Antibodies that block T-cell-regulatory checkpoints have recently emerged as a transformative approach to cancer treatment. However, the clinical efficacy of checkpoint blockade depends upon inherent tumor immunogenicity, with variation in infiltrating T cells contributing to differences in objective response rates. Here, we sought to understand the molecular correlates of tumor-infiltrating T lymphocytes (TIL) in squamous cell carcinoma (SCC), using a systems biologic approach to integrate publicly available omics datasets with histopathologic features. We provide evidence that links TIL abundance and therapeutic outcome to the regulation of tumor glycolysis by EGFR and HIF, both of which are attractive molecular targets for use in combination with immunotherapeutics. Cancer Res; 76(14); 4136-48. Ó2016 AACR.

Background Metabolic changes in tumour cells are used in clinical imaging and may provide potential therapeutic targets. Human papillomavirus (HPV) status is important in classifying head and neck cancers (HNSCC), identifying a distinct clinical phenotype; metabolic differences between these HNSCC subtypes remain poorly understood. Methods We used RNA sequencing to classify the metabolic expression profiles of HPV +ve and HPV −ve HNSCC, performed a meta-analysis on FDG-PET imaging characteristics and correlated results with in vitro extracellular flux analysis of HPV −ve and HPV +ve HNSCC cell lines. The monocarboxylic acid transporter-1 (MCT1) was identified as a potential metabolic target and tested in functional assays. Results Specific metabolic profiles were associated with HPV status, not limited to carbohydrate metabolism. There was dominance of all energy pathways in HPV-negative disease, with elevated expression of genes associated with glycolysis and oxidative phosphorylation. In vitro analysis confirmed comparative increased rates of oxidative phosphorylation and glycolysis in HPV-negative cell lines. PET SUV(max) scores however were unable to reliably differentiate between HPV-positive and HPV-negative tumours. MCT1 expression was significantly increased in HPV-negative tumours, and inhibition suppressed tumour cell invasion, colony formation and promoted radiosensitivity. Conclusion HPV-positive and negative HNSCC have different metabolic profiles which may have potential therapeutic applications.

This study is the first reported study of a high-fidelity microlaryngoscopy simulator with task-specific rating tools. Use of these tools is recommended within otolaryngology training programs, with the global rating assessment for use as a frequently used feedback tool, and the checklist assessment as a confirmatory evaluation of competency at transitions of professional training.

Summary The sites of tumour development for 6 rat tumours injected into syngeneic rats via different vascular routes was determined. Xenografts of human tumours were also injected intra-arterially (i.a.) into immunosuppressed rats.Following intravenous (i.v.) In explaining the mechanism of site selectivity by bloodborne metastasis the haemodynamic theory of Ewing (1928) stressed the importance of the mechanics of the circulation whereas the Soil/Seed hypothesis of Paget (1889) emphasized the importance of the environment in which the trapped emboli found themselves. The eventual sites of metastasis are, however, determined by both haemodynamic and soil/seed factors. Haemodynamic factors are important following the venous discharge of tumour cells since the 'organs of first encounter' are the commonest site for bloodborne metastasis -the lung after systemic venous discharge of tumour cells and the liver after portal venous discharge (Viadana et al., 1978). The present study emphasizes that the 'soil' becomes important when tumour cells have entered the systemic arterial circulation and are thereby delivered to all organs. Clinically this situation can occur when cells are released from primary or secondary lung tumours or possibly when cells released into the venous circulation manage to traverse the lung capillaries.In this paper we extend earlier data (Murphy et al., 1986) on the pattern of spread of rat syngeneic non-lymphoid and non-haemopoietic tumours following intravenous (i.v.), intraportal (i.ptl.) and intra-arterial (i.a.) injection. In our i.v. and i.ptl. studies as well as previously reported studies tumour growth is essentially limited to the 'organs of first encounter' and the study of mechanisms of site selectivity is therefore limited. In order to deliver tumour cells to all organs we have injected them intra-arterially via the intracardiac (i.c.) route. Labelled cell distribution after i.c. injection has been compared with the distribution of cardiac output (measured using the microsphere technique) in order to establish whether cells disseminate and arrest passively or whether they recirculate and localise in certain organs. The 'arterial pattern' of tumour growth after unlabelled cell injection has then been compared with the arterial distribution of labelled tumour cells to establish and quantitate the 'soil effect'.Having established a 'soil effect' after arterial injection of tumour cells we have attempted to determine the mechanisms using several approaches. Firstly a correlation of site selectivity with organ vascularity (using data obtained from the microsphere studies) was sought since there have been reports that more vascular organs might be more susceptible to metastasis (Weiss et al., 1981). Secondly the rate of autolysis of trapped labelled cells in different organs has been compared with the organs susceptibility to tumour growth. Thirdly we have intervened pharmacologically to see if site preference can be altered and finally we have rendered refractory organs susceptible to tum...

Video assessment of myringotomy and ventilation tube insertion may represent a valid, feasible tool for use in summative and formative assessments of trainee ENT surgeons. Remote scoring of assessment procedures minimises bias and enables blinding of raters. ENT is well positioned to benefit from video assessment due to the high number of surgical procedures within the specialty that are performed utilising digital technology.

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Objectives Sinonasal mucosal melanoma (SNMM) is an extremely rare and challenging sinonasal malignancy with a poor prognosis. Standard treatment involves complete surgical resection, but the role of adjuvant therapy remains unclear. Crucially, our understanding of its clinical presentation, course, and optimal treatment remains limited, and few advancements in improving its management have been made in the recent past. Methods We conducted an international multicenter retrospective analysis of 505 SNMM cases from 11 institutions across the United States, United Kingdom, Ireland, and continental Europe. Data on clinical presentation, diagnosis, treatment, and clinical outcomes were assessed. Results One-, three-, and five-year recurrence-free and overall survival were 61.4, 30.6, and 22.0%, and 77.6, 49.2, and 38.3%, respectively. Compared with disease confined to the nasal cavity, sinus involvement confers significantly worse survival; based on this, further stratifying the T3 stage was highly prognostic (p < 0.001) with implications for a potential modification to the current TNM staging system. There was a statistically significant survival benefit for patients who received adjuvant radiotherapy, compared with those who underwent surgery alone (hazard ratio [HR] = 0.74, 95% confidence interval [CI]: 0.57–0.96, p = 0.021). Immune checkpoint blockade for the management of recurrent or persistent disease, with or without distant metastasis, conferred longer survival (HR = 0.50, 95% CI: 0.25–1.00, p = 0.036). Conclusions We present findings from the largest cohort of SNMM reported to date. We demonstrate the potential utility of further stratifying the T3 stage by sinus involvement and present promising data on the benefit of immune checkpoint inhibitors for recurrent, persistent, or metastatic disease with implications for future clinical trials in this field.