The comparison between intratympanic gentamicin prehabilitation and postoperative virtual reality exposure to standard vestibular training in patients with vestibular schwannoma.

OBJECTIVE: Resection of the vestibular schwannoma causes acute peripheral vestibular loss. The process of central compensation starts immediately afterward. The rehabilitation goal is to support this process and restore the quality of life. MATERIALS AND METHODS: In this prospective single-center study, 67 consecutive patients underwent vestibular schwannoma resection (40 females, mean age 52 ± 12 years). The patients were divided into three groups: the prehabilitation with intratympanic gentamicin group, the virtual reality group (optokinetic stimulation via virtual reality goggles in the first ten days after the surgery), and the control group. All patients were examined with objective methods and completed questionnaires before the prehabilitation, before the surgery, at the hospital discharge, and after three months. RESULTS: Intratympanic gentamicin prehabilitation leads ipsilaterally to a significant aVOR reduction in all semicircular canals (p < 0.050), the increase of the unilateral weakness in air calorics (p = 0.026), and loss of cVEMPs responses (p = 0.017). Prehabilitation and postoperative exposure to virtual reality scenes improved the patient's perception of vertigo problems according to Dizziness Handicap Inventory (p = 0.039 and p = 0.076, respectively). These findings conform with the optokinetic testing results, which showed higher slow phase velocities at higher speeds (40 deg/s) in both targeted groups compared to the control group. CONCLUSION: Preoperative intratympanic gentamicin positively affects peripheral vestibular function, influencing balance perception after VS resection. In long-term follow-up, prehabilitation and postoperative exposure to virtual reality improve patients' quality of life in the field of vertigo problems.

Does vestibular function correlate with objective MRI findings after vestibular schwannoma surgery?

Objective: Vestibular schwannoma surgery leads to acute unilateral vestibular loss. In some patients, however, the process of post-operatively initiated central compensation proceeds more rapidly than in others. This study aimed to evaluate post-operative vestibular function and correlate it with morphological findings of MRI scans. Methods: The study included 29 patients who underwent surgery for vestibular schwannoma. Vestibular function was analysed post-operatively by video head impulse test (vHIT). Subjective symptoms were evaluated using validated questionnaires. All patients underwent MRI 3 months post-operatively, and the presence of the facial and vestibulocochlear nerves in the internal auditory canal was assessed. Results: The vestibulo-ocular reflex gain measured by the vHIT correlated positively with audiological findings. Subjective perception of vestibular disorder did not correlate with objectively measured vestibular impairment or with MRI findings. Conclusions: After the resection of vestibular schwannoma, some patients may still have preserved vestibular function as measured by vHIT. The preserved function does not correlate with subjective symptoms. Patients with partially deteriorated vestibular function showed lower sensitivity to combined stimuli.

Extended high-frequency audiometry: hearing thresholds in adults.

PURPOSE: This study aimed to determine hearing thresholds in an otologically normal population without occupational noise exposure aged 18 to 64 years using extended high-frequency audiometry (EHFA). METHODS: Individuals from the general population who have never had hearing problems and whose job was not associated with noise exposure were included in the study and classified by age into 5 categories: 18-24 and, further, by 10 years of age. Each of these groups was further divided according to gender. All subjects underwent tympanometry, conventional pure-tone audiometry within the 0.125-8 kHz range, and extended high-frequency audiometry within the 9-16 kHz range, performed according to the standards. The significance level for statistical testing was set at 5%. RESULTS: Here, we established hearing thresholds in an otologically healthy population within the extended high-frequency (EHF) range (9-16 kHz). We found the EHFA to be a highly sensitive method for early detection of hearing loss, with hearing thresholds decreasing as soon as 35 years of age. In males, the hearing thresholds grew with age more rapidly than in women. The ability to respond at EHF gradually decreased with age and increasing frequency. CONCLUSION: Our results can help improve the knowledge of EHF hearing thresholds for individual sexes and age groups. So far, the standard 7029:2017 is not binding and, moreover, it only reaches up to the frequency of 12.5 kHz. EHFA is a highly sensitive method for the evaluation of hearing loss depending on age and sex.

Hearing improvement after vestibular schwannoma surgery in the era of the hearing preservation rule - case report and literature review.

OBJECTIVES: Hearing preservation after vestibular schwannoma (VS) surgery remains a surgical challenge. In some patients with preserved inner ear function, hearing improvement is achievable. As it is currently impossible to determine which patients will present this outcome, predictions must rely on previously published reports. Our case report describes a patient who experienced hearing improvement from an unuseful level to a useful one after vestibular schwannoma surgery. METHODS: Surgery was performed via suboccipital retrosigmoid approach. The patient underwent a basic audiovestibular protocol before and after the surgery - pure tone and speech audiometry, otoacoustic emissions, auditory brainstem responses, electronystagmography - together with a detailed questionnaire study. Usefulness of hearing was evaluated using the AAO-HNS guidelines, supplemented by a frequency of 4 kHz. RESULTS: Hearing was preserved and even improved from an unuseful level to a useful one. Based on the available literature, the most informative predictive factors for such a result seem to be: sudden sensorineural hearing loss prior to surgery, elicitable otoacoustic emissions and the origin from the superior vestibular nerve. CONCLUSION: There are a limited number of studies on this topic and it is still impossible to regularly improve hearing in properly selected patients. Furthermore, the importance of postoperative hearing quality compared to other symptoms and complications remains debatable.

Hemihypoglossal-facial nerve anastomosis: results and electromyographic characterization.

INTRODUCTION: The facial nerve surgery belongs to the basic procedures during lateral skull base approaches. Its damage has serious medical and psychological consequences, and therefore mastery of reconstruction and correction techniques should belong to the repertoire of skull base surgeons. The goal of this study was to demonstrate usefulness of electromyographic follow-up in facial nerve reconstruction. MATERIAL AND METHODS: A total of 16 patients underwent hemihypoglossal-facial anastomosis between 2005 and 2017. Most of the primary lesions came from vestibular schwannoma surgery. All patients were examined with electromyography and scored according to the House-Brackmann and IOWA grading scales. Function of the tongue has been evaluated. RESULTS: Ten patients achieved definitive House-Brackmann grade 3 score (62.5%). We did not observe any association with the patient's age, previous irradiation and the etiology of the damage. Electromyography showed pathological spontaneous activity after the first surgery. Incipient regeneration potentials were detected in 4-17 months (average 7.6) and reached maximum in 6.5-18 months (average 16). Electromyographic assessment of the effect of tongue movement showed better mimic voluntary activity by swallowing or by moving the tongue up. There was no relationship between the start of activity and the interval to achieving maximal activity. CONCLUSION: Hemihypoglossal-facial nerve anastomosis is a safe procedure and it is an optimal solution for cases lacking a proximal stump or in the case of reconstruction in the second stage. Electromyography can predict initial reinnervation activity after reconstructive procedures. During subsequent follow-up it can help to discover insufficiently recovering patients, however clinical characteristics are crucial.

High-Frequency Audiometry in Women with and without Exposure to Workplace Noise.

For this study, high-frequency audiometry was used to compare the hearing thresholds, with respect to age, among women exposed to noise in their working environment, as well as those not exposed to such noise. The cohort comprised 243 women (average age 36.2 years), of which 88 women were employed in a noisy (LAeq,8h 85-105 dB) workplace, while 155 women did not experience noise. Age categories were determined according to the World Health Organization (Geneva, Switzerland). Hearing thresholds were measured at frequencies of 0.125-16 kHz. Higher hearing thresholds were found in the youngest age groups (18-29 and 30-44 years) among those exposed to noise, as compared to those who were not. The difference in hearing thresholds between the exposed and unexposed groups increased with age, as well as with the frequencies. The highest difference in hearing thresholds for these age categories was measured at 11.25 kHz. The oldest age group (45-63 years) exposed to noise showed lower hearing thresholds than the unexposed group at all frequencies from 4 kHz to 16 kHz. High-frequency audiometry can be used for the early detection of increased hearing thresholds at high frequencies. High-frequency audiometry could be included in preventive programs, especially for younger people exposed to noise, in order to enable earlier detection of noise-induced hearing loss.

The Importance of Screening for Hearing Loss in the Elderly.

<b>Aim:</b> The aim was to compare hearing loss between men and women over 65 in pure tone audiometry and to evaluate the sensitivity of the abbreviated version of the Hearing Handicap Inventory (HHIE-S). This questionnaire highlights hearing handicaps in understanding speech. </br></br><b> Materials and Methods:</b> The data was collected in the years 2011-2015 from respondents above 18 years of age using a standar-dized HHIE-S questionnaire and specialized tests. The cohort was divided into groups based on the severity of hearing loss in the better ear according to the World Health Organization (WHO) as measured by tone threshold audiometry at 500 Hertz (Hz), 1000 Hz, 2000 Hz and 4000 Hz. </br></br> <b> Results:</b> Of the 7070 people (61.8% female and 38.2% male), 68.93% had hearing impairment. Most people had a slight he-aring loss. Based on HHIE-S, 56.94% reported impaired hearing. A statistically significant difference was found between the genders, but according to HHIE-S, females with impaired hearing were not statistically significantly more numerous than males. The diagnostic sensitivity of the HHIE-S was assessed in particular by its sensitivity (75.43%) and specificity (82.53%). The probability that a person has a hearing impairment when the HHIE-S test is positive is 90.21%. </br></br> <b> Conclusions:</b> The HHIE-S is fast, inexpensive and short, and can be included as a screening test for hearing impairment in ca-ring for the elderly. Even a minor hearing impairment can be a significant handicap in elderly patients by restricting not only social interactions but also weakening mental functioning.

Spectrum and frequencies of non GJB2 gene mutations in Czech patients with early non-syndromic hearing loss detected by gene panel NGS and whole-exome sequencing.

Non-syndromic autosomal recessive hearing loss is an extremely heterogeneous disease caused by mutations in more than 80 genes. We examined Czech patients with early/prelingual non-syndromic, presumably genetic hearing loss (NSHL) without known cause after GJB2 gene testing. Four hundred and twenty-one unrelated patients were examined for STRC gene deletions with quantitative comparative fluorescent PCR (QCF PCR), 197 unrelated patients with next-generation sequencing by custom-designed NSHL gene panels and 19 patients with whole-exome sequencing (WES). Combining all methods, we discovered the cause of the disease in 54 patients. The most frequent type of NSHL was DFNB16 (STRC), which was detected in 22 patients, almost half of the clarified patients. Other biallelic pathogenic mutations were detected in the genes: MYO15A, LOXHD1, TMPRSS3 (each gene was responsible for five clarified patients, CDH23 (four clarified patients), OTOG and OTOF (each gene was responsible for two clarified patients). Other genes (AIFM1, CABP2, DIAPH1, PTPRQ, RDX, SLC26A4, TBC1D24, TECTA, TMC1) that explained the cause of hearing impairment were further detected in only one patient for each gene. STRC gene mutations, mainly deletions remain the most frequent NSHL cause after mutations in the GJB2.

Assessment of visual sensation, psychiatric profile and quality of life following vestibular schwannoma surgery in patients prehabituated by chemical vestibular ablation.

AIMS: Preoperative chemical vestibular ablation can reduce vestibular symptoms in patients who have gone through vestibular schwannoma resection. The goal of this study was to determine whether chemical vestibular prehabituation influences the patients' post-operative perception of visual stimulation, mental status and quality of life. We also tried to find out whether increases of optokinetic nystagmus, measured by routine electronystagmography, correlate with subjective symptoms. METHODS: We preoperatively administered (2 months prior to surgery) 0.5 - 1.0 mL of 40 mg/mL nonbuffered gentamicin in three intratympanic instillations in 11 patients. Head impulse and caloric tests confirmed reduction of vestibular function in all patients. The control group consisted of 21 patients. Quality of life in both groups was evaluated using the Glasgow Benefit Inventory, the Glasgow Health Status Inventory and the Dizziness Handicap Inventory questionnaires. Visual symptoms and optokinetic sensation were evaluated using a specific questionnaire developed by our team and by measuring gains preoperatively and postoperatively in both groups using routine electronystagmography. The psychological profile was evaluated using the Zung Self-Rating Depression Scale and the Generalised Anxiety Disorder Assessment questionnaires. RESULTS: There were no statistically significant differences between both groups with regards to the results of the questionnaires. Patients who received preoperative gentamicin were less sensitive to visual stimulation (P<0.10) and many of them had a significantly higher gain in the optokinetic nystagmus than the control group in the preoperative stage. CONCLUSION: Pre-treatment with gentamicin helps to lower anxiety levels in patients and improves their general postoperative status. Pre-treated patients are also less sensitive to optokinetic stimulation. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03638310.

Moderate sensorineural hearing loss is typical for DFNB16 caused by various types of mutations affecting the STRC gene.

INTRODUCTION: Hearing loss is the most frequent sensory disorder and is genetically extremely heterogeneous. By far the most frequent cause of nonsyndromic autosomal recessive hearing loss (AR-NSHL) are biallelic pathogenic mutations in the GJB2 gene causing DFNB1. The worldwide search for the second most common type of AR-NSHL took almost two decades. Recently reported alterations (mostly deletions) of the STRC gene, also named DFNB16, seem to be the second most frequent cause of AR-NSHL. Genetic testing of STRC is very challenging due to the highly homologous pseudogene. Anecdotal evidence from single patients shows that STRC mutations have their typical audiological findings and patients usually have moderate hearing loss. The aim of this study is to discover if audiological findings in patients with biallelic pathogenic mutations affecting STRC have the characteristic features and shape of audiological curves and if there are genotype/phenotype correlations in relation to various types of STRC mutations. METHODS: Eleven hearing loss patients with pathogenic mutations on both alleles of the STRC gene were detected during routine genetic examination of AR-NSHL patients. Audiological examination consisted of pure tone audiometry, stapedial reflexes, tympanometry and otoacoustic emission tests. RESULTS: The threshold of pure tone average (PTA) was 46 dB and otoacoustic emissions were not detectable in these DFNB16 patients. All patients were without vestibular irritation or asymmetry. CONCLUSION: Moderate sensorineural hearing loss is typical for DFNB16-associated hearing loss and there are no significant differences in audiological phenotypes among different types of mutations affecting STRC.

The evaluation of vestibular compensation by vestibular rehabilitation and prehabilitation in short-term postsurgical period in patients following surgical treatment of vestibular schwannoma.

PURPOSE: Vestibular schwannoma removal causes unilateral vestibular deafferentation, which results in dizziness and postural unsteadiness. Vertigo and balance problems together are among the most important aspects affecting quality of life. Intensive vestibular rehabilitation, which starts before surgery, with following postsurgical supervised rehabilitation, using visual biofeedback propose an instrument to accelerate a recovery process. Another option how to accelerate the vestibular compensation, is employment of presurgical gentamicin ablation together with vestibular rehabilitation (prehabilitation) of vestibular function. Purpose of present study was to examine the dynamics of vestibular compensation process using supervised intensive vestibular rehabilitation with visual biofeedback in the short-term postsurgical period. The second aim was to compare both studied groups mainly to evaluate if prehabilitation has potential to accelerate the compensation process in the early postoperative course. METHODS: The study included 52 patients who underwent the retrosigmoid vestibular schwannoma removal. They were divided into two groups. The first group was prehabilitated with intratympanic application of gentamicin before surgery to cause unilateral vestibular loss (14 patients), the second group (38 patients) was treated in standard protocol without prehabilitation. All patients underwent at home vestibular training before surgery to learn new movement patterns. Following the surgery supervised intensive vestibular rehabilitation including visual biofeedback was employed daily in both groups between the 5th and 14th postoperative day. Outcome measurements included an evaluation of subjective visual vertical (SVV), posturography and the Activities-Specific Balance Confidence Scale (ABC). ANOVA for repeated measurements was used for statistical analysis. RESULTS: We observed significant improvement in SVV (p < 0.05), posturography parameters (p < 0.05) and ABC scores (p < 0.05) with postoperative rehabilitation program following surgery in both groups. There was no statistically significant difference between group treated by prehabilitation and group without prehabilitation. CONCLUSIONS: Results of this study showed that intensive postsurgical rehabilitation represents key factor in compensation process following retrosigmoid vestibular schwannoma surgery. Prehabilitation did not speed up recovery process.

[30 years of the cochlear implantations in the Czech Republic]. / 30 let kochleárních implantací v Ceské republice.

Cochlear implant is the unique sensory neuroprosthesis and still the only one used in clinical praxis. The function of the inner ear is replaced with direct electrical stimulation of the cochlear nerve. It is 30 years since the first cochlear implantation has been performed with the Czech single-channel cochlear neuroprosthesis. There are more than one thousand users of cochlear implants in the Czech Republic nowadays. Cochlear implants have become a standard of care of patients with severe hearing loss. It allows user inclusion to the society with only a minimum of obstacles.Key words: cochlear implant, history, neuroprosthesis, severe hearing loss.

Genome-wide Expression Profiling (with Focus on the Galectin Network) in Tumor, Transition Zone and Normal Tissue of Head and Neck Cancer: Marked Differences Between Individual Patients and the Site of Specimen Origin.

BACKGROUND/AIM: Expression profiling was performed to delineate and characterize the impact of malignancy by comparing tissues from three sites of head and neck cancer of each patient, also determining interindividual variability. MATERIALS AND METHODS: Genome-wide analysis was carried out covering the expression of 25,832 genes with quantification for each site of seven patients with tonsillar or oropharyngeal squamous cell carcinoma. Immunohistochemical analysis was performed for adhesion/growth-regulatory galectins, three pro-inflammatory chemo- and cytokines and keratins. RESULTS: Up- and down-regulation was found for 281 (tumor vs. normal) and 276 genes (transition zone vs. normal), respectively. The profile of the transition zone had its own features, with similarity to the tumor. Galectins were affected in a network manner, with differential regulation and interindividual variability between patients, also true for keratins and the chemo- and cytokines. CONCLUSION: These results underline special features at each site of specimen origin as well as the importance of analyzing galectins as a network and of defining the expression status of the individual patient prior to reaching clinically relevant conclusions.

Vertigo Perception and Quality of Life in Patients after Surgical Treatment of Vestibular Schwannoma with Pretreatment Prehabituation by Chemical Vestibular Ablation.

Surgical removal of vestibular schwannoma causes acute vestibular symptoms, including postoperative vertigo and oscillopsia due to nystagmus. In general, the dominant symptom postoperatively is vertigo. Preoperative chemical vestibular ablation can reduce vestibular symptoms postoperatively. We used 1.0 mL of 40 mg/mL nonbuffered gentamicin in three intratympanic installations over 2 days, 2 months preoperatively in 10 patients. Reduction of vestibular function was measured by the head impulse test and the caloric test. Reduction of vestibular function was found in all gentamicin patient groups. After gentamicin vestibular ablation, patients underwent home vestibular exercising for two months. The control group consisted of 10 patients who underwent only home vestibular training two months preoperatively. Postoperative rates of recovery and vertigo in both groups were evaluated with the Glasgow Benefit Inventory (GBI), the Glasgow Health Status Inventory (GHSI), and the Dizziness Handicap Inventory questionnaires, as well as survey of visual symptoms by specific questionnaire developed by us. There were no statistically significant differences between both groups with regard to the results of questionnaires. Patients who received preoperative gentamicin were more resilient to optokinetic and optic flow stimulation (p < 0.05). This trial is registered with clinical study registration number NCT02963896.

Microarray analysis of serum mRNA in patients with head and neck squamous cell carcinoma at whole-genome scale.

With the increasing demand for noninvasive approaches in monitoring head and neck cancer, circulating nucleic acids have been shown to be a promising tool. We focused on the global transcriptome of serum samples of head and neck squamous cell carcinoma (HNSCC) patients in comparison with healthy individuals. We compared gene expression patterns of 36 samples. Twenty-four participants including 16 HNSCC patients (from 12 patients we obtained blood samples 1 year posttreatment) and 8 control subjects were recruited. The Illumina HumanWG-6 v3 Expression BeadChip was used to profile and identify the differences in serum mRNA transcriptomes. We found 159 genes to be significantly changed (Storey's P value <0.05) between normal and cancer serum specimens regardless of factors including p53 and B-cell lymphoma family members (Bcl-2, Bcl-XL). In contrast, there was no difference in gene expression between samples obtained before and after surgery in cancer patients. We suggest that microarray analysis of serum cRNA in patients with HNSCC should be suitable for refinement of early stage diagnosis of disease that can be important for development of new personalized strategies in diagnosis and treatment of tumours but is not suitable for monitoring further development of disease.

Upregulation of IL-6, IL-8 and CXCL-1 production in dermal fibroblasts by normal/malignant epithelial cells in vitro: Immunohistochemical and transcriptomic analyses.

BACKGROUND INFORMATION: Considering an analogy between wound healing and tumour progression, we studied chemokine and cytokine transcription and expression in normal fibroblasts by co-culture and in situ. RESULTS: Whole-genome transcriptome profiling revealed strong upregulation for the interleukin (IL)-6, IL-8 and the chemokine CXCL-1 in in vitro co-cultures of normal fibroblasts with either normal or malignant epithelial cells compared to fibroblast cultures. The same ILs/chemokines were distinctly upregulated in clinical samples of squamous cell carcinoma when compared with paired normal mucosae. Analysis of culture supernatants showed that during the course of co-culture of the fibroblasts with the epithelial cells, IL-6, IL-8 and CXCL-1 were secreted to the culture medium. Experiments with addition of any of the proteins to the culture medium supported the notion that these ILs/chemokines strongly contributed to maintenance of a low-differentiation phenotype of epithelial cells, evaluated by the detection of keratin-8. Simultaneous addition of all factors increased the extent of the effect. These studies were extended by experiments with epithelial cells, either cultured in medium conditioned by preceding use for malignant keratinocytes without and in the presence of normal or cancer-associated fibroblasts or medium containing antibodies against IL-6, IL-8 and CXCL-1. CONCLUSIONS: Our results indicate an analogy between wound healing and tumour growth, support the importance of epithelial-mesenchymal interaction in this model system and establish a potential bio-inspired anticancer therapy.

Smooth muscle actin-expressing stromal fibroblasts in head and neck squamous cell carcinoma: increased expression of galectin-1 and induction of poor prognosis factors.

Tumor stroma is an active part influencing the biological properties of malignancies via molecular cross-talk. Cancer-associated fibroblasts play a significant role in this interaction. These cells frequently express smooth muscle actin and can be classified as myofibroblasts. The adhesion/growth-regulatory lectin galectin-1 is an effector for their generation. In our study, we set the presence of smooth muscle actin-positive cancer-associated fibroblasts in relation to this endogenous lectin and an in vivo competitor (galectin-3). In squamous cell carcinomas of head and neck, upregulation of galectin-1 presence was highly significantly correlated to presence of smooth muscle actin-positive cancer-associated fibroblasts in the tumor (p = 4 × 10(-8)). To pinpoint further correlations on the molecular level, we applied microarray analyses to the transcription profiles of the corresponding tumors. Significant correlations of several transcripts were detected with the protein level of galectin-1 in the cancer-associated fibroblasts. These activated genes (MAP3K2, TRIM23, PTPLAD1, FUSIP1, SLC25A40 and SPIN1) are related to known squamous-cell-carcinoma poor-prognosis factors, NF-κB upregulation and splicing downregulation. These results provide new insights into the significance of presence of myofibroblasts in squamous cell carcinoma.

Complications of total laryngectomy in the era of chemoradiation.

As more total laryngectomies (TLE) are nowadays performed as salvage procedures, the rate of postoperative complications increases. The primary aim was to report the rates of postoperative local complications for total laryngectomy in patients with previous radiotherapy or chemoradiotherapy (RT/CRT) in comparison with primary TLE data. We attempted to identify patient- and tumor-related factors predictive of postoperative pharyngocutaneous fistula (PCF) formation. The secondary aims were to analyze the survival rate in relation to postoperative complications and to study prognostic factors of survival in TLE patients. A retrospective study was conducted in 208 patients. Logistic regression was used to determine the most significant risk factors for fistula formation. Survival was analyzed by the Kaplan-Meier method, log-rank test, and Cox multivariate regression. PCF developed in 20.7% of cases. In the group of patients with previous RT/CRT, the fistula rate was significantly higher (34%). In multivariate analysis, significant risk factors for fistula formation were previous radiotherapy or chemoradiotherapy (p = 0.02), higher N classification (p = 0.03), and procedure performed by a less experienced surgeon (p = 0.003). The survival and recurrence rates were not influenced by PCF formation. The overall survival rates were lower in patients with previous RT/CRT and in patients with lymph node involvement.

Epithelial-stromal interaction in squamous cell epithelium-derived tumors: an important new player in the control of tumor biological properties.

Mesenchymal-epithelial interaction is important in the morphogenesis of squamous epithelia and their appendages, and in the control of the hair cycle postnatally. This review summarizes data regarding the interaction between stromal fibroblasts and tumor cells, with an emphasis on tumors originating from squamous epithelium. Tumor stromal fibroblasts as important element of the cancer stem cell niche are able to participate in the control of the biological properties of tumors. We propose these stromal cells and their products as novel targets for anticancer therapy.

Head and neck squamous cancer stromal fibroblasts produce growth factors influencing phenotype of normal human keratinocytes.

Epithelial-mesenchymal interaction between stromal fibroblasts and cancer cells influences the functional properties of tumor epithelium, including the tumor progression and spread. We compared fibroblasts prepared from stroma of squamous cell carcinoma and normal dermal fibroblasts concerning their biological activity toward normal keratinocytes assessed by immunocytochemistry and profiling of gene activation for growth factors/cytokines by microarray chip technology. IGF-2 and BMP-4 were determined as candidate factors responsible for tumor-associated fibroblast activity that influences normal epithelia. This effect was confirmed by addition of recombinant IGF-2 and BMP4, respectively, to the culture medium. This hypothesis was also verified by inhibition experiments where blocking antibodies were employed in the medium conditioned by cancer-associated fibroblast. Presence of these growth factors was also detected in tumor samples.