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• Re-irradiation (re-RT) for recurrent head and neck cancer (rHNC) is clinically challenging. • Methods to better select patients for re-RT is of paramount importance. • Proton therapy re-RT of rHNC affords good local control and an acceptable toxicity profile. • Distant failures are common, and are associated with TP53, NOTCH4, and ARID1B somatic mutations. • Validation may provide rationale for inclusion of genomic alterations in the decision process. Re-irradiation (re-RT) for recurrent head and neck cancer (rHNC) is challenging. We describe clinical outcomes and toxicity of proton therapy (PT) for recurrent HNC, and report genomic alterations associated with patterns of failure. We performed a retrospective analysis of rHNC patients treated with PT. Outcomes were estimated using the Kaplan-Meier method. Univariate (UVA) and multivariate analyses (MVA) were performed to assess multiple patient factors. Next-generation sequencing and genomic analyses were performed on available samples. Eighty-nine patients treated with PBS-PT for rHNC with a median follow-up of 12 mo (0–71 mo) were included. The 1- and 2-y local control (LC) rates were 80.8 % (95 % CI: 70.8–90.8) and 66.2 % (95 % CI: 50.7–81.7), and 1- and 2-y distant metastasis-free survival (DMFS) were 41.0 % (95 % CI: 30.0–52.0) and 26.3 % (95 % CI: 15.7–36.9). The median overall survival (OS) was 13 mo (95 % CI: 9.3–16.7). On UVA and MVA, smaller gross tumor volume (GTV) was associated with improved OS (HR 1.002, P = 0.004), DMFS (HR 1.002, P = 0.004), and PFS (HR 1.002, P = 0.014). There were 35 late Gr3 + toxicity events (30.3 %). Patients with higher candidate gene-specific mutation burden (genes with [OR] > 2, P < 0.05) had inferior PFS. TP53 , NOTCH4, and ARID1B mutations were associated with inferior DMFS (OR > 2, P < 0.05). PBS-PT is effective at achieving LC for rHNC with favorable toxicity. Distant metastases are common, and associated with TP53 , NOTCH4 , and ARID1B mutations. Inclusion of genomic alterations in the clinical decision process may be warranted. [ABSTRACT FROM AUTHOR]

• We developed a risk prediction model for cisplatin-induced acute kidney injury. • Three-weekly high-dose cisplatin administration was counted as a risk factor. • The primary site, serum albumin level, and creatinine clearance were also included. • Patients undergoing postoperative chemoradiotherapy prefer a weekly regimen. Acute kidney injury (AKI) represents a major toxicity associated with cisplatin. We developed a risk prediction model for cisplatin-induced AKI in patients with postoperative high-risk head and neck cancer who received chemoradiotherapy during a randomized phase II/III trial, JCOG1008. Two hundred and fifty-one patients received radiotherapy with weekly cisplatin at 40 mg/m2 (weekly arm) or 3-weekly cisplatin at 100 mg/m2 (3-weekly arm). AKI was defined using the AKI Network classification/staging system as increased serum creatinine of ≥0.3 mg/dL or a ≥1.5-fold increase from baseline 30 days after completing chemoradiotherapy. The Akaike information criterion was used to explore the optimal model by combining explanatory variables at registration. Among the 251 patients (210 men and 41 women (median age; 62 years)), 94 (37.5 %) developed cisplatin-induced AKI. The optimal cisplatin-induced AKI risk prediction model comprised four factors, including a primary site of hypopharynx/larynx (vs. oral cavity/oropharynx), 3-weekly arm (vs. weekly arm), serum albumin of ≤3.5 g/dL (vs. >3.5 g/dL) and creatinine clearance (CCr) of <90 mL/min (vs. ≥90 mL/min). The incidence of cisplatin-induced AKI rose with cumulative count of the four factors. When the cumulative count was ≥2, the positive predictive value for cisplatin-induced AKI was 50.3 %. We developed a risk prediction model for cisplatin-induced AKI in patients with head and neck cancer who received postoperative chemoradiotherapy using primary site, cisplatin administration method, serum albumin, and CCr. Patients with risk factors unrelated to the cisplatin administration method should adopt a weekly cisplatin regimen. [ABSTRACT FROM AUTHOR]

• Neck lymph nodes were imaged intraoperatively by ultra-fast confocal microscopy (UFCM) • UFCM is a cell-scale imaging technique without laborious processing of the specimen. • The concordance rate between two pathologists was 95.5% on UFCM images. • The accuracy of UFCM was 95.5% (95%CI: 91.7%-97.9%) We evaluated ultra-fast confocal fluorescence microscopy (UFCM) as a new modality for pathology practice in head and neck cancer (HNC). This was assessed through an ex vivo study to estimate the accuracy, specificity, and sensitivity of interpretation of UFCM images by pathologists for the detection of metastatic lymph nodes in HNC patients undergoing sentinel lymph node biopsy or selective or complete neck dissection. 44 patients with 32 cN0 and 12 cN+ HNC were included. The macroscopically non-invaded fresh bisected lymph nodes were stained with acridine orange and imaged with Histolog® Scanner (UFCM). Two pathologists interpreted independently the UFCM images postoperatively and gave a consensus diagnosis in case of disagreement. The gold standard was the diagnosis based on hematoxylin-eosin-saffron (HES) sections. 201 lymph nodes were imaged by UFCM. Thirty nodes (15 %) were invaded on final histology: 3 with micrometastases and 27 with macrometastases. The concordance rate between the pathologists on the UFCM images was 192/201 = 95.5 % and the Cohen kappa coefficient was 0.80. The accuracy of UFCM was 95.5 % (95 %CI: 91.7 %-97.9 %) with a high specificity at 98.8 % (95 %CI: 95.8 %-99.9 %) but an insufficient sensitivity at 76.7 % (95 %CI: 57.7 %-90.1 %). The three micrometastases and four of the 27 macrometastases were missed on UFCM images. The UFCM is providing promising detection values with a very good specificity and moderate sensitivity carrying room for improvement. [ABSTRACT FROM AUTHOR]

• We present a prospective study evaluating the impact of tobacco on severe acute toxicities during radiotherapy for head and neck cancers. • For secondary endpoints, association was found in the multivariate analysis between grade 3–4 acute toxicities and concurrent chemotherapy, 2.12 Gy fractionation dose, V30 oral cavity, BMI and alcohol exposure. • Current smokers during radiotherapy showed a tendency to present more grade 3–4 acute toxicities, but the association was not statistically significant. The association between smoking and acute radiation toxicities of head and neck cancer (HNC) is currently unproven. The aim of the study was to compare the occurrence of acute severe toxicity between active and non-active smokers treated for HNC by radiotherapy. A prospective monocentric cohort study included patients treated by (chemo)radiotherapy for HNC from January 2021 to January 2023. Smoking status was recorded. Patients underwent a medical exam weekly during the radiotherapy to report acute toxicities according to the Common Terminology Criteria for Adverse Effects system version 5.0. Primary endpoint was the occurrence of at least one grade ≥ 3 acute toxicity among mucositis, dysphagia and dermatitis. Among the 102 patients included, 27.4 % were active smokers, 58.8 % were former smokers and 13.7 % had never smoked. Regarding toxicity, 23.5 % (n = 24) patients experienced severe mucositis, 37.2 % (n = 38) severe dysphagia, 13.7 % (n = 14) severe dermatitis and 54.9 % (n = 56) experienced at least one of them. Occurrence of severe acute toxicity was not statistically associated with smoking during radiotherapy (64.3 % among active smokers versus 51.3 % among non-active smokers; p = 0.24). On multivariate analysis, concurrent chemotherapy (87.5 % vs 65.2 %; OR = 5.04 [1.64–15.52]; p = 0.004) and 2.12 Gy versus 2 Gy fractionation schedule (64.3 % vs 41.3 %; OR = 2.53 [1.09–5.90]; p = 0.03) were significantly associated with severe acute toxicity. This study did not find an association between smoking during radiotherapy for HNC and occurrence of severe acute toxicities. [ABSTRACT FROM AUTHOR]

• First meta-analysis investigating the efficacy and safety of VEGF/VEGFR inhibitors plus PD-1/PD-L1 inhibitors in R/M HNSCC. • Combining VEGF/VEGFR inhibitors with PD-1/PD-L1 inhibitors are effective and safe in R/M HNSCC cases. • The TKI group exhibited an improved overall response rate and disease control rate, compared to the antibody group. • Urgent high-quality research is needed to optimize the efficacy of this combination strategy and minimize potential toxicity. Exploration into the use of vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) inhibitors alongside programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors has been undertaken for treating recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC). We conducted a meta -analysis to provide a more precise assessment of the efficacy and safety of this integrated approach in managing R/M HNSCC. A systematic exploration encompassing PubMed, Embase, the Cochrane Library, and Web of Science databases was undertaken to figure out relevant studies. It was attempted to analyze critical endpoints, such as overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs) utilizing a random-effects model. Eleven studies, encompassing 413 patients, were analyzed. The combined data revealed an ORR of 41 % (95 % CI: 34–49 %), a DCR of 67 % (95 % CI: 51–83 %), a median PFS of 5.87 months (95 % CI: 3.90–7.85), and a median OS of 9.63 months (95 % CI: 6.78–12.49). Furthermore, the rates for 1-year PFS and OS were 45 % (95 % CI: 27–64 %) and 65 % (95 % CI: 49–81 %), respectively. The occurrence of grade 3 or higher adverse events related to the drugs was 20 % (95 % CI: 10–30 %). Subgroup analysis within the tyrosine kinase inhibitor (TKI) group revealed an ORR of 47 % (95 % CI: 39 %–55 %) and a DCR of 67 % (95 % CI: 46 %–88 %). In summary, combining VEGF/VEGFR inhibitors with PD-1/PD-L1 inhibitors shows considerable effectiveness with manageable side effects in cases with R/M HNSCC. Registered with the International Prospective Register of Systematic Reviews, identifier CRD42023486345. [ABSTRACT FROM AUTHOR]

• Mainly functional HRQOL domains are affected in survivors of head and neck cancer. • Psychological HRQOL domains are affected less, except following major surgery. • The most significant negative predictor for HRQOL is bone resection. • Functional aspects of HRQOL frequently remain affected over time. • Psychological disability is usually present after treatment but resolves over time. Long-term health-related quality of life (HRQOL) is frequently affected in head and neck cancer (HNC) survivors. Due to the shortage of studies investigating long-term patient-reported outcomes, we investigated long-term HRQOL using the novel FACE-Q HNC Module. A retrospective cross-sectional single-center study was performed, including all patients who underwent curative treatment for HNC between 2006 and 2013. All eligible patients (n = 863) were invited to participate of whom 540 completed the questionnaires. Additionally, a prospective longitudinal cohort of 43 HNC patients treated between 2020 and 2022 was included who preoperatively filled in the FACE-Q, and at three, six, and 12 months postoperatively. HRQOL domain scores were analyzed to visualize group characteristics by tumor site and type of surgical resection. Both surgical and non-surgical HNC treatments predominantly affected long-term functional HRQOL domains (eating, salivation, speech, and swallowing), eating distress, and speaking distress, with distinct profiles depending on tumor site and type of treatment. In contrast, few long-term intergroup differences between HNC patients were observed for appearance, smiling, drooling distress, and smiling distress. Longitudinal data showed significant deterioration across all functional HRQOL domains in the short-term following treatment. Patients predominantly reported long-lasting negative treatment effects at 12 months follow-up for functional domains, whereas psychological domains showed near-complete recovery at group level. At long-term, various function-related and psychosocial HRQOL domains still are affected in head and neck cancer survivors. The results may serve to better inform patients with regard to specific treatments and highlight HRQOL domains which may potentially be optimized. [ABSTRACT FROM AUTHOR]

• PD-L1 expression in HNSCC patients is significantly correlated with improved overall survival when treated with PD-1 or PD-L1 inhibitors. • Patients with higher levels of PD-L1 expression demonstrate an even more pronounced survival benefit from PD-1/PD-L1 inhibitor therapies. • The study reveals no clear improvement in progression-free survival based on PD-L1 expression among patients undergoing immunotherapy. • Variability in response to PD-1/PD-L1 inhibitors across studies suggests potential influences of patient characteristics and previous treatments. This systematic review and meta -analysis investigates the predictive and prognostic role of PD-L1 expression in treating head and neck squamous cell carcinoma (HNSCC). Recognizing the importance of PD-L1 in patient response to treatment, the main objective was to assess its impact on overall survival and progression-free survival in HNSCC patients. A thorough search of databases such as PubMed, Scopus, and Web of Science from 2010 to 2022, along with relevant articles and references, yielded 120 studies. Of these, 7 met the criteria focusing on HNSCC patients, PD-L1 expression evaluation, and treatment with PD-1 or PD-L1 inhibitors. Data extraction followed PRISMA guidelines and involved independent review and consensus for discrepancies. The primary outcomes analyzed were overall survival and progression-free survival in relation to PD-L1 expression levels in patients undergoing immunotherapy. The seven randomized controlled trials selected had a total of 4,477 participants. Results showed that patients with positive PD-L1 expression experienced improved overall survival when treated with PD-1 or PD-L1 inhibitors, particularly those with high PD-L1 expression. However, PD-L1 expression did not significantly affect progression-free survival. These findings suggest that PD-L1 expression can be a predictive marker for better overall survival in HNSCC patients treated with immunotherapy. However, its influence on progression-free survival remains unclear, indicating the need for further research. [ABSTRACT FROM AUTHOR]

• Commercial multi-cancer early detection (MCED) tests can detect head and neck cancers. • False-positive MCED tests are possible. • MCED cancer tissue of origin indicators may not be accurate. • Guidelines for positive head and neck MCED tests are needed. Blood-based multi-cancer early detection (MCED) tests are now commercially available. However, there are currently no consensus guidelines available for head and neck cancer (HNC) providers to direct work up or surveillance for patients with a positive MCED test. We seek to describe cases of patients with positive MCED tests suggesting HNC and provide insights for their evaluation. Retrospective chart review of patients referred to Otolaryngology with an MCED result suggesting HNC. Patients enrolled in prospective MCED clinical trials were excluded. Cancer diagnoses were confirmed via frozen-section pathology. Five patients were included (mean age: 69.2 years, range 50–87; 4 male) with MCED-identified-high-risk for HNC or lymphoma. Only patient was symptomatic. After physical exam and follow-up head and neck imaging, circulating tumor HPV DNA testing, two patients were diagnosed with p16 + oropharyngeal squamous cell carcinomas and underwent appropriate therapy. A third patient had no evidence of head and neck cancer but was diagnosed with sarcoma of the thigh. The remaining two patients had no evidence of malignancy after in-depth workup. In this retrospective study, 2 of 5 patients referred to Otolaryngology with a positive MCED result were diagnosed with HPV + oropharyngeal squamous cell carcinoma. We recommend that positive HNC MCED work up include thorough head and neck examination with flexible laryngoscopy and focused CT or MRI imaging. Given the potential for inaccurate MCED tissue of origin classification, PET/CT may be useful in specific situations. For a patient with no cancer identified, development of clear guidelines is warranted. [ABSTRACT FROM AUTHOR]

• This is the first systematic review and meta-analysis to assess CBI use in RM-NPC. • EBV-specific CTL and DC second/subsequent line monotherapy have good safety profiles. • CBI combination therapy/first-line monotherapy may be evaluated with more studies. Recurrent/Metastatic Nasopharyngeal Carcinoma (RM-NPC) remains difficult to treat and contributes to considerable mortality. The first-line treatment for RM-NPC is Gemcitabine and Cisplatin and second-line treatment options differ. The endemic variant of NPC is associated with Epstein-Barr Virus (EBV). Therefore, Cell-based Immunotherapy (CBI) targeting EBV-specific RM-NPC may be effective. We systematically searched PubMed, Embase and the Cochrane Library for randomised or observational studies investigating the efficacy and safety of CBI in the treatment of RM-NPC. We performed all meta-analyses using the random-effects model. Studies were further stratified by endemicity, nature of disease and drug type to investigate for potential between-study heterogeneity and additional pre-specified tests were employed to assess for publication bias. We screened 1,671 studies and included 13 studies with 403 participants in the systematic review, of which nine studies were eligible for meta-analysis. The use of CBI monotherapy as second or subsequent line treatment for EBV-positive RM-NPC revealed an ORR of 10 % (95 %CI = 3 %–29 %), median PFS of 2.37 months (95 %CI = 1.23–3.51) and median OS of 10.16 months (95 %CI = 0.67–19.65). For EBV-specific Cytotoxic T-Lymphocyte monotherapy, the pooled PD rate was 54 % (95 %CI = 9 %–93 %), SD rate was 22 % (95 %CI = 2 %–75 %) and incidence rate of any grade adverse events was 45 %. For Dendritic Cell monotherapy, a PD rate of 80 % (95 % CI = 29 %–98 %), SD rate of 11 % (95 % CI = 0 %–82 %) and incidence rate of any grade adverse events of 29 % was achieved. CBI monotherapy demonstrates some activity in pre-treated RM-NPC. More trials are needed to better understand how to integrate CBI into RM-NPC care. [ABSTRACT FROM AUTHOR]

• RICTOR amplification was most frequently observed in patients with OMM. • MAPK and PI3K pathways were activated by mutations in RICTOR, KIT, and NF1 in OMM. • OMM and NMM had different mutational landscapes despite a common head and neck mucosal origin. • Whether recurrent mutations play pathogenic roles in OMM requires further study. • This analysis offers insights about future personalized therapeutics for OMM. Oral mucosal melanoma (OMM) is a rare but aggressive melanoma subtype. Due to its rarity, the genomic landscape of OMM remains unknown despite a relatively thorough understanding of the genetic profile of cutaneous melanoma (CM). In this study, we analyzed the genomic mutational profiles of Japanese patients with OMM and compared them with those of patients with nose/sinuses mucosal melanoma (NMM) and CM to identify potential therapeutic targets. We extracted clinical and genomic information of patients with OMM (n = 15), NMM (n = 63), and CM (n = 413) who underwent comprehensive genomic profiling tests under the National Health Insurance between June 2019 and November 2023 from the Center for Cancer Genomics and Therapeutics database. The most frequent genomic alteration identified in OMM was RICTOR (40%) followed by CDK 4 (33.3%), MDM2 (33.3%), KDR (30%), KIT (26.7%), and NF1 (26.7%). CDK4 and MDM2 were co-amplified. Gene alterations in MYC and NRAS were the highest in patients with NMM, followed by those with CM, and no MYC alteration was observed in patients with OMM. BRAF V600 mutation, which is frequently observed in patients with CM (23.2%) were only present in 1.6% of patients with NMM and none in patients with OMM. This study clarified the genetic differences between OMM and NMM, and the first to report the frequent occurrence of RICTOR amplification in OMM. This analysis offers insights into the development of personalized therapeutics for OMM. [ABSTRACT FROM AUTHOR]

• Oral tumors induced enhanced antigen specific T cell responses compared to the flank. • cDC1s in oral TDLNs are highly functional and elicit a robust T cell response. • Anti-PD1 treatment induces rejection of oral but not flank tumors. Understanding head and neck tissue specific immune responses is important for elucidating immunotherapy resistance mechanisms to head and neck squamous cell carcinoma (HNSCC). In this study, we aimed to investigate HNSCC-specific immune response differences between oral and subcutaneous flank tumor transplantation in preclinical models. The MOC1 syngeneic mouse oral carcinoma cell line or versions expressing either the H2Kb-restricted SIINFEKL peptide from ovalbumin (MOC1OVA) or ZsGreen (MOC1ZsGreen) were inoculated into mouse oral mucosa (buccal space) or subcutaneous flank and compared for immune cell kinetics in tumors and tumor-draining lymph nodes (TDLNs) and for anti-PD1 response. Compared to subcutaneous flank tumors, orthotopic oral MOC1OVA induced a higher number of OVA-specific T cells, PD1 + or CD69 + activated OVA-specific T cells in both primary tumors and TDLNs. Tumors were also larger in the flank site and CD8 depletion eliminated the difference in tumor weight between the two sites. Oral versus flank SIINFEKL peptide vaccination showed enhanced TDLN lymphocyte response in the former site. Notably, cDC1 from oral TDLN showed enhanced antigen uptake and co-stimulatory marker expression, resulting in elicitation of an increased antigen specific T cell response and increased activated T cells. Parental MOC1 in the oral site showed increased endogenous antigen-reactive T cells in TDLNs and anti-PD1 blockade rejected oral MOC1 tumors but not subcutaneous flank MOC1. Collectively, we find distinct immune responses between orthotopic oral and heterotopic subcutaneous models, including priming by cDC1 in TDLN, revealing important implications for head and neck cancer preclinical studies. [ABSTRACT FROM AUTHOR]

• Many head/neck squamous cell cancer patients develop recurrence or second primary. • Re-irradiation is a curative treatment option for these patients. • However, it is associated with significant risk of toxicity. • Pulsed Reduced Dose Rate radiation may reduce re-irradiation toxicity. Pulsed reduced dose rate (PRDR) radiation (RT) is a re-irradiation (Re-RT) technique that potentially overcomes dose/volume constraints in the setting of previous RT. There is minimal data for its use for recurrent or secondary primary head and neck squamous cell carcinoma (HNSCC). In this study, we report preliminary data from our institution of a consecutive cohort of HNSCC patients who received PRDR Re-RT. Nine patients received PRDR Re-RT from August 2020 to January 2023 and had analyzable data. Intensity modulated RT was used for treatment delivery and a wait time between 20 cGy arc/helical deliveries was used to achieve the effective low dose rate. Data collected included patient demographic information, prior interventions, diagnosis, radiation therapy dose and fractionation, progression free survival, overall survival, and toxicity rates. The median time to PRDR-RT from completion of initial RT was 13 months (range, 6–50 months). All but one patient underwent salvage surgery prior to PRDR-RT. The median follow-up after Re-RT was 7 months. The median OS from PRDR-RT was 7 months (range, 1–32 months). Median PFS was 7 months (range, 1–32 months). One patient (11.1 %) had acute grade 3 toxicity, and two patients (22.2 %) had late grade 3 toxicities. There were no grade 4+ toxicities. PRDR Re-RT is a feasible treatment strategy for patients with recurrent or second primary HNSCC. Initial findings from this retrospective review suggest reasonable survival outcomes and potentially improved toxicity; prospective data is needed to establish the safety and efficacy of this technique. [ABSTRACT FROM AUTHOR]

Intracranial metastatic disease is rarely found in head and neck cancer (HNC), in particular, cavernous sinus (CS) involvement is difficult to recognize, because of its rarity, not specific symptoms associated and challenging imaging features. We report our experience in 4 cases, reviewing also the English literature. We analysed data from 21 patients showing that CS metastasis is a dramatic event, with rapid onset, usually starting with neurological manifestations (ophthalmoplegia, headache and trigeminal dysesthesia) and almost unavoidable outcome (DOD in 18/21 patients). Furthermore, we assessed that the diagnostic confirmation could be difficult to perform because of the need for multiple exams and time consuming procedures. Unfortunately, usual antineoplastic therapies seem to be not effective in prolonging survival, also because patients are already weakened by primary tumour treatments. The only option that seems useful in improving outcomes is immunotherapy. [ABSTRACT FROM AUTHOR]

• Synchronous de novo metastatic Head and Neck Squamous Cell Carcinoma (HNSCC) patients, constituting 10% of all recurrent/metastatic cases, necessitating a tailored and multidisciplinary therapeutic approach. • The impact of on-site primary tumors on patients' prognosis and Quality of Life (QoL) highlights the need for improved treatment strategies. • Integration of locoregional radiotherapy may enhance primary tumour control and enhance systemic efficacy of immunotherapy treatment. Patients selection is crucial in order to avoid unnecessary toxicity and maximizing the potential benefit of such an aggressive treatment. De novo metastatic Head and Neck Squamous Cell Carcinoma (HNSCC) constitutes 10% of recurrent/metastatic (RM) cases. Radiotherapy (RT) has a crucial role in the treatment of locally advanced HNSCC, however its application on RM diseases is still limited. The advent of immune checkpoint inhibitors (ICIs) improves the survival of RM HNSCC, however median overall survival is still limited. Integration of locoregional RT with ICIs in de novo metastatic HNSCC represents a promising treatment option. This perspective aims to explore the role of the combination of locoregional and systemic treatment in improving outcomes for synchronous de novo metastatic HNSCC patients and highlights the principal crucial point in decision making. [ABSTRACT FROM AUTHOR]

• Development of machine-learning algorithm for objective classification of TIL with QuPath. • Standardized methodology for TIL assessment considering tumor microenvironment. • Independent prognostic value of TIL in HPV positive and negative HNSCC. The prognostic and predictive significance of pathologist-read tumor infiltrating lymphocytes (TILs) in head and neck cancers have been demonstrated through multiple studies over the years. TILs have not been broadly adopted clinically, perhaps due to substantial inter-observer variability. In this study, we developed a machine-based algorithm for TIL evaluation in head and neck cancers and validated its prognostic value in independent cohorts. A network classifier called NN3-17 was trained to identify and calculate tumor cells, lymphocytes, fibroblasts and "other" cells on hematoxylin-eosin stained sections using the QuPath software. These measurements were used to construct three predefined TIL variables. A retrospective collection of 154 head and neck squamous cell cancer cases was used as the discovery set to identify optimal association of TIL variables and survival. Two independent cohorts of 234 cases were used for validation. We found that electronic TIL variables were associated with favorable prognosis in both the HPV-positive and -negative cases. After adjusting for clinicopathologic factors, Cox regression analysis demonstrated that electronic total TILs% (p = 0.025) in the HPV-positive and electronic stromal TILs% (p < 0.001) in the HPV-negative population were independent markers of disease specific outcomes (disease free survival). Neural network TIL variables demonstrated independent prognostic value in validation cohorts of HPV-positive and HPV-negative head and neck cancers. These objective variables can be calculated by an open-source software and could be considered for testing in a prospective setting to assess potential clinical implications. [ABSTRACT FROM AUTHOR]

• In a database comprising 8,134 patients, the 5-year overall survival rate for rare head and neck cancers was 71% (95% CI: 0.69–0.73), while the 5-year event-free survival rate was comparatively lower at 46% (95% CI: 0.44–0.48). • Among the ten most common histologies, acinar cell carcinoma demonstrated a more favourable prognosis. Conversely, mucous melanoma exhibited the poorest prognosis, with a median survival of 43 months. • Furthermore, patients diagnosed with salivary gland cancers exhibited superior 5-year overall survival rates and a lower incidence of recurrences compared to those with rare cancers in the nasal fossae/sinus or laryngeal/hypopharyngeal regions. Rare cancers constitute less than 10% of head and neck cancers and lack sufficient evidence for standardized care. The French Rare Head and Neck Cancer Expert Network (REFCOR) as established a national database to collect data on these rare cancers. This study aims to describe patient and tumour characteristics in this database. Prospective data collection was conducted across multiple centers. Survival analyses were performed using Kaplan Meier method and Log Rank test. Odds ratios were used for comparing proportions. A total of 7208 patients were included over a period of 10 years. The most frequent histologies were: Not Otherwise Specified (NOS) adenocarcinoma 13 %, adenoid cystic carcinoma 12 %, squamous cell carcinoma of rare locations 10 %, mucoepidermoid carcinoma 9 %, intestinal-type adenocarcinoma (8 %). Tumours were located in sinonasal area (38 %); salivary glands (32 %); oral cavity / oropharynx / nasopharynx (16 %); larynx / hypopharynx (3 %); ears (1 %); others (3 %). Tumours were predominantly classified as T4 (23 %), N0 (54 %), and M0 (62 %). Primary treatment approach involved tumour resection (78 %) and / or radiotherapy (63 %). Patients with salivary gland cancers exhibited better 5-year overall survival (OS) rates (p < 0.05), and lower recurrence rates compared to patients with sinonasal, laryngeal/ hypopharyngeal cancers. No significant differences were observed in the other comparisons. Acinar cell carcinoma demonstrated the best OS while mucous melanoma had the poorest prognosis. Melanoma, carcinoma NOS, and sinonasal undifferenciated carcinoma still have poor prognoses. Efforts are being made, including training and guidelines, to expand network coverage (REFCOR, EURACAN), improve data collection and contribute to personalized therapies. [ABSTRACT FROM AUTHOR]

• This study assesses survival of patients with HNSCC, stratified by time of day of immunotherapy infusions. • Immunotherapy early in the day showed improved response rates in HNSCC, consistent with data in other malignancies. • These results offer insights for optimizing scheduling times to improve treatment response in HNSCC patients. The adaptive immune response is physiologically regulated by the circadian rhythm. Data in lung and melanoma malignancies suggests immunotherapy infusions earlier in the day may be associated with improved response; however, the optimal time of administration for patients with head and neck squamous cell carcinoma (HNSCC) is not known. We aimed to evaluate the association of immunotherapy infusion time with overall survival (OS) and progression free survival (PFS) in patients with HNSCC in an Institutional Review Board-approved, retrospective cohort study. 113 patients met study inclusion criteria and 98 patients were included in a propensity score-matched cohort. In the full unmatched cohort (N = 113), each additional 20 % of infusions received after 1500 h conferred an OS hazard ratio (HR) of 1.35 (95 % C.I.1.2–1.6; p-value = 0.0003) and a PFS HR of 1.34 (95 % C.I.1.2–1.6; p-value < 0.0001). A propensity score-matched analysis of patients who did or did not receive ≥20 % of infusions after 1500 h showed that those who were administered ≥20 % of infusions after 1500 h trended towards a shorter OS (HR = 1.35; p-value = 0.26) and a shorter PFS (HR = 1.57, 95 % C.I. 1.02–2.42, p-value = 0.04). Each additional 20 % of infusions received after 1500 h remained robust in the matched cohort multivariable analysis and was associated with shorter OS (adjusted HR = 1.4 (95 % C.I.1.2–1.8), p-value < 0.001). Patients with advanced HNSCC who received more of their infusions in the afternoon were associated with shorter OS and PFS and scheduling immunotherapy infusions earlier in the day may be warranted. [ABSTRACT FROM AUTHOR]

• High alternative MYB promoter usage is found in adenoid cystic carcinoma metastases. • MYB alternative promoter high tumors showed similar gene expression profiles. • High MYB alternative promoter cases had increased drug resistance gene expression. • Canonical MYB target genes were upregulated in MYB alternative promoter high cases. • P53 pathway genes were downregulated in MYB alternative promoter high tumors. Adenoid cystic carcinoma (ACC) is a head and neck cancer with a poor long-term prognosis that shows frequent local recurrences and distant metastases. The tumors are characterized by MYB oncogene activation and are notoriously unresponsive to systemic therapies. The biological underpinnings behind therapy resistance of disseminated ACC are largely unknown. Here, we have studied the molecular and clinical significance of MYB alternative promoter (TSS2) usage in ACC metastases. MYB TSS2 activity was investigated in primary tumors and metastases from 26 ACC patients using RNA-sequencing and quantitative real-time PCR analysis. Differences in global gene expression between MYB TSS2 high and low cases were studied, and pathway analyses were performed. MYB TSS2 activity was significantly higher in ACC metastases than in primary tumors (median activity 15.1 vs 3.0, P = 0.0003). MYB TSS2 high ACC metastases showed a specific gene expression signature, including increased expression of multi-drug resistance genes and canonical MYB target genes, and suppression of the p53 and NOTCH pathways. Collectively, our findings indicate that elevated MYB TSS2 activity is associated with metastases, potential drug resistance, and augmented MYB-driven gene expression in ACC. Our study advocates the need for new therapies that specifically target MYB and drug resistance mechanisms in disseminated ACC. [ABSTRACT FROM AUTHOR]

• QUAD shot regimen using VMAT provides appropriate palliative effect. • QUAD shot regimen toxicities were minimal. • Higher-number QUAD shot cycle administration yields better treatment outcomes. We aimed to evaluate the outcomes of the Radiation Therapy Oncology Group 8502 "QUAD shot" regimen using volumetric modulated arc therapy (VMAT) for incurable head and neck cancer (HNC). We included 105 patients with HNC in the study, undergoing at least one QUAD shot regimen cycle. We planned the radiotherapy using VMAT with 6 MV photons. One QUAD shot cycle included 14.8 Gy in 4 fractions with at least 6-hour intervals over 2 consecutive days, repeated every 3–6 weeks up to 3 cycles. We completed 1, 2, and 3 cycles in 11 (10 %), 17 (16 %), and 77 (73 %) patients, respectively. We concurrently performed systemic therapy in 13 (12 %) patients. Tumor response was observed in 92 (88 %) patients and at least one symptom relief in 51 (71 %) of 72 patients. We observed an overall response (tumor response or symptom relief) in 98 (93 %) patients with all patients who completed 3 cycles achieving it. The median overall survival (OS) was 6.8 months. Our multivariate analysis revealed that non-squamous cell carcinoma (p < 0.001), T category of 0–2 (p = 0.021), and 3 QUAD shot cycles (p < 0.001) were independent prognostic factors of better OS. We observed Grade 3 toxicity in 2 (2 %) patients while no ≥ Grade 4 acute or ≥ Grade 3 late toxicity. The QUAD shot regimen using VMAT exerts appropriate palliative effect in patients with incurable HNC. Treatment with higher QUAD shot cycle number would be recommended for better treatment outcomes. [ABSTRACT FROM AUTHOR]

Chemo-radiotherapy and head and neck cancers are common adverse outcomes that impact patients' quality of life. The increasing cancer incidence and healthcare service shortages necessitate new strategies for optimal treatments and follow-ups. Digitalized healthcare, including digital health, telemedicine, and telemonitoring, is promising. HNC requires multidisciplinary team intervention, including speech language pathology telepractice models. Mobile health-based interventions can help cancer survivors increase physical activity and improve rehabilitation services. Effective self-management skills can improve outcomes. Advancements in communication technologies have led to telecommunication-based interventions incorporating swallowing exercises, education, monitoring, feedback, self-management, and communication. Home-based remote rehabilitation is urgent, especially during the COVID-19 pandemic, but the optimal strategy and effectiveness of remote interventions remain unclear. Telehealth interventions represent a possible novel approach to increase access to care across the cancer continuum, strengthen patients' knowledge and self-management, provide continuity of services, and enable remote monitoring of symptoms and response to treatment. Telehealth patients are typically younger, more likely to be English-speaking, and more likely to be female. These disparities widened slightly after the start of the pandemic but were also present prior to the pandemic. [ABSTRACT FROM AUTHOR]

• HPV + OPC with high-risk features is more sensitive to treatment delays. • Starting radiation < 6 weeks after TORS prolongs time to recurrence by 4.3 years. • Treatment package time > 14 weeks curtails recurrence free and disease specific survival. Guidelines recommend treatment package time < 85 days and time from surgery to radiation initiation < 6 weeks in head and neck cancer patients. However, HPV positive primaries treated with TORS and adjuvant radiotherapy traditionally demonstrate favorable outcomes. Single center retrospective chart review of patients diagnosed with HPV positive treatment naïve primary squamous cell carcinoma treated with TORS and postoperative radiation therapy with or without Chemotherapy from 2012 to 2022 with data collection from December 2022-April 2023. Kaplan-Meier survival analysis with log-rank testing assessed the impact of time intervals between diagnosis, TORS, radiation initiation and radiation completion on recurrence free and disease specific survival. Univariate Cox proportional hazards regression analysis was performed to identify factors associated with recurrence free and disease specific survival. Subgroup analysis was done with high risk (positive lymph nodes > 5, >1mm extracapsular extension, positive margins) patients who underwent concurrent Chemotherapy. Of 255 patients (225 males [89 %], average age 58 years, 163 [64 %] high-risk, median follow-up 4.3 years), 22 (8.6 %) had recurrence and 14 died due after disease recurrence. Only radiation length of 5–7 weeks prolonged survival in the entire population. In the high-risk cohort, time from TORS to radiation initiation < 6 weeks improved recurrence free survival, while total package time < 14 weeks was associated with greater recurrence free and disease specific survival. [ABSTRACT FROM AUTHOR]

• 2 patients treated with ICIs achieved major responses at 4 irradiated sites. • Responses lasted for 5–24 months. • Two radiation modalities were used: electron-beam and photon-beam radiotherapies. • These cases highlight the potentially powerful synergistic effect of RT and ICIs. The immuno-modulatory effects of ionizing radiation are well-known and preclinical studies suggest a synergistic effect of combining radiotherapy (RT) and IO. However, data regarding the clinical activity and safety of this approach are limited. We present the cases of two patients with SCCHN primary progressing to PDL1-based IO within a clinical trial (NCT03383094), that received subsequent but not concurrent palliative RT using two different modalities (electron beam and photon beam therapies). Both patients achieved major and durable responses at 4 irradiated sites, with excellent tolerance and no grade ≥ 3 toxicities. Complete response occurred in 3 of the disease areas (all locoregional) and partial response in 1 metastatic lesion. Palliative radiotherapy after progression to IO was safe and demonstrated profound and durable responses in the cases presented. [ABSTRACT FROM AUTHOR]

• Intratumoral CD20+ B cell abundance is prognostic for improved overall survival. • CD20+CD27+ Memory B cells are the predominant B cell subtype. • Intratumoral CD20+ and CD103+ immune cells prognostically stratify HPV + OPC patients. • B cell abundance has the potential to be used as a prognostic biomarker in HPV + OPC. • Adding CD20+ to CD103+ abundance may have utility in selecting low risk HPV + OPC. The incidence of human papillomavirus positive oropharyngeal cancer (HPV+OPC) is increasing, and new biomarkers are required to better define prognostic groups and guide treatment. Infiltrating T cells have been well studied in head and neck cancer, however the presence and role of B cells and tertiary lymphoid structures (TLS) in the tumor microenvironment has not, even though the interplay between T and B cells is increasingly being recognised. Using CD20 immunohistochemistry (IHC) to identify B cells and TLS in a cohort of 159 HPV + OPC patients, we semi-quantitatively scored abundance and location (intra-tumoral or stromal) and correlated findings with patient survival. 32% (51/157) of patients had high intra-tumoral (IT) abundance of CD20+ B cells (≥5%) and this was prognostic for improved overall survival (OS) with an adjusted hazard ratio (HR) of 0.2 (95 % CI 0.0–0.7, p = 0.014). We validated our results in an independent cohort comprising 171 HPV + OPC where 14% (23/171) were IT CD20+ high, again showing improved survival with an adjusted HR for OS of 0.2 (95 % CI 0.0–1.4, p = 0.003). Neither stromal abundance nor the presence of TLS were prognostic in either cohort. B cells were subtyped by multispectral IHC, identifying CD20+CD27+ cells, consistent with memory B cells, as the predominant subtype. Combined with validated biomarker CD103, a marker of tissue-resident memory T cells, IT CD20+ B cells abundance was able to prognostically stratify patients further. CD20+ B cell abundance has the potential to be used as a biomarker to identify good and poor prognosis HPV + OPC patients. [ABSTRACT FROM AUTHOR]

• Particulate matter levels were associated with head and neck cancers in the US. • Robust relationships were found for overall oral cavity and pharynx. • Less significant associations were present for esophagus and tonsil subsite. Early studies show conflicting findings regarding particulate matter ≤ 2.5 μm in diameter (PM 2.5) exposure and development of head and neck cancers (HNC). We analyzed the relationship between PM 2.5 exposure and various types of HNC in a nationally representative ecological sample. We determined HNC incidence in 608 US counties from 2011 to 2019 using the Surveillance, Epidemiology and End Results (SEER) Program from the National Cancer Institute. We also collected information on sociodemographic factors from SEER and data on smoking and alcohol intake from CDC data frames (county level). PM 2.5 exposure levels were estimated using satellite and meteorological data via previously validated general additive models. Flexible semi-nonparametric regression models were used to test the relationship between PM 2.5 exposure levels and HNC incidence, adjusting for demographics, socioeconomic factors, and comorbidity. Increased PM 2.5 exposure levels were associated with higher incidence-rates of oral cavity and pharyngeal cancers controlling for confounders in our primary analyses (IRR = 1.04, 95 % CI 1.01, 1.07, p = 0.02 per 1 μg/m3 increase in PM 2.5). This relationship was maintained after adjusting for multiple testing (Holm s method, p = 0.04) and in ordinary least squares (OLS) regression (β = 0.17, 95 % CI 0.01, 0.57, p = 0.01). Increased exposure was also associated with other HNC: esophagus (IRR = 1.06, 95 % CI 1.01, 1.11, p = 0.02), lip (IRR = 1.16, 95 % CI 1.03, 1.31, p = 0.01), tonsil (IRR = 1.10, 95 % CI 1.03, 1.16, p < 0.01). However, these relationships were not maintained in secondary analyses. This nationally representative ecological study shows that increased levels of air pollution are associated with increased incidence of overall oral cavity and pharyngeal cancers in the US. [ABSTRACT FROM AUTHOR]

• Tipifarnib is the first biomarker-selected targeted therapy for HNSCC; however, the mechanisms of resistance are poorly understood. • Tumor microenvironment in HRAS-mutated HNSCC shifts from immune-enriched to fibrotic with increased angiogenesis during tipifarnib therapy. • Tipifarnib efficacy is constrained by AKT pathway activation; dual therapy with PI3K inhibition enhances anti-tumor efficacy. Head and neck squamous cell carcinoma (HNSCC) is a highly prevalent malignancy worldwide, with a significant proportion of patients developing recurrent and/or metastatic (R/M) disease. Despite recent advances in therapy, the prognosis for patients with advanced HNSCC remains poor. Here, we present the case of a patient with recurrent metastatic HNSCC harboring an HRAS G12S mutation who achieved a durable response to treatment with tipifarnib, a selective inhibitor of farnesyltransferase. The patient was a 48-year-old woman who had previously received multiple lines of therapy with no significant clinical response. However, treatment with tipifarnib resulted in a durable partial response that lasted 8 months. Serial genomic and transcriptomic analyses demonstrated upregulation of YAP1 and AXL in metastatic lesions compared with the primary tumor, the evolution of the tumor microenvironment from an immune-enriched to a fibrotic subtype with increased angiogenesis, and activation of the PI3K/AKT/mTOR pathway in tipifarnib treatment. Lastly, in HRAS-mutated PDXs and in the syngeneic HRAS model, we demonstrated that tipifarnib efficacy is limited by activation of the AKT pathway, and dual treatment with tipifarnib and the PI3K inhibitor, BYL719, resulted in enhanced anti-tumor efficacy. Our case study highlights the potential of targeting HRAS mutations with tipifarnib in R/M HNSCC and identifies potential mechanisms of acquired resistance to tipifarnib, along with immuno-, chemo-, and radiation therapy. Preclinical results provide a firm foundation for further investigation of drug combinations of HRAS-and PI3K -targeting therapeutics in R/M HRAS-driven HNSCC. [ABSTRACT FROM AUTHOR]

• Analysis of recurrent/metastatic head and neck cancer. • Feasibility of a 231-gene NanoString panel in determining the molecular subtypes. • Tumor budding prognostically significant in recurrent/metastatic state. We aimed to evaluate the applicability of a customized NanoString panel for molecular subtyping of recurrent or metastatic head and neck squamous cell carcinoma (R/M−HNSCC). Additionally, histological analyses were conducted, correlated with the molecular subtypes and tested for their prognostic value. We conducted molecular subtyping of R/M−HNSCC according to the molecular subtypes defined by Keck et al. For molecular analyses a 231 gene customized NanoString panel (the most accurately subtype defining genes, based on previous analyses) was applied to tumor samples from R/M−HNSCC patients that were treated in the CeFCiD trial (AIO/IAG-KHT trial 1108). A total of 130 samples from 95 patients were available for sequencing, of which 80 samples from 67 patients passed quality controls and were included in histological analyses. H&E stained slides were evaluated regarding distinct morphological patterns (e.g. tumor budding, nuclear size, stroma content). Determination of molecular subtypes led to classification of tumor samples as basal (n = 46, 45 %), inflamed/mesenchymal (n = 31, 30 %) and classical (n = 26, 25 %). Expression levels of Amphiregulin (AREG) were significantly higher for the basal and classical subtypes compared to the mesenchymal subtype. While molecular subtypes did not have an impact on survival, high levels of tumor budding were associated with poor outcomes. No correlation was found between molecular subtypes and histological characteristics. Utilizing the 231-gene NanoString panel we were able to determine the molecular subtype of R/M−HNSCC samples by the use of FFPE material. The value to stratify for different treatment options remains to be explored in the future. The prognostic value of tumor budding was underscored in this clinically well annotated cohort. [ABSTRACT FROM AUTHOR]

• 10 % of HNSCC patients show long-term response to ICIs with 93 months follow-up. • Most long-term ICI responders avoid relapse post-discontinuation. • Initial ICI responders often respond well to post-cessation re-challenge. • Extended ICI use leads to irAEs in 74%, severe in 37% Immune checkpoint inhibitors (ICI) have introduced a new era in the treatment of recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC). Optimal duration for ICI therapy is still unclear and the long-term outcomes and toxicity in patients responding to these therapies warrant further exploration. This study attempts to identify the clinical and biological determinants of a durable response and evaluate outcomes following ICI treatment discontinuation. A retrospective review of 181 patients treated with ICI for R/M HNSCC was conducted. Long-term responders were defined as patients who sustained disease control at least two years after initiating ICI therapy. We compared clinical and biological characteristics associated with these long-term responders against the broader treatment population. 10 % of R/M HNSCC patients treated with ICIs demonstrated a durable long-term response. Only three relapses (16 %) occurred after discontinuing ICI treatment in this subset, with a median follow-up of 52 months. Upon retreatment with ICI, two attained a documented response. Extended ICI response was observed even with < 2 years of treatment. 74 % of long-term responders experienced immune-related adverse events (irAEs), 37 % of which severe irAEs. Hypothyroidism was the most frequently reported irAEs. The predictive potential of systemic inflammation indices for clinical response appears to be limited. ICI present an optimistic avenue for HNSCC patients, offering substantial long-term responses. The study suggests that a two-year treatment could be optimal and irAEs, although common, are typically mild. [ABSTRACT FROM AUTHOR]

• Delphi method used captured a multidisciplinary perspective for managing LA-HNSCC. • Systemic treatment of LA-HNSCC depend on patient tolerability of high-dose cisplatin. • Strong consensus on cisplatin regimens shows evidence-based practice in the region. • Practice variability due to access, practical factors and areas of limited evidence. To develop consensus on patient characteristics and disease-related factors considered in deciding treatment approaches for locally advanced head and neck squamous cell carcinoma (LA-HNSCC) based on real-world treatment patterns in 4 territories in Asia-Pacific. A three-round modified Delphi involving a multidisciplinary panel of HN surgeons, medical oncologists, and radiation oncologists was used. Of 41 panelists recruited, responses of 26 from Australia, Japan, Singapore, and Taiwan were analyzed. All panelists had ≥five years' experience managing LA-HNSCC patients and treated ≥15 patients with LA-HNSCC annually. All statements on definitions of LA-HNSCC, treatment intolerance and cisplatin dosing reached consensus. 4 of 7 statements on unresectability, 2 of 4 on adjuvant chemoradiotherapy, 7 of 13 on induction chemotherapy, 1 of 8 on absolute contraindications and 7 of 11 on relative contraindications to high-dose cisplatin did not reach consensus. In all territories except Taiwan, high-dose cisplatin was preferred in definitive and adjuvant settings for patients with no contraindications to cisplatin; weekly cisplatin (40 mg/m2) preferred for patients with relative contraindications to high-dose cisplatin. For Taiwan, the main treatment option was weekly cisplatin. For patients with absolute contraindications to cisplatin, carboplatin ± 5-fluorouracil or radiotherapy alone were preferred alternatives in both definitive and adjuvant settings. This multidisciplinary consensus provides insights into management of LA-HNSCC in Asia-Pacific based on patient- and disease-related factors that guide selection of treatment modality and systemic treatment. Despite strong consensus on use of cisplatin-based regimens, areas of non-consensus showed that variability in practice exists where there is limited evidence. [ABSTRACT FROM AUTHOR]

• There is a survival benefit to primary tumor detection regardless of HPV status. • Oropharyngeal primary tumor detection rates are increasing over time. • Female, non-white, and HPV negative patients have lower odds of primary detection. Head and neck cancer of unknown primary (CUP) poses significant therapeutic challenges. We compare CUP and oropharyngeal primary (OP) cases to identify factors associated with tumor detection. The 2004–2019 National Cancer Database was queried to identify CUP and OP cases based on clinical and pathologic TNM staging. Clinical and demographic characteristics were compared by primary detection and HPV status with descriptive statistics. Multivariable logistic regression models to characterize OP detection were constructed. Among HPV-positive and negative patients, respectively, OP and CUP patients were matched by clinical nodal disease. Cox proportional-hazards models were constructed using matched cohorts to characterize survival. 81,053 CUP and OP cases were identified; 64.3 % were HPV-positive. OP detection increased over time in HPV-positive and negative disease. HPV-positive status had higher odds of OP detection (odds ratio (OR) = 1.77, p < 0.001), while females (OR = 0.95, p = 0.008), and black (OR = 0.82, p < 0.001) and Asian (OR = 0.7, p < 0.001) patients had lower odds compared to males and whites, respectively. In HPV-positive and negative disease, OP patients had higher 2 and 5-year survival rates than CUP (p < 0.001). Primary detection status conferred lower death risk in HPV-positive (hazard ratio (HR) = 0.85, p < 0.001) and negative disease (HR = 0.87, p < 0.001) when controlling for age, sex, race, comorbidities, insurance, treatment facility, and income. In the largest cohort of CUP to date, we report a survival benefit in primary tumor detection regardless of HPV status. Groups with higher persistent CUP rates, including non-white, female, HPV-negative, and low income patients, may benefit from increased diagnostic workup to improve detection and treatment. [ABSTRACT FROM AUTHOR]

• The pooled grade 3 or more ORN rate following proton therapy in patients with head and neck cancer is 0.01(95 % CI = 0.01–0.03). • The pooled grade 1 or more ORN rate following proton therapy in patients with head and neck cancer is 0.05(95 %CI = 0.03–0.08). • IMPT didn't reduce grade 3 or more ORN following proton therapy in patients with head and neck cancer compared with 3DCPT. Head and neck cancer ranks as the seventh most common cancer worldwide. Proton therapy is widely used in head and neck cancer. Osteoradionecrosis(ORN) is currently a commonly investigated side effect of proton therapy. A meta-analysis is needed to investigate this topic. Two authors searched three databases, including PubMed, Embase, and Cochrane Library; the search period was from inception to June 2023. The search keyword was set to be ((("osteoradionecrosis") OR ("osteonecrosis")) AND ("proton")). We initially collected 410 articles, and after article selections, 22 articles remained in our systematic reviews. Due to the overlapping of patient populations, 17 studies were finally included in our meta-analysis. The pooled grade 3 or more ORN rate is 0.01(95 % CI = 0.01–0.03). Subgroup analysis showed that IMPT didn't reduce grade 3 or more ORN compared with 3DCPT (p = 0.15). Our meta-analysis showed that severe ORN rarely occurred in proton therapy for head and neck cancer patients. [ABSTRACT FROM AUTHOR]

• Frailty assessment is often overlooked in non-elderly patients with cancer, possibly due to the lack of an effective frailty screening tool. • The present study evaluated the performance of two frailty screening tools, the Flemish version of the Triage Risk Screening Tool (fTRST) and the modified 5-Item Frailty Index (mFI-5), in predicting frailty compared with the gold standard method of geriatric assessment among non-elderly patients with head and neck cancer. • The results demonstrated that both the fTRST and mFI-5 are reliable screening tools with good predictive value for identifying frail patients. Frailty assessment is often overlooked in non-elderly patients with cancer, possibly due to the lack of an effective frailty screening tool. This study aimed to evaluate the performance of two modern frailty screening tools, the Flemish version of the Triage Risk Screening Tool (fTRST) and the modified 5-Item Frailty Index (mFI-5), compared to the gold standard comprehensive geriatric assessment (GA) among non-elderly patients with head and neck cancer (HNC). We prospectively included 354 consecutive patients aged < 65 years with newly diagnosed HNC scheduled for definitive concurrent chemoradiotherapy (CCRT) at three academic hospitals in Taiwan between January 2020 and December 2022. Frailty assessment using the GA, fTRST, and mFI-5 was performed in all patients to evaluate the relationship between frailty and treatment outcomes. The prevalence of frailty was 27.1%, 37.0%, and 42.4% based on GA, mFI-5, and fTRST, respectively. mFI-5 and fTRST demonstrated good predictive value in identifying frail patients compared to the GA. Patients with frailty, as defined by GA, mFI-5, and fTRST, exhibited higher risks of treatment-related complications, incomplete treatment, and poorer baseline quality of life (QoL). However, only GA showed significant prognostic value for overall survival. Frailty assessment using fTRST and mFI-5 is valuable for predicting treatment-related adverse events, treatment tolerance, and QoL in non-elderly patients with HNC. Incorporating frailty assessment into the management of non-elderly cancer patients can aid in the identification of high-risk individuals. However, the performance of these tools varies, highlighting the need for further validation and refinement. [ABSTRACT FROM AUTHOR]

• Circulating tumour DNA can be detected in advanced SDC. • Longitudinal ctDNA analysis can be informative to understand disease dynamics in SDC. • ctDNA levels seem to correlate with radiological response in SDC. [ABSTRACT FROM AUTHOR]

• Many oral cavity cancer patients present with sarcopenia. • Pre-treatment sarcopenia is associated with significantly worse outcomes. • Radiographic sarcopenia may be a convenient tool in oral cancer prognostication. We performed a systematic review of the literature and meta -analysis to determine how radiographic sarcopenia assessment methods and the presence of pre-treatment sarcopenia impact oncologic outcomes in patients with oral cavity cancer. Pre-treatment sarcopenia has been associated with poor outcomes in many different malignancies, including head and neck cancers. However, the impact sarcopenia has on outcomes for oral cavity cancer patients is not well understood. Twelve studies met our inclusion criteria, totaling 1007 patients. 359 (36%) of these patients were reported as sarcopenic. The most commonly utilized sarcopenia assessment methods were L3 skeletal muscle index (n = 5) and C3 skeletal muscle index to estimate L3 skeletal muscle index (n = 5). The majority of studies established their sarcopenia cutoffs as the lowest quartile skeletal muscle index in their patient cohorts. Five studies were included in our meta -analysis, totaling 251 sarcopenic and 537 non-sarcopenic patients. Compared to non-sarcopenic patients, sarcopenic patients were found to have significantly poorer overall survival (univariate: HR = 2.24, 95% CI: 1.71–2.93, I2 = 0%; multivariate: HR = 1.93, 95% CI: 1.47–2.52, I2 = 0%) and disease-free survival (univariate: HR = 2.10, 95% CI: 1.50–2.92, I2 = 0%; multivariate: HR = 1.79, 95% CI: 1.29–2.47, I2 = 10%). Over one-third of oral cavity cancer patients may present with sarcopenia. Pre-treatment sarcopenia is associated with significantly worse overall and disease-free survival. [ABSTRACT FROM AUTHOR]

• Patient characteristics associated with higher odds of non-adherence to the timely receipt of adjuvant radiation therapy within then 42-day benchmark from surgery to radiation included race, non-English speaking status, and low socioeconomic status. • Black and Latino patients were more likely to experience delays in the initiation of adjuvant radiation therapy for head and neck cancer. • Initiatives designed to improve these disparities are much needed for patients with head and neck cancer. To evaluate the influence of socioeconomic and demographic factors which might predict for excessive delays in the receipt of adjuvant radiotherapy for head and neck cancer. The medical records of 430 consecutive patients referred for adjuvant radiation after surgical resection for squamous cell carcinoma of the head and neck were reviewed. The number of days from surgery to initiation of radiation was recorded. To study the variability in which adjuvant radiation was delivered, descriptive statistics were used to determine the percentage of patients who deviated from starting treatment beyond the recommended benchmark of 42 days. The chi-square statistic was used to compare differences in proportion among subsets. A Cox proportional hazards model was constructed to perform a multi-variate analysis to identify factors which independently influenced the likelihood for non-adherence. The interval between surgery and the start of radiation therapy ranged from 5 to 128 days (mean, 36 days). The mean number of days from surgery to radiation therapy was 31 days, 35 days, 40 days, and 42 days for Caucasians, Asians, Latino, and Black patients (p = 0.01). In all, 359 of 430 patients (83 %) started adjuvant radiation within 42 days. The proportion of patients who initiated radiation therapy within 42 days of surgery was 91 %, 86 %, 71 %, 65 %, and 80 % for Caucasians, Asians, Latinos, Blacks, and Native Hawaiian/Pacific Islanders, respectively (p < 0.001). Patient characteristics associated with higher odds of non-adherence to the timely receipt of adjuvant radiation therapy within then 42-day benchmark from surgery to radiation included race ([OR] = 4.23 95 % CI (1.30–7.97), non-English speaking status ([OR] = 2.38, 95 % CI: 0.61–4.50), and low socioeconomic status ([OR] = 1.21, 95 % CI: 1.01–1.86). Underrepresented minorities are more likely to experience delays in the receipt of adjuvant radiation for head and neck cancer. The potential underlying reasons are discussed. [ABSTRACT FROM AUTHOR]

Low skeletal muscle mass is emerging as an adverse predictive and prognostic factor in cancer patients. The use of this parameter as a risk factor for complications after surgery is not currently used in clinical practice. This meta-analysis aims to assess the association of low skeletal muscle mass defined by radiological criteria and complications after reconstructive microsurgery in head and neck cancer patients. A systematic review for articles was performed using the PubMed, EMBASE database and by manual search. Articles that assessed low skeletal muscle mass and its impact on postoperative complications in head and neck cancer patients undergoing free flap surgery were selected. Pooled estimates of postoperative outcome data were calculated by extracting the odds ratio (OR) and 95% confidence interval (CI). The search strategy returned with 6 studies meeting the inclusion criteria. A total of 1082 patients were analyzed. The prevalence of low skeletal muscle mass between studies ranged from 24.6% to 61.5%. The meta-analysis showed an OR for complications after surgery of 2.42 (95% CI 1.53–3.32, p = 0.00). The study therefore concludes that skeletal muscle mass is an independent risk factor for postoperative complications in head and neck cancer reconstructive surgery patients. This argues for implementing screening for low skeletal muscle in preoperative management to optimize surgical decision making. [ABSTRACT FROM AUTHOR]

Immunotherapies such as immune checkpoint inhibitors have shown promising results in solid tumors associated with BRCA2, but there are no consistent predictors for who will respond to immunotherapy. More research is needed on the impact of this mutation in head and neck squamous cell carcinomas, particularly for recurrent/metastatic tumors. We report a case of stage IV oral squamous cell carcinoma associated with BRCA2 mutation that achieved complete remission with pembrolizumab treatment for relapsed disease. [ABSTRACT FROM AUTHOR]

• OS was numerically longer with pembrolizumab in all subgroups. • PFS was similar between treatment arms in all subgroups. • More patients receiving pembrolizumab versus SOC had an objective response. • Responses with pembrolizumab were durable. • Results suggest benefit from pembrolizumab regardless of recurrence pattern. In the phase 3 KEYNOTE-040 study, pembrolizumab prolonged OS versus chemotherapy in previously treated recurrent or metastatic (R/M) HNSCC. We present a post hoc subgroup analysis by disease recurrence pattern: recurrent-only, recurrent and metastatic (recurrent-metastatic), and metastatic-only HNSCC. Patients had HNSCC that progressed during or after platinum-containing treatment for R/M disease or had recurrence or progression within 3–6 months of previous platinum-containing definitive therapy for locally advanced disease. Patients were randomly assigned (1:1) to pembrolizumab 200 mg Q3W or investigator's choice of standards of care (SOC): methotrexate, docetaxel, or cetuximab. Outcomes included OS, PFS, ORR, and DOR. The data cutoff was May 15, 2017. There were 125 patients (pembrolizumab, 53; SOC, 72) in the recurrent-only subgroup, 204 in the recurrent-metastatic subgroup (pembrolizumab, 108; SOC, 96), and 166 in the metastatic-only subgroup (pembrolizumab, 86; SOC, 80). The hazard ratio (95% CI) for death for pembrolizumab versus SOC was 0.83 (0.55–1.25) in the recurrent-only, 0.78 (0.58–1.06) in the recurrent-metastatic, and 0.74 (0.52–1.05) in the metastatic-only subgroups. PFS was similar between treatment arms in all subgroups. ORR was 22.6% for pembrolizumab versus 16.7% for SOC in the recurrent-only, 10.2% versus 6.3% in the recurrent-metastatic, and 15.1% versus 8.8% in the metastatic-only subgroups. DOR was numerically longer with pembrolizumab in all subgroups. Pembrolizumab provided numerically longer OS and durable responses in all subgroups compared with SOC, suggesting that patients with previously treated R/M HNSCC benefit from pembrolizumab regardless of recurrence pattern. [ABSTRACT FROM AUTHOR]

• TTMV-HPV DNA testing to aid HPV-positive OPSCC diagnosis was prospectively evaluated. • Testing was feasible and perceived as clinically useful by treating physicians. • Among 3 subjects diagnosed with HPV-positive OPSCC, 2 had detectable TTMV-HPV DNA. • Undetectable TTMV-HPV DNA may not reliably indicate absence of disease. • Clinicians using this test should be aware of both its strengths and limitations. While survival outcomes are favorable for Human Papillomavirus (HPV)-positive oropharyngeal squamous cell carcinomas (OPSCCs), early diagnosis may minimize treatment-related morbidity and mortality. This study evaluated circulating tumor tissue-modified viral (TTMV)-HPV DNA plasma testing to facilitate early diagnosis of HPV-positive OPSCCs. In this prospective exploratory cohort study, patients presenting to an Otolaryngology-Head and Neck Surgery clinic with unexplained signs or symptoms considered high-risk for HPV-positive OPSCC were recruited between March 2021-October 2022. Circulating TTMV-HPV DNA testing was performed, and results were shared with subjects and treating clinicians. Clinicians were surveyed regarding the perceived clinical utility of the test. Thirty-nine subjects were included. Most subjects were women (N = 23, 59 %), white (N = 32, 82 %) and never-smokers (N = 20, 51 %) with median age 60 years. Circulating TTMV-HPV DNA was detected in 2/39 subjects, both subsequently diagnosed with HPV-positive OPSCC. Both were white men aged 70–80 years with a neck mass. One subject with undetectable TTMV-HPV DNA was also diagnosed with HPV-positive OPSCC through excisional neck mass biopsy. Other eventual diagnoses included 3 HPV-negative head and neck squamous cell carcinomas and 4 other malignancies. Testing was perceived as helpful in clinical decision-making for 26/38 (68 %) subjects, and useful for similar future patients for 32/37 (86 %) subjects. Circulating TTMV-HPV DNA testing is feasible and holds potential as a diagnostic aid for HPV-positive OPSCC alongside standard clinical workup. Clinicians should be cognizant of its limitations, as a negative test does not necessarily indicate the absence of disease. Further studies to evaluate its utility are warranted. [ABSTRACT FROM AUTHOR]

• Deletion of LRP1B was enriched in recurrent HPV+ve OPSCC patient samples. • Knockout of LRP1B drove an aggressive phenotype in HPV+ve HNSCC cell lines. • Loss of LRP1B expression promoted chemo and radio resistance both in vitro and in vivo. • Loss of LRP1B might be a potential biomarker for treatment resistant HPV+OPSCC. Although human papillomavirus positive (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) patients typically experience excellent survival, 15–20 % of patients recur after treatment with chemotherapy and radiation. Therefore, there is a need for biomarkers of treatment failure to guide treatment intensity. Whole genome sequencing was carried out on HPV+OPSCC patients who were primarily treated with concurrent chemotherapy (cisplatin) and radiation. We then explored whether the loss of LRP1B was sufficient to drive an aggressive phenotype, and promote a resistance to cisplatin and radiation therapy both in vitro using HPV+ cell lines (93VU147T, UMSCC47, UWO37 and UWO23) and in vivo. Through integrative genomic analysis of three HPV+OPSCC tumour datasets, we identified that deletion of LRP1B was enriched in samples that recurred following chemo-radiation. Knockdown using siRNA in four HPV+ cell lines (UWO23, UWO37, UMSCC47 and 93VU147T) resulted in increased proliferation of all cases. CRISPR/Cas9 deletion of LRP1B in the same cell line panel demonstrated increased proliferation, clonogenic growth and migration, as well as resistance to both cisplatin and radiation in LRP1B deleted cells compared to their respective non-targeting control cells. Cell line derived xenograft studies indicated that the LRP1B knockout tumours were more resistant to cisplatin and radiation therapy compared to their controls invivo. Taken together, our work implicates LRP1B deletion as a potential biomarker for identifying treatment resistant HPV+ OPSCC cases. [ABSTRACT FROM AUTHOR]

• Cisplatin is the mainstay of systemic treatment for concomitant chemoradiation in HNC. • Identifying factors to predict early cisplatin-related nephrotoxicity is essential. • Predictive factors were age, baseline creatinine, concomitant drugs, CDDP schedule. • Avoidance of CDDP dose adjustments, interruptions, and delays may impact on outcome. Cisplatin is essential in the curative treatment of locally advanced head and neck squamous cell carcinoma (LA-HNSCC) patients. The assessment of risk factors to predict an early cisplatin-induced nephrotoxicity could help in better managing one of the most relevant cisplatin-related dose-limiting factors. We retrospectively collected data of LA-HNSCC patients treated at our Institution from 2008 to 2019. Patients received cisplatin in a curative setting concurrently with radiation. Acute Kidney Injury (AKI) was assessed as a dichotomous variable (CreaIncr) based on pre-treatment values, and values recorded at days 6–20 post-first cycle of cisplatin. Univariable logistic regression models were performed to investigate associations between CreaIncr and clinical characteristics. A multivariable logistic model on a priori selected putative covariates was performed. Of the 350 LA-HNSCC treated patients, 204 were analyzed. Ninety (44 %) suffered from any grade AKI (grade I 51.1 %): out of them, 84.4 % received high-dose cisplatin (100 mg/m2 q21). On the univariable logistic regression model, male sex, age, serum uric acid, creatinine, concomitant drugs, and cisplatin schedule were significantly associated with a higher rate of AKI. At multivariable model, age (p = 0.034), baseline creatinine (p = 0.027), concomitant drugs (p = 0.043), and cisplatin schedule (one-day bolus or fractionated high-dose vs. weekly; p = 0.001) maintained their significant association. Identifying pre-treatment risk factors in LA-HNSCC patients may improve decision-making in a setting where cisplatin has a curative significance. A strict monitoring of AKI could avoid cisplatin dose adjustments, interruptions, and treatment delays, thus limiting a negative impact on outcomes. [ABSTRACT FROM AUTHOR]

• Head and neck cancer organoids maintain histologic and molecular characteristics of original tissues. • Head and neck cancer organoids recapitulate genetic characteristics of cancer tissues. • Head and neck cancer organoids display clonal evolution during serial passaging. • Impact of clonal evolutions on responses to radiotherapy and chemotherapy can be validated in 3D ex vivo organoid culture models. In biobanking based on patient-derived organoids (PDO), the genetic stability of organoid lines is critical for the clinical relevance of PDO with parental tumors. However, data on mutational heterogeneity and clonal evolution of PDO and their effects on treatment response are insufficient. To investigate whether head and neck cancer organoids (HNCOs) could maintain the genetic characteristics of their original tumors and elucidate the clonal evolution process during a long-term passage, we performed targeted sequencing, covering 377 cancer-related genes and adopted a sub-clonal fraction model. To explore therapeutic response variability between an early and late passage (>passage 6), we generated dose-response curves for drugs and radiation using two HNCO lines. Using 3D ex vivo organoid culture protocol, we successfully established 27 HNCOs from 39 patients with an overall success rate of 70% (27/39). Their mutational profiles were highly concordant, with three of the HNCOs analyzed showing greater than 70% concordance. Only one HNCO displayed less than 50% concordance. However, many of these organoid lines displayed clonal evolution during serial passaging, although major cancer driver genes and VAF distributions were shared between early and later passages. We also found that all late passages of HNCOs tended to be more sensitive to radiation than early passages, similar to drug response results. We report the establishment of HNCO lines derived from 27 patients and demonstrate their genetic concordance with corresponding parental tumors. Furthermore, we show serial changes in mutational profiles of HNCO along with long passage culture and the impact of these clonal evolutions on response to radiotherapy. [ABSTRACT FROM AUTHOR]

Intravital microscopy (IVM) and optical coherency tomography (OCT) are powerful optical imaging tools that allow visualization of dynamic biological activities in living subjects with subcellular resolutions. They have been used in preclinical and clinical cancer imaging, providing insights into the complex physiological, cellular, and molecular behaviors of tumors. They have revolutionized cancer diagnosis and therapies, allowing for real-time observation of biologic processes in vivo, including angiogenesis and immune cell interactions. Recent developments in techniques for observing deep tissues of living animals have improved bioluminescent proteins, fluorescent proteins, fluorescent dyes, and detection technologies like two-photon excitation microscopy. These technologies have become indispensable tools in basic sciences, preclinical research, and modern drug development. In Vivo imaging can detect subcellular signaling or metabolic events in living animals, but depth-dependent signal attenuation limits the depth from which significant data can be obtained. Cancer cell motility and invasion are key features of metastatic tumors, but only a small portion of tumor cells are motile and metastasize due to genetic, epigenetic, and microenvironmental heterogeneities. [ABSTRACT FROM AUTHOR]