Gemeinsame Stellungnahme der Deutschen Gesellschaft für HNO-Heilkunde, Kopf- und Hals-Chirurgie (DGHNO-KHC) und des Deutschen Berufsverbandes der HNO-Ärzte (BVHNO) für ärztliches Personal in der Hals-, Nasen- und Ohrenheilkunde/Kopf- und Hals-Chirurgie zum Arbeiten in der Schwangerschaft und Stillzeit.

Working during pregnancy and breastfeeding is a special situation for both the employee and the employer/supervisor. The amended version of the Maternity Protection Act (MuSchG), which came into force on January 1st, 2018, protects the health of women and their children while working, training or studying during pregnancy, after giving birth and while breastfeeding. Women should be able to continue their employment or related activities during this time without jeopardising their health or that of their child. This law was furthermore reformed to prevent discrimination against the working mother during this time. In order to create the best and safest possible framework conditions for employment during pregnancy and breastfeeding, the DGHNO-KHC and the BVHNO would like to present a "general positive list" and a "positive list for surgical activities" as part of this statement, which should serve as a guideline for all relevant parties. This agreed positive list is intended to enable pregnant and breastfeeding doctors to carry out patient-related activities as well as head and neck surgeries in accordance with the MuSchG of 2018. Hereby, affected colleagues should have the opportunity to continue working self-determined.

Patients' Reflections on Treatment Decision After Surgery for Laryngeal Cancer.

Importance: Clinicians should understand how patients who were treated with laryngeal cancer surgery think about this later on and what factors may be related with regretting surgery. Objective: To assess variables associated with a positive attitude toward laryngeal cancer surgery. Design, Setting, and Participants: This combination of 2 cohorts, based on patient interviews and questionnaires, was studied in 16 hospitals in Germany. Participants scheduled for laryngeal cancer surgery were enrolled before surgery and followed up until 1 year after surgery. Data collection began on November 28, 2001, and ended on March 15, 2015. Statistical analysis was performed from August 21, 2023, to January 19, 2024. Main Outcomes and Measures: The attitude toward surgery was measured with the Psychosocial Adjustment After Laryngectomy Questionnaire (scores range from 0 to 100, with high scores representing a positive attitude toward the surgery) at 1 year after surgery. In multivariate regression analysis, the following variables were investigated: type of surgery, number of surgeries to the larynx, receipt of radiotherapy and chemotherapy, quality of life, speech intelligibility (objectively measured), age, sex, educational level, employment status, having a partner or not, counseling by patient association, and shared decision-making. Results: Patients (n = 780; mean [SD] age, 60.6 [10.4] years; 701 [90%] male) who had received counseling from the patient association reported a more positive attitude toward surgery (adjusted B = 8.8; 95% CI, 1.0-16.6). Among patients after total laryngectomy, those with a university degree had a less positive attitude toward their surgery (adjusted B = -50.8; 95% CI, -84.0 to -17.6); this result was not observed in patients after partial laryngectomy (adjusted B = -4.8; 95% CI, -15.1 to 5.4). Among patients after partial laryngectomy, the attitude toward surgery was most positive in those who had experienced shared decision-making (mean [SD] questionnaire score, 84 [20] in those without a wish and 83 [20] in those with a wish for shared decision-making). Those who had wished they could decide together with the physician but where this eventually was not experienced expressed the most regret toward surgery (mean [SD] score, 71 [22]). There was no association between attitudes toward surgery and type of surgery (total vs partial laryngectomy) and all other variables tested. Conclusion and Relevance: In this cohort study, most patients with head and neck cancer reported a positive attitude toward surgery, suggesting low levels of decision regret. Counseling by members of patient associations as well as individualized shared decision-making prior to surgery may have a positive impact on decision regret and is advisable in daily practice.

Tolerability and efficacy of the cancer vaccine UV1 in patients with recurrent or metastatic PD-L1 positive head and neck squamous cell carcinoma planned for first-line treatment with pembrolizumab - the randomized phase 2 FOCUS trial.

Background: Globally, head and neck squamous cell carcinoma (HNSCC) is the seventh most common malignancy. Despite aggressive multimodal treatment approaches, recurrent and/or metastatic (R/M) disease develops in >50% of patients. In this setting, pembrolizumab was approved for patients with PD-L1 expression. However, response rates with checkpoint inhibitor monotherapy remain limited and strategies to strengthen tumor-directed immune responses are needed. Objective: The FOCUS trial is designed to estimate the effectiveness of UV1 vaccination in combination with pembrolizumab versus pembrolizumab as a single agent in patients with R/M HNSCC. Methods and analysis: The FOCUS trial is a two-armed, randomized, multicenter phase II study which was designed to evaluate the efficacy and feasibility of the hTERT-targeted cancer vaccine UV1 as add-on to pembrolizumab in the 1st line treatment of patients with R/M PD-L1 positive (combined positive score ≥1) HNSCC. Secondary objectives are the exploration of patient subgroups most likely deriving benefit from this novel combination and the establishment of liquid biopsy tumor monitoring in HNSCC. Ethics and dissemination: This clinical study was designed and will be conducted in compliance with Good Clinical Practice and in accordance with the Declaration of Helsinki. It is intended to publish the results of this study in peer-reviewed scientific journals and to present its content at academic conferences. Conclusions: A significant number of patients with R/M HNSCC are frail and may not tolerate chemotherapy, these patients may only be suitable for pembrolizumab monotherapy. However, long term disease stabilizations remain the exception and there is a need for the development of efficacious combination regimens for this patient population. The FOCUS study aims to optimize treatment of R/M HNSCC patients with this promising new treatment approach. Clinical Trial Registration: https://clinicaltrials.gov/study/NCT05075122, identifier NCT05075122.

Prevalence of Obstructive Sleep Apnea in Head and Neck Squamous Cell Carcinoma Patients before and after Treatment.

Background and Objectives: Obstructive sleep apnea (OSA) is common not only in the general population but even more so in patients with tumors of the head and neck region. Untreated, it leads to reduced quality of life, increased daytime sleepiness, and other comorbidities. The aim of this study was to determine the difference in the occurrence of OSA in the patient population with head and neck tumors compared with the general population as represented by the Trend cohort of the Study of Health in Pomerania (SHIP), and to assess the influence of tumor treatment. Materials and Methods: Between July 2018 and December 2021, preoperative polysomnography was conducted in 47 patients with histologically confirmed squamous cell carcinoma in the oropharynx, hypopharynx, or larynx. A follow-up polysomnography was performed in 23 patients 2-11 months after completing treatment. The collected data were correlated with tumor treatment and tumor size. Results: Of the included patients, 43 were male and 4 were female. Age ranged from 54 to 90 years. The pretherapeutic measurement found no significant difference in the prevalence of a pathologically elevated apnea-hypopnea index (AHI) in our patients compared with the SHIP Trend cohort. In the follow-up measurement after completion of treartment, a significant deterioration in AHI was observed. Initially, 70% of patients had an AHI > 5; after therapy, this increased to 87% (p = 0.008). The effect was particularly pronounced in the group of patients with advanced tumor stages who had received primary chemoradiation. Conclusions: OSA is a relevant condition in patients with head and neck cancer. Tumor treatment can lead to an increased occurrence of sleep-related breathing disorders, especially in patients with advanced tumor stages undergoing primary chemoradiation. Additional studies are necessary to better understand the exact mechanism involved.

[Patient-reported outcomes in head and neck cancer treatment: relevance, challenges, and benefit]. / Patientenberichtete Endpunkte in der Kopf-Hals-Tumortherapie: Relevanz, Herausforderungen und Nutzen.

Next to overall survival, quality of life is becoming more and more pivotal for cancer patients. The various domains of quality of life are complex and have different value to each patient. However, not only patients but also health care professionals, the pharmaceutical industry, and regulatory bodies ask: How can quality of life be reliably ascertained in clinical trials? For this purpose, carefully developed and validated specific questionnaires are needed: the patient-reported outcome measures (PROMs). A key challenge is to define how results based on PROMs can be used for shared decision-making. Next to clinical factors such as health and nutritional status, quality of life acts as a prognostic factor for overall survival in cancer. Thus, it is crucial to take quality of life into account in daily clinical practice.

[Current trends in liquid biopsy and diagnostics-contributions from ASCO and ESMO 2022]. / Aktueller Stand zu "liquid biopsy" und Diagnostik ­ Beiträge vom ASCO und ESMO 2022.

BACKGROUND: Liquid biopsy is a promising new diagnostic tool that is already used in clinical practice for multiple tumor entities and which also has great potential for head and neck cancer. Herein, the authors discuss a selection of publications from the American Society of Clinical Oncology (ASCO) and European Society of Medical Oncology (ESMO) meetings in 2022. OBJECTIVE: Relevant publications are evaluated and summarized. METHODS: Using a databank inquiry, abstracts from the 2022 ASCO and ESMO conferences regarding liquid biopsy and related diagnostics for head and neck squamous cell carcinoma were collected. Work without relevant data and statements of intent were not included. Duplicate articles across conferences were only quoted once. A total of 532 articles were screened, 50 articles were selected for further review, and 9 articles were selected for presentation. RESULTS: Six articles on cell- and RNA-based liquid biopsy and three articles on more general diagnostic tools in the treatment of head and neck cancer are presented. The results are discussed in relation to current treatment standards. CONCLUSION: Multiple studies show promising results for the use of circulating tumor DNA (ctDNA) for treatment surveillance in head and neck cancer. Integration into clinical practice will depend on larger study cohorts and sinking costs.

[Suitability of determining percentage hearing loss for monitoring cochlear implant rehabilitation]. / Eignung der Bestimmung prozentualer Hörverluste zum Monitoring der Cochlea Implantat Rehabilitation.

BACKGROUND: Calculation of percentage hearing loss (pHV) from the pure-tune audiogram according to Röser in 1973 or from the speech audiogram according to Boenninghaus and Röser in 1973 is a method still applied for quantitative assessment of hearing. However, this is not common for the evaluation of postoperative results of implantable hearing systems. During the regular work-up after cochlear implantation (CI) in Germany, all necessary parameters are available for calculation of pHV either from categorical loudness scaling (pHVKLS) or speech-recognition threshold (pHVFB). OBJECTIVE: The parameters pHVKLS and pHVFB are introduced and calculated from data available from clinical routine. Their potential applicability for assessment of the result of CI is evaluated. MATERIALS AND METHODS: This study comprises retrospective chart review of audiological parameters from 66 CI procedures in one tertiary referral center. pHVKLS was calculated from the equal loudness curve 5 CU, pHVFB from the Freiburg speech test in free field. RESULTS: While pHVKLS shows small variation, the variation in pHVFB is initially larger but decreases over time. Furthermore, starting from initial fitting, the mean pHV shows convergence over time. The difference between pHVFB and pHVKLS is positive and statistically significant. CONCLUSION: It is possible to calculate pHVKLS and pHVFB from routine data. A correlation of the difference between pHVFB and pHVKLS with successful CI performance seems plausible.

Recapitulating the Pharmacological Interactions of Cetuximab with Sunitinib and Cisplatin in Head and Neck Carcinoma Cells in vitro.

INTRODUCTION: Cisplatin is extensively used in the treatment of head and neck carcinomas. Cetuximab combination therapy is employed in recurrent and metastatic settings. Sunitinib showed positive results in the treatment of head and neck carcinomas, both as monotherapy or in combination with cetuximab. Nonetheless, the mechanism governing these pharmacological interactions is largely unresolved. This study investigates the impact of cetuximab on the cytotoxicity of cisplatin and sunitinib using cells representative of head and neck carcinoma and the oral epithelium. METHODS: The uptake and efflux activities of cells were determined using the prototypical fluorescent substrates 4-[4-[dimethylamino]styryl)-1-methyl pyridinium iodide, Hoechst 33342, and calcein-AM in the presence or absence of specific inhibitors in cells pretreated with cetuximab. The expression of key uptake and efflux drug transporters was analyzed using qPCR and immunofluorescence. Cisplatin and sunitinib cytotoxicities after cetuximab pretreatment were evaluated using the PrestoBlue viability assay. RESULTS: Both tumor and nontumor cells showed significant active drug transport activity. Cetuximab substantially deregulated the expression of key transporters involved in drug resistance in head and neck cancer cells. Transporter expression in the nontumor cell was unaffected. Upon cetuximab pretreatment, the half maximal effective toxic concentration of cisplatin was reduced by 0.75-fold and sunitinib by 0.82-fold in cancer cells. Nontumor cells were not sensitive to cisplatin or sunitinib under the conditions tested. CONCLUSION: Cetuximab regulates the expression and activity of key membrane drug transporters in head and neck cancer cells, involved in drug resistance. The deregulation of the transport mechanism behind cisplatin and sunitinib uptake reverses drug resistance and enhances the cytotoxicity of both drugs.

Population Based Average Parotid Gland Volume and Prevalence of Incidental Tumors in T1-MRI.

Representative epidemiologic data on the average volume of the parotid gland in a large population-based MRI survey is non-existent. Within the Study of Health in Pomerania (SHIP), we examined the parotid gland in 1725 non-contrast MRI-scans in T1 weighted sequence of axial layers. Thus, a reliable standard operating procedure (Intraclass Correlation Coefficient > 0.8) could be established. In this study, we found an average, single sided parotid gland volume of 27.82 cm3 (95% confidence interval (CI) 27.15 to 28.50) in male and 21.60 cm3 (95% CI 21.16 to 22.05) in female subjects. We observed positive associations for age, body mass index (BMI), as well as male sex with parotid gland size in a multivariate model. The prevalence of incidental tumors within the parotid gland regardless of dignity was 3.94% in the Northeast German population, slightly higher than assumed. Further epidemiologic investigations regarding primary salivary gland diseases are necessary.

Investigating the Association Between the Co-Occurrence of Behavioral Health Risk Factors and Sick Days in General Hospital Patients.

Objectives: To investigate the co-occurrence of 4 behavioral health risk factors (BHRFs), namely tobacco smoking, alcohol at-risk drinking, physical inactivity and unhealthy diet and their association with sick days prior to hospitalization in general hospital patients. Methods: Over 10 weeks (11/2020-04/2021), all 18-64-year-old patients admitted to internal medicine, general and trauma surgery, and otorhinolaryngology wards of a tertiary care hospital were systematically approached. Among 355 eligible patients, 278 (78.3%) participated, and 256 (72.1%) were analyzed. Three BHRF sum scores were determined, including current tobacco smoking, alcohol use, physical inactivity and 1 of 3 indicators of unhealthy diet. Associations between BHRF sum scores and sick days in the past 6 months were analyzed using multivariate zero-inflated negative binomial regressions. Results: Sixty-two percent reported multiple BHRFs (≥2). The BHRF sum score was related to the number of sick days if any (p = 0.009) with insufficient vegetable and fruit intake as diet indicator. Conclusion: The majority of patients disclosed multiple BHRFs. These were associated with sick days prior to admission. The findings support the need to implement interventions targeting multiple BHRFs in general hospitals.

Detection of stage I HPV-driven oropharyngeal cancer in asymptomatic individuals in the Hamburg City Health Study using HPV16 E6 serology - A proof-of-concept study.

Background: The lack of detectable precancerous lesions poses challenges to the early detection of human papillomavirus-driven oropharyngeal cancer (HPV-OPC). Antibodies against HPV16 early proteins, especially E6, are uniquely sensitive and specific biomarkers detectable years prior to HPV-OPC diagnosis. Thus, HPV16 early protein serology warrants clinical investigation for HPV-OPC screening. Methods: Using multiplex serology, we analyzed HPV16 serum antibodies of the first 5000 participants (n=4,424 sera, recruited 2016-2017) of the Hamburg City Health Study, a population-based prospective cohort (45-74 years). Participants seropositive for HPV16 E6 and at least one additional early protein (E1, E2, E7) were considered at high risk for HPV-OPC development and invited to six-monthly non-invasive head and neck follow-up (FU) examinations (visual inspection, endoscopy, ultrasonography, performed 2019-2020). Participants with suspicious lesions were examined by magnetic resonance imaging and panendoscopy with biopsy. Histologically confirmed OPC cases were treated according to standard of care. Findings: In total, 35 out of 4,424 study participants (0·8%, 95% confidence interval (CI) 0·6-1·1%) were HPV16 E6 seropositive. Among these, eleven (0·3%, 95%CI 0·1-0·5%) were considered at high risk for HPV-OPC of which nine were successfully re-contacted and invited to regular clinical FU examinations. Two males and one female were diagnosed with stage I HPV-OPC within 1·3 years of clinical FU (3-4 years after initial blood draw), representing one diagnosis of prevalent advanced disease, one incident diagnosis of advanced disease, and one incident diagnosis of early disease. The remaining participants showed no detectable signs of cancer, and undergo regular examinations (median clinical FU: 1·0 years, median total FU from blood draw to last clinical FU visit: 4·7 years). Interpretation: HPV16 early antibodies allowed identifying three asymptomatic stage I HPV-OPC patients, out of eleven participants considered at high risk. However, two of the three cases already showed signs of advanced disease at diagnosis. Targeting multiple early proteins may considerably improve the positive predictive value of HPV16 serology and may have clinical utility for HPV-OPC screening. Funding: This work was funded by DKFZ and UKE intramural funding.

Reliability of the Acoustic Voice Quality Index AVQI and the Acoustic Breathiness Index (ABI) when wearing CoViD-19 protective masks.

PURPOSE: Investigating whether the Acoustic Voice Quality Index (AVQI) and the Acoustic Breathiness Index (ABI) are valid and comparable to previous unmasked measurements if the speaker wears a surgical mask or a FFP-2 mask to reduce the risk of transmitting air-borne viruses such as SARS-CoV-2. METHODS: A convenience sample of 31 subjectively healthy participants was subjected to AVQI and ABI voice examination four times: Twice wearing no mask, once with a surgical mask and once with a FFP-2 mask as used regularly in our hospital. The order of the four mask conditions was randomized. The difference in the results between the two recordings without a mask was then compared to the differences between the recordings with each mask and one recording without a mask. RESULTS: Sixty-two percent of the AVQI readings without a mask represented perfectly healthy voices, the largest AVQI without a mask value was 4.0. The mean absolute difference in AVQI was 0.45 between the measurements without masks, 0.48 between no mask and surgical mask and 0.51 between no mask and FFP-2 mask. The results were neither clinically nor statistically significant. For the ABI the resulting absolute differences (in the same order) were 0.48, 0.69 and 0.56, again neither clinically nor statistically different. CONCLUSION: Based on a convenience sample of healthy or only mildly impaired voices wearing CoViD-19 protective masks does not substantially impair the results of either AVQI or ABI results.

Tissue Microarray Analyses Suggest Axl as a Predictive Biomarker in HPV-Negative Head and Neck Cancer.

The receptor tyrosine kinase Axl is described to promote migration, metastasis and resistance against molecular targeting, radiotherapy, and chemotherapy in various tumor entities, including head and neck squamous cell carcinoma (HNSCC). Since clinical data on Axl and its ligand Gas6 in HNSCC are sparse, we assessed the association of Axl and Gas6 expression with patient survival in a single center retrospective cohort in a tissue microarray format. Expression was evaluated manually using an established algorithm and correlated with clinicopathological parameters and patient survival. A number of 362 samples yielded interpretable staining, which did not correlate with T- and N-stage. Protein expression levels were not associated with the survival of patients with p16-positive oropharyngeal SCC. In HPV-negative tumors, Axl expression did not impact patients treated with primary or adjuvant radio(chemo)therapy, but was significantly associated with inferior overall and recurrence-free survival in patients treated with surgery alone. Gas6 was a positive predictor of survival in patients whose treatment included radiotherapy. Associations remained significant in multivariable analysis. Our data question a meaningful contribution of the Axl/Gas6 pathway to radio-resistance in HNSCC and instead suggest that strong Axl expression identifies tumors requiring adjuvant radio(chemo)therapy after surgery.

[Chemotherapy and targeted therapy of head and neck squamous cell carcinomas at the 2021 ASCO meeting]. / Chemotherapie und zielgerichtete Therapie von Kopf-Hals-Plattenepithelkarzinomen beim ASCO-Kongress 2021.

BACKGROUND: This article summarizes new findings on chemo- and targeted therapy of head and neck squamous cell carcinoma presented at the 2021 American Society of Clinical Oncology (ASCO) conference. OBJECTIVE: Relevant publications were evaluated and summarized. METHODS: The abstract database of the 2021 ASCO conference was searched. Publications were selected if they focused on chemo- or targeted therapies in head and neck squamous cell carcinoma. Publications covered in other articles of this issue were omitted, as were study proposals without results. RESULTS: The authors present six articles. Dosage and novel forms of application are shown for cisplatin. Cetuximab is used in the neoadjuvant setting and for progressive disease following immune therapy. Lastly, two new drugs in the form of liposomal irinotecan and the mHRAS inhibitor tipifarnib are discussed. CONCLUSION: Patient-specific and possibly local application of cisplatin might be considered in the future. Moreover, mHRAS inhibition might also be useful for selected patients after sequencing.

Patient derived ex vivo tissue slice cultures demonstrate a profound DNA double-strand break repair defect in HPV-positive oropharyngeal head and neck cancer.

BACKGROUND: HPV-positive head and neck squamous cell carcinoma of the oropharynx (OPSCC) are more sensitive towards radiation than HPV-negative OPSCC. Two main theories exist regarding the underlying mechanism. Stronger lymphocyte infiltration points to an enhanced immunogenicity, whereas data from HPV-positive HNSCC cell lines suggest an enhanced cellular radiosensitivity based on a defect in DNA double-strand break (DSB) repair. The critical limitation of the latter theory is that the evidence was largely derived from a small number of established HPV-positive HNSCC cell lines. METHODS AND MATERIALS: Fresh patient-derived OPSCC samples were cut in 400 µm sections and cultured on cell culture inserts. Slice cultures were irradiated, in part combined with ATM inhibition, and fixed and frozen after 2 and 24 h. DSBs were analyzed by quantification of 53BP1 foci in nuclei co-stained with the SCC marker p63 via immunofluorescence microscopy. RESULTS: Ex vivo OPSCC tumor slice cultures maintained stable oxygenation and proliferation characteristics for at least 3 days. Areas of p63-positivity in immunofluorescence microscopy matched histologically confirmed tumor cell areas in serial sections, indicating the suitability of p63 as a tumor cell marker. p63-positive nuclei in HPV-positive OPSCC tissues (n = 14) showed profoundly elevated numbers of residual radiation-induced DSBs as compared to those from HPV-negative OPSCC (n = 12) (3 Gy: on average 4.9 vs. 1.2 foci per nucleus; p < 0.0001). Within the HPV-positive subgroup, samples derived from patients with a smoking history of less than 10 pack years demonstrated higher residual DSBs as compared to those derived from patients with 10 or more pack years (3 Gy: on average 6.5 vs. 3.2 foci per nucleus; p = 0.0105). Additional ATM inhibition resulted in a substantial increase in residual foci in all 4 HPV-negative samples tested but strikingly only in 2 out of 11 HPV-positive samples. CONCLUSIONS: In summary, our data provide robust, cell line-independent experimental evidence for an intrinsic DSB repair deficiency in HPV-positive OPSCC, strongly suggesting a meaningful contribution to the enhanced clinical radiosensitivity. The reduced effectiveness of ATM inhibition indicates a defect in the ATM-orchestrated DNA damage response. Lower numbers of residual 53BP1 nuclear foci in the ex vivo assay may identify HPV-positive patients with effective DSB repair who should potentially be excluded from de-intensification approaches.

Kinomic comparison of snap frozen and ex vivo-cultured head and neck tumors.

OBJECTIVES: The use of primary tumor tissue in experimental and pre-clinical cancer research is becoming increasingly important. Especially the use of tissue slice cultures of tumor specimen, so called ex vivo cultures or tumor explants, promises functional analysis under approximate physiological conditions. This includes screening and testing of targeted therapeutics directed against deregulated protein kinases. However, it is unclear if ex vivo cultures indeed represent the in situ situation especially with respect to very sensitive and transient molecular processes such as kinase dependent signaling. We now asked here, if and to what extent ex vivo culturing affects kinase activity. MATERIALS AND METHODS: We analyzed the activity of protein tyrosine kinases (PTK) using functional kinome profiling of either snap frozen or ex vivo-cultured tumor tissue samples of head and neck cancer patients. RESULTS: Although we observed a quantitative decline in overall kinase activity after 24 h or 48 h of ex vivo cultivation, we most importantly noticed that the signaling characteristics were conserved in most samples; approximately two thirds of all ex vivo-cultured samples displayed a signaling pattern which was qualitatively comparable to the parental tumor. We could also demonstrate kinase inhibition by treatment of ex vivo slice cultures with the multi-kinase inhibitor staurosporine, although higher concentrations were needed compared to cell cultures. CONCLUSION: We here demonstrate that the tyrosine kinase dependent signaling is conserved under exvivo culturing conditions in the majority of samples, which highlights the power of this method in experimental and pre-clinical cancer research.

Analyzing tyrosine kinase activity in head and neck cancer by functional kinomics: Identification of hyperactivated Src family kinases as prognostic markers and potential targets.

Signal transduction via protein kinases is of central importance in cancer biology and treatment. However, the clinical success of kinase inhibitors is often hampered by a lack of robust predictive biomarkers, which is also caused by the discrepancy between kinase expression and activity. Therefore, there is a need for functional tests to identify aberrantly activated kinases in individual patients. Here we present a systematic analysis of the tyrosine kinases in head and neck cancer using such a test-functional kinome profiling. We detected increased tyrosine kinase activity in tumors compared with their corresponding normal tissue. Moreover, we identified members of the family of Src kinases (Src family kinases [SFK]) to be aberrantly activated in the majority of the tumors, which was confirmed by additional methods. We could also show that SFK hyperphosphorylation is associated with poor prognosis, while inhibition of SFK impaired cell proliferation, especially in cells with hyperactive SFK. In summary, functional kinome profiling identified SFK to be frequently hyperactivated in head and neck squamous cell carcinoma. SFK may therefore be potential therapeutic targets. These results furthermore demonstrate how functional tests help to increase our understanding of cancer biology and support the expansion of precision oncology.