Dysphagia is one of the most serious adverse events in the treatment of head and neck cancer. This cross-sectional study aimed to assess pharyngeal residue, and penetration/aspiration in oropharyngeal cancer patients (OPC) after radiotherapy using flexible endoscopic evaluation of swallowing (FEES).

A total of 35 OPC patients who had received radio-(chemo) therapy (R(C)T), including 8 patients with primary R(C)T), were included and examined by FEES to determine the swallowing status and were asked to indicate their swallowing ability on a visual scale to reflect the problem perceived by the patient. During FEES the patients were given three standardized bolus consistencies and four test pills. Penetration, aspiration, and residue were evaluated and classified.

Relevant dysphagia was present in 23/35 (66%) patients. Almost half of all patients (15/35) showed aspiration (53% (8/15) silent). Residue occurred in 91% but without correlation to aspiration. A significant association between dysphagia and impaired pill swallowing was found (P = .003) occurring in 20 of 35 patients. Even in patients with small tumors and without prior surgery severe dysphagia was found.

Severe dysphagia is frequent after R(C)T affecting more than half of the patients with OPC. The frequent impaired pill swallowing ability should be considered Therefore, regular dysphagia diagnostics in the follow-up setting are advisable to initiate appropriate treatment and raise patients' quality of life, prevent aspiration pneumonia, and improve overall outcomes after tumor therapy.

The aim of this study was to investigate the effect of inconsistent expression of p16 and HPV on the prognosis of patients with Oropharyngeal squamous cell carcinoma (OPSCC) in Chinese/Asian populations.

The study included 130 patients. Inclusion criteria were primary OPSCC. The primary outcome was the proportion of cohort patients showing different combinations of p16 and HPV outcomes, as well as overall survival (OS) and progression-free survival (PFS). Patients with relapsed or metastatic disease or palliative care were excluded from the survival analysis. A multivariate analysis model was used to calculate the adjusted hazard ratio for overall survival for different p16 and HPV tests, adjusted for pre-specified confounders.

Among the 130 patients, 25 (19.2%) demonstrated inconsistency between HPV and p16 expressions. The inconsistency in HPV/p16 status was significantly associated with patient age, smoking history, and alcohol consumption, leading to significant differences in tumor site, TNM staging, and differentiation, thereby influencing treatment decisions. There were significant differences in OS (P = 0.04) and PFS (P = 0.011) among the three groups, with the inconsistent group falling between the HPV+/p16 + group and the HPV-/p16- group but closer to the latter. Out of 54 p16-positive patients, only 33 (61.1%) were HPV-positive, indicating a lower predictive value of p16 for HPV positivity in OPSCC than observed in Western populations. Moreover, the study suggested a potential positive correlation between p16 expression intensity and improved patient prognosis.

In the China/Asia region, where HPV infection rates are relatively low, the predictive power of p16 for HPV-related OPSCC is low. We recommend additional HPV testing in patients with p16 + OPSCC to improve diagnostic accuracy, thereby enabling the selection of the best de-escalation treatment strategy, increasing treatment response rates, and ultimately improving the overall prognosis in these patients.

The incidences of human papillomavirus-positive (HPV+) tonsillar and base tongue squamous cell carcinomas (TSCC and BOTSCC) have increased in recent decades. Notably, HPV+ TSCC and BOTSCC have a significantly better prognosis than their HPV-negative counterparts when treated with current surgical options, radiotherapy, or intensified chemoradiotherapy. However, a cure is not achieved in 20% of patients with HPV+ TSCC/BOTSCC. Meanwhile, cured patients often present with severe chronic side effects. This necessitates novel tailored alternatives, such as targeted therapy, immune checkpoint inhibitors (ICIs), and treatment de-escalation, together with better follow-up. Current precision medicine therefore focuses on detecting predictive and driver cancer genes to better stratify patient treatment, provide those with poor prognostic markers targeted therapy, and select those with favorable markers for de-escalated therapy. Moreover, detecting cell-free HPV DNA (cfHPV DNA) in plasma before and after treatment has been attempted to improve follow-up. In this context, this perspective discusses the significance of optimally defining HPV+ status, which requires HPV DNA and p16INKa overexpression, using prognostic markers, such as high CD8+ T-cell counts and HPV E2 mRNA expression, tumor size, and following cfHPV DNA for patient selection for specific therapies. Clinical trials with ICI with/without chemotherapy, targeted therapy with specific inhibitors-such as phosphoinositide 3-kinase and fibroblast growth factor receptor inhibitors-or immune therapy with various HPV-based vaccines for treating recurrences have yielded promising results.

The feasibility of sparing tubarial glands in oropharyngeal radiotherapy was assessed using IMPT and IMRT. Tubarial gland absolute mean dose differences of up to 18 Gy were observed between clinical and re-optimized plans without compromising target coverage. IMPT plans met tubarial gland mean dose constraints more often than IMRT plans.

The incidence of Human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) has risen over the past two decades, now accounting for 44-75 % of cases in Europe and the USA. This review synthesized data from PubMed, additional academic sources, and ongoing studies to summarize the potential role of proton therapy (PT) role in treating HPV-related OPSCC. In vitro studies support PT radiosensitization of HPV-positive cells and clinical experiences report high locoregional control (LRC) rates of 88.6-97 % with significantly reduced side effects such as xerostomia by 12.5 % and brain necrosis by 2.3 %, compared to intensity-modulated radiation therapy (IMRT). A randomized trial (NCT01893307) has also recently provided level 1 evidence showing that PT is non-inferior to IMRT for tumor control while reducing treatment-related toxicities, such as feeding tube dependence (28 % vs. 42 %, p = 0.019) and facilitating better work resumption outcomes (71 % vs. 52 % at 2 years). Despite the success of radiation de-escalation achieving LRC up to 95 %, recent trials indicate potential survival risks when standard treatments are modified. Failure pattern analysis showed that up to 70 % of locoregional recurrences occurred in-field, highlighting the potential role of PT in achieving LRC while minimizing toxicity. PT could also play a role in the reirradiation of recurrent OPSCC, with reported 1-year LRC rates of 71.8-80.8 %, 2-year LRC rates of 72.8-80.3 %, 1-year overall survival (OS) rates of 65.2-81.3 %, 2-year OS rates of 32.7-69 %, and late grade ≥2 toxicities of 11.9-36.3 %. Methodologies improving reRT approaches include dose/volume histogram comparisons, which recommended PT when it resulted in lower predicted toxicities.

Patients with oropharyngeal squamous cell carcinoma (OPSCC) are highly prone to malnutrition and sarcopenia due to the tumor's location and treatment-related toxicity. Human papillomavirus (HPV)-related and HPV-unrelated OPSCC represent two distinct biological entities. This study aimed to assess nutritional characteristics and body composition differences at diagnosis, as well as 3- and 6-months post- (chemo) radiation treatment, stratified by HPV status in OPSCC patients.

Retrospective data analysis of a prospective cohort of OPSCC patients diagnosed and treated with curative intent from 2016 to 2022 at our center. Sociodemographic, clinical, and nutritional data were retrieved from medical records from diagnosis to 6 months post-treatment. Body composition parameters were assessed by analyzing the cross-sectional area of the third lumbar vertebra (L3) using available positron emission tomography (PET) and computed tomography (CT) scans at baseline, 3- and 6-months post-treatment.

Seventy patients were included, 33 (47.1 %) of whom had HPV-related OPSCC. HPV-related patients had higher body mass index (27.3 vs 21.9 kg/m2; p < 0.001) and better baseline nutritional status (p = 0.023), but no differences in skeletal muscle index (SMI, p = 0.103) compared to HPV-unrelated patients. At 3- and 6-months post-treatment the two groups showed similar SMI and total adipose tissue index loss (p > 0.05 for both). HPV status was not independently associated with body composition changes over time (p = 0.624).

Although HPV-related patients were better nourished than HPV-unrelated patients at diagnosis, by the end of treatment, both groups exhibited similar nutritional deterioration.

Human Papillomavirus (HPV)-positive Head and Neck (HNC) cancer responds better to radiotherapy and platinum-based chemotherapy than HPV-negative HNC, likely due to impaired DNA damage repair. Inhibiting PARP1 enhances the effects of radiation and chemotherapy in tumours with defective DNA repair, such as HPV-positive cancers. In this study we investigated the role of HPV in the upregulation of PARP1, determining HNC cell sensitivity to both olaparib and cisplatin.

PARP1 expression was assessed in HPV-positive and HPV-negative HNC using TCGA data, HNC cell lines and frozen tumour tissue samples from HNC patients. HPV16 expression was modulated by E6/E7 transduction in Human Primary keratinocytes (HK). Sensitivity to the PARP inhibitor olaparib and cisplatin, alone and in combination, was assessed in HNC cell lines.

HPV-positive tumours and cell lines showed upregulated PARP1 expression and activity, mediated by HPV16 oncoproteins. HPV-positive cell lines were more sensitive to olaparib or cisplatin treatment than HPV-negative ones. Combining cisplatin with olaparib synergistically inhibited cell viability in all HNC cell lines tested, regardless of HPV status.

Our study demonstrates that PARP1 is upregulated in HPV-positive HN tumours and cell lines, compared to HPV-negative. Despite the higher sensitivity of HPV-positive HNC cell lines to olaparib and cisplatin compared to HPV-negative cells, the combination of cisplatin with olaparib synergistically inhibits cell viability across all HNC cell lines tested, regardless of HPV status. This combination may allow for reduced drug concentrations, potentially decreasing side effects and enhancing therapeutic efficacy in HN tumours.

This study aimed to determine whether different distant metastasis (DM) sites at the time of diagnosis exhibit distinct survival outcomes human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC), and to assess whether intensifying treatment with local surgery or radiotherapy (RT) offers particular advantages for specific subcategories of patients.

A retrospective cohort study included patients with invasive OPSCC with single-site DM at diagnosis between 2010 and 2020 from the US National Cancer Database (NCDB). Hazard ratios (HR) for overall survival were estimated with the corresponding 95% confidence interval (95% CI).

A total of 780 patients were included. Patients with distant lymph node demonstrated better survival compared to lung (adjusted HR: 1.45; 95 % CI: 1.10 - 1.93; p = 0.009), liver (adjusted HR: 1.97; 95 % CI: 1.35 - 2.88; p < 0.001), and bone (adjusted HR: 1.90; 95 % CI: 1.39 - 2.59; p < 0.001) metastases. Locoregional RT showed survival benefit compared to no treatment (adjusted HR: 0.71; 95 % CI: 0.57 - 0.88; p = 0.002), particularly for patients with distant lymph node (adjusted HR: 0.64; 95 % CI: 0.41 - 1.00; p = 0.05) and lung (adjusted HR: 0.72; 95 % CI: 0.51 - 1.00; p = 0.05) metastases.

Patients diagnosed with isolated distant lymph node metastases in HPV-positive OPSCC demonstrate a more favorable prognosis compared to those with metastases at other sites. Our results suggest that RT may confer a survival advantage for patients with distant lymph node and lung metastases, potentially enhancing their long-term outcomes.

In 2018, an evidence-based guideline was published by the College of American Pathologists to develop recommendations for the testing, application, interpretation, and reporting of high-risk human papillomavirus and surrogate marker tests in head and neck carcinomas. Substantial new evidence has prompted a review, including data on human papillomavirus (HPV) in nonoropharyngeal anatomic sites, HPV global rates, p16 immunohistochemistry, and HPV testing performance in cytology specimens, and performance of p16 immunohistochemistry as a surrogate marker.

To assess research published since the release of the original 2018 guideline and to update evidence-based recommendations for HPV testing in head and neck carcinomas.

The College of American Pathologists convened a panel of experts to update the guideline following the standards established by the National Academy of Medicine for developing trustworthy clinical practice guidelines. The expert panel defined the key questions and performed a systematic review of the literature. Using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, recommendations were updated on the basis of available evidence, certainty of that evidence, and key judgments.

Seven strong recommendations, 4 conditional recommendations, and 5 good practice statements are offered in the guideline update.

The updated guideline statements provide direction on the nature of HPV testing in various head and neck specimens (including key updates based on new research on sinonasal squamous cell carcinoma) and expanded guidance on specific scenarios and practice settings. The goal is to improve and standardize, where possible, HPV testing across diverse pathology practice settings and different countries.

In the HECKTOR 2022 challenge set [1], several state-of-the-art (SOTA, achieving best performance) deep learning models were introduced for predicting recurrence-free period (RFP) in head and neck cancer patients using PET and CT images.

This study investigates whether a conventional DenseNet architecture, with optimized numbers of layers and image-fusion strategies, could achieve comparable performance as SOTA models.

The HECKTOR 2022 dataset comprises 489 oropharyngeal cancer (OPC) patients from seven distinct centers. It was randomly divided into a training set (n = 369) and an independent test set (n = 120). Furthermore, an additional dataset of 400 OPC patients, who underwent chemo(radiotherapy) at our center, was employed for external testing. Each patients' data included pre-treatment CT- and PET-scans, manually generated GTV (Gross tumour volume) contours for primary tumors and lymph nodes, and RFP information. The present study compared the performance of DenseNet against three SOTA models developed on the HECKTOR 2022 dataset.

When inputting CT, PET and GTV using the early fusion (considering them as different channels of input) approach, DenseNet81 (with 81 layers) obtained an internal test C-index of 0.69, a performance metric comparable with SOTA models. Notably, the removal of GTV from the input data yielded the same internal test C-index of 0.69 while improving the external test C-index from 0.59 to 0.63. Furthermore, compared to PET-only models, when utilizing the late fusion (concatenation of extracted features) with CT and PET, DenseNet81 demonstrated superior C-index values of 0.68 and 0.66 in both internal and external test sets, while using early fusion was better in only the internal test set.

The basic DenseNet architecture with 81 layers demonstrated a predictive performance on par with SOTA models featuring more intricate architectures in the internal test set, and better performance in the external test. The late fusion of CT and PET imaging data yielded superior performance in the external test.

To correlate between immunohistochemical expression of tumor-infiltrating lymphocytes (TILs), tumor-associated macrophages (TAMs), and natural killer (NK) cells with the AJCC 8th edition TNM staging system and other disease-modifying clinico-pathological variables.

The representative histology sections of tumor invasive margin (IM) and tumor core (TC) were selected according to the International Immuno-Oncology Biomarker Working Group and were subjected to immunohistochemistry with antibodies for TILs (CD3, CD8, FOXP3), NK Cells (CD57), TAMs (CD68, CD163) and pan-leukocyte marker (CD45). Histo-immuno-density-intensity (HIDI) scoring was calculated as a product of the proportion and intensity of staining. Ordinal-ordinal and continuous-ordinal variables were correlated using Kendall's tau-b (τb), and binary-ordinal variables were correlated using Rank-Biserial (rrb) statistics.

A total of 111 patients were included in the study. None of the clinical and pathological parameters showed a strong correlation with any of the immune infiltrates including TNM staging.

We hypothesize an independent activity of tumor immunology in the disease prognosis.

CTRI/2020/07/026335.

This commentary addresses methodological limitations in the recent study by Kang et al. [1] on the prognostic role of diagnosis-to-surgery interval (DSI) in oral cavity squamous cell carcinoma (OSCC). While the study highlights the clinical importance of timely surgery, key concerns include potential immortal time bias due to its retrospective design, oversimplified DSI categorization (14/28 days) ignoring non-linear survival trends, and unaddressed competing risks in disease-specific survival analysis. Additionally, critical variables such as molecular markers such as TP53 mutations) and missing data handling were not adequately discussed. To enhance validity, we recommend employing advanced statistical approaches such as Fine-Gray models for competing risks, cubic splines for DSI effects and integrating molecular profiling. Addressing these issues may improve prognostic accuracy and guide optimal surgical timing in OSCC management.

Blood-borne, cell-free DNA has been proposed as a means of individualizing the management of human papillomavirus (HPV)-positive oropharyngeal carcinoma.

This study was designed based on the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) statement. A comprehensive literature search of peer-reviewed publications from January 2013 to January 2024 was undertaken to identify prospective studies pertaining to the use of circulating HPV-DNA for oropharyngeal carcinoma.

A total of 11 prospective studies were identified and differed in their clinical design, methods, and endpoints. Five included patients treated by chemoradiation; 3 by surgery; 2 by both; and 1 not specified. The timing and frequency of HPV-DNA draws was highly variable. The sample size ranged from 16 to 262 (mean, 99 patients).

While interest is growing with integrating circulating HPV-DNA into clinical practice, the supporting evidence is limited by the heterogeneity of the evidence.

The optimal timing of pembrolizumab with chemoradiation (CRT) in locally advanced (LA) head and neck squamous cell carcinoma (HNSCC) is unknown.

Our phase II trial randomly assigned patients 1:1 to concurrent pembrolizumab (200 mg once every 3 weeks × 8) starting 1 week before CRT (cisplatin 40 mg/m2 once weekly + radiation 70 Gy) versus sequential pembrolizumab starting 2 weeks after CRT. Human papillomavirus (HPV)+ (>10 pack-years or T4 or N3) and HPV(-) LA HNSCC were included, stratified by HPV and N stage. In our pick-the-winner design, if both arms met the trivariate primary end point (1-year locoregional failure <60%, progression-free survival [PFS] ≥60%, and dose limiting toxicity rate ≤20%), the arm with numerically superior 1-year PFS would be selected. Survival end points were compared by a univariate Cox model. Pretreatment and on-treatment tumor biopsies (week 2 of CRT) were evaluated by multispectral imaging and compared using two-sided paired t-tests.

Treated patients (41 concurrent and 39 sequential) were 71% oropharynx (53% HPV+), 92.5% stage IV (46% T4, 76% N2), similar by arm. Both arms met the trivariate primary end point, with superior 1-year PFS in the sequential arm (84% v 71%) and favorable 4-year outcomes: locoregional control (96% v 64%; hazard ratio [HR], 0.11 [95% CI, 0.01 to 0.89]; P = .012), PFS (69% v 49%; HR, 0.55 [95% CI, 0.25 to 1.22]; P = .132), and overall survival (83% v 71%; HR, 0.51 [95% CI, 0.19 to 1.37]; P = .17). There was a significant increase in macrophages, PD-L1+ macrophages, and PD-L1+ tumor cells with treatment in the concurrent but not the sequential arm.

CRT with sequential pembrolizumab met criteria for further study. Immunosuppressive changes in the TME differed between arms, reflecting the impact of one dose of pembrolizumab in the concurrent arm.

Objective.To predict radiotherapy treatment response for head and neck cancer (HNC) using multimodality imaging and personalized radiobiological modeling.Approach.A mechanistic radiobiological model was combined with multi-modality imaging data from diffusion weighted-magnetic resonance imaging and positron emission tomography scans with [18F]Fluorodeoxyglucose (FDG) and [18F]Fluoromisonidazole (FMISO) tracers to develop personalized treatment response models for human papilloma virus associated HNC patients undergoing chemo-radiotherapy. Models were initialized to incorporate patient-specific imaging and updated to reflect longitudinal measurements of nodal gross tumor volume throughout treatment. Prediction accuracy was assessed based on mean absolute error (MAE) of weekly volume predictions and in predicting locoregional recurrence (LRR) following treatment.Main results.Personalized modeling based on pretreatment imaging significantly improved longitudinal volume prediction accuracy and correlation with measurement compared with a generic population model (MAE = 23.4 ± 10.0% vs 24.9 ± 9.0%,p= 0.002 on pairedt-test,R= 0.82 vs 0.72). Adding volume measurements from weeks 1 and 2 further improved prediction accuracy for subsequent weeks (MAE = 12.5 ± 8.1%, 10.7 ± 9.9%). When incorporating feedback with longitudinal measurements, penalizing large deviations from pretreatment model parameters using a variational regularization method was necessary to maintain model stability. Model-predicted volumes based on baseline + week-1 information significantly improved LRR prediction compared with week-1 volume data alone (area under the curve, AUC = 0.83 vs 0.77,p= 0.03) and was similar to prediction using week-3 volume data (AUC = 0.83 vs 0.85,p= non-significant).Significance.The proposed approach, which integrates clinical imaging and radiobiological principles, could be a basis to guide pretreatment prescription personalization as well as on-treatment adaptations.

Cancer patients are at risk of developing a wide range of treatment-related toxicities that may affect the head and neck region. Iatrogenic necrosis of bone and soft tissue in this area represents a distinct clinical entity characterized by significant complexities and challenges, arising as a consequence of radiotherapy (osteoradionecrosis) or the administration of bone-modifying and/or antiangiogenic therapies (medication-related osteonecrosis of the jaw).

This review provides a comprehensive understanding of this potentially highly impactful complication of cancer therapy and antiresorptive therapy by examining its pathophysiology, risk factors, clinical presentation, and management strategies.

Risk factors associated with these conditions include radiotherapy-related variables, medication-related factors, and local predisposing conditions.

This review highlights the importance of preventive strategies, including comprehensive dental evaluations and the development of personalized treatment plans before, during, and after cancer therapy, as well as when patients are undergoing or are expected to undergo treatment with bone-modifying medications. By addressing these critical aspects, clinicians can better manage and mitigate the impact of this challenging complication on the quality of life and morbidity outcomes.

This study investigated the characteristics and clinical efficacy of transoral endoscopy-assisted low-temperature plasma surgery for the treatment of oropharyngeal malignant tumours.

The clinical data of 14 patients who underwent transoral endoscopy-assisted low-temperature plasma resection of oropharyngeal malignant tumours in the Department of Otolaryngology-Head and Neck Surgery from January 2017 to October 2024 were retrospectively analysed. The general characteristics, clinical pathology results, surgical methods, operative time, volume of blood loss, length of hospitalization, and follow-up status of the patients were analysed.

The 14 patients included 13 males and 1 female, and the average age was 60 ± 9 years. Three patients received flaps for wound repair (1 forearm flap, 1 platysma myocutaneous flap, and 1 submental flap), 6 patients underwent unilateral neck lymph node dissection, 5 patients underwent bilateral neck lymph node dissection, and 1 patient underwent preventive tracheotomy. The average duration of the operations was 231 ± 114 min, and the average duration of tumour resection was 53 ± 15 min. The average volume of blood loss was 66 ± 55 ml, and the average duration of hospitalization was 10 ± 5 days. Postoperative pathology confirmed that 13 patients had squamous cell carcinoma, and 1 patient had mucoepidermoid carcinoma. The average duration of postoperative follow-up was 20 ± 14 months. One patient developed multisystem metastases, and one patient experienced tumour recurrence. all other patients survived well.

Transoral surgery has become more common as a minimally invasive approach for treating oropharyngeal tumours. Transoral endoscopy-assisted low-temperature plasma-assisted resection of oropharyngeal malignant tumours may be used as a surgical approach.

P-cadherin (CDH3) is a transmembrane protein that plays a crucial role in maintaining the structural integrity of epithelial tissue and homeostasis. Its role in carcinogenesis remains a subject of debate, as its behavior can vary depending on the molecular context and the specific tumor cell model under study. In this study, we explored the role of P-cadherin in head and neck squamous cell carcinoma (HNSCC) and the mechanisms underlying its function.

We analyzed P-cadherin expression in HNSCC patients using The Cancer Genome Atlas (TCGA), The Chungnam National University Hospital (CNUH) cohort and Gene Expression Omnibus (GEO) database. For in vitro functional analysis, we conducted proliferation, migration, invasion, and western blot assays after either suppressing or overexpressing P-cadherin. For in vivo functional analysis, we utilized mouse xenograft models.

P-cadherin was significantly overexpressed in tumor samples compared to normal samples in the TCGA-HNSCC and CNUH-HNSCC cohorts. P-cadherin knockdown resulted in decreased proliferation, migration, and invasion compared to control cells, while P-cadherin overexpression increased cell proliferation and migration in HNSCC cells. We discovered that c-Met functions as an upstream regulator of P-cadherin. Surprisingly, we found that P-cadherin knockdown increased the phosphorylation of c-Met and STAT3. Combining P-cadherin siRNA with the c-Met inhibitor SU11274 or c-Met siRNA resulted in a more effective reduction in HNSCC cell growth, both in vitro and in vivo, compared to either treatment alone.

Our study uncovered a previously unknown aspect of P-cadherin-mediated c-Met regulation. The enhanced activation of c-Met/STAT3 following P-cadherin inhibition could be responsible for the survival of resistant tumor cells. Therefore, dual inhibition of P-cadherin and c-Met may be an effective approach for treating HNSCC.

The transforming growth factor-β (TGFβ) paradox refers to the well-established role of TGFβ in suppressing cancer in healthy tissues yet promoting malignancy in established cancers. Although this positioned TGFβ inhibitors as a potential therapeutic strategy for malignancy, therapuetic blockade has failed in multiple clinical trials. The general lack of selection principles for defining which patients would most benefit from the addition of a TGFβ inhibitor has probably hindered its deployment. Here, we highlight the therapeutic potential in TGFβ regulation of DNA repair using human papillomavirus (HPV)-driven head and neck squamous cell carcinoma (HNSCC) as an illustrative example. HPV inhibits TGFβ signalling, which in turn reduces DNA damage repair, ultimately conferring sensitivity to cancer treatments and thus contributing to the favourable prognosis of HPV-positive HNSCC. Here, we review the DNA repair deficit caused by a loss of TGFβ signalling and how this could be targeted to induce synthetic lethality. Moreover, we explore its role in predicting response to immune checkpoint inhibitors and the potential of biomarkers to select which patients with cancer could ultimately benefit from TGFβ inhibition.

Around 70% of head and neck cancer (HNC) cases are diagnosed in an advanced stage. Improvements in treatment have led to a cure rate of up to 80-90% for early-stage and 40-50% for advanced-stage disease. However, routine follow-up involves social and financial burdens, including frequent imaging associated with radiation exposure and costs. Currently, there is no consensus on the follow-up strategy after HNC treatment, and no conclusive evidence shows a survival advantage for routine follow-up over symptom-driven self-referrals. The DeintensiF study aims to provide robust evidence, comparing standard follow-up with a tailored deintensified approach. Additionally, it seeks to explore whether early detection of recurrence/second primary malignancy in asymptomatic patients impacts survival and quality of life. The pilot phase aims to assess feasibility of patients' recruitment and adherence to the assigned follow-up strategy and patient-reported outcomes (PROs) questionnaire in the first 2 years.

This randomized-controlled, multicenter, open-label, pilot study has the goal to randomize a minimum of 16 patients across three Swiss sites into two arms within 1 year. The Experimental Arm A: scheduled clinical exams every 6 months and monthly PRO with evaluation and possibility to alert for open urgent appointments; and the Control Arm B: regular visits every 3 months for the first 2 years and less frequent thereafter plus multiple scheduled imaging appointments for head and neck magnet resonance imaging (MRI) and computed tomography (CT) with contrast and chest CT scans. Patients' motivation for participation or not will be explored by additional questionnaire before randomization. The primary objective during the pilot phase is to evaluate the feasibility of recruiting and randomizing patients with complete remission 6 months after treatment of head and neck squamous cell carcinoma to a deintensified and to a conventional follow-up. The secondary objective is to assess adherence to the two different follow-up strategies.

If feasible, the DeintensiF pilot study will expand from the recruited patients (detailed in the "Methods" section) to a larger cohort of advanced HNC cases in the main trial, integrating electronic PRO tailored follow-up care. This approach aims to reshape follow-up practices, enhancing patient-centered strategies and outcomes in head and neck oncology.

ClinicalTrials.gov (NCT05388136); Swiss National Clinical Trial Portal (SNCTP000005198).

The incidence of human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) has increased substantially over the past three decades, and since 2017, it has been recognized in the AJCC staging system as distinct from its HPV-negative counterpart. The underlying mechanisms of HPV-associated carcinogenesis, tumor microenvironment, and host immune response represent opportunities for therapeutic development. While anti-PD-1 immunotherapy is now part of standard treatment for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) in general, there are no established immunotherapeutic strategies specifically for HPV-related HNSCC. In this context, multiple emerging approaches are being actively studied-among these are therapeutic vaccines with or without anti-PD-(L)1 adjuvants, peptide-HLA-based immunotherapeutic platforms, and adoptive cell therapies including tumor-infiltrating lymphocytes (TILs), T-cell receptor (TCR) therapy, and chimeric antigen receptor (CAR) T-cell therapy. Beyond further maturation of these novel immunotherapeutic strategies, additional work is needed to delineate the optimal disease state of application (localized versus recurrent/metastatic), as well as in the development of small molecule inhibitors targeting HPV-specific mechanisms of viral oncogenesis.

Post-diagnosis smoking remains prevalent among head and neck squamous cell carcinoma (HNSCC) patients. Smoking cessation may improve patient outcomes.

A prospective longitudinal cohort study (2008-2014) included 835 newly diagnosed HNSCC patients and followed up for 7 years. Participants were categorized by smoking behavior (never smokers, former smokers, quitters, continuing smokers, and intermittent smokers). The primary outcomes were overall survival (OS) and recurrence-free survival (RFS).

Smoking cessation after diagnosis was associated with significantly improved OS. Quitters had a 61% reduction in mortality risk compared to continuing smokers (HR: 0.39, 95% CI: 0.22, 0.69), with the greatest benefit in oral cavity cancer patients (HR: 0.28, 95% CI: 0.12, 0.65). Intermittent smokers also showed improved survival (HR: 0.50, 95% CI: 0.31, 0.79). RFS did not significantly differ based on smoking behavior.

Smoking cessation post-diagnosis improves OS, particularly in oral cavity cancer patients, highlighting the importance of targeted smoking cessation interventions in HNSCC care.

Nutritional outcomes following transoral robotic surgery (TORS) for human papillomavirus (HPV) associated oropharyngeal squamous cell carcinoma (OPSCC) are poorly understood. This study evaluates how TORS, with or without adjuvant treatment, impacts swallowing and weight loss.

All patients treated with TORS for HPV-associated OPSCC from January 2016 to December 2023 were included. Weight loss, functional oral intake, feeding tube dependence, patient demographics, and treatment course were collected from patients' electronic medical records.

In total, 160 patients with HPV-associated OSPCC treated with TORS were included. 87.5% were male, with a median age of 60.0 years. Most patients were diagnosed with pT1 (53.8%) or pT2 (40.0%) and pN1 (78.1%) disease. 31.9% underwent TORS alone, while 42.5% received adjuvant radiation and 25.6% adjuvant chemoradiation. The median follow-up time was 2.27 (range 0.26-7.56) years. 87.4% of patients underwent nasogastric tube placement during TORS. Prolonged postoperative nasogastric tube dependence was significantly associated with increased rates of feeding tube replacement (p < 0.001; 95% CI, 1.051-1.181) later during treatment. Weight loss from three months to three years postoperatively was significantly greater in patients who received adjuvant radiation and chemoradiation (p < 0.001), despite no significant difference in swallowing outcomes. There was no significant difference in weight loss between adjuvant radiation and chemoradiation groups.

Adjuvant treatment following TORS is associated with significantly greater long-term weight loss but does not significantly alter swallowing outcomes. Longer duration of nasogastric tube dependence in the postoperative period is associated with higher rates of enteral feeding dependence later in treatment.

Objective : To investigate the prognostic utility of systemic inflammatory response index (SIRI) as a biological readout of stress associated immune modulation in head and neck cancer patients who underwent radiation therapy. Methods : Random survival forest machine learning was used to model survival in 568 head and neck cancer patients. SIRI was calculated via pre-treatment bloodwork. Model validation was performed in an external cohort of 345 patients. Baseline financial toxicity (FT) and SIRI were studied in 638 patients. Results : Incorporation of SIRI (with performance status and smoking history) into a machine learning model identified three risk-groups that significantly stratified overall survival (p<0.0001,) and these findings were validated in the external validation cohort (p<0.001.) Increasing levels of FT were significantly associated with increasing SIRI levels. (p=0.001.) Conclusions and Relevance : An integrated machine learning model using clinical features was successfully developed and externally validated. SIRI was significantly associated with increasing FT. Our findings highlight the potential utility of SIRI as a biological marker of FT in head and neck cancer patients.

This study aimed to evaluate swallow outcomes in head and neck cancer (HNC) survivors enrolled in a long-term dysphagia surveillance protocol following curative intent radiotherapy (RT).

We conducted a retrospective review of videofluoroscopic swallow studies from 2015 to 2023 in HNC patients treated with RT. Swallow kinematics and function were assessed at baseline, 0-1, 1-2, 2-5, and 5+ years post-RT. Logistic regression models assessed kinematic deviations beyond 2SD from normative and dichotomized outcomes.

Among 638 patients with 1167 VFSS, 14.6% were 2 years post-RT, primarily oral cavity (29.6%) and oropharyngeal (46.7%) cancers treated with adjuvant (chemo) RT (53.3%). At 2 years, 51.3% exhibited abnormal hyolaryngeal movement, 27.5% had pharyngeal contraction abnormalities, and 9.0% had impaired pharyngoesophageal opening. Unsafe swallow was seen in 51.6% with moderate-to-profound dysphagia in 45%.

Dysphagia surveillance revealed significant swallowing impairments in HNC survivors, with unsafe swallowing prevalent in over half of cases 2 years post-RT.

Human papillomaviruses are causative agents in around 5 % of all cancers, and in a number of other human diseases. While prophylactic vaccines will alleviate the HPV disease burden on future generations, there are currently no therapeutic anti-viral strategies for combating HPV infections or lesions. HPV induce the proliferation of infected epithelial cells and modulate the host differentiation response, and both of these controls are required for a successful viral life cycle. Enhanced understanding of viral-host interactions during the viral life cycle will identify potential novel anti-viral strategies for therapeutic development. This minireview will summarize the critical role of the host enzyme CK2 in regulating the function of the viral proteins E1, E2 and E7; such control makes CK2 a critical enzyme for regulating HPV life cycles. Therapeutic strategies blocking CK2 function to combat HPV infections and treat HPV diseases will be described.

The optimal treatment de-escalation approach for HPV-related oropharyngeal squamous cell carcinomas (OPSCC) is unknown. The objective was to assess two de-escalation approaches: primary radiotherapy (RT) vs. transoral surgical (TOS).

Patients with T1-T2 N0-2 HPV-related OPSCC were randomly assigned to primary RT (60 Gy with concurrent weekly cisplatin in node-positive) vs. TOS + neck dissection (ND) (and adjuvant reduced-dose RT depending on pathology). The primary endpoint was 2-year OS (hypothesized to be 94 % in each arm, compared to 84 %). Secondary endpoints included comparisons of survival and quality of life between arms. The trial was stopped early due to two treatment related deaths in the surgical arm.

Sixty-one patients were randomized (n = 30 in RT arm and n = 31 in TOS+ND arm), with a median age of 62 years (IQR: 57-68). The majority were male (n = 51) and never-smokers (n = 31). Median follow-up was 3.7 years (IQR: 3.1-4.5 years). In the RT arm, the primary endpoint for acceptability was met (p = 0.008), and two-year OS was 100 % (95 % confidence interval [CI]: 100-100 %). In the TOS+ND arm, the primary endpoint was not met (p = 0.296) and two-year OS was 90 % (95 % CI: 71-97 %), significantly worse than the RT arm (p = 0.041). Two-year progression-free survival (PFS) were 100 % (95 % CI: 100-100 %) vs. 86 % (95 % CI: 67-95 %) respectively (p = 0.012). Mean (± SD) 2-year MDADI total scores were 89 ± 13 vs. 83 ± 11, respectively (p = 0.11), and grade 2-5 toxicity rates were similar (n = 21 vs. n = 24 respectively, p = 0.51), with no additional grade 5 events.

For treatment de-escalation, a primary RT approach achieved excellent oncologic and functional outcomes and should be tested in phase III de-escalation trials.

Clinicaltrials.gov NCT03210103.

Esophageal and head and neck cancers often coexist due to field cancerization, which causes multiple squamous cell carcinomas (SCCs) in the upper aerodigestive tract. However, guidelines for the differential diagnosis and optimal treatment of synchronous esophageal and head and neck SCC are lacking. This study highlights the diagnostic and therapeutic challenges of these coexisting malignancies.

A 52-year-old man presenting with dysphagia was diagnosed with esophageal SCC, and an incidental retropharyngeal tumorous lesion was found during staging.

Biopsy revealed SCC in both lesions. To differentiate between metastatic disease and a second primary SCC, immunohistochemistry (IHC) and next-generation sequencing (NGS) were performed. The retropharyngeal SCC showed strong p16 staining, indicating human papilloma virus (HPV)-related origin, while the esophageal SCC was p16-negative. NGS revealed distinct genetic profiles for each lesion, confirming synchronous double primary SCCs.

The patient underwent definitive concurrent chemoradiotherapy for both SCCs.

The patient achieved a complete response for both lesions and remains recurrence-free 1 year after treatment.

This case underscores the importance of HPV testing and/or NGS in patients with multiple SCCs in the upper aerodigestive tract to accurately differentiate primary cancers from metastases.

While KEYNOTE-048 established anti-PD1 with or without chemotherapy as first-line treatment for recurrent and metastatic head and neck squamous cell carcinoma (HNSCC) with combined positive score (CPS) ≥ 1, treatment choice remains ambiguous given additional toxicity of combination treatment.

Patients treated first-line with anti-PD1 monotherapy, anti-PD1+chemotherapy, or cetuximab+chemotherapy in the Flatiron Health database were included. Treatment group differences were assessed with chi-squared and t-tests, and selection factors were analyzed with logistic regressions. Survival was assessed with Kaplan-Meier curves, log-rank tests, and Cox regressions.

Of 2577 patients included, Anti-PD1 monotherapy (n=1410) improved survival over cetuximab+chemotherapy (n=577, median survival 14.6 vs. 12.6 months, p=0.015), while anti-PD1+chemotherapy (n=590) showed a nonsignificant trend towards improvement (median survival 14.3 vs. 12.6 months, p=0.053). In HPV-associated disease, survival was equal between regimens. Addition of chemotherapy improved survival over anti-PD1 monotherapy in non-HPV associated tumors with CPS 1-9 (median survival 18.0 vs. 10.3 months, p=0.029) and in oral cavity primaries (median survival 10.3 vs. 7.6 months, p=0.003).

Subgroups of patients with recurrent or metastatic HNSCC, including non-HPV associated disease with CPS 1-9 and oral cavity primaries, may derive benefits from the addition of chemotherapy to anti-PD1 therapy.

Radical management of the N3 neck for head and neck squamous cell cancer (HNSCC) remains unclear. We aimed to investigate the use of primary surgery including neck dissection versus primary radiotherapy followed by imaging.

We retrospectively reviewed consecutive patients with HNSCC and N3 nodal disease, excluding nasopharyngeal primaries. Patients had either surgical management of the primary and neck dissection followed by postoperative radiotherapy or primary radiotherapy followed by surveillance if complete response was found on post-treatment imaging. Patients were imaged at a mean of 16 weeks post radiotherapy. Patients identified with presence of resectable residual disease on imaging were treated with neck dissection.

Between July 2012 and February 2023, 53 patients with T0-4N3M0 HNSCC were treated radically. The median (range) follow-up was 25.5 (3-146) months, with an opportunity for follow-up of 64 (19-147) months. Twenty-two patients had primary surgical management and 31 had primary radiotherapy. Two-year overall survival was 64% in patients treated with primary surgery, 55% in patients treated with primary radiotherapy, 87% in patients with complete response after radiotherapy, and 92% in complete responders who were p16 positive. Response assessment was done with positron emission tomography-computed tomography (PET-CT) in 77% of patients and predicted subsequent disease-free survival better than computed tomography (CT). p16-positive patients were more likely to achieve complete response (63% vs 25%), but extracapsular spread was not predictive of response.

Surveillance for patients with complete response on postradiotherapy PET-CT is a reasonable approach, especially for p16-positive patients, sparing them the morbidity of neck dissection. Patients with p16-negative disease are less likely to achieve a complete response and may be better managed with primary neck dissection.

Neoadjuvant immunotherapy in human papillomavirus (HPV)-negative locoregionally advanced (LA) head and neck squamous cell carcinoma (HNSCC) appears promising, yet its role in nonsurgical treatment for head and neck cancer remains undefined. Neoadjuvant nivolumab plus chemotherapy followed by response-stratified de-escalated chemoradiation therapy (CRT) in HPV-negative LA stage IVa/b HNSCC may improve treatment efficacy while reducing treatment-related toxic effects.

To determine the deep response rate and tolerability of neoadjuvant nivolumab plus chemotherapy followed by response-stratified CRT in nonvirally mediated stage IVa/b HNSCC.

In this investigator-initiated phase 2 nonrandomized clinical trial conducted at a single academic center, patients with stage IVa/b (American Joint Committee on Cancer Tumor Classification, 8th edition) HPV-negative LA HNSCC were enrolled between 2019 and 2022. Data were analyzed from February 2023 to January 2024.

The DEPEND trial evaluated neoadjuvant nivolumab plus carboplatin and paclitaxel, followed by response-stratified CRT. Patients with 50% or greater reduction per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 received de-escalated CRT to 66 Gy with elimination of elective nodal volumes; patients with less than 50% reduction received standard CRT to 70 to 75 Gy. Adjuvant nivolumab was administered for 9 cycles.

The primary end point was deep response rate (DRR; 50% or greater shrinkage per RECIST version 1.1) following neoadjuvant nivolumab plus chemotherapy. Secondary end points included progression-free survival (PFS), overall survival (OS), locoregional control, and distant control. Exploratory end points included acute toxic effects in patients who received response-adapted de-escalated CRT.

Of 36 included patients, 28 (78%) were male, and the median (range) age was 58.9 (27-77) years. All patients started treatment and were available for analysis. The median (range) follow-up was 20 (13-40) months. The primary end point was met, with a DRR following neoadjuvant nivolumab/chemotherapy of 53% (95% CI, 35-70). The objective response rate was 86% (95% CI, 71-95). A total of 19 received de-escalated CRT and 16 received standard CRT. PFS and OS at 2 years were 66% (95% CI, 34-76) and 73% (95% CI, 52-86), respectively. The most common treatment-emergent adverse events for de-escalated and standard CRT were mucositis (14 of 19 [74%] and 15 of 16 [94%], respectively), radiation dermatitis (13 of 19 [68%] and 14 of 16 [88%], respectively), and dry mouth (7 of 19 [37%] and 10 of 16 [63%], respectively).

In this phase 2 nonrandomized clinical trial, neoadjuvant nivolumab/chemotherapy led to deep responses in 53% of patients with HPV-negative LA stage IVa/b HNSCC, and response-adapted de-escalated CRT led to favorable survival with lower acute toxic effects among deep responders.

ClinicalTrials.gov Identifier: NCT03944915.

While the oncogenic potential of HPV has been well-established in other disease sites (e.g. cervix, vulva, anus), it is increasingly evident that a significant proportion of oropharyngeal cancer cases are related to the virus. Although considerable progress has been made in the understanding of this disease with respect to its underlying biology and clinical behavior, numerous questions persist. From a therapeutic standpoint, HPV-positive oropharyngeal cancer has been shown to be more radiosensitive than HPV-negative disease. However, how HPV mediates this radiosensitivity is relatively uncertain.

Given that it has been firmly established that patients with HPV-positive oropharyngeal cancer have a significantly improved prognosis as a result of their exquisite response to radiation and can be treated with less-than-standard doses, logical questions pertain to how HPV confers this benefit to infected patients. Although the exact reason for the improved radiosensitivity of HPV-positive oropharyngeal carcinoma is unclear, multiple theories have been proposed. Indeed, it is likely that no single explanation exists for the increased radiosensitivity, and instead, HPV likely exerts its influence through a cascade of activated pathways at both the cellular level and tumor microenvironment. As will be discussed in this review, the proposed mechanisms for HPV-induced radiation response have generally centered on the disruption of such cellular pathways as DNA repair, cell cycle checkpoints, metabolic-induced stress, immunology, and cancer stem cells. Given that HPV-positive oropharyngeal cancer is increasingly recognized as a public health problem, the search to better understand its unique biological radiosensitivity has important societal and treatment-related implications.

To describe utilization and outcomes of submandibular gland flap (SGF) reconstruction after transoral robotic surgery (TORS) for oropharyngeal squamous cell carcinoma (OPSCC).

A multi-institutional retrospective case series of patients who underwent TORS for OPSCC followed by SGF reconstruction with harvest via transcervical approach from 1/1/2016 to 4/1/2023.

In total, 14 patients underwent SGF reconstruction after TORS for OPSCC. All patients had HPV-positive disease, predominantly in early local (N = 10 with pT1/pT2 disease, 71%) and regional stages (N = 11 with pN0/pN1 disease, 79%). Most patients received adjuvant radiation treatment (N = 9, 64%). Median hospital LOS after surgery was 4 days (IQR 2 days) with median functional oral intake scale (FOIS) score of 5 (IQR 0.8) at 1-3 weeks after surgery.

SGF reconstruction is a useful technique for closure of appropriately selected TORS defects requiring reconstruction beyond healing by secondary intention and mobilization of adjacent tissue but not large enough to warrant free flap reconstruction.