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Background/objectives: Most studies on the interaction between the immune system and cancer focus on T-cells, whereas studies on tumor-infiltrating B-lymphocytes (TIL-Bs) are still underrepresented. The aim of this study was to assess the prognostic impact of TIL-Bs in early- and advanced-stage oral cavity squamous cell carcinoma (OCSCC)., Methods: In total, 222 OCSCCs were studied. Consecutive sections were stained for CD45 and CD19. OCSCCs were categorized as either "TIL-B-rich" or "TIL-B-poor", and the survival of both groups was analyzed. Similar analyses were performed for CD45+ TILs and the CD19/CD45 ratio. Matched subgroups of twelve TIL-B-rich and TIL-B-poor tumors were stained for CD3 and CD8 to determine differences in T-cell infiltration, and further spatial interaction between T- and B-cells was evaluated in six samples., Results: Five-year OS was 75.0% for TIL-B-rich and 54.2% for TIL-B-poor OCSCCs ( p < 0.001). The survival benefit of TIL-B-rich OCSCCs remained significant after correction for the histopathological characteristics ( p = 0.033). While for early-stage tumors, TIL-B richness benefited OS independent of demographic-, clinical, or histopathological features, for advanced-stage disease, this was not the case, although a clear benefit of a TIL-B-rich status was observed, specifically up until 36 months after diagnosis. TIL-B-rich tumors contained more CD3+ TILs ( p = 0.007), but not CD8+ TILs. Spatial characterization suggested that TIL-Bs mostly co-localized with CD3+CD8- TILs and that this interaction was increased in TIL-B-rich OCSCC., Conclusions: The presence of TIL-Bs is associated with a more favorable prognosis in OCSCC, in particular for early-stage disease.

Purpose: Limited data exists on the long-term course of fear of cancer recurrence (FCR) in head and neck cancer (HNC) patients. One in five patients was found to experience persistent high FCR in the first months after diagnosis. This study assessed the 3-year trajectories and associated factors of FCR in newly diagnosed HNC patients., Methods: Six hundred twenty-one patients from the NETherlands Quality of life and Biomedical Cohort study (NET-QUBIC) completed the FCR assessment at baseline, 3-, 6-, 12-, 24-, and 36-months posttreatment. Trajectories of FCR were identified using latent class growth analysis. Multinominal logistic regression analysis was used to assess associations between FCR trajectories and baseline demographic and medical variables, personality, and coping., Results: Three FCR trajectories were identified: "consistently high" (n = 45, 7%), "elevated and declining" (n = 209, 34%), and "low and declining" (n = 367, 59%). Patients in the "elevated and declining" and "consistently high" trajectory were younger, had more comorbidities, higher negative adjustment, a higher level of neuroticism, more social support seeking, and more reliance on passive and palliative coping strategies., Conclusion: Three years following diagnosis, the majority of HNC patients showed a resilient FCR trajectory whereas a small percentage of HNC patients (7%) showed persistent high FCR over time., Implications for Cancer Survivors: Younger patients and those with a higher level of neuroticism or maladaptive coping strategies were more vulnerable to have a consistent high level of FCR over time. It is important to identify these patients to provide optimal and tailored psychosocial support., Competing Interests: Declarations. Ethics approval: The study protocol has been approved by the Institutional Review Board of Amsterdam UMC2013.301(A2018.307)-NL45051.029.13). NET-QUBIC gave permission for conducting the specific analyses in the current study. Consent to participate: All individuals participating in the current study provided written informed consent. Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The current study presents the effort of a global collaborative group to review the management and outcomes of malignant tumors of the skull base worldwide., Patients and Methods: A total of 28 institutions contributed data on 3061 patients. Analysis evaluated clinical variables, survival outcomes, and multivariable factors associated with outcomes., Results: The median age was 56 years (IQR 44-67). The open surgical approach was used in 55% (n = 1680) of cases, endoscopic resection was performed in 36% (n = 1087), and the combined approach in 9.6% (n = 294). With a median follow-up of 7.1 years, the 5-year OS DSS and RFS were 65%, 71.7% and 53%, respectively. On multivariable analysis, older age, comorbidities, histology, dural/intracranial involvement, positive margins, advanced stage, and primary site were independent prognostic factors for OS, DSS, and RFS. Adjuvant RT was a protective prognostic factor., Conclusion: The progress across various disciplines may have contributed to improved OS and DSS in this study compared to previous reports., (© 2024 Wiley Periodicals LLC.)

Objectives: Robotic transoral mucosectomy of the base of tongue was introduced as a diagnostic procedure in patients treated for head and neck cancer with unknown primary (CUP), increasing the identification rate of the primary tumour. For the treatment of CUP, a considerable percentage of patients require adjuvant (chemo)radiation. The aim of this study was to investigate swallowing outcomes among CUP patients after TORS and adjuvant treatment., Subjects and Methods: A systematic review was carried out on studies investigating the impact of TORS and adjuvant treatment on swallowing-related outcomes among CUP patients In addition, a cross-sectional study was carried out on swallowing problems (measured using the SWAL-QOL questionnaire) among CUP patients in routine care who visited the outpatient clinic 1-5 years after TORS and adjuvant treatment., Results: The systematic review (6 studies; n = 98) showed that most patients returned to a full oral diet. The cross-sectional study (n = 12) showed that all patients were able to return to a full oral diet, nevertheless, 50% reported swallowing problems in daily life (SWAL-QOL total score ≥14)., Conclusion: Although after TORS and adjuvant treatment for CUP a full oral diet can be resumed, patients still experience problems with eating and drinking in daily life., (© 2024 The Author(s). Oral Diseases published by Wiley Periodicals LLC.)

Cancer is caused by an accumulation of somatic mutations and copy number alterations (CNAs). Besides mutations, these copy number changes are key characteristics of cancer development. Nonetheless, some tumors show hardly any CNAs, a remarkable phenomenon in oncogenesis. Head and neck squamous cell carcinomas (HNSCCs) arise by either exposure to carcinogens, or infection with the human papillomavirus (HPV). HPV-negative HNSCCs are generally characterized by many CNAs and frequent mutations in CDKN2A, TP53, FAT1, and NOTCH1. Here, we present the hallmarks of the distinct subgroup of HPV-negative HNSCC with no or few CNAs (CNA-quiet) by genetic profiling of 802 oral cavity squamous cell carcinomas (OCSCCs). In total, 73 OCSCC (9.1%) are classified as CNA-quiet and 729 as CNA-other. The CNA-quiet group is characterized by wild-type TP53, frequent CASP8 and HRAS mutations, and a less immunosuppressed tumor immune microenvironment with lower density of regulatory T cells. Patients with CNA-quiet OCSCC are older, more often women, less frequently current smokers, and have a better 5-year overall survival compared to CNA-other OCSCC. This study demonstrates that CNA-quiet OCSCC should be considered as a distinct, clinically relevant subclass. Given the clinical characteristics, the patient group with these tumors will rapidly increase in the aging population., (© 2024. The Author(s).)

Objective: two new cases of temporal bone squamous cell carcinoma (TBSCC) with a bilateral occurrence are presented. Furthermore, a review of the literature was performed and the yearly incidence was calculated., Methods: A systematic review of the literature was conducted using PRISMA guidelines., Results: Twenty-two more cases were found in literature. With a total of 24 cases, the calculated yearly incidence of bilateral TBSCC is 49:10^12 A history of chronic otitis or regional radiotherapy was found in respectively 50% and 12% of patients. In nine patients, the tumors developed synchronously (within 6 months) and in 13 metachronously., Conclusions: The calculated incidence is 89 times higher than mathematically expected considering the incidence of unilateral cases. An explanation might be a history of chronic otitis or prior radiotherapy. The tumor staging of both the first tumor group and the contralateral tumor group are similar to unilateral temporal bone squamous cell carcinoma series., Competing Interests: none., (© [copyright 2024] PLA General Hospital Department of Otolaryngology Head and Neck Surgery. Production and hosting by Elsevier (Singapore) Pte Ltd.)

Immune checkpoint inhibitors are approved for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) but the response rate is only 13-18%. For an effective antitumor immune response, trafficking of immune cells to the tumor microenvironment (TME) is essential. We aimed to better understand immune cell migration as well as the involved chemokines in HNSCC. A transwell assay was used to study immune cell migration toward TME-conditioned medium. While T cell migration was not observed, conventional dendritic cell (cDC) migration was induced by TME-conditioned media. cDC migration correlated with various proteins in the TME secretome. CCL8, CXCL5, CCL13 and CCL7 were tested in validation experiments and addition of these chemokines induced cDC migration. Using single cell RNA-sequencing, we observed expression of CCL8, CXCL5, CCL13 and CCL7 in cancer-associated fibroblasts (CAFs). Depleting fibroblasts led to reduced cDC migration. Thus CAFs, while often seen as suppressors of antitumor immunity, play a role in attracting cDCs toward the head and neck cancer TME, which might be crucial for effective antitumor immunity and response to therapies. Indeed, we found RNA expression signatures of the indicated chemokines, cDC and CAF subpopulations, to be significantly higher in baseline tumor specimen of patients with a major pathological response to pre-surgical anti-PD-1 treatment compared to non-responding patients., (© 2024. The Author(s).)

Background: A major challenge in the clinical management of oral cavity squamous cell carcinoma is local relapse. Even when surgical margins are tumor-free, local relapses occur frequently, and relapse prediction by histology remains suboptimal. In leukoplakia, an oral potentially malignant disorder, the presence of architectural dysplasia is a critical risk factor for malignant transformation. This study aimed to investigate whether the presence of architectural dysplasia in oral cavity squamous cell carcinoma surgical margins is a risk factor for local relapse., Methods: Hematoxylin and eosin-stained slides of resection margins from a consecutive cohort of surgically treated patients diagnosed with stage I-IV oral cavity squamous cell carcinoma between 2008 and 2014 were assessed for the presence of architectural dysplasia (N = 311). Five-year local relapse-free survival rates of oral cavity squamous cell carcinoma with architectural dysplasia were compared to those of oral cavity squamous cell carcinoma without architectural dysplasia., Results: In total, 92 of 311 (29.6%) of oral cavity squamous cell carcinoma displayed architectural dysplasia in the margins. The presence of architectural dysplasia was associated with higher patient age, female sex, less pack years, lower cT-stage, and a cohesive tumor growth pattern. In oral cavity squamous cell carcinomas with architectural dysplasia, postoperative (chemo)radiotherapy was less often indicated compared with oral cavity squamous cell carcinoma without architectural dysplasia (19.5% vs. 36.1%, p = 0.009). Five-year local relapse-free survival was significantly lower in oral cavity squamous cell carcinoma with architectural dysplasia than in oral cavity squamous cell carcinoma without architectural dysplasia (83.1% vs. 94.9%, p = 0.017)., Conclusions: Oral cavity squamous cell carcinoma arising in the background of architectural dysplasia displays relatively favorable clinical and histopathological characteristics. Nonetheless, the presence of architectural dysplasia in oral cavity squamous cell carcinoma surgical margins is associated with a higher risk of local relapse, indicating its clinical relevance., (© 2024 The Author(s). Journal of Oral Pathology & Medicine published by John Wiley & Sons Ltd.)

Purpose: To systematically review current literature on the treatment of lymphatic malformations (LMs) of the head and neck to guide treatment strategy., Methods and Materials: A systematic review and meta-analysis of literature until 16 November 2021 was performed on treatments of LMs in the head and neck., Results: Out of 9044 articles, 54 studies were eligible for inclusion with 26 studies providing detailed participant data. A total number of 1573 patients with a mean age of 21.22 months were analysed. Comparative meta-analysis did not reveal significant differences two proportions of volume reduction (≥ 50% and 100%) between sclerotherapy and surgical treatment. Regression demonstrated that positive predictors for volume reduction were surgery 17 (95% CI 0.26-34; p = 0.047) and treatment of macrocystic lesions 19 (95% CI 5.5-32; p = 0.006). Treatment of mixed lesions also demonstrated a trend towards achieving a greater volume reduction (p = 0.052). A higher de Serres stage of the lesion had a negative effect on the amount of volume reduction - 3.7 (95% CI - 7.0 to - 0.35; p = 0.030)., Conclusion: This comprehensive meta-analysis demonstrated no significant difference in volume reduction between various treatment modalities at study level. However, individual patient data indicated that surgery and larger cyst types are associated with a significant higher percentage of volume reduction, whereas a higher de Serres stage negatively impacted the amount of volume reduction. These findings can be used for patient counseling and treatment planning based on cyst type and de Serres stage. However volume reduction constitutes just one objective within a more complex treatment spectrum., (© 2024. The Author(s).)

Background: Approximately 50% of head and neck squamous cell carcinomas (HNSCC) recur after treatment with curative intent. Immune checkpoint inhibitors are treatment options for recurrent/metastatic HNSCC; however, less than 20% of patients respond. To increase this response rate, it is fundamental to increase our understanding of the spatial tumor immune microenvironment (TIME)., Methods: In total, 53 HNSCC specimens were included. Using a seven-color multiplex immunohistochemistry panel we identified tumor cells, CD163+macrophages, B cells, CD8+T cells, CD4+T helper cells and regulatory T cells (Tregs) in treatment-naive surgical resection specimens (n=29) and biopsies (n=18). To further characterize tumor-infiltrating CD8+T cells, we stained surgical resection specimens (n=12) with a five-color tumor-resident panel including CD103, Ki67, CD8 and pan-cytokeratin. Secretome analysis was performed on matched tumor suspensions (n=11) to measure protein levels., Results: Based on CD8+T cell infiltrates, we identified four different immunotypes: fully infiltrated, stroma-restricted, immune-excluded, and immune-desert. We found higher cytokine levels in fully infiltrated tumors compared with other immunotypes. While the highest immune infiltrates were observed in the invasive margin for all immune cells, CD163+macrophages and Tregs had the highest tendency to infiltrate the tumor center. Within the tumor center, especially B cells stayed at the tumor stroma, whereas CD163+macrophages, followed by T cells, were more often localized within tumor fields. Also, B cells were found further away from other cells and often formed aggregates while T cells and CD163+macrophages tended to be more closely located to each other. Across resection specimens from various anatomical sites within the head and neck, oral cavity tumors exhibited the highest densities of Tregs. Moreover, the distance from B cells and T cells to tumor cells was shortest in oral cavity squamous cell carcinoma (OCSCC), suggesting more interaction between lymphocytes and tumor cells. Also, the fraction of T cells within 10 µm of CD163+macrophages was lowest in OCSCC, indicating fewer myeloid/T-cell suppressive interactions in OCSCC., Conclusions: We comprehensively described the TIME of HNSCC using a unique data set of resection specimens. We discovered that the composition, as well as the relative localization of immune cells in the TIME, differed in distinct anatomical sites of the head and neck., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Addition of neoadjuvant immune checkpoint inhibition to standard-of-care interventions for locally advanced oral cancer could improve clinical outcome., Methods: In this study, 16 evaluable patients with stage III/IV oral cancer were treated with one dose of 480 mg nivolumab 3 weeks prior to surgery. Primary objectives were safety, feasibility, and suitability of programmed death receptor ligand-1 positron emission tomography (PD-L1 PET) as a biomarker for response. Imaging included 18 F-BMS-986192 (PD-L1) PET and 18 F-fluorodeoxyglucose (FDG) PET before and after nivolumab treatment. Secondary objectives included clinical and pathological response, and immune profiling of peripheral blood mononuclear cells (PBMCs) for response prediction. Baseline tumor biopsies and postnivolumab resection specimens were evaluated by histopathology., Results: Grade III or higher adverse events were not observed and treatment was not delayed in relation to nivolumab administration and other study procedures. Six patients (38%) had a pathological response, of whom three (19%) had a major (≥90%) pathological response (MPR). Tumor PD-L1 PET uptake (quantified using standard uptake value) was not statistically different in patients with or without MPR (median 5.3 vs 3.4). All major responders showed a significantly postnivolumab decreased signal on FDG PET. PBMC immune phenotyping showed higher levels of CD8 + T cell activation in MPR patients, evidenced by higher baseline expression levels of PD-1, TIGIT, IFNγ and lower levels of PD-L1., Conclusion: Together these data support that neoadjuvant treatment of advanced-stage oral cancers with nivolumab was safe and induced an MPR in a promising 19% of patients. Response was associated with decreased FDG PET uptake as well as activation status of peripheral T cell populations., Competing Interests: Competing interests: RvdV has received research funding from Genmab BV. TDdG is scientific advisor to Immunicum, GE Health, and Lava Therapeutics, holds stock from LAVA Therapeutics and received research funding from Idera Pharmaceuticals (now Aceragen). RHB received research grants from KWF Kankerbestrijding/Dutch Cancer Society, Cancer Center Amsterdam Foundation, ZonMW and NWO, Genmab BV and the Hanarth Foundation and is on the advisory board of Nanobiotix. He has a scientific collaboration with Orfenix BV and Qialix DoT. CRL received research grants from KWF Kankerbestrijding/Dutch Cancer Society, Cancer Center Amsterdam Foudation, Genmab BV, BMS and the Hanarth Foundation and is on the advisory board of Merck & Co. CWM-vdHvO received research grants from BMS, Boeringher Ingelheim, GSK, Pfizer and AstraZeneca and consulted for GE Health Care, Novartis and EliLilly. All other authors report no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Head and neck squamous cell carcinomas are treated by surgery, radiotherapy (RT), chemoradiotherapy (CRT) or combinations thereof, but locoregional recurrences (LRs) occur in 30-40% of treated patients. We have previously shown that in approximately half of the LRs after CRT, cancer driver mutations are not shared with the index tumor., Aim: To investigate two possible explanations for these genetically unrelated relapses, treatment-induced genetic changes and intratumor genetic heterogeneity., Methods: To investigate treatment-induced clonal DNA changes, we compared copy number alterations (CNAs) and mutations between primary and recurrent xenografted tumors after treatment with (C)RT. Intratumor genetic heterogeneity was studied by multi-region sequencing on DNA from 31 biopsies of 11 surgically treated tumors., Results: Induction of clonal DNA changes by (C)RT was not observed in the xenograft models. Multi-region sequencing demonstrated variations in CNA profiles between paired biopsies of individual tumors, with copy number heterogeneity scores varying from 0.027 to 0.333. In total, 32 cancer driver mutations could be identified and were shared in all biopsies of each tumor. Remarkably, multi-clonal mutations in these same cancer driver genes were observed in 6 of 11 tumors. Genetically distinct heterogeneous cell cultures could also be established from single tumors, with different biomarker profiles and drug sensitivities., Conclusion: Intratumor genetic heterogeneity at the level of the cancer driver mutations might explain the discordant mutational profiles in LRs after CRT, while there are no indications in xenograft models that these changes are induced by CRT., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: The response rate to immune checkpoint inhibitors targeting programmed cell death 1 (PD-1) receptor is 13%-18% for patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). Detailed understanding of the tumor immune microenvironment (TIME) is crucial in order to explain and improve this response rate. HNSCCs arise at various anatomical locations including the oral cavity, hypopharynx, larynx and oropharynx. Studies directly comparing immune infiltration between anatomical sites are scarce. Since the distinct locations could drive deviating microenvironments, we questioned whether the immune composition varies across these HNSCC sites., Methods: Here, we characterized the TIME of 76 fresh tumor specimens using flow cytometry and performed single-cell RNA-sequencing on nine head and neck tumor samples., Results: We found major differences in the composition of the TIME between patients. When comparing anatomical sites: tumors originating from the oral cavity had higher T cell infiltrates than tumors from other anatomical sites. The percentage of tumor-infiltrating T-lymphocytes positive for the immune checkpoint PD-1 varied considerably between patients, with the highest fraction of PD-1+ T cells found in larynx squamous cell carcinomas (SCCs). While we had hypothesized that the anatomical sites of tumor origin would drive sample clustering, our data showed that the type of TIME was more dominant and was particularly driven by the fraction of T cells positive for PD-1. Moreover, a high proportion of PD-1+ CD8+ T cells associated with an improved overall survival. Using single-cell RNA-sequencing, we observed that PD-1 expression was highest in the CD8-ENTPD1 tissue resident memory T cell/exhausted T cell and CD4-CXCL13 type 1 T helper cell clusters., Conclusions: We found that oral cavity SCCs had the highest frequencies of T cells. We also observed considerable interpatient heterogeneity for PD-1 on T cells, with noticeably higher frequencies of PD-1+ CD4+ T helper cells in larynx SCCs. Within the entire cohort, a higher fraction of CD8+ T cells positive for PD-1 was linked to improved overall survival. Whether the fraction of PD-1+ T cells within the TIME enables immune checkpoint inhibitor response prediction for patients with head and neck cancer remains to be determined., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To investigate utilization of mental healthcare among head and neck cancer (HNC) patients from diagnosis to 2 years after treatment, in relation to psychological symptoms, mental disorders, need for mental healthcare, and sociodemographic, clinical and personal factors., Methods: Netherlands Quality of life and Biomedical Cohort study data as measured before treatment, at 3 and 6 months, and at 1 and 2 years after treatment was used (n = 610). Data on mental healthcare utilization (iMCQ), psychological symptoms (Hospital Anxiety and Depression Scale, Cancer Worry Scale), mental disorders (CIDI interview), need for mental healthcare (Supportive Care Needs Survey Short-Form 34, either as continuous outcome indicating the level of need or dichotomized into unmet need (yes/no)) and several sociodemographic, clinical and personal factors were collected. Factors associated with mental healthcare utilization were investigated using generalized estimating equations (p < 0.05)., Results: Of all HNC patients, 5%-9% used mental healthcare per timepoint. This was 4%-14% in patients with mild-severe psychological symptoms, 4%-17% in patients with severe psychological symptoms, 15%-35% in patients with a mental disorder and 5%-16% in patients with an unmet need for mental healthcare. Among all patients, higher symptoms of anxiety, a higher need for mental healthcare, lower age, higher disease stage, lower self-efficacy and higher social support seeking were significantly associated with mental healthcare utilization., Conclusion: Mental health care utilization among HNC patients is limited, and is related to psychological symptoms, need for mental healthcare, and sociodemographic, clinical and personal factors., (© 2023 The Authors. Psycho-Oncology published by John Wiley & Sons Ltd.)

The aim of this study was to investigate changes in sexuality and sexual dysfunction in head and neck cancer (HNC) patients in the first two years after treatment, in relation to the type of treatment. Data were used of 588 HNC patients participating in the prospective NETherlands Quality of life and Biomedical Cohort Study (NET-QUBIC) from diagnosis to 3, 6, 12 and 24 months after treatment. Primary outcome measures were the International Index of Erectile Function (IIEF) and the Female Sexual Function Index (FSFI). The total scores of the IIEF and FSFI were dichotomized into sexual (dys)function. In men, type of treatment was significantly associated with change in erectile function, orgasm, satisfaction with intercourse, and overall satisfaction. In women, type of treatment was significantly associated with change in desire, arousal, and orgasm. There were significant differences between treatment groups in change in dysfunctional sexuality. A deterioration in sexuality and sexual dysfunction from baseline to 3 months after treatment was observed especially in patients treated with chemoradiation. Changes in sexuality and sexual dysfunction in HNC patients were related to treatment, with an acute negative effect of chemoradiation. This effect on the various domains of sexuality seems to differ between men and women.

Objective: Head and neck cancer care is highly complex, and multidisciplinary team meetings (MDTs) are vital for improved outcomes. In the Netherlands, head and neck cancer care is practiced in eight high-volume head and neck oncologic centers (HNOC) and six affiliated hospitals preferred partner (PP) centers. Patients treated in the PP are presented and discussed in the HNOC. To evaluate the importance of these mandatory and decisive steps in decision making, we have assessed the changes in treatment., Materials and Methods: Retrospective evaluation of head and neck cancer patients referred between January 2011 and October 2018 for a MDT evaluation to the HNOC was conducted. The differences in MDT recommendation were classified with regards to major and minor changes., Results: Management recommendation(MR) changed after 113 of 515 MDT discussions within the PP (487 patients; 22%), of which 86 cases (16%) were major changes. In 67 cases (59.3%), escalation of management was recommended, while in 43 cases (38.1%) de-escalation was recommended., Conclusion: There was a high rate of change of MRs, when comparing the PP recommendations with the HNOC recommendations. Since patient and tumor characteristics seem unable to predict these changes, we recommend all patients be seen for a clinical presentation, revision of diagnostics, and MDT discussion in a high volume HNOC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest, (Copyright © 2023 Hendrickx, Mennega, Uppelschoten and Leemans.)

Background: . At present, the prognostic prediction in advanced oral cavity squamous cell carcinoma (OCSCC) is based on the tumor-node-metastasis (TNM) staging system, and the most used imaging modality in these patients is magnetic resonance image (MRI). With the aim to improve the prediction, we developed an MRI-based radiomic signature as a prognostic marker for overall survival (OS) in OCSCC patients and compared it with published gene expression signatures for prognosis of OS in head and neck cancer patients, replicated herein on our OCSCC dataset., Methods: For each patient, 1072 radiomic features were extracted from T1 and T2-weighted MRI (T1w and T2w). Features selection was performed, and an optimal set of five of them was used to fit a Cox proportional hazard regression model for OS. The radiomic signature was developed on a multi-centric locally advanced OCSCC retrospective dataset (n = 123) and validated on a prospective cohort (n = 108)., Results: The performance of the signature was evaluated in terms of C-index (0.68 (IQR 0.66-0.70)), hazard ratio (HR 2.64 (95% CI 1.62-4.31)), and high/low risk group stratification (log-rank p < 0.001, Kaplan-Meier curves). When tested on a multi-centric prospective cohort (n = 108), the signature had a C-index of 0.62 (IQR 0.58-0.64) and outperformed the clinical and pathologic TNM stage and six out of seven gene expression prognostic signatures. In addition, the significant difference of the radiomic signature between stages III and IVa/b in patients receiving surgery suggests a potential association of MRI features with the pathologic stage., Conclusions: Overall, the present study suggests that MRI signatures, containing non-invasive and cost-effective remarkable information, could be exploited as prognostic tools., (© 2023. The Author(s).)

Purpose: The aim of this prospective cohort study was to estimate the relationship between the course of HRQOL in the first 2 years after diagnosis and treatment of head and neck cancer (HNC) and personal, clinical, psychological, physical, social, lifestyle, HNC-related, and biological factors., Methods: Data were used from 638 HNC patients of the NETherlands QUality of life and BIomedical Cohort study (NET-QUBIC). Linear mixed models were used to investigate factors associated with the course of HRQOL (EORTC QLQ-C30 global quality of life (QL) and summary score (SumSc)) from baseline to 3, 6, 12, and 24 months after treatment., Results: Baseline depressive symptoms, social contacts, and oral pain were significantly associated with the course of QL from baseline to 24 months. Tumor subsite and baseline social eating, stress (hyperarousal), coughing, feeling ill, and IL-10 were associated with the course of SumSc. Post-treatment social contacts and stress (avoidance) were significantly associated with the course of QL from 6 to 24 months, and social contacts and weight loss with the course of SumSc. The course of SumSc from 6 to 24 months was also significantly associated with a change in financial problems, speech problems, weight loss, and shoulder problems between baseline and 6 months., Conclusion: Baseline clinical, psychological, social, lifestyle, HNC-related, and biological factors are associated with the course of HRQOL from baseline to 24 months after treatment. Post-treatment social, lifestyle, and HNC-related factors are associated with the course of HRQOL from 6 to 24 months after treatment., (© 2023. The Author(s).)

Objectives: c-Met, a receptor tyrosine kinase, is involved in the growth, invasion and metastasis of a variety of cancers. In a set of cell lines from several solid tumors, a five-fold increase in c-Met expression after irradiation has been reported. This study aimed to assess if c-Met is likewise abundantly expressed in oral tongue squamous cell carcinoma (OTSCC) upon exposure to irradiation, followed by a Met-induced biological response., Materials and Methods: Six OTSCC cell lines were exposed to gamma radiation doses of 2, 4, and 6 Gray. The changes in c-Met protein levels were assessed by western blot and flow cytometry. c-Met gene expression, cell migration, proliferation and cell cycle assays were performed as phenotypic readouts., Results: Irradiation resulted in upregulation of c.Met in all cell lines with different time kinetics. On average the cells displayed minimal c-Met expression on their surface ranging from 5 to 30% of total protein. Abrupt downregulation of c-Met surface expression occurred one hour after radiation but recovered 48 h post-radiation. Intracellularly, the highest level of expression was found on day 5 after radiation exposure. Irradiation induced aggressive invasive potential of the cells as determined in cell migration assays, particularly in cell lines with the highest c-Met expression., Conclusions: These results provide novel insights into both intracellular and extracellular dynamics of c-Met expression profiles upon irradiation of OTSCC cells in vitro. It might also suggest that radiation enhances cell migration, indicative of invasiveness, through c-Met up-regulation, at least for certain types of OTSCC cells., (© 2022. The Author(s).)

Objective: Informal caregivers of head and neck cancer (HNC) patients have a high caregiver burden and often face complex practical caregiving tasks. This may result in unmet supportive care needs, which can impact their quality of life (QoL) and cause psychological distress. In this study, we identify caregivers' unmet needs during long-term follow-up and identify caregivers prone to unmet supportive care needs., Methods: Data were used from the multicenter prospective cohort study NETherlands QUality of life and Biomedical cohort studies In Cancer (NET-QUBIC). The unmet supportive care needs, psychological distress, caregiver burden, and QoL were measured for 234 informal caregivers and their related patients at baseline, 3, 6, 12, and 24 months after. Mixed effect models for repeated measurements were used., Results: At baseline, most caregivers (70.3%) reported at least one unmet supportive care need, with most of the identified needs in the "healthcare & illness" domain. During the follow-up period, caregivers' unmet needs decreased significantly in all domains. Nevertheless, 2 years after treatment, 28.3% were still reporting at least one unmet need. Financial problems were increasingly associated with unmet needs over time. Furthermore, caring for a patient who themselves had many unmet needs, an advanced tumor stage, or severe comorbidity was associated with significantly more unmet needs in caregivers., Conclusions: The current study shows the strong likelihood of caregivers of HNC patients facing unmet supportive care needs and the interaction between the needs of patients and caregivers. It is important to optimally support informal caregivers by involving them from the start when counseling patients, by providing them with relevant and understandable information, and by referring vulnerable caregivers for (psychosocial) support., (© 2023. The Author(s).)

Purpose of Review: The brachial plexus is an important anatomical structure that is regularly encountered by head and neck surgeons and radiation oncologists. Surgical or radiation-induced brachial plexus injury have great impact on arm function and quality of life. Anatomical variations and management of the brachial plexus in head and neck cancer treatment are discussed., Recent Findings: The brachial plexus consists of spinal roots from C5-C8 and T1. The most prevalent anatomical variations in brachial plexus anatomy include the prefixed brachial plexus (additional contribution from C4) in 11%, the roots of C5 and C6 piercing the belly of the anterior scalene muscle in 6.8%, and presence of the scalenus minimus muscle in 4.1-46%. Due to its location, the brachial plexus is at risk of inadvertent division or neuropraxia during surgical procedures such as neck dissection or robot-assisted transaxillary thyroid surgery (RATS). In case of inadvertent division, nerve reconstruction surgery is warranted and may lead to improved function. The risk of radiation-induced brachial plexus injury is dose-dependent and occurs in approximately 12-22%. Currently, no successful treatment options exist for radiation-induced injury., Summary: Knowledge of anatomical variations is important for head and neck surgeons to minimize the risk of brachial plexus injury. Limiting radiation therapy dose to the brachial plexus is desirable to decrease the risk of brachial plexus injury., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: To externally validate a pre-treatment MR-based radiomics model predictive of locoregional control in oropharyngeal squamous cell carcinoma (OPSCC) and to assess the impact of differences between datasets on the predictive performance., Methods: Radiomic features, as defined in our previously published radiomics model, were extracted from the primary tumor volumes of 157 OPSCC patients in a different institute. The developed radiomics model was validated using this cohort. Additionally, parameters influencing performance, such as patient subgroups, MRI acquisition, and post-processing steps on prediction performance will be investigated. For this analysis, matched subgroups (based on human papillomavirus (HPV) status of the tumor, T-stage, and tumor subsite) and a subgroup with only patients with 4-mm slice thickness were studied. Also the influence of harmonization techniques (ComBat harmonization, quantile normalization) and the impact of feature stability across observers and centers were studied. Model performances were assessed by area under the curve (AUC), sensitivity, and specificity., Results: Performance of the published model (AUC/sensitivity/specificity: 0.74/0.75/0.60) drops when applied on the validation cohort (AUC/sensitivity/specificity: 0.64/0.68/0.60). The performance of the full validation cohort improves slightly when the model is validated using a patient group with comparable HPV status of the tumor (AUC/sensitivity/specificity: 0.68/0.74/0.60), using patients acquired with a slice thickness of 4 mm (AUC/sensitivity/specificity: 0.67/0.73/0.57), or when quantile harmonization was performed (AUC/sensitivity/specificity: 0.66/0.69/0.60)., Conclusion: The previously published model shows its generalizability and can be applied on data acquired from different vendors and protocols. Harmonization techniques and subgroup definition influence performance of predictive radiomics models., Key Points: • Radiomics, a noninvasive quantitative image analysis technique, can support the radiologist by enhancing diagnostic accuracy and/or treatment decision-making. • A previously published model shows its generalizability and could be applied on data acquired from different vendors and protocols., (© 2022. The Author(s), under exclusive licence to European Society of Radiology.)

This study aimed at investigating the change in social eating problems from diagnosis to 24 months after primary (chemo)radiotherapy and its associations with swallowing, oral function, and nutritional status, in addition to the clinical, personal, physical, psychological, social, and lifestyle dimensions. Adult patients from the NETherlands QUality of life and BIomedical Cohort (NET-QUBIC) treated with curative intent with primary (chemo)radiotherapy for newly-diagnosed HNC and who provided baseline social eating data were included. Social eating problems were measured at baseline and at 3-, 6-, 12-, and 24-month follow-up, with hypothesized associated variables at baseline and at 6 months. Associations were analyzed through linear mixed models. Included patients were 361 (male: 281 (77.8%), age: mean = 63.3, SD = 8.6). Social eating problems increased at the 3-month follow-up and decreased up to 24 months (F = 33.134, p < 0.001). The baseline-to-24 month change in social eating problems was associated with baseline swallowing-related quality of life (F = 9.906, p < 0.001) and symptoms (F = 4.173, p = 0.002), nutritional status (F = 4.692, p = 0.001), tumor site (F = 2.724, p = 0.001), age (F = 3.627, p = 0.006), and depressive symptoms (F = 5.914, p < 0.001). The 6-24-month change in social eating problems was associated with a 6-month nutritional status (F = 6.089, p = 0.002), age (F = 5.727, p = 0.004), muscle strength (F = 5.218, p = 0.006), and hearing problems (F = 5.155, p = 0.006). Results suggest monitoring social eating problems until 12-month follow-up and basing interventions on patients' features.

Background: p16 INK4a (p16) immunohistochemistry is the most widely used biomarker assay for inferring HPV causation in oropharyngeal cancer in clinical and trial settings. However, discordance exists between p16 and HPV DNA or RNA status in some patients with oropharyngeal cancer. We aimed to clearly quantify the extent of discordance, and its prognostic implications., Methods: In this multicentre, multinational individual patient data analysis, we did a literature search in PubMed and Cochrane database for systematic reviews and original studies published in English between Jan 1, 1970, and Sept 30, 2022. We included retrospective series and prospective cohorts of consecutively recruited patients previously analysed in individual studies with minimum cohort size of 100 patients with primary squamous cell carcinoma of the oropharynx. Patient inclusion criteria were diagnosis with a primary squamous cell carcinoma of oropharyngeal cancer; data on p16 immunohistochemistry and on HPV testing; information on age, sex, tobacco, and alcohol use; staging by TNM 7th edition; information on treatments received; and data on clinical outcomes and follow-up (date of last follow-up if alive, date of recurrence or metastasis, and date and cause of death). There were no limits on age or performance status. The primary outcomes were the proportion of patients of the overall cohort who showed the different p16 and HPV result combinations, as well as 5-year overall survival and 5-year disease-free survival. Patients with recurrent or metastatic disease or who were treated palliatively were excluded from overall survival and disease-free survival analyses. Multivariable analysis models were used to calculate adjusted hazard ratios (aHR) for different p16 and HPV testing methods for overall survival, adjusted for prespecified confounding factors., Findings: Our search returned 13 eligible studies that provided individual data for 13 cohorts of patients with oropharyngeal cancer from the UK, Canada, Denmark, Sweden, France, Germany, the Netherlands, Switzerland, and Spain. 7895 patients with oropharyngeal cancer were assessed for eligibility. 241 were excluded before analysis, and 7654 were eligible for p16 and HPV analysis. 5714 (74·7%) of 7654 patients were male and 1940 (25·3%) were female. Ethnicity data were not reported. 3805 patients were p16-positive, 415 (10·9%) of whom were HPV-negative. This proportion differed significantly by geographical region and was highest in the areas with lowest HPV-attributable fractions (r=-0·744, p=0·0035). The proportion of patients with p16+/HPV- oropharyngeal cancer was highest in subsites outside the tonsil and base of tongue (29·7% vs 9·0%, p<0·0001). 5-year overall survival was 81·1% (95% CI 79·5-82·7) for p16+/HPV+, 40·4% (38·6-42·4) for p16-/HPV-, 53·2% (46·6-60·8) for p16-/HPV+, and 54·7% (49·2-60·9) for p16+/HPV-. 5-year disease-free survival was 84·3% (95% CI 82·9-85·7) for p16+/HPV+, 60·8% (58·8-62·9) for p16-/HPV-; 71·1% (64·7-78·2) for p16-/HPV+, and 67·9% (62·5-73·7) for p16+/HPV-. Results were similar across all European sub-regions, but there were insufficient numbers of discordant patients from North America to draw conclusions in this cohort., Interpretation: Patients with discordant oropharyngeal cancer (p16-/HPV+ or p16+/HPV-) had a significantly worse prognosis than patients with p16+/HPV+ oropharyngeal cancer, and a significantly better prognosis than patients with p16-/HPV- oropharyngeal cancer. Along with routine p16 immunohistochemistry, HPV testing should be mandated for clinical trials for all patients (or at least following a positive p16 test), and is recommended where HPV status might influence patient care, especially in areas with low HPV-attributable fractions., Funding: European Regional Development Fund, Generalitat de Catalunya, National Institute for Health Research (NIHR) UK, Cancer Research UK, Medical Research Council UK, and The Swedish Cancer Foundation and the Stockholm Cancer Society., Competing Interests: Declaration of interests HMe reports grants from UK National Institute of Health research, Cancer Research UK, the UK Medical Research Council, and AstraZeneca; advisory board fees from AstraZeneca, MSD, Merck, Nanobiotix, and Seagen; and is Director of Warwickshire head neck clinic and Docpsert Health. CRL reports a grant from the Dutch Cancer society, consulting fees from Merck & Co, and expenses from the European Head and Neck Society. JPK reports grant funding from MSD (funding for the project Implementation of a German Oropharyngeal Cancer Registry Providing State-of-the-Art-HPV-Diagnostics). Data derived from this project were used in the present study. The funders had no influence on the design of the study, the collection, analysis, or interpretation of the data, the writing of the manuscript, or the decision to publish the results. JPK also declares research grant funding from the European fund for regional development (EFRE) for ImmunPredict (FKZ EFRE EFRE-0801308). LM reports payment to institution from 20200059/Stockholms Läns Landsting. NW reports a grant from Merk, Sharpe, & Dohme (MSD; for the project Implementation of a German Oropharyngeal Cancer Registry Providing State-of-the-Art-HPV-Diagnostics). Data derived from this project were used in the present study. The funders had no influence on the design of the study, the collection, analysis, or interpretation of the data, the writing of the manuscript, or the decision to publish the results. LM is also supported by the Cologne Clinician Scientist Programme, funded by the German Research Council (FI 773/15-1; 50% salary funding for the project Monitoring disease status in patients with oropharyngeal squamous cell carcinoma by detection of cell-free human papillomavirus DNA in liquid biopsies); funding from EFRE (salary funding for the project ImmunPredict FKZ EFRE EFRE-0801308); honoraria for lectures from MSD, and has a patent for CRISPR-based HPV-diagnostics (EP 22197523.8). RHB declares grants from the Dutch Cancer Society to institution; from ZonMW Government to institution; GenMab BV to institution; consulting fees from Nanobiotix; and payment from the Italian Association for Cancer Research as an unpaid board member. SW declares a grant from MSD under the administration of the University of Cologne (for the project Implementation of a German Oropharyngeal Cancer Registry Providing State-of-the-Art-HPV-Diagnostics). Data derived from this project were used in the present study. The funders had no influence on the design of the study, the collection, analysis, or interpretation of the data, the writing of the manuscript, or the decision to publish the results. TD reports a research grant from the Swedish Cancer Foundation. ST reports grants from Merck, Roche, GlaxoSmithKline, Vitro, Hologic, and Seagene and consulting fees from Merck. All other authors declare no other competing interests. HMe is a National Institute for Health Research (NIHR) Senior Investigator. The views expressed in this article are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Objectives: Human papillomavirus- (HPV) positive oropharyngeal squamous cell carcinoma (OPSCC) differs biologically and clinically from HPV-negative OPSCC and has a better prognosis. This study aims to analyze the value of magnetic resonance imaging (MRI)-based radiomics in predicting HPV status in OPSCC and aims to develop a prognostic model in OPSCC including HPV status and MRI-based radiomics., Materials and Methods: Manual delineation of 249 primary OPSCCs (91 HPV-positive and 159 HPV-negative) on pretreatment native T1-weighted MRIs was performed and used to extract 498 radiomic features per delineation. A logistic regression (LR) and random forest (RF) model were developed using univariate feature selection. Additionally, factor analysis was performed, and the derived factors were combined with clinical data in a predictive model to assess the performance on predicting HPV status. Additionally, factors were combined with clinical parameters in a multivariable survival regression analysis., Results: Both feature-based LR and RF models performed with an AUC of 0.79 in prediction of HPV status. Fourteen of the twenty most significant features were similar in both models, mainly concerning tumor sphericity, intensity variation, compactness, and tumor diameter. The model combining clinical data and radiomic factors (AUC = 0.89) outperformed the radiomics-only model in predicting OPSCC HPV status. Overall survival prediction was most accurate using the combination of clinical parameters and radiomic factors (C-index = 0.72)., Conclusion: Predictive models based on MR-radiomic features were able to predict HPV status with sufficient performance, supporting the role of MRI-based radiomics as potential imaging biomarker. Survival prediction improved by combining clinical features with MRI-based radiomics., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Objectives: A previously developed decision model to prioritize surgical procedures in times of scarce surgical capacity used quality of life (QoL) primarily derived from experts in one center. These estimates are key input of the model, and might be more context-dependent than the other input parameters (age, survival). The aim of this study was to validate our model by replicating these QoL estimates., Methods: The original study estimated QoL of patients in need of commonly performed procedures in live expert-panel meetings. This study replicated this procedure using a web-based Delphi approach in a different hospital. The new QoL scores were compared with the original scores using mixed effects linear regression. The ranking of surgical procedures based on combined QoL values from the validation and original study was compared to the ranking based solely on the original QoL values., Results: The overall mean difference in QoL estimates between the validation study and the original study was - 0.11 (95% CI:  -0.12 - -0.10). The model output (DALY/month delay) based on QoL data from both studies was similar to the model output based on the original data only: The Spearman's correlation coefficient between the ranking of all procedures before and after including the new QoL estimates was 0.988., Discussion: Even though the new QoL estimates were systematically lower than the values from the original study, the ranking for urgency based on health loss per unit of time delay of procedures was consistent. This underscores the robustness and generalizability of the decision model for prioritization of surgical procedures., (© 2023. The Author(s).)

Objective: In order to understand how informal caregivers of head and neck cancer (HNC) patients deal with the consequences of the disease, we investigated their self-efficacy and coping style in relation to symptoms of anxiety and depression (distress) and quality of life (QoL) over time. In addition, factors associated with self-efficacy and coping style were investigated., Methods: A total of 222 informal caregivers and their related HNC patients were prospectively followed as part from the multicenter cohort NETherlands QUality of life and Biomedical cohort studies In Cancer (NET-QUBIC). Self-efficacy and coping style were measured at baseline, and distress and QoL at baseline and 3, 6, 12, and 24 months after treatment., Results: Informal caregivers had a high level of self-efficacy comparable with patients. Caregivers used "seeking social support," "passive reacting," and "expression of emotions" more often than patients. Factors associated with self-efficacy and coping were higher age and lower education. Higher self-efficacy was related with better QoL and "active tackling" was associated with less depression symptoms. "Passive reacting" and "expression of emotions" were associated with higher psychological distress and reduced QoL., Conclusion: Among informal caregivers of HNC patients, higher self-efficacy and "active tackling" were associated with better functioning over time, while "passive reacting" and "expression of negative emotions" were associated with worse functioning. Awareness of the differences in self-efficacy skills and coping and their relationship with QoL and psychological distress will help clinicians to identify caregivers that may benefit from additional support that improve self-efficacy and "active tackling" and reduce negative coping styles., (© 2023. The Author(s).)

(1) Background: The aim of this study was to investigate caregiver burden among informal caregivers of head and neck cancer patients, in relation to distress and quality of life (QoL), and the relationship between informal caregivers and patients. (2) Methods: Data of 234 dyads from the multicenter prospective cohort study Netherlands Quality of life and Biomedical Cohort studies in cancer was used. Caregiver burden, psychological distress, global QoL, physical and social functioning were measured from baseline until 24 months after treatment. (4) Conclusions: This prospective cohort study shows the high burden of caring for HNC patients, the impact of this burden and the interaction between caregiver and patient. We suggest that healthcare professionals include caregivers in counseling and support.

Background: There is significant interest in treatment de-escalation for human papillomavirus-associated (HPV + ) oropharyngeal squamous cell carcinoma (OPSCC) patients given the generally favourable prognosis. However, 15-30% of patients recur after primary treatment, reflecting a need for improved risk-stratification tools. We sought to develop a molecular test to risk stratify HPV + OPSCC patients., Methods: We created an immune score (UWO3) associated with survival outcomes in six independent cohorts comprising 906 patients, including blinded retrospective and prospective external validations. Two aggressive radiation de-escalation cohorts were used to assess the ability of UWO3 to identify patients who recur. Multivariate Cox models were used to assess the associations between the UWO3 immune class and outcomes., Findings: A three-gene immune score classified patients into three immune classes (immune rich, mixed, or immune desert) and was strongly associated with disease-free survival in six datasets, including large retrospective and prospective datasets. Pooled analysis demonstrated that the immune rich group had superior disease-free survival compared to the immune desert (HR = 9.0, 95% CI: 3.2-25.5, P = 3.6 × 10 -5 ) and mixed (HR = 6.4, 95% CI: 2.2-18.7, P = 0.006) groups after adjusting for age, sex, smoking status, and AJCC8 clinical stage. Finally, UWO3 was able to identify patients from two small treatment de-escalation cohorts who remain disease-free after aggressive de-escalation to 30 Gy radiation., Interpretation: With additional prospective validation, the UWO3 score could enable biomarker-driven clinical decision-making for patients with HPV + OPSCC based on robust outcome prediction across six independent cohorts. Prospective de-escalation and intensification clinical trials are currently being planned., Funding: CIHR, European Union, and the NIH., Competing Interests: Declaration of interests PYFZ, JWB, PCB, JSM and ACN have a US patent pending for the UWO3 score. All other authors declare no conflict of interest., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: Head and neck cancer (HNC) and its treatment often negatively impact swallowing function. The aim was to investigate the course of patient-reported swallowing problems from diagnosis to 3, 6, 12, and 24 months after treatment, in relation to demographic, clinical, and lifestyle factors., Methods: Data were used of the Netherlands Quality of Life and Biomedical Cohort Study in head and neck cancer research (NET-QUBIC). The primary outcome measures were the subscales of the Swallowing Quality of Life Questionnaire (SWAL-QOL). Linear mixed-effects models (LMM) were conducted to investigate changes over time and associations with patient, clinical, and lifestyle parameters as assessed at baseline., Results: Data were available of 603 patients. There was a significant change over time on all subscales. Before treatment, 53% of patients reported swallowing problems. This number increased to 70% at M3 and decreased to 59% at M6, 50% at M12, and 48% at M24. Swallowing problems (i.e., longer eating duration) were more pronounced in the case of female, current smoking, weight loss prior to treatment, and stage III or IV tumor, and were more prevalent at 3 to 6 months after treatment. Especially patients with an oropharynx and oral cavity tumor, and patients receiving (C)RT following surgery or CRT only showed a longer eating duration after treatment, which did not return to baseline levels., Conclusion: Half of the patients with HNC report swallowing problems before treatment. Eating duration was associated with sex, smoking, weight loss, tumor site and stage, and treatment modality, and was more pronounced 3 to 6 months after treatment., (© 2022. The Author(s).)

Objectives: Tinnitus is highly prevalent, but only a few risk factors for developing tinnitus are known and little is known about factors associated with the degree of annoyance of new-onset tinnitus. Longitudinal analysis can reveal risk factors associated with the development of tinnitus and might lead to targeted prevention. The aim of this study is twofold. (1) To identify risk factors that are longitudinally associated with the odds of developing tinnitus 5 years later. (2) To identify factors that are cross-sectionally associated with tinnitus annoyance in adults with new-onset tinnitus., Methods: Baseline, 5-year, and 10-year follow-up data of participants in the Netherlands Longitudinal Study on Hearing (NL-SH) were used. The NL-SH is a web-based prospective cohort study, which started in 2006 and includes both normal hearing and hearing-impaired adults aged 18 to 70 years at baseline. The NL-SH uses an online digit-triplet speech-in-noise test to asses speech recognition ability in noise, and online questionnaires on various aspects of life. At follow-up, participants are asked (1) if they suffer from tinnitus and (2) to rate tinnitus annoyance on a 0 to 100 numeric rating scale. We investigated whether demographic (age, sex, living arrangement, educational level), lifestyle (history of tobacco smoking, alcohol use), health (asthma, severe heart disease, hypertension, history of stroke, osteoarthritis, rheumatoid arthritis, epilepsy, multiple sclerosis, and migraine), hearing (speech recognition ability in noise, hyperacusis, and occupational noise exposure), and psychological variables (distress, somatization, depression, and anxiety) were potential risk factors for new-onset tinnitus, or associated with annoyance caused by new-onset tinnitus. Generalized estimating equations were used to longitudinally analyze the association between potential risk factors and new-onset tinnitus measured 5 years later. A multivariable association model was constructed using a forward selection procedure with p < 0.05 for model entry. Linear regression analysis was used to cross-sectionally analyze the association between potential factors and tinnitus annoyance in new-onset tinnitus. For this purpose, a multivariable association model was constructed using a forward selection procedure with p <0.05 for model entry., Results: In total, 734 participants without tinnitus at baseline were included, from which 137 participants reported to suffer from new-onset tinnitus 5 or 10 years later. Risk factors for new-onset tinnitus were history of smoking (odds ratio 1.5, 95% confidence interval [CI] 1.0 to 2.2, p = 0.027) and higher levels of somatization (odds ratio 2.0, 95% CI 1.2 to 3.3, overall p = 0.024). Factors associated with the degree of tinnitus annoyance were increased levels of anxiety (β = 11.6, 95% CI 2.3-20.8, overall p = 0.035) and poor speech recognition ability in noise (β = 13.5, 95% CI, 4.4 to 22.6, overall p = 0.014)., Conclusions: Higher levels of somatization and a history of smoking were found to be risk factors for new-onset tinnitus 5 years later. Anxiety and poor speech recognition ability in noise were associated with higher degrees of tinnitus annoyance in new-onset tinnitus. Somatization deserves to be addressed in future research and clinical practice as it might provide part of a model for the development of chronic tinnitus., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 The Authors. Ear & Hearing is published on behalf of the American Auditory Society, by Wolters Kluwer Health, Inc.)

Background: Definitive concomitant cisplatin-based chemoradiotherapy (CRT) is the current gold standard for most patients with advanced stage head and neck squamous cell carcinoma (HNSCC) of the pharynx and larynx. Since previous meta-analysis on CRT outcomes in HNSCC have been reported, advances have been made in radiotherapy techniques and clinical management, while HPV-status has been identified as a strong confounding prognostic factor in oropharyngeal cancer. Here, we present real-world outcome data from a large multicenter cohort of HPV-negative advanced stage HNSCC treated with CRT using contemporary IMRT-based techniques., Method: Retrospective data were collected from a multicenter cohort of 513 patients treated with definitive concurrent platinum-based CRT with curative intent between January 2009 and August 2017. Only patients with HPV-negative advanced stage (III-IV) HNSCC were included. A prognostic model for outcome was developed based on clinical parameters and compared to TNM., Results: Nearly half of the 513 patients (49%) had an oropharyngeal tumor, often locally advanced (73.3% T3-T4b) and with involvement of the regional lymph nodes (84%). Most patients (84%) received cisplatin as single agent. In total 66% received the planned number of cycles and 75% reached a cumulative cisplatin dose of ≥200 mg/m 2 . Locoregional control was achieved in 324 (63%) patients during follow-up, and no association with tumor sites was observed (p = 0.48). Overall survival at 5 year follow-up was 47%, with a better survival for laryngeal cancer (p = 0.02) compared to other sites. A model with clinical variables (gender, high pre-treatment weight loss, N2c/N3-stage and <200 mg/m 2 dose of cisplatin) provided a noticeably stronger association with overall survival than TNM-staging (C- index 0.68 vs 0.55). Simultaneous Integrated Boosting (SIB) significantly outperformed Sequential Boosting (SEQ) to reduce the development of distant metastasis (SEQ vs SIB: OR 1.91 (1.11-3.26; p = 0.02)., Conclusion: Despite advances in clinical management, more than a third of patients with HPV-negative HNSCC do not complete CRT treatment protocols due to cisplatin toxicity. A model that consists of clinical variables and treatment parameters including cisplatin dose provided the strongest association with overall survival. Since cisplatin toxicity is a major obstacle in completing definitive CRT, the development of alternative and less toxic radiosensitizers is therefore warranted to improve treatment results. The association of RT-boost technique with distant metastasis is an important finding and requires further study., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Survivors of head and neck cancer can experience long-term consequences of the cancer and subsequent treatments even after the cancer has resolved. Increasingly clinicians are aware of the social, psychological, financial, and emotional impacts of these cancers, in addition to the support required for the physical symptoms. This review provides recommendations on the long-term management and support required for survivors of head and neck cancer in the European healthcare setting., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Psychoneurological symptoms are commonly reported by newly diagnosed head and neck cancer (HNC) patients, yet there is limited research on the associations of these symptoms with biomarkers of stress and inflammation. In this article, pre-treatment data of a multi-center cohort of HNC patients were analyzed using a network analysis to examine connections between symptoms (poor sleep quality, anxiety, depression, fatigue, and oral pain), biomarkers of stress (diurnal cortisol slope), inflammation markers (c-reactive protein [CRP], interleukin [IL]-6, IL-10, and tumor necrosis factor alpha [TNF-α]), and covariates (age and body mass index [BMI]). Three centrality indices were calculated: degree (number of connections), closeness (proximity of a variable to other variables), and betweenness (based on the number of times a variable is located on the shortest path between any pair of other variables). In a sample of 264 patients, poor sleep quality and fatigue had the highest degree index; fatigue and CRP had the highest closeness index; and IL-6 had the highest betweenness index. The model yielded two clusters: a symptoms-cortisol slope-CRP cluster and a IL-6-IL-10-TNF-α-age-BMI cluster. Both clusters were connected most prominently via IL-6. Our findings provide evidence that poor sleep quality, fatigue, CRP, and IL-6 play an important role in the interconnections between psychoneurological symptoms and biomarkers of stress and inflammation in newly diagnosed HNC patients., Competing Interests: The authors declare no conflict of interest.

Cancer patients benefit from early tumor detection since treatment outcomes are more favorable for less advanced cancers. Platelets are involved in cancer progression and are considered a promising biosource for cancer detection, as they alter their RNA content upon local and systemic cues. We show that tumor-educated platelet (TEP) RNA-based blood tests enable the detection of 18 cancer types. With 99% specificity in asymptomatic controls, thromboSeq correctly detected the presence of cancer in two-thirds of 1,096 blood samples from stage I-IV cancer patients and in half of 352 stage I-III tumors. Symptomatic controls, including inflammatory and cardiovascular diseases, and benign tumors had increased false-positive test results with an average specificity of 78%. Moreover, thromboSeq determined the tumor site of origin in five different tumor types correctly in over 80% of the cancer patients. These results highlight the potential properties of TEP-derived RNA panels to supplement current approaches for blood-based cancer screening., Competing Interests: Declaration of interests M.G. Best, R.J.A.N., and T.W. are inventors on relevant patent applications (PCT/NL2011/050518 and PCT/NL2018/050110). R.J.A.N. and T.W. are shareholders of Illumina, Inc. M.H. is chief formulation officer at Nurish.Me, Inc., and Camelina Sun LLC and has equity in those companies (whose business activities are unrelated to the present work). D.M.P. and D.K.L. are shareholders of ExBiome BV., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

This study aimed to assess the prognostic value of intratumoral CD57+ cells in head and neck squamous cell carcinoma (HNSCC) and to examine the reproducibility of these analyses using QuPath. Pretreatment biopsies of 159 patients with HPV-negative, stage III/IV HNSCC treated with chemoradiotherapy were immunohistochemically stained for CD57. The number of CD57+ cells per mm 2 tumor epithelium was quantified by two independent observers and by QuPath, software for digital pathology image analysis. Concordance between the observers and QuPath was assessed by intraclass correlation coefficients (ICC). The correlation between CD57 and clinicopathological characteristics was assessed; associations with clinical outcome were estimated using Cox proportional hazard analysis and visualized using Kaplan-Meier curves. The patient cohort had a 3-year OS of 65.8% with a median follow-up of 54 months. The number of CD57+ cells/mm 2 tumor tissue did not correlate to OS, DFS, or LRC. N stage predicted prognosis (OS: HR 0.43, p = 0.008; DFS: HR 0.41, p = 0.003; LRC: HR 0.24, p = 0.007), as did WHO performance state (OS: HR 0.48, p = 0.028; LRC: 0.33, p = 0.039). Quantification by QuPath showed moderate to good concordance with two human observers (ICCs 0.836, CI 0.805-0.863, and 0.741, CI 0.692-0.783, respectively). In conclusion, the presence of CD57+ TILs did not correlate to prognosis in advanced stage, HPV-negative HNSCC patients treated with chemoradiotherapy. Substantial concordance between human observers and QuPath was found, confirming a promising future role for digital, algorithm driven image analysis., (© 2022. The Author(s).)

Background: T4-classified squamous cell carcinoma (SCC) of external auditory canal (EAC) can potentially involve different anatomical structures, which could translate into different treatment strategies and survival outcomes within one classification. Our aim is to evaluate the clinical added value of T4-subclasses proposed by Lavieille and by Zanoletti., Methods: Retrospective data, including patients with primary operated cT4-classified EAC SCC, was obtained from 12 international hospitals. We subclassified according to the T4-subclasses. The treatment strategies, disease-free survival (DFS) and overall survival per subclass were calculated., Results: A total of 130 T4-classified EAC SCC were included. We found commonly used treatment strategies per subclass according to Lavieille and the DFS seems also to differ per subclass. Subclass according to Zanoletti showed comparable treatment strategies and survival outcomes per subclass., Conclusion: Our study suggests that the subclass according Lavieille might have added value in clinical practice to improve care of T4-classified EAC SCC., (© 2022 The Authors. Head & Neck published by Wiley Periodicals LLC.)

Purpose: Mucoepidermoid carcinoma (MEC) of the head and neck is a prevalent malignant salivary gland tumour with a reported good outcome. The aim of this study was to report the outcome in our centre., Methods: A retrospective chart analysis with survival analyses was performed combined with fluorescence in situ hybridization (FISH) analysis to assess CRTC1/3 MAML 2 fusion gene presence., Results: Sixty-four cases of MEC were identified. Median age at presentation was 51.4 years with a predominance for parotid gland involvement. Five, 10- and 20- year disease-free survival was 98%, 90% and 68%, respectively. Overall survival was 94%, 90% and 64%, respectively. Local recurrence was seen up to 14 years after primary diagnosis; distant metastases were diagnosed up to 17 years later. The overall recurrence rate was less than 20 per cent. CRTC1/3 MAML 2 fusion gene presence showed no survival benefit., Conclusion: MEC of the head and neck has a favorable outcome with the exception of high-grade MEC. PNI and nodal involvement are not rare. CRTC1/3 MAML 2 fusion gene presence showed no survival benefit. The tendency for late onset of loco-regional and distant recurrence should not be underestimated., (© 2021. The Author(s).)

Background: To investigate associations between psychological problems and the use of healthcare and informal care and total costs among head and neck cancer (HNC) patients., Method: Data were used of the NETherlands QUality of Life and Biomedical Cohort study. Anxiety and depression disorder (diagnostic interview), distress, symptoms of anxiety and depression (HADS), and fear of cancer recurrence (FCR) and cancer worry scale (CWS) were measured at baseline and at 12-month follow-up. Care use and costs (questionnaire) were measured at baseline, 3-, 6-, 12-, and 24-month follow-up. Associations between psychological problems and care use/costs were investigated using logistic and multiple regression analyses., Results: Data of 558 patients were used. Distress, symptoms of anxiety or depression, FCR, and/or anxiety disorder at baseline were significantly associated with higher use of primary care, supportive care, and/or informal care (odds ratios (ORs) between 1.55 and 4.76). Symptoms of anxiety, FCR, and/or depression disorder at 12-month follow-up were significantly associated with use of primary care, supportive care, and/or informal care (ORs between 1.74 and 6.42). Distress, symptoms of anxiety, and FCR at baseline were associated with higher total costs., Discussion: HNC patients with psychological problems make more use of healthcare and informal care and have higher costs. This is not the result of worse clinical outcomes.

Background: This study assessed the course of fear of cancer recurrence (FCR) in patients newly diagnosed with head and neck cancer (HNC), identified FCR trajectories and factors associated with FCR trajectories., Methods: Six hundred and seventeen HNC patients from the NET-QUBIC cohort study completed the Cancer Worry Scale-6 at diagnosis, 3 and 6 months post-treatment. FCR trajectories were identified using Latent Class Growth Analysis. Associations were explored between FCR trajectories and baseline demographic and medical variables, coping and self-efficacy., Results: Overall, FCR decreased slightly between baseline and 3 months post-treatment and remained stable up to 6 months. Two FCR trajectories were identified: "high stable" (n = 125) and "low declining" (n = 492). Patients with high stable FCR were younger, reported more negative adjustment, passive coping, and reassuring thoughts, and less avoidance., Conclusions: The majority of HNC patients have low declining FCR after diagnosis, but one in five patients experience persistent high FCR up to 6 months post-treatment., (© 2022 The Authors. Head & Neck published by Wiley Periodicals LLC.)

Incidence of oropharyngeal squamous cell carcinoma (OPSCC) is increasing globally and the human papillomavirus (HPV) has been linked to this increase. This study aimed to present a comprehensive overview of OPSCC trends in incidence rates by age group and investigate differences in risk factors profile. Netherlands Cancer Registry data from 1989-2018 were analyzed to calculate the annual percentage change (APC) over European standardized incidence rates by gender and age group using joinpoint regression software. Smoking, alcohol drinking and HPV-status were available for 2015-2018. During 1989-2018, 13 048 cases of OPSCC were reported with a male-to-female ratio of 2.1:1. The overall incidence rate increased by 5.4% (APC) annually from 1989 to 1996 but slowed thereafter by 1.2%. Significant declines were found in patients of 35-44 years (APCs -3.7%). Adults aged 45-59 years displayed significant increases from 1989 to 2001, followed by a significant decline. In patients ≥60 years, the incidence rates increased overall, with APC for women being consistently higher than men. The data on HPV status was available for 69% of the patients, of whom 47% were HPV+. Smoking and alcohol consumption were more prevalent, that is 75 and 76 % respectively. The declining trends of OPSCC for Dutch people aged 35-44 years from 1989 to 2018 and for those aged 45-59 years from 2002 onwards are inconsistent to trends reported elsewhere in the developed countries. The prevalence of smoking and drinking alcohol was quite high in all age groups, whereas the proportion of HPV-positivity was relatively low., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: The aim was to analyse prognosticators in acinic cell carcinoma (AciCC) in two head and neck referral centers in Amsterdam, the Netherlands., Materials and Methods: Eighty- nine cases of AciCC treated between 1979 and 2016 were retrospectively reviewed. Five, - 10 -and 20- year estimates of survival were executed as well as univariate analysis of prognosticators., Results: The majority of AciCC were T1-T2; 89%. Two percent had nodal disease (2%). The most affected organ was the parotid gland (84%) with a female preponderance (67%). Mean age was 52 years with most cases diagnosed in the fourth to sixth decade. The majority of patients received adjuvant radiotherapy. Elective neck dissection (END) in the N0 neck showed no metastases. High grade transformation (HGT) was found in 21% of cases. Median follow up was 101.9 months. Median time to recurrence was 26 months. Nine patients developed distant metastases (DM) of whom 6 had HGT-AciCC. Median survival with DM was 7 months. Five,- ten -and twenty- year estimates were 84%, 81% and 81% for recurrence free survival respectively. Negative clinical features were advanced stage disease and tumour size > 2.6 cm. Negative histological features were a high mitotic rate, HGT, close and involved surgical margins and necrosis., Conclusion: AciCC- HGT excluded- of the head and neck has an excellent prognosis and shows acceptable long term results. END can be considered as part of the standard treatment due to the relative high incidence of HGT- AciCC and low accuracy of cytology., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Longitudinal observational cohort studies in cancer patients are important to move research and clinical practice forward. Continued study participation (study retention) is of importance to maintain the statistical power of research and facilitate representativeness of study findings. This study aimed to investigate study retention and attrition (drop-out) and its associated sociodemographic and clinical factors among head and neck cancer (HNC) patients and informal caregivers included in the Netherlands Quality of Life and Biomedical Cohort Study (NET-QUBIC)., Methods: NET-QUBIC is a longitudinal cohort study among 739 HNC patients and 262 informal caregivers with collection of patient-reported outcome measures (PROMs), fieldwork data (interview, objective tests and medical examination) and biobank materials. Study retention and attrition was described from baseline (before treatment) up to 2-years follow-up (after treatment). Sociodemographic and clinical characteristics associated with retention in NET-QUBIC components at baseline (PROMs, fieldwork and biobank samples) and retention in general (participation in at least one component) were investigated using Chi-square, Fisher exact or independent t-tests (p< 0.05)., Results: Study retention at 2-years follow-up was 80% among patients alive (66% among all patients) and 70% among caregivers of patients who were alive and participating (52% among all caregivers). Attrition was most often caused by mortality, and logistic, physical, or psychological-related reasons. Tumor stage I/II, better physical performance and better (lower) comorbidity score were associated with participation in the PROMs component among patients. No factors associated with participation in the fieldwork component (patients), overall sample collection (patients and caregivers) or PROMs component (caregivers) were identified. A better performance and comorbidity score (among patients) and higher age (among caregivers) were associated with study retention at 2-years follow-up., Conclusions: Retention rates were high at two years follow-up (i.e. 80% among HNC patients alive and 70% among informal caregivers with an active patient). Nevertheless, some selection was shown in terms of tumor stage, physical performance, comorbidity and age, which might limit representativeness of NET-QUBIC data and samples. To facilitate representativeness of study findings future cohort studies might benefit from oversampling specific subgroups, such as patients with poor clinical outcomes or higher comorbidity and younger caregivers., (© 2022. The Author(s).)

BACKGROUND : Accurate segmentation of head and neck squamous cell cancer (HNSCC) is important for radiotherapy treatment planning. Manual segmentation of these tumors is time-consuming and vulnerable to inconsistencies between experts, especially in the complex head and neck region. The aim of this study is to introduce and evaluate an automatic segmentation pipeline for HNSCC using a multi-view CNN (MV-CNN)., Methods: The dataset included 220 patients with primary HNSCC and availability of T1-weighted, STIR and optionally contrast-enhanced T1-weighted MR images together with a manual reference segmentation of the primary tumor by an expert. A T1-weighted standard space of the head and neck region was created to register all MRI sequences to. An MV-CNN was trained with these three MRI sequences and evaluated in terms of volumetric and spatial performance in a cross-validation by measuring intra-class correlation (ICC) and dice similarity score (DSC), respectively., Results: The average manual segmented primary tumor volume was 11.8±6.70 cm 3 with a median [IQR] of 13.9 [3.22-15.9] cm 3 . The tumor volume measured by MV-CNN was 22.8±21.1 cm 3 with a median [IQR] of 16.0 [8.24-31.1] cm 3 . Compared to the manual segmentations, the MV-CNN scored an average ICC of 0.64±0.06 and a DSC of 0.49±0.19. Improved segmentation performance was observed with increasing primary tumor volume: the smallest tumor volume group (<3 cm 3 ) scored a DSC of 0.26±0.16 and the largest group (>15 cm 3 ) a DSC of 0.63±0.11 (p<0.001). The automated segmentation tended to overestimate compared to the manual reference, both around the actual primary tumor and in false positively classified healthy structures and pathologically enlarged lymph nodes., Conclusion: An automatic segmentation pipeline was evaluated for primary HNSCC on MRI. The MV-CNN produced reasonable segmentation results, especially on large tumors, but overestimation decreased overall performance. In further research, the focus should be on decreasing false positives and make it valuable in treatment planning., (© 2022. The Author(s).)

Immunotherapy with immune checkpoint inhibitors (ICI) has improved treatment outcomes in many cancer types and has focused attention on cancer immunity and the role of the tumor microenvironment (TME). Studies into efficacy of immunotherapy and TME are generally restricted to tumors in one anatomical location, while the histological type may have substantial influence on the contexture of the TME, perhaps more so than anatomical location, and subsequently to the response to immunotherapy. This review aims to focus on the TME in ICI-treated tumors of the same histological type, namely carcinogen-induced squamous cell carcinoma developing within the aerodigestive tract, at three locations, i.e. head and neck (HNSCC), esophagus (ESCC) and lung (LUSC)., Competing Interests: The authors declare no conflicts of interest., (© 2022 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.)

Background: Patients with locally-advanced head and neck squamous cell carcinoma (HNSCC) have variable responses to (chemo)radiotherapy. A reliable prediction of outcomes allows for enhancing treatment efficacy and follow-up monitoring., Methods: Fifty-seven histopathologically-proven HNSCC patients with curative (chemo)radiotherapy were prospectively included. All patients had an MRI (DW,-IVIM, DCE-MRI) and 18 F-FDG-PET/CT before and 10 days after start-treatment (intratreatment). Primary tumor functional imaging parameters were extracted. Univariate and multivariate analysis were performed to construct prognostic models and risk stratification for 2 year locoregional recurrence-free survival (LRFFS), distant metastasis-free survival (DMFS) and overall survival (OS). Model performance was measured by the cross-validated area under the receiver operating characteristic curve (AUC)., Results: The best LRFFS model contained the pretreatment imaging parameters ADC&#95;kurtosis, K ep and SUV&#95;peak, and intratreatment imaging parameters change (Δ) Δ-ADC&#95;skewness, Δ-f, Δ-SUV&#95;peak and Δ-total lesion glycolysis (TLG) (AUC = 0.81). Clinical parameters did not enhance LRFFS prediction. The best DMFS model contained pretreatment ADC&#95;kurtosis and SUV&#95;peak (AUC = 0.88). The best OS model contained gender, HPV-status, N-stage, pretreatment ADC&#95;skewness, D, f, metabolic-active tumor volume (MATV), SUV&#95;mean and SUV&#95;peak (AUC = 0.82). Risk stratification in high/medium/low risk was significantly prognostic for LRFFS ( p = 0.002), DMFS ( p < 0.001) and OS ( p = 0.003)., Conclusions: Intratreatment functional imaging parameters capture early tumoral changes that only provide prognostic information regarding LRFFS. The best LRFFS model consisted of pretreatment, intratreatment and Δ functional imaging parameters; the DMFS model consisted of only pretreatment functional imaging parameters, and the OS model consisted ofHPV-status, gender and only pretreatment functional imaging parameters. Accurate clinically applicable risk stratification calculators can enable personalized treatment (adaptation) management, early on during treatment, improve counseling and enhance patient-specific post-therapy monitoring.