METTL3 and N6-Methyladenosine Promote Homologous Recombination-Mediated Repair of DSBs by Modulating DNA-RNA Hybrid Accumulation.

Double-strand breaks (DSBs) are the most deleterious DNA lesions, which, if left unrepaired, may lead to genome instability or cell death. Here, we report that, in response to DSBs, the RNA methyltransferase METTL3 is activated by ATM-mediated phosphorylation at S43. Phosphorylated METTL3 is then localized to DNA damage sites, where it methylates the N6 position of adenosine (m6A) in DNA damage-associated RNAs, which recruits the m6A reader protein YTHDC1 for protection. In this way, the METTL3-m6A-YTHDC1 axis modulates accumulation of DNA-RNA hybrids at DSBs sites, which then recruit RAD51 and BRCA1 for homologous recombination (HR)-mediated repair. METTL3-deficient cells display defective HR, accumulation of unrepaired DSBs, and genome instability. Accordingly, depletion of METTL3 significantly enhances the sensitivity of cancer cells and murine xenografts to DNA damage-based therapy. These findings uncover the function of METTL3 and YTHDC1 in HR-mediated DSB repair, which may have implications for cancer therapy.

Circulating tumour cells predict recurrences and survival in head and neck squamous cell carcinoma patients.

Patients with head and neck squamous cell carcinoma (HNSCC) are at a high risk of developing recurrence and secondary cancers. This study evaluates the prognostic and surveillance utilities of circulating tumour cells (CTCs) in HNSCC. A total of 154 HNSCC patients were recruited and followed up for 4.5 years. Blood samples were collected at baseline and follow-up. CTCs were isolated using a spiral microfluid device. Recurrence and death due to cancer were assessed during the follow-up period. In patients with HNSCC, the presence of CTCs at baseline was a predictor of recurrence (OR = 8.40, p < 0.0001) and death (OR= ∞, p < 0.0001). Patients with CTCs at baseline had poor survival outcomes (p < 0.0001). Additionally, our study found that patients with CTCs in a follow-up appointment were 2.5 times more likely to experience recurrence or death from HNSCC (p < 0.05) prior to their next clinical visit. Our study highlights the prognostic and monitoring utilities of CTCs' in HNSCC patients. Early identification of CTCs facilitates precise risk assessment, guiding treatment choices and ultimately enhancing patient outcomes.

Assessment of endpoint definitions in curative-intent trials for mucosal head and neck squamous cell carcinomas: Head and Neck Cancer International Group consensus recommendations.

Robust time-to-event endpoint definitions are crucial for the assessment of treatment effect and the clinical value of trial interventions. Here, the Head and Neck Cancer International Group investigated endpoint use in phase 3 trials and trials considered potentially practice-changing published between 2008 and 2021 in the curative-intent setting for patients with mucosal head and neck squamous cell carcinoma. Of the 92 trials reviewed, we show that all core components of endpoint reporting were heterogeneous, including definitions of common terms, such as overall survival and progression-free survival. Our report highlights the urgent need for harmonisation of fundamental components of clinical trial endpoints and the engagement of all stakeholders to ensure the transparent reporting of endpoint details.

Assessment of endpoint definitions in recurrent and metastatic mucosal head and neck squamous cell carcinoma trials: Head and Neck Cancer International Group consensus recommendations.

Transparent and precise endpoint definitions are a crucial aspect of clinical trial conduct and reporting, and are used to communicate the benefit of an intervention. Previous studies have identified inconsistencies in endpoint definitions across oncological clinical trials. Here, the Head and Neck Cancer International Group assessed endpoint definitions from phase 3 trials or trials considered practice-changing for patients with recurrent or metastatic mucosal head and neck squamous cell carcinoma, published between 2008 and 2021. We identify considerable and global heterogeneity in endpoint definitions, which undermines the interpretation of results and development of future studies. We show how fundamental components of even incontrovertible endpoints such as overall survival vary widely, highlighting an urgent need for increased rigour in reporting and harmonisation of endpoints.

Pembrolizumab plus concurrent chemoradiotherapy versus placebo plus concurrent chemoradiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (KEYNOTE-412): a randomised, double-blind, phase 3 trial.

BACKGROUND: Despite multimodal therapy, 5-year overall survival for locally advanced head and neck squamous cell carcinoma (HNSCC) is about 50%. We assessed the addition of pembrolizumab to concurrent chemoradiotherapy for locally advanced HNSCC. METHODS: In the randomised, double-blind, phase 3 KEYNOTE-412 trial, participants with newly diagnosed, high-risk, unresected locally advanced HNSCC from 130 medical centres globally were randomly assigned (1:1) to pembrolizumab (200 mg) plus chemoradiotherapy or placebo plus chemoradiotherapy. Randomisation was done using an interactive response technology system and was stratified by investigator's choice of radiotherapy regimen, tumour site and p16 status, and disease stage, with participants randomly assigned in blocks of four per stratum. Participants, investigators, and sponsor personnel were masked to treatment assignments. Local pharmacists were aware of assignments to support treatment preparation. Pembrolizumab and placebo were administered intravenously once every 3 weeks for up to 17 doses (one before chemoradiotherapy, two during chemoradiotherapy, 14 as maintenance therapy). Chemoradiotherapy included cisplatin (100 mg/m2) administered intravenously once every 3 weeks for two or three doses and accelerated or standard fractionation radiotherapy (70 Gy delivered in 35 fractions). The primary endpoint was event-free survival analysed in all randomly assigned participants. Safety was analysed in all participants who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03040999, and is active but not recruiting. FINDINGS: Between April 19, 2017, and May 2, 2019, 804 participants were randomly assigned to the pembrolizumab group (n=402) or the placebo group (n=402). 660 (82%) of 804 participants were male, 144 (18%) were female, and 622 (77%) were White. Median study follow-up was 47·7 months (IQR 42·1-52·3). Median event-free survival was not reached (95% CI 44·7 months-not reached) in the pembrolizumab group and 46·6 months (27·5-not reached) in the placebo group (hazard ratio 0·83 [95% CI 0·68-1·03]; log-rank p=0·043 [significance threshold, p≤0·024]). 367 (92%) of 398 participants treated in the pembrolizumab group and 352 (88%) of 398 participants treated in the placebo group had grade 3 or worse adverse events. The most common grade 3 or worse adverse events were decreased neutrophil count (108 [27%] of 398 participants in the pembrolizumab group vs 100 [25%] of 398 participants in the placebo group), stomatitis (80 [20%] vs 69 [17%]), anaemia (80 [20%] vs 61 [15%]), dysphagia (76 [19%] vs 62 [16%]), and decreased lymphocyte count (76 [19%] vs 81 [20%]). Serious adverse events occurred in 245 (62%) participants in the pembrolizumab group versus 197 (49%) participants in the placebo group, most commonly pneumonia (43 [11%] vs 25 [6%]), acute kidney injury (33 [8%] vs 30 [8%]), and febrile neutropenia (24 [6%] vs seven [2%]). Treatment-related adverse events led to death in four (1%) participants in the pembrolizumab group (one participant each from aspiration pneumonia, end-stage renal disease, pneumonia, and sclerosing cholangitis) and six (2%) participants in the placebo group (three participants from pharyngeal haemorrhage and one participant each from mouth haemorrhage, post-procedural haemorrhage, and sepsis). INTERPRETATION: Pembrolizumab plus chemoradiotherapy did not significantly improve event-free survival compared with chemoradiotherapy alone in a molecularly unselected, locally advanced HNSCC population. No new safety signals were seen. Locally advanced HNSCC remains a challenging disease that requires better treatment approaches. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.

The use of pembrolizumab monotherapy for the management of head and neck squamous cell carcinoma (HNSCC) in the UK.

Pembrolizumab has received approval in the UK as first-line monotherapy for recurrent and/or metastatic HNSCC (R/M HNSCC) following the results of the KEYNOTE-048 trial, which demonstrated a longer overall survival (OS) in comparison to the EXTREME chemotherapy regimen in patients with a combined positive score (CPS) ≥1. In this article, we provide retrospective real-world data on the role of pembrolizumab monotherapy as first-line systemic therapy for HNSCC across 18 centers in the UK from March 20, 2020 to May 31, 2021. 211 patients were included, and in the efficacy analysis, the objective response rate (ORR) was 24.7%, the median progression-free survival (PFS) was 4.8 months (95% confidence interval [CI]: 3.6-6.1), and the median OS was 10.8 months (95% CI 9.0-12.5). Pembrolizumab monotherapy was well tolerated, with 18 patients having to stop treatment owing to immune-related adverse events (irAEs). 53 patients proceeded to second-line treatment with a median PFS2 of 10.2 months (95% CI: 8.8-11.5). Moreover, patients with documented irAEs had a statistically significant longer median PFS (11.3 vs. 3.3 months; log-rank p value = <.001) and median OS (18.8 vs. 8.9 months; log-rank p value <.001). The efficacy and safety of pembrolizumab first-line monotherapy for HNSCC has been validated using real-world data.

Potentially functional variants of CHMP4A and PANX1 in the pyroptosis-related pathway predict survival of patients with non-oropharyngeal head and neck squamous cell carcinoma.

BACKGROUND: Pyroptosis has been implicated in the advancement of various cancers. Triggering pyroptosis within tumors amplifies the immune response, thereby fostering an antitumor immune environment. Nonetheless, few published studies have evaluated associations between functional variants in the pyroptosis-related genes and clinical outcomes of patients with non-oropharyngeal head and neck squamous cell carcinoma (NON-ORO HNSCC). METHODS: We conducted an association study of 985 NON-ORO HNSCC patients who were randomly divided into two groups: the discovery group of 492 patients and the replication group of 493 patients. We used Cox proportional hazards regression analysis to examine associations between genetic variants of the pyroptosis-related genes and survival of patients with NON-ORO HNSCC. Bayesian false discovery probability (BFDP) was used for multiple testing correction. Functional annotation was applied to the identified survival-associated genetic variants. RESULTS: There are 8254 single-nucleotide polymorphisms (SNPs) located in 82 pyroptosis-related genes, of which 202 SNPs passed multiple testing correction with BFDP < 0.8 in the discovery and six SNPs retained statistically significant in the replication. In subsequent stepwise multivariable Cox regression analysis, two independent SNPs (CHMP4A rs1997996 G > A and PANX1 rs56175344 C > G) remained significant with an adjusted hazard ratios (HR) of 1.31 (95% confidence interval [CI] = 1.09-1.57, p = 0.004) and 0.65 (95% CI = 0.51-0.83, p = 0.0005) for overall survival (OS), respectively. Further analysis of the combined genotypes revealed progressively worse OS associated with the number of unfavorable genotypes (ptrend < 0.0001 and 0.021 for OS and disease-specific survival, respectively). Moreover, both PANX1 rs56175344G and CHMP4A rs1997996A alleles were correlated with reduced mRNA expression levels. CONCLUSIONS: Genetic variants in the pyroptosis pathway genes may predict the survival of NON-ORO HNSCC patients, likely by reducing the gene expression, but our findings need to be replicated by larger studies.

Prevalence and Association of Sarcopenia with Mortality in Patients with Head and Neck Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: The objective of this meta-analysis was to assess the association of sarcopenia defined on computed tomography (CT) head and neck with survival in head and neck cancer patients. METHODS: Following a PROSPERO-registered protocol, two blinded reviewers extracted data and evaluated the quality of the included studies using the Quality In Prognostic Studies (QUIPS) tool, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The quality of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework. A meta-analysis was conducted using maximally adjusted hazard ratios (HRs) with the random-effects model. Heterogeneity was measured using the I2 statistic and was investigated using meta-regression and subgroup analyses where appropriate. RESULTS: From 37 studies (11,181 participants), sarcopenia was associated with poorer overall survival (HR 2.11, 95% confidence interval [CI] 1.81-2.45; p < 0.01), disease-free survival (HR 1.76, 95% CI 1.38-2.24; p < 0.01), disease-specific survival (HR 2.65, 95% CI 1.80-3.90; p < 0.01), progression-free survival (HR 2.24, 95% CI 1.21-4.13; p < 0.01) and increased chemotherapy or radiotherapy toxicity (risk ratio 2.28, 95% CI 1.31-3.95; p < 0.01). The observed association between sarcopenia and overall survival remained significant across different locations of cancer, treatment modality, tumor stages and geographical region, and did not differ between univariate and multivariate HRs. Statistically significant correlations were observed between the C3 and L3 cross-sectional area, skeletal muscle mass, and skeletal muscle index. CONCLUSIONS: Among patients with head and neck cancers, CT-defined sarcopenia was consistently associated with poorer survival and greater toxicity.

Impact of head and neck radiation on long-term outcomes after carotid revascularization.

OBJECTIVE: Radiation-induced carotid artery stenosis (RICS) is a well-described phenomenon seen after head and neck cancer radiation. Previously published literature suggests that, compared with atherosclerotic disease, RICS may result in worse long-term outcomes and early restenosis. This study aims to evaluate the effect of radiation on long-term outcomes after various carotid revascularization techniques using a multi-center registry database. METHODS: Patients in the Society for Vascular Surgery (SVS) Vascular Quality Initiative (VQI) registry for carotid artery intervention (carotid endarterectomy [CEA]; transfemoral carotid artery stenting [CAS]; transcarotid artery revascularization [TCAR]), who are 65 years or older were included in the study. VQI Vascular Implant Surveillance and Interventional Outcomes Network (VISION) Medicare-linked database was used to obtain long-term procedure-specific outcomes. Primary endpoints were 3-year death, stroke, and reintervention. We performed propensity matching between patients with prior radiation and those without. Kaplan-Meier analysis and a multivariate logistic regression model were used to analyze the outcome variables. RESULTS: A total of 56,472 patients had undergone carotid revascularization (CEA, n = 48,307; TCAR, n = 4593; CAS, n = 3572), 1244 patients with prior radiation and 54,925 patients without prior radiation. The prior radiation group was more likely to be male (71.9% vs 60.3%; P < .01), to receive a stent (47.5% vs 13.5%; P < .01), and to be on P2Y12 inhibitor (55.2% vs 38.3%; P < .01). Propensity matching was performed on 1223 patients (CEA, n = 655; TCAR, n = 292; CAS, n = 287). There were no significant differences in 30-day outcomes for death, stroke, or major adverse cardiovascular events for all three procedures. The prior radiation group had higher rates of cranial nerve injury (3.7% vs 1.8%; P = .04) and 90-day readmission (23.5% vs 18.3%; P = .01) after CEA. For long-term outcomes, prior radiation significantly increased mortality risk for CEA and CAS (hazard ratio [HR], 1.77; 95% confidence interval [CI], 1.38-2.27 and HR, 1.56; 95% CI, 1.02-2.36, respectively). The 3-year risk of stroke for CEA in radiated patients was also significantly higher (HR, 1.47; 95% CI, 1.03-2.09) compared with non-radiated patients. Prior radiation did not significantly affect death and stroke in patients undergoing TCAR. Prior radiation also did not impact the rates of short and long-term reintervention after CEA, CAS, or TCAR. CONCLUSIONS: Prior head and neck radiation significantly increases the risk for mortality and stroke for CEA and the risk for mortality after CAS. Long-term outcomes for TCAR are not significantly affected by prior radiation. TCAR may be the preferred treatment modality for patients with radiation-induced carotid stenosis.

Prognostic factors and risk-stratification model of recurrent or metastatic head and neck squamous cell carcinoma treated with cetuximab containing regimen.

BACKGROUND: In recent years, the addition of cetuximab to chemotherapy has improved treatment outcomes for patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). In this study, we present the real-world survival data of R/M HNSCC patients who received cetuximab-containing regimens from thirteen medical centers in Taiwan, as well as a three-level risk stratification model for this patient population. METHODS: This study enrolled R/M HNSCC patients from thirteen medical centers in Taiwan who received cetuximab-containing regimens from January 1, 2017 to June 6, 2022. The cases were divided into a training cohort and a validation cohort based on the start of treatment. Overall survival (OS) was evaluated in both cohorts and exploratory analysis was performed to identify associated adverse clinical and laboratory factors. The results of the exploratory analysis were used to construct a three-level risk stratification prediction model for OS. RESULTS: A total of 1434 patients with R/M HNSCC were enrolled in this study and received cetuximab-containing regimens. The overall population had a median OS of 8.57 months (95% CI: 8.07 - 9.08). Multivariate analysis of the training cohort identified poor ECOG performance status, heavy alcohol consumption, and prior adjuvant CCRT or lack of prior RT as adverse prognostic factors. Comparison of laboratory data between patients with OS≦6 and OS > 6 also revealed unfavorable factors, including increased white blood cell count, decreased hemoglobin level, increased platelet count, increased absolute neutrophil count, decreased absolute lymphocyte count, and increased neutrophil-to-lymphocyte ratio. Using forward prediction, a three-level risk stratification prediction model was constructed using the variables of ECOG performance status, alcohol consumption, skin metastasis, modality of radiation therapy, hemoglobin level, and neutrophil-to-lymphocyte ratio. The median OS in the low-risk, intermediate-risk, and high-risk groups were 12.02 months (95% CI 10.44-13.61), 7.5 months (95% CI 7.33-8.17), and 4.01 months (95% CI 3.94-4.08), respectively, with a log-rank test p-value < 0.001. CONCLUSION: This study presents a three-level risk stratification model with strong prediction ability for OS in R/M HNSCC patients who received cetuximab-containing regimens. The results are based on real-world data and may provide valuable information for clinicians in treatment planning and future drug development.

Association of low adherence to weekly cisplatin with outcomes in patients with head and neck squamous cell carcinoma: a retrospective cohort study.

BACKGROUND: The National Comprehensive Cancer Network (NCCN) guideline recommends consideration of weekly cisplatin as an alternative option for patients with head and neck cancer undergoing definitive chemoradiation. However, in a recent phase III trial (ConCERT), 20% of patients treated with weekly cisplatin could not receive a total of 200 mg/m2, and the association of low adherence to weekly cisplatin and cancer control outcomes remains unclear. To fill this knowledge gap, we performed an observational cohort study of patients with head and neck cancer undergoing definitive chemoradiation with weekly cisplatin. METHODS: Our institutional database was queried for patients with non-metastatic head and neck cancer who underwent definitive chemoradiation with weekly cisplatin (40 mg/m2) between November 2007 and April 2023. Adherence to weekly cisplatin was defined as receiving at least 5 cycles with a total cumulative dose of 200 mg/m2. Survival outcomes were evaluated using Kaplan-Meier method, log-rank tests, Cox proportional hazard multivariable (MVA) analyses. Logistic MVA was performed to identify variables associated with low adherence to weekly cisplatin. Fine-Gray MVA was performed to analyze failure outcomes with death as a competing event. RESULTS: Among 119 patients who met our criteria, 51 patients (42.9%) had low adherence to weekly cisplatin. Median follow up was 19.8 months (interquartile range 8.8-65.6). Low adherence to weekly cisplatin was associated with worse overall survival (adjusted hazards ratio [aHR] 2.94, 95% confidence interval [CI] 1.58-5.47, p < 0.001) and progression-free survival (aHR 2.32, 95% CI 1.29-4.17, p = 0.005). It was also associated with worse distant failure (aHR 4.55, 95% CI 1.19-17.3, p = 0.03), but not locoregional failure (aHR 1.61, 95% CI 0.46-5.58, p = 0.46). KPS < 90 was the only variable associated with low adherence to weekly cisplatin (adjusted odds ratio [aOR] 2.67, 95% CI 1.10-6.65, p = 0.03). CONCLUSION: Our study suggested that over 40% of patients underwent fewer than 5 weekly cisplatin cycles and that low adherence to weekly cisplatin was an independent, adverse prognostic factor for worse survival and distant failure outcomes. Those with reduced adherence to weekly cisplatin were more likely to have poor performance status. Further studies are warranted to improve the adherence to chemotherapy and outcomes.

Exosomal transcript cargo and functional correlation with HNSCC patients' survival.

BACKGROUND: HPV status in a subset of HNSCC is linked with distinct treatment outcomes. Present investigation aims to elucidate the distinct clinicopathological features of HPV-positive and HPV-negative HNSCC and investigate their association with the HNSCC patient survival. MATERIALS AND METHODS: The total RNA of exosomes from HPV-positive (93VU147T) and HPV-negative (OCT-1) HNSCC cells was isolated, and the transcripts were estimated using Illumina HiSeq X. The expression of altered transcripts and their clinical relevance were further analyzed using publicly available cancer transcriptome data from The Cancer Genome Atlas (TCGA). RESULTS: Transcriptomic analyses identified 3785 differentially exported transcripts (DETs) in HPV-positive exosomes compared to HPV-negative exosomes. DETs that regulate the protein machinery, cellular redox potential, and various neurological disorder-related pathways were over-represented in HPV-positive exosomes. TCGA database revealed the clinical relevance of altered transcripts. Among commonly exported abundant transcripts, SGK1 and MAD1L1 showed high expression, which has been correlated with poor survival in HNSCC patients. In the top 20 DETs of HPV-negative exosomes, high expression of FADS3, SGK3, and TESK2 correlated with poor survival of the HNSCC patients in the TCGA database. CONCLUSION: Overall, our study demonstrates that HPV-positive and HPV-negative cells' exosomes carried differential transcripts cargo that may be related to pathways associated with neurological disorders. Additionally, the altered transcripts identified have clinical relevance, correlating with patient survival in HNSCC, thereby highlighting their potential as biomarkers and as therapeutic targets.

Retinol-binding protein type 1 expression predicts poor prognosis in head and neck squamous cell carcinoma.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent malignancy worldwide, with high incidence and poor survival rates. RBP1 is highly expressed in several kinds of cancer and plays a potential prognostic factor. However, the relationship between RBP1 and HNSCC were analyzed based on The Cancer Genome Atlas (TCGA) database. MATERIALS AND METHODS: RBP1 expression and clinical information were obtained from the Cancer Genome Atlas (TCGA) database. Tumor tissue and adjacent normal tissue of 6 HNSCC patients were collected to analyze the RBP1 mRNA expression level by quantitative PCR. Cox regression analysis was used to evaluate the prognostic values of RBP1 and clinical data in HNSCC. A nomogram was also established to predict the impact of RBP1 on prognosis based on Cox multivariate results. The methylation level of RBP1 in HNSC and its prognosis were analyzed in UALACN and MethSurv. Finally, the potential biological functions of RBP1 were investigated using gene set enrichment analysis (GSEA) and single sample GSEA (ssGSEA). RESULTS: The mRNA expression levels of RBP1 were highly expressed in HNSCC tissue. The Cox analyses demonstrate that highly-expressed RBP1 is an independent prognosis marker(P < 0.05). ROC curve analysis showed that performances of RBP1 (area under the ROC curve: 0.887, sensitivity: 84.1%, specificity: 79.9%). The methylation was increased in HNSCC patients compared with normal subjects(P < 0.05) and was associated with better prognosis at sites cg06208339, cg12298268, cg12497564, cg15288618, cg20532370, cg23448348. Additionally, RBP1 expression is mildly associated with immune cell infiltration and immunological checkpoints. CONCLUSION: RBP1 is overexpressed and associated with poor patient prognosis in head and neck squamous cell carcinoma.

Lymph node metastasis in cutaneous squamous cell carcinoma of the head and neck.

BACKGROUND: The study aimed to assess the impact of parotid lymph nodes (LNs) on the prognosis of patients with cutaneous squamous cell carcinomas of the head and neck (HNcSCC), and to develop an alternative LN assessment method to enhance locoregional control (LRC) and overall survival (OS) stratification. METHODS: We retrospectively enrolled patients with surgically treated HNcSCC. Primary outcome variables were LRC and OS. The influence of parotid LNs and different LN assessment methods on prognosis was analyzed using Cox models, and comparisons were made using the C-index, Akaike Information Criterion, and Bayesian Information Criterion. RESULTS: A total of 126 patients were included. Both intraparotid and periparotid LN statuses significantly linked with prognosis. The presence of extranodal extension (ENE) in cervical LNs, rather than parotid LNs, was predictive of decreased LRC and OS. In the Cox analysis, only N3 of the AJCC N classification, when compared to N0, showed reduced LRC and OS. In comparison to N0P1, only N0P3/N1P1 and N2P2/N2P3 of the O'Brien staging system tended to predict poorer LRC, with no subgroup emerging as an independent predictor for OS. The proposed LN assessment method, based on the number of metastatic LNs and ENE status in cervical LNs, demonstrated superior performance in terms of C-index, Akaike Information Criterion, and Bayesian Information Criterion compared to other systems. CONCLUSION: Parotid LNs were significant determinants of prognosis in metastatic HNcSCC. The novel LN assessment method proposed (1-2 vs. 3-4 vs. 5 + or ENE) displayed similar survival stratification to the AJCC N and O'Brien staging systems.

Prognostic Impact of Malignant Wounds in Patients With Head and Neck Cancer: Secondary Analysis of a Prospective Cohort Study.

INTRODUCTION: Malignant wounds are lesions caused by metastasis from distant primary cancers or by direct invasion of the cutaneous structures of a primary cancer, and are most common in patients with breast or head and neck cancers. Malignant wounds not only cause physical symptoms, but also affect survival. Recognizing prognosis in terminal-stage cancer patients is necessary for both patients and health care providers. The prognostic impact of malignant wounds in patients with head and neck cancer has been poorly investigated. METHODS: This is a secondary analysis of the results of a prospective cohort study that investigated the dying process in patients with advanced cancer in 23 palliative care units in Japan. The primary outcome of this study was the prognostic impact of malignant wounds in patients with head and neck cancer. The difference in survival between patients with head and neck cancer who had malignant wounds and those who did not was compared using the log-rank test. RESULTS: Of 1896 patients admitted to palliative care units, 68 had head and neck cancer, and 29 of these had malignant wounds. Overall survival was significantly shorter in patients with malignant wounds than that in those without (median: 19.0 days vs 32.0 days, P = 0.046). CONCLUSION: Patients with head and neck cancer who had malignant wounds had worse overall survival than those who did not.

A Network Meta-Analysis of the Systemic Therapies in Unresectable Head and Neck Squamous Cell Carcinoma.

The current standard treatment for locally advanced squamous cell carcinoma of the head and neck (LASCCHN) comprises concurrent radiotherapy (CRT) alongside platinum-based chemotherapy. However, innovative therapeutic alternatives are being evaluated in phase II/III randomized trials. This study employed a Bayesian network meta-analysis (NMA) using fixed effects to provide both direct and indirect comparisons of all existing treatment modalities for unresectable LASCCHN. METHODS: We referenced randomized controlled trials (RCTs) from January 2000 to July 2023 by extensively reviewing PubMed, EMBASE, and Web of Science databases, adhering to the Cochrane methodology. Relevant data, including summary estimates of overall survival (OS) and progression-free survival (PFS), were extracted from these selected studies and recorded in a predefined database sheet. Subsequently, we conducted a random effects network meta-analysis using a Bayesian framework. RESULTS: Based on the Surface Under the Cumulative Ranking (SUCRA) values, the league table organizes the various treatments for OS in the following order: IC + RT&MTT, MTT-CRT, IC + CRT&MTT, CRT, IC + CRT, MTT-RT, IC + MTT-RT, and RT. In a similar order, the treatments rank as follows according to the league table: IC + CRT&MTT, MTT-CRT, IC + CRT, IC + RT&MTT, CRT, IC + MTT-RT, MTT-RT, and RT. Notably, none of these treatments showed significant advantages over concurrent chemoradiotherapy. CONCLUSION: Despite concurrent chemoradiotherapy being the prevailing treatment for LASCCHN, our findings suggest the potential for improved outcomes when concurrent chemoradiotherapy is combined with targeted therapy or induction chemotherapy.

The current standard treatment for advanced head and neck cancer involves combining radiation therapy with chemotherapy. However, there are ongoing trials exploring alternative therapies. In this study, we conducted a comprehensive analysis of existing treatments using a statistical method called network meta-analysis. Our analysis included data from randomized controlled trials published between January 2000 and July 2023. We focused on overall survival and progression-free survival as key outcome measures. The results of our analysis showed that none of the alternative treatments demonstrated significant advantages over the standard concurrent chemoradiotherapy. Nevertheless, there is potential for improved outcomes when targeted therapy or induction chemotherapy is combined with concurrent chemoradiotherapy.

Comprehensive Analysis Identifies Hyaluronan Mediated Motility Receptor and Cell Division Cycle 25C as Potential Prognostic Biomarkers in Head and Neck Squamous Cell Carcinoma.

INTRODUCTION: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, but its pathogenic mechanisms remain unclear. This study aimed to identify the potential biomarkers underlying the diagnosis and treatment of HNSCC. METHODS: Weighted gene co-expression network analysis (WGCNA) followed by pathway enrichment analysis, analysis of infiltrating immune cells, survival analysis, and methylation analysis were applied to identify the potential hub genes underlying the prognosis of HNSCC. The expression of hub genes was validated by immunofluorescence staining. RESULTS: A total of 10,274 differentially expressed genes (DEGs) were identified. Through WGCNA, the yellow module (R2 = 0.33, P = 2e-14) was confirmed to be the most significantly associated with the histological grade of HNSCC, and the "Cell Cycle" proved to be the most enriched signaling pathway. Based on the results of survival analysis and immune cell infiltration, 10 hub genes (HMMR, CENPK, AURKA, CDC25C, FEN1, CKS1B, MAJIN, PCLAF, SPC25, and STAG3) were identified. Eight of these (excluding MAJIN and STAG3) were confirmed by performing survival analysis using another dataset (GSE41613). Further, we identified 4 methylation loci in 3 hub genes (cg15122828 and cg20554926 in HMMR, cg12519992 in CDC25C, and cg2655739 in KIAA0101/PCLAF) as being significantly related to survival. Finally, we demonstrated the high mRNA and protein expression of HMMR and CDC25C in HNSCC patients. CONCLUSION: Two real hub genes (HMMR and CDC25C) and 3 methylation loci were identified that could potentially serve as prognostic and therapeutic targets for HNSCC, which is significant for studying the pathological mechanisms underlying HNSCC and for developing novel therapies for this disease.

Anxiety symptoms predict head and neck cancer survival: Exploring mediation by systemic inflammation and tumor response to treatment.

BACKGROUND: Head and neck cancers (HNC) are associated with high rates of anxiety. Anxiety has been linked to biological pathways implicated in cancer progression, though little is known about its effects on overall survival. We hypothesized that higher pretreatment anxiety levels in patients with HNC would predict poorer 2-year overall survival and expected this relationship to be mediated by both systemic inflammation and tumor response to treatment. METHODS: Patients (N = 394) reported anxiety symptomatology via the GAD-7 at treatment planning. Pre-treatment hematology workup provided an index of systemic inflammation (SII; N = 292). Clinical data review yielded tumor response and overall survival. Logistic and multiple regressions and Cox proportional hazard models tested hypothesized relationships. RESULTS: Higher pretreatment anxiety levels were significantly associated with poorer 2-year survival (hazard ratio [HR], 1.039; 95% confidence interval [CI], 1.014-1.066, p = 0.002). The association between anxiety and SII was not significant, though anxiety was associated with poorer tumor response (odds ratio [OR], 1.033; 95% CI, 1.001-1.066, p = 0.043). Tumor response fully mediated the relationship between anxiety symptoms and 2-year survival (HR, 9.290, 95% CI, 6.152-14.031, p < 0.001). CONCLUSIONS: Anxiety was associated with overall survival. Tumor response, but not systemic inflammation, emerged as a potential biological pathway mediating this effect. Screening for anxiety may be beneficial to help prospectively address these concerns and ameliorate potentially detrimental impact on clinically meaningful cancer outcomes.

Survivorship Needs in Patients With Head and Neck Cancer in Regional, Rural and Remote Areas: A Systematic Review.

OBJECTIVE: Understanding survivorship issues among people with head and neck cancer (HNC) is important as survival rates increase. Most research has focused on urban patients, leaving a gap in understanding the challenges faced by those in rural areas. This study aims to summarise the literature on survivorship needs for people with HNC in rural areas. METHODS: PubMed, PsycINFO, Scopus, Medline, CINAHL, Web of Science, and Embase were searched from database inception to 10 July 2024, with no restriction on publication period, country, or language. Data on study aims, country, methodology, and major findings related to HNC survivors in rural areas were extracted. Study quality was assessed using the Joanna Briggs Institute critical appraisal checklists. RESULTS: Twenty-one studies met the inclusion criteria. Eight studies were qualitative, 11 were quantitative, and two adopted a mixed-methods approach. Results demonstrate the impact of complex treatments on physical (n = 13) and psychosocial (n = 14) functioning. This study also emphasises multifaceted challenges, including reduced access to specialised services, resulting in greater travel and financial burden, extending to caregivers. Hence, primary healthcare services are crucial in supporting these patients closer to home. CONCLUSIONS: Addressing the gaps in equitable post-treatment care requires an even distribution of healthcare funding and workforce in rural areas. Future research could target these issues to develop tailored interventions or models of care, such as shared care, to ease access and financial burden.

The epidemiology of dermatofibrosarcoma protuberans incidence, metastasis, and death among various population groups: A Surveillance, Epidemiology, and End Results database analysis.

BACKGROUND: Limited information exists regarding the epidemiology, metastasis, and survival of dermatofibrosarcoma protuberans (DFSP). OBJECTIVE: To measure DFSP incidence and assess metastasis and survival outcomes. METHODS: Incidence rate, overall and DFSP-specific survival outcomes for primary DFSP tumors contained in the Surveillance, Epidemiology, and End Results (SEER) registry were analyzed via quasi-Poisson regression, Cox, and competing risk analyses. RESULTS: DFSP incidence rate was 6.25 (95% CI, 5.93-6.57) cases per million person-years with significantly higher incidence observed among Black individuals than White individuals (8.74 vs 4.53). DFSP with larger tumor size (≥3 cm, odds ratio [OR]: 2.24; 95% CI, 1.62-3.12; P < .001) and tumors located on the head and neck (OR: 4.88; 95% CI, 3.31-7.18; P < .001), and genitalia (OR: 3.16; 95% CI, 1.17-8.52; P = .023) were associated with significantly increased risk of metastasis whereas higher socioeconomic status was associated with significantly decreased risk of metastasis. Larger tumor size (≥3 cm), regardless of location, and age (≥60 years) were associated with significantly worse overall and cancer-specific survival. LIMITATIONS: Retrospective design of SEER. CONCLUSION: DFSP incidence is 2-fold higher among Black than White individuals. The risk of DFSP metastasis is significantly increased with tumor size ≥3 cm and tumors located on head and neck, and genitalia. Larger tumor size (≥ 3 cm), regardless of location, and age (≥60 years) are the most important prognostic indicators of survival.