Human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) is characterised by hyperactivation of the cyclin-dependent kinase 4/6 (CDK4/6) pathway. As immunotherapy has become the first-line treatment for HNSCC, resistance to anti-programmed death-1 (PD-1) agents has emerged as a pivotal challenge. This prospective, single arm, phase II study (NCT05721443) evaluated the efficacy and safety of dalpiciclib, a CDK4/6 inhibitor, combined with cetuximab in patients with anti-PD-1-resistant, HPV-negative recurrent and/or metastatic HNSCC. Patients diagnosed with p16-negative R/M HNSCC resistant to first-line anti-PD-1 therapy without prior cetuximab treatment were enroled. Patients received oral dalpiciclib (150 mg daily on days 1-21 of each 28-day cycle) and intravenous cetuximab (400 mg/m2 on day 1 of cycle 1, followed by 250 mg/m2 weekly in each cycle). The primary endpoint was objective response rate (ORR), secondary endpoints were overall survival, progression-free survival, duration of response, and safety. Between March 2023 and November 2024, a total of 28 patients were enroled. The ORR was 67.9

INTRODUCTION:Oral mucosal melanoma (OMM) is a rare subtype of melanoma but exhibits highly invasive biological behavior. Programmed cell death protein 1 (PD-1) monotherapy showed lower response in OMM than other subtypes of melanoma. MATERIALS AND METHODS:We retrospectively analyzed the efficacy and safety of pembrolizumab with anlotinib in patients with advanced OMM between August 2018 and September 2024. The primary endpoint was objective response rate (ORR); the secondary endpoints included disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (TRAEs). RESULTS:Forty-one patients were enrolled in our study. Seventeen patients (41.4%) achieved an objective response. The median PFS was 6.4 months (95% confidence interval [CI], 4.5-8.3 months), and the median OS was 10.0 months (95% CI, 8.3-11.7 months). Thirty-three patients (80.5%) experienced at least one TRAE. The most common TRAEs were hypertension (29.3%), hand-foot syndrome (19.5%), and anemia (19.5%). Grade 3 or higher TRAEs occurred in two patients (4.8%), and no grade 5 TRAEs were observed. CONCLUSIONS:Our study suggested that pembrolizumab with anlotinib in patients with advanced OMM showed potential efficacy and manageable adverse effects. Further studies are needed to confirm the efficacy of this combination strategy.

PURPOSE:To evaluate the accuracy of intraoral scanning (IOS) impressions for multiple implants by comparing them to analog impressions. MATERIALS AND METHODS:Patients with three adjacent implants in partially edentulous arches were recruited. For each arch, IOS impressions were obtained. Using the analog splinted-impression technique, casts were obtained and scanned with an extraoral scanner. Using metrology software, the distances and angles between the implants were measured in all IOS and analog impression STL files. The absolute values of the distance and angular deviation were calculated and analyzed by comparing the two impression methods. RESULTS:A total of 34 patients with partially edentulous arches were enrolled. The distance deviation between the IOS and analog impressions was 85.09 ± 58.73 µm, which was significantly lower than the clinically acceptable threshold for error (150 µm; P < .001). The angular deviation was 0.515 ± 0.426 degrees. Distance deviations were significantly correlated with the interimplant distances (r = 0.384, P = .001) and angulations (r = 0.278, P = .022). CONCLUSIONS:For prostheses supported by multiple implants in partially edentulous arches, the distance deviation between the IOS and analog impression was within the clinically acceptable range of misfit and increased with increasing interimplant distance and angulation.

BackgroundThe KEYNOTE-048 and KEYNOTE-040 study have demonstrated the efficacy of pembrolizumab in recurrent or metastatic squamous cell carcinoma of the head and neck (R/M HNSCC), we conducted this real-world study to investigate the efficacy of pembrolizumab in patients with R/M HNSCC.MethodsThis is a single-center retrospective study conducted in the Shanghai Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (Shanghai, China). Between December 2020 and December 2022, a total of 77 patients with R/M HNSCC were included into analysis. The primary endpoint of the study was overall survival (OS), and the secondary endpoints were progression-free survival (PFS), overall response rate (ORR)and toxicity.Efficacy was assessed according to RECIST version 1.1.SPSS 27.0 and GraphPad Prism 8.0 software were utilized to perform the statistical analysis.ResultsBy the cut-off date (February 28, 2023), the median OS,PFS and ORR were 15.97 months,8.53 months and 48.9% in patients treated with the pembrolizumab regimen in the first line therapy. Among these patients, 17 patients received pembrolizumab with cetuximab,and 18 received pembrolizumab with chemotherapy.We observed no significant differences between two groups neither in median OS (13.9 vs 19.4 months, P=0.3582) nor PFS (unreached vs 8.233 months, P= 0.2807). In the ≥2nd line therapy (n=30), the median OS, PFS and ORR were 5.7 months, 2.58 months and 20% respectively. Combined positive score (CPS) was eligible from 54 patients. For first line therapy, the median OS and PFS were 14.6 and 8.53 months in patients with CPS ≥1, and median OS and PFS were 14.6 and 12.33 months in patients with CPS ≥20. The immune-related adverse events (irAEs) were occurred in the 31 patients (31/77, 40.26%), and the most common potential irAEs were hypothyroidism (25.97%), and pneumonitis (7.79%).ConclusionOur real-world results indicated that pembrolizumab regimen is a promising treatment in patients with R/M HNSCC

BACKGROUND:Reactive cutaneous capillary endothelial proliferation (RCCEP), a special adverse event (AE) only observed in patients treated with camrelizumab, was reported to be correlated with the efficacy of camrelizumab in patients with advanced hepatocellular carcinoma. This study to analyze the possible correlation between the occurrence of RCCEP and efficacy of camrelizumab in patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC).MATERIAL AND METHODS:In this study, we retrospectively analyzed the efficacy and RCCEP occurrence of camrelizumab in 58 patients with R/M HNSCC in the Shanghai Ninth People's Hospital affiliated to Shanghai JiaoTong University School of Medicine between January 2019 and June 2022. Kaplan-Meier analysis was used to assess the correlation between the occurrence of RCCEP and the survival of enrolled patients, and COX multifactor analysis was adopted to evaluate associated factors that affected the efficacy of camrelizumab immunotherapy.RESULTS:A significant correlation between the incidence of RCCEP and a higher objective response rate was observed in this study (p=0.008). The occurrence of RCCEP was associated with better median overall survival (17.0 months vs. 8.7 months, p<0.0001, HR=5.944, 95% CI:2.097-16.84) and better median progression-free survival (15.1 months vs. 4.0 months, p<0.0001, HR=4.329,95% CI:1.683-11.13). In COX multifactor analysis, RCCEP occurrence was also an independent prognostic factor affecting OS and PFS in patients with R/M HNSCC.CONCLUSIONS:The occurrence of RCCEP can show a better prognosis, it could be used as a clinical biomarker to predict the efficacy of camrelizumab treatment.

Abstract Purpose This systematic review aimed to investigate the accuracy of intraoral scan (IOS) impressions of implant-supported restorations in in vivo studies. Methods A systematic electronic search and review of studies on the accuracy of IOS implant impressions were conducted to analyze the peer-reviewed literature published between 1989 and August 2023. The bias analysis was performed by two reviewers. Data on the study characteristics, accuracy outcomes, and related variables were extracted. A meta-analysis of randomized control trials was performed to investigate the impact of IOS on peri-implant crestal bone loss and the time involved in the impression procedure. Results Ten in vivo studies were included in this systematic review for final analysis. Six studies investigated the trueness of IOS impressions, but did not reach the same conclusions. One study assessed the precision of IOS impressions for a single implant. Four clinical studies examined the accuracy of IOS implant impressions with a follow-up of 1–2 years. In full arches, IOS impression procedure needed significantly less time than conventional one (mean difference for procedure time was 8.59 min [6.78, 10.40 min], P < 0.001), prosthetic survival rate was 100%, and marginal bone levels of all participants could be stably maintained (mean difference in marginal bone loss at 12 months was 0.03 mm [-0.08, 0.14 mm], P = 0.55). Conclusions The accuracy of IOS impressions of implant-supported restorations varied greatly depending on the scanning strategy. The trueness and precision of IOS in the partial and complete arches remain unclear and require further assessment. Based on follow-up clinical studies, IOS impressions were accurate in clinical practice. However, these results should be interpreted with caution, as some evidences are obtained from the same research group.

DNA-based liquid biopsy as a diagnostic strategy of head and neck squamous cell carcinoma (HNSCC) has emergingly gained momentum. In this letter, we identified 6 studies contained 274 patients with HNSCC focused on gene mutations in salivary DNA. We observe that the incidence of DNA mutations with at least one gene mutated ranges from 63% to 95.9%, and the most frequently examined gene mutations are TP53, CDKN2A, PIK3CA, FAT1, and NOTCH1. Meanwhile, studies have demonstrated that saliva had a greater sensitivity and much higher quantitative values than plasma in both tumor DNA count and variant allele frequency. Interestingly, more tumor-derived mutations were detected in salivary DNA among patients with tumors arising in oral cavity compared to in oropharynx, larynx, and hypopharynx. Collectively, it is feasibility to identify somatic mutations in driver genes using saliva samples to noninvasively diagnose HNSCC, especially in oral cavity cancer and even at early stages of the disease. Larger well-designed studies are needed to consolidate the evidence.

Induction chemotherapy in oral squamous cell carcinoma is a controversial issue in clinical practice. To investigate the evolution of cancer cells and tumor microenvironment (TME) response to chemotherapy in oral squamous cell carcinoma, single-cell transcriptome analysis was performed in a post-chemotherapy squamous cell carcinoma located in oral cavity. The main cell types were identified based on gene expression patterns determined using dimensionality reduction and unsupervised cell clustering. Non-negative matrix factorization clustering of the gene expression of Cancer-associated fibroblasts (CAFs) and macrophages was performed. Kyoto Encyclopedia of Genes and Genomes pathway analyses and gene set enrichment analysis were performed to explore significant functional pathways. CellPhoneDB and NicheNet were used to detect the intercellular communication between cell types. CAFs were divided into "inflammatory CAFs," "antigen-presenting CAFs" and "myofibroblastic CAFs." Three classic subgroups of tumor-associated macrophages (TAMs) were detected, namely C1Q (+), FCN1 (+) and SPP1(+) TAMs. The inflammatory cytokine expression is elevated, and several molecular pathways, such as PI3K/Akt/mTORC1, TNF-α via NFκB, TGF-β, IL-6/JAK2/STAT3 and CXCL12/CXCR4 axis associated with epithelial-mesenchymal transition were enriched in TME. Also, CD74-MIF/COPA/APP interactions were expressed in TME of oral squamous cell carcinoma after chemotherapy. The results revealed the characteristics of TME in post-chemotherapy oral squamous cell carcinoma at single-cell transcriptome level, providing new insights and clues for further investigation.

Background Hyperthermia has been reported to cause cancer stage regression, thus providing surgical opportunities in patients with unresectable tumors and improving the quality of life of patients by preserving certain organs. Methods A prospective open-label phase II trial was conducted to evaluate the efficacy of hyperthermia combined with induction chemotherapy in patients with locally advanced resectable oral squamous cell carcinoma (OSCC). Patients received hyperthermia combined with two cycles of 5-fluorouracil, cisplatin, and docetaxel (TPF) induction chemotherapy regimens or TPF induction chemotherapy alone, followed by radical surgery with postoperative radiotherapy. The primary endpoint was the clinical response rate of the induction chemotherapy. The secondary endpoints were overall survival (OS), disease-free survival (DFS), and toxicity. Results A total of 120 patients were enrolled, and 115 patients were included in the clinical response analysis. The clinical response rate was significantly higher in the experimental arm than in the control arm (65.45% vs. 40.00%, p = 0.0088). There were no unexpected toxicities, and hyperthermia and induction chemotherapy did not increase the perioperative morbidity rate. Moreover, there was a significant improvement in DFS, but no significant difference in OS between the two arms. In the subgroup analysis, increased OS and DFS rates were associated with patients with favorable clinical response after induction chemotherapy in the total population, experimental arm, and control arm. Conclusions Our study demonstrates that hyperthermia combined with induction chemotherapy is associated with a high response rate and provides a new treatment option for patients with resectable stage III or IVA OSCC.

头颈黏膜黑色素瘤(HNMM)是一类高度恶性的实体肿瘤,5年生存率长期徘徊在20％左右,其致病因素、驱动基因、临床表现及治疗手段等与皮肤黑色素瘤差异较大.2015年,国内首个头颈黏膜黑色素瘤诊治专家共识建立,经过6年多的推广应用,HNMM临床诊治规范性有了很大提高.随着黏膜黑色素瘤临床与基础研究的不断深入,HNMM的诊治与预后在近些年发生了较大变化,特别是头颈部各分支学科的蓬勃发展,口腔、鼻腔鼻窦、眼部等黏膜黑色素瘤各自发展出独特的诊治模式,该共识已不能满足当前临床的实际需求.对此,专家组认为头颈部黏膜包含的解剖范围较广,涉及的临床科室较多,不同学科之间黑色素瘤诊疗模式差异明显,临床亟须符合个体化治疗及精准治疗的更加专科化的诊治共识.为了进一步提高口腔黏膜黑色素瘤(OMM)的远期生存率和生存质量,让共识更好地指导临床工作,专家组聚焦OMM,深入讨论,基于循证医学证据和经验医学,完成专家共识的制定.考虑到患者的个体化差异,本共识可作为OMM临床实践的参考.

Background: The purpose of the present study was to investigate the clinicopathological characteristics and prognostic factors of second primary oral squamous cell carcinoma after radiotherapy for head and neck cancer. Methods: The clinicopathological characteristics of 48 second primary oral squamous cell carcinoma patients with a history of radiotherapy for head and neck cancer were retrospectively analyzed by Kaplan-Meier survival analysis and Cox proportional hazards model, including gender, age, alcohol consumption, smoking, clinical stage, margin status, regional lymph node status, tumor differentiation and treatment mode. Results: The second primary oral squamous cell carcinoma mostly occurred on the tongue [18/48], buccal [12/48] and gingiva [10/48], and the 3- and 5-year overall survival (OS) was 60.3% and 39.4%, respectively. Margin status and extranodal extension were significantly associated with OS, while only margin status was found to be an independent prognostic factor of OS in the Cox proportional hazards model (P=0.003, HR =3.976, 95% CI: 1.596-9.904). Conclusions: Oral squamous cell carcinoma patients underwent radiotherapy for head and neck cancer show poor survival outcomes. Margin status is an independent prognostic factor of second primary oral squamous cell carcinoma.

Head and neck cancer represents the seventh most common cancer worldwide. Although multidisciplinary sequential treatments have been used, there is still an urgent need for new treatment approaches that can effectively improve the outcomes of patients with advanced stages of head and neck cancer. Gene therapy is a rapidly evolving field in cancer therapy that has been shown to improve the efficacy of antitumor treatment. China is at the forefront in clinical trials and practice of gene therapy. Chinese researchers have mainly focused on gene therapeutics based on oncolytic virus and recombinant adenovirus expressing p53, antiangiogenesis factor or herpes simplex virus-thymidine kinase. Currently, two gene therapy drugs, Gendicine and Oncorine, have been marketed in China, and a number of upcoming gene therapy agents are under development for the treatment of head and neck cancer. Most gene therapy agents have demonstrated excellent tolerance. However, the therapeutic effects need further improvement. With current innovations in tumor biology and knowledge, gene therapy has great potential as a safe and effective anticancer treatment. In recent years, new gene therapy agents with promising effects have been incorporated into clinical trials in China. Thus, gene therapy may become an important part of anticancer therapy and is expected to improve the therapeutic effect of head and neck cancers in the near future.

Background: To investigate the relationship between clinical and histopathological characteristics and overall survival of patients with oral mucosal melanoma (OMM) without distal metastasis in order to provide predictive prognostic information of OMM. Methods: Ki67 expression was assessed by immunohistochemistry in 123 patients with OMM without distant metastases. The associations between Ki67 expression and clinical features and overall survival (OS) of patients were statistically analyzed. The Ki67 levels of the primary and recurrent lesions from 14 OMM patients were compared. Results: Univariate analysis showed that tumor type and cervical lymph node (CLN) status, as well as Ki67 expression, were all correlated with survival. Cox proportional hazards regression analysis identified Ki67 expression and CLN status as independent prognostic factors in OMM patients. Further, we found that Ki67 expression was associated with clinical tumor type of OMM. Moreover, with a cut-off point of 20%, patients with lower Ki67 scores showed a survival advantage over those with higher Ki67 scores. Conclusions: Ki67 expression may be a useful pathological predictor of survival of OMM patients without distant metastases.

Oral mucosal melanoma (OMM) is a rare and aggressive subtype of melanoma with little known about its pathogenesis or carcinogenesis. We therefore performed whole-exome sequencing (WES) on 19 matched OMM tumor/normal pairs in order to gain insight into potential genetic drivers of tumor formation. For the first time, we describe the comprehensive mutational profile of OMM. Our data suggest that the genetic background of OMM differs from those of other melanoma subtypes. We identified recurrent mutations involving KIT, POLE, PTPRD, PTCHD2, and DMXL2. Notably, copy number analysis revealed recurrently amplified regions of 12q14 (57.9%, containing CDK4) and 5p15 (47.4%, containing TERT). CNV analysis in a separate cohort of 15 samples validated the frequent CNV in CDK4 and TERT. We also observed that the melanocyte development and pigmentation signaling pathway is frequently altered in OMM. Furthermore, our data suggest several altered genes that may be amenable for targeted therapy. We identified one patient with metastatic OMM in our cohort who was identified to harbor a targetable KIT mutation using our WES results. This patient was able to achieve complete remission following implementation of KIT-targeted therapy. These findings provide further insight into the genetic underpinnings of OMM development and suggest that patients with OMM may benefit from WES analysis to identify potential targetable genetic mutations. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Oral mucosal melanoma (OMM) is an aggressive neoplasm with an extremely poor prognosis. BAP1 is a tumor suppressor that has been associated with the outcome of melanomas and other malignancies. In this study, we investigated the genetic alterations in BAP1 and the prognostic potential of BAP1 protein expression in oral mucosal melanoma. DNA sequence analysis of BAP1 from 12 OMM patient samples revealed missense mutations in the tissues from four patients. Based on immunohistochemical staining, loss of nuclear BAP1 expression was associated with poor overall survival (P < 0.001, Log-rank = 21.308) and distant metastasis (P = 0.034, OR = 0.320). Multivariate analysis showed BAP1 to be an independent prognostic factor (P = 0.027, HR = 0.479). It thus appears that loss of nuclear BAP1 expression is an independent prognostic factor of poor overall survival and associated with distant metastasis in OMM.

c-Kit mutations are frequently detected in mucosal melanomas, but their clinical significance in metastatic oral mucosal melanomas (OMM) remains unclear. The main purpose of this study was to investigate the clinical and pathological features of metastatic OMMs with c-Kit mutations and the efficiency of the tyrosine kinase inhibitor imatinib in treating metastatic OMMs. We found thatresidual primary lesion and neck lymph nodes could act as independent prognostic factors in metastatic OMM patients. c-Kit mutations were detected in 22 out of 139 (15.8%) metastatic OMM patients. Under chemotherapy, the overall survival (OS) of c-Kit mutant patients was significantly shorter than that of wild-type patients. The Ki67 expression was significantly higher in c-Kit mutant patients than in wild-type patients. In distant metastatic OMM patients with c-Kit mutations, the treatment with c-Kit inhibitor resulted in a better OS. In conclusion, residual primary lesion, cervical lymph nodes and c-Kit mutations act as adverse prognostic factors of metastatic OMMs. The Kit inhibitor imatinib could benefit metastatic OMM patients with c-Kit mutations.

The prognostic factors of oral mucosal melanoma (OMM), a rare and aggressive neoplasm, remain to be determined. The aim of this study is to investigate the prognostic significance of vasculogenic mimicry in OMM. The clinical data of 62 patients with primary OMM treated in Shanghai Ninth People’s Hospital from April 2007 to April 2012 were retrieved and analyzed retrospectively. Staining of periodic acid–Schiff (PAS) and CD31 immunohistochemistry were performed to evaluate the prognostic value of PAS-positive patterns, blood lakes, and microvascular density. PAS-positive loops and networks (P<0.001) as well as blood lakes (P=0.040) were found to be predictors of overall survival (OS). The presence of PAS-positive loops and networks was an independent prognostic factor of poor OS in multivariate analysis (P=0.002). Although the presence of PAS-positive loops and networks was associated with hematogenous metastasis (P=0.041) and lymphogenous metastasis (P=0.041), it was not an independent predictor of both types of metastasis in multivariate analysis. Microvascular density was not associated with OS (P=0.627) and metastasis of OMM patients. PAS-positive loops and networks have a significant prognostic value in OMM. Detection of PAS-positive patterns may lead to better staging and serve as a prognostic parameter of OMM.

OBJECTIVE:Molecular alterations in downstream effectors of epidermal growth factor receptor may confer resistance to epidermal growth factor receptor inhibitors. Our aim is to investigate whether PTEN/pAKT expression predicts response to cetuximab-based chemotherapy in oral squamous cell carcinoma.STUDY DESIGN:We analyzed a cohort of 50 patients with oral squamous cell carcinoma treated with cetuximab-based induction chemotherapy. PTEN expression and pAKT expression were assessed by immunohistochemistry and their correlation with treatment outcome was analyzed.RESULTS:Of the study patients, 18.4% had low PTEN expression, and 38.8% had high pAKT expression. Lower pAKT expression were associated with pathologic remission (P = .034) and better disease-free survival (P = .031).CONCLUSION:Our study demonstrates that pAKT expression is a predictive biomarker of cetuximab-based induction chemotherapy in OSCC.

BACKGROUNDRecent advances in novel targeted therapies have created the need for molecular characterization of cancer to allow accurate personalized treatments. In this study, our aim was to investigate the incidence of activating mutations of oncogenes BRAF, NRAS, KIT, and GNAQ/GNA11 in oral mucosal melanoma.METHODSWe analyzed a cohort of 57 oral mucosal melanoma samples, including 27 frozen samples and 30 formalin-fixed paraffin-embedded samples. The tumors were screened for hotspot mutations of BRAF (exon 15), NRAS (exons 2 and 3), KIT (exons 9, 11, 13, and 17), and GNAQ/GNA11 (exon 5) by high-resolution melting and direct sequencing.RESULTSIn oral mucosal melanoma, 7.0% of tumors harbored KIT mutations and 3.5% harbored BRAF mutations, while classic BRAF V600E mutation was not detected. We found no mutations of NRAS or GNAQ/GNA11 in oral mucosal melanoma.CONCLUSIONWe demonstrated that driver mutations are rare in mutational hotspots of BRAF, NRAS, KIT, and GNAQ/GNA11 in oral mucosal melanoma. The majority of patients will not benefit from KIT and BRAF inhibitors.

Purpose: Lip melanoma (LM) is a rare malignant tumor and well-established treatment protocols for it are in short supply. The objective of this study was to evaluate the outcome of treatment modalities and explore the prognostic factors.Patients and Methods: A retrospective chart review was performed on 48 patients with primary LM treated in the authors' hospital from January 1992 to November 2013. The clinical characteristics and treatment modalities were identified and correlated with the outcomes.Results: The 5-year overall survival (OS) rate was 56.1%, and the rate of cervical lymph node (CLN) metastasis was 46% (22 of 48). A tumor of at least 4 cm (P = .001), nodular types (P = .003), and CLN (P < .0001) were independent prognostic factors for OS. Twenty-five patients died during follow-up, mainly from to neck recurrence (14 of 25). Chemotherapy significantly improved the 5-year OS rate in patients with stage IV LM (P = .03), but not in those with stage III (P = .8).Conclusions: LM has a lower CLN and distant metastasis rate and a better prognosis than other oral mucosal melanomas. A long history of melanin pigmentation is a dangerous sign for all patients, and smoking seems to be associated with LM in male patients. Tumor size (>= 4 cm), nodular type, and CLN positivity are poor prognostic factors. A wide excision with close observation is advocated as the primary treatment for stage III LM. Adjuvant chemotherapy is useful for patients with stage IV cancer, but not for those with stage III. (C) 2015 American Association of Oral and Maxillofacial Surgeons