6105 Background: Neoadjuvant immunochemotherapy (NICT) results in high pathologic response rates in locally advanced head and neck squamous cell carcinoma (LA-HNSCC). However, whether it is safe to omit postoperative radiotherapy (PORT) for patients who achieved pathologic complete response (pCR) after NICT and surgery remains unclear. We assessed the survival and patient-reported outcomes (PROs) for LA-HNSCC patients who achieved pCR to NICT. Methods: This retrospective cohort study included LA-HNSCC patients who achieved pCR to NICT between July 2019 and June 2025. Patients were categorized into two groups based on whether they received PORT. Propensity score matching (PSM) was performed to minimize confounding and balance baseline characteristics. Kaplan-Meier survival analysis was performed to estimate local recurrence-free survival (LRFS), locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS), and overall survival (OS). EORTC QLQ-C30 and EORTC QLQ-HN35 questionnaires before NICT, preoperatively, and at month 1, 3, and 12 postoperatively were collected. Least-squares mean (LS mean) changes from baseline were estimated using linear mixed-effects models for repeated measures (group, time, and group×time), adjusting for baseline scores. Results: A total of 236 HNSCC patients who achieved pCR after NICT and surgery were included (non-PORT, n = 98; PORT, n = 138). After 1:1 PSM to balance baseline characteristics, 164 patients (82 matched pairs) with comparable baseline characteristics were analyzed. With a median follow-up of 31.67 months (95% CI, 29.57-35.35), survival analysis showed no significant differences between the non-PORT and PORT groups in 2-year LRFS, LRRFS, DMFS or OS (all p > 0.05). Longitudinal EORTC QLQ-C30 global health/QOL analyses showed poorer recovery in the PORT group. PORT was associated with significantly greater postoperative QOL decline at 1 and 3 months postoperatively, with a persistent deficit at 12 months , while non-PORT improved above baseline by 12 months whereas PORT remained slightly reduced. On the EORTC QLQ-HN35, PORT was associated with persistently higher symptom burden, peaking at 3 months postoperatively and remaining elevated up to 1 year compared with non-PORT, suggesting potential QOL benefits of omitting PORT in pCR patients. Conclusions: In this propensity score-matched cohort of LA-HNSCC patients achieving pCR after NICT and surgery, omitting PORT was associated with comparable 2-year disease control and survival but better recovery of multidimensional QOL and lower symptom burden on head and neck-specific PROs. These findings favor omission of PORT for this patient population, while prospective validation and longer follow-up are warranted.

6070 Background: Neoadjuvant PD-1 blockade plus chemotherapy can induce deep pathologic responses in HNSCC. However, pCR is an imperfect surrogate for OS, and the prior study showed that >50% of patients achieving CR after neoadjuvant chemo-immunotherapy relapse rapidly without local therapy, suggesting post-treatment ecosystems may retain programs supporting residual cell persistence and relapse. Methods: We profiled tumors from treatment-naïve patients and from patients receiving neoadjuvant taxane/platinum (TP) plus PD-1 blockade with partial response or pCR using scRNA-seq and Xenium spatial transcriptomics. Integrated computational analyses mapped residual epithelial/microenvironmental programs and spatial organization, with validation by immunoblotting, flow cytometry, and mIHC. Translational strategies were evaluated in a 4NQO-induced murine model and a PD-1–resistant murine tongue cancer line. Results: We identified a KRT15+IL1R2+ stem-like epithelial population enriched after therapy, most prominent in pCR (61/78 patients), localized to post-treatment regression beds but not discernible on H&E. They were viable and quiescent, lacking DNA damage and cell-death activation; CytoTRACE indicated high differentiation potential, suggesting tumor-repopulating cells. Concerning the microenvironment, across the response continuum from treatment-naïve to partial pathologic response to pCR, scRNA-seq revealed stepwise enrichment of infiltrating non-exhausted cytotoxic CD8 effector T cells, consistent with progressively strengthened tumoricidal immunity. In contrast, deep responders displayed a shift toward a repair-dominant niche: macrophages progressively transitioned from CXCL9+ inflammatory monocytes to SPP1+ macrophages with reduced antigen-presentation programs and enhanced tissue-remodeling features, accompanied by enrichment of multiple repair-associated fibroblast states. Xenium further supported spatial proximity and putative interactions among IL1R2+ epithelium, macrophages, and fibroblasts, which may limited T cell–tumor contact. IL1R2 upregulation was also observed in a PD-1–resistant murine tongue cancer line. In vivo, IL-1β co-administration with PD-1 blockade attenuated treatment efficacy, whereas anti–IL-1β antibody combined with PD-1 blockade enhanced efficacy. Conclusions: Deep responses to neoadjuvant chemo-immunotherapy are coupled with a paradoxical repair program and enrichment of IL1R2+ stem-like epithelium that may permit residual persistence and recurrence. The IL-1β–IL1R2 axis is a translationally actionable lever to improve durability and mitigate relapse. Given residual risk even after pCR, de-escalation of local therapy (such as reducing surgical extent or altering definitive treatment strategies) warrants caution.

Background:Neoadjuvant chemotherapy combined with immunotherapy results in high pathologic response rates in locally advanced oral and oropharyngeal cancer (OC/OPC). It is unclear if patients with clinical T3-4 (cT3-4) OC/OPC at initial diagnosis can safely omit adjuvant radiotherapy (ART) after significant pathological downstaging. Methods:This retrospective cohort study included cT3-4 OC/OPC patients who achieved a major pathologic response (MPR) after neoadjuvant immunochemotherapy between July 2019 and May 2024. Patients were categorized by whether they received ART. Propensity score matching was used to balance baseline characteristics. Local recurrence-free survival (LRFS), locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS), and overall survival (OS) were compared between cohorts. Results:A total of 247 patients were eligible, with a median follow-up of 31 months (IQR, 20-41). The 2-year survival outcomes were favorable: LRFS 93.4%, LRRFS 85.0%, DMFS 95.6%, and OS 93.0%. In the matched cohorts (74 pairs), ART significantly improved 2-year LRFS (100% vs. 85.5%, p = 0.001), and LRRFS (91.5% vs. 77.5%, p = 0.014), but not DMFS (96.4% vs. 95.6%, p = 0.740), and OS (96.5% vs. 90.0%, p = 0.093). These benefits remained significant among patients with ypT0-2 tumors after matching. Conclusions:Omitting ART in patients with cT3-4 OC/OPC who achieve MPR after neoadjuvant immunochemotherapy and surgery significantly compromises oncological outcomes. Further investigation is necessary to optimize adaptive de-escalation strategies for this population.

e18145 Background: Anaplastic thyroid carcinoma (ATC) and poorly differentiated thyroid carcinoma (PDTC) are rare and aggressive thyroid cancers, with limited data on their clinicopathological features and survival outcomes. This study aimed to characterize the real-world features of ATC and PDTC and identify prognostic factors, with an emphasis on evaluating therapeutic strategies. Methods: This retrospective study analyzed 92 ATC and 89 PDTC patients diagnosed at a tertiary institution between 1997 and 2025. Demographic, clinical, pathological, molecular, and treatment data were collected, including combined positive score (CPS), treatments (surgery, radiotherapy, chemotherapy, targeted therapies [TT], immunotherapy [IO]), and follow-up information. Overall survival (OS) was estimated using the Kaplan-Meier method and compared via the log-rank test. Prognostic factors were evaluated using univariate and multivariate Cox regression models. Results: The median OS for ATC and PDTC was 15 months and 62 months, respectively. ATC patients were older at diagnosis (p<0.001), presented with more advanced local disease (p=0.002), and exhibited fewer distant metastases (p=0.033) compared to PDTC patients. The ATC group showed higher gene mutation rates (p=0.009), more CPS-positive cases (CPS>1, p=0.035), and received more intensive treatments, including higher rates of IO (p=0.006), TT+IO (p=0.015), and multimodal therapy (≥3 modalities, p=0.001). Univariate and multivariate Cox regression analyses identified age, TP53 mutation, TT+IO, and multimodal treatment as significant prognostic factors for ATC. Multimodal treatment significantly improved survival in ATC (p=0.003), with surgery combined with TT+IO yielding better outcomes for metastatic ATC (p=0.019). TP53 mutation and co-mutation (≥3 mutations) were associated with significantly worse survival (p=0.003 and p=0.008). Metastatic PDTC patients benefited from IO-based multimodal therapies (p=0.031). Additionally, both ATC and PDTC showed improved survival post-2018, coinciding with the introduction of immunotherapy (p=0.017 and p=0.045). Conclusions: ATC and PDTC exhibit distinct clinicopathological features and survival outcomes. Multimodal treatment significantly benefits ATC patients, while TT+IO offers promising survival advantages for metastatic ATC. IO-based multimodal therapy shows potential efficacy for metastatic PDTC. These findings support a disease-specific, IO-based multimodal strategy, which warrants prospective validation and extended follow-up.

Cuproptosis is a type of recently reported cell death characterized by aberrant accumulation of copper ions within cells, leading to mitochondrial stress and protein aggregation. Recent studies suggest that certain cancer cells are particularly susceptible to cuproptosis-inducing agents. However, the genetic determinants of cellular sensitivity to cuproptosis and the therapeutic potential of cuproptosis inducers in cancer treatment remain unclear. Here, we report the discovery of a small molecule, N1,N1-dimethyl-N4-(4-(pyridin-2-yl)thiazol-2-yl)benzene-1,4-diamine (dPTBD), that targets KRAS-driven cancer via a tetracycline-inducible cell-based drug screening. dPTBD exhibited significant antitumor efficacy in KRAS-driven cancers both in vitro and in vivo. Mechanistic studies revealed that dPTBD acted as a copper ionophore, promoting intracellular copper accumulation particularly in the mitochondria, leading to metabolic disruption and cuproptotic cell death. Adding trace amount of copper massively enhanced the cytotoxic effect of dPTBD, resulting in an immediate mitochondrial dysfunction and cuproptosis. In preclinical models, dPTBD, either alone or combined with physiologically tolerable amount of copper, significantly suppressed tumor growth in KRAS-mutant pancreatic and colon cancer xenografts. Taken together, our study reveals that induction of cuproptosis is a new therapeutic strategy for KRAS-driven cancer and identifies dPTBD as a lead compound for future development.

To explore the trajectories of shoulder-related quality of life (QoL) in patients with head and neck cancer undergoing neck dissection, identify factors associated with each trajectory, and determine whether shoulder function differs across different trajectories. Patients with head and neck cancer who underwent neck dissection were followed up at 3 days, 2 weeks, 1 month and 3 months after surgery. A sociodemographic information questionnaire, the Neck Dissection Impairment Index, and the Constant-Murley score were completed. A latent class growth analysis was used to explore the trajectories of shoulder-related QoL. The average age of the 92 patients with head and neck cancer who underwent neck dissection was 37.68 years. The majority of participants had thyroid cancer (88.0

6095 Background: The current standard of care for locally advanced laryngeal squamous cell carcinoma (LA-LSCC), including surgery and chemoradiotherapy, might cause long-term toxicities and laryngeal dysfunctions. The study aims to investigate the efficacy and safety of neoadjuvant cetuximab, sintilimab and stereotactic body radiation therapy (SBRT) treating patients with LA-LSCC for larynx preservation. Methods: In this phase II, single-arm trial, patients with LA-LSCC (cT2N1-3M0 or cT3-4aN0-3M0, AJCC 8.0 th ) were recruited. Eligible patients received SBRT (8 Gy × 3 fractions), followed by sintilimab (200mg, Q3W, 2 cycles) and cetuximab (a loading dose of 400 mg/m 2 , followed by 250 mg/m 2 , QW, 6 cycles). Further treatment was determined by a radiographic evaluation per RECIST 1.1: patients who reached CR or PR would receive intensity modulated radiation therapy (The initial IMRT dose to the primary tumor was 46 Gy in 23 fractions, with a pre-specified plan to reduce the dose to 37.8 Gy based on early tolerance data from the cohort.) or minimally invasive surgery, while ones with SD or PD would receive radical surgery. The primary endpoint was the larynx-preservation rate (LPR) at 1-year post-radiation. Results: Between July 1, 2024 and June 30, 2025, 20 patients were enrolled. 15 (75%) were clinical stage III and 5 were stage IVa. 19 finished neoadjuvant SBRT, sintilimab and cetuximab (one withdrawn due to personal reasons after SBRT), with the ORR of 100% (12 had CR and 7 had PR). Then 18 patients received sequential IMRT, with a median dose of 37.8 Gy (one refused and chose active surveillance). During the whole treatment, grade 3 TRAEs occurred in 5/20 patients (25%), including 3 cases of post-radiation pharyngitis, 1 myocarditis and 1 rash. All 3 cases of grade 3 pharyngitis occurred in the first 6 patients with 46 Gy IMRT. Following a protocol amendment, subsequent patients (n=12) received a reduced dose of 37.8 Gy. In the reduced-dose cohort, no further grade 3+ pharyngitis was observed, while the LPR remained high. After a median follow-up of 7.4 months, 3 patients failed to larynx preservation, including 2 cases with tracheotomies due to pharyngitis and 1 receiving total laryngectomy due to tumor recurrence. Based on results of EORTC QLQ-H&N35 questionnaires, compared to the baseline, most patients reported similar or improved symptoms, including pain, speech and dry mouth, at 6 months post-radiation. Conclusions: Neoadjuvant combination of immunotherapy, targeted therapy and SBRT showed excellent efficacy and tolerant toxicity for patients with LA-LSCC. Importantly, dose reduction of sequential IMRT appears to mitigate severe toxicity without compromising laryngeal preservation, outlining a promising de-escalation strategy for future practice. Clinical trial information: ChiCTR2500100185.

Background:Head and neck squamous cell carcinoma (HNSCC) remains a global health challenge with rising incidence, especially in HPV-associated subtypes. The mismatch repair (MMR) system maintains genomic stability, and its deficiency has been linked to tumor immunogenicity and response to immunotherapy in several cancers. However, its role in HNSCC, particularly in the context of HPV status, remains poorly defined. Objectives:The aim of this study was to compare the imbalance expression of MMR proteins and their association with clinical features and survival in HNSCC. Design:A retrospective, clinicopathological correlation study. Methods:We retrospectively analyzed 369 HNSCC specimens. Tissue microarrays were constructed and immunohistochemically stained for four key MMR proteins (MSH2, MSH6, PMS2, and MLH1) and p16 (as an HPV surrogate). Expression patterns were correlated with clinicopathological variables, immune cell infiltration, and survival outcomes. Results:Among all HNSCC patients, MMR protein expression was preserved in all but one case. MSH2 and PMS2 showed consistently higher nuclear positivity than their partners, MSH6 and MLH1. These imbalances were more pronounced in p16-negative tumors (p < 0.001), whereas p16-positive tumors showed balanced expression. Expression patterns varied by sex, tumor site, drinking history, and AJCC stage. Moreover, MSH6 was significantly lower than MSH2 in nondrinkers (p = 0.039), and PMS2 was lower in advanced-stage patients (p = 0.023). Immunologically, MSH2 expression positively correlated with CD8⁺ T cells in nontumor tissue, while MSH6 and PMS2/MLH1 ratios were inversely correlated with CD4⁺ T cells in tumor tissue. Kaplan-Meier survival analysis revealed that lower MSH2 expression was significantly associated with improved overall survival (p = 0.030). Conclusion:MMR protein expression in HNSCC varies by HPV status and demographic factors and is linked to differential immune infiltration. These findings suggest that MMR protein imbalance may influence tumor immunogenicity and could potentially serve as a biomarker to inform therapeutic strategies in the immunotherapy era, especially in p16-negative tumors.

BACKGROUND:The role of radiation therapy in patients with distant metastatic squamous cell carcinoma of the head and neck (mHNSCC) is unclear. In this study, we compare the differences in survival among mHNSCC patients treated with chemotherapy plus radiotherapy (RT) vs. chemotherapy alone. MATERIALS AND METHODS:This study included patients with distant mHNSCC recruited from 2 cohorts: The Surveillance, Epidemiology, and End Results (SEER [N=885]) database and a Chinese single-institution registry in Sun Yat-sen University Cancer Center (SYSUCC [N=60]). The SEER cohort included 600 patients received RT plus chemotherapy and 285 patients received chemotherapy alone; in the SYSUCC cohort, 40 patients received RT plus chemotherapy and 20 patients received chemotherapy alone were recruited. The period of data collection for the SEER study was from January 2010 to December 2015, and that for SYSUCC was from January 2010 to December 2020. The study's primary outcome was overall survival (OS), with disease-specific survival (DSS) as a secondary outcome. RESULTS:Of the 885 patients in the SEER cohort, the addition of RT to chemotherapy increased one-year OS from 46.6% to 56.0% compared with chemotherapy alone (P =0.009) and from 10.4% to 25.1% for three-year OS (P <0.001). Patients who received RT in addition to chemotherapy were also more likely to have better three-year DSS than those who received chemotherapy alone (28.9% vs. 14.0%, P<0.001). Similarly, in the SYSUCC cohort, patients who received chemotherapy plus RT had better three-year OS than chemotherapy alone (62.8% vs. 21.0%, P=0.003). The addition of RT to chemotherapy increased median OS among patients with mHNSCC from 10 months to 13 months in the SEER cohort and from 14 months to 29 months in the SYSUCC cohort. CONCLUSION:Radiotherapy in addition to chemotherapy significantly improved OS and DSS in patients with mHNSCC.

e18097 Background: Neoadjuvant immunochemotherapy (NICT) showed favorable efficacies and anticipated outcomes for locally advanced head and neck squamous cell carcinoma (LA-HNSCC). However, optimal adjuvant therapy remains uncertain for LA-HNSCC patients who achieved pathological complete response (pCR) after NICT and surgery. This study aims to explore an optimal adjuvant strategy with low-toxicity and survival benefits for these patients. Preliminary results were presented at the 2024 ESMO Congress (Poster 865P), and the consecutively updated results were presented in this report. Methods: In this single-arm, phase II trial, 27 LA-HNSCC patients were planned to be enrolled. Key inclusion criteria were: pathologically confirmed LA-HNSCC patients (stage III-IVB for non-oropharyngeal cancers and HPV-negative oropharyngeal cancer; stage II-III or stage I with adverse features for HPV-positive oropharyngeal cancer, according to the 8th edition of the AJCC staging manual), receipt of at least 1 cycle of NICT (platinum-based chemotherapy and anti-PD-1 immunotherapy) and surgical resection, and achievement of pCR to the primary tumor and regional lymph nodes. Eligible patients received adjuvant immunotherapy with toripalimab (240mg) on day 1 of each 21-day cycle for 8 cycles. The primary end point was 2-year disease-free survival rate. Secondary end points included 2-year overall survival rate, 2-year disease specific survival rate, quality of life, and safety. Results: From Jan 2023 to Nov 2024, a total of 27 patients were enrolled and 24 finished the planned therapy. The median age was 52 years (29-75) and 88.9% were males. After a median follow-up time of 17.7 months, 2 (7.4%) patients suffered local recurrence, one underwent salvage surgery, and one underwent chemotherapy combined with cetuximab. No deaths occurred. Most common treatment-related adverse events (TRAEs) included increased blood creatinine (18.5%), hypothyroidism (14.8%), and skin toxicity (11.1%). 2 (7.4%) patients experienced grade 3 TRAEs including 1 (3.7%) anaemia and 1 (3.7%) ulcerative colitis. Conclusions: The preliminary results highlighted that adjuvant toripalimab for LA-HNSCC patients who achieved pCR after NICT and surgery showed encouraging efficacy and tolerable toxicity. Furthermore, these conclusions required to be confirmed in subsequent trials. Clinical trial information: ChiCTR2300067960 .

ABSTRACT Background The aim of this study is to establish a novel and reproducible orthotopic mouse model, aiming to facilitate research related to laryngeal cancer. Methods Implantation of mouse squamous cell carcinoma cell line, Meer‐LUC, into the larynx of C57BL/6 mice ( n = 16). Tumor growth and survival were observed using magnetic resonance imaging and optical in vivo three‐dimensional imaging. Laryngeal and cervical lymph node specimens were obtained for HE staining and evaluation. Single‐cell sequencing was performed on laryngeal cancer patients, orthotopic mouse models, and subcutaneous tumor models to investigate the immune microenvironment of laryngeal cancer. Results We successfully established 15 cases of in situ laryngeal cancer mouse models. Tumors maintained steady growth at each observation time point, and histopathological evaluation confirmed the successful construction of the model. Single‐cell sequencing results suggest that the orthotopic model better simulates the immune microenvironment alterations of real laryngeal cancer. Conclusions We have developed a novel and reproducible orthotopic mouse model, which more faithfully mimics the immune system response of the human body and better simulates the biological evolution process of tumors. This model provides an essential animal research framework for investigating the molecular mechanisms underlying the occurrence and development of laryngeal cancer.

OBJECTIVE:To analyze the role of lymph node level ratio (LNLR) in predicting prognosis and the benefits of postoperative radiotherapy (PORT) in patients with pathological N1 (pN1) head and neck squamous cell carcinoma (HNSCC). METHODS:Patients with pN1 HNSCC from January 2011 to February 2021 were included. Patients were grouped by the LNLR, lymph node yield (LNY), and lymph node ratio (LNR) and were analyzed with the Kaplan-Meier method and multivariate Cox model. RESULTS:This study identified 310 patients. Time-dependent receiver operating characteristic analyses showed superior prognostic ability for LNLR in comparison with LNY and LNR. Patients with an LNLR ≤ 5.25 had the worst survival. Multivariate regressions demonstrated larger hazard ratios (HRs) and a higher concordance index for the LNLR model versus the LNY and LNR models. The HRs (95 % confidence interval) for a LNLR ≤ 5.25 were 2.46 (1.71-3.54, p < 0.001) for DFS, 1.95 (1.38-2.75, p < 0.001) for OS, 2.25 (1.53-3.29, p < 0.001) for DSS. Furthermore, postoperative radiotherapy-related significant improvement in survival was observed exclusively in the LNLR ≤ 5.25 subgroup. CONCLUSION:The LNLR is a more robust quality indicator for neck dissection. An LNLR of ≤ 5.25 significantly compromises survival and indicates the need for PORT in patients with pN1 HNSCC.

Papillomaviruses (PVs) are groups of ubiquitous DNA viruses infecting a wide range of vertebrate hosts, including human. The infection of some human PVs (i.e., HPVs) are strongly associated with cancers, but it remains elusive how such pathogenicity got evolved at the genomic level. Here we performed a comprehensive super-pangenome analysis on a compendium of well-curated 3562 human and animal PV genomes. We found their global genomic diversity being strongly associated with their body sites and tissue origins, but not with their host, geographical, or disease specificity. By reconciling time-resolved phylogenies of PVs and their hosts, we revealed a high-resolution view on how intra-host codivergence, niche adaptation, horizontal host switches, and duplication/loss turnovers collectively shaped the evolution of PVs. We identified key selection-driven mutations that defined the genus-specific divergence and pathogenic risks of PVs, with the former highly enriched in the E1 gene and the latter showing contrasting genotype patterns between low-risk and high-risk HPVs. With independent clinical cohorts, we further demonstrated how these variants can be highly informative for HPV risk classification even at single site level, underscoring their application values in large-scale HPV screening tests. Finally, with cervical and oropharyngeal cancer patient cohorts assembled by this study, we further evaluated the prognostic value of specific HPV16 variants in predicting patient survival. Taken together, such illumination on the genome and pathogenicity evolution of PVs paves the road for better prevention, control, and treatment of PV-related cancers. Significance Statement Papillomaviruses (PVs) are ancient and widespread DNA viruses co-evolved with many vertebrate hosts, including human. Some human PVs (e.g., HPV16 and HPV18) bear strong association with cancers, raising a pressing public health challenge. A better understanding of how such pathogenicity got evolved holds the key in addressing this challenge. Here we systematically investigated the genomic and evolutionary diversity of PVs via a pangenome study on over 3500 human and animal PV isolates, which revealed key selection-driven mutations shaping their genome and pathogenicity evolution. With independently acquired HPV-associated cancer cohorts, we further demonstrated how some of these important HPV variants can serve as clinically informative predictive and prognostic biomarkers. Such comprehensive characterization on PVs’ genome diversity, pathogenicity evolution, and clinical implication paves the road for better prevention, control, and treatment of PV-related cancers. ### Competing Interest Statement A patent application related to the findings reported in this manuscript has been filed by the authors (Application No. 202510142620.7, China, 2025.02.08). A corresponding international application under the PCT (PCT/CN2025/076515) has also been filed. National Natural Science Foundation of China, https://ror.org/01h0zpd94, 32470663, 32000395 Guangdong Provincial Pearl River Talents Program, 2019QN01Y183, 2021QN02Y168 Natural Science Foundation of Guangdong Province, 2022A1515010717, 2022A1515011873 Young Talents Program of Sun Yat-sen University Cancer Center, YTP-SYSUCC-0042, YTP-SYSUCC-0040

Cathepsin L (CTSL) is an important oncogene. However, its mechanism of action in laryngeal cancer is still unclear. This study aims to explore the role of CTSL in laryngeal cancer and its clinical significance. Conducting bioinformatics analysis utilising the Cancer Genome Atlas (TCGA) database and the Gene Expression Omnibus (GEO) database. Performing CCK8 analysis, Western blotting, qRT-PCR, wound healing assay and transwell invasion assay. Additionally, conducting immunoprecipitation experiments and immunohistochemical staining to investigate the impact of CTSL on cell proliferation, autophagy and related signalling pathways. We observed a significant upregulation of CTSL in laryngeal cancer tissues, and its elevated levels are indicative of poor prognosis in laryngeal cancer patients. The proliferation of laryngeal cancer cells relies on the expression of CTSL, with overexpression of this gene enhancing the proliferative capacity of these cells. Concurrently, CTSL is closely associated with the autophagic levels in laryngeal cancer cells. During the autophagic process mediated by CTSL, the IL6-JAK-STAT3 signalling pathway is activated, suggesting that CTSL promotes autophagy through the IL6-JAK-STAT3 pathway. Considering the correlation between CTSL and autophagy, we developed and validated a multi-gene signature. The risk score derived from this signature demonstrates significant potential in predicting various aspects. We found that CTSL upregulates autophagy in laryngeal cancer cells by activating the IL6-JAK-STAT3 signalling pathway. By taking into account the autophagy-regulating role of CTSL, the clinical predictive ability of CTSL in HNSC can be enhanced.

(编者按:随着现代科学技术的飞速发展临床诊疗技术和方法不断发展和完善.本专栏的开辟旨在创建一个学术交流平台针对本学科临床工作中的热点和难点邀请在相关领域做出大量工作并颇有建树的专家和教授介绍他们的见解和经验以飨读者.圆桌论坛为个人意见不具共识性.)

Head and neck squamous cell carcinoma (HNSCC) is the most prevalent type of head and neck cancer; however, treatment outcomes and patient prognosis remain suboptimal. Although the survival of patients with HNSCC has improved with the widespread use of anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) and immune checkpoint inhibitors (ICIs), there remains considerable potential for further improvement. Recent studies suggest that the combination of anti-EGFR monoclonal antibodies and ICIs demonstrates promising efficacy and safety, which has been recommended by international guidelines for patients with recurrent or metastatic disease. Nevertheless, the application of this combination therapy remains in the early stages of exploration, and numerous questions concerning its standardized clinical use remain unanswered, including the mechanisms underlying the synergistic effects of individual agents, therapeutic value across different patient populations, and safety considerations. The Expert Committee of Head and Neck Cancer of the Chinese Society of Clinical Oncology (CSCO) organized an expert panel to develop this expert consensus on the combination of anti-EGFR mAbs and ICIs in the treatment of HNSCC through multiple rounds of discussion based on evidence-based medicine and clinical practice experience. This consensus provides guidance on the mechanisms of treatment with anti-EGFR mAbs plus ICIs, stratified treatment approaches, applications in special populations, and safety management. It is hoped that this consensus will provide clearer and more practical guidance for clinicians, promote the rational application of this combination therapy in clinical practice, and offer more treatment options for patients with HNSCC.

TPS6116 Background: Postoperative radiotherapy (PORT) significantly enhances the prognosis for high-risk patients with locally advanced squamous cell carcinoma of the head and neck (LA HNSCC). However, elective nodal irradiation (ENI) in low-risk areas can lead to serious acute and long-term toxicities, which negatively impact quality of life. In a study by Contreras (NCT00593840), 72 patients with LA HNSCC experienced a remarkable 97% regional control rate at five years after eliminating PORT to the pathologically negative (pN0) neck. Additionally, patients who responded well to neoadjuvant therapy showed better local control rates, suggesting a possible reduction in the need for radiotherapy. The RAVD study (NCT01133678) demonstrated that the elimination of ENI in patients with good response to neoadjuvant chemotherapy did not appear to compromise outcomes and resulted in significantly decreased late toxicity. Preclinical studies have also suggested that the elimination of ENI may preserve beneficial T cells in normally draining lymph nodes, enhancing the efficacy of radioimmunotherapy. The study was designed to evaluate regional control rates and quality of life in LA HNSCC patients undergoing sequential elimination of ENI to the pN0 neck by neoadjuvant chemo-immunotherapy. Methods: REPORT-HNSCC is a phase 2, single-arm, single-center trial assessing patients with newly diagnosed LA HNSCC. Patients receive neoadjuvant chemo-immunotherapy (flexibility in regimens and cycles). This trial targets patients with an ipsilateral and/or bilateral pN0 neck, while surgical resection will be guided by the surgeon’s discretion. Key treatment components include 60 to 66 Gy to the primary tumor bed (CTVtb), 60 Gy to CTV1, and 54 to 60 Gy to CTV2, with appropriate expansion margins to optimize target volume. Eliminating ENI (that is, CTV2) to the pN0 neck. A symmetric 0.3-cm expansion around the CTV defined the corresponding planning target volume (PTV). Radiation doses were prescribed to the PTV. Intensity-modulated radiotherapy (IMRT) will be administered to all patients, while select patients with positive surgical margins or extranodal extension receive concurrent chemotherapy. The primary endpoint is 2-year region-free recurrence survival rate. Secondary endpoints include 2-year PFS, 2-year OS, 2-year DMFS, 2-year LRFS, acute and late toxicities, and quality of life. We will also explore predictive biomarkers for better understanding of responses and survival. As of January 2025, we have enrolled 14 of the planned 50 patients since the study began in October 2024, with results expected by December 2029. Clinical trial information: NCT06630780 .

BACKGROUND:Squamous cell carcinoma of the soft palate (SCCSP) represents a rare subtype of oropharyngeal cancer. This study aims to evaluate the treatment outcomes of SCCSP and to assess the prognostic significance of HPV status. METHODS:Patients diagnosed with SCCSP between January 1981 and December 2021 were collected. Survival outcomes were compared. RESULTS:In univariate analysis, primary surgery resulted in superior progression-free survival (PFS), overall survival (OS), and disease-specific survival (DSS) compared with definitive radiotherapy (p < 0.05). Furthermore, multivariate analysis revealed that primary surgery independently correlated with superior PFS (HR = 0.37, p = 0.002), OS (HR = 0.55, p = 0.012), and DSS (HR = 0.45, p = 0.020) in early-stage SCCSPs. Additionally, no significant prognostic differences were observed between HPV/p16 positive and HPV/p16 negative SCCSPs (p > 0.05). CONCLUSION:Surgery yields superior oncological outcomes for early-stage SCCSP patients. HPV status does not demonstrate prognostic significance in SCCSP.

Background:Treatment deintensification, such as neoadjuvant immunochemotherapy and transoral surgery, has shown promise but remains under investigation in human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPV+OPSCC). We aimed to explore the efficacy and safety of neoadjuvant immunochemotherapy and the feasibility of sequential transoral surgery in patients with resectable HPV+OPSCC. Methods:In this single-arm, two-centre, phase 2 trial, patients with resectable HPV+OPSCC (clinical stage T2-4N0-3M0) were recruited and received two cycles of neoadjuvant sintilimab, cisplatin, and nab-paclitaxel every three weeks, followed by transoral surgery, including transoral robotic surgery (TORS). The primary endpoint was major pathological response (MPR), defined as the residual viable tumor of less than or equal to 10% in the primary lesion. The study is registered with Chinese Clinical Trial Registry (ChiCTR2200058650) and is ongoing. Findings:Between April 13, 2022 and November 17, 2023, 27 patients were enrolled and all received two cycles of neoadjuvant immunochemotherapy, which all achieved partial responses. Among them, 25 patients received radical surgery (21 TORSs and 4 transoral surgeries). MPR was achieved in 24 patients (24/25, 96.0%), including 17 (17/25, 68.0%) with pathological complete response (pCR). Grade 1-2 treatment-related adverse events (TRAE) occurred in 24 of 27 patients (88.9%), including skin rash (12/27, 44.4%), alopecia (10/27, 37.0%), nausea (8/27, 29.6%), fatigue (8/27, 29.6%), and pain (8/27, 29.6%). Only one patient (1/27, 3.7%) experienced grade 3 TRAEs with no treatment-related death. For the per-protocol population, the 2-year DFS and OS were both 96.0% (95% CI: 88.6%-100.0%). Most patients experienced improved symptoms including pain and swallowing at 3 months post-surgery, and remained stable at 6 months and 1 year post-surgery. Circulating tumor HPV-DNA clearance had a trend to occur in patients with pCR. Interpretation:Neoadjuvant immunochemotherapy and sequential transoral surgery, including TORS, appears to be a feasible strategy that yields favorable oncologic and functional outcomes for patients with resectable HPV+OPSCC. Funding:Innovent Biologics.

XGBoost, a gradient boosting algorithm, is widely recognized for its efficiency and robustness in multiclass classification tasks. Metabolomics serves as a powerful tool for biomarker discovery; however, metabolic biomarkers associated with the progression from chronic hepatitis B (CHB) to liver cirrhosis (LC) to hepatocellular carcinoma (HCC), as well as those related to treatment effects in HCC (HCCAT), remain unclear. In this study, an XGBoost-based machine learning approach combined with mass spectrometry was used to analyze the metabolic profiles of 30 healthy controls (HC), 29 CHB patients, 30 LC patients, 30 HCC patients, and 30 HCCAT patients. Biomarker screening was conducted through three comparative analyses: (1) HC, CHB, LC, HCC, and HCCAT; (2) HC, CHB, LC, and HCC; and (3) HC, HCC, and HCCAT. A total of 17 metabolic biomarkers were identified, among which nine had not been previously associated with HBV-related liver diseases. Notably, a potential biomarker panel composed of eicosenoic acid, dihydromorphine, cysteine, acetic acid, sitosterol, and hypoxanthine showed promise for disease prognosis and therapeutic evaluation. These findings highlight the great potential of integrating metabolomics with machine learning to identify novel metabolic biomarkers related to HBV-associated liver disease progression and treatment response.