Systematic sequencing of human cancer genomes has identified many recurrent mutations in the protein-coding regions of genes but rarely in gene regulatory regions. Here, we describe two independent ...mutations within the core promoter of telomerase reverse transcriptase (TERT), the gene coding for the catalytic subunit of telomerase, which collectively occur in 50 of 70 (71%) melanomas examined. These mutations generate de novo consensus binding motifs for E-twenty-six (ETS) transcription factors, and in reporter assays, the mutations increased transcriptional activity from the TERT promoter by two- to fourfold. Examination of 150 cancer cell lines derived from diverse tumor types revealed the same mutations in 24 cases (16%), with preliminary evidence of elevated frequency in bladder and hepatocellular cancer cells. Thus, somatic mutations in regulatory regions of the genome may represent an important tumorigenic mechanism.
Over 90% of head and neck cancers overexpress the epidermal growth factor receptor (EGFR). In diverse tumor types, EGFR overexpression has been associated with poorer prognosis and outcomes. ...Therapies targeting EGFR include monoclonal antibodies, tyrosine kinase inhibitors, phosphatidylinositol 3-kinase (PI3K) inhibitors, and antisense gene therapy. Few EGFR-targeted therapeutics are approved for clinical use. The monoclonal antibody cetuximab is a Food and Drug Administration (FDA)-approved EGFR-targeted therapy, yet has exhibited modest benefit in clinical trials. The humanized monoclonal antibody nimotuzumab is also approved for head and neck cancers in Cuba, Argentina, Colombia, Peru, India, Ukraine, Ivory Coast, and Gabon in addition to nasopharyngeal cancers in China. Few other EGFR-targeted therapeutics for head and neck cancers have led to as significant responses as seen in lung carcinomas, for instance. Recent genome sequencing of head and neck tumors has helped identify patient subgroups with improved response to EGFR inhibitors, for example, cetuximab in patients with the KRAS-variant and the tyrosine kinase inhibitor erlotinib for tumors harboring MAPK1
E322K
mutations. Genome sequencing has furthermore broadened our understanding of dysregulated pathways, holding the potential to enhance the benefit derived from therapies targeting EGFR.
A significant barrier to the clinical translation of systemically administered therapeutic nanoparticles is their tendency to be removed from circulation by the mononuclear phagocyte system. The ...addition of a targeting ligand that selectively interacts with cancer cells can improve the therapeutic efficacy of nanomaterials, although these systems have met with only limited success. Here, we present a cooperative nanosystem consisting of two discrete nanomaterials. The first component is gold nanorod (NR) "activators" that populate the porous tumor vessels and act as photothermal antennas to specify tumor heating via remote near-infrared laser irradiation. We find that local tumor heating accelerates the recruitment of the second component: a targeted nanoparticle consisting of either magnetic nanoworms (NW) or doxorubicinloaded liposomes (LP). The targeting species employed in this work is a cyclic nine-amino acid peptide LyP-1 (Cys-Gly-Asn-Lys-Arg-Thr-Arg-Gly-Cys) that binds to the stress-related protein, p32, which we find to be upregulated on the surface of tumor-associated cells upon thermal treatment. Mice containing xenografted MDA-MB-435 tumors that are treated with the combined NR/LyP-1LP therapeutic system display significant reductions in tumor volume compared with individual nanoparticles or untargeted cooperative system.
Objective
To prospectively compare the impact of treatment modality on patient‐reported quality of life (QOL) in human papillomavirus‐associated oropharynx squamous cell carcinoma (HPV + OPSCC).
...Study Design
Prospective cohort study.
Setting
Academic medical center.
Methods
One hundred one patients with American Joint Committee on Cancer (AJCC) 8th edition T1‐3 N0‐2 HPV + OPSCC completed the European Organization for Research and Treatment of Cancer Quality of Life Core questionnaire and Head and Neck Module pretreatment and 3‐month and 1‐year posttreatment. Mean score changes were compared to published minimal clinically important differences.
Results
Patients underwent surgery alone (SA: N = 42, 42%), surgery with adjuvant radiation (S‐RT: N = 10, 10%), surgery with adjuvant chemoradiation (S‐CRT: N = 8, 8%), definitive radiation (RT: N = 11, 11%), or definitive chemoradiation (CRT: N = 30, 30%). SA, S‐CRT, and CRT patients all reported clinically significant difficulty with sense of taste/smell persisting at 1 year. S‐CRT and CRT patients reported statistically and clinically significant worse salivary dysfunction and problems with social eating at 1 year than SA. S‐CRT patients reported statistically and clinically significant worse fatigue and head and neck pain compared to CRT and SA patients at 3 months, but normalized at 1 year. S‐CRT compared to S‐RT had statistically and clinically worse physical and role functioning and swallowing difficulties at 3 months but this difference was resolved by 1‐year posttreatment.
Conclusion
HPV + OPSCC patients after SA report the lowest posttreatment QOL impact, whereas after S‐CRT report the highest symptom burden. Careful selection for definitive surgery is important given the possibility of adjuvant CRT. Patients can experience persistent sense taste and smell difficulties at 1 year with all treatment modalities.
Level of Evidence
3 Laryngoscope, 134:1687–1695, 2024
Objectives/Hypothesis
Compare treatment‐related quality of life (QOL) impact for early‐stage human papillomavirus–associated oropharynx squamous cell carcinoma (HPV+ OPSCC) patients.
Study Design
...Retrospective cohort at a tertiary center.
Methods
Stage I (T0‐2/N0‐1) HPV+ OPSCC patients (n = 76) with pretreatment Karnofsky scores ≥80 reported QOL after surgery alone (n = 17, 22%), surgery with adjuvant radiation ± chemotherapy (S‐aCXRT) (n = 23, 30%), or definitive radiation ± chemotherapy (dCXRT) (n = 36, 47%) with the University of Washington QOL version 4 (UW‐QOL); European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, Core Module (EORTC QLQ‐C30) and Head and Neck Module (EORTC QLQ‐HN35); University of Michigan Xerostomia, and Neck Dissection Impairment Index questionnaires (median follow‐up = 2.2 years, interquartile range = 1.0–4.2 years). Treatment adverse events and gastrostomy tube rates were assessed.
Results
Over 87% of each treatment group reported good or better overall QOL. Each group had low gastrostomy tube and treatment‐specific complication rates. S‐a(C)XRT and d(C)XRT patients had similar mean scores with wide ranges for most individual and all composite categories. S‐a(C)XRT compared to d(C)XRT patients reported significantly fewer dental problems (EORTC QLQ‐C30/HN35 means = 10.1 vs. 34.3, P = .007), worse appearance (UW‐QOL means = 72.8 vs. 82.6, P = .02), and worse coughing (EORTC QLQ‐C30/HN35 means = 31.9 vs. 15.7, P = .007). Surgery alone compared to d(C)XRT and S‐a(C)XRT patients reported significantly better salivary/taste/oral functions and less pain, financial, oral/dental, and sexual problems.
Conclusions
For early‐stage HPV+ OPSCC, patients usually achieve acceptable QOL regardless of treatment. S‐a(C)XRT and d(C)XRT patients report generally similar QOL including neck/shoulder pain/function, but with a wide range in a limited patient sample. Surgery alone should be considered, when oncologically and functionally safe, given the better associated QOL.
Level of Evidence
4 Laryngoscope, 130:E48–E56, 2020
Background
Historically, graduating head and neck (HN) fellows outpace available academic HN positions, resulting in a highly competitive job market. We identified factors that associate with ...full‐time academic HN positions post‐HN fellowship.
Methods
Graduates of American Head and Neck Society (AHNS)‐accredited fellowships from 2005 to 2017 (n = 356) were extracted from the AHNS website.
Results
From 2015 to 2017, the supply–demand mismatch for academic HN jobs improved. Of the 57.3% (n = 204) of graduating HN fellows who entered academia, 64% (n = 130) trained at just 10 fellowship institutions, 47% (n = 94) attended OHNS residency at an NIH top 40 funded institution, and 54% (n = 111) attended OHNS residency at an AHNS‐accredited institution offering HN fellowship. After multivariate regression, number of manuscripts (OR = 1.14; p = 0.01) was significantly associated with initial academic job post‐fellowship.
Conclusion
The recent improvement in supply–demand mismatch for academic jobs is promising for future HN fellows interested in academia.
Background
Guidelines regarding head and neck surgical care have evolved during the coronavirus‐19 (COVID‐19) pandemic. Data on operative management have been limited.
Methods
We compared two cohorts ...of patients undergoing head and neck or reconstructive surgery between March 16, 2019 and April 16, 2019 (pre‐COVID‐19) and March 16, 2020 and April 16, 2020 (COVID‐19) at an academic center. Perioperative, intraoperative, and postoperative outcomes were recorded.
Results
There were 63 operations during COVID‐19 and 84 operations during pre‐COVID‐19. During COVID‐19, a smaller proportion of patients had benign pathology (12% vs 20%, respectively) and underwent thyroid procedures (2% vs 23%) while a greater proportion of patients underwent microvascular reconstruction±ablation (24% vs 12%,). Operative times increased, especially among patients undergoing microvascular reconstruction±ablation (687 ± 112 vs 596 ± 91 minutes, P = .04). Complication rates and length of stay were similar.
Conclusions
During COVID‐19, perioperative outcomes were similar, operative time increased, and there were no recorded transmissions to staff or patients. Continued surgical management of head and neck cancer patients can be provided safely.
Global trends in human papillomavirus (HPV)-associated head and neck cancers (HNC), specifically in the oropharynx subsite, have been dynamically changing, leading to new staging and treatment ...paradigms. Epidemiologic studies have noted regional variations in HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). While HPV vaccination remains the main preventative approach, vaccination policy in relation to gender neutrality is heterogeneous and particularly sparse in low- and middle-income countries, where the burden of global cancer cases and HPV-associated HNC are not well-characterized in certain regions. This review summarizes the existing literature on regional variations of HPV-associated OPSCC and gender-neutral vaccine policies. Based on available data, the incidence of HPV-associated OPSCC is highest in North America, Europe, and Oceania. As of 2022, 122 of 195 (63%) World Health Organization (WHO) member states had incorporated HPV vaccinations nationally; of these, 41 of 122 (34%) member states have introduced gender-neutral vaccine coverage. Future research is needed to describe continued evolving trends in HPV-associated OPSCC, understand underlying risk factors leading to regional variation in disease, and implement gender-neutral policy more broadly.
The objective of this study was to develop an international expert consensus on priority otolaryngology-head and neck surgery conditions and procedures globally for which national health systems ...should be capable of caring.
The Delphi method was employed via a multiround online survey administered to attending otolaryngologists in an international research collaborative of >180 otolaryngologists in >40 countries.
International online survey.
In round 1, participants listed the top 15 otolaryngologic conditions and top 15 otolaryngology procedures for their World Bank regions. In round 2, participants ranked round 1 responses in order of global importance on a 5-point Likert scale. In round 3, participants reranked conditions and procedures that did not achieve consensus, defined as 50% of the round 2 Likert responses being ranked as "important" or "very important." Descriptive statistics were calculated for each round.
The survey was distributed to 53 experts globally, with a response rate of 38% (n = 20). Fifty percent (n = 10) of participants were from low- and middle-income countries, with at least 1 participant from each World Bank region. Ten consensus surgical procedures and 10 consensus conditions were identified.
This study identified a list of priority otolaryngology-head and neck surgery conditions and surgical procedures for which all national health systems around the world should be capable of managing. Acute and infectious conditions with preventative and emergent procedures were highlighted. These findings can direct future research and guide international collaborations.
Abstract
Ear- and hearing-related conditions pose a significant global health burden, yet public health policy surrounding ear and hearing care (EHC) in low- and middle-income countries is poorly ...understood. The present study aims to characterize the inclusion of EHC in national health policy by analysing national health policies, strategies and plans in English, French, Spanish, Portuguese and Arabic. Three EHC keywords were searched, including ear*, hear* and deaf*. The terms ‘human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS)’, ‘tuberculosis’ and ‘malaria’ were included as comparison keywords as these conditions have historically garnered political priority in global health. Of the 194 World Health Organization Member States, there were 100 national policies that met the inclusion criteria of document availability, searchable format, language and absence of an associated national EHC strategy. These documents mentioned EHC keywords significantly less than comparison terms, with mention of hearing in 15 documents, ears in 11 documents and deafness in 3 documents. There was a mention of HIV/AIDS in 92 documents, tuberculosis in 88 documents and malaria in 70 documents. Documents in low- and middle-income countries included significantly fewer mentions of EHC terms than those of high-income countries. We conclude that ear and hearing conditions pose a significant burden of disease but are severely underrepresented in national health policy, especially in low- and middle-income countries.
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