What is the role of the surgeon in the management of head and neck mucosal melanoma in the immunotherapy era?

INTRODUCTION: The advent of immunotherapy has impacted both the management and, to a lesser extent, the outcomes for patients with head and neck mucosal melanoma. As a consequence, one might expect that the role of the surgeon would be limited to the diagnostic work-up and that systemic therapies would be the mainstay of treatment. METHODS AND RESULTS: Here, we present the surgical aspects of the recently published United Kingdom Head and Neck Mucosal Melanoma Guideline to highlight the continued role of surgeons in the management of this disease. We highlight key areas where surgeons remain the lead clinician and reinforce the multidisciplinary requirement for exemplary patient care. CONCLUSIONS: Despite the advent of immunotherapy, surgeons continue to have a key role to play in this disease. When indicated, it is essential that appropriate surgery is offered by a suitably experienced team.

Delayed Post-Operative Subcutaneous Emphysema.

The authors present the case of an 87-year-old woman who developed a delayed onset of subcutaneous emphysema post-operatively. We discuss the causative factors - in this case, presumed injury to her hypo-pharynx during a reportedly uneventful endotracheal intubation, the investigations and the management of this rare complication.

Head and neck mucosal melanoma: The United Kingdom national guidelines.

The United Kingdom head and neck mucosal melanoma guideline development group used an evidence-based systematic approach to make recommendations in key areas of uncertainty in the field, including accurate diagnosis and staging; the appropriate treatment pathway including surgery, adjuvant radiation and new systemic treatments, such as targeted agents and immunotherapy; and the surveillance of patients after treatment. The guidelines were sent for international peer review and have been accredited by the National Institute for Health and Care Excellence. A summary of key recommendations is presented. The full documents are available on the Melanoma Focus website (https://melanomafocus.com/activities/mucosal-guidelines/mucosal-melanoma-resources/).

A Systematic Review on Outcomes of Anterior Skull Base Reconstruction.

INTRODUCTION: Anterior skull base resection often results in large defects that need to be reconstructed. This can be done using loco-regional, free flaps or both. OBJECTIVE: The aim of this systematic review is to evaluate the surgical outcomes (mortality, complication rates and functional outcomes) for patients undergoing anterior skull base reconstruction. METHODS: Electronic databases (MEDLINE, EMBASE and Scopus) were systematically searched for relevant articles from 1974 to March 2018. A total of 41 studies were included in this systematic review. No randomized controlled trials were identified; therefore, a meta-analysis was not performed. RESULTS: Mortality from anterior skull base reconstruction were about 0-4% for loco-regional flaps while free flaps were around 0-7%. Overall complications ranged from 0% to 43% in loco-regional flaps, while rate of complications for free flaps ranged from 25% to 66.7%. Flap complications ranged from 0% to 14% for free flaps and 0% to 35% for local flaps. Quality-of-life measures did not differ significantly depending on surgical approach but were worse for patients with malignancies. CONCLUSION: Due to varying standards of reporting of outcomes, lack of a standardized classification system for anterior skull base defects and absence of clinical trials, we were unable to perform a meta-analysis in this systematic review. Recommendations to guide future studies are proposed.

Phase II trial of sorafenib in advanced salivary adenoid cystic carcinoma of the head and neck.

BACKGROUND: There is a need to improve the systemic treatment of advanced adenoid cystic carcinoma (ACC). Response rates to chemotherapy are poor and preliminary investigations of molecularly targeted agents have been disappointing. In this study, we evaluate sorafenib, an oral multikinase inhibitor, which has an attractive targeting profile for this disease. METHODS: In a single-arm phase II trial, patients with unresectable locally recurrent and/or metastatic ACC were treated with sorafenib 400 mg bid. RESULTS: Twenty-three patients, median age 51 years, were recruited from 2009 to 2011. Median progression-free survival (PFS) and overall survival (OS) were 11.3 and 19.6 months, respectively. PFS at 6 and 12 months were 69.3% and 46.2%, respectively. Sorafenib was only reasonably well tolerated, and 13 patients (57%) experienced grade 3 toxicity. CONCLUSION: Sorafenib showed modest activity in ACC with a 12-month PFS of 46.2%. Sorafenib 400 mg bid was associated with significant toxicity and, taken together with limited effectiveness, cannot be enthusiastically recommended for further evaluation.

Prognostic significance of tumor hypoxia inducible factor-1alpha expression for outcome after radiotherapy in oropharyngeal cancer.

PURPOSE: Head-and-neck squamous cell carcinoma (HNSCC) represents a heterogeneous group of patients in terms of subsite, treatment, and biology. Currently most management decisions are based on clinical parameters with little appreciation of patient differences in underlying tumor biology. We investigated the prognostic significance of clinicopathologic features and tumor hypoxia-inducible factor-1alpha (HIF-1alpha) expression in a homogeneous series of patients who underwent radiotherapy. METHODS AND MATERIALS: An audit identified 133 consecutive patients with histologically proven squamous cell carcinoma of the tonsil or tongue base. All patients received primary radiotherapy between 1996 and 2001. Tumor HIF-1alpha expression was examined in 79 patients. RESULTS: Features associated with poor locoregional control were low Hb level (p = 0.05) and advancing T (p = 0.008), N (p = 0.03), and disease (p = 0.008) stage. HIF-1alpha expression was a more significant adverse prognostic factor in the tonsil (hazard ratio [HR], 23.1; 95% confidence interval [CI]. 3.04-176.7) than the tongue-base tumor (HR, 2.86; 95% CI, 1.14-7.19) group (p = 0.03, test for interaction). High tumor HIF-1alpha expression was associated with low blood Hb levels (p = 0.03). In a multivariate analysis HIF-1alpha expression retained prognostic significance for locoregional control (HR, 7.10; 95% CI, 3.07-16.43) and cancer-specific survival (HR, 9.19; 95% CI, 3.90-21.6). CONCLUSIONS: There are significant differences in radiation therapy outcome within a homogeneous subsite of the oropharynx related to molecular marker expression. The work highlights the importance of studying homogeneous groups of patients in HNSCC, and the complex interrelationships between tumor biology and clinicopathologic factors. The establishment of tumor-type specific markers would represent a major advance in this area.

Tumor expression of major vault protein is an adverse prognostic factor for radiotherapy outcome in oropharyngeal carcinoma.

PURPOSE: Vaults are multi-subunit structures that may be involved in nucleo-cytoplasmic transport, with the major vault protein (MVP or lung resistance-related protein [LRP]) being the main component. The MVP gene is located on chromosome 16 close to the multidrug resistance-associated protein and protein kinase c-beta genes. The role of MVP in cancer drug resistance has been demonstrated in various cell lines as well as in ovarian carcinomas and acute myeloid leukemia, but nothing is known about its possible role in radiation resistance. Our aim was to examine this in head-and-neck squamous cell carcinoma (HNSCC). METHODS AND MATERIALS: Archived biopsy material was obtained for 78 patients with squamous cell carcinoma of the oropharynx who received primary radiotherapy with curative intent. Immunohistochemistry was used to detect MVP expression. Locoregional failure and cancer-specific survival were estimated using cumulative incidence and Cox multivariate analyses. RESULTS: In a univariate and multivariate analysis, MVP expression was strongly associated with both locoregional failure and cancer-specific survival. After adjustment for disease site, stage, grade, anemia, smoking, alcohol, gender, and age, the estimated hazard ratio for high MVP (2/3) compared with low (0/1) was 4.98 (95% confidence interval, 2.17-11.42; p = 0.0002) for locoregional failure and 4.28 (95% confidence interval, 1.85-9.95; p = 0.001) for cancer-specific mortality. CONCLUSION: These data are the first to show that MVP may be a useful prognostic marker associated with radiotherapy resistance in a subgroup of patients with HNSCC.

Relation of a hypoxia metagene derived from head and neck cancer to prognosis of multiple cancers.

Affymetrix U133plus2 GeneChips were used to profile 59 head and neck squamous cell cancers. A hypoxia metagene was obtained by analysis of genes whose in vivo expression clustered with the expression of 10 well-known hypoxia-regulated genes (e.g., CA9, GLUT1, and VEGF). To minimize random aggregation, strongly correlated up-regulated genes appearing in >50% of clusters defined a signature comprising 99 genes, of which 27% were previously known to be hypoxia associated. The median RNA expression of the 99 genes in the signature was an independent prognostic factor for recurrence-free survival in a publicly available head and neck cancer data set, outdoing the original intrinsic classifier. In a published breast cancer series, the hypoxia signature was a significant prognostic factor for overall survival independent of clinicopathologic risk factors and a trained profile. The work highlights the validity and potential of using data from analysis of in vitro stress pathways for deriving a biological metagene/gene signature in vivo.