Comparison of margins and survival between transoral robotic surgery (TORS) and non-robotic endoscopic surgery for oropharyngeal cancer.

OBJECTIVE: To evaluate the impact of transoral robotic surgery (TORS) and non-robotic transoral endoscopic surgery on margin positivity, rates of adjuvant therapy and survival in early stage oropharyngeal squamous cell carcinoma. STUDY DESIGN: Retrospective cohort review. SUBJECTS AND METHODS: The National Cancer Database was queried to form a cohort of patients with T1-T2 N0-N1 MO oropharyngeal squamous cell carcinoma who underwent TORS or Non-robotic endoscopic surgery from 2010 to 2015. Demographics, disease characteristics and rate of positive margin and adjuvant therapy were summarized. A binary logistic regression and a cox-proportional hazard model were performed to evaluate patient demographic, disease, and treatment factors that could predict margin positivity and survival respectively. RESULTS: 1026 patients received TORS treatment while 734 patients received non-robotic endoscopic primary surgery. Non-robotic surgery was more likely to have residual tumor (31.6 % of all cases) compared to TORS procedures (13.6 % of TORS cases); p < .0001. Non-robotic surgery more frequently had non-evaluable margins at 8.1 % compared to only 1.4 % of TORS cases (p < .0001). Non-robotic cases had a significantly higher proportion of patients receiving adjuvant radiotherapy and systemic therapy compared to TORS (66.4 % vs 51.3 % for radiotherapy; p < .0001 and 33.4 % vs 22.2 % for chemotherapy; p < .0001). There was no difference in mortality between the two modalities (non-robotic vs TORS, HR 1.357, 95 % CI 0.937-1.967). CONCLUSION: TORS and non-robotic surgery may have a similar impact on survival in early-stage OPSCC, but non-robotic surgery was found to have a higher likelihood of positive margins and a higher rate of adjuvant chemoradiation therapy.

The impact of socioeconomic and geographic factors on access to transoral robotic/endoscopic surgery for early stage oropharyngeal malignancy.

OBJECTIVE: To evaluate the role of social and geographic factors on the likelihood of receiving transoral robotic surgery (TORS) or non-robotic transoral endoscopic surgery treatment in early stage oropharyngeal squamous cell carcinoma (OPSCC). MATERIALS AND METHODS: The National Cancer Database was queried to form a cohort of patients with T1-T2 N0-N1 M0 OPSCC (AJCC v.7) who underwent treatment from 2010 to 2016. Demographics, tumor characteristics, treatment type, social, and geographic factors were all collected. Univariate analysis and multivariate logistic regression were then performed. RESULTS: Among 9267 identified patients, 1774 (19.1%) received transoral robotic surgery (TORS), 1191 (12.9%) received transoral endoscopic surgery, and 6302 (68%) received radiation therapy. We found that lower cancer stage, lower comorbidity burden and HPV- positive status predicted a statistically significant increased likelihood of receiving surgery. Patients who reside in suburban or small urban areas (>1 million population), were low-to- middle income, or rely on Medicaid were less likely to receive surgery. Patients that reside in Medicaid-expansion states were more likely to receive TORS (p > .0001). Patients that reside in states that expanded Medicaid January 2014 and after were more likely to receive non-robotic transoral endoscopic surgery (p > .0001). CONCLUSIONS: Poorer baseline health, lower socioeconomic status and residence in small urban areas may act as barriers to accessing minimally invasive transoral surgery while residence in a Medicaid-expansion state may improve access. Barriers to accessing robotic surgery may be greater than accessing non-robotic surgery.

Increasing prevalence of human papillomavirus-positive oropharyngeal cancers among older adults.

BACKGROUND: The incidence of oropharyngeal squamous cell carcinoma (OPSCC) is increasing among older adults. It is unknown whether these trends can be explained by human papillomavirus (HPV) and whether HPV-related tumors remain associated with an improved prognosis among older patients. METHODS: In a retrospective study of OPSCCs diagnosed from 1995 to 2013 at 2 National Comprehensive Cancer Network-designated cancer centers, p16 immunohistochemistry and in situ hybridization (ISH) for HPV-16, high-risk DNA, and/or E6/E7 RNA were performed. The median age at diagnosis was compared by p16 and ISH tumor status. Trends in age were analyzed with nonparametric trends. Survival was analyzed with the Kaplan-Meier method and Cox proportional hazards models. RESULTS: Among 239 patients, 144 (60%) were p16-positive. During 1998-2013, the median age increased among p16-positive patients (Ptrend = .01) but not among p16-negative patients (Ptrend = .71). The median age of p16-positive patients increased from 53 years (interquartile range [IQR] in 1995-2000, 45-65 years) to 58 years (IQR for 2001-2013, 53-64 years). Among patients ≥ 65 years old, the proportion of OPSCCs that were p16-positive increased from 41% during 1995-2000 to 75% during 2007-2013 (Ptrend = .04). Among all age groups, including older patients, a p16-positive tumor status conferred improved overall survival in comparison with a p16-negative status. CONCLUSIONS: The median age at diagnosis for HPV-related OPSCC is increasing as the proportion of OPSCCs caused by HPV rises among older adults. The favorable survival conferred by an HPV-positive tumor status persists in older adults. Cancer 2018;124:2993-9. © 2018 American Cancer Society.

The prognostic role of sex, race, and human papillomavirus in oropharyngeal and nonoropharyngeal head and neck squamous cell cancer.

BACKGROUND: Human papillomavirus (HPV) is a well-established prognostic marker for oropharyngeal squamous cell cancer (OPSCC). Because of the limited numbers of women and nonwhites in studies to date, sex and racial/ethnic differences in prognosis have not been well explored. In this study, survival differences were explored by the tumor HPV status among 1) patients with OPSCCs by sex and race and 2) patients with nonoropharyngeal (non-OP) head and neck squamous cell cancers (HNSCCs). METHODS: This retrospective, multi-institution study included OPSCCs and non-OP HNSCCs of the oral cavity, larynx, and nasopharynx diagnosed from 1995 to 2012. Race/ethnicity was categorized as white non-Hispanic, black non-Hispanic, Asian non-Hispanic, and Hispanic of any race. Tumors were centrally tested for p16 overexpression and the presence of HPV by HPV16 DNA and high-risk HPV E6/E7 messenger RNA in situ hybridization. Kaplan-Meier and Cox proportional hazards models were used to evaluate overall survival (OS). RESULTS: The study population included 239 patients with OPSCC and 621 patients with non-OP HNSCC with a median follow-up time of 3.5 years. After adjustments for the tumor HPV status, age, current tobacco use, and stage, the risk of death was lower for women versus men with OPSCC (adjusted hazard ratio, 0.55; P = .04). The results were similar with p16. In contrast, for non-OP HNSCCs, HPV positivity, p16 positivity, and sex were not associated with OS. CONCLUSIONS: For OPSCC, there are differences in survival by sex, even after the tumor HPV status has been taken into account. For non-OP HNSCC, the HPV status and the p16 status are not of prognostic significance. Cancer 2017;123:1566-1575. © 2017 American Cancer Society.

A multi-institutional comparison of outcomes of immunosuppressed and immunocompetent patients treated with surgery and radiation therapy for cutaneous squamous cell carcinoma of the head and neck.

BACKGROUND: Patients who are chronically immunosuppressed have higher rates of cutaneous squamous cell carcinoma of the head and neck (cSCC-HN). This is the largest multi-institutional study to date investigating the effect of immune status on disease outcomes in patients with cSCC-HN who underwent surgery and received postoperative radiation therapy (RT). METHODS: Patients from 3 institutions who underwent surgery and also received postoperative RT for primary or recurrent, stage I through IV cSCC-HN between 1995 and 2015 were included in this institutional review board-approved study. Patients categorized as immunosuppressed had chronic hematologic malignancy, human immunodeficiency/acquired immunodeficiency syndrome, or had received immunosuppressive therapy for organ transplantation ≥6 months before diagnosis. Overall survival, locoregional recurrence-free survival, and progression-free survival were calculated using the Kaplan-Meier method. Univariate and multivariate analyses were performed using Cox proportional-hazards regression. RESULTS: Of 205 patients, 138 (67.3%) were immunocompetent, and 67 (32.7%) were immunosuppressed. Locoregional recurrence-free survival (47.3% vs 86.1%; P < .0001) and progression-free survival (38.7% vs 71.6%; P = .002) were significantly lower in immunosuppressed patients at 2 years. The 2-year OS rate in immunosuppressed patients demonstrated a similar trend (60.9% vs 78.1%; P = .135) but did not meet significance. On multivariate analysis, immunosuppressed status (hazard ratio [HR], 3.79; P < .0001), recurrent disease (HR, 2.67; P = .001), poor differentiation (HR, 2.08; P = .006), and perineural invasion (HR, 2.05; P = .009) were significantly associated with locoregional recurrence. CONCLUSIONS: Immunosuppressed patients with cSCC-HN had dramatically lower outcomes compared with immunocompetent patients, despite receiving bimodality therapy. Immune status is a strong prognostic factor that should be accounted for in prognostic systems, treatment algorithms, and clinical trial design. Cancer 2017;123:2054-2060. © 2017 American Cancer Society.

How, when, and from whom neck dissection operative technique is learned: An international survey on neck dissection education among head and neck oncologic surgeons.

BACKGROUND: There is a paucity of evidence on how neck dissection (ND) technique is best learned. METHODS: Online survey of the American Head and Neck Society (AHNS). RESULTS: 283 of the 1010 (28%) AHNS surgeon members completed the survey. Most respondents had 3-4 mentors [n=157 (55.5%)] that they felt were most influential their ND technique. 134 (47.3% of surgeons who completed a fellowship) felt that fellowship training had the most impact on their ND technique. Most respondents ranked the most effective methods of learning ND operative technique in the following order: 1) physically performing the operation yourself (70.1%), 2) observing the attending perform maneuvers independent of verbal teaching (37.7%) and 3) verbal teaching by an attending in the operating room independent of actual maneuvers (36.3%). CONCLUSION: When learning an ND, the most benefit comes from empirical learning in the context a small group of surgeon mentors.

Clinicopathologic characteristics and outcomes of recurrent oropharyngeal squamous cell carcinoma.

PURPOSE: Positive p16 immunohistochemical staining is predictive of improved survival and response to treatment. The purpose of this study is to determine the clinicopathologic characteristics and outcomes of patients with p16+ oropharynx cancer who fail initial treatment. MATERIALS AND METHODS: Case series including all patients with recurrent oropharyngeal squamous cell carcinoma from 2002 to 2014. RESULTS: Forty patients met inclusion criteria. Thirty-one (77.5%) tumors were p16+ and 9 (22.5%) were p16-. There was no difference in T/M stage at diagnosis; more patients with p16+ tumors presented initially with ≥N2 disease (p=0.04). Regional and/or metastatic recurrence was more common in the p16+ group as compared to the p16- group - 71% vs 22.2%, p=0.003. Outcomes for both groups were poor - 67.7% p16+ and 44.4% p16- patients died from disease. CONCLUSIONS: Compared to p16- recurrent tumor patients, p16+ recurrent tumor patients were more likely to experience regional or distant metastatic recurrence. Overall outcomes for both p16+ and p16- recurrent oropharynx tumors were poor.

Surveillance radiologic imaging after treatment of oropharyngeal cancer: a review.

The increasing proportion of human papilloma virus-related oropharynx cancers has led to improved success in the treatment of this disease. However, the current low recurrence rate after treatment of oropharyngeal cancer highlights the continued need for, as well as the challenges of, designing an effective follow-up surveillance program. There are frequently multiple modalities used in the treatment of oropharyngeal cancer, resulting in short- and long-term tissue changes to the head and neck that challenge clinical distinction of recurrence versus treatment-related changes. The oropharynx subsite is characterized by complex anatomy not always accessible to physical exam, making radiologic imaging a potentially useful supplement for effective follow-up assessment. In this manuscript, the literature regarding the type of radiologic imaging modality and the frequency of obtaining imaging studies in the surveillance follow-up after treatment of oropharyngeal cancer is reviewed. While ultrasound and MRI have useful characteristics that deserve further study, PET/CT appears to have the best sensitivity and specificity for imaging surveillance follow-up of head and neck cancers including oropharyngeal cancer. A negative PET/CT is particularly useful as a predictor of prognosis and can guide the clinician as to when to stop obtaining additional imaging studies in the absence of clinical signs of recurrence. However, there is scant evidence that imaging surveillance can improve survival outcomes. Suggestions to guide future imaging surveillance research studies are provided.

Sentinel node biopsy using indocyanine green in oral/oropharyngeal cancer.

BACKGROUNDS: Radioactive tracer-based detection has been proposed as a standard procedure in identifying sentinel nodes for cN0 oral/oropharyngeal carcinoma. However, access to radioactive isotopes may be limited in some surgical centers, and there is potential risk of the radioactive tracers to the operators. This study was designed to evaluate the feasibility of near-infrared fluorescence imaging with indocyanine green combined with blue dye mapping in sentinel node biopsy for cN0 oral/oropharyngeal carcinoma. METHODS: Twenty-six cases of previously untreated oral/oropharyngeal carcinoma staged cT1-2N0M0 were enrolled in this study. One milliliter of indocyanine green (5 mg/ml) and 1.5 ml of methylene blue (1 mg/ml) were injected sequentially around the primary tumor in a four-quadrant pattern before skin incision. After elevation of the platysma flap and posterior retraction of the sternocleidomastoid muscle, fluorescence images were taken with a near-infrared detector, with special attention paid to any blue-dyed lymph nodes. Lymph nodes identified first with fluorescent hot spots with or without blue dye were defined as sentinel nodes, and they were harvested and sent for pathologic study. RESULTS: Sentinel nodes were successfully harvested in all 26 cases. The number of sentinel nodes (SNs) per case varied from 1 to 9, with an average of 3.4. Routine pathology demonstrated occult metastasis exclusively in SNs in four cases (15.4 %). No tracer-associated side effects occurred in this series. CONCLUSIONS: Near-infrared imaging using indocyanine green combined with methylene blue mapping is a feasible and reliable new method for SN biopsy in cN0 oral/oropharyngeal carcinoma.

The advantages and drawbacks of routine magnetic resonance imaging for long-term post-treatment locoregional surveillance of oral cavity squamous cell carcinoma.

PURPOSE: Assess the clinical utility and accuracy of routine surveillance head and neck magnetic resonance imaging (HN-MRI) for the detection of locoregional recurrence in patients with a history of oral cavity squamous cell carcinoma (OCSCC) without concurrent suspicious symptoms or signs 6 months or more after treatment. MATERIALS AND METHODS: For OCSCC patients who underwent routine (defined as: without concurrent suspicious symptoms or signs) surveillance HN-MRI at 6 months or more after treatment completion, we retrospectively determined the detection rate of locoregional disease and false positive rate. RESULTS: Out of an original cohort of 533 OCSCC patients, 46 patients, who were disease-free 6 months after treatment, had undergone 108 routine HN-MRIs from 6 to 48 months after surgery without the presence of concurrent suspicious symptoms or signs and had 6 months of subsequent follow up. 1 out of 46 (2.2%) had a true positive regional recurrence. 10 out of 46 (21.7%) patients experienced a false positive locoregional finding. CONCLUSIONS: Routine HN-MRI for locoregional surveillance of OCSCC, when used in patients without concurrent suspicious symptoms or exam findings over 6 months since treatment, may be unnecessary and costly given the very low rate of recurrence and high false positive rate. Our study supports the National Comprehensive Cancer Network guideline of limiting imaging after 6 months of primary treatment completion to patients with suspicious clinical findings. Nonetheless, managing physicians should continue to be empowered to use surveillance imaging based on risk profiles and unique circumstances for each patient.

The Limitations of Routine Magnetic Resonance Imaging for Long-Term Post-Treatment Locoregional Surveillance of Salivary Carcinoma.

BACKGROUND/AIMS: To determine the utility of head and neck magnetic resonance imaging (HN-MRI) for the routine surveillance of patients without concurrent symptoms or signs of recurrence more than 6 months after treatment for salivary gland carcinoma (SGC). METHODS: This is a retrospective single-institution review of SGC patients from 2000 to 2011 who underwent one or more HN-MRI scans without concurrent suspicious symptoms or signs of recurrence more than 6 months after the completion of treatment, with at least 6 months of follow-up after each scan. RESULTS: Out of an original 283 SGC patients treated surgically, 41 patients, who were disease free 6 months after treatment, had undergone 96 routine HN-MRIs without concurrent suspicious symptoms or signs. Ten out of the 41 patients (24%) experienced a false-positive finding with routine HN-MRI. None of the 96 HN-MRIs demonstrated a true-positive or false-negative finding. CONCLUSION: More than 6 months after treatment, routine HN-MRI for the detection of locoregional recurrence of SGC has a low utility in patients without concurrent suspicious symptoms or signs. While these data support the judicious use of routine HN-MRIs, the managing physician should ultimately decide on the best course of surveillance for an individual patient based on the unique risk factors and circumstances present.

Rare complication after thyroidectomy-cervical esophageal stenosis: a case report and literature review.

The most common complications after thyroidectomy are injuries associated with the recurrent laryngeal nerve and parathyroid gland. Cervical esophagus perforation is an exceptionally rare complication after thyroidectomy; it can usually be resolved by conservative care. Cervical esophageal stenosis secondary to intraoperative esophageal injury during thyroidectomy is much rarer and has not been reported in the literature to date. We report a case of esophageal stenosis following thyroidectomy performed at a peripheral hospital. The patient initially underwent a thyroidectomy for papillary thyroid carcinoma involving the cervical esophagus; esophageal perforation was noted intraoperatively, and closed using three number 4 silk sutures. Cervical esophageal stenosis subsequently developed after conservative care. The patient was successfully treated with cervical esophagectomy and reconstruction using a tubed forearm free flap after a failed attempt at endoscopic recanalization. This case is discussed in conjunction with a review of the literature.

Oral cavity squamous cell carcinoma in never smokers: analysis of clinicopathologic characteristics and survival.

PURPOSE: To examine the relationship between tobacco smoking history and the clinicopathologic and survival characteristics of patients with oral cavity squamous cell carcinoma (OCSCC). MATERIALS AND METHODS: This is a retrospective review of 531 patients treated for OCSCC from January 1998 to December 2009 at a tertiary care medical center. RESULTS: Thirty-two percent of OCSCC patients were never smokers. There were significant differences in tumor location between ever smokers and never smokers (p<0.001), with never smokers more likely to have oral tongue tumors. Smokers were significantly (p<0.001) more likely than never smokers to present with locally advanced (T3 or T4) disease (57.8% vs. 35.4%). Never smokers demonstrated improved overall survival (78.8 months in never smokers vs. 44.7 months in ever smokers, p=.03). However, there were no survival differences when the two groups were compared separately for locally early (T1/T2) or advanced (T3/T4) disease. For T1/T2 tumors, mean survival was 88.2 months for never smokers and 78.5 months for smokers (p=.10). For T3/T4 tumors, median survival was 29.1 months for never smokers and 23.8 months for smokers (p=.09). CONCLUSIONS: Primary tumor location and T-status in OCSCC differed between never smokers and smokers. Compared to smokers, never smokers had fewer locally advanced tumors and better overall survival.

American Head and Neck Society position statement on the use of PD-1 inhibitors for treatment of advanced cutaneous squamous cell carcinoma.

BACKGROUND: A position statement put forth by the American Head and Neck Society (AHNS) was constructed to provide evidence-based treatment recommendations for PD-1 inhibitor use in advanced cutaneous squamous cell carcinoma (cSCC). Secondarily, we sought to identify knowledge gaps warranting further investigation. METHODS: A literature search utilizing key terms: cutaneous squamous cell carcinoma, cutaneous cancer, checkpoint inhibitors, systemic therapy, Program Cell Death, PD-1 (PubMed, Cochrane, and Google Scholar) was carried out to generate evidence-based statements. The statements were distributed among the AHNS membership. Delphi methodology was applied to identify statements achieving 70% or greater consensus among the leadership team. RESULTS: Twenty-six position statements achieved consensus. Knowledge gaps for future research included: impact of immunosuppression on cSCC staging and associated treatment; role of PD-1 inhibitors in immunosuppressed patients. CONCLUSION: This comprehensive position statement put forth by the AHNS represents majority consensus by practicing head and neck surgeons throughout the country.

Role of hyaluronan-mediated CD44 signaling in head and neck squamous cell carcinoma progression and chemoresistance.

Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy that may involve the oral cavity, pharynx, larynx, and paranasal sinuses. The mechanisms of tumor progression underlying the clinical behavior of HNSCC remain unclear. CD44 comprises a family of transmembrane receptors that can give rise to multiple CD44 variant isoforms. Hyaluronan (HA), a major extracellular matrix component is the primary ligand for CD44 receptors. HA and CD44 signaling play an important role in HNSCC progression. Several CD44 variant isoforms (including v3-, v6-, and v10-containing isoforms) are associated with advanced disease, possibly through unique growth factor interactions with binding domains in the inserted variant regions of the cytoplasmic domain of CD44. In HNSCC, HA mediates the formation of a complex including CD44 and the epidermal growth factor receptor (EGFR) which is overexpressed in a large proportion of HNSCCs. Downstream effectors under EGFR regulation are activated, promoting promote cell growth and tumor survival. The leukemia-associated Rho-guanine nucleotide exchange factor (LARG) also associates with CD44 and EGFR to promote several Ras and RhoA pathway effectors, leading to cell migration, growth, and tumor survival. The secretion of matrix metalloproteinases, necessary for tumor cell invasion, is also regulated by these HA/CD44-mediated pathways. Finally, EGFR-mediated pathways play major roles in the HA/CD44 promotion of chemoresistance in HNSCC. Understanding HA/CD44-mediated signaling pathways may lead to improved treatment of HNSCC.

Identification, optimisation and in vivo evaluation of oxadiazole DGAT-1 inhibitors for the treatment of obesity and diabetes.

A novel series of DGAT-1 inhibitors was discovered from an oxadiazole amide high throughput screening (HTS) hit. Optimisation of potency and ligand lipophilicity efficiency (LLE) resulted in a carboxylic acid containing clinical candidate 53 (AZD3988), which demonstrated excellent DGAT-1 potency (0.6 nM), good pharmacokinetics and pre-clinical in vivo efficacy that could be rationalised through a PK/PD relationship.

Parotidectomy--Anatomical considerations.

The parotid glands are paired major salivary glands and are located in the preauricular region. Parotidectomy is a surgical procedure that entails removal of all or a portion of the parotid gland. The most common indications for this operative procedure are a neoplasm of the parotid gland or metastases to parotid lymph nodes. An intimate knowledge of the anatomy of the parotid gland and related structures is necessary for the performance of safe and successful parotid surgery. This report will discuss the anatomy of the parotid gland as it pertains to parotid surgery and the avoidance of complications related to this surgery.

Association of Perioperative Complications with Vitamin D Levels in Major Head and Neck Surgery.

OBJECTIVES/HYPOTHESIS: To investigate the association of vitamin D level and perioperative complications in patients undergoing major head and neck surgery. STUDY DESIGN: Retrospective Cohort Study. METHODS: A retrospective chart review was performed for all patients undergoing reconstructive head and neck surgery between December 2017 and December 2019. Data regarding patient demographics, serum 25-hydroxyvitamin D (calcidiol) level, hospital course, prior radiation, and fistula formation were collected. Patients were categorized by serum calcidiol level as deficient (<20 ng/mL) or sufficient (≧20 ng/mL) and outcomes were compared between groups. RESULTS: Fifty-seven patients were included in the analysis. Average age at time of surgery was 62.6 ± 10.6 years. Patients with vitamin D levels <20 ng/mL were considered deficient and ≧20 ng/mL were considered sufficient. Individuals in the deficient group (n = 29) had a mean serum calcidiol level of 13.95 ± 3.95 ng/mL, whereas those in the sufficient group (n = 28) had a mean calcidiol level of 28.53 ± 5.73 ng/mL. The rate of fistula was 41.4% in the deficient group, whereas patients in the sufficient group had a rate of fistula of 14.3% (P = .038). On multivariate analysis, higher serum calcidiol level above 20 ng/mL was associated with a lower likelihood of developing fistulae with an odds ratio 0.830 (95% confidence interval: 0.718-0.960, P = .012). CONCLUSION: Vitamin D deficiency may play a role in development of fistula after major head and neck surgery. LEVEL OF EVIDENCE: 4 Laryngoscope, 132:578-583, 2022.

Impact of Close Margins in Head and Neck Mucosal Squamous Cell Carcinoma: A Systematic Review.

OBJECTIVES/HYPOTHESIS: The aim of the study is to investigate whether close surgical margins impact oncologic outcomes compared to clear or involved surgical margins. We hypothesize that close surgical margins portend worse outcomes compared with clear margins, but improved outcomes compared with involved margins. STUDY DESIGN: Systematic review. METHODS: Using the Preferred Reporting Items for Systematic Reviews and Meta-analysis statement standards, a systematic search was conducted for studies that reported oncologic outcomes following excision of primary mucosal head and neck squamous cell carcinoma (HNSCC). A meta-analysis was then performed, comparing local recurrence (LR), locoregional recurrence (LRR), and overall survival (OS) in patients with clear, close, and involved margins. RESULTS: Twenty-six studies met the inclusion criteria, totaling 8,435 patients. About 96% of our included cases involved the oral cavity, 2% involved the oropharynx, and 2% other. Also, 68% of cases were T1/T2 and 32% were T3/T4. On meta-analysis, clear margins were associated with lower incidence of 5-year LR relative risk (RR) 0.50, 95% confidence interval [CI] 0.38-0.65) and higher 5-year OS (RR 1.22, 1.11-1.35), when compared with close margins. Involved margins had higher incidence of 5-year LR (RR 1.75, 1.16-2.64), higher incidence of LRR at last follow-up (RR 1.66, 1.37-2.00), and no difference in 5-year OS (RR 0.82, 0.60-1.11), when compared with close margins. CONCLUSIONS: There is a stepwise improvement in oncologic outcomes as surgical margin categorically improves from involved to close to clear. Patients with close margins therefore may benefit from adjuvant therapy. Further research is required to investigate whether these findings are seen in non-oral cavity cases because they were underrepresented in this analysis. Laryngoscope, 132:307-321, 2022.

STAT3 Activation as a Predictive Biomarker for Ruxolitinib Response in Head and Neck Cancer.

PURPOSE: Increased activity of STAT3 is associated with progression of head and neck squamous cell carcinoma (HNSCC). Upstream activators of STAT3, such as JAKs, represent potential targets for therapy of solid tumors, including HNSCC. In this study, we investigated the anticancer effects of ruxolitinib, a clinical JAK1/2 inhibitor, in HNSCC preclinical models, including patient-derived xenografts (PDX) from patients treated on a window-of-opportunity trial. EXPERIMENTAL DESIGN: HNSCC cell lines were treated with ruxolitinib, and the impact on activated STAT3 levels, cell growth, and colony formation was assessed. PDXs were generated from patients with HNSCC who received a brief course of neoadjuvant ruxolitinib on a clinical trial. The impact of ruxolitinib on tumor growth and STAT3 activation was assessed. RESULTS: Ruxolitinib inhibited STAT3 activation, cellular growth, and colony formation of HNSCC cell lines. Ruxolitinib treatment of mice bearing an HNSCC cell line-derived xenograft significantly inhibited tumor growth compared with vehicle-treated controls. The response of HNSCC PDXs derived from patients on the clinical trial mirrored the responses seen in the neoadjuvant setting. Baseline active STAT3 (pSTAT3) and total STAT3 levels were lower, and ruxolitinib inhibited STAT3 activation in a PDX from a patient whose disease was stable on ruxolitinib, compared with a PDX from a patient whose disease progressed on ruxolitinib and where ruxolitinib treatment had minimal impact on STAT3 activation. CONCLUSIONS: Ruxolitinib exhibits antitumor effects in HNSCC preclinical models. Baseline pSTAT3 or total STAT3 levels in the tumor may serve as predictive biomarkers to identify patients most likely to respond to ruxolitinib.