Wojciech Golusiński

Oral cavity and oropharyngeal squamous cell carcinoma in young adults: a review of the literature

Abstract Background. Head and neck squamous cell carcinoma (HNSCC) is a disease of middle-aged to elderly adults. However, an increased incidence of HNSCC in young people under 45 years of age has been reported recently. In the present review, we focused on the epidemiology and aetiology of HNSCC in adults under 45 years of age. Methods. We reviewed literature related to HNSCC in adult patients less than 45 years of age and discussed current treatment options and prognosis. Results. HNSCC in young adults is associated with a higher incidence rate in nonsmokers, lower female-to-male ratio, a higher percentage of oral cavity and oropharynx tumours, and fewer second primary tumours. However, aside from traditional risk factors of tobacco and alcohol exposure, the causes of these cancers in young adults remain unclear. Agents that might contribute to risk include infection with high-risk human papillomavirus subtypes as well as genetic factors or immunodeficiency status. The expected increase in incidence and mortality of the young with HNSCC may become a major public health concern if current trends persist, particularly lifestyle habits that may contribute to this disease. Conclusions. Given the younger age and potential long-term adverse sequelae of traditional HNSCC treatments, young adults should be treated on a case-by-case basis and post-therapy quality of life must be considered in any treatment-decision making process.

Assay-based response evaluation in head and neck oncology: requirements for better decision making

This article gives an overview on different current strategies of assay-based response evaluation in head and neck squamous cell carcinomas (HNSCC) and critically summarizes their role and needs for future clinical evaluation. Due to a growing amount of data of phase III clinical trials of multimodality treatment options for HNSCC, treatment planning in regard to optimal outcome is becoming an interdisciplinary challenge. New concepts such as induction chemotherapy with bi- or ternary combinations of chemotherapeutics, integration of targeted therapies, concurrent and sequential chemoradiation concepts, and multimodality-based organ preservation strategies strongly compete with traditional definitive surgical procedures. Moreover, the outcome is difficult to predict due to heterogeneity of a tumor’s response, impaired late functional outcome, and increased late toxicity if simultaneously applied to radiation. Retrospectively looking at non-responders with tumors classified as resectable, primary surgery is very likely to have achieved better results, since chemoradiation causes a high degree of early and late toxicities leading to extremely complicated terms and conditions in surgery following current multimodal therapeutic strategies. Unfortunately, predictive information on response characteristics of a given tumor before starting the therapy is not available in daily routine, although heterogeneity in response of a given tumor entity to treatments has been known for decades. Therefore, current therapy strategies for HNSCC still have to ignore this fact, creating an urgent need for the development of proper predictive assays. There are interesting clinical observations showing that response on induction chemotherapy may predict the outcome after radiotherapy. Some trials use this empiric phenomenon to pre-select non-responders for primary surgical treatment avoiding severe salvage complications after failure of complete chemoradiation treatment. Moving one step further, recent literature and our own investigations implicate that response evaluation of the individual patient’s HNSCC in a suitable ex vivo assay just before starting the treatment is mature for clinical research. To this end, essential needs and hints are addressed and discussed.

Treatment of recurrent respiratory papillomatosis and adverse reactions following off-label use of cidofovir (Vistide®)

Recurrent respiratory papillomatosis (RRP) is caused by a human papilloma virus (HPV). It is a rare, sometimes debilitating disease compromising voice and airway. RRP is characterized by a variable course of disease, potentially leading to frequent annual surgical procedures, the number of which may exceed a hundred during the life time. The therapy focuses on surgical removal of the mucosal lesions in order to keep the airway open and the voice satisfactory. Till now, there is no curative therapy for the virus infection in itself. As recurrent surgery alone has proven to be insufficient in many cases, adjuvant therapy is increasingly being used. One of the mainstays of adjuvant therapy is the administration of intralesional cidofovir (Vistide®). Cidofovir is an antiviral agent, registered for the treatment of cytomegalovirus (CMV) retinitis in patients with AIDS. Since 1998 the drug has been used to treat patients with RRP [1]. Cidofovir can be regarded as a prodrug. It exerts the antiviral effect by decreasing the efficiency of DNA transcription following incorporation into the growing DNA chain [2]. Its use has been advocated in cases of papilloma refractive to repeated surgery, either due to its spread, or to its recurrence rate. Some case reports and series showed the effect of cidofovir treatment with few or no side effects [3–8]. The only prospective double-blind randomized controlled trail showed a significant improvement in the Derkay severity score between the cidofovir and placebo group but failed to show significant benefit in number of procedures performed [9]. On January 31 2011, an alarming news was communicated by Gilead (the producer of cidofovir) concerning very serious side effects of its off-label use [10]. The warning included reports on nephrotoxicity, neutropenia, oncogenicity and even some fatalities. The manufacturer emphasized that cidofovir is formulated for intravenous infusion only and the indication is CMV infection of AIDS patients. The manufacturer did not specify the severity of the reported complications, neither the off-label indication of the drug nor its way of administration. Unfortunately, up to the end of May 2011 the above mentioned communication was not received by the laryngologists in most countries. The warning caused a lot of discussion within the European Laryngological Society (ELS). The ELS (having >350 active members) is the main laryngological organization in Europe, representing laryngologists from more than 55 countries on all continents (http://www.elsoc.org). The ELS has taken its responsibility and initiated a research project on the side effects of off-label use of cidofovir in RRP patients. The purpose of such a study is to determine whether there are known nephrotoxic, neutropenic, or oncogenic side effects after having used intralesional cidofovir in patients with RRP. Facts are needed to decide whether or not intralesional use of cidofovir in the larynx is safe or not. Side effects might be dose dependent, and occur as a consequence of the number of administrations, the interval between applications or the cumulative dose. To determine the aforementioned, a multicenter retrospective analysis has been initiated among members of the ELS for which, among others, all members of its Scientific Council have been approached. Parallel to the retrospective study we are conducting an update on reported side effects in the literature. Reports of the studies will be submitted for publication in the official journal of the ELS, the European Archives of Otorhinolaryngology, Head and Neck Surgery.

Safety of intralesional cidofovir in patients with recurrent respiratory papillomatosis: an international retrospective study on 635 RRP patients

Intralesional use of cidofovir (Vistide®) has been one of the mainstays of adjuvant therapy in patients with recurrent respiratory papillomatosis (RRP) since 1998. In 2011, a communication provided by the producer of cidofovir addressed very serious side effects concerning its off-label use. As this was a general warning, it was inconclusive whether this would account for its use in RRP. The aim of this study is to determine whether nephrotoxic, neutropenic, or oncogenic side effects have occurred after intralesional use of cidofovir in patients with RRP. Update of recent developments in RRP, a multicentre questionnaire and a multicentre retrospective chart review. Sixteen hospitals from eleven countries worldwide submitted records of 635 RRP patients, of whom 275 were treated with cidofovir. RRP patients received a median of three intralesional injections (interquartile range 2–6). There were no statistical differences in occurrence of neutropenia or renal dysfunction before and after cidofovir. There was no statistical difference in occurrence of upper airway and tracheal malignancies between the cidofovir and the non-cidofovir group. In this retrospective patient chart review, no clinical evidence was found for more long-term nephrotoxicity, neutropenia or laryngeal malignancies after the administration of intralesional cidofovir in RRP patients.

A comprehensive analysis of selected diagnostic methods with respect to their usefulness in evaluating the biology of neoplastic cells in patients with laryngeal cancer

Abstract The difficult and complicated mechanism of cancer development with little knowledge about the biology of existing cancers can lead to a permanent search for new examination techniques to improve the precision of life expectancy in patients and the selection of the most efficient methods of treatment. The aim of this study was to analyze certain prognostic factors, i.e., p53, Ki67, proliferating cell nuclear antigen (PCNA), DNA ploidy and cell proliferating activity, as well as the degree of morphological differentiation and cell maturity evaluated on an ultrastructural level in patients with laryngeal cancers in connection with data obtained from follow-up examinations and the clinical course of the disease. Neoplastic tissue was taken from 120 patients with laryngeal cancers. All underwent surgical treatment, radiotherapy and combined treatment in the Department of Otolaryngology, Karol Marcinkowski University School of Medical Sciences, Poznań, Poland, and the Department of Otolaryngology – Head and Neck Surgery, Haukeland University, Bergen, Norway. Before beginning treatment all patients underwent histological verification of their neoplastic tissues. Histopathological examination proved that the majority of cases (95%) had a squamous cell carcinoma. The occurrence of changes within the lymph nodes of the neck (N) was significantly correlated with T, S, Ki67, metastases to lymph nodes, DNA ploidy, site and surgery performed. The degree of clinical progression (S) was intercorrelated with T, N, p53, Ki67, PCNA, DNA ploidy, site and laryngectomy. The occurrence of oncoprotein p53 in neoplastic cells was measured by the staining degree of their nuclei and was correlated with T, S, DNA ploidy, metastases to lymph nodes, PCNA and site. The degree of staining of neoplastic cells for the nuclear antigen Ki67 was correlated to T, N, G, S, DNA ploidy, metastases to lymph nodes and surgical treatment. The proliferative antigen PCNA in the examined population of patients was intercorrelated with T, p53, Ki67, metastases to lymph nodes and surgical treatment. The results obtained from DNA flow cytometry could be associated with N, G, p53, Ki67 and metastases to lymph nodes. On the basis of the results obtained, the techniques suggested for the morphological and biological evaluation of neoplastic cells in cancer of the larynx should include TNM classification + G + DNA + p53 + Ki67.

Analysis of chromosome aberrations in cell lines derived from laryngeal cancer in relation to tumor progression

Abstract Cell lines provide a good model for studies on molecular and cellular events accompanying neoplastic transformation and cancer progression. The data in recent literature suggest an occurrence of repetitive chromosome aberrations that can be linked with particular stages of cancer. Ten cell lines derived from squamous cell carcinoma of the larynx at the University of Turku were karyotyped. The studied cell lines represented a variety of primary locations of the tumors, TNM staging and histological grading. Karyotyping was done by the classical cytogenetic technique with the application of GTG, QFQ and other banding techniques; some complex aberrations were analyzed by the FISH technique. The results document several numerical and structural aberrations. Attention was focused on the monosomy of chromosomes 13, 17 and 18, frequent deletions of the Y chromosome. Structural aberrations were frequently seen at chromosomes 1, 3, 4, 7, 8, 9 and 11, mostly as deletions (usually deletions of a whole arm), translocations, isochromosomes, duplications and marker chromosomes. The study is in progress and aims to find a correlation between particular aberrations and disease staging. At present, two observations seem to be firm: the amplification of the 11q13 region appeared in tumors with a short survival. However, the primary location of the tumor should be taken into account when considering 11q13 as a prognostic marker. The same is applicable for del(9p), which indicates an early stage of disease. Besides the frequent chromosome aberrations, attention should be paid to marker chromosomes that are potentially specific for laryngeal cancer.

Molecular mechanisms of glucocorticoids action: implications for treatment of rhinosinusitis and nasal polyposis

Intra-nasal glucocorticoids are the most effective drugs available for rhinosinusitis and nasal polyposis treatment. Their effectiveness depends on many factors and not all of them have been well recognized so far. The authors present the basic information on molecular mechanisms of glucocorticoid action, direct and indirect effects of glucocorticoids on transcription of genes encoding inflammatory mediators. They focus on recently proved nongenomic mechanisms which appear quickly, from several seconds to minutes after glucocorticoid administration and discuss clinical implications resulting from this knowledge. Discovery of nongenomic glucocorticoid actions allows for better use of these drugs in clinical practice.

Expression levels of insulin-like growth factors 1 and 2 in head and neck squamous cell carcinoma

Insulin-like growth factors (IGF) 1 and 2 are known as potential mitogens for normal and neoplastic cells. IGF2 is a main fetal growth factor while IGF1 is activated through growth hormone action during postnatal growth and development. However, there is strong evidence that activation of IGF2 by its E2F transcription factor 3 (E2F3) is present in different types of cancer. Also high levels of IGF1 strongly correlate with cancer development due to anti-apoptotic properties and enhancement of cancer cell differentiation, which can be attenuated by IGFBP3. Head and neck cancer is known as one of the six most common human cancers. The main risk factor for head and neck cancer is consumption of tobacco and alcohol as well as viral infection and bacterial infection by stimulation of chronic local inflammation. There is also a genetic basis for this form of cancer; however, the genetic markers are not yet established. In this study we investigated the levels of the expression of IGF2, IGF1, E2F3 and IGFBP3 in human cancers and healthy tissues surrounding the tumor obtained from each of 41 patients. Our study indicated that there is no alteration of the levels of expression of IGF2, E2F3 and IGF1 in head and neck squamous cell carcinoma (HNSCC) cases studied in selected experimental population, but there was evidence for upregulation of pro-apoptotic IGFBP3 in cancer when comparing to healthy tissue. These important findings indicate that insulin-growth factors are not directly associated with HNSCC showing some variability between patients and location of tumor. However, elevated level of IGFBP3 suggests possible regulatory role of IGF signal by its binding protein in this type of tumor.

Alteration of p53 gene structure and function in laryngeal squamous cell cancer.

The p53 gene is known as an anti-oncogene that manifests its function by controlling the cell cycle and is responsible for apoptosis of cells with unrepaired DNA. An accelerated p53 protein synthesis is the first response of a cell following DNA damage. However, mutations of the p53 gene can disturb protein synthesis or may be responsible for synthesis of a changed protein unable to control the cell cycle. Laryngeal tissue specimens from 120 patients were tested by immunohistopathological staining to detect mutated wild-type p53 protein. It was found that p53-positive specimens correlated with TNM staging and histopathological grading. Another indication of entering the cell cycle and undertaking an active proliferation by laryngeal cells was shown by detection of proliferating cell nuclear antigen (PCNA) and Ki67 nuclear antigen, which appeared in proliferating cells (late G1, S-G2 and M phase), but was absent in resting cells. Scoring of the staining for p53 protein, PCNA and Ki67 correlated with each other. DNA from 40 specimens was then isolated, amplified by polymerase chain reaction and analysed by single-strand conformation polymorphism and DNA sequencing for mutation in the p53 gene. Fifteen DNA samples were found to be positive, while mutations were detected in exons 5–8 in 13 samples. The majority of mutations were found in tissue specimens from T3 and T4 tumors. A possible explanation is almost half was attributable to genotoxic effects of tobacco smoking. Changes in the p53 gene and its products may also reflect early changes in laryngeal carcinogenesis and be of prognostic value.

Assessment of the influence of osteopathic myofascial techniques on normalization of the vocal tract functions in patients with occupational dysphonia.

ObjectivesOccupational voice disorders are accompanied by increased tension of the external laryngeal muscle which changes the position of the larynx and consequently disturbs the conditions of functioning of the vocal tract. The aim of the study is to assess the use of osteopathic procedures in the diagnosis and treatment of occupational dysphonia.Material and MethodsStudy subjects included 40 teachers with chronic diseases of the voice organ (38 women and 2 men) aged from 39 to 59 (mean age: 48.25). Before and after the voice therapy the osteopathic examination according to Libermann’s protocol was performed as well as phoniatric examination including laryngovideostroboscopy (LVSS), assessment of the maximum phonation time (MPT) and the Voice Handicap Index (VHI) score. The voice therapy, scheduled and supervised by a laryngologist-phoniatrician and conducted by a speech-language pathologist, was supplemented with osteopathic myofascial rehabilitation of the larynx. The chi-square McNemar test and non-parametric Wilcoxon matched pairs test were applied in the statistical assessment.ResultsThe applied interdisciplinary treatment including osteopathic and vocal therapy resulted in a statistically significant decrease in tenderness of muscles raising the larynx (cricothyroid ligament, sternocleidomastoid muscles, and pharyngeal constrictor muscles) and in lowering the tonus (geniohyoid muscles, pharyngeal constrictor muscles and sternocleidomastoid muscles). A significant improvement was also observed in the case of dysfunction of the cricothyroid joint examined during glissando and yawning, as well as in asymmetry of the thyrohyoid apparatus. Moreover, the therapy resulted in significantly better normalization of the head position and better control of the centre of gravity of the body. Statistically significant post-therapy improvement was observed in the phoniatric examination, including VHI scores, MPT results and parameters of videostroboscopic examination.ConclusionsThe use of osteopathic therapy helps significantly improve the functions of the vocal tract in patients with occupational dysphonia.