Laser surgery of head and neck lesions at the National Institute of Oncology, Budapest

In spite of the continued expansion of non-surgical therapeutic modalities surgery still plays an important role in the treatment of head and neck cancer. Parallel with the use of conventional approaches, more sophisticated surgical approaches, like the use of laser in oncologic surgery, appeared with a more favorable outcome. Laser is a precise surgical tool, particularly when coupled to an operating microscope (with a variable spot size micromanipulator), allowing microprecision and hemostatic ability. The benefits of the use of laser are: bloodless operation field, high hit probability, "no touch" technique, ablasticity, support of tissue repair, and the lack of edema and scar formation. Between 1981 and 2008, 7934 surgical procedures were performed at the Department of Head and Neck Surgery, National Institute of Oncology, Budapest, Hungary. The aim is to present our results and experience with laser surgery of cutaneous lesions of the head and neck, oral, pharyngeal and laryngeal pathologies including cases of laryngotracheal stenosis.     

Tissue engineering in otorhinolaryngology

Tissue engineering is a field of research with interdisciplinary cooperation between clinicians, cell biologists, and materials research scientists. Many medical specialties apply tissue engineering techniques for the development of artificial replacement tissue. Stages of development extend from basic research and preclinical studies to clinical application. Despite numerous established tissue replacement methods in otorhinolaryngology, head and neck surgery, tissue engineering techniques opens up new ways for cell and tissue repair in this medical field. Autologous cartilage still remains the gold standard in plastic reconstructive surgery of the nose and external ear. The limited amount of patient cartilage obtainable for reconstructive head and neck surgery have rendered cartilage one of the most important targets for tissue engineering in head and neck surgery. Although successful in vitro generation of bioartificial cartilage is possible today, these transplants are affected by resorption after implantation into the patient. Replacement of bone in the facial or cranial region may be necessary after tumor resections, traumas, inflammations or in cases of malformations. Tissue engineering of bone could combine the advantages of autologous bone grafts with a minimal requirement for second interventions. Three different approaches are currently available for treating bone defects with the aid of tissue engineering: (1) matrix-based therapy, (2) factor-based therapy, and (3) cell-based therapy. All three treatment strategies can be used either alone or in combination for reconstruction or regeneration of bone. The use of respiratory epithelium generated in vitro is mainly indicated in reconstructive surgery of the trachea and larynx. Bioartificial respiratory epithelium could be used for functionalizing tracheal prostheses as well as direct epithelial coverage for scar prophylaxis after laser surgery of shorter stenoses. Before clinical application animal experiments have to prove feasability and safety of the different experimental protocols. All diseases accompanied by permanently reduced salivation are possible treatment targets for tissue engineering. Radiogenic xerostomia after radiotherapy of malignant head and neck tumors is of particular importance here due to the high number of affected patients. The number of new diseases is estimated to be over 500,000 cases worldwide. Causal treatment options for radiation-induced salivary gland damage are not yet available; thus, various study groups are currently investigating whether cell therapy concepts can be developed with tissue engineering methods. Tissue engineering opens up new ways to generate vital and functional transplants. Various basic problems have still to be solved before clinically applying in vitro fabricated tissue. Only a fraction of all somatic organ-specific cell types can be grown in sufficient amounts in vitro. The inadequate in vitro oxygen and nutrition supply is another limiting factor for the fabrication of complex tissues or organ systems. Tissue survival is doubtful after implantation, if its supply is not ensured by a capillary network.     

Experimental use of a gastric flap on an omental pedicle to close defects in the trachea, pharynx, or cervical esophagus.

The use of local or regional skin flaps for repairs after head and neck cancer surgery often increases the deformity of the patient. We present a new procedure using a gastric flap on an omental pedicle. It has been successful in dog experiments where we transferred it to the head and neck region, to serve as a substitute for the standard skin flaps.     

The importance of stem cell engineering in head and neck oncology

Head and neck squamous cell carcinoma is the sixth leading cause of cancer worldwide. The most common risk factors are carcinogens (tobacco, alcohol), and infection of the human papilloma virus. Surgery is still considered as the treatment of choice in case of head and neck cancer, followed by a reconstructive surgery to enhance the quality of life in the patients. However, the widespread use of artificial implants does not provide appropriate physiological activities and often cannot act as a long-term solution for the patients. Here we review the applicability of multiple stem cell types for tissue engineering of cartilage, trachea, vocal folds and nerves for head and neck injuries. The ability of the cells to self-renew and maintain their pluripotency state makes them an attractive tool in tissue engineering.     

Report on the first year of the activity of the National Oncological RD Consortium

The project focuses on cancer types with outstanding publich health importance (breast-, colorectalhead and neck cancers and childhood tumors). Epidemiological studies revealed significant regional differences in the mobidity/mortality of these cancer types in Hungary. Molecular epidemiological studies revealed characteristic BRCA1 mutation patterns of familiar breast cancer and DNA repair enzyme polymorphism in head and neck cancer. New methods have been developed for the screening (lactoferrin), prognostication (c-met expression) or the prediction of therapeutic sensitivity (TS expression) of colorectal cancer. In the pediatric oncology program alternative way of MRD monitoring (WT1 expression) and a potential new therapeutic modality (IFN-alpha) of ALL was developed. Experimental studies demonstrated that the tumoral matrix significantly influences the effects of the classic chemotherapeutic agents. We have identified several genes the expression of which could serve efficiently as markers or targets for therapy of the progression of melanoma (alphaIIbbeta3 integrin, CD44v3 and decorin proteoglycans, AMF receptor).     

Monitoring free flaps using the laser Doppler flowmeter: five-year experience

Over a 5-year period, 232 microvascular composite-tissue transfers to the head and neck, trunk, and extremities were monitored using the laser Doppler flowmeter. Thirteen free flaps (5.6 percent) developed vascular complications, all within 4 days after surgery. The laser Doppler flowmeter detected vascular compromise in all cases with no false positives or negatives. Failure to monitor the flap according to protocol by nursing staff occurred in one patient, which led to a delay in detection of venous compromise and subsequent flap loss. The salvage rate was 69.2 percent, leading to an overall flap viability of 98.3 percent. Our series of free-flap monitoring using the laser Doppler flowmeter is the largest reported to date. Review of the English literature shows consistent support by numerous clinical series for the use of the laser Doppler as a valuable postoperative monitor after free-flap transfers.     

Constitutive and acquired mechanisms of resistance to immune checkpoint blockade in human cancer

Cancer immunotherapy with monoclonal antibodies directed against regulatory pathways in T lymphocytes has been revolutionizing medical oncology, and the clinical success of monoclonal antibodies targeting either cytotoxic T lymphocyte antigen-4 (CTLA-4) or program death-1 (PD-1) in patients affected by melanoma, Hodgkin’s lymphoma, Merkel cell carcinoma, and head and neck, bladder, renal cell or non-small cell lung cancer is way beyond the most optimistic expectation. However, immune checkpoint blockade (ICB) has failed to arrest progression in a consistent amount of patients affected by those tumors, and various histological types, including breast, colon and prostate cancer, are less sensitive to this therapeutic approach. Such clinical findings have fueled massive research efforts in the attempt to identify pre-existing and acquired mechanisms of resistance to ICB. Here we focus on evidences emerging from studies in humans on how tumor cells and the tumor microenvironment contribute to the heterogeneous clinical responses, and we propose strategies stemming from pre-clinical models that might improve clinical outcomes for patients.     

免疫治疗背景下提高临床肿瘤教学水平的探讨

肿瘤发病率的日益攀升以及临床肿瘤学的迅速发展,对培养专业的临床肿瘤学人才提出了更高的要求。随着第一个细胞免疫治疗药物Sipuleucel-T被美国FDA批准用于晚期前列腺癌的治疗,肿瘤治疗进入免疫治疗的新时代,现有传统临床肿瘤学教学方法及观念已经不能适应目前的要求,因此必须提高临床教学水平。本文在肿瘤免疫治疗迅速发展背景下,对如何提高临床肿瘤教学水平进行思考与探讨,通过加强肿瘤分子生物学及细胞分子免疫学理论教学,以及在教学过程中贯穿循证医学与个体化治疗相结合的理念、引入多学科参与的肿瘤综合治疗模式,并强调心理干预和人文关怀的重要性,兼顾教学理论和临床实践最新进展及趋势,有效地帮助学生树立全面、科学的临床肿瘤治疗理念,掌握改善临床肿瘤治疗的有效方法,切实提升临床肿瘤学的教学质量和水平,培养出能胜任现代临床肿瘤学实践需求的专业人才。     

EphA3 maintains radioresistance in head and neck cancers through epithelial mesenchymal transition

Radiotherapy is a well-established therapeutic modality used in the treatment of many cancers. However, radioresistance remains a serious obstacle to successful treatment. Radioresistance can cause local recurrence and distant metastases in some patients after radiation treatment. Thus, many studies have attempted to identify effective radiosensitizers. Eph receptor functions contribute to tumor development, modulating cell-cell adhesion, invasion, neo-angiogenesis, tumor growth and metastasis. However, the role of EphA3 in radioresistance remains unclear. In the current study, we established a stable radioresistant head and neck cancer cell line (AMC HN3R cell line) and found that EphA3 was expressed predominantly in the radioresistant head and neck cancer cell line through DNA microarray, real time PCR and Western blotting. Additionally, we found that EphA3 was overexpressed in recurrent laryngeal cancer specimens after radiation therapy. EphA3 mediated the tumor invasiveness and migration in radioresistant head and neck cancer cell lines and epithelial mesenchymal transition- related protein expression. Inhibition of EphA3 enhanced radiosensitivity in the AMC HN 3R cell line in vitro and in vivo study. In conclusion, our results suggest that EphA3 is overexpressed in radioresistant head and neck cancer and plays a crucial role in the development of radioresistance in head and neck cancers by regulating the epithelial mesenchymal transition pathway.     

Population-based retrospective study to investigate preexisting and new depression diagnosis among head and neck cancer patients

This study aimed to estimate the pre-cancer prevalence and post-cancer incidence of depression in older adult head and neck cancer patients. Using SEER-Medicare files, cancer was identified from SEER data and depression diagnosis was identified using Medicare claims. Of 3533 head and neck cancer patients, 10.6% were diagnosed with depression during the two years prior to cancer diagnosis, and an additional 8.9% developed depression in the year following cancer diagnosis. This study supports the critical need of screening for depression throughout cancer diagnosis and treatment, as well as a preventative approach in depression development in the older head and neck cancer patient population.     

Guggulsterone targets smokeless tobacco induced PI3K/Akt pathway in head and neck cancer cells

Background

Epidemiological association of head and neck cancer with smokeless tobacco (ST) emphasizes the need to unravel the molecular mechanisms implicated in cancer development, and identify pharmacologically safe agents for early intervention and prevention of disease recurrence. Guggulsterone (GS), a biosafe nutraceutical, inhibits the PI3K/Akt pathway that plays a critical role in HNSCC development. However, the potential of GS to suppress ST and nicotine (major component of ST) induced HNSCC remains unexplored. We hypothesized GS can abrogate the effects of ST and nicotine on apoptosis in HNSCC cells, in part by activation of PI3K/Akt pathway and its downstream targets, Bax and Bad.

Methods and Results

Our results showed ST and nicotine treatment resulted in activation of PI3K, PDK1, Akt, and its downstream proteins - Raf, GSK3β and pS6 while GS induced a time dependent decrease in activation of PI3K/Akt pathway. ST and nicotine treatment also resulted in induction of Bad and Bax phosphorylation, increased the association of Bad with 14-3-3ζresulting in its sequestration in the cytoplasm of head and neck cancer cells, thus blocking its pro-apoptotic function. Notably, GS pre-treatment inhibited ST/nicotine induced activation of PI3K/Akt pathway, and inhibited the Akt mediated phosphorylation of Bax and Bad.

Conclusions

In conclusion, GS treatment not only inhibited proliferation, but also induced apoptosis by abrogating the effects of ST / nicotine on PI3K/Akt pathway in head and neck cancer cells. These findings provide a rationale for designing future studies to evaluate the chemopreventive potential of GS in ST / nicotine associated head and neck cancer.     

Role of impaired DNA repair in genotoxic susceptibility of patients with head and neck cancer

DNA repair is critical for genotoxic susceptibility and cancer development. Forty-seven patients with head and neck squamous cell carcinoma (HNSCC) and 38 healthy controls were enrolled in this study. Among the patients, 16 subjects had metastasis of HNSCC. The extent of DNA damage, including oxidative lesions, and efficiency of repair after genotoxic treatment with hydrogen peroxide were examined using the alkaline comet assay. HNSCC cells were sensitive to genotoxic treatment and displayed impaired DNA repair. In particular, lesions caused by hydrogen peroxide were repaired less effectively in cancer cells from patients with metastasis than in cells from healthy controls. We suggest that impaired DNA repair might play a role in genotoxic susceptibility of patients with head and neck cancer. Finally, as a consequence of this finding we have shown that treatment with DNA-reactive drugs could be considered as an effective therapy strategy for head and neck cancer.     

Mitochondrial genotype in vulvar carcinoma - cuckoo in the nest

Vulvar squamous cell carcinoma (VSCC) is a rare female genital neoplasm. Although numerous molecular changes have been reported in VSCC, biomarkers of clinical relevance are still lacking. On the other hand, there is emerging evidence on the use of mtDNA as a diagnostic tool in oncology. In order to investigate mtDNA status in VSCC patients, haplogroup distribution analysis and D-loop sequencing were performed. The results were compared with available data for the general Polish population, cancer free-centenarians as well as patients with endometrial and head and neck cancer. The obtained data were also compared with the current status of mitochondrial databases. Significant differences in haplogroup distribution between VSCC cohort, general Polish population and cancer-free centenarians cohort were found. Moreover, a correlation between the VSCC patients haplogroup and HPV status was observed. Finally, a specific pattern of mtDNA polymorphisms was found in VSCC. Our results suggest that the mitochondrial genetic background may influence the risk of VSCC occurrence as well as susceptibility to HPV infection.     

Application of radiomics and machine learning in head and neck cancers

With the continuous development of medical image informatics technology, more and more high-throughput quantitative data could be extracted from digital medical images, which has resulted in a new kind of omics-Radiomics. In recent years, in addition to genomics, proteomics and metabolomics, radiomic has attracted the interest of more and more researchers. Compared to other omics, radiomics can be perfectly integrated with clinical data, even with the pathology and molecular biomarker, so that the study can be closer to the clinical reality and more revealing of the tumor development. Mass data will also be generated in this process. Machine learning, due to its own characteristics, has a unique advantage in processing massive radiomic data. By analyzing mass amounts of data with strong clinical relevance, people can construct models that more accurately reflect tumor development and progression, thereby providing the possibility of personalized and sequential treatment of patients. As one of the cancer types whose treatment and diagnosis rely on imaging examination, radiomics has a very broad application prospect in head and neck cancers (HNC). Until now, there have been some notable results in HNC. In this review, we will introduce the concepts and workflow of radiomics and machine learning and their current applications in head and neck cancers, as well as the directions and applications of artificial intelligence in the treatment and diagnosis of HNC.     

Management of intraoral stents for radiotherapy during COVID-19 pandemic

Radiotherapy is being performed in many situations as a curative approach for head and neck cancer instead of surgery due to the current novel coronavirus disease (COVID-19) pandemic. A recent publication reported that even hypofractionation was being conducted in order to reduce the daily exposure of both patients and the medical staff involved in cancer therapies. As a result, dental teams may be requested more frequently than usual to fabricate intraoral stents (IOS). Given that IOS may be a potential source of COVID-19 contagion, the main purpose of the present correspondence is to offer a guide on how health professionals may be safely presented in the room, on the management of the IOS and also how to sanitize the stents.     

Musculo-cutaneous flaps in the reconstruction of the organs after oncological operations in the head and neck areas

A method of skin-muscular flaps construction is being discussed together with their use for the reconstruction of the organs after oncological surgery of the head and neck. Own experience with the use of such flaps in 83 cases are also discussed.     

Overexpression of EMMPRIN Isoform 2 Is Associated with Head and Neck Cancer Metastasis

Extracellular matrix metalloproteinase inducer (EMMPRIN), a plasma membrane protein of the immunoglobulin (Ig) superfamily, has been reported to promote cancer cell invasion and metastasis in several human malignancies. However, the roles of the different EMMPRIN isoforms and their associated mechanisms in head and neck cancer progression remain unknown. Using quantitative real-time PCR, we found that EMMPRIN isoform 2 (EMMPRIN-2) was the only isoform that was overexpressed in both head and neck cancer tissues and cell lines and that it was associated with head and neck cancer metastasis. To determine the effects of EMMPRIN-2 on head and neck cancer progression, we transfected head and neck cancer cells with an EMMPRIN-2 expression vector and EMMPRIN-2 siRNA to exogenously modulate EMMPRIN-2 expression and examined the functional importance of EMMPRIN-2 in head and neck cancer invasion and metastasis. We found that EMMPRIN-2 promoted head and neck cancer cell invasion, migration, and adhesion in vitro and increased lung metastasis in vivo. Mechanistic studies revealed that EMMPRIN-2 overexpression promoted the secretion of extracellular signaling molecules, including matrix metalloproteinases-2(MMP-2), urokinase-type plasminogen activator(uPA) and Cathepsin B, in head and neck cancer cells. While MMP-2 and uPA have been demonstrated to be important mediators of EMMPRIN signaling, the role of Cathepsin B in EMMPRIN-mediated molecular cascades and tumorigenesis has not been established. We found that EMMPRIN-2 overexpression and Cathepsin B down-regulation significantly inhibited the invasion, migration and adhesion of Tca8133 cells, suggesting that Cathepsin B is required for EMMPRIN-2 enhanced cell migration and invasion in head and neck cancer. The results of our study demonstrate the important role of EMMPRIN-2 in head and neck cancer progression for the first time and reveal that increased extracellular secretion of Cathepsin B may be a novel mechanism underlying EMMPRIN-2 enhanced tumor progression in head and neck cancer.     

Amniotic membrane: from structure and functions to clinical applications

Amniotic membrane (AM) or amnion is a thin membrane on the inner side of the fetal placenta; it completely surrounds the embryo and delimits the amniotic cavity, which is filled by amniotic liquid. In recent years, the structure and function of the amnion have been investigated, particularly the pluripotent properties of AM cells, which are an attractive source for tissue transplantation. AM has anti-inflammatory, anti-bacterial, anti-viral and immunological characteristics, as well as anti-angiogenic and pro-apoptotic features. AM is a promoter of epithelialization and is a non-tumorigenic tissue and its use has no ethical problems. Because of its attractive properties, AM has been applied in several surgical procedures related to ocular surface reconstruction and the genito-urinary tract, skin, head and neck, among others. So far, the best known and most auspicious applications of AM are ocular surface reconstruction, skin applications and tissue engineering. However, AM can also be applied in oncology. In this area, AM can prevent the delivery of nutrients and oxygen to cancer cells and consequently interfere with tumour angiogenesis, growth and metastasis.     

Pectoralis major myocutaneous flap for hypopharyngeal reconstruction

The reconstruction of total or subtotal defects after surgical treatment for hypopharyngeal cancer is a challenging problem in head and neck surgery. The authors discuss reconstructive surgery performed in 37 patients affected by advanced hypopharyngeal cancer using the pectoralis major myocutaneous flap. In 22 cases of total pharyngolaryngectomy, the reconstructive procedure originally proposed by the authors was based on the use of a pectoralis major myocutaneous flap directly sutured to the pharyngeal and esophageal stumps and the prevertebral fascia, which eventually represented the posterior wall of the neohypopharynx. In 15 cases of subtotal pharyngolaryngectomy, the posterior wall of the neohypopharynx consisted of a residual strip of pharyngeal mucosa. In each patient, removal of the tumor and reconstruction were performed during the same operation, with only a few complications. Neither flap necrosis nor strictures were encountered; five patients had pharyngeal fistula and one patient died because of massive pneumonia. Although the use of microvascular free flaps is a reliable procedure, the pectoralis major myocutaneous flap is still applicable for hypopharyngeal reconstruction, thanks to its feasibility and low complication rate. The other reconstructive options require surgical transgression of the abdomen and/or thorax in patients affected by malnutrition and other chronic systemic disorders.