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.

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.

[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.

[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.

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.

[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.

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.

Parotid sparing and quality of life in long-term survivors of locally advanced head and neck cancer after intensity-modulated radiation therapy.

PURPOSE: Intensity-modulated radiation therapy (IMRT) enables radiation oncologists to optimally spare organs at risk while achieving homogeneous dose distribution in the target volume. Despite great advances in technology, xerostomia is one of the most detrimental long-term side effects after multimodal therapy in patients with locally advanced head and neck cancer (HNC). This prospective observational study examines the effect of parotid sparing on quality of life in long-term survivors. PATIENTS AND METHODS: A total of 138 patients were grouped into unilateral (n = 75) and bilateral (n = 63) parotid sparing IMRT and questioned at 3, 24, and 60-month follow-up using the European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-H&N35 questionnaires. Treatment-related toxicity was scored according to the RTOG/EORTC toxicity criteria. Patients' QoL 24 and 60 months after IMRT was analyzed by ANCOVA using baseline QoL (3 months after IMRT) as a covariate. RESULTS: Patients with bilateral and unilateral parotid-sparing IMRT surviving 60 months experience similar acute and late side effects and similar changes in QoL. Three months after IMRT, physical and emotional function as well as fatigue, nausea and vomiting, pain, dyspnea, and financial problems are below (function scales) or above (symptom scales) the threshold of clinical importance. In both groups, symptom burden (EORTC H&N35) is high independent of parotid sparing 3 months after IMRT and decreases over time in a similar pattern. Pain and financial function remain burdensome throughout. CONCLUSION: Long-term HNC survivors show a similar treatment-related toxicity profile independent of unilateral vs. bilateral parotid-sparing IMRT. Sparing one or both parotids had no effect on global QoL nor on the magnitude of changes in function and symptom scales over the observation period of 60 months. The financial impact of the disease and its detrimental effect on long-term QoL pose an additional risk to unmet needs in this special patient population. These results suggest that long-term survivors need and most likely will benefit from early medical intervention and support within survivorship programs.

Comparative effectiveness trial of transoral head and neck surgery followed by adjuvant radio(chemo)therapy versus primary radiochemotherapy for oropharyngeal cancer (TopROC).

BACKGROUND: For loco-regionally advanced, but transorally resectable oropharyngeal cancer (OPSCC), the current standard of care includes surgical resection and risk-adapted adjuvant (chemo) radiotherapy, or definite chemoradiation with or without salvage surgery. While transoral surgery for OPSCC has increased over the last decade for example in the United States due to transoral robotic surgery, this treatment approach has a long history in Germany. In contrast to Anglo-Saxon countries, transoral surgical approaches have been used frequently in Germany to treat patients with oro-, hypopharyngeal and laryngeal cancer. Transoral laser microsurgery (TLM) has had a long tradition since its introduction in the early 70s. To date, the different therapeutic approaches to transorally resectable OPSCC have not been directly compared to each other in a randomized trial concerning disease control and survival. The goal of this study is to compare initial transoral surgery to definitive chemoradiation for resectable OPSCC, especially with regards to local and regional control. METHODS: TopROC is a prospective, two-arm, open label, multicenter, randomized, and controlled comparative effectiveness study. Eligible patients are ≥18 years old with treatment-naïve, histologically proven OPSCC (T1, N2a-c, M0; T2, N1-2c, M0; T3, N0-2c, M0 UICC vers. 7) which are amenable to transoral resection. Two hundred eighty patients will be randomly assigned (1:1) to surgical treatment (arm A) or chemoradiation (arm B). Standard of care treatment will be performed according to daily routine practice. Arm A consists of transoral surgical resection with neck dissection followed by risk-adapted adjuvant therapy. Patients treated in arm B receive standard chemoradiation, residual tumor may be subject to salvage surgery. Follow-up visits for 3 years are planned. Primary endpoint is time to local or locoregional failure (LRF). Secondary endpoints include overall and disease free survival, toxicity, and patient reported outcomes. Approximately 20 centers will be involved in Germany. This trial is supported by the German Cancer Aid and accompanied by a scientific support program. DISCUSSION: This study will shed light on an urgently-needed randomized comparison of the strategy of primary chemoradiation vs. primary surgical approach. As a comparative effectiveness trial, it is designed to provide data based on two established regimens in daily clinical routine. TRIAL REGISTRATION: NCT03691441 Registered 1 October 2018 - Retrospectively registered.

Rationale and Design of the Hamburg City Health Study.

The Hamburg City Health Study (HCHS) is a large, prospective, long-term, population-based cohort study and a unique research platform and network to obtain substantial knowledge about several important risk and prognostic factors in major chronic diseases. A random sample of 45,000 participants between 45 and 74 years of age from the general population of Hamburg, Germany, are taking part in an extensive baseline assessment at one dedicated study center. Participants undergo 13 validated and 5 novel examinations primarily targeting major organ system function and structures including extensive imaging examinations. The protocol includes validate self-reports via questionnaires regarding lifestyle and environmental conditions, dietary habits, physical condition and activity, sexual dysfunction, professional life, psychosocial context and burden, quality of life, digital media use, occupational, medical and family history as well as healthcare utilization. The assessment is completed by genomic and proteomic characterization. Beyond the identification of classical risk factors for major chronic diseases and survivorship, the core intention is to gather valid prevalence and incidence, and to develop complex models predicting health outcomes based on a multitude of examination data, imaging, biomarker, psychosocial and behavioral assessments. Participants at risk for coronary artery disease, atrial fibrillation, heart failure, stroke and dementia are invited for a visit to conduct an additional MRI examination of either heart or brain. Endpoint assessment of the overall sample will be completed through repeated follow-up examinations and surveys as well as related individual routine data from involved health and pension insurances. The study is targeting the complex relationship between biologic and psychosocial risk and resilience factors, chronic disease, health care use, survivorship and health as well as favorable and bad prognosis within a unique, large-scale long-term assessment with the perspective of further examinations after 6 years in a representative European metropolitan population.

Phase III study of nivolumab alone or combined with ipilimumab as immunotherapy versus standard of care in resectable head and neck squamous cell carcinoma.

Locally advanced head and neck squamous cell carcinoma (LA-HNSCC) often requires postoperative chemoradiation with high risk of toxicity. Disease-free survival (DFS) after 2 years is approximately 70%. Combining nivolumab (N), a PD-1-inhibitor and ipilimumab (I), a CTLA4- inhibitor, may improve DFS due to antitumor effects of immunotherapy. The IMSTAR-HN study compares neoadjuvant N and N ± I 6 months after adjuvant therapy versus standard therapy as first-line treatment for LA-HNSCC. Eligible patients have treatment-naive LA-HNSCC, Eastern cooperative oncology group performance score (PS) ≤1 and no distant metastasis. 276 patients will be randomized into two arms. Primary endpoint is DFS and secondary endpoint includes locoregional control (LRC) and overall survival (OS). This study is one of the first in HNSCCs implementing immunotherapy in first-line treatment in a curative setting. Clinical Trial Registration: NCT03700905 (ClinicalTrials.gov).

Oral Human Papillomavirus in Women With High-Grade Cervical Intraepithelial Neoplasia.

OBJECTIVE: This study was designed to investigate the co-prevalence of cervical and oropharyngeal human papillomavirus (HPV) infection in patients with HPV-related high-grade disease of the uterine cervix (high-grade squamous intraepithelial lesion [HSIL]). MATERIALS AND METHODS: In a prospective cohort study, women with abnormal cervical cytology admitted to our colposcopy units received HPV testing of the uterine cervix and the oropharynx via smear. From a subset of patients, oral lavage was collected to compare detection rates of HPV DNA between lavage and swab. Patients with confirmed high-risk HPV (HR-HPV)-positive HSIL of the cervix were further investigated. Sexual behavior and lifestyle factors were documented with a standardized questionnaire. RESULTS: Two hundred thirty-five women were included in the study. Of the 235 women, 135 (57.5%) were cervically HR-HPV positive with histologically confirmed high-grade cervical intraepithelial lesion (median [range] age = 30 [21-45] years). Of these, only 6 (4.4%) also had a positive oral specimen. In 3 (50%) of the 6 cases, the same HPV type was detected in oral and cervical samples (HPV 16, 35, and 45). Oral HPV detection was not higher when combining swab and lavage compared with swab alone. A relation between sexual behavior and oral HPV detection could not be demonstrated. CONCLUSIONS: Oral HPV prevalence in women with cervical HPV infection and HSIL is low. Simultaneous testing of oropharyngeal and cervical HPV infection does not seem promising as future screening strategy.

Perspectives in chemosensitivity and chemoresistance assays and their implementation in head and neck cancer.

Therapeutic options for patients with head and neck squamous cell carcinoma include surgery, radiation and chemotherapy. The latter plays a major role in the treatment selection of recurrent, metastatic or therapy resistant tumours, these being some of the major challenges in head and neck oncology. For these patients, chemosensitivity and chemoresistance assays would be paramount to identify their individual therapy options. In this review, seven common assays will be described and discussed in the context of several studies. Further, a new assay will also be presented, currently being validated in a European Union funded project. Comparisons will be drawn to evaluate the sensitivity and specificity of these assays in identifying individual treatment options, and their potential implementation in head and neck malignancies will be discussed. There is an unmet demand for the development of ex vivo diagnostic tools that may predict response in head and neck cancer on the way towards an individualized treatment for these patients.

Two-Year Survival Analysis of 50 Consecutive Head and Neck Cancer Patients Treated with Transoral Robotic Surgery in a Single European Centre.

BACKGROUND: To date, this prospective cohort study is the largest of its kind from a single European academic tertiary care center to report 2-year survival outcomes for head and neck squamous cell carcinoma treated primarily with transoral robotic-assisted resection. PATIENTS AND METHODS: Fifty consecutive, appropriately staged patients were enrolled prospectively, and underwent transoral robotic surgery (TORS) between September 2011 and August 2013. Overall, 24 patients had a T1 primary tumor, 23 had a T2 primary tumor, 2 had a T3 primary tumor, and 1 had a T4a primary tumor. Eighteen patients had overall stage I-II disease, and 32 patients had stage III-IV disease. Following transoral robotic resection of their primaries and appropriate neck dissection(s) as indicated, adjuvant treatment could be spared for 20 patients; another 5 patients refused the recommended adjuvant treatment. Seventeen patients received 60 Gy adjuvant radiotherapy and 8 patients underwent 66 Gy adjuvant chemoradiotherapy. RESULTS: At the time of the last follow-up visit (median 27 months), overall survival was 94 %, with two disease-specific deaths and one unrelated death (heart attack). The 2-year disease-free and recurrence-free survival rates were 88 and 80 %, respectively; however, the local recurrence rate was only 10 % after 2 years. CONCLUSION: Using TORS as their primary modality, 40 % of patients did not need adjuvant treatment and showed similar survival rates to that of conventional surgery or primary chemoradiotherapy. In another 34 % of patients, adjuvant chemotherapy could be spared and adjuvant radiotherapy could be reduced by 10 Gy compared with primary chemoradiotherapy of 70 Gy. Further studies are warranted with respect to long-term survival.

Feasibility and safety of transoral robotic surgery (TORS) for early hypopharyngeal cancer: a subset analysis of the Hamburg University TORS-trial.

Over the past 5 years, transoral robotic surgery (TORS) has become well established as one of the standard treatment options for T1 and T2 oropharyngeal squamous cell carcinoma. Besides this main indication, TORS can provide with improved access to other subsites of the upper aerodigestive tract as well, such as the supraglottic larynx and the hypopharynx, with superior visibility and maneuverability to that of transoral laser microsurgery (TOLM). Since September 2011, over one hundred TORS procedures have been performed at our institution, predominantly for oropharyngeal cancer. As part of our first 50 transoral robotic cases making up our initial TORS-trial, five patients underwent TORS for early hypopharyngeal carcinoma. The present case series evaluates its feasibility, safety and the completeness of resection in this well-defined subgroup of patients. Main outcome measures were completeness of resection, the presence or lack of postoperative bleeding, number of days intubated, rate of elective tracheotomy, duration of intensive care and/or intermediate care, speech and swallowing function, and duration of nasogastric and/or gastrostomy tube dependency. All patients have been free of recurrence to date. One patient died of other disease. Four patients are alive and free of tumour, three of them did not need adjuvant therapy. Transoral robotic surgery with appropriate neck dissection is a valid primary treatment option for select early hypopharyngeal carcinoma, especially in cases that did not require adjuvant treatment. In contrast to TOLM, TORS allows a multi-planar en bloc resection in the hypopharynx which makes histopathological evaluation more reliable. In addition to this, its faster learning curve makes the results less dependent on the individual surgeons' capabilities.

A comparison of hearing results following stapedotomy under local versus general anesthesia.

Advances in operative technique, instrumentation, and prosthesis design in otosclerosis surgery continue since Shea performed the first successful surgery. This is the first analysis to specifically compare post-operative hearing outcomes following stapedotomy surgery performed under local versus general anesthesia. Hearing outcomes were further stratified by comparing conventional perforator and Er:YAG laser ablation perforation techniques. Pre- and post-operative audiograms were retrospectively analyzed together with the method of anesthesia and the perforation technique for all patients with otosclerosis who underwent stapedotomy between 1998 and 2007. Pre-operative individual standard audiometry frequency thresholds (IFTs), air (AC) and bone conduction pure tone averages (PTA), and air bone gaps (ABG) were compared against post-operative results. Differences between pre- and post-operative PTAs and ABGs were compared between patients who received stapedotomy under local versus general anesthesia, as well as for patients who underwent conventional versus Er:YAG laser ablation perforations. Eighty-six patients were identified of which 24 % (n = 21) received local and 76 % (n = 65) received general anesthesia. Post-operative audiograms were available for 84 and 48 patients, respectively. Significant improvements were seen across all groups for standard 4-frequency AC-PTA and ABG and for IFTs up to 3 kHz. No significant difference was seen for IFTs between 4 and 6 kHz. A significant decline in post-operative hearing thresholds was seen at 8 kHz. Significant improvements in PTA and ABG were seen for all groups. There was a trend toward general compared to local anesthesia post-operative hearing results furthermore in combination with conventional perforation technique then with laser technique.

Simultaneous cytoplasmic and nuclear protein expression of melanoma antigen-A family and NY-ESO-1 cancer-testis antigens represents an independent marker for poor survival in head and neck cancer.

The prognosis of head and neck squamous cell carcinoma (HNSCC) patients remains poor. The identification of high-risk subgroups is needed for the development of custom-tailored therapies. The expression of cancer-testis antigens (CTAs) has been linked to a worse prognosis in other cancer types; however, their prognostic value in HNSCC is unclear because only few patients have been examined and data on CTA protein expression are sparse. A tissue microarray consisting of tumor samples from 453 HNSCC patients was evaluated for the expression of CTA proteins using immunohistochemistry. Frequency of expression and the subcellular expression pattern (nuclear, cytoplasmic, or both) was recorded. Protein expression of melanoma antigen (MAGE)-A family CTA, MAGE-C family CTA and NY-ESO-1 was found in approximately 30, 7 and 4% of tumors, respectively. The subcellular expression pattern in particular had a marked impact on the patients' prognosis. Median overall survival (OS) of patients with (i) simultaneous cytoplasmic and nuclear expression compared to (ii) either cytoplasmic or nuclear expression and (iii) negative patients was 23.0 versus 109.0 versus 102.5 months, for pan-MAGE (p < 0.0001), 46.6 versus 50.0 versus 109.0 for MAGE-A3/A4 (p = 0.0074) and 13.3 versus 50.0 versus 100.2 months for NY-ESO-1 (p = 0.0019). By multivariate analysis, these factors were confirmed as independent markers for poor survival. HNSCC patients showing protein expression of MAGE-A family members or NY-ESO-1 represent a subgroup with an extraordinarily poor survival. The development of immunotherapeutic strategies targeting these CTA may, therefore, be a promising approach to improve the outcome of HNSCC patients.