To demonstrate whether the benefit of locoregional radiotherapy in de novo metastatic nasopharyngeal carcinoma remains in the immunotherapy era and which patients can benefit from radiotherapy. A total of 273 histopathology-confirmed de novo metastatic nasopharyngeal carcinoma was enrolled between May 2017 and October 2021 if receiving immunochemotherapy with or without subsequent intensity-modulated radiotherapy to the nasopharynx and neck. We compared the progression-free survival, overall survival, and safety between the two groups. Additionally, subgroup analysis was conducted and a scoring model was developed to identify suitable patients for radiation. There were 95 (34.8%) patients with immunochemotherapy alone, and 178 (65.2%) with immunochemotherapy plus subsequent locoregional radiotherapy. With a median follow-up time of 18months, patients with immunochemotherapy plus subsequent radiotherapy had higher 1-year progression-free survival (80.6% vs. 65.1%, P<0.001) and overall survival (98.3% vs. 89.5%, P=0.001) than those with immunochemotherapy alone. The benefit was retained in multivariate analysis and propensity score-matched analysis. Mainly, it was more significant in patients with oligometastases, EBV DNA below 20,200 copies/mL, and complete or partial relapse after immunochemotherapy. The combined treatment added grade 3 or 4 anemia and radiotherapy-related toxicities. Immunochemotherapy plus subsequent locoregional radiotherapy prolonged the survival of de novo metastatic nasopharyngeal carcinoma with tolerable toxicities. A scoring model based on oligometastases, EBV DNA level, and response after immunochemotherapy could facilitate individualized management.

This systematic review aims to provide insight into the ideal reconstructive approach of the oral tongue in oral tongue cancer (OTC) by investigating the relationship between functional outcomes and the extent of tongue resection. A structured search was performed in Ovid MEDLINE, EMBASE, and Web of Science. Studies comparing patient-reported and objective measurements of the oral tongue function between flap vs. non-flap reconstruction were included. Functional outcomes of interest were speech production, deglutition efficiency, tongue mobility, overall quality of life, and postoperative complications. A total of nine studies were retrieved and critically appraised. Patients with 20% or less of oral tongue resected had superior swallowing efficiency and speech intelligibility with a non-flap reconstruction while patients with a tongue defect of 40-50% self-reported or demonstrated better swallowing function with a flap repair. The data in intermediate tongue defects (20-40% tongue resected) was inconclusive, with several studies reporting comparable functional outcomes between approaches. A longitudinal multi-institutional prospective study that rigidly controls the extent of tongue resected and subsites involved is needed to determine the percentage of tongue resected at which a flap reconstruction yields a superior functional result in OTC.

To characterize the change in sensory function following partial glossectomy for oral tongue cancer (OTC) and to identify predictors of loss of tongue-tip sensation (LoTTS). Patients with at least three months follow-up after partial glossectomy for primary OTC were included. All patients underwent a qualitative tongue sensation assessment and an objective tongue sensory exam of the native tongue tip. Additional details regarding the oncologic resection, surgical reconstruction, and pathological stage were collected. Multiple linear and logistic regressions were used for statistical analysis. Sixty-four patients were enrolled, including 34 (53%) men with a median age of 65 at enrollment. Ten (15%) patients reported LoTTS. Increased depth of resection (DOR) was an independent predictor of LoTTS on multivariate analysis, with an increased risk at a threshold of 1.3cm. LoTTS was also associated with worse subjective quality of life and perceptive speech performance in our qualitative tongue assessment. In this pilot study, we found that DOR is a critical prognostic factor in predicting post treatment function. Patients with an increased DOR, particularly above 1.3cm, are at greatest risk of LoTTS and associated morbidity. These findings may be used to predict post-operative sensory deficits, manage patients' expectations, and optimize the reconstructive approach. Future studies are needed to validate and replicate our results.

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 60years. Circulating TTMV-HPV DNA was detected in 2/39 subjects, both subsequently diagnosed with HPV-positive OPSCC. Both were white men aged 70-80years 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.

To investigate the role of induction chemotherapy (IC) in lymph node-positive (LN-positive) stage III nasopharyngeal carcinoma (NPC) receiving concurrent chemoradiotherapy (CCRT). In total, 627 patients with newly diagnosed LN-positive stage III NPC receiving CCRT or IC plus CCRT were included. The primary endpoint was progression-free survival (PFS). Propensity-score matching (PSM) was conducted to balance the intergroup covariates. Kaplan-Meier method with log-rank test was employed to compare survival curves. Subgroup analyses were conducted based on baseline characteristics. After 1:1 PSM, 414 patients were identified (207 patients per group). Compared with CCRT, IC plus CCRT provided better survival (5-year PFS 88.4% vs. 78.6%, P = 0.01; overall survival [OS] 94.8% vs. 85.3%, P = 0.003; and distant metastasis-free survival [DMFS] 93.1% vs. 85.6%, P = 0.03). The IC beneficial effects on PFS were mainly present in patients with grade 2-3 ENE, elevated serum lactate dehydrogenase (LDH > 170U/L), and N2 disease. Patients with grade 2 CNN had comparable PFS benefits to those with grade 0-1 CNN. For patients with grade 0-1 ENE combined with LDH ≤ 170U/L, survival between the two groups was similar with 5-year PFS 93.6% vs. 90.4% (P = 0.50), OS 94.2% vs. 93.0% (P = 0.72), and DMFS 98.6% vs. 97.7% (P = 0.98). Adding IC before CCRT improved survival in LN-positive stage III NPC patients. Additional IC did not provide better survival for patients with grade 0-1 ENE combined with LDH ≤ 170U/L and could be avoided in this population. CNN may not be a good risk factor for tailoring a personalized treatment plan.

To develop and validate a prognostic nomogram based on MRI-detected features of retropharyngeal and cervical lymph nodes and Epstein-Barr virus (EBV) DNA in patients with stage II nasopharyngeal carcinoma (NPC) to distinguish low-risk patients for whom intensity-modulated radiotherapy (IMRT) alone is sufficient. This retrospective study enrolled 894 patients with stage II NPC (596 and 298 in the training and validation cohorts, respectively) with pretreatment MRI between August 2010 and May 2019. All patients received IMRT with or without additional chemotherapy. We identified independent risk factors using univariate and multivariate Cox regression analyses. Survival was compared using Kaplan-Meier curves with the log-rank test. Independent factors derived from the multivariate analysis include cervical nodal necrosis (CNN), the extracapsular spread (ECS) of cervical and retropharyngeal lymph nodes, and gamma-glutamyl transferase (γ-GGT). Nomograms A, B, and C were established based on the clinical [tumor-node-metastasis (TNM) stage+Epstein-Barr virus (EBV) DNA], the clinical-radiological [all independent predictors] and the combined models [the clinical-radiological model+EBV DNA], respectively. Nomogram C (C-index 0.769 [0.718-0.820]) demonstrated better risk discrimination than nomogram B (0.762 [0.715-0.809]), nomogram A (0.619 [0.564-0.674]), and the TNM stage (0.560 [0.509-0.611]). In the low-risk group divided by nomogram C, no significant survival differences were observed between patients treated with radiotherapy (RT) alone and other regimens including additional chemotherapy. The nomogram combining MRI-detected retropharyngeal and cervical lymph node features with pretreatment EBV-DNA improved the prognostic risk stratification for stage II NPC.

Head and neck squamous cell carcinomas (HNSCC) are associated with significant treatment-related morbidity and poor disease-free and disease-specific survival, especially in the recurrent and metastatic (R/M HNSCC) setting. Inhibition of the programmed death-1/ligand-1 (PD-1/PD-L1) immune checkpoint is accepted as a first-line treatment strategy for R/M HNSCC and has expanded into the neoadjuvant, definitive, and adjuvant settings. To understand cellular signals modulating the PD-L1 in HNSCC, we profiled a HNSCC cell-line with a genome-wide open reading frame (ORF) library of 17,000 individual constructs (14,000 unique genes). We identified 335 ORFs enriched in PD-L1high cells and independently validated five of these ORFs (FGF6, IL17A, CD300C, KLR1C and NFKBIA) as drivers of PD-L1 upregulation. We showed that exogenous FGF ligand is sufficient to induce PD-L1 expression in multiple HNSCC cell lines and human immature dendritic cells. Accordingly, overexpression of FGFR1, FGFR3 or the FGFR3 S249C and D786N mutants common to HNSCC tumors also induced PD-L1 overexpression on tumor cells. Small molecule inhibition of FGF signaling abrogated PD-L1 upregulation in these models and also blocked "classical" IFNγ-regulated PD-L1 expression in a STAT1-independent manner. Finally, we found that FGF specifically upregulated a glycosylated form of PD-L1 in our study, and exogenous FGF led to concomitant upregulation of glycosyltransferases that may stabilize PD-L1 on the surface of HNSCC cells. Taken together, our study supports a potential role for FGF/FGFR pathway signaling as a mechanism driving immune escape and rationalizes further exploration of novel combination therapies to improve clinical responses to PD-1/PD-L1 axis inhibition in HNSCC.

To investigate and describe the patterns of regional metastases and recurrences after surgical treatment of oropharyngeal squamous cell cancer (OPSCC). Retrospective study of patients diagnosed with OPSCC from 2006 to 2021 at a tertiary referral center. Only patients treated with surgery including a neck dissection were included. Patients with unknown human papillomavirus (HPV) status, prior head and neck cancer, distant metastases, or synchronous head and neck cancer were excluded. A total of 928 patients were included. 89% were males, the average age was 58.6years (range: 25.2-87.5), 874 (94%) were HPV(+), and 513 (55.3%) had a tonsil cancer. Among cN+patients, the most commonly involved levels at presentation were level II (85.2%), level III (33.3%), and level IV (9.4%). In cN0 patients, metastases were only observed in level II (16.2%) and level III (9.2%). Nodal recurrence occurred in 48 (5.2%) patients after a median time of 1.0years (interquartile range: 0.6-2.0). Nodal recurrence incidence was similar in HPV(+) and HPV(-) patients (5.0% vs. 7.4%, p=0.44). The most common levels for regional recurrence were ipsilateral level II (45.8%), contralateral level II (43.8%), and ipsilateral level V (25.0%). Multivariable analysis revealed that pN was a significant predictor for regional recurrence (p=0.02). There is no difference in the distribution of regional metastases and recurrences in HPV(+) and HPV(-) OPSCC patients. Our findings align with the established understanding that regional metastases predominantly manifest in the ipsilateral level II-IV at presentation. Moreover, the data support the clinical recommendation to restrict elective neck dissection in cN0 patients to ipsilateral levels IIa and III, excluding level IIb. Regional recurrence is significantly associated with pN status.