal Squamous Cell Carcinogenesis: New Insights.

Cancers of the laryngopharynx represent the most devastating of the head and neck malignancies and additional risk factors are now epidemiologically linked to this disease. Using an in vivo model (Mus musculus C57Bl/6J), we provide novel evidence that acidic bile (pH 3.0) progressively promotes invasive cancer in the hypopharynx. Malignant lesions are characterized by increasing: i) oxidative DNA-damage, ii) γH2AX expression, iii) NF-κB activation, and iv) p53 expression. Histopathological changes observed in murine hypopharyngeal mucosa exposed to acidic bile were preceded by the overexpression of Tnf, Il6, Bcl2, Egfr, Rela, Stat3, and the deregulation of miR-21, miR-155, miR-192, miR-34a, miR-375, and miR-451a. This is the first study to document that acidic bile is carcinogenic in the upper aerodigestive tract. We showed that oxidative DNA-damage produced by acidic bile in combination with NF-κB-related anti-apoptotic deregulation further supports the underlying two-hit hypothesized mechanism. Just as importantly, we reproduced the role of several biomarkers of progression that served as valuable indicators of early neoplasia in our experimental model. These findings provide a sound basis for proposing translational studies in humans by exposing new opportunities for early detection and prevention.

The role of bile reflux and its related NF-κB activated pathway in progression of hypopharyngeal squamous cell cancer.

BACKGROUND: Prognosis for hypopharyngeal cancer is usually poor, and recurrence is common. Identifying new factors or related mechanisms that promote its progression may have clinical implications. Although, recent studies support bile reflux in hypopharyngeal carcinogenesis, it remains to be explored how bile and its related NF-κB activated pathway may further affects its progression in already established hypopharyngeal cancer. METHODS: Hypopharyngeal squamous cell carcinoma (HSCC) cell lines, FaDu and UMSCC11A, both negative for HPV, were repetitively exposed to bile acids (400 µM) at variable pH points (4.0, 5.5 and 7.0). Immunofluorescence, western blotting, luciferase assay, and qPCR were used to detect NF-κB activation, bcl-2 overexpression and gene expression. RESULTS: Bile at strongly acidic pH (4.0) potentiated the activation of NF-κB and its related mRNA phenotype in HSCC cells. IL-6, TNF-α, and BCL2 were found among the highest overexpressed genes as was previously found in HSCCs excised from patients with documented biliary reflux. An enhanced transcriptional activity of EGFR, RELA, STAT3, and WNT5Α and higher survival rates were observed in HSCC cells exposed to acidic bile compared to those exposed to bile at weakly acidic or neutral pH. CONCLUSION: Our novel findings support the observation that bile reflux has the potential for actively influencing the progression of hypopharyngeal cancer, mediated by NF-κB. In patients with hypopharyngeal cancer and known gastroesophageal reflux disease, antacid therapy may exert a role in furthering control of disease recurrence and progression.

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

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.

Temporal characteristics of NF-κB inhibition in blocking bile-induced oncogenic molecular events in hypopharyngeal cells.

Biliary esophageal reflux at acidic pH is considered a risk factor in laryngopharyngeal cancer. We previously showed the key role NF-κB in mediating acidic bile-induced pre-neoplastic events in hypopharyngeal cells, and that co-administration of specific NF-κB inhibitor, BAY 11-7082, together with acidic bile, can effectively prevent its related oncogenic molecular effects. We hypothesize that the addition of BAY 11-7082 (10µM) either before or after application of acidic bile (400µM conjugated bile acids; pH 4.0), is capable of comparably blocking acidic bile-induced oncogenic molecular phenotypes in murine hypopharyngeal primary cells. We performed immunofluorescence, luciferase assay, western blot and qPCR analysis, demonstrating that 15-min of pre- or post-application of BAY 11-7082 effectively inhibits acidic bile-induced NF-κB activation, transcriptional activation of RELA(p65), STAT3, EGFR, IL-6, bcl-2, WNT5A, "upregulation" of "oncomirs" miR-21, miR-155, miR-192 and "downregulation" of "tumor suppressor" miR-34a, miR-375, miR-451a. Our observations support the understanding that acidic bile-induced deregulation of anti-apoptotic or oncogenic factors, bcl-2, STAT3, EGFR, IL-6, WNT5A, miR-21, miR-155, miR-375, is highly NF-κB-dependent, showing that even post-application of inhibitor can suppress their deregulation. In conclusion, application of specific NF-κB inhibitor, has the capability of adequately blocking the early oncogenic molecular events produced by acidic bile whether it is applied pre or post exposure. In addition to therapeutic implications these findings provide a window of observation into the complex kinetics characterizing the mechanistic link between acidic bile and early neoplasia. Although BAY 11-7082 itself may not be suitable for clinical use, the application of other NF-κB inhibitors merits exploration.

Hypopharyngeal Diverticulum: Toward a Unified Understanding of Its Etiopathogenesis.

The etiopathogenesis of Zenker's diverticulum (ZD) remains uncertain. Increased hypopharyngeal pressure due to a hypertonic upper esophageal sphincter results in herniation proximal to the sphincter producing a pulsion diverticulum. Gastroesophageal reflux, which is known to induce shortening of the injured esophagus, likely plays a prominent role in ZD formation by pulling the cricopharyngeus muscle (CPM) away from the anchored inferior constrictor muscle. This creates a "weak zone" encouraging herniation. A bilobed diverticulum may originate from continuation of the fibrous midline raphe inferiorly to developmentally include part of the CPM. We report using laser endoscopy to divide the inter-diverticular septum followed by transmucosal cricopharyngeus myotomy. Presentation of a rare, bilobed diverticulum emphasizes the importance of the midline prevertebral raphe in anchoring the pharyngeal constrictor muscles with respect to the CPM. This lends support to the hypothesis that the etiopathogenesis of ZD is multifactorial while guiding us to a unified understanding of ZD.

Biliary tumorigenic effect on hypopharyngeal cells is significantly enhanced by pH reduction.

Biliary reflux has been considered a potential risk factor in upper aerodigestive tract malignancies. It is not yet clearly known how pH affects the bile-induced activation of NF-κB and its related oncogenic pathway previously linked to hypopharyngeal carcinogenesis. In this study, repetitive applications of conjugated primary bile acids with unconjugated secondary bile acid, deoxycholic acid (DCA), on human hypopharyngeal primary cells reveal that strongly acidic pH (4.0) optimally enhances the tumorigenic effect of bile, by inducing activation of NF-κB, STAT3 nuclear translocation, bcl-2 overexpression and significant overexpression of the oncogenic mRNA phenotype, compared to weakly acidic pH (5.5) or neutral pH (7.0). As the pH becomes less acidic the partially activated primary bile acids and activated DCA begin to exert their influence; however, with significantly less intensity compared to bile acids at strongly acidic pH. Our findings suggest that biliary tumorigenic effect is strongly pH dependent. Controlling pH during reflux events may be therapeutically effective in reducing the potential risk of bile-induced hypopharyngeal cancer.

A Clinical Care Pathway to Reduce ICU Usage in Head and Neck Microvascular Reconstruction.

OBJECTIVE: To design and implement a postoperative clinical care pathway designed to reduce intensive care usage on length of stay, readmission rates, and surgical complications in head and neck free flap patients. METHODS: A postoperative clinical care pathway detailing timelines for patient care was developed by a multispecialty team. In total, 108 matched patients receiving free tissue transfer for reconstruction of head and neck defects in the year before (prepathway), year after (early pathway), and second year after (late pathway) pathway implementation were compared based on postoperative length of stay, 30-day readmission rate, intensive care unit (ICU) admission, and rates of medical/surgical complications. RESULTS: Median length of stay decreased from 10 to 7.5 and 7 days in the pre-, early, and late-pathway groups, respectively ( P = .012). Readmission rate decreased from 16% in the prepathway group to 0% and 3% in the early and late-pathway groups. The number of patients admitted to the ICU postoperatively decreased from 100% to 36% and 6% in the pre-, early, and late-pathway groups, respectively ( P = .025). The rates of surgical and medical complications were equivalent. DISCUSSION: This pathway effectively reduced ICU admission, length of stay, and readmission rates, without increasing postoperative complications. These outcomes were sustainable over 2 years. IMPLICATIONS FOR PRACTICE: Free flap patients may not require routine ICU admission and may be taken off ventilatory support in the operating room. This effectively reduces costly resource use in this patient population. Similar pathways could be introduced at other institutions.

In search of a longitudinal animal model of evoked swallow function.

BACKGROUND: A malfunction or impairment of swallow function can potentiate aspiration events and interfere with both quality of life and survival. Establishing an animal model for swallow research would provide a better understanding of its pathophysiology and would also allow for the development and validation of physiologically based clinical interventions to improve swallow function. Two requirements define the ideal model for longitudinal exploration: 1) identification of species similar to human in form and function; and 2) provision for reliable and reproducible evoked swallow under general anesthesia and one that would also support a longitudinal study design. OBJECTIVE: We hypothesize that an anesthetized porcine model under dexmedetomidine-based or ketamine-based anesthesia will support a reproducible and stable evoked swallow response. METHODS: Seven neutered male Yorkshire pigs were anesthetized using combinations of dexmedetomidine-based or ketamine-based anesthesia for induction and maintenance of anesthesia during the experimental portion of our study. Single stimulation of iSLN or vagus nerve, bilateral simultaneous single stimulation of iSLN or vagus nerve, and stimulus trains applied to afferent nerves were performed. RESULTS: None of the seven pigs demonstrated evoked swallow events, both during inhalational anesthesia (1.0 MAC) or during post-washout intravenous anesthesia (dexmedetomidine, ketamine/fentanyl or ketamine alone). CONCLUSION: Our results support a high degree of organizational neurophysiologic complexity characterizing the swallow reflex and highlight the challenges and limitations of intraoperative study in survival models. LEVEL OF EVIDENCE: NA Laryngoscope, 2018.

Treatment Delays in Primarily Resected Oropharyngeal Squamous Cell Carcinoma: National Benchmarks and Survival Associations.

OBJECTIVE: To characterize treatment delays in surgically treated oropharyngeal cancer, identify factors associated with delays, and associate delays with survival. STUDY DESIGN: Retrospective cross-sectional analysis. SETTING: Commission on Cancer-accredited institutions. SUBJECTS AND METHODS: We identified patients in the National Cancer Database with surgically treated oropharyngeal cancer. We characterized the durations of diagnosis-to-treatment initiation, surgery-to-radiation treatment, radiation treatment duration, total treatment package, and diagnosis-to-treatment end intervals as medians. We associated delays with patient, tumor, and treatment factors via multivariable logistic regression analysis and with overall survival by Cox proportional hazards regression. RESULTS: In total, 3708 patients met inclusion criteria. Median durations of diagnosis-to-treatment initiation, surgery-to-radiation treatment, radiation treatment duration, total treatment package, and diagnosis-to-treatment end intervals were 27, 42, 47, 90, and 106 days, respectively. Medicaid and human papillomavirus (HPV) negativity were associated with delays. Delayed total treatment package and diagnosis-to-treatment end intervals were associated with decreased survival (hazard ratio [HR] = 1.81 [1.29-2.54], P = .001 and HR = 1.97 [1.39-2.78], P < .001, respectively); this was maintained following HPV stratification. Delays in the surgery-to-radiation treatment interval were associated with decreased overall survival in HPV-negative but not HPV-positive patients (HR = 2.05 [1.19-3.52], P = .010 and HR = 1.15 [0.74-1.80], P = .535, respectively). Diagnosis-to-treatment initiation and radiation treatment duration were not associated with overall survival in the overall cohort (HR = 1.21 [0.86-1.72], P = .280 and HR = 1.40 [0.99-1.99], P = .061, respectively); however, following stratification, delayed radiation treatment duration approached significance in HPV-negative but not HPV-positive patients (HR = 1.60 [0.96-2.68], P = .072 and HR = 1.35 [0.84-2.18], P = .220). CONCLUSION: Treatment durations identified here can serve as national benchmarks and for institutions to compare quality to their peers. Distinct benchmarks should be applied to HPV-negative and HPV-positive patients.

Permanent Interstitial Brachytherapy for Previously Irradiated Head and Neck Cancer.

OBJECTIVE: To evaluate our institutional experience using brachytherapy for the re-irradiation of the head and neck. STUDY DESIGN/METHODS: We reviewed the records of patients who received brachytherapy for head and neck cancer in a previously irradiated field between 2007 and 2016. RESULTS: Sixty-nine patients received brachytherapy-based re-irradiation. Forty-nine patients (71%) were treated for recurrent cancers, 15 patients (22%) had second primary cancers, and five patients (7%) were treated for persistent tumors. The median dose was 90 Gy (range 30-180). Median follow-up was 3.0 years for surviving patients and 0.6 years for all patients. Overall survival at one, three, and five years was 58%, 19%, and 12%, respectively. Local control at one, three, and five years was 55%, 38%, and 28%, respectively. A disease-free interval of less than one year was associated with significantly worse local control (p=.04). Patients who received brachytherapy for a neck disease had significantly worse locoregional control than those who received brachytherapy for mucosal disease (heart rate (HR) 2.14, 95% CI 1.00-4.56, p=.05). Patients who had an extranodal extension had significantly worse overall survival than those without an extranodal extension (HR 2.57, 95% CI 1.28-5.37, p=.008). Seventy-four percent of patients who had pain before brachytherapy (with or without surgery) had an improvement of symptoms. Acute and chronic toxicity of at least Common Terminology Criteria for Adverse Events Grade 3 was seen in 27% and 19% of the patients, respectively. CONCLUSIONS: Brachytherapy-based re-irradiation is an effective approach for patients undergoing re-irradiation for head and neck cancer. Brachytherapy may be more effective for mucosal recurrences than neck recurrences.

Curcumin prevents the bile reflux-induced NF-κB-related mRNA oncogenic phenotype, in human hypopharyngeal cells.

The presence of bile is not an uncommon finding in acidic oesophageal and extra-oesophageal refluxate, possibly affecting the hypopharyngeal mucosa and leading to neoplastic events. We recently demonstrated that acidic bile (pH ≤ 4.0) can induce NF-κB activation and oncogenic mRNA phenotype in normal hypopharyngeal cells and generate premalignant changes in treated hypopharyngeal mucosa. We hypothesize that curcumin, a dietary inhibitor of NF-κB, may effectively inhibit the acidic bile-induced cancer-related mRNA phenotype, in treated human hypopharyngeal primary cells (HHPC), supporting its potential preventive use in vivo. Luciferase assay, immunofluorescence, Western blot, qPCR and PCR microarray analysis were used to explore the effect of curcumin in HHPC exposed to bile (400 µmol/L) at acidic and neutral pH. Curcumin successfully inhibited the acidic bile-induced NF-κB signalling pathway (25% of analysed genes), and overexpression of NF-κB transcriptional factors, c-REL, RELA(p65), anti-apoptotic bcl-2, oncogenic TNF-α, EGFR, STAT3, WNT5A, ΔNp63 and cancer-related IL-6. Curcumin effectively reduced bile-induced bcl-2 overexpression at both acidic and neutral pH. Our novel findings suggest that, similar to pharmacologic NF-κB inhibitor, BAY 11-7082, curcumin can suppress acidic bile-induced oncogenic mRNA phenotype in hypopharyngeal cells, encouraging its future in vivo pre-clinical and clinical explorations in prevention of bile reflux-related pre-neoplastic events mediated by NF-κB.

National treatment times in oropharyngeal cancer treated with primary radiation or chemoradiation.

OBJECTIVE: To characterize treatment delays in oropharyngeal cancer treated with radiation in a national sample, identify factors associated with delays, and associate treatment delays with survival. MATERIALS AND METHODS: We included adults in the National Cancer Database treated for oropharyngeal cancer with primary radiation or chemoradiation 2010-2013. We characterized diagnosis-to-treatment initiation, radiation treatment duration, and diagnosis-to-treatment end intervals as medians. We examined delays for association with patient, tumor, and treatment characteristics and with overall survival with multivariable logistic and Cox proportional hazards regression, respectively. RESULTS: 4089 patients were included; 12% received radiation alone and 88% chemoradiation. The incidence of human papilloma virus-associated tumors was 64%. Median durations of diagnosis-to-treatment initiation, radiation duration, and diagnosis-to-treatment end were 35, 50, and 87 days, respectively. Human papilloma virus-positive tumors were linked to decreased delays in radiation treatment duration and diagnosis-to-treatment end (OR = 0.72 (0.60-0.85), p < 0.001 and OR = 0.79 (0.66-0.95), p = 0.010, respectively). Delays in radiation treatment duration and diagnosis-to-treatment end were negatively associated with overall survival (HR = 1.23 (1.03-1.47), p = 0.024 and 1.24 (1.04-1.48), p = 0.017, respectively). When examined separately, radiation duration remained associated with decreased overall survival in patients with human papilloma virus-negative (HR = 1.29 (1.03-1.63), p = 0.030) but not human papilloma virus-positive tumors (HR = 1.17 (0.89-1.54), p = 0.257). CONCLUSION: These median durations can serve as national benchmarks. Diagnosis-to-treatment end interval is associated with overall survival in all patients, and radiation treatment duration in patients with human papilloma virus-negative tumors. These intervals could be considered quality indicators for oropharyngeal squamous cell carcinoma treated with primary radiation or chemoradiation.

NF-κB inhibition reverses acidic bile-induced miR-21, miR-155, miR-192, miR-34a, miR-375 and miR-451a deregulations in human hypopharyngeal cells.

We previously demonstrated that acidic bile activates NF-κB, deregulating the expression of oncogenic miRNA markers, in pre-malignant murine laryngopharyngeal mucosa. Here, we hypothesize that the in vitro exposure of human hypopharyngeal cells to acidic bile deregulates cancer-related miRNA markers that can be reversed by BAY 11-7082, a pharmacologic NF-κB inhibitor. We repetitively exposed normal human hypopharyngeal primary cells and human hypopharyngeal keratinocytes to bile fluid (400 µmol/L), at pH 4.0 and 7.0, with/without BAY 11-7082 (20 µmol/L). We centred our study on the transcriptional activation of oncogenic miR-21, miR-155, miR-192, miR-34a, miR-375, miR-451a and NF-κB-related genes, previously linked to acidic bile-induced pre-neoplastic events. Our novel findings in vitro are consistent with our hypothesis demonstrating that BAY 11-7082 significantly reverses the acidic bile-induced oncogenic miRNA phenotype, in normal hypopharyngeal cells. BAY 11-7082 strongly inhibits the acidic bile-induced up-regulation of miR-192 and down-regulation of miR-451a and significantly decreases the miR-21/375 ratios, previously related to poor prognosis in hypopharyngeal cancer. This is the first in vitro report that NF-κB inhibition reverses acidic bile-induced miR-21, miR-155, miR-192, miR-34a, miR-375 and miR-451a deregulations in normal human hypopharyngeal cells, suggesting that acidic bile-induced events are directly or indirectly dependent on NF-κB signalling.