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Purpose: Individual prediction of treatment response is crucial for personalized treatment in multimodal approaches against head-and-neck squamous cell carcinoma (HNSCC). So far, no reliable predictive parameters for treatment schemes containing immunotherapy have been identified. This study aims to predict treatment response to induction chemo-immunotherapy based on the peripheral blood immune status in patients with locally advanced HNSCC., Methods: The peripheral blood immune phenotype was assessed in whole blood samples in patients treated in the phase II CheckRad-CD8 trial as part of the pre-planned translational research program. Blood samples were analyzed by multicolor flow cytometry before (T1) and after (T2) induction chemo-immunotherapy with cisplatin/docetaxel/durvalumab/tremelimumab. Machine Learning techniques were used to predict pathological complete response (pCR) after induction therapy., Results: The tested classifier methods (LDA, SVM, LR, RF, DT, and XGBoost) allowed a distinct prediction of pCR. Highest accuracy was achieved with a low number of features represented as principal components. Immune parameters obtained from the absolute difference (lT2-T1l) allowed the best prediction of pCR. In general, less than 30 parameters and at most 10 principal components were needed for highly accurate predictions. Across several datasets, cells of the innate immune system such as polymorphonuclear cells, monocytes, and plasmacytoid dendritic cells are most prominent., Conclusions: Our analyses imply that alterations of the innate immune cell distribution in the peripheral blood following induction chemo-immuno-therapy is highly predictive for pCR in HNSCC., Competing Interests: Declaration of competing interest M.H. conflict of interest with Merck Serono (advisory role, speakers’ bureau, honoraria, travel expenses, research funding); MSD (advisory role, speakers’ bureau, honoraria, travel expenses, research funding); AstraZeneca (advisory role, speakers’ bureau, honoraria, travel expenses, research funding); Novartis (research funding); BMS (advisory role, speakers’ bureau, honoraria, travel expenses, research funding); Teva (travel expenses); Sanofi (advisory role, honoraria). M.E. conflict of interest with Diaceutics (employment, honoraria, advisory role, speakers’ bureau, travel expenses); Cepheid (research funding, advisory role); AstraZeneca (honoraria, advisory role, speakers’ bureau, travel expenses); Roche (honoraria, travel expenses); MSD (honoraria, speakers’ bureau); GenomicHealth (honoraria, advisory role, speakers bureau, travel expenses); Astellas (honoraria, speakers’ bureau); Janssen-Cilag (honoraria, advisory role, research funding, travel expenses); Stratifyer (research funding, patents). G.K. conflict of interest with BMS (advisory role); Lilly (advisory role); Roche (advisory role) S.L. conflict of interest with AstraZeneca (honoraria, advisory role); BMS (honoraria, advisory role, speakers’ bureau); MSD (honoraria, advisory role); Merck Serono (honoraria, speakers’ bureau); ISA-Pharmaceuticals (research funding) M.G.H. conflict of interest with Roche (stock); Varian (stock); Sanofi (stock); AstraZeneca (honoraria); BMS (honoraria, advisory role); MSD (honoraria, advisory role); Merck Serono (honoraria); Celgene (honoraria). B.T. conflict of interest with BMS (advisory role, honoraria); Merck Serono (advisory role, speakers’ bureau, honoraria); MSD (advisory role, speakers’ bureau, honoraria); Sanofi (advisory role, honoraria). A.Hi. conflict of interest with Roche (honoraria). A.H. conflict of interest with BMS (honoraria, advisory role); MSD (honoraria, advisory role); Roche (honoraria, advisory role, research funding); AstraZeneca (honoraria, advisory role, research funding); Boehringer Ingelheim (honoraria); Abbvie (honoraria); Cepheid (advisory role, research funding); Quiagen (advisory role); Janssen-Cilag (honoraria, advisory role, research funding); Ipsen (honoraria, advisory role); NanoString Technologies (advisory role, research funding, expert testimony); Illumina (advisory role); 3DHistech (advisory role); Diaceutics (advisory role); BioNTech (research funding). W.B. conflict of interest with BMS (advisory role); MSD (advisory role); Merck Serono (advisory role); Pfitzer (advisory role); AstraZeneca (advisory role). U.S.G. conflict of interest with AstraZeneca (advisory role, research funding); BMS (advisory role); MSD (research funding); MedUpdate (literature research and presentation activities), Dr. Sennewald Medizintechnik (travel expenses and advisory role), Merck (presentation activities). R.F. conflict of interest with MSD (honoraria, advisory role, research funding, travel expenses); Fresenius (honoraria); BrainLab (honoraria); AstraZeneca (honoraria, advisory role, research funding, travel expenses); Merck Serono (advisory role, research funding, travel expenses); Novocure (advisory role, speakers’ bureau, research funding); Sennewald (speakers’ bureau, travel expenses). The other authors declare no conflicts of interest. All other not listed authors do not have a conflict of Interest, (Copyright © 2024. Published by Elsevier Inc.)

Aim: In the CheckRad-CD8 trial patients with locally advanced head and neck squamous cell cancer are treated with a single cycle of induction chemo-immunotherapy (ICIT). Patients with pathological complete response (pCR) in the re-biopsy enter radioimmunotherapy. Our goal was to study the value of F-18-FDG PET/CT in the prediction of pCR after induction therapy., Methods: Patients treated within the CheckRad-CD8 trial that additionally received FDG- PET/CT imaging at the following two time points were included: 3-14 days before (pre-ICIT) and 21-28 days after (post-ICIT) receiving ICIT. Tracer uptake in primary tumors (PT) and suspicious cervical lymph nodes (LN +) was measured using different quantitative parameters on EANM Research Ltd (EARL) accredited PET reconstructions. In addition, mean FDG uptake levels in lymphatic and hematopoietic organs were examined. Percent decrease (Δ) in FDG uptake was calculated for all parameters. Biopsy of the PT post-ICIT acquired after FDG-PET/CT served as reference. The cohort was divided in patients with pCR and residual tumor (ReTu)., Results: Thirty-one patients were included. In ROC analysis, ΔSUVmax PT performed best (AUC = 0.89) in predicting pCR (n = 17), with a decline of at least 60% (sensitivity, 0.77; specificity, 0.93). Residual SUVmax PT post-ICIT performed best in predicting ReTu (n = 14), at a cutpoint of 6.0 (AUC = 0.91; sensitivity, 0.86; specificity, 0.88). Combining two quantitative parameters (ΔSUVmax ≥ 50% and SUVmax PT post-ICIT ≤ 6.0) conferred a sensitivity of 0.81 and a specificity of 0.93 for determining pCR. Background activity in lymphatic organs or uptake in suspected cervical lymph node metastases lacked significant predictive value., Conclusion: FDG-PET/CT can identify patients with pCR after ICIT via residual FDG uptake levels in primary tumors and the related changes compared to baseline. FDG-uptake in LN + had no predictive value., Trial Registry: ClinicalTrials.gov identifier: NCT03426657., (© 2022. The Author(s).)

Purpose: The first aim of the trial is to study feasibility of combined programmed death protein ligand 1/cytotoxic T-lymphocyte-associated protein 4 inhibition concomitant to radiotherapy. In addition, efficacy of the entire treatment scheme consisting of induction chemoimmunotherapy followed by chemotherapy-free radioimmunotherapy (RIT) after intratumoral CD8 +immune cell-based patient selection will be analyzed., Methods: Patients with stage III-IVB head and neck squamous cell carcinoma were eligible for this multicenter phase II trial. Treatment consisted of a single cycle of cisplatin 30 mg/m² days 1-3, docetaxel 75 mg/m² day 1, durvalumab 1500 mg fix dose day 5 and tremelimumab 75 mg fix dose day 5. Patients with increased intratumoral CD8 +immune cell density or pathological complete response (pCR) in the rebiopsy entered RIT up to a total dose of 70 Gy. Patients received further three cycles of durvalumab/tremelimumab followed by eight cycles of durvalumab mono (every 4 weeks). The intended treatment for patients not meeting these criteria was standard radiochemotherapy outside the trial. Primary endpoint was a feasibility rate of patients entering RIT to receive treatment until at least cycle 6 of immunotherapy of ≥80%., Results: Between September 2018 and May 2020, 80 patients were enrolled (one excluded). Out of these, 23 patients had human papilloma virus (HPV)-positive oropharyngeal cancer. Median follow-up was 17.2 months. After induction chemoimmunotherapy 41 patients had pCR and 31 had increased intratumoral CD8 +immune cells. Of 60 patients entering RIT (primary endpoint cohort), 10 experienced imiting toxic (mainly hepatitis) and four discontinued for other reasons, resulting in a feasibility rate of 82%. The RIT cohort (n=60) had a progression-free survival (PFS) rate at one and 2 years of 78% and 72%, respectively, and an overall survival rate at one and 2 years of 90% and 84%, respectively. Patients with HPV-positive oropharyngeal cancers had greater benefit from RIT with a 2-year PFS rate of 94% compared with 64% for HPV-negative oropharyngeal cancers and other locations. In the entire study cohort (n=79) the 2-year PFS rate was 68% (91% for HPV-positive oropharynx vs 59% for others). Toxicity grade 3-4 mainly consisted of dysphagia (53%), leukopenia (52%) and infections (32%)., Conclusions: The trial met the primary endpoint feasibility of RIT. Induction chemo-immunotherapy followed by chemotherapy-free RIT after intratumoral CD8 +immune cell-based patient selection has promising PFS., Trial Registration Number: The trial was registered with ClinicalTrials.gov (identifier: NCT03426657). The trial was conducted as investigator-sponsored trial (IST)., Competing Interests: Competing interests: MH conflict of interest with Merck Serono (advisory role, speakers’ bureau, honoraria, travel expenses, research funding); MSD (advisory role, speakers’ bureau, honoraria, travel expenses, research funding); AstraZeneca (research funding); Novartis (research funding); BMS (advisory role, honoraria, speakers’ bureau); Teva (travel expenses). ME conflict of interest with Diaceutics (employment, honoraria, advisory role, speakers’ bureau, travel expenses); Cepheid (research funding, advisory role); AstraZeneca (honoraria, advisory role, speakers’ bureau, travel expenses); Roche (honoraria, travel expenses); MSD (honoraria, speakers’ bureau); GenomicHealth (honoraria, advisory role, speakers bureau, travel expenses); Astellas (honoraria, speakers’ bureau); Janssen-Cilag (honoraria, advisory role, research funding, travel expenses); Stratifyer (research funding, patents). SR conflict of interest with AstraZeneca (research funding); MSD (research funding). GK conflict of interest with BMS (advisory role); Lilly (advisory role); Roche (advisory role). SL conflict of interest with AstraZeneca (honoraria, advisory role); BMS (honoraria, advisory role, speakers’ bureau); MSD (honoraria, advisory role); Merck Serono (honoraria, speakers’ bureau); ISA-Pharmaceuticals (research funding). MGH conflict of interest with Roche (stock); Varian (stock); Sanofi (stock); AstraZeneca (honoraria); BMS (honoraria, advisory role); MSD (honoraria, advisory role); Merck Serono (honoraria); Celgene (honoraria). AHi conflict of interest with Roche (honoraria). SS conflict of interest with Strycker (stock); Varian (stock); Abbot (stock); Crispr Techn. (stock); Pfitzer (stock); Merck Serono (stock); Symrise (stock); Ortho (honoraria, advisory role, speakers’ bureau, research funding, travel expenses); PharmaMar (speakers’ bureau, travel expenses); Haema (speakers’ bureau). AHa. conflict of interest with BMS (honoraria, advisory role); MSD (honoraria, advisory role); Roche (honoraria, advisory role, research funding); AstraZeneca (honoraria, advisory role, research funding); Boehringer Ingelheim (honoraria); Abbvie (honoraria); Cepheid (advisory role, research funding); Quiagen (advisory role); Janssen-Cilag (honoraria, advisory role, research funding); Ipsen (honoraria, advisory role); NanoString Technologies (advisory role, research funding, expert testimony); Illumina (advisory role); 3DHistech (advisory role); Diaceutics (advisory role); BioNTech (research funding). WB conflict of interest with BMS (advisory role); MSD (advisory role); Merck Serono (advisory role); Pfitzer (advisory role); AstraZeneca (advisory role). UG conflict of interest with AstraZeneca (advisory role, research funding); BMS (advisory role); MSD (research funding); Sennewald Medizintechnik (advisory role, travel expenses). RF conflict of interest with MSD (honoraria, advisory role, research funding, travel expenses); Fresenius (honoraria); BrainLab (honoraria); AstraZeneca (honoraria, advisory role, research funding, travel expenses); Merck Serono (advisory role, research funding, travel expenses); Novocure (advisory role, speakers’ bureau, research funding); Sennewald (speakers’ bureau, travel expenses). The other authors declare no conflicts of interest., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Radiotherapy aggravates implant-based prosthetic rehabilitation in patients with head and neck cancer., Purpose: To evaluate the impact of radiation dose at implant and parotid gland site for prosthetic rehabilitation., Material and Methods: The retrospective study includes 121 irradiated head and neck cancer patients with 751 inserted implants. Radiation doses on implant bed and parotid gland site were recorded by 3-dimensional modulated radiation plans. Implant success was clinically and radiographically evaluated according to modified Albrektsson criteria and compared to treatment- and patient-specific data., Results: Implant overall survival after 5 years was 92.4% with an implant success rate of 74.9%. Main reasons for implant failure were marginal bone resorption (20.9%), implant not in situ or unloaded (9.6%) and peri-implantitis (7.5%). A mean radiation dose of 62.6 Gy was applied with a mean parotid dose of 35 Gy. Modulating radiation techniques went along with lower grades of xerostomia (p < 0.001). At implant site mean doses of 57.5, 42.0, and 32.3 Gy were recorded for oral, oropharyngeal, and hypopharyngeal/laryngeal carcinoma, respectively. Implant success inversely correlated to radiation dose at implant site. Strong predictors for implant failure in uni- and multivariate analysis were implant-specific dose >50 Gy (HR 7.9), parotid dose >30 Gy (HR 2.3), bone (HR 14.5) and soft tissue (HR 4.5) transplants, bad oral hygiene (HR 3.8), nonmodulated radiation treatment planning (HR 14.5), and nontelescopic prosthetics (HR 5.2)., Conclusion: Radiotherapy impedes implant success in a dose-dependent manner at implant site. Modern radiation techniques effectively reduce xerostomia favoring implant-based prosthetic rehabilitation. Implantation in bone grafts is more critical and telescopic-retained overdentures should be preferred., (© 2021 The Authors. Clinical Implant Dentistry and Related Research Published by Wiley Periodicals LLC.)

Objectives: The aim of this study was to investigate the influence of CD4 + , CD8 + and Forkhead box protein 3 (FoxP3 + ) tumor-infiltrating lymphocytes, as well as CD1a + tumor-infiltrating dendritic cells on the radiosensitivity and survival of primarily chemoirradiated advanced head and neck squamous cell carcinomas., Study Design: Immunohistochemical staining for CD4, CD8, FoxP3 and CD1a was performed in 82 primarily chemoirradiated head and neck squamous cell carcinomas. Associations with clinicopathologic data, programmed cell death protein-1 (PD-1), programmed cell death ligand-1 (PD-L1), p16, radiation response, and survival were examined., Results: High CD4 expression was associated with complete response after radiation (P = .006) and high CD1a expression (P = .024). High CD8 + tumor-infiltrating lymphocyte counts were associated with absence of tumor relapse (P = .032) and better disease-free survival (P = .051). Strong overall T-cell infiltration was found more often in tumors with high-grade differentiation (P = .004), complete response after radiation (P = .022), and better overall survival and disease-specific survival (each P = .052). Tumors with high FoxP3 + T regulatory (T reg ) infiltration more often showed high-grade tumor differentiation (P = .017), advanced patient age (P = .02), high PD-1 (P = .007), high CD4 (P = .002), and high CD8 expression (P = .002), as well as better disease-free survival (P = .019)., Conclusions: T-cell activation (high CD4, CD8 and FoxP3 expression) is associated with radio response and favorable survival in advanced head and neck cancer treated with definitive chemoradiation., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background and Purpose: This multicenter, phase 3 trial investigates whether the incorporation of concurrent paclitaxel and cisplatin together with a reduced total dose of radiotherapy is superior to standard fluorouracil-cisplatin based CRT., Materials and Methods: Patients with SCCHN, stage III-IVB, were randomized to receive paclitaxel/cisplatin (PacCis)-CRT (arm A; paclitaxel 20 mg/m 2 on days 2, 5, 8, 11 and 25, 30, 33, 36; cisplatin 20 mg/m 2 , days 1-4 and 29-32; RT to a total dose of 63.6 Gy) or fluorouracil/cisplatin (CisFU)-CRT (arm B; fluorouracil 600 mg/m 2 ; cisplatin 20 mg/m 2 , days 1-5 and 29-33; RT: 70.6 Gy). Endpoint was 3-year-disease free survival (3y-DFS)., Results: A total of 221 patients were enrolled between 2010 and 2015. With a median follow-up of 3.7 years, 3y-DFS in the CisFU arm and PacCis arm was 58.2% and 48.4%, respectively (HR 0.82, 95% CI 0.56-1.21, p = 0.52). The 3y-OS amounted to 64.6% in the CisFU arm, and to 59.2% in the PacCis arm (HR 0.82, 95% CI 0.54-1.24, p = 0.43). In the subgroup of p16-positive oropharyngeal carcinomas, 3y-DFS and 3y-OS was 84.6% vs 83.9% (p = 0.653), and 92.3% vs. 83.5% (p = 0.76) in arm A and B, respectively. Grade 3-4 hematological toxicities were significantly reduced in arm A (anemia, p = 0.01; leukocytopenia, p = 0.003), whereas grade 3 infections were reduced in arm B (p = 0.01)., Conclusion: Paclitaxel/cisplatin-CRT with a reduced RT-dose is not superior to standard fluorouracil/cisplatin-CRT. Subgroup analyses indicate that a reduced radiation dose seems to be sufficient for p16+ oropharyngeal cancer or non-smokers., Clinical Trial Information: NCT01126216; EudraCT Number 2005-003484-23., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objectives: The aim of this study is to investigate the influence of prognostic biomarkers on radiosensitivity and survival of advanced head and neck squamous cell carcinomas treated by primary (chemo)radiation., Material and Methods: The clinicopathological data and immunohistochemical staining of p16, c-Met, survivin, PD-1, and PD-L1 of 82 primarily (chemo)irradiated patients with head and neck squamous cell carcinoma were analyzed. Associations with local and locoregional radiation response, overall survival (OS), disease-free (DFS), and disease-specific survival (DSS) were assessed., Results: Complete tumor response was associated with increased patient age (p = 0.007), N0-status (p = 0.022), M0-status (p = 0.007), and p16-positivity (p = 0.022). High PD-L1 was associated with M0-status (p = 0.026) and indicated tumor response to irradiation (p = 0.057); survivin expression showed higher rates of response failure (p = 0.073). Low PD-1 was associated with increased T-stage (p = 0.029) and local recurrence (p = 0.014). High PD-1 was strongly correlated with PD-L1-positive tumor infiltrating lymphocytes (p < 0.001). Low PD-L1 showed a significant correlation with high c-Met expression (p = 0.01). Significant predictors for unfavorable univariate survival were incomplete tumor response (DSS, p < 0.001), single radiotherapy (DSS, p = 0.002), M1-status (DSS, p < 0.001), decreased radiation dose (DSS, p = 0.014), high survivin (DSS, p = 0.045), and high c-Met (OS, p < 0.05). Survivin and c-Met also showed prognostic significance in multivariate survival analysis., Conclusions: P16 and PD-L1 indicate radiosensitivity, whereas survivin and c-Met implicate radioresistance in primarily (chemo)irradiated head and neck squamous cell carcinomas. The role of the PD-1/PD-L1 immune checkpoints in radiation response and survival merits further investigation., Clinical Relevance: The findings may improve patient-specific therapy according to individual tumor characteristics.

Tumor immune microenvironment and tumor metabolism are major determinants of chemoradiotherapy response. The interdependency and prognostic significance of specific immune and metabolic phenotypes in head and neck squamous cell carcinoma (HNSCC) were assessed and changes in reactive oxygen species were evaluated as a mechanism of treatment response in tumor spheroid/immunocyte co-cultures. Pretreatment tumor biopsies were immunohistochemically characterized in 73 HNSCC patients treated by definitive chemoradiotherapy and correlated with survival. The prognostic significance of CD8A, GLUT1, and COX5B gene expression was analyzed within The Cancer Genome Atlas database. HNSCC spheroids were co-cultured in vitro with peripheral blood mononuclear cells (PBMCs) in the presence of the glycolysis inhibitor 2-deoxyglucose and radiation treatment followed by PBMC chemotaxis determination via fluorescence microscopy. In the chemoradiotherapy-treated HNSCC cohort, mitochondrial-rich (COX5B) metabolism correlated with increased and glucose-dependent (GLUT1) metabolism with decreased intratumoral CD8/CD4 ratios. High CD8/CD4, together with mitochondrial-rich or glucose-independent metabolism, was associated with improved short-term survival. The Cancer Genome Atlas analysis confirmed that patients with a favorable immune and metabolic gene signature (high CD8A, high COX5B, low GLUT1) had improved short- and long-term survival. In vitro, 2-deoxyglucose and radiation synergistically up-regulated reactive oxygen species-dependent PBMC chemotaxis to HNSCC spheroids. These results suggest that glucose-independent tumor metabolism is associated with CD8-dominant antitumor immune infiltrate, and together, these contribute to improved chemoradiotherapy response in HNSCC., (Copyright © 2018 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background: Based on epidemiological (HPV status, smoking habits) and clinical risk factors (T/N stage), three subgroups of patients suffering from locally advanced oropharyngeal carcinoma with significantly different outcome after concurrent chemoradiation (cCRTX) can be distinguished. Mutational profiling by targeted next-generation sequencing (NGS) might further improve risk stratification., Patients and Methods: Patients with stage IV squamous cell carcinoma of the oropharynx and hypopharynx who had been enrolled in a randomized phase III trial (ARO-0401) comparing two regimens of cCRTX and from whom archival tumor specimens were available were included. The HPV status was determined by p16 immunostaining and detection of HPV DNA. Targeted NGS covering 45 genes frequently altered in squamous cell carcinoma of the head and neck (SCCHN) was applied for detection of non-synonymous somatic and germline mutations. Interference of mutational profiles with cCRTX efficacy was determined., Results: The prognostic value of the 'Ang' risk model could be confirmed in the total biomarker study cohort (N = 175) as well as the patient subgroup for which mutational profiles could be established (N = 97). Mutations in genes involved in phosphoinositide 3-kinase (PI3K), receptor tyrosine kinase (RTK), and p53 signaling pathways were significantly enriched in the low- (N = 7), intermediate- (N = 20), and high-risk group (N = 70), respectively. Mutations in TP53 identified a subgroup of high-risk patients with dismal outcome after cCRTX. No prognostic relevance was observed for mutations in PI3K and RTK signaling pathways in the low- and intermediate-risk groups, respectively. Mutated NOTCH1 and two functional KDR germline variants (rs2305948, rs1870377) were associated with improved outcome in all risk groups. All genetic markers (TP53, NOTCH1, KDR) remained independent prognosticators of OS in the multivariate model., Conclusion: A potential of targeted NGS for risk classification of SCCHN cases beyond HPV status and clinical factors was demonstrated., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose/objective(s): Intensification of radiotherapy and chemotherapy for head-and-neck cancer (HNC) may lead to increased rates of long term dysphagia as a severe side effect. Mucositis and consequent swallowing problems require artificial nutrition in many HNC patients undergoing radiotherapy or chemoradiation. It is unknown, which predict factors for prophylactic PEG tube insertion appear useful., Materials/methods: From an institutional database, 101 patients (72 male, 29 female, mean age 59.5years) were identified who underwent radiotherapy or chemoradiation for HNC. Primary end point of the investigation was the need for artificial nutrition for more than 4days during radiotherapy. Dose volume parameters of defined normal tissue structures potentially of relevance for swallowing ability as well as clinical factors were used to develop a predictive model using a binary multiple logistic regression model., Results: Whereas several dosimetric and clinical factors were significant predictors for the need of artificial nutrition on univariate analysis, on multivariate analysis only three factors remained independently significant: mean dose to the oropharynx+1cm circumferential margin, ECOG performance state (0-1 vs. 2-4), and the use of chemotherapy (yes vs. no)., Conclusions: Using a 3 parameter model we could distinguish HNC-patients with different risks for the need of artificial nutrition during radiotherapy. After independent validation, the model could be helpful to decision on prophylactic PEG tube insertion., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objectives: Induction of apoptosis is a major mechanism of radiosensitivity in different types of cancer. In contrast, EGFR/PI3K/AKT signalling and recently the presence of so-called cancer stem cells are discussed as reasons for radioresistance., Materials and Methods: The study investigates mechanisms of apoptosis, key oncogenes of the PI3K/AKT pathway and the presence of cancer cells with stem cell properties during irradiation in two cell lines (PCI-9A, and PCI-15) of head and neck squamous cell carcinoma. WST-1-tests, qRT-PCR, western blots and FACS analysis were performed for analysis., Results: The two cell lines presented different degrees of cell death upon irradiation. The radiosensitive cell line PCI-9A showed increased apoptosis after irradiation measured by expressed cleaved caspases 3 and 7 while the radioresistant cell line PCI-15 upregulated antiapoptotic Survivin and BCL2A1 mRNA. Besides, increased PI3K/AKT- and ERK1/2-signalling was associated with radioresistance accompanied by loss of PTEN function through phosphorylation on S380. Blockade of pAKT increased radiation-induced cell death, and moreover, led to an upregulation of pMET in the radioresistant cell line. The percentage of ALDH-positive tumour cells was markedly decreased after irradiation in the radiosensitive cell line., Conclusions: Functional apoptosis is mandatory for sensitivity to irradiation in head neck cancer cells. Upregulation of the AKT-pathway seems to be one reason for poor radioresponse. Activated MET may also predict radioresistance, possibly through ERK1/2 signalling. Moreover MET may indicate the presence of cancer stem cells facilitating radioresistance as shown by increased ALDH expression., (Copyright © 2014 Elsevier Ltd. All rights reserved.)