RESUMO
Squamous cell carcinoma of the head and neck (SCCHN) is a devastating disease that continues to have low cure rates despite the recent advances in therapies. Cisplatin is the most used chemotherapy agent, and treatment failure is largely driven by resistance to this drug. Amplification of chromosomal band 11q13 occurs in â¼30% of SCCHN tumors. This region harbors the ANO1 gene that encodes the TMEM16A ion channel, which is responsible for calcium-activated chloride transport in epithelial tissues. TMEM16A overexpression is associated with cisplatin resistance, and high TMEM16A levels correlate with decreased survival. However, the mechanistic underpinning of this effect remains unknown. Lysosomal biogenesis and exocytosis have been implicated in cancer because of their roles in the clearance of damaged organelles and exocytosis of chemotherapeutic drugs and toxins. Here, we show that TMEM16A overexpression promotes lysosomal biogenesis and exocytosis, which is consistent with the expulsion of intracellular cisplatin. Using a combination of genetic and pharmacologic approaches, we find that TMEM16A promotes lysosomal flux in a manner that requires reactive oxygen species, TRPML1, and the activation of the ß-cateninmelanocyte-inducing transcription factor pathway. The lysosomal inhibitor hydroxychloroquine (HCQ) synergizes with cisplatin in killing SCCHN cells in vitro. Using a murine model of SCCHN, we show that HCQ and cisplatin retard the growth of cisplatin-resistant patient-derived xenografts in vivo. We propose that TMEM16A enables cell survival by the up-regulation of lysosomal sequestration and exocytosis of the cytotoxic drugs. These results uncover a model of treatment for resistance in cancer, its reversal, and a role for TMEM16A.
Assuntos
Anoctamina-1 , Antineoplásicos , Cisplatino , Neoplasias de Cabeça e Pescoço , Proteínas de Neoplasias , Anoctamina-1/genética , Anoctamina-1/metabolismo , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Canais de Cloreto , Cisplatino/farmacologia , Humanos , Lisossomos/metabolismo , Proteínas de Neoplasias/metabolismoRESUMO
Genetic factors underlying lymphocyte telomere length (LTL) may provide insights into genomic stability and integrity, with direct links to susceptibility to cancer recurrence. Polymorphisms in telomere-associated genes are strongly associated with LTL and cancer risk, while few large studies have explored the associations between LTL-related polymorphisms and recurrence risk of non-oropharyngeal head and neck squamous cell carcinoma (non-OPHNSCC). Totally 1403 non-OPHNSCC patients were recruited and genotyped for 16 LTL-related polymorphisms identified by genome-wide association studies. Univariate and multivariate analyzes were performed to evaluate associations between the polymorphisms and non-OPHNSCC recurrence risk. Patients carrying rs755017 GA/GG, rs2487999 TC/TT, rs2736108 TC/TT, or rs6772228 AT/AA genotypes exhibited shorter DFS than those with the rs755017 AA, rs2487999 CC, rs2736108 CC, or s6772228 TT genotypes, respectively (all log-rank p < 0.05). Multivariable analysis confirmed an increased risk of recurrence for patients carrying rs755017 GA/GG, rs2487999 TC/TT, rs2736108 TC/TT, or rs6772228 AT/AA genotypes (adjusted hazard ratio [aHR]: 1.66, 95% confidence interval [CI]: 1.32-2.07; aHR: 1.77, 95% CI: 1.41-2.23; aHR: 1.56, 95% CI: 1.22-1.99; aHR: 1.52, 95% CI: 1.20-1.93, respectively). Further stratified analysis revealed stronger associations between these genotypes and recurrence risk in ever-smokers and patients undergoing chemoradiotherapy. The similar but particularly pronounced results were observed for the combined risk genotypes of the four significant polymorphisms. This is the first large study on non-OPHNSCC patients showing that LTL-related polymorphisms may modify risk of non-OPHNSCC recurrence individually and jointly, particularly when analyzed in the context of smoking status and personized treatment. Larger studies are needed to validate these results.
Assuntos
Predisposição Genética para Doença , Neoplasias de Cabeça e Pescoço , Recidiva Local de Neoplasia , Polimorfismo de Nucleotídeo Único , Carcinoma de Células Escamosas de Cabeça e Pescoço , Humanos , Masculino , Feminino , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Pessoa de Meia-Idade , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , Homeostase do Telômero/genética , Telômero/genética , Idoso , Estudo de Associação Genômica Ampla , Genótipo , Fatores de Risco , Prognóstico , AdultoRESUMO
PURPOSE OF REVIEW: This review aims to provide a comprehensive overview of the current advances in managing and preventing progression of oral potentially malignant disorders (OPMDs), focusing on their histological and clinicopathological features, and management. RECENT FINDINGS: Recent studies, including a multicenter cross-sectional study, have identified oral leukoplakia as the most prevalent form of OPMD, comprising over half of the cases examined. Advances in histological grading, specifically the World Health Organization's three-tier system (mild, moderate, and severe dysplasia), have significantly enhanced the accuracy of risk assessment for malignant transformation. Additionally, treatments such as surgical interventions, photodynamic therapy, and chemopreventive and molecularly targeted agents are being evaluated for their safety and efficacy as well as, immune checkpoint inhibitors being evaluated as potential preventive strategies to halt the progression of OPMDs. The management of OPMDs remains challenging due to the lack of standardized screening protocols and varied clinical management approaches. Despite this, recent advancements in diagnostic grading and therapeutic interventions provide a framework for improved treatment outcomes. Continued research into the molecular and cellular mechanisms driving development and progression of OPMDs and innovative treatment trials are essential to optimize strategies that prevent malignant progression and thereby reduce the global health burden of oral cancer.
RESUMO
Progressive remodeling of the heart, resulting in cardiomyocyte (CM) loss and increased inflammation, fibrosis, and a progressive decrease in cardiac function, are hallmarks of myocardial infarction (MI)-induced heart failure. We show that MCB-613, a potent small molecule stimulator of steroid receptor coactivators (SRCs) attenuates pathological remodeling post-MI. MCB-613 decreases infarct size, apoptosis, hypertrophy, and fibrosis while maintaining significant cardiac function. MCB-613, when given within hours post MI, induces lasting protection from adverse remodeling concomitant with: 1) inhibition of macrophage inflammatory signaling and interleukin 1 (IL-1) signaling, which attenuates the acute inflammatory response, 2) attenuation of fibroblast differentiation, and 3) promotion of Tsc22d3-expressing macrophages-all of which may limit inflammatory damage. SRC stimulation with MCB-613 (and derivatives) is a potential therapeutic approach for inhibiting cardiac dysfunction after MI.
Assuntos
Cicloexanonas/farmacologia , Infarto do Miocárdio/fisiopatologia , Piridinas/farmacologia , Receptores de Esteroides/metabolismo , Remodelação Ventricular/efeitos dos fármacos , Animais , Diferenciação Celular/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose , Testes de Função Cardíaca , Inflamação/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Camundongos , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Células RAW 264.7 , RNA/genética , RNA/metabolismo , Transcrição Gênica/efeitos dos fármacosRESUMO
Historically, human breast cancer has been modeled largely in vitro using long-established cell lines primarily in two-dimensional culture, but also in three-dimensional cultures of varying cellular and molecular complexities. A subset of cell line models has also been used in vivo as cell line-derived xenografts (CDX). While outstanding for conducting detailed molecular analysis of regulatory mechanisms that may function in vivo, results of drug response studies using long-established cell lines have largely failed to translate clinically. In an attempt to address this shortcoming, many laboratories have succeeded in developing clinically annotated patient-derived xenograft (PDX) models of human cancers, including breast, in a variety of host systems. While immunocompromised mice are the predominant host, the immunocompromised rat and pig, zebrafish, as well as the chicken egg chorioallantoic membrane (CAM) have also emerged as potential host platforms to help address perceived shortcomings of immunocompromised mice. With any modeling platform, the two main issues to be resolved are criteria for "credentialing" the models as valid models to represent human cancer, and utility with respect to the ability to generate clinically relevant translational research data. Such data are beginning to emerge, particularly with the activities of PDX consortia such as the NCI PDXNet Program, EuroPDX, and the International Breast Cancer Consortium, as well as a host of pharmaceutical companies and contract research organizations (CRO). This review focuses primarily on these important aspects of PDX-related research, with a focus on breast cancer.
Assuntos
Neoplasias da Mama , Animais , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular , Modelos Animais de Doenças , Feminino , Xenoenxertos , Humanos , Camundongos , Ratos , Suínos , Ensaios Antitumorais Modelo de Xenoenxerto , Peixe-ZebraRESUMO
BACKGROUND: Persons living with HIV/AIDS have a higher incidence of virus-related and tobacco/alcohol-related cancers. This study is the first to estimate the effect of HIV versus HIV-negative veterans on the risk of head and neck squamous cell carcinoma incidence in a large retrospective cohort study. METHODS: The authors constructed a retrospective cohort study using patient data from 1999 to 2016 from the National Veterans Administration Corporate Data Warehouse and the VA Central Cancer Registry. This cohort study included 45,052 veterans living with HIV/AIDS and 162,486 HIV-negative patients matched by age, sex, and index visit (i.e., HIV diagnosis date or clinic visit date). The age-standardized incidence rates and estimated adjusted hazard ratios were calculated with a Cox proportional hazards regression for oropharyngeal and nonoropharyngeal head and neck cancer squamous cell carcinoma (HNSCC). The authors also abstracted human papillomavirus (HPV) status from oropharyngeal HNSCC diagnosed after 2010. RESULTS: Veterans living with HIV/AIDS (VLWH) have 1.71 (95% confidence interval [CI], 1.36, 2.14) times the risk of oropharyngeal cancer and 2.06 (95% CI, 1.76, 2.42) times the hazard of nonoropharyngeal cancer compared with HIV-negative veterans. VLWH with oropharyngeal squamous cell carcinoma (OPSCC) were more likely to be HPV-positive (N = 30 [81.1%]) than the HIV-negative veterans with OPSCC (N = 50 [67.6%]), although this difference was not significant (p = .135). For nonoropharyngeal cancer, the increased risk of oral cavity cancer among VLWH drove the increased risk. CONCLUSIONS: The study results suggest that HIV may play a role in virally mediated and nonvirally mediated HNSCC. As the HIV prevalence rises in the United States due to better survival and the incidence of HPV-positive oropharyngeal HNSCC increases, the interaction between HPV and HIV becomes increasingly relevant.
Assuntos
Carcinoma de Células Escamosas , Infecções por HIV , Neoplasias de Cabeça e Pescoço , Neoplasias Orofaríngeas , Infecções por Papillomavirus , Veteranos , Estudos de Coortes , Humanos , Incidência , Papillomaviridae , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço , Estados UnidosRESUMO
BACKGROUND: Understanding biological differences between different racial groups of human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) patients, who have differences in terms of incidence, survival, and tumor morphology, can facilitate accurate prognostic biomarkers, which can help develop personalized treatment strategies. METHODS: This study evaluated whether there were morphologic differences between HPV-associated tumors from Black and White patients in terms of multinucleation index (MuNI), an image analysis-derived metric that measures density of multinucleated tumor cells within epithelial regions on hematoxylin-eosin images and previously has been prognostic in HPV-associated OPSCC patients. In this study, the authors specifically evaluated whether the same MuNI cutoff that was prognostic of overall survival (OS) and disease-free survival in their previous study, TTR , is valid for Black and White patients, separately. We also evaluated population-specific cutoffs, TB for Blacks and TW for Whites, for risk stratification. RESULTS: MuNI was statistically significantly different between Black (mean, 3.88e-4; median, 3.67e-04) and White patients (mean, 3.36e-04; median, 2.99e-04), with p = .0078. Using TTR , MuNI was prognostic of OS in the entire population with hazard ratio (HR) of 1.71 (p = .002; 95% confidence interval [CI], 1.21-2.43) and in White patients with HR of 1.72 (p = .005; 95% CI, 1.18-2.51). Population-specific cutoff, TW , yielded improved HR of 1.77 (p = .003; 95% CI, 1.21-2.58) for White patients, whereas TB did not improve risk-stratification in Black patients with HR of 0.6 (p = .3; HR, 0.6; 95% CI, 0.2-1.80). CONCLUSIONS: Histological difference between White and Black patient tumors in terms of multinucleated tumor cells suggests the need for considering population-specific prognostic biomarkers for personalized risk stratification strategies for HPV-associated OPSCC patients.
Assuntos
Alphapapillomavirus , Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Orofaríngeas , Infecções por Papillomavirus , Biomarcadores , Carcinoma de Células Escamosas/patologia , Amarelo de Eosina-(YS) , Neoplasias de Cabeça e Pescoço/complicações , Hematoxilina , Humanos , Papillomaviridae , Prognóstico , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço/complicaçõesRESUMO
Oropharyngeal squamous cell carcinoma (OPSCC), largely fueled by the human papillomavirus (HPV), has a complex biological and immunologic phenotype. Although HPV/p16 status can be used to stratify OPSCC patients as a function of survival, it remains unclear what drives an improved treatment response in HPV-associated OPSCC and whether targetable biomarkers exist that can inform a precision oncology approach. We analyzed OPSCC patients treated between 2000 and 2016 and correlated locoregional control (LRC), disease-free survival (DFS) and overall survival (OS) with conventional clinical parameters, risk parameters generated using deep-learning algorithms trained to quantify tumor-infiltrating lymphocytes (TILs) (OP-TIL) and multinucleated tumor cells (MuNI) and targeted transcriptomics. P16 was a dominant determinant of LRC, DFS and OS, but tobacco exposure, OP-TIL and MuNI risk features correlated with clinical outcomes independent of p16 status and the combination of p16, OP-TIL and MuNI generated a better stratification of OPSCC risk compared to individual parameters. Differential gene expression (DEG) analysis demonstrated overlap between MuNI and OP-TIL and identified genes involved in DNA repair, oxidative stress response and tumor immunity as the most prominent correlates with survival. Alteration of inflammatory/immune pathways correlated strongly with all risk features and oncologic outcomes. This suggests that development of OPSCC consists of an intersection between multiple required and permissive oncogenic and immunologic events which may be mechanistically linked. The strong relationship between tumor immunity and oncologic outcomes in OPSCC regardless of HPV status may provide opportunities for further biomarker development and precision oncology approaches incorporating immune checkpoint inhibitors for maximal anti-tumor efficacy.
Assuntos
Neoplasias de Cabeça e Pescoço , Neoplasias Orofaríngeas , Infecções por Papillomavirus , Inibidor p16 de Quinase Dependente de Ciclina/análise , Humanos , Neoplasias Orofaríngeas/patologia , Papillomaviridae , Infecções por Papillomavirus/patologia , Medicina de Precisão , Prognóstico , Carcinoma de Células Escamosas de Cabeça e PescoçoRESUMO
Sinonasal inverted papillomas (IPs) are rare tumours arising from the nasal epithelial mucosa. Most lesions are benign, but a subset of IPs progress to dysplasia and squamous cell carcinoma. Although the epidemiology and clinical features of IPs are well known, the pathogenesis is still unclear. Given the established role of human papillomaviruses (HPVs) in the formation of other mucosal tumours including cervical and oropharyngeal cancer, some have suggested the virus may play a role in IP development. However, the association between HPV and IPs has not yet been proven, and the variable detection of HPV DNA in IPs has cast uncertainty on whether the virus plays a major role in pathogenesis. In this review, we summarize early clinical reports and synthesize recent studies that may elucidate the association between HPV and IPs. We also discuss the role HPV may have in the progression of benign IP to dysplasia and malignancy, as well as potential pathological mechanisms. We hope that synthesizing the initial and recent studies on this topic will not only lead to a better understanding of research in the role of HPV in IP development, but also help guide and contextualize future studies.
Assuntos
Alphapapillomavirus/isolamento & purificação , Neoplasias Nasais/virologia , Papiloma Invertido/virologia , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus , Neoplasias dos Seios Paranasais/virologia , Humanos , Neoplasias Nasais/patologia , Papiloma Invertido/patologia , Papillomaviridae/genética , Infecções por Papillomavirus/complicações , Neoplasias dos Seios Paranasais/patologiaRESUMO
BACKGROUND: Treatment of human papillomavirus-related oropharyngeal squamous cell carcinoma (HPVOPC) results in unprecedented high survival rates but possibly unnecessary toxicity. We hypothesized that upfront surgery and neck dissection followed by reduced-dose adjuvant therapy for early and intermediate HPVOPC would ultimately result in equivalent progression-free survival (PFS) and overall survival while reducing toxicity. METHODS: This study was a nonrandomized phase II trial for early-stage HPVOPC treated with transoral robotic surgery (TORS) followed by reduced-dose radiotherapy. Patients with previously untreated p16-positive HPVOPC and <20 pack years' smoking history were enrolled. After robotic surgery, patients were assigned to group 1 (no poor risk features; surveillance), group 2 (intermediate pathologic risk factors [perineural invasion, lymphovascular invasion]; 50-Gy radiotherapy), or group 3 (poor prognostic pathologic factors [extranodal extension [ENE], more than three positive lymph nodes and positive margin]; concurrent 56-Gy chemoradiotherapy with weekly cisplatin). RESULTS: Fifty-four patients were evaluable; there were 25 in group 1, 15 in group 2, and 14 in group 3. Median follow-up was 43.9 months (9.6-75.8). Disease-specific survival was 98.1%, and PFS was 90.7%. PFS probability via Kaplan-Meier was 91.3% for group 1, 86.7% for group 2, and 93.3% for group 3. There were five locoregional failures (LRFs), including one distant metastasis and one contralateral second primary. Average time to LRF was 18.9 months (9.6-59.0); four LRFs were successfully salvaged, and the patients remain disease free (11.0-42.7 months); one subject remains alive with disease. CONCLUSION: The results indicate that upfront surgery with neck dissection with reduced-dose radiation for T1-2, N1 stage (by the eighth edition American Joint Committee on Cancer staging manual) HPVOPC results in favorable survival with excellent function in this population. These results support radiation dose reduction after TORS as a de-escalation strategy in HPVOPC. IMPLICATIONS FOR PRACTICE: Transoral robotic surgery can provide a safe platform for de-escalation in carefully selected patients with early-stage human papillomavirus-related oropharyngeal cancer. In this clinical trial, disease-specific survival was 100%, over 90% of the cohort had a reduction of therapy from standard of care with excellent functional results, and the five patients with observed locoregional failures were successfully salvaged.
Assuntos
Alphapapillomavirus , Carcinoma de Células Escamosas , Neoplasias Orofaríngeas , Infecções por Papillomavirus , Procedimentos Cirúrgicos Robóticos , Carcinoma de Células Escamosas/patologia , Humanos , Estadiamento de Neoplasias , Neoplasias Orofaríngeas/tratamento farmacológico , Neoplasias Orofaríngeas/radioterapia , Neoplasias Orofaríngeas/cirurgia , Papillomaviridae , Infecções por Papillomavirus/patologia , Síndrome de Resposta Inflamatória SistêmicaRESUMO
By serving as intermediaries between cellular metabolism and the bioenergetic demands of proliferation, endolysosomes allow cancer cells to thrive under normally detrimental conditions. Here, we show that an endolysosomal TRP channel, TRPML1, is necessary for the proliferation of cancer cells that bear activating mutations in HRAS Expression of MCOLN1, which encodes TRPML1, is significantly elevated in HRAS-positive tumors and inversely correlated with patient prognosis. Concordantly, MCOLN1 knockdown or TRPML1 inhibition selectively reduces the proliferation of cancer cells that express oncogenic, but not wild-type, HRAS Mechanistically, TRPML1 maintains oncogenic HRAS in signaling-competent nanoclusters at the plasma membrane by mediating cholesterol de-esterification and transport. TRPML1 inhibition disrupts the distribution and levels of cholesterol and thereby attenuates HRAS nanoclustering and plasma membrane abundance, ERK phosphorylation, and cell proliferation. These findings reveal a selective vulnerability of HRAS-driven cancers to TRPML1 inhibition, which may be leveraged as an actionable therapeutic strategy.
Assuntos
Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Canais de Potencial de Receptor Transitório/antagonistas & inibidores , Canais de Potencial de Receptor Transitório/genética , Animais , Cálcio/metabolismo , Sinalização do Cálcio , Membrana Celular/metabolismo , Proliferação de Células , Drosophila , Endossomos/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Expressão Gênica , Redes Reguladoras de Genes , Humanos , Lisossomos/metabolismo , Modelos Biológicos , Mutação , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/mortalidade , Neoplasias/patologia , Fosforilação , Prognóstico , Transdução de Sinais , Transcriptoma , Canais de Potencial de Receptor Transitório/metabolismoRESUMO
No single cancer immunotherapy will likely defeat all evasion mechanisms of solid tumors, including plasticity of tumor antigen expression and active immune suppression by the tumor environment. In this study, we increase the breadth, potency, and duration of anti-tumor activity of chimeric antigen receptor (CAR) T cells using an oncolytic virus (OV) that produces cytokine, checkpoint blockade, and a bispecific tumor-targeted T cell engager (BiTE) molecule. First, we constructed a BiTE molecule specific for CD44 variant 6 (CD44v6), since CD44v6 is widely expressed on tumor but not normal tissue, and a CD44v6 antibody has been safely administered to cancer patients. We then incorporated this BiTE sequence into an oncolytic-helper binary adenovirus (CAdDuo) encoding an immunostimulatory cytokine (interleukin [IL]-12) and an immune checkpoint blocker (PD-L1Ab) to form CAdTrio. CD44v6 BiTE from CAdTrio enabled HER2-specific CAR T cells to kill multiple CD44v6+ cancer cell lines and to produce more rapid and sustained disease control of orthotopic HER2+ and HER2-/- CD44v6+ tumors than any component alone. Thus, the combination of CAdTrio with HER2.CAR T cells ensures dual targeting of two tumor antigens by engagement of distinct classes of receptor (CAR and native T cell receptor [TCR]), and significantly improves tumor control and survival.
Assuntos
Adenoviridae/metabolismo , Anticorpos Biespecíficos/uso terapêutico , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia Adotiva/métodos , Interleucina-12/uso terapêutico , Neoplasias/terapia , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/metabolismo , Receptores de Antígenos Quiméricos/uso terapêutico , Animais , Feminino , Humanos , Receptores de Hialuronatos/imunologia , Receptores de Hialuronatos/metabolismo , Inibidores de Checkpoint Imunológico/metabolismo , Interleucina-12/metabolismo , Masculino , Camundongos Endogâmicos NOD , Camundongos SCID , Neoplasias/metabolismo , Neoplasias/patologia , Células PC-3 , Receptor ErbB-2/imunologia , Receptor ErbB-2/metabolismo , Receptores de Antígenos Quiméricos/imunologia , Resultado do Tratamento , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: The incidence of oropharyngeal squamous cell carcinoma (OPSCC) in the US is rapidly increasing, driven largely by the epidemic of human papillomavirus (HPV)-mediated OPSCC. Although survival for patients with HPV mediated OPSCC (HPV+ OPSCC) is generally better than that of patients with non-virally mediated OPSCC, this effect is not uniform. We hypothesized that tobacco exposure remains a critical modifier of survival for HPV+ OPSCC patients. METHODS: We conducted a retrospective analysis of 611 OPSCC patients with concordant p16 and HPV testing treated at a single institute (2002-2013). Survival analysis was performed using Kaplan-Meier analysis and Cox regression. Recursive partitioning analysis (RPA) was used to define tobacco exposure associated with survival (p < 0.05). RESULTS: Tobacco exposure impacted overall survival (OS) for HPV+ patients on univariate and multivariate analysis (p = 0.002, p = 0.003 respectively). RPA identified 30 pack-years (PY) as a threshold at which survival became significantly worse in HPV+ patients. OS and disease-free survival (DFS) for HPV+ > 30 PY patients didn't differ significantly from HPV- patients (p = 0.72, p = 0.27, respectively). HPV+ > 30 PY patients had substantially lower 5-year OS when compared to their ≤30 PYs counterparts: 78.4% vs 91.6%; p = 0.03, 76% vs 88.3%; p = 0.07, and 52.3% vs 74%; p = 0.05, for stages I, II, and III (AJCC 8th Edition Manual), respectively. CONCLUSIONS: Tobacco exposure can eliminate the survival benefit associated with HPV+ status in OPSCC patients. Until this effect can be clearly quantified using prospective datasets, de-escalation of treatment for HPV + OPSCC smokers should be avoided.
Assuntos
Carcinoma de Células Escamosas/etiologia , Carcinoma de Células Escamosas/mortalidade , Neoplasias Orofaríngeas/etiologia , Neoplasias Orofaríngeas/mortalidade , Infecções por Papillomavirus/mortalidade , Fumar/mortalidade , Alphapapillomavirus/isolamento & purificação , Carcinoma de Células Escamosas/epidemiologia , Carcinoma de Células Escamosas/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Orofaríngeas/patologia , Neoplasias Orofaríngeas/virologia , Infecções por Papillomavirus/patologia , Estudos Retrospectivos , Fumar/patologia , Análise de SobrevidaRESUMO
Tumor immune microenvironment and tumor metabolism are major determinants of chemoradiotherapy response. The interdependency and prognostic significance of specific immune and metabolic phenotypes in head and neck squamous cell carcinoma (HNSCC) were assessed and changes in reactive oxygen species were evaluated as a mechanism of treatment response in tumor spheroid/immunocyte co-cultures. Pretreatment tumor biopsies were immunohistochemically characterized in 73 HNSCC patients treated by definitive chemoradiotherapy and correlated with survival. The prognostic significance of CD8A, GLUT1, and COX5B gene expression was analyzed within The Cancer Genome Atlas database. HNSCC spheroids were co-cultured in vitro with peripheral blood mononuclear cells (PBMCs) in the presence of the glycolysis inhibitor 2-deoxyglucose and radiation treatment followed by PBMC chemotaxis determination via fluorescence microscopy. In the chemoradiotherapy-treated HNSCC cohort, mitochondrial-rich (COX5B) metabolism correlated with increased and glucose-dependent (GLUT1) metabolism with decreased intratumoral CD8/CD4 ratios. High CD8/CD4, together with mitochondrial-rich or glucose-independent metabolism, was associated with improved short-term survival. The Cancer Genome Atlas analysis confirmed that patients with a favorable immune and metabolic gene signature (high CD8A, high COX5B, low GLUT1) had improved short- and long-term survival. In vitro, 2-deoxyglucose and radiation synergistically up-regulated reactive oxygen species-dependent PBMC chemotaxis to HNSCC spheroids. These results suggest that glucose-independent tumor metabolism is associated with CD8-dominant antitumor immune infiltrate, and together, these contribute to improved chemoradiotherapy response in HNSCC.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Escamosas/terapia , Quimiorradioterapia , Neoplasias de Cabeça e Pescoço/terapia , Idoso , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Antígenos CD8/genética , Antígenos CD8/metabolismo , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/mortalidade , Linhagem Celular Tumoral , Grupo dos Citocromos c/genética , Grupo dos Citocromos c/metabolismo , Bases de Dados Genéticas , Complexo IV da Cadeia de Transporte de Elétrons , Feminino , Transportador de Glucose Tipo 1/genética , Transportador de Glucose Tipo 1/metabolismo , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Espécies Reativas de Oxigênio/metabolismo , Taxa de SobrevidaRESUMO
Objective: There are currently three licensed human papillomavirus (HPV) vaccines that protect against cervical cancer. Here we compare the prevalence of bi-, quadri-, and nonavalent vaccine-related HPV genotypes in a multi-ethnic sample of non-Hispanic white, non-Hispanic black, Hispanic, and Asian women. Design: Patients in this analysis (n = 419) represent a subset of women with a previous abnormal Pap test participating in a clinical trial. HPV genotyping was conducted using the Roche Linear Array. Prevalent HPV genotypes were grouped according to their inclusion in each of the vaccines: bivalent (16, 18), quadrivalent (16, 18, 6, 11), and nonavalent (16, 18, 31, 33, 45, 52, 58, 6, 11). Results: The prevalence of HPV genotypes covered by the bi-/quadrivalent vaccines was lowest among non-Hispanic black (15%) and Hispanic women (20%), compared to non-Hispanic white (38%) and Asian women (38%). Across all racial/ethnic groups, a large proportion of infections (38%-49%) were with genotypes included in the nonavalent vaccine. However, the prevalence of HPV genotypes not covered by any vaccine was significantly higher among non-Hispanic black (36%) and Hispanic women (42%), compared to non-Hispanic white (24%) and Asian women (16%) (p < 0.001). Racial/ethnic differences in HPV genotype prevalence were observed when controlling for demographic and sexual behavior characteristics, as well as when restricting the analysis to women with CIN 2+. Conclusion: Our data suggest racial/ethnic differences in the prevalence of vaccine-related HPV genotypes. In particular, non-Hispanic black and Hispanic women had the lowest prevalence of HPV genotypes covered by the bi-/quadrivalent vaccines. While a large proportion of their infections were covered by the nonavalent vaccine, non-Hispanic black and Hispanic women also had the highest prevalence of HPV genotypes not covered by any vaccine.
Assuntos
Asiático/estatística & dados numéricos , Negro ou Afro-Americano/estatística & dados numéricos , Hispânico ou Latino/estatística & dados numéricos , Vacinas contra Papillomavirus/genética , População Branca/estatística & dados numéricos , Adulto , Feminino , Genótipo , Humanos , Papillomaviridae/genética , Infecções por Papillomavirus/epidemiologia , Infecções por Papillomavirus/etnologia , Infecções por Papillomavirus/virologia , Vacinas contra Papillomavirus/uso terapêutico , Prevalência , Estados Unidos/epidemiologia , Neoplasias do Colo do Útero/etnologia , Neoplasias do Colo do Útero/prevenção & controle , Neoplasias do Colo do Útero/virologia , Cobertura Vacinal/estatística & dados numéricosRESUMO
In solid tumors, chimeric antigen receptor (CAR)-modified T cells must overcome the challenges of the immunosuppressive tumor microenvironment. We hypothesized that pre-treating tumors with our binary oncolytic adenovirus (CAd), which produces local oncolysis and expresses immunostimulatory molecules, would enhance the antitumor activity of HER2-specific CAR T cells, which alone are insufficient to cure solid tumors. We tested multiple cytokines in conjunction with PD-L1-blocking antibody and found that Ad-derived IL-12p70 prevents the loss of HER2.CAR-expressing T cells at the tumor site. Accordingly, we created a construct encoding the PD-L1-blocking antibody and IL-12p70 (CAd12_PDL1). In head and neck squamous cell carcinoma (HNSCC) xenograft models, combining local treatment with CAd12_PDL1 and systemic HER2.CAR T cell infusion improved survival to >100 days compared with approximately 25 days with either approach alone. This combination also controlled both primary and metastasized tumors in an orthotopic model of HNSCC. Overall, our data show that CAd12_PDL1 augments the anti-tumor effects of HER2.CAR T cells, thus controlling the growth of both primary and metastasized tumors.
Assuntos
Adenoviridae/imunologia , Carcinoma de Células Escamosas/terapia , Terapia Combinada/métodos , Neoplasias de Cabeça e Pescoço/terapia , Imunoterapia Adotiva/métodos , Terapia Viral Oncolítica/métodos , Adenoviridae/genética , Animais , Anticorpos Antineoplásicos/genética , Anticorpos Antineoplásicos/imunologia , Anticorpos Neutralizantes/genética , Anticorpos Neutralizantes/imunologia , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/patologia , Feminino , Expressão Gênica , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/imunologia , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Interleucina-12/genética , Interleucina-12/imunologia , Transfusão de Linfócitos , Camundongos , Receptor ErbB-2/genética , Receptor ErbB-2/imunologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/imunologia , Análise de Sobrevida , Linfócitos T/citologia , Linfócitos T/imunologia , Linfócitos T/transplante , Carga Tumoral , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: The burden of human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) is disproportionately high among men, yet empirical evidence regarding the difference in prevalence of oral HPV infection between men and women is limited. Concordance of oral and genital HPV infection among men is unknown. OBJECTIVE: To determine the prevalence of oral HPV infection, as well as the concordance of oral and genital HPV infection, among U.S. men and women. DESIGN: Nationally representative survey. SETTING: Civilian noninstitutionalized population. PARTICIPANTS: Adults aged 18 to 69 years from NHANES (National Health and Nutrition Examination Survey), 2011 to 2014. MEASUREMENTS: Oral rinse, penile swab, and vaginal swab specimens were evaluated by polymerase chain reaction followed by type-specific hybridization. RESULTS: The overall prevalence of oral HPV infection was 11.5% (95% CI, 9.8% to 13.1%) in men and 3.2% (CI, 2.7% to 3.8%) in women (equating to 11 million men and 3.2 million women nationwide). High-risk oral HPV infection was more prevalent among men (7.3% [CI, 6.0% to 8.6%]) than women (1.4% [CI, 1.0% to 1.8%]). Oral HPV 16 was 6 times more common in men (1.8% [CI, 1.3% to 2.2%]) than women (0.3% [CI, 0.1% to 0.5%]) (1.7 million men vs. 0.27 million women). Among men and women who reported having same-sex partners, the prevalence of high-risk HPV infection was 12.7% (CI, 7.0% to 18.4%) and 3.6% (CI, 1.4% to 5.9%), respectively. Among men who reported having 2 or more same-sex oral sex partners, the prevalence of high-risk HPV infection was 22.2% (CI, 9.6% to 34.8%). Oral HPV prevalence among men with concurrent genital HPV infection was 4-fold greater (19.3%) than among those without it (4.4%). Men had 5.4% (CI, 5.1% to 5.8%) greater predicted probability of high-risk oral HPV infection than women. The predicted probability of high-risk oral HPV infection was greatest among black participants, those who smoked more than 20 cigarettes daily, current marijuana users, and those who reported 16 or more lifetime vaginal or oral sex partners. LIMITATION: Sexual behaviors were self-reported. CONCLUSION: Oral HPV infection is common among U.S. men. This study's findings provide several policy implications to guide future OPSCC prevention efforts to combat this disease. PRIMARY FUNDING SOURCE: National Cancer Institute.
Assuntos
Doenças dos Genitais Femininos/epidemiologia , Doenças dos Genitais Masculinos/epidemiologia , Doenças da Boca/epidemiologia , Infecções por Papillomavirus/epidemiologia , Doenças Faríngeas/epidemiologia , Adolescente , Adulto , Idoso , Feminino , Doenças dos Genitais Femininos/etnologia , Doenças dos Genitais Masculinos/etnologia , Homossexualidade , Humanos , Masculino , Pessoa de Meia-Idade , Doenças da Boca/etnologia , Doenças da Boca/virologia , Inquéritos Nutricionais , Infecções por Papillomavirus/etnologia , Doenças Faríngeas/etiologia , Doenças Faríngeas/virologia , Prevalência , Fatores de Risco , Distribuição por Sexo , Comportamento Sexual , Adulto JovemRESUMO
This study tests the hypothesis that prediagnostic serum levels of 20 cancer-associated inflammatory biomarkers correlate directly with future development of head and neck, esophageal, and lung cancers in a high-risk prospective cohort. This is a nested case-control pilot study of subjects enrolled in the Golestan Cohort Study, an ongoing epidemiologic project assessing cancer trends in Golestan, Iran. We measured a panel of 20 21 cytokines, chemokines, and inflammatory molecules using Luminex technology in serum samples collected 2 or more years before cancer diagnosis in 78 aerodigestive cancer cases and 81 controls. Data was analyzed using Wilcoxon rank sum test, odds ratios, receiver operating characteristic areas of discrimination, and multivariate analysis. Biomarkers were profoundly and globally elevated in future esophageal and lung cancer patients compared to controls. Odds ratios were significant for association between several biomarkers and future development of esophageal cancer, including interleukin-1Rα (IL-1Ra; 35.9), interferon α2 (IFN-a2; 34.0), fibroblast growth factor-2 (FGF-2; 17.4), and granulocyte/macrophage colony-stimulating factor (GM-CSF; 17.4). The same pattern was observed among future lung cancer cases for G-CSF (27.7), GM-CSF (13.3), and tumor necrosis factor-α (TNF-a; 8.6). By contrast, the majority of biomarkers studied showed no significant correlation with future head and neck cancer development. This study provides the first direct evidence that multiple inflammatory biomarkers are coordinately elevated in future lung and esophageal cancer patients 2 or more years before cancer diagnosis.
Assuntos
Biomarcadores Tumorais/sangue , Neoplasias Esofágicas/sangue , Mediadores da Inflamação/sangue , Neoplasias Pulmonares/sangue , Idoso , Carcinogênese/metabolismo , Estudos de Casos e Controles , Neoplasias Esofágicas/diagnóstico , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Curva ROCRESUMO
The recent emergence of a clinically distinct subset of head and neck cancers (HNC) caused by infection with the human papillomavirus (HPV) necessitates critical reevaluation of the existing counseling paradigm for patients with newly diagnosed HNC. Herein we propose a structural framework for patient counseling in which HPV testing is incorporated and the impact of HPV-status is discussed in the context of multiple medical and psychosocial domains. We strive to maintain a balance between making recommendations based on the best available scientific evidence and acknowledgment of uncertainty for both patients and providers. We anticipate that both the standard-of-care diagnostic workup and treatment, and counseling guidelines for these patients will change rapidly in the years ahead, as data from ongoing and planned prospective clinical trials become available.