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Human papillomavirus positive oropharyngeal cancer (HPV-positive OPC) is a distinct subtype of head and neck carcinoma (HNC) distinguished from HPV-negative HNC by its risk factor profile, clinical behavior, and molecular biology. Compared to HPV-negative HNC, HPV-positive OPC exhibits significantly better prognosis and an enhanced response to treatment. Recognition of the survival benefit of HPV-positive tumors has led to therapeutic de-intensification strategies aiming to mitigate treatment-related toxicities while maintaining high response rates. In this review, we summarize key aspects of oral HPV infection and the molecular mechanisms of HPV-related carcinogenesis. We review the clinical and molecular characteristics of HPV-positive OPC that contribute to its improved prognosis compared to HPV-negative HNC. We also discuss current and emerging treatment strategies, emphasizing potential mechanisms of treatment sensitivity and the role of therapeutic de-intensification in HPV-positive OPC. Lastly, we examine literature on the management and prognosis of recurrent/metastatic HPV-positive OPC with a focus on the role of salvage surgery in its management.

Despite the promise of immune checkpoint inhibition (ICI), therapeutic responses remain limited. This raises the possibility that standard of care treatments delivered in concert may compromise the tumor response. To address this, we employ tobacco-signature head and neck squamous cell carcinoma murine models in which we map tumor-draining lymphatics and develop models for regional lymphablation with surgery or radiation. We find that lymphablation eliminates the tumor ICI response, worsening overall survival and repolarizing the tumor- and peripheral-immune compartments. Mechanistically, within tumor-draining lymphatics, we observe an upregulation of conventional type I dendritic cells and type I interferon signaling and show that both are necessary for the ICI response and lost with lymphablation. Ultimately, we provide a mechanistic understanding of how standard oncologic therapies targeting regional lymphatics impact the tumor response to immune-oncology therapy in order to define rational, lymphatic-preserving treatment sequences that mobilize systemic antitumor immunity, achieve optimal tumor responses, control regional metastatic disease, and confer durable antitumor immunity. Response rates to immune checkpoint inhibitors (ICI) in patients with head and neck squamous cell carcinoma (HNSCC) remain low. Here the authors show that ablative treatment of tumor-draining regional lymphatics, a standard of care approach in patients, impairs the tumor response to ICI in preclinical HNSCC models.

Tumor initiation represents the first step in tumorigenesis during which normal progenitor cells undergo cell fate transition to cancer. Capturing this process as it occurs in vivo, however, remains elusive. Here we employ spatiotemporally controlled oncogene activation and tumor suppressor inhibition together with multiomics to unveil the processes underlying oral epithelial progenitor cell reprogramming into tumor initiating cells at single cell resolution. Tumor initiating cells displayed a distinct stem-like state, defined by aberrant proliferative, hypoxic, squamous differentiation, and partial epithelial to mesenchymal invasive gene programs. YAP-mediated tumor initiating cell programs included activation of oncogenic transcriptional networks and mTOR signaling, and recruitment of myeloid cells to the invasive front contributing to tumor infiltration. Tumor initiating cell transcriptional programs are conserved in human head and neck cancer and associated with poor patient survival. These findings illuminate processes underlying cancer initiation at single cell resolution, and identify candidate targets for early cancer detection and prevention. The molecular mechanisms underlying tumour initiation remain elusive. Here, the authors use spatiotemporally controlled oncogene activation and tumour suppressor inhibition with multi-omics to unveil the role of YAP-mediated oral epithelial progenitor cell reprogramming into tumour-initiating cells.

Surgical ablation or broad radiation of tumor-draining lymph nodes can eliminate the primary tumor response to immunotherapy, highlighting the crucial role of these nodes in mediating the primary tumor response. Here, we show that immunoradiotherapy efficacy is dependent on treatment sequence and migration of modulated dendritic cells from tumor to sentinel lymph nodes. Using a tamoxifen-inducible reporter paired with CITE-sequencing in a murine model of oral cancer, we comprehensively characterize tumor immune cellular migration through lymphatic channels to sentinel lymph nodes at single-cell resolution, revealing a unique immunologic niche defined by distinct cellular phenotypic and transcriptional profiles. Through a structured approach of sequential immunomodulatory radiotherapy and checkpoint inhibition, we show that sequenced, lymphatic-sparing, tumor-directed radiotherapy followed by PD-1 inhibition achieves complete and durable tumor responses. Mechanistically, this treatment approach enhances migration of activated CCR7+ dendritic cell surveillance across the tumor-sentinel lymph node axis, revealing a shift from their canonical role in promoting tolerance to driving antitumor immunity. Overall, this work supports rationally sequencing immune-sensitizing, lymphatic-preserving, tumor-directed radiotherapy followed by immune checkpoint inhibition to optimize tumor response to immunoradiotherapy by driving activated dendritic cells to draining sentinel lymph nodes. Tumor draining lymph nodes are essential for immunotherapy efficacy in head and neck squamous cell carcinoma (HNSCC). Here, the authors show that sequential tumor-directed radiotherapy and PD-1 inhibition and migratory CCR7+ dendritic cells are required for complete and durable tumor responses in HNSCC.

Mechanisms of tumorigenesis in sinonasal squamous cell carcinoma (SNSCC) remain poorly understood due to its rarity. A subset of SNSCC is associated with human papillomavirus (HPV), but it is unclear whether HPV drives tumorigenesis or acts as a neutral bystander. Here, we show that HPV-associated SNSCC shares mutational patterns found in HPV-associated cervical and head and neck squamous cell carcinoma, including lack of TP53 mutations, hotspot mutations in PI3K and FGFR3 , enrichment of APOBEC mutagenesis, viral integration at known hotspots, and frequent epigenetic regulator alterations. We identify HPV-associated SNSCC-specific recurrent mutations in KMT2C , UBXN11 , AP3S1 , MT-ND4 , and MT-ND5 , with KMT2D and FGFR3 mutations correlating with reduced overall survival. We establish an HPV-associated SNSCC cell line, showing that combinatorial small-molecule inhibition of YAP/TAZ and PI3K synergistically suppresses clonogenicity. Combining YAP/TAZ blockade with vertical PI3K inhibition may benefit HPV-associated SNSCC, whereas targeting MYC and horizontal inhibition of RAS/PI3K may suit HPV-independent SNSCC. Sinonasal squamous cell carcinoma (SNSCC) is an uncommon tumor, which has been associated with the human papillomavirus (HPV). Here the authors perform comprehensive genome-wide characterization of HPV-associated and HPV-independent SNSCC patient samples to reveal molecular patterns of tumorigenesis and identify HPV-driven mutational profiles.

The frog Xenopus, an important research organism in cell and developmental biology, currently lacks tools for targeted mutagenesis. Here, we address this problem by genome editing with zinc-finger nucleases (ZFNs). ZFNs directed against an eGFP transgene in Xenopus tropicalis induced mutations consistent with nonhomologous end joining at the target site, resulting in mosaic loss of the fluorescence phenotype at high frequencies. ZFNs directed against the noggin gene produced tadpoles and adult animals carrying up to 47% disrupted alleles, and founder animals yielded progeny carrying insertions and deletions in the noggin gene with no indication of off-target effects. Furthermore, functional tests demonstrated an allelic series of activity between three germ-line mutant alleles. Because ZFNs can be designed against any locus, our data provide a generally applicable protocol for gene disruption in XENOPUS:

Head and neck squamous cell carcinoma (HNSCC) represents a highly prevalent and deadly malignancy worldwide. The prognosis for locoregionally advanced HNSCC has not appreciably improved over the past 30 years despite advances in surgical, radiation, and targeted therapies and less than 20% of HNSCC patients respond to recently approved immune checkpoint inhibitors. The Hippo signaling pathway, originally discovered as a mechanism regulating tissue growth and organ size, transduces intracellular and extracellular signals to regulate the transcriptional co-activators YAP and TAZ. Alterations in the Hippo pathway resulting in persistent YAP and TAZ activation have emerged as major oncogenic drivers. Our analysis of the human HNSCC oncogenome revealed multiple genomic alterations impairing Hippo signaling and activating YAP and TAZ, which in turn contribute to HNSCC development. This includes mutations and deletions of the FAT1 gene (29%) and amplification of the WWTR1 (encoding TAZ, 14%) and YAP1 genes (8%), together representing one of the most genetically altered signaling mechanisms in this malignancy. Here, we discuss key elements of the mammalian Hippo pathway, detail mechanisms by which perturbations in Hippo signaling promote HNSCC initiation and progression and outline emerging strategies to target Hippo signaling vulnerabilities as part of novel multimodal precision therapies for HNSCC.

Objective The use of standing electronic scooters associated with micromobility applications (e‐scooters) has risen nationally. The aim of this study was to obtain a detailed view of soft tissue and bony craniofacial injury associated with e‐scooter‐related trauma. Methods Single‐institution retrospective case series of patients presenting to a level 1 trauma center emergency department or trauma unit with documented e‐scooter‐related craniofacial injury. Results Of 203 included patients, 188 (92.6%) patients sustained craniofacial injury. One hundred thirty‐one (64.5%) had exclusively soft tissue injury, 3 (1.5%) exclusively bony injury, 51 (25.1%) both soft and bony injuries, and twenty‐five (12.3%) patients sustained dental injury. Aesthetic units most frequently sustaining acute soft tissue injury were the forehead (n = 106, 34.6%), scalp (n = 36, 11.8%), chin (n = 34, 11.1%), upper lip (n = 32, 10.5%), and cheek (n = 31, 10.1%). Aesthetic subunits most often sustaining acute soft tissue injury included the brow (42, 13.7%), central forehead (39, 12.7%), lateral forehead (n = 25, 8.2%), and upper lip vermillion (n = 23, 7.5%). Craniofacial osseous fracture most often occurred in the orbit (n = 42, 24.6%) and maxilla (n = 40, 23.4%). Individual osseous segments most frequently sustaining acute fracture included the anterior maxillary sinus wall (n = 22, 12.9%), nasal bone (n = 20, 11.7%), lateral orbital wall (n = 16, 9.4%), orbital floor (n = 15, 8.8%), and zygomatic bone (13, 7.6%). Conclusions Our analysis demonstrates that most patients presenting to our center with craniofacial trauma sustained acute bony fracture, most often to the midface. Our data of common injuries associated with e‐scooter trauma could inform implementation in the form of facial safety equipment or safety skills training for e‐scooter riders. Level of evidence 4

Accumulating evidence supports the role of an aberrant transcriptome as a driver of metastatic potential. Deadenylation is a general regulatory node for post-transcriptional control by microRNAs and other determinants of RNA stability. Previously, we demonstrated that the CCR4-NOT scaffold component Cnot2 is an inherited metastasis susceptibility gene. In this study, using orthotopic metastasis assays and genetically engineered mouse models, we show that one of the enzymatic subunits of the CCR4-NOT complex, Cnot7, is also a metastasis modifying gene. We demonstrate that higher expression of Cnot7 drives tumor cell autonomous metastatic potential, which requires its deadenylase activity. Furthermore, metastasis promotion by CNOT7 is dependent on interaction with CNOT1 and TOB1. CNOT7 ribonucleoprotein-immunoprecipitation (RIP) and integrated transcriptome wide analyses reveal that CNOT7-regulated transcripts are enriched for a tripartite 3'UTR motif bound by RNA-binding proteins known to complex with CNOT7, TOB1, and CNOT1. Collectively, our data support a model of CNOT7, TOB1, CNOT1, and RNA-binding proteins collectively exerting post-transcriptional control on a metastasis suppressive transcriptional program to drive tumor cell metastasis.

Thyroglossal duct cysts (TGDCs) are among the most common congenital anomalies of the neck, typically presenting as painless midline masses inferior to the hyoid bone. Distinguishing TGDCs from other cystic neck lesions, such as ranulas or dermoid cysts, can be challenging, particularly when they arise in uncommon locations such as the sublingual space. Here, we report an atypical presentation of a TGDC in the sublingual space of a 31‐year‐old Hispanic/Latino White male. The patient, with no significant medical history, presented to the emergency department at the University of California San Diego Health (Hillcrest Medical Center, San Diego, California, United States), in June 2023 after sustaining blunt facial trauma. Imaging revealed an incidental cystic lesion in the right paramedian floor of the mouth. Magnetic resonance imaging (MRI) confirmed a circumscribed cystic mass (21 × 21 × 20 mm) within the sublingual space. Imaging characteristics, including the lesion’s close approximation to the hyoid bone and absence of restricted diffusion, were most compatible with a TGDC. MRI also confirmed a normal thyroid gland and no cervical lymphadenopathy. Surgical excision of the cyst, including a segment of the hyoid bone, was performed. Histopathological examination confirmed the diagnosis of a TGDC with respiratory and squamous epithelial lining. At the 1‐week postoperative follow‐up, flexible laryngoscopy showed no complications, with normal vocal fold function. TGDCs in the sublingual space are extremely rare, with only nine previously reported cases in the English literature. This report underscores the significance of recognizing atypical presentations of TGDCs, particularly in rare locations such as the sublingual space, expanding the understanding of their diverse clinical manifestations.