Long-term health-related quality of life in head and neck cancer survivors: A large multinational study.

Head and neck cancer (HNC) patients suffer from a range of health-related quality of life (HRQoL) issues, but little is known about their long-term HRQoL. This study explored associations between treatment group and HRQoL at least 5 years' post-diagnosis in HNC survivors. In an international cross-sectional study, HNC survivors completed the European Organization for Research and Treatment of Cancer (EORTC) quality of life core questionnaire (EORTC-QLQ-C30) and its HNC module (EORTC-QLQ-H&N35). Meaningful HRQoL differences were examined between five treatment groups: (a) surgery, (b) radiotherapy, (c) chemo-radiotherapy, (d) radiotherapy ± chemotherapy and neck dissection and (e) any other surgery (meaning any tumour surgery that is not a neck dissection) and radiotherapy ± chemotherapy. Twenty-six sites in 11 countries enrolled 1105 survivors. They had a median time since diagnosis of 8 years, a mean age of 66 years and 71% were male. After adjusting for age, sex, tumour site and UICC stage, there was evidence for meaningful differences (10 points or more) in HRQoL between treatment groups in seven domains (Fatigue, Mouth Pain, Swallowing, Senses, Opening Mouth, Dry Mouth and Sticky Saliva). Survivors who had single-modality treatment had better or equal HRQoL in every domain compared to survivors with multimodal treatment, with the largest differences for Dry Mouth and Sticky Saliva. For Global Quality of Life, Physical and Social Functioning, Constipation, Dyspnoea and Financial Difficulties, at least some treatment groups had better outcomes compared to a general population. Our data suggest that multimodal treatment is associated with worse HRQoL in the long-term compared to single modality.

Initial surgical management of sporadic medullary thyroid cancer: Guidelines based optimal care - A systematic review.

INTRODUCTION: Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor from parafollicular cells that produce calcitonin (Ct). Despite several existing guidelines for the surgical management of sporadic MTC (sMTC), optimal initial surgical management of the thyroid, the central and the lateral neck remains a matter of debate. METHODS: A systematic review in PubMed and Scopus for current guidelines addressing the surgical management of sMTC and its referenced citations was conducted as per the PRISMA guidelines. RESULTS: Two-hundred and one articles were identified, of which 7 met the inclusion criteria. Overall, guidelines vary significantly in their recommendations for the surgical management of sMTC. Only one guideline recommended partial thyroidectomy for limited disease, but the possibility to avoid completion thyroidectomy in selected cases is acknowledged in 42% (3/7) of the remaining guidelines. The majority of guidelines (71.4%; 5/7) recommended prophylactic central neck dissection (CND) for all patients while the remaining two guidelines recommended CND based on Ct level and tumor size. The role of prophylactic lateral neck dissection based on preoperative Ct levels was recommended by 42% (3/7) of guidelines. Overall, these guidelines are based on low-quality evidence, mostly single-center retrospective series, some of which are over 20 years old. CONCLUSION: Current surgical management guidelines of sMTC should be revised, and ought to be based on updated data challenging current recommendations, which are based on historic, low-quality evidence. Partial thyroidectomy may become a viable option for small, limited tumors. Prospective, multi-center studies may be useful to conclude whether prophylactic ND is necessary in all sMTC patients.

Prophylactic Swallowing Therapy During Head-and-Neck Cancer Radiotherapy: Effect of Service-Delivery Mode and Overall Adherence Level on Swallowing Function and Muscle Strength-the PRESTO Trial.

Prophylactic swallowing exercises (PSE) during head-and-neck cancer (HNC) (chemo)radiotherapy (CRT) have a positive effect on swallowing function and muscle strength. Adherence rates to PSE are, however, moderate to low, undermining these effects. PRESTO already showed that the service-delivery mode (SDM), the way the exercises are offered, can influence adherence. The aim of this study was to investigate the effect of SDM on swallowing function and muscle strength during and post-CRT. In addition, the effect of overall adherence (OA), independent of SDM, was also investigated. A total of 148 HNC patients, treated with CRT, were randomly assigned to one of the three SDM's (paper-supported, app-supported, or therapist-supported PSE) and performed a 4-week PSE program. OA was calculated based on the percentage of completed exercises. Patients were divided into OA levels: the OA75+ and OA75- group performed respectively ≥ 75 and < 75% of the exercises. Swallowing function based on Mann Assessment of Swallowing Ability-Cancer (MASA-C), tongue and suprahyoid muscle strength during and up to 3 months after CRT were compared between the SDM's and OA levels. Linear Mixed-effects Models with post hoc pairwise testing and Bonferroni-Holm correction was used. No significant differences were found between the three SDMs. Significant time effects were found: MASA-C scores decreased and muscle strength increased significantly during CRT. By the end of CRT, the OA75+ showed significantly better swallowing function compared to OA75-. Muscle strength gain was significantly higher in the OA75+ group. SDM had no impact on swallowing function and muscle strength; however, significant effects were shown for OA level. Performing a high level of exercise repetitions is essential to benefit from PSE.Trial registration ISRCTN, ISRCTN98243550. Registered December 21, 2018-retrospectively registered, https://www.isrctn.com/ISRCTN98243550?q=gwen%20van%20nuffelen&filters=&sort=&offset=1&totalResults=2&page=1&pageSize=10&searchType=basic-search.

The prognostic effect of radiological extranodal extension in HPV-positive oropharyngeal squamous cell carcinomas: a retrospective cohort analysis.

PURPOSE: Radiological extranodal extension (rENE) is a well-known negative prognosticator in head and neck squamous cell carcinoma (HNSCC). However, controversy remains regarding the prognostic effect of rENE in HPV-positive oropharyngeal SCCs (OPSCC). This single-center retrospective cohort analysis assessed the prognostic role of rENE in an HPV + OPSCC population and tried to validate a recently proposed modification of the TNM8 N-classification. METHODS: 129 patients with HPV + OPSCC, of whom 106 cN + patients, were included. Radiological imaging (CT, MRI or both) was reanalyzed by a senior head and neck radiologist. Overall survival (OS), disease-free survival (DFS), locoregional recurrence-free survival (LRFS), and disease-specific survival (DSS) were evaluated. Cox proportional hazard models were used for estimating hazard ratios (HR). RESULTS: A non-significant trend towards better outcomes in the rENE- group, as compared to the rENE + population, was observed for 5 year OS [80.99% vs 68.70%, HR: 2.05, p = 0.160], 5 year RFS [78.81% vs 67.87%, HR: 1.91, p = 0.165], 5 year DFS [77.06% vs 60.16%, HR: 2.12, p = 0.0824] and 5 year DSS [88.83% vs 81.93%, HR: 2.09, p = 0.195]. OS declined with ascending levels of rENE (p = 0.020). Multivariate analysis identified cT-classification and smoking as independent negative predictors for OS/DFS. The proposed modification of the TNM8 N-classification could not be validated. CONCLUSIONS: Although rENE could not be identified as an independent negative prognosticator for outcome in our HPV + OPSCC population, outcomes tend to deteriorate with increasing rENE.

Increasing Adherence to Prophylactic Swallowing Exercises During Head and Neck Radiotherapy: The Multicenter, Randomized Controlled PRESTO-Trial.

BACKGROUND: Prophylactic swallowing exercises (PSE) during radiotherapy can significantly reduce dysphagia after radiotherapy in head and neck cancer (HNC). However, its positive effects are hampered by low adherence rates during the burdensome therapy period. Hence, the main goal of this multicenter randomized controlled trial (RCT) was to investigate the effect of 3 different service-delivery modes on actual patients' adherence. METHODS: A total of 148 oropharyngeal cancer patients treated with primary (chemo)radiotherapy were randomly assigned to a 4 weeks PSE program, either diary-supported (paper group; n = 49), app-supported (app group; n = 49) or therapist-supported (therapist group; n = 50). Participants practiced 5 days/week, daily alternating tongue strengthening exercises with chin tuck against resistance exercises. Adherence was measured as the percentage of completed exercise repetitions per week (%reps). Statistical analysis was performed by means of SPSSv27, using Linear Mixed-effects Models with post hoc pairwise testing and Bonferroni-Holm correction. RESULTS: Adherence and evolution of adherence over time was significantly different between the three groups (p < .001). Adherence rates decreased in all three groups during the 4 training weeks (p < .001). During all 4 weeks, the therapist group achieved the highest adherence rates, whilst the app group showed the lowest adherence rates. CONCLUSIONS: PSE adherence decreased during the first 4 radiotherapy weeks regardless of group, but with a significant difference between groups. The therapist group achieved the highest adherence rates with a rather limited decline, therefore, increasing the face-to-face contact with a speech-language therapist can overcome the well-known problem of low adherence to PSE in this population. TRIAL REGISTRATION: Trial registration: ISRCTN, ISRCTN98243550. Registered December 21, 2018 - retrospectively registered, https://www.isrctn.com/ISRCTN98243550?q=gwen%20van%20nuffelen&filters=&sort=&offset=1&totalResults=2&page=1&pageSize=10&searchType=basic-search .

Use of 3D Spheroid Models for the Assessment of RT Response in Head and Neck Cancer.

Radiotherapy (RT) is a key player in the treatment of head and neck cancer (HNC). The RT response, however, is variable and influenced by multiple tumoral and tumor microenvironmental factors, such as human papillomavirus (HPV) infections and hypoxia. To investigate the biological mechanisms behind these variable responses, preclinical models are crucial. Up till now, 2D clonogenic and in vivo assays have remained the gold standard, although the popularity of 3D models is rising. In this study, we investigate the use of 3D spheroid models as a preclinical tool for radiobiological research by comparing the RT response of two HPV-positive and two HPV-negative HNC spheroid models to the RT response of their corresponding 2D and in vivo models. We demonstrate that HPV-positive spheroids keep their higher intrinsic radiosensitivity when compared to HPV-negative spheroids. A good correlation is found in the RT response between HPV-positive SCC154 and HPV-negative CAL27 spheroids and their respective xenografts. In addition, 3D spheroids are able to capture the heterogeneity of RT responses within HPV-positive and HPV-negative models. Moreover, we demonstrate the potential use of 3D spheroids in the study of the mechanisms underlying these RT responses in a spatial manner by whole-mount Ki-67 and pimonidazole staining. Overall, our results show that 3D spheroids are a promising model to assess the RT response in HNC.

An Integrated Approach Reveals DNA Damage and Proteotoxic Stress as Main Effects of Proton Radiation in S. cerevisiae.

Proton radiotherapy (PRT) has the potential to reduce the normal tissue toxicity associated with conventional photon-based radiotherapy (X-ray therapy, XRT) because the active dose can be more directly targeted to a tumor. Although this dosimetric advantage of PRT is well known, the molecular mechanisms affected by PRT remain largely elusive. Here, we combined the molecular toolbox of the eukaryotic model Saccharomyces cerevisiae with a systems biology approach to investigate the physiological effects of PRT compared to XRT. Our data show that the DNA damage response and protein stress response are the major molecular mechanisms activated after both PRT and XRT. However, RNA-Seq revealed that PRT treatment evoked a stronger activation of genes involved in the response to proteotoxic stress, highlighting the molecular differences between PRT and XRT. Moreover, inhibition of the proteasome resulted in decreased survival in combination with PRT compared to XRT, not only further confirming that protons induced a stronger proteotoxic stress response, but also hinting at the potential of using proteasome inhibitors in combination with proton radiotherapy in clinical settings.

Saccharomyces cerevisiae as a Model System for Eukaryotic Cell Biology, from Cell Cycle Control to DNA Damage Response.

The yeast Saccharomyces cerevisiae has been used for bread making and beer brewing for thousands of years. In addition, its ease of manipulation, well-annotated genome, expansive molecular toolbox, and its strong conservation of basic eukaryotic biology also make it a prime model for eukaryotic cell biology and genetics. In this review, we discuss the characteristics that made yeast such an extensively used model organism and specifically focus on the DNA damage response pathway as a prime example of how research in S. cerevisiae helped elucidate a highly conserved biological process. In addition, we also highlight differences in the DNA damage response of S. cerevisiae and humans and discuss the challenges of using S. cerevisiae as a model system.

Obstructive sleep apnea in head and neck cancer survivors.

IMPORTANCE: Chronic fatigue is present in 33.0% of all head and neck cancer (HNC) survivors; this impacts their quality of life negatively. A plausible cause is obstructive sleep apnea (OSA) after HNC treatment. However, studies regarding this topic are scarce. OBJECTIVE: To confirm if OSA is more prevalent after receiving radiotherapy for HNC. In addition, investigation of the risk factors for developing OSA in this population. DESIGN: A retrospective review of prospective data. METHODS: Treatment for HNC took place between 2016 and 2017 at the University Hospital of Leuven. One hundred sixty-four patients were eligible for participating in this study. Sixty-five responded (39.4%). Upon consulting their medical files, 15 patients were excluded based on the in- and exclusion criteria. Presence of OSA was estimated using standardized questionnaires, namely the Berlin Questionnaire, the Epworth Sleepiness Scale, and the CIS-20. This was compared to the proportion of OSA in the general population. RESULTS: Fifty patients (33 men, 17 women) with a mean age of 64.2 years (range 32-88) were included. Based on the questionnaires, OSA was suspected in twenty. The prevalence of suspected OSA in our study group (40.0%) was significantly greater (p < 0.0001) than our estimated prevalence of OSA in the general population (10.9%). No significant risk factors could be identified. CONCLUSION: Patients treated for HNC are at risk of developing OSA. When complaints of fatigue and sleeping problems persist, referral to a sleep clinic is suggested. Further investigation remains necessary to identify potential risk factors along with prevention and treatment strategies.

Patterns and quality of care for head and neck cancer in Belgium: A population-based study.

OBJECTIVES: We evaluated the quality of care for patients with squamous cell carcinoma (SCC) of the oral cavity, oropharynx, hypopharynx or larynx in Belgium. METHODS: Data of the Belgian Cancer Registry were coupled with health insurance data and hospital discharge data. Quality of care and the association with hospital volume were evaluated based on six quality indicators. RESULTS: Half of the patients were treated with primary radiotherapy, with or without systemic therapy (49.7%) and 38.1% with surgery, with or without (neo)adjuvant therapy. Single-modality treatment was provided to 78.1% of early-disease patients. Of the patients with cN0 disease, 56.4% underwent neck dissection. Postoperative radiotherapy was completed timely in 48.5% of patients. Concomitant chemotherapy was administered to 58.2% of patients <70 years with locally advanced disease. Imaging of the neck after radiotherapy was performed appropriately in 32.7% of patients. Variability between centres was considerable. No clear relationship between hospital volume and results of the individual QIs was observed. CONCLUSIONS: Results show that for the measured QIs, targets are not met and variability between centres is considerable. Through individual feedback, centres are motivated to improve the quality of care for head and neck cancer patients in Belgium.

Effect of ATR Inhibition in RT Response of HPV-Negative and HPV-Positive Head and Neck Cancers.

Radiotherapy (RT) has a central role in head and neck squamous cell carcinoma (HNSCC) treatment. Targeted therapies modulating DNA damage response (DDR) and more specific cell cycle checkpoints can improve the radiotherapeutic response. Here, we assessed the influence of ataxia-telangiectasia mutated and Rad3-related (ATR) inhibition with the ATR inhibitor AZD6738 on RT response in both human papillomavirus (HPV)-negative and HPV-positive HNSCC. We found that ATR inhibition enhanced RT response in HPV-negative and HPV-positive cell lines independent of HPV status. The radiosensitizing effect of AZD6738 was correlated with checkpoint kinase 1 (CHK1)-mediated abrogation of G2/M-arrest. This resulted in the inhibition of RT-induced DNA repair and in an increase in the percentage of micronucleated cells. We validated the enhanced RT response in HPV-negative and HPV-positive xenograft models. These data demonstrate the potential use of ATR inhibition in combination with RT as a treatment option for both HPV-negative and HPV-positive HNSCC patients.

Radiosensitization approaches for HPV-positive and HPV-negative head and neck squamous carcinomas.

Radiotherapy is one of the most used treatment approaches for head and neck squamous cell carcinoma (HNSCC). Targeted inhibition of DNA repair machinery has the potential to improve treatment response by tailoring treatment to cancer cells lacking specific DNA repair pathways. Human papillomavirus (HPV)-negative and HPV-positive HNSCCs respond differently to radiotherapy treatment, suggesting that different approaches of DNA repair inhibition should be employed for these HNSCC groups. Here, we searched for optimal radiosensitization approaches for HPV-positive and HPV-negative HNSCCs by performing a targeted CRISPR-Cas9 screen. We found that inhibition of base excision repair resulted in a better radiotherapy response in HPV-positive HNSCC, which is correlated with upregulation of genes involved in base excision repair. In contrast, inhibition of nonhomologous end-joining and mismatch repair showed strong effects in both HNSCC groups. We validated the screen results by combining radiotherapy with targeted inhibition of DNA repair in several preclinical models including primary and recurrent patient-derived HNSCC xenografts. These findings underline the importance of stratifying HNSCC patients for combination treatments.

Prognostic value of a 15-gene hypoxia classifier in oropharyngeal cancer treated with accelerated chemoradiotherapy.

PURPOSE: A 15-gene hypoxia classifier has been developed and validated as a predictive factor for patients with head and neck squamous cell carcinoma treated with radiotherapy and nimorazole. This paper aimed to investigate the role of this hypoxia classifier as a prognostic factor for patients with oropharyngeal cancer (OPC) treated with accelerated chemoradiotherapy. METHODS: P16 and 15-gene hypoxia classifier status, categorising tumours as more or less hypoxic, were determined for 136 OPC patients. Locoregional recurrence rate (LRR) and overall survival (OS) were estimated with cumulative incidence function and Kaplan-Meier method, respectively, stratified according to p16 and hypoxia status. RESULTS: P16-positive patients (34.6%) had significantly better LRR and OS than p16-negative patients. The 5­year LRR of patients with more hypoxic OPC was similar to those with less hypoxic OPC in the overall patient population (27.3% versus 25.1%; p = 0.98; HR = 1.01 [CI95% 0.47;2.17]) and in the p16-negative OPC (36.4% versus 30.1%; p = 0.70; HR = 1.17 [CI95% 0.53;2.56]). No significant OS differences could be observed in neither p16-negative nor p16-positive subgroup with a 5-year OS for p16-negative more hypoxic OPC of 44.2% versus 49.0% in the less hypoxic OPC (p = 0.92; HR 0.97 [CI95% 0.51;1.84]). CONCLUSION: No significant outcome differences were observed between more or less hypoxic tumours, as determined by the 15-gene hypoxia classifier. These results suggest that the 15-gene hypoxia classifier may not have prognostic value in an OPC patient cohort treated with accelerated chemoradiotherapy.

Dual role for p16 in the metastasis process of HPV positive head and neck cancers.

Several studies show that human papillomavirus (HPV) positive head and neck cancers (HNSCC) are typically characterized by low tumor and high regional node stages, intrinsically indicating high local metastatic potential. Despite this, the distant metastasis rates of HPV positive and negative HNSCC are similar. To date, majority of the studies focus on molecular characterization of HPV positive disease and on treatment outcome. Here we assessed the biological mechanisms of metastasis by combining in vitro and in vivo head and neck carcinoma xenograft models with patient data. We provide experimental evidence for a dual role of p16, a surrogate marker for HPV infections, in the metastasis process of HNSCC. We found that p16 regulates the invasiveness and metastatic potential of HNSCC cells by impairing angiogenesis. In parallel, we found that p16 is regulating the nodal spread by mediating lymphatic vessel formation through the upregulation of integrins. These findings not only provide understanding of the biology of the different dissemination patterns but also suggest that inhibition of lymphangiogenesis in HPV positive cancers and inhibition of angiogenesis in HPV negative cancers can form a treatment strategy against metastasis.

Panitumumab plus radiotherapy versus chemoradiotherapy in patients with unresected, locally advanced squamous-cell carcinoma of the head and neck (CONCERT-2): a randomised, controlled, open-label phase 2 trial.

BACKGROUND: We aimed to compare panitumumab, a fully human monoclonal antibody against EGFR, plus radiotherapy with chemoradiotherapy in patients with unresected, locally advanced squamous-cell carcinoma of the head and neck. METHODS: In this international, open-label, randomised, controlled, phase 2 trial, we recruited patients with locally advanced squamous-cell carcinoma of the head and neck from 22 sites in eight countries worldwide. Patients aged 18 years and older with stage III, IVa, or IVb, previously untreated, measurable (≥ 10 mm for at least one dimension), locally advanced squamous-cell carcinoma of the head and neck (non-nasopharygeal) and an Eastern Cooperative Oncology Group performance status of 0-1 were randomly assigned (2:3) by an independent vendor to open-label chemoradiotherapy (two cycles of cisplatin 100 mg/m(2) during radiotherapy) or to radiotherapy plus panitumumab (three cycles of panitumumab 9 mg/kg every 3 weeks administered with radiotherapy) using a stratified randomisation with a block size of five. All patients received 70-72 Gy to gross tumour and 54 Gy to areas of subclinical disease with accelerated fractionation radiotherapy. The primary endpoint was local-regional control at 2 years, analysed in all randomly assigned patients who received at least one dose of their assigned protocol-specific treatment (chemotherapy, radiation, or panitumumab). The trial is closed and this is the final analysis. This study is registered with ClinicalTrials.gov, number NCT00547157. FINDINGS: Between Nov 30, 2007, and Nov 16, 2009, 152 patients were enrolled, and 151 received treatment (61 in the chemoradiotherapy group and 90 in the radiotherapy plus panitumumab group). Local-regional control at 2 years was 61% (95% CI 47-72) in the chemoradiotherapy group and 51% (40-62) in the radiotherapy plus panitumumab group. The most frequent grade 3-4 adverse events were mucosal inflammation (25 [40%] of 62 patients in the chemoradiotherapy group vs 37 [42%] of 89 patients in the radiotherapy plus panitumumab group), dysphagia (20 [32%] vs 36 [40%]), and radiation skin injury (seven [11%] vs 21 [24%]). Serious adverse events were reported in 25 (40%) of 62 patients in the chemoradiotherapy group and in 30 (34%) of 89 patients in the radiotherapy plus panitumumab group. INTERPRETATION: Panitumumab cannot replace cisplatin in the combined treatment with radiotherapy for unresected stage III-IVb squamous-cell carcinoma of the head and neck, and the role of EGFR inhibition in locally advanced squamous-cell carcinoma of the head and neck needs to be reassessed. FUNDING: Amgen.

Clinical and dosimetric evaluation of RapidArc versus standard sliding window IMRT in the treatment of head and neck cancer.

BACKGROUND: Several planning studies have already proven the substantial dosimetric advantages of RapidArc (RA) over standard intensity-modulated radiotherapy. We retrospectively compared RapidArc and standard sliding window IMRT (swIMRT) in locally advanced head and neck cancer, looking both at dosimetrics as well as toxicity and outcome. METHODS: CT datasets of 78 patients treated with swIMRT and 79 patients treated with RA were included. To compare the resulting dose distributions, the dose-volume parameters were evaluated for the planning target volumes (PTVs), clinical target volumes (CTVs), and organs at risk (OARs), and the number of MU were calculated. Acute toxicity was assessed by the Common Toxicity Criteria version 3.0. RESULTS: PTV coverage with the 95% isodose was slightly better for RA. Dose distribution has proven to be significantly more homogenous with RA and led to a reduction of 62% in MU with better OAR sparing. As for toxicity, more grade 3 mucositis and dysphagia was observed for swIMRT, though we observed more grade 3 dermatitis for RA. CONCLUSION: In our retrospective analysis, RA had better target coverage and better sparing of the OAR. Overall, the grade of acute toxicity was lower for RA than for swIMRT for the same types of tumor locations, except for the grade of dermatitis.

Postoperative photodynamic therapy as a new adjuvant treatment after robot-assisted salvage surgery of recurrent squamous cell carcinoma of the base of tongue.

BACKGROUND: For patients who remain with involved resection margins after transoral robot-assisted salvage surgery (TORS) for recurrent squamous cell carcinoma (SCC) at the base of tongue (BOT) following primary (chemo)radiotherapy, further adjuvant treatment options are very limited. We want to report on our preliminary experience with a new adjuvant strategy using postoperative temoporfin-mediated photodynamic therapy for this indication. METHODS: Two patients with recurrent SCC after primary (chemo)radiotherapy of the BOT were treated with TORS, but unfortunately remained with involved resection margins on the postoperative pathology report. If left without additional treatment, these patients are prone to further recurrence. Temoporfin-mediated photodynamic therapy was used as a new adjuvant approach to treat the remaining microscopic disease at the resection margins. RESULTS: Good oncological and functional results were obtained in these patients, now treated for a recurrence, after a preceding full course of radiotherapy. Both are disease free at 42 and 24 months of follow-up and are able to speak, breathe, and eat normally. CONCLUSIONS: In selected patients that have undergone salvage surgery with positive resection margins, postoperative temoporfin-mediated photodynamic therapy can result in a good oncological and functional outcome.

FLT1 kinase is a mediator of radioresistance and survival in head and neck squamous cell carcinoma.

UNLABELLED: Head and neck squamous cell carcinoma (HNSCC) is the fifth most common malignancy worldwide, responsible for approximately half a million new cases every year. The treatment of this disease is challenging and characterised by high rates of therapy failure and toxicity, stressing the need for new innovative treatment strategies. MATERIAL AND METHODS: In this study we performed a shRNAmir-based screen on HNSCC cells with the aim to identify tyrosine kinases that are mediating radiotherapy resistance. RESULTS: The receptor tyrosine kinase FLT1 (VEGFR1) was identified as an important driver of cell survival and radioresistance. We show that FLT1 is phosphorylated in HNSCC cells, and document autocrine production of FLT1 ligands VEGFA and VEGFB, leading to receptor activation. Immunohistochemistry on HNSCC patient samples demonstrated FLT1 and VEGFA to be uniformly expressed. Interestingly, FLT1 was selectively overexpressed in tumour tissue as compared to non-cancerous epithelium. Remarkably, we found only membrane permeable FLT1 kinase inhibitors to be effective, which was in agreement with the intracellular localisation of FLT1. DISCUSSION AND CONCLUSION: Taken together, we document expression of FLT1 in HNSCC and demonstrate this kinase to modulate radioresistance and cancer cell survival. Given the fact that FLT1 kinase is selectively upregulated in tumour tissue and that its kinase function seems expendable for normal life and development, this kinase holds great promise as a new potential therapeutic target.

Radiobiology of Proton Therapy in Human Papillomavirus-Negative and Human Papillomavirus-Positive Head and Neck Cancer Cells.

Photon-based radiotherapy (XRT) is one of the most frequently used treatment modalities for HPV-negative and HPV-positive locally advanced head and neck squamous cell carcinoma (HNSCC). However, locoregional recurrences and normal RT-associated toxicity remain major problems for these patients. Proton therapy (PT), with its dosimetric advantages, can present a solution to the normal toxicity problem. However, issues concerning physical delivery and the lack of insights into the underlying biology of PT hamper the full exploitation of PT. Here, we assessed the radiobiological processes involved in PT in HPV-negative and HPV-positive HNSCC cells. We show that PT and XRT activate the DNA damage-repair and stress response in both HPV-negative and HPV-positive cells to a similar extent. The activation of these major radiobiological mechanisms resulted in equal levels of clonogenic survival and mitotic cell death. Altogether, PT resulted in similar biological effectiveness when compared to XRT. These results emphasize the importance of dosimetric parameters when exploiting the potential of increased clinical effectiveness and reduced normal tissue toxicity in PT treatment.