Dirk Halama

Bio: Dirk Halama is an academic researcher from Leipzig University. The author has contributed to research in topics: Medicine & Psychosocial. The author has an hindex of 6, co-authored 24 publications receiving 225 citations.

The role of HPV RNA transcription, immune response-related gene expression and disruptive TP53 mutations in diagnostic and prognostic profiling of head and neck cancer.

Abstract: Stratification of head and neck squamous cell carcinomas (HNSCC) based on HPV16 DNA and RNA status, gene expression patterns, and mutated candidate genes may facilitate patient treatment decision. We characterize head and neck squamous cell carcinomas (HNSCC) with different HPV16 DNA and RNA (E6*I) status from 290 consecutively recruited patients by gene expression profiling and targeted sequencing of 50 genes. We show that tumors with transcriptionally inactive HPV16 (DNA+ RNA-) are similar to HPV-negative (DNA-) tumors regarding gene expression and frequency of TP53 mutations (47%, 8/17 and 43%, 72/167, respectively). We also find that an immune response-related gene expression cluster is associated with lymph node metastasis, independent of HPV16 status and that disruptive TP53 mutations are associated with lymph node metastasis in HPV16 DNA- tumors. We validate each of these associations in another large data set. Four gene expression clusters which we identify differ moderately but significantly in overall survival. Our findings underscore the importance of measuring the HPV16 RNA (E6*I) and TP53-mutation status for patient stratification and identify associations of an immune response-related gene expression cluster and TP53 mutations with lymph node metastasis in HNSCC.

Monitoring of microvascular free flaps following oropharyngeal reconstruction using infrared thermography: first clinical experiences.

Abstract: The aim of this study is to investigate static and dynamic infrared (IR) thermography for intra- and postoperative free-flap monitoring following oropharyngeal reconstruction Sixteen patients with oropharyngeal reconstruction by free radial forearm flap were included in this prospective, clinical study (05/2013-08/2014) Prior ("intraop_pre") and following ("intraop_post") completion of the microvascular anastomoses, IR thermography was performed for intraoperative flap monitoring Further IR images were acquired one day ("postop_1") and 10 days ("postop_10") after surgery for postoperative flap monitoring Of the 16, 15 transferred free radial forearm flaps did not show any perfusion failure A significant decreasing mean temperature difference (∆T: temperature difference between the flap surface and the surrounding tissue in Kelvin) was measured at all investigation points in comparison with the temperature difference at "intraop_pre" (mean values on all patients: ∆T intraop_pre = -264 K; ∆T intraop_post = -122 K, p < 00015; ∆T postop_1 = -054 K, p < 00001; ∆T postop_10 = -058 K, p < 00001) Intraoperative dynamic IR thermography showed typical pattern of non-pathological rewarming due to re-established flap perfusion after completion of the microvascular anastomoses Static and dynamic IR thermography is a promising, objective method for intraoperative and postoperative monitoring of free-flap reconstructions in head and neck surgery and to detect perfusion failure, before macroscopic changes in the tissue surface are obvious A lack of significant decrease of the temperature difference compared to surrounding tissue following completion of microvascular anastomoses and an atypical rewarming following a thermal challenge are suggestive of flap perfusion failure

Lower eyelid complications associated with transconjunctival versus subciliary approaches to orbital floor fractures

Abstract: The aim of this study was to compare the frequencies of lower eyelid complications after subciliary versus transconjunctival approaches to orbital floor fractures. The investigators implemented a retrospective cohort study and enrolled a sample composed of subjects who had orbital floor repair. The predictor variable was surgical approach, classified as subciliary or transconjunctival. The primary outcome variable was postoperative lower eyelid complications (ectropion, entropion, and eyelid retraction). Other variables were demographic, anatomic, or time to surgery. Descriptive and bivariate statistics were computed. Statistical significance was set at P ≤ 0.05. The study samples were composed of 346 patients (98 [28.3%] females; 225 [65%] underwent a subciliary approach) with a mean age of 42.7 ± 21.1 years. The subciliary approach was significantly linked to the higher rates of ectropion and the lower rates of entropion at 7 days and 6 months postoperatively. There was no statistically significant difference in the frequency of eyelid retraction between both groups. In the setting of orbital floor fractures, these results suggest that the use of the subciliary approach increases the frequency of ectropion, while the transconjunctival approach increases the frequency of entropion. The authors decline to comment on what the better surgical approach to the orbital floor fractures is. The selection should be based on an individual patient basis and surgeon’s preference.

Donor-site morbidity after harvesting of radial forearm free flaps-comparison of vacuum-assisted closure with conventional wound care: A randomized controlled trial.

Abstract: Introduction Radial forearm free flaps (RFFF) are often used to replace tissue removed in head and neck surgery. In recent years, many attempts have been made to reduce donor-site morbidity and to prevent common complications such as infection, skin-graft necrosis, tendon exposure and subsequent impairment of hand function. One promising option is the use of vacuum-assisted-closure wound therapy (VAC). The objective of this study was to evaluate the effectiveness of VAC compared with a conventional bolster dressing (CBD). Material and methods A randomized controlled trial was enrolled. Our study was prospective in design and included patients with a skin-grafted forearm defect after harvesting of RFFF. Patients who met the inclusion criteria were randomly assigned into two study arms. The predictor variable was the type of wound therapy (VAC therapy compared with CBD) and the outcome variables were (1) the size of the wound area, (2) wrist movement and (3) grip strength. Outcome variables were assessed 12 days, three weeks and eight weeks after surgery. Results Fifty patients (33 males, mean age 61.7 years [SD 15.5]; 17 females, mean age 54.7 years [SD 10.5]) were included consecutively in the study. Patients in the VAC group experienced a faster postsurgical reduction of wound area and had better wrist movement; nonetheless, the differences between the VAC group and CBD group did not reach statistical significance. In contrast, the recovery of postsurgical grip strength was significantly faster in the VAC group. Conclusions Our study failed to prove that VAC therapy is significantly superior to CBD for all the variable studied. Because VAC therapy has some positive effects, however, we recommend further development of this negative-pressure wound treatment, rather than the termination of its use.

Psychosocial acceptance of cleft patients: has something changed?

Abstract: The main purpose of this study was to analyse the reactions of a panel (non-cleft adults) when observing cleft lip morphology. Although rehabilitation of cleft lip and palate is improving, there are still indications of social rejection of cleft patients by the people around them. Polarity profiles have been used since 1973 to measure social distance with regard to cleft patients. Because rehabilitation results and education of the society have improved in recent decades, we investigated whether social distance has been affected. The setting of this study is the Department of Oral, Craniomaxillofacial, and Facial Plastic Surgery, University Hospital of Leipzig, Germany Using a cross-sectional study design, we enrolled a sample of adult laypersons (n = 273). For the survey, we followed the concept of photograph presentation and questionnaire investigation reported by Sergl and Schmid (1973). We presented anonymised frontal and profile pictures of the faces of 50 cleft patients and asked the laypersons to specify social distance. Three predictor variables (layperson gender, profession and year of evaluation) were grouped. Although social distance has reduced during the last 40 years, life situations which require emotional proximity still cause some concern. Professional background and gender affect laypersons’ attitudes. Although rehabilitation of cleft lip and palate is much better than 40 years ago, social distance remains a problem in society. It is necessary to improve both results of rehabilitation of cleft patients and social acceptance by the people around them.

The molecular landscape of head and neck cancer

Abstract: 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.

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

Abstract: 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.

The Mutational Landscape of Head and Neck Squamous Cell Carcinoma

Abstract: 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.

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

Abstract: 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.

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

Abstract: 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.