Olfactory neuroblastoma (ONB) is a rare cancer of the sinonasal region. We provide a comprehensive analysis of this malignancy with molecular and clinical trial data on a subset of our cohort to ...report on the potential efficacy of somatostatin receptor 2 (SSTR2)-targeting imaging and therapy.
We conducted a retrospective analysis of 404 primary, locally recurrent, and metastatic olfactory neuroblastoma (ONB) patients from 12 institutions in the United States of America, United Kingdom and Europe. Clinicopathological characteristics and treatment approach were evaluated. SSTR2 expression, SSTR2-targeted imaging and the efficacy of peptide receptor radionuclide therapy PRRT(177Lu-DOTATATE) were reported in a subset of our cohort (LUTHREE trial; NCT03454763).
Dural infiltration at presentation was a significant predictor of overall survival (OS) and disease-free survival (DFS) in primary cases (n = 278). Kadish-Morita staging and Dulguerov T-stage both had limitations regarding their prognostic value. Multivariable survival analysis demonstrated improved outcomes with lower stage and receipt of adjuvant radiotherapy. Prophylactic neck irradiation significantly reduces the rate of nodal recurrence. 82.4% of the cohort were positive for SSTR2; treatment of three metastatic cases with SSTR2-targeted peptide-radionuclide receptor therapy (PRRT) in the LUTHREE trial was well-tolerated and resulted in stable disease (SD).
This study presents pertinent clinical data from the largest dataset, to date, on ONB. We identify key prognostic markers and integrate these into an updated staging system, highlight the importance of adjuvant radiotherapy across all disease stages, the utility of prophylactic neck irradiation and the potential efficacy of targeting SSTR2 to manage disease.
•Dural infiltration is prognostic and integrated into the Kadish-INSICA staging system (International Network for Sinonasal Cancer and Skull Base Tumours (www.insica.org).•Adjuvant radiotherapy is beneficial across all stage groups, including early stage.•Prophylactic neck irradiation prevents neck nodal recurrence.•82.4% express Somatostatin Receptor 2 (SSTR2) protein which can be used for SSTR2-targeted imaging.•SSTR2-targeted peptide receptor radionuclide therapy is useful in metastatic disease.
•HPV status will play an increasingly important role in the management of HNSCC.•p16INK4A (p16) is routinely used as the biomarker for diagnosis of HPV(+) HNSCC.•p16INK4A (p16) is frequently ...upregulated in HPV(−) non-oropharyngeal HNSCC.•Tumours with high levels of wild-type p16 are enriched for mutations in NSD1.•Alternative HPV biomarkers are required for HPV-driven non-oropharyngeal HNSCC.
p16INK4A (p16) is the most widely used clinical biomarker for Human Papillomavirus (HPV) in head and neck squamous cell cancer (HNSCC). HPV is a favourable prognostic marker in HNSCC and is used for patient stratification. While p16 is a relatively accurate marker for HPV within the oropharynx, recent reports suggest it may be unsuitable for use in other HNSCC subsites, where a smaller proportion of tumors are HPV-driven.
We integrated reverse phase protein array (RPPA) data for p16 with HPV status based on detection of viral transcripts by RNA-seq in a set of 210 HNSCCs profiled by The Cancer Genome Atlas project. Samples were queried for alterations in CDKN2A, and other pathway genes to investigate possible drivers of p16 expression.
While p16 levels as measured by RPPA were significantly different by HPV status, there were multiple HPV (−) samples with similar expression levels of p16 to HPV (+) samples, particularly at non-oropharyngeal subsites. In many cases, p16 overexpression in HPV (−) tumors could not be explained by mutation or amplification of CDKN2A or by RB1 mutation. Instead, we observed enrichment for inactivating mutations in the histone H3 lysine 36 methyltransferase, NSD1 in HPV (−)/p16-high tumors.
RPPA data suggest high p16 protein expression in many HPV (−) non-oropharyngeal HNSCCs, limiting its potential utility as an HPV biomarker outside of the oropharynx. HPV-independent overexpression of wild-type p16 in non-oropharyngeal HNSCC may be linked to global deregulation of chromatin state by inactivating mutations in NSD1.
Human papillomavirus positive (HPV+) head and neck squamous cell carcinoma (HNSCC) is an emerging disease, representing a distinct clinical and epidemiological entity. Understanding the genetic basis ...of this specific subtype of cancer could allow therapeutic targeting of affected pathways for a stratified medicine approach.
Twenty HPV+ and 20 HPV- laser-capture microdissected oropharyngeal carcinomas were used for paired-end sequencing of hybrid-captured DNA, targeting 3,230 exons in 182 genes often mutated in cancer. Copy number alteration (CNA) profiling, Sequenom MassArray sequencing and immunohistochemistry were used to further validate findings.
HPV+ and HPV- oropharyngeal carcinomas cluster into two distinct subgroups. TP53 mutations are detected in 100% of HPV negative cases and abrogation of the G1/S checkpoint by CDKN2A/B deletion and/or CCND1 amplification occurs in the majority of HPV- tumors.
These findings strongly support a causal role for HPV, acting via p53 and RB pathway inhibition, in the pathogenesis of a subset of oropharyngeal cancers and suggest that studies of CDK inhibitors in HPV- disease may be warranted. Mutation and copy number alteration of PI3 kinase (PI3K) pathway components appears particularly prevalent in HPV+ tumors and assessment of these alterations may aid in the interpretation of current clinical trials of PI3K, AKT, and mTOR inhibitors in HNSCC.
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.
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.
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 (
< 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,
= 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,
= 0.036).
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.
Human papillomavirus-positive (HPV+) head and neck squamous cell carcinoma (HNSCC) represents a distinct clinical and epidemiological condition compared with HPV-negative (HPV-) HNSCC. To test the ...possible involvement of epigenetic modulation by HPV in HNSCC, we conducted a genome-wide DNA-methylation analysis.
Using laser-capture microdissection of 42 formalin-fixed paraffin wax-embedded (FFPE) HNSCCs, we generated DNA-methylation profiles of 18 HPV+ and 14 HPV- samples, using Infinium 450 k BeadArray technology. Methylation data were validated in two sets of independent HPV+/HPV- HNSCC samples (fresh-frozen samples and cell lines) using two independent methods (Infinium 450 k and whole-genome methylated DNA immunoprecipitation sequencing (MeDIP-seq)). For the functional analysis, an HPV- HNSCC cell line was transduced with lentiviral constructs containing the two HPV oncogenes (E6 and E7), and effects on methylation were assayed using the Infinium 450 k technology.
Unsupervised clustering over the methylation variable positions (MVPs) with greatest variation showed that samples segregated in accordance with HPV status, but also that HPV+ tumors are heterogeneous. MVPs were significantly enriched at transcriptional start sites, leading to the identification of a candidate CpG island methylator phenotype in a sub-group of the HPV+ tumors. Supervised analysis identified a strong preponderance (87%) of MVPs towards hypermethylation in HPV+ HNSCC. Meta-analysis of our HNSCC and publicly available methylation data in cervical and lung cancers confirmed the observed DNA-methylation signature to be HPV-specific and tissue-independent. Grouping of MVPs into functionally more significant differentially methylated regions identified 43 hypermethylated promoter DMRs, including for three cadherins of the Polycomb group target genes. Integration with independent expression data showed strong negative correlation, especially for the cadherin gene-family members. Combinatorial ectopic expression of the two HPV oncogenes (E6 and E7) in an HPV- HNSCC cell line partially phenocopied the hypermethylation signature seen in HPV+ HNSCC tumors, and established E6 as the main viral effector gene.
Our data establish that archival FFPE tissue is very suitable for this type of methylome analysis, and suggest that HPV modulates the HNSCC epigenome through hypermethylation of Polycomb repressive complex 2 target genes such as cadherins, which are implicated in tumor progression and metastasis.
Background: Thyroid storm is a rare but life-threatening emergency that prompts urgent intervention to halt its potentially disastrous outcomes. There is not much literature available on thyroid ...storm in head neck trauma and non-thyroid/parathyroid head neck surgery. Due to rarity of thyroid storm in head and neck trauma/surgery patients, its diagnosis becomes challenging, is often misdiagnosed and causes delay in the diagnosis and management. Therefore, the aim of this work was to compile, analyze and present details to develop a consensus and augment available literature on thyroid storm in this group of patients. Materials and methods: A comprehensive literature search of the last 30 years was performed on PUBMED/MEDLINE, EMBASE, CINAHL and Science Citation Index for thyroid storm using MeSH words and statistical analyses were performed. Results: Seven articles describing seven cases of thyroid storm were reviewed. All patients required medical management and one patient (14.3%) required adjunctive surgical management. Burch and Wartofsky Diagnostic criteria for thyroid storm were used in diagnosis of 42% patients. Time of diagnosis varied from immediately upon presentation to formulating a retrospective diagnosis of having a full-blown thyroid storm at 4 days post presentation. It was misdiagnosed and unthought of initially in majority of these cases, (71.4%) were not diagnosed in the first day of hospital stay. Conclusion: Early recognition of thyroid storm in head and neck patients markedly reduce morbidity/mortality. Albeit unexpected, it should be ruled out in any symptomatic head and neck trauma or post-surgery patient.
Thyroid storm is most commonly caused by underlying Grave's disease, a solitary toxic nodule or toxic thyroid goiter. Although hypothyroidism is a recognised complication of head and neck cancer ...treatment 3,4, thyrotoxicosis is rare. To date there are no reported cases in literature of thyroid storm following head and neck surgery. We report a case of thyroid storm following a laryngopharyngoesophagectomy with gastric pullup for laryngeal cancer in a previously euthyroid patient without known thyroid disease. We discuss the patient's journey, make recommendations in preventing and then addressing this rare complication postoperatively, should it occur.
Introduction
The COVID‐19 pandemic has resulted in an unprecedented need for critical care intervention. Prolonged intubation and mechanical ventilation has resulted in the need for tracheostomy in ...some patients. The purpose of this international survey was to assess optimal timing, technique and outcome for this intervention.
Methods
An online survey was generated. Otorhinolaryngologists from both the United Kingdom and Abroad were polled with regards to their experience of tracheostomy in COVID‐19 positive ventilated patients.
Results
The survey was completed by 50 respondents from 16 nations. The number of ventilated patients totalled 3403, on average 9.7% required a tracheostomy. This was on average performed on day 14 following intubation. The majority of patients were successfully weaned (mean 7.4 days following tracheostomy).
Conclusion
The results of this brief survey suggest that tracheostomy is of benefit in selected patients. There was insufficient data to suggest improved outcomes with either percutaneous vs an open surgical technique.
The dentist's chair presents an opportunity to pick up ear nose and throat lesions, by virtue of the close proximity of the anatomical areas. Urgent two-week wait referral can expedite assessment and ...management of head and neck malignancies, thereby improving the prognosis. In this paper, we attempt to highlight the ear, nose and throat (ENT) conditions that need a two week referral, as well as the benign head and neck lesions which can potentially be picked up in a dentist's chair.
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