RESUMO
The diverse malignant, stromal, and immune cells in tumors affect growth, metastasis, and response to therapy. We profiled transcriptomes of â¼6,000 single cells from 18 head and neck squamous cell carcinoma (HNSCC) patients, including five matched pairs of primary tumors and lymph node metastases. Stromal and immune cells had consistent expression programs across patients. Conversely, malignant cells varied within and between tumors in their expression of signatures related to cell cycle, stress, hypoxia, epithelial differentiation, and partial epithelial-to-mesenchymal transition (p-EMT). Cells expressing the p-EMT program spatially localized to the leading edge of primary tumors. By integrating single-cell transcriptomes with bulk expression profiles for hundreds of tumors, we refined HNSCC subtypes by their malignant and stromal composition and established p-EMT as an independent predictor of nodal metastasis, grade, and adverse pathologic features. Our results provide insight into the HNSCC ecosystem and define stromal interactions and a p-EMT program associated with metastasis.
Assuntos
Carcinoma de Células Escamosas/patologia , Neoplasias de Cabeça e Pescoço/patologia , Metástase Neoplásica/patologia , Carcinoma de Células Escamosas/genética , Células Cultivadas , Transição Epitelial-Mesenquimal , Perfilação da Expressão Gênica , Neoplasias de Cabeça e Pescoço/genética , Humanos , Masculino , Análise de Célula Única , Microambiente TumoralRESUMO
Conditional reprogramming is a cell culture technique that effectively immortalizes epithelial cells with normal genotypes by renewing epidermal stem cells. Y-27632, a compound that promotes conditional reprogramming through an unknown mechanism, was developed to inhibit the two Rho-associated kinase (ROCK) isoforms. We used human foreskin keratinocytes (HFKs) to study the role of Y-27632 in conditional reprogramming and learn how ROCKs control epidermal stem cell renewal. In conditional reprogramming, Y-27632 increased HFK adherence to culture dishes, progression through S, G2 and M phases of the cell cycle, and epidermal stem cell marker levels. Although this correlated with ROCK inhibition by Y-27632, we generated CRISPR-Cas9-mediated HFK ROCK knockouts to test the direct role of ROCK inhibition. Knockout of single ROCK isoforms was insufficient to disrupt ROCK activity or promote HFK propagation without Y-27632. Although ROCK activity was reduced, HFKs with double knockout of ROCK1 and ROCK2 still required Y-27632 to propagate. Y-27632 was the most effective among the ROCK inhibitors we tested at promoting HFK proliferation and epidermal stem cell marker expression. Thus, the ability of Y-27632 to promote an epidermal stem cell state in conditional reprogramming not only depends upon ROCK inhibition but also acts via as-yet-unidentified mechanisms. Epidermal stem cell renewal might in part be regulated by ROCKs, but also involves additional pathways.
Assuntos
Células Epidérmicas , Células-Tronco , Humanos , Epiderme , Queratinócitos , Quinases Associadas a rhoRESUMO
Head and neck squamous cell carcinoma (HNSCC) accounts for over 10,000 deaths in the United States annually. Approximately 80% of HNSCC are human papillomavirus (HPV)-negative which have an overall poorer prognosis compared to the HPV-positive disease. Treatment options are mainly nontargeted chemotherapy, radiation, and surgery. The cyclin-d-CDK4/6-RB pathway, which regulates cell cycle progression, is often deregulated in HNSCC, making it an attractive therapeutic target. In the current study, we investigated the therapeutic effects of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in preclinical models of HNSCCs. Our results show that the specific CDK4/6 inhibitor, abemaciclib, inhibited cell growth, and induced apoptosis in HNSCC cell lines. We also demonstrated that both the pro-survival autophagy pathway and the ERK pathway in HNSCC cells were activated with abemaciclib treatment through the generation of reactive oxygen species (ROS). Coinhibition of CDK4/6 and autophagy synergistically decreased cell viability, induced apoptosis, and inhibited tumor growth in both in vitro and in vivo preclinical HNSCC models. These results reveal a potential therapeutic strategy that supports the rationale for further clinical development of a combination of CDK4/6 and autophagy inhibitors in HNSCC.
Assuntos
Neoplasias de Cabeça e Pescoço , Infecções por Papillomavirus , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 4 Dependente de Ciclina/farmacologia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Apoptose , Autofagia , Linhagem Celular TumoralRESUMO
Head and neck cancer is the seventh most common type of cancer worldwide and comprise of a diverse group of tumours affecting the upper aerodigestive tract. Although many different histologies exist, the most common is squamous cell carcinoma. Predominant risk factors include tobacco use, alcohol abuse, and oncogenic viruses, including human papillomavirus and Epstein-Barr virus. Head and neck malignancies remain challenging to treat, requiring a multidisciplinary approach, with surgery, radiotherapy, and systemic therapy serving as key components of the treatment of locally advanced disease. Although many treatment principles overlap, treatment is generally site-specific and histology-specific. This Seminar outlines the current understanding of head and neck cancer and focuses on treatment principles, while also discussing future directions to improve the outcomes of patients with these malignancies.
Assuntos
Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/terapia , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/terapia , Carcinoma de Células Escamosas/virologia , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/virologia , Neoplasias de Cabeça e Pescoço/virologia , Herpesvirus Humano 4 , Humanos , Papillomaviridae , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/virologiaRESUMO
BACKGROUND: Immune checkpoint inhibitors (ICI) treatment in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) offers new therapeutic venues. We have previously developed a predictive survival model in this patient population based on clinical parameters, and the purpose of this study was to expand the study cohort and internally validate the model. METHODS: A single institutional retrospective analysis of R/M HNSCC patients treated with ICI. Clinical parameters collected included p-16 status, hemoglobin (Hb), albumin (Alb), lactate dehydrogenase (LDH), neutrophil, lymphocyte and platelet counts. Cox proportional hazard regression was used to assess the impact of patient characteristics and clinical variables on survival. A nomogram was created using the rms package to generate individualized survival prediction. RESULTS: 201 patients were included, 47 females (23%), 154 males (77%). Median age was 61 years (IQR: 55-68). P-16 negative (66%). Median OS was 12 months (95% CI: 9.4, 14.9). Updated OS model included age, sex, absolute neutrophil count, absolute lymphocyte count, albumin, hemoglobin, LDH, and p-16 status. We stratified patients into three risk groups based on this model at the 0.33 and 0.66 quantiles. Median OS in the optimal risk group reached 23.7 months (CI: 18.5, NR), 13.8 months (CI: 11.1, 20.3) in the average risk group, and 2.3 months (CI: 1.7, 4.4) in the high-risk group. Following internal validation, the discriminatory power of the model reached a c-index of 0.72 and calibration slope of 0.79. CONCLUSIONS: Our updated nomogram could assist in the precise selection of patients for which ICI could be beneficial and cost-effective.
Assuntos
Neoplasias de Cabeça e Pescoço , Inibidores de Checkpoint Imunológico , Albuminas/uso terapêutico , Feminino , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Hemoglobinas , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Prognóstico , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológicoRESUMO
The NCCN Guidelines for Head and Neck Cancers address tumors arising in the oral cavity (including mucosal lip), pharynx, larynx, and paranasal sinuses. Occult primary cancer, salivary gland cancer, and mucosal melanoma (MM) are also addressed. The specific site of disease, stage, and pathologic findings guide treatment (eg, the appropriate surgical procedure, radiation targets, dose and fractionation of radiation, indications for systemic therapy). The NCCN Head and Neck Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel's most recent recommendations regarding management of HPV-positive oropharynx cancer and ongoing research in this area.
Assuntos
Neoplasias de Cabeça e Pescoço , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/terapia , HumanosRESUMO
BACKGROUND: During the last two decades, significant advancements in the treatment of laryngeal cancer have occurred. Although survival of head and neck cancer patients has improved over time, the temporal trend of laryngeal cancer survival is an area of controversy. METHODS: From 2004 to 2016, 77,527 patients who had laryngeal cancer treated with curative intent in the United States were identified in the National Cancer Database. Relative and observed survival rates were assessed for temporal trends. Multinomial logistic regression investigated the relationship between American Joint Committee on Cancer (AJCC) stage and increasing calendar year. RESULTS: No significant improvement in 2- or 5-year observed survival (OS) or relative survival (RS) was observed. The 5-year RS ranged from 61.72 to 63.97%, and the 5-year OS ranged from 54.26 to 56.52%. With each increasing year, the proportion of stage 4 disease increased, with risk for stage 4 disease at the time of diagnosis increasing 2.2% annually (adjusted odds ratio [aOR], 1.022; 95% confidence interval [CI], 1.017-1.028; p < 0.001). This increase was driven by a 4.7% yearly increase in N2 disease (aOR, 1.047; 95% CI, 1.041-1.053; p < 0.001), with an annual 1.2% increase in T3 disease (aOR, 1.012; 95% CI, 1.007-1.018; p < 0.001) and a 1.2% increase in T4 disease (aOR, 1.012; 95% CI, 1.005-1.018; p < 0.001). CONCLUSION: Despite advances in the field, laryngeal cancer survival in the United States is not improving over time. This may be due to an increase in the proportion of stage 4 disease, driven primarily by increasing nodal disease. To achieve survival improvement commensurate with scientific and technologic advances, efforts should be made to diagnose and treat laryngeal cancer at earlier stages to prevent further stage migration.
Assuntos
Neoplasias de Cabeça e Pescoço , Neoplasias Laríngeas , Humanos , Neoplasias Laríngeas/patologia , Neoplasias Laríngeas/terapia , Estadiamento de Neoplasias , Estudos Retrospectivos , Taxa de Sobrevida , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: The COVID-19 pandemic has required triage and delays in surgical care throughout the world. The impact of these surgical delays on survival for patients with head and neck squamous cell carcinoma (HNSCC) remains unknown. METHODS: A retrospective cohort study of 37 730 patients in the National Cancer Database with HNSCC who underwent primary surgical management from 2004 to 2016 was performed. Uni- and multivariate analyses were used to identify predictors of overall survival. Bootstrapping methods were used to identify optimal time-to-surgery (TTS) thresholds at which overall survival differences were greatest. Cox proportional hazard models with or without restricted cubic splines were used to determine the association between TTS and survival. RESULTS: The study identified TTS as an independent predictor of overall survival (OS). Bootstrapping the data to dichotomize the cohort identified the largest rise in hazard ratio (HR) at day 67, which was used as the optimal TTS cut-point in survival analysis. The patients who underwent surgical treatment longer than 67 days after diagnosis had a significantly increased risk of death (HR, 1.189; 95% confidence interval [CI], 1.122-1.261; P < 0.0001). For every 30-day delay in TTS, the hazard of death increased by 4.6%. Subsite analysis showed that the oropharynx subsite was most affected by surgical delays, followed by the oral cavity. CONCLUSIONS: Increasing TTS is an independent predictor of survival for patients with HNSCC and should be performed within 67 days after diagnosis to achieve optimal survival outcomes.
Assuntos
Neoplasias Hipofaríngeas/cirurgia , Neoplasias Laríngeas/cirurgia , Neoplasias Bucais/cirurgia , Neoplasias Orofaríngeas/cirurgia , Procedimentos Cirúrgicos Otorrinolaringológicos/estatística & dados numéricos , Carcinoma de Células Escamosas de Cabeça e Pescoço/cirurgia , Tempo para o Tratamento/estatística & dados numéricos , Idoso , COVID-19 , Estudos de Coortes , Atenção à Saúde , Feminino , Humanos , Neoplasias Hipofaríngeas/mortalidade , Neoplasias Laríngeas/mortalidade , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/mortalidade , Neoplasias Orofaríngeas/mortalidade , Modelos de Riscos Proporcionais , Estudos Retrospectivos , SARS-CoV-2 , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Oncologia CirúrgicaRESUMO
BACKGROUND: After surgery for head and neck squamous cell carcinoma (HNSCC), decisions regarding adjuvant radiotherapy (RT) or chemoradiotherapy (CRT) are based on staging and the presence of high-risk pathology. Because higher mutant allele tumor heterogeneity (MATH; a measure of intratumor genetic heterogeneity) is associated with shorter overall survival (OS) in patients with HNSCC, the authors sought to determine whether MATH analysis might further inform these decisions. METHODS: Adjuvant therapy-associated relationships between MATH and OS were analyzed for 389 patients with HNSCC who were treated surgically. Data were obtained from The Cancer Genome Atlas and analyzed with Cox proportional hazards multiple regression accounting for 7 other patient characteristics. RESULTS: The relationship between MATH and OS differed with adjuvant therapy in a way that could inform therapy decisions. Adjuvant RT alone was found to provide substantial benefit for patients having high-MATH tumors (RT vs no adjuvant therapy: hazard ratio, 0.29 [95% CI, 0.17-0.51]) but no benefit for those having low-MATH tumors. In contrast, adjuvant CRT provided no benefit beyond that of adjuvant RT for patients with high-MATH tumors but substantially improved OS among patients with low-MATH tumors (CRT vs no adjuvant therapy: hazard ratio, 0.34 [95% CI, 0.15-0.78]). CONCLUSIONS: The results of the current analysis suggested that patients with HNSCC with high-MATH tumors who underwent surgical treatment could benefit from adjuvant RT, even when current clinical guidelines indicate otherwise. The addition of adjuvant chemotherapy for patients with high-MATH tumors would not be indicated. Adding chemotherapy might be necessary to radiosensitize low-MATH tumors to adjuvant RT. This potential predictive role of tumor MATH analysis should be evaluated in prospective clinical trials.
Assuntos
Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/terapia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Idoso , Quimioterapia Adjuvante , Terapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Cuidados Pós-Operatórios , Modelos de Riscos Proporcionais , Radioterapia Adjuvante , Análise de SobrevidaRESUMO
BACKGROUND: Human papillomavirus (HPV)-mediated oropharyngeal cancer (OPC) is associated with dramatically improved survival in comparison with HPV-negative OPC and can be successfully treated with surgical and nonsurgical approaches. National treatment trends for OPC were investigated with the National Cancer Data Base (NCDB). METHODS: The NCDB was reviewed for primary HPV-mediated OPC in 2010-2014. Multivariable regression was used to identify predictors of both nonsurgical therapy and receipt of adjuvant chemoradiation (CRT). RESULTS: There were 13,363 patients identified with a median age at diagnosis of 58 years. The incidence of triple-modality treatment (surgery with adjuvant chemotherapy) decreased from 23.7% in 2010 to 16.9% in 2014 (R2 = 0.96), whereas the incidence of nonsurgical treatment increased from 63.9% to 68.7% (R2 = 0.89). Hospitals in the top treatment volume quartile (quartile 1 [Q1]; n = 29) had a lower rate of positive margins (16.3%) than bottom-quartile centers (n = 741; rate of positive margins, 36.4%; P < .001); Q1 hospitals used surgical therapy significantly more. Independent predictors of nonsurgical therapy included older age, advanced disease, lower hospital volume, and living closer to the hospital or outside the Pacific United States. In surgically treated patients, younger age, lower hospital volume, nodal disease, positive surgical margins, and extranodal extension (ENE) also predicted more adjuvant CRT use. CONCLUSIONS: The use of upfront surgical treatment decreased from 2010 to 2014. Hospital volume shows a strong, inverse correlation with the rate of positive surgical margins. The upfront treatment strategy is predicted not only by staging but also by patient-, geographic-, and hospital-specific factors. Lower hospital volume remains independently associated with increased triple-modality therapy after adjustments for positive margins, ENE, and pathologic staging.
Assuntos
Carcinoma de Células Escamosas/terapia , Neoplasias Orofaríngeas/terapia , Infecções por Papillomavirus/complicações , Fatores Etários , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/virologia , Quimiorradioterapia Adjuvante/estatística & dados numéricos , Distribuição de Qui-Quadrado , Terapia Combinada/tendências , Feminino , Acessibilidade aos Serviços de Saúde , Hospitais com Alto Volume de Atendimentos/estatística & dados numéricos , Hospitais com Baixo Volume de Atendimentos/estatística & dados numéricos , Humanos , Masculino , Margens de Excisão , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Orofaríngeas/patologia , Neoplasias Orofaríngeas/virologia , Faringectomia , Análise de Regressão , Estudos Retrospectivos , Estatísticas não Paramétricas , Estados UnidosRESUMO
Treatment is complex for patients with head and neck (H&N) cancers with specific site of disease, stage, and pathologic findings guiding treatment decision-making. Treatment planning for H&N cancers involves a multidisciplinary team of experts. This article describes supportive care recommendations in the NCCN Guidelines for Head and Neck Cancers, as well as the rationale supporting a new section on imaging recommendations for patients with H&N cancers. This article also describes updates to treatment recommendations for patients with very advanced H&N cancers and salivary gland tumors, specifically systemic therapy recommendations.
Assuntos
Neoplasias de Cabeça e Pescoço , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/terapia , Humanos , Oncologia , Guias de Prática Clínica como AssuntoRESUMO
BACKGROUND: The status of surgical margins is the most important prognosticator for patients undergoing surgical resection of head and neck squamous cell carcinoma (HNSCC). Despite this, analysis of surgical margins is fraught with inconsistencies, including the ways in which margins are sampled and interpreted. Fundamentally, even the definition what constitutes a "clear" (or negative) margin may vary between institutions, surgeons, and pathologists. METHODS: The PubMed database was queried for articles relevant to the topic, and experts in the field were consulted regarding key articles for inclusion. Abstracts were reviewed and the full text was accessed for articles of particular interest. RESULTS: Data regarding various approaches to traditional margin analysis have been published without consensus. Several next-generation technologies have emerged in recent years that hold promise. CONCLUSION: An overview and appraisal of traditional margin analysis techniques are provided. Additionally, we explore novel technologies that may assist in more accurate margin assessment, guide the extent of surgical resections intraoperatively, and inform decisions regarding adjuvant treatment postoperatively.
Assuntos
Neoplasias de Cabeça e Pescoço/patologia , Margens de Excisão , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/cirurgia , Humanos , Prognóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/cirurgiaRESUMO
The authors review and discuss the implications of genomic analyses documenting the diversity of tumors, both among patients and within individual tumors. Genetic diversity among solid tumors limits targeted therapies, because few mutations that drive tumors are both targetable and at high prevalence. Many more driver mutations and how they affect cellular signaling pathways must be identified if targeted therapy is to become widely useful. Genetic diversity within a tumor-intratumor genetic heterogeneity-makes the tumor a collection of subclones: related yet distinct cancers. Selection for pre-existing, resistant subclones by conventional or targeted therapies may explain many treatment failures. Immune therapy faces the same fundamental challenges. Nevertheless, the processes that generate and maintain heterogeneity might provide novel therapeutic targets. Addressing both types of diversity requires genomic tumor analyses linked to detailed clinical data. The trend toward sequencing restricted cancer gene panels, however, limits the ability to discover new driver mutations and assess intratumor heterogeneity. Clinical data currently collected with genomic analyses often lack critical information, substantially limiting their use in understanding tumor diversity. Now that diversity among and within tumors can no longer be ignored, research and clinical practice must adapt to take diversity into account. Cancer 2017;123:917-27. © 2016 American Cancer Society.
Assuntos
Heterogeneidade Genética , Variação Genética , Neoplasias/genética , Animais , Biomarcadores Tumorais , Evolução Clonal , Predisposição Genética para Doença , Humanos , Terapia de Alvo Molecular , Mutação , Neoplasias/mortalidade , Neoplasias/patologia , Neoplasias/terapia , Medicina de Precisão , PrognósticoRESUMO
Genomic instability is a hallmark of human cancers, including the 5% caused by human papillomavirus (HPV). Here we report a striking association between HPV integration and adjacent host genomic structural variation in human cancer cell lines and primary tumors. Whole-genome sequencing revealed HPV integrants flanking and bridging extensive host genomic amplifications and rearrangements, including deletions, inversions, and chromosomal translocations. We present a model of "looping" by which HPV integrant-mediated DNA replication and recombination may result in viral-host DNA concatemers, frequently disrupting genes involved in oncogenesis and amplifying HPV oncogenes E6 and E7. Our high-resolution results shed new light on a catastrophic process, distinct from chromothripsis and other mutational processes, by which HPV directly promotes genomic instability.
Assuntos
Replicação do DNA/genética , Instabilidade Genômica , Papillomavirus Humano 16/genética , Neoplasias/genética , DNA Viral/genética , Feminino , Papillomavirus Humano 16/crescimento & desenvolvimento , Humanos , Masculino , Neoplasias/classificação , Neoplasias/patologia , Neoplasias/virologia , Proteínas Oncogênicas Virais/genética , Proteínas Oncogênicas Virais/metabolismo , Proteínas E7 de Papillomavirus/genética , Proteínas E7 de Papillomavirus/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Integração Viral/genéticaRESUMO
BACKGROUND: Although the involvement of intra-tumor genetic heterogeneity in tumor progression, treatment resistance, and metastasis is established, genetic heterogeneity is seldom examined in clinical trials or practice. Many studies of heterogeneity have had prespecified markers for tumor subpopulations, limiting their generalizability, or have involved massive efforts such as separate analysis of hundreds of individual cells, limiting their clinical use. We recently developed a general measure of intra-tumor genetic heterogeneity based on whole-exome sequencing (WES) of bulk tumor DNA, called mutant-allele tumor heterogeneity (MATH). Here, we examine data collected as part of a large, multi-institutional study to validate this measure and determine whether intra-tumor heterogeneity is itself related to mortality. METHODS AND FINDINGS: Clinical and WES data were obtained from The Cancer Genome Atlas in October 2013 for 305 patients with head and neck squamous cell carcinoma (HNSCC), from 14 institutions. Initial pathologic diagnoses were between 1992 and 2011 (median, 2008). Median time to death for 131 deceased patients was 14 mo; median follow-up of living patients was 22 mo. Tumor MATH values were calculated from WES results. Despite the multiple head and neck tumor subsites and the variety of treatments, we found in this retrospective analysis a substantial relation of high MATH values to decreased overall survival (Cox proportional hazards analysis: hazard ratio for high/low heterogeneity, 2.2; 95% CI 1.4 to 3.3). This relation of intra-tumor heterogeneity to survival was not due to intra-tumor heterogeneity's associations with other clinical or molecular characteristics, including age, human papillomavirus status, tumor grade and TP53 mutation, and N classification. MATH improved prognostication over that provided by traditional clinical and molecular characteristics, maintained a significant relation to survival in multivariate analyses, and distinguished outcomes among patients having oral-cavity or laryngeal cancers even when standard disease staging was taken into account. Prospective studies, however, will be required before MATH can be used prognostically in clinical trials or practice. Such studies will need to examine homogeneously treated HNSCC at specific head and neck subsites, and determine the influence of cancer therapy on MATH values. Analysis of MATH and outcome in human-papillomavirus-positive oropharyngeal squamous cell carcinoma is particularly needed. CONCLUSIONS: To our knowledge this study is the first to combine data from hundreds of patients, treated at multiple institutions, to document a relation between intra-tumor heterogeneity and overall survival in any type of cancer. We suggest applying the simply calculated MATH metric of heterogeneity to prospective studies of HNSCC and other tumor types.
Assuntos
Alelos , DNA de Neoplasias/análise , Variação Genética , Neoplasias de Cabeça e Pescoço/genética , Mutação , Idoso , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/virologia , Exoma , Feminino , Neoplasias de Cabeça e Pescoço/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Orofaríngeas/genética , Neoplasias Orofaríngeas/virologia , Papillomaviridae , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Análise de Sequência de DNARESUMO
Oropharyngeal squamous cell carcinoma caused by high-risk types of human papillomavirus (HPV) is now a well-recognized tumor entity whose incidence is on the rise. Most HPV-related oropharyngeal squamous cell carcinomas have a distinct histomorphology, and most patients fit a typical clinical profile. Importantly, HPV-related oropharyngeal carcinoma patients overall have significantly improved outcomes when compared to their HPV-negative counterparts, and the differences in tumor biology may soon lead to modifications in how they are treated. While high-risk HPV can be detected in a significant minority of head and neck squamous cell carcinomas across anatomic subsites in the head and neck, it has become clear in recent years that the biologically and clinically favorable features are limited to tumors that harbor transcriptionally active, high-risk HPV, something that occurs predominantly (but certainly not exclusively) in the oropharynx. It is now acknowledged that detecting transcriptionally active, high-risk HPV is a necessity in routine clinical practice, but there is considerable confusion among pathologists and clinicians alike about the subsites and settings in which HPV testing should be performed. Compounding this lack of clarity is the fact that there are multiple HPV testing options available, but currently there is no clear consensus on which test or combination of tests is optimal for routine diagnostic use. This review serves as an update for practicing pathologists on the current status of HPV (and surrogate marker) testing in head and neck cancers.
Assuntos
Biomarcadores Tumorais , Carcinoma de Células Escamosas/diagnóstico , Inibidor p16 de Quinase Dependente de Ciclina/análise , DNA Viral/genética , Neoplasias de Cabeça e Pescoço/diagnóstico , Testes de DNA para Papilomavírus Humano , Papillomaviridae/genética , Infecções por Papillomavirus/diagnóstico , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Biópsia por Agulha Fina , Carcinoma de Células Escamosas/química , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/virologia , Neoplasias de Cabeça e Pescoço/química , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/virologia , Humanos , Imuno-Histoquímica , Hibridização In Situ , Infecções por Papillomavirus/patologia , Infecções por Papillomavirus/virologia , Reação em Cadeia da Polimerase , Valor Preditivo dos Testes , Carcinoma de Células Escamosas de Cabeça e PescoçoRESUMO
We demonstrate that deltaNp63alpha is an essential survival factor in head and neck squamous cell carcinoma (HNSCC) through its ability to suppress p73-dependent apoptosis. Inhibition of endogenous p63 expression by RNAi induces apoptosis selectively in HNSCC cells that overexpress deltaNp63alpha. Knockdown of p63 induces the proapoptotic bcl-2 family members Puma and Noxa, and both their induction and subsequent cell death are p53 independent but require transactivating isoforms of p73. Inhibition of p73-dependent transcription by deltaNp63alpha involves both direct promoter binding and physical interaction with p73. In HNSCC cells lacking endogenous deltaNp63alpha expression, bcl-2 is instead upregulated and can suppress p73-mediated death. Together, these data define a pathway whereby deltaNp63alpha promotes survival in squamous epithelial malignancy by repressing a p73-dependent proapoptotic transcriptional program.
Assuntos
Apoptose , Carcinoma de Células Escamosas/metabolismo , Sobrevivência Celular , Proteínas de Ligação a DNA/fisiologia , Genes Supressores de Tumor/fisiologia , Neoplasias de Cabeça e Pescoço/metabolismo , Proteínas Nucleares/fisiologia , Fosfoproteínas/fisiologia , Transativadores/fisiologia , Proteínas Reguladoras de Apoptose/metabolismo , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/genética , Genes bcl-2 , Genes p53 , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Proteínas Nucleares/genética , Fosfoproteínas/antagonistas & inibidores , Regiões Promotoras Genéticas , Ligação Proteica , Isoformas de Proteínas/genética , Isoformas de Proteínas/fisiologia , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transdução de Sinais , Transativadores/antagonistas & inibidores , Fatores de Transcrição , Ativação Transcricional , Proteína Tumoral p73 , Proteínas Supressoras de TumorRESUMO
Little is known about the extent of prior authorization requirements in otolaryngology. We performed a secondary analysis of data comparing prior authorization (PA) policies across 5 major Medicare Advantage insurers to estimate the counterfactual proportion of 2021 Medicare Part B fee-for-service spending and utilization for commonly performed otolaryngologic procedures that would have required PA. The counterfactual proportion of spending (range: 20.4%-27.6%) and utilization (range: 1.8%-4.5%) requiring PA was relatively consistent across insurers and largely attributable to rhinologic procedures. However, PA requirements for specific services varied widely among insurers. Among the 70 (of 196; 35.7%) services subject to PA by any insurer, nearly half were subject to PA by a single insurer (n = 34; 48.6%). Only 10 (14.3%) services were subject to PA by 4 (n = 6; 8.6%) or 5 (n = 4; 5.7%) insurers. These discrepancies illustrate the challenges of navigating discordant insurer policies for otolaryngologists and raise concerns about the validity of certain PA requirements.
RESUMO
OBJECTIVES: Large language model (LLM)-based chatbots such as ChatGPT have been publicly available and increasingly utilized by the general public since late 2022. This study sought to investigate ChatGPT responses to common patient questions regarding Human Papilloma Virus (HPV) positive oropharyngeal cancer (OPC). METHODS: This was a prospective, multi-institutional study, with data collected from high volume institutions that perform >50 transoral robotic surgery cases per year. The 100 most recent discussion threads including the term "HPV" on the American Cancer Society's Cancer Survivors Network's Head and Neck Cancer public discussion board were reviewed. The 11 most common questions were serially queried to ChatGPT 3.5; answers were recorded. A survey was distributed to fellowship trained head and neck oncologic surgeons at 3 institutions to evaluate the responses. RESULTS: A total of 8 surgeons participated in the study. For questions regarding HPV contraction and transmission, ChatGPT answers were scored as clinically accurate and aligned with consensus in the head and neck surgical oncology community 84.4% and 90.6% of the time, respectively. For questions involving treatment of HPV+ OPC, ChatGPT was clinically accurate and aligned with consensus 87.5% and 91.7% of the time, respectively. For questions regarding the HPV vaccine, ChatGPT was clinically accurate and aligned with consensus 62.5% and 75% of the time, respectively. When asked about circulating tumor DNA testing, only 12.5% of surgeons thought responses were accurate or consistent with consensus. CONCLUSION: ChatGPT 3.5 performed poorly with questions involving evolving therapies and diagnostics-thus, caution should be used when using a platform like ChatGPT 3.5 to assess use of advanced technology. Patients should be counseled on the importance of consulting their surgeons to receive accurate and up to date recommendations, and use LLM's to augment their understanding of these important health-related topics.