Head and neck squamous cell carcinomas (HNSCCs) arise in the mucosal linings of the upper aerodigestive tract and are unexpectedly heterogeneous in nature. Classical risk factors are smoking and excessive alcohol consumption, and in recent years, the role of human papillomavirus (HPV) has emerged, particularly in oropharyngeal tumours. HPV-induced oropharyngeal tumours are considered a separate disease entity, which recently has manifested in an adapted prognostic staging system while the results of de-intensified treatment trials are awaited. Carcinogenesis caused by HPV in the mucosal linings of the upper aerodigestive tract remains an enigma, but with some recent observations, a model can be proposed. In 2015, The Cancer Genome Atlas (TCGA) consortium published a comprehensive molecular catalogue on HNSCC. Frequent mutations of novel druggable oncogenes were not demonstrated, but the existence of a subgroup of genetically distinct HPV-negative head and neck tumours with favourable prognoses was confirmed. Tumours can be further subclassified based on genomic profiling. However, the amount of molecular data is currently overwhelming and requires detailed biological interpretation. It also became apparent that HNSCC is a disease characterized by frequent mutations that create neoantigens, indicating that immunotherapies might be effective. In 2016, the first results of immunotherapy trials with immune checkpoint inhibitors were published, and these may be considered as a paradigm shift in head and neck oncology.

The molecular landscape of head and neck cancer

Head and neck squamous cell carcinomas (HNSCCs) are an aggressive, genetically complex and difficult to treat group of cancers. In lieu of truly effective targeted therapies, surgery and radiotherapy represent the primary treatment options for most patients. But these treatments are associated with significant morbidity and a reduction in quality of life. Resistance to both radiotherapy and the only available targeted therapy, and subsequent relapse are common. Research has therefore focussed on identifying biomarkers to stratify patients into clinically meaningful groups and to develop more effective targeted therapies. However, as we are now discovering, the poor response to therapy and aggressive nature of HNSCCs is not only affected by the complex alterations in intracellular signalling pathways but is also heavily influenced by the behaviour of the extracellular microenvironment. The HNSCC tumour landscape is an environment permissive of these tumours' aggressive nature, fostered by the actions of the immune system, the response to tumour hypoxia and the influence of the microbiome. Solving these challenges now rests on expanding our knowledge of these areas, in parallel with a greater understanding of the molecular biology of HNSCC subtypes. This update aims to build on our earlier 2014 review by bringing up to date our understanding of the molecular biology of HNSCCs and provide insights into areas of ongoing research and perspectives for the future.

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Clinical update on head and neck cancer: molecular biology and ongoing challenges.

Head and neck squamous cell carcinoma (HNSCC) is a common, morbid, and frequently lethal malignancy. To uncover its mutational spectrum, we analyzed whole-exome sequencing data from 74 tumor-normal pairs. The majority exhibited a mutational profile consistent with tobacco exposure; human papillomavirus was detectable by sequencing DNA from infected tumors. In addition to identifying previously known HNSCC genes (TP53, CDKN2A, PTEN, PIK3CA, and HRAS), our analysis revealed many genes not previously implicated in this malignancy. At least 30% of cases harbored mutations in genes that regulate squamous differentiation (for example, NOTCH1, IRF6, and TP63), implicating its dysregulation as a major driver of HNSCC carcinogenesis. More generally, the results indicate the ability of large-scale sequencing to reveal fundamental tumorigenic mechanisms.

The Mutational Landscape of Head and Neck Squamous Cell Carcinoma

Cancer is a disease caused by the accumulation of genetic and epigenetic changes in two types of genes: tumor suppressor genes (TSGs) and proto-oncogenes. Extensive research has been conducted over the last few decades to elucidate the role of TSGs in cancer development. In cancer, loss of TSG function occurs via the deletion or inactivation of two alleles, according to Knudson's two-hit model hypothesis. It has become clear that mutations in TSGs are recessive at the level of an individual cell; therefore, a single mutation in a TSG is not sufficient to cause carcinogenesis. However, many studies have identified candidate TSGs that do not conform with this standard definition, including genes inactivated by epigenetic silencing rather than by deletion. In addition, proteasomal degradation by ubiquitination, abnormal cellular localization, and transcriptional regulation are also involved in the inactivation of TSGs. This review incorporates these novel additional mechanisms of TSG inactivation into the existing two-hit model and proposes a revised multiple-hit model that will enable the identification of novel TSGs that can be used as prognostic and predictive biomarkers of cancer.

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Loss of Tumor Suppressor Gene Function in Human Cancer: An Overview.

Because most studies have focused on the intrinsic carcinogenic pathways of tumors, the underlying role of N6-methyladenosine (m6A) methylation in tumor immune microenvironment (TIME) remains elusive. Herein, we systematically explored the correlations of prominent m6A regulators with PD-L1 and immune infiltrates in 769 head and neck squamous cell carcinomas (HNSCCs; The Cancer Genome Atlas [TCGA] cohort, n = 499; GSE65858 cohort, n = 270). The PD-L1 expression evidently associated with m6A regulators. Two molecular subtypes (cluster1/2) were identified by consensus clustering for 15 m6A regulators. The cluster2 preferentially associated with favorable prognosis, upregulated PD-L1 expression, higher immunoscore, and distinct immune cell infiltration. The hallmarks of G2M checkpoint, mTORC1 signaling, and PI3K/AKT/mTOR signaling were remarkably enriched in the cluster1. A prognostic risk score was constructed using seven m6A regulator-associated signatures that represented an independent prognosis factor for HNSCC. Patients with low-risk score exhibited higher immunoscore and upregulated PD-L1 expression than patients with high-risk score. Consistently, m6A regulators showed the same influence on immune modulation and survival in external GSE65858 cohort. Further analysis revealed that m6A regulator-based signatures were implicated in TIME and their copy-number alterations dynamically affected the abundance of tumor-infiltrating immune cells. Collectively, our study elucidated the important role of m6A methylation in TIME of HNSCC. The proposed m6A regulator-based signatures might serve as crucial mediators of TIME in HNSCC, representing promising therapeutic targets in improving immunotherapeutic efficacy.

Comprehensive Analysis of the PD-L1 and Immune Infiltrates of m6A RNA Methylation Regulators in Head and Neck Squamous Cell Carcinoma.

Osteocalcin is a noncollagenous protein produced by osteoblasts and odontoblasts. It is used as a marker for bone formation in regenerative medical approaches. In addition, serum levels in humans are used to indicate bone turnover. Expression is usually determined by real-time reverse transcription PCR. Analysis of sequence data revealed that the frequently used primers for the determination of osteocalcin expression also detect the expression of messenger RNA (mRNA) encoding polyamine-modulated factor 1 (PMF1). In the present study we developed a method to determine the real amount of mRNA encoding osteocalcin. Bone-derived cells were treated with osteogenic differentiation medium and expression of osteocalcin was determined to test the method. It was found that the classic method that does not correct for PMF1 expression leads to overestimations as high as 70%.

Real-time RT-PCR discriminating mRNA encoding osteocalcin from unspecific targets

Background Cerebral vasospasm (CVS) continues to account for high morbidity and mortality in patients surviving the initial aneurysmal subarachnoid hemorrhage (SAH). Nimodipine is the only drug known to reduce delayed cerebral ischemia (DCI), but it is believed not to affect large vessel CVS. Milrinone has emerged as a promising option. Our retrospective study focused on the effectiveness of the intra-arterial application of both drugs in monotherapy and combined therapy. Methods We searched for patients with aneurysmal SAH, angiographically confirmed CVS, and at least one intra-arterial pharmacological angioplasty. Ten defined vessel sections on angiograms were assessed before and after vasodilator infusion. The improvement in vessel diameters was compared to the frequency of DCI-related cerebral infarction before hospital discharge and functional outcome reported as the modified Rankin Scale (mRS) score after 6 months. Results Between 2014 and 2021, 132 intra-arterial interventions (144 vascular territories, 12 bilaterally) in 30 patients were analyzed for this study. The vasodilating effect of nimodipine was superior to milrinone in all intradural segments. There was no significant intergroup difference concerning outcome in mRS (p = 0.217). Only nimodipine or the combined approach could prevent DCI-related infarction (both 57.1%), not milrinone alone (87.5%). Both drugs induced a doubled vasopressor demand due to blood pressure decrease, but milrinone alone induced tachycardia. Conclusions The monotherapy with intra-arterial nimodipine was superior to milrinone. Nimodipine and milrinone may be used complementary in an escalation scheme with the administration of nimodipine first, complemented by milrinone in cases of severe CVS. Milrinone monotherapy is not recommended.

Nimodipine vs. Milrinone – Equal or Complementary Use? A Retrospective Analysis

INTRODUCTION: The COVID-19 pandemic affects basic health care in maxillofacial surgery (MFS) due to the shift in resources and the change in patient disorders treated during the pandemic. This paper aims to elucidate the medical and financial consequences driven by the measures for COVID-19 treatment in a tertiary care centre. MATERIAL AND METHODS: To evaluate the impact of pandemic measures on daily routines of MFS, the surgical schedule during the first 2 weeks after the onset of the curfew (March 2020), and to compare it with the schedule of the same period of time 1 year earlier. Furthermore, postponed surgeries as well as cancelled follow-ups are listed. The loss of earning was calculated as well as the number and kind of postponed procedures. RESULTS: The number of surgeries decreased by 45% (n = 163 in 2019 vs n = 89 in 2020), and the duration of the surgeries decreased from 94.2 minutes to 62.1 minutes. No elective surgeries, such as implantology, aesthetic surgery, or orthognathic surgery, took place. Furthermore, also trauma cases decreased from 9 to 3 cases. Considering all variables, the financial loss can be calculated as approximately 100,256.50 Euros per week. CONCLUSION: The impact of COVID-19 on MFS is certainly of medical and economic importance and is related to the duration of the pandemic.

Impact of Corona Virus Disease 2019 on Oral- and Maxillofacial Surgery: Preliminary Results After the Curfew.

Purpose
The purpose of this study was to identify risk factors associated with postrhinoplasty mucous cyst (PMC) among adult cleft patients undergoing rhinoplasty. PMC has been reported sporadically in the literature. Its aetiology is uncertain. The purpose of this study was to determine whether three factors, (1) patient age, (2) surgical trauma, and/or (3) use of a nasal septal cartilage graft (NSCG), were risk factors for PMC.

Factors associated with postrhinoplasty mucous cyst in cleft lip patients

BACKGROUND Orbital decompression surgery is frequently the last therapeutic measure in the surgical treatment of endocrine orbitopathy (EO). Additional rehabilitative and corrective surgical treatments are often used to improve the resulting eyelid stigmata, such as an increased lid aperture and scleral show. The aim of the study was to evaluate the effect of adjunctive surgical procedures after orbital decompression surgery in patients with EO. METHODS A total of 120 orbitae from 65 patients with EO from 2010 to 2020 at a tertiary care center in Germany were retrospectively evaluated. Ocular surface area (OSA) and vertical palpebral fissures were three-dimensionally analyzed at the following stages: presurgical decompression, postsurgical decompression, and post-adjunctive surgical procedures. For the analysis of vertical palpebral fissures, predefined vertical line distances were measured on the upper and lower lids in the central, medial, and lateral pupillary regions. RESULTS The initial OSA was 2,98 ± 0.85 cm2, and it decreased significantly after decompression surgery to 2.52 ± 0.62 cm2. After adjunct surgical procedures, OSA further decreased to 2,31 ± 0,55 cm2. Furthermore, a statistically significant reduction in all pupillary parameters was noted after each treatment step. More lid-lengthening procedures were performed on the lower lid than on the upper lid. Canthoplasty (n = 13) was the most frequently performed procedure during rehabilitation. CONCLUSION Surgical decompression surgery improves OSA and leads to a significant reduction in lid aperture. Adjunctive surgical procedures, addressing the upper and lower lid, have a significant influence on the ongoing clinical course and contribute to a reduction in OSA.

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Dirk Halama

Papers

Real-time RT-PCR discriminating mRNA encoding osteocalcin from unspecific targets

Nimodipine vs. Milrinone – Equal or Complementary Use? A Retrospective Analysis

Impact of Corona Virus Disease 2019 on Oral- and Maxillofacial Surgery: Preliminary Results After the Curfew.

Factors associated with postrhinoplasty mucous cyst in cleft lip patients

Eyes wide shut: necessity and effect of adjunctive procedures after decompression surgery in patients with endocrine orbitopathy.