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A biomarker that is useful for the detection of human papillomavirus (HPV)-related oropharyngeal cancer (OPC) and cancer of unknown primary (CUP) is indispensable. We evaluated the diagnostic performance of HPV DNA and mRNA in oral gargle samples and circulating tumor HPV16 DNA (ctHPV16DNA) in blood samples. Oral HPV DNA and mRNA were analyzed using commercially available HPV assays of the GENOSEARCH HPV31 and Aptima, respectively. ctHPV16DNA was analyzed using in-house droplet digital polymerase chain reaction. Seventy-four patients with OPC and eight patients with CUP were included. The sensitivity and specificity of oral HPV DNA, oral HPV mRNA, and ctHPV16DNA were 82% (95% confidence interval [CI] = 66-92) and 100% (95% CI = 88-100), 85% (95% CI = 69-94) and 94% (95% CI = 73-100), and 93% (95% CI = 81-99) and 97% (95% CI = 84-100), respectively, for HPV16-related OPC, while those were 20% (95% CI = 1-72) and 100% (95% CI = 3-100), 0% (95% CI = 0-52) and 100% (95% CI = 3-100), and 100% (95% CI = 54-100) and 100% (95% CI = 16-100), respectively, for HPV16-related CUP. The sensitivity of ctHPV16DNA for HPV16-related OPC was higher than that of oral biomarkers, though the difference was not statistically significant. ctHPV16DNA remarkably correlated with the anatomic extent of disease, total metabolic tumor volume and HPV16 copy number per tumor genome in patients with HPV16-related OPC/CUP, whereas oral biomarkers did not. In conclusion, ctHPV16DNA is a potentially promising biomarker for HPV16-related OPC, while further studies are required for HPV16-related CUP.
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Alphapapillomavirus/genética , ADN Tumoral Circulante/genética , Neoplasias Primarias Desconocidas/diagnóstico , Neoplasias Orofaríngeas/diagnóstico , Infecciones por Papillomavirus/complicaciones , ARN Mensajero/genética , Adulto , Anciano , Anciano de 80 o más Años , Alphapapillomavirus/aislamiento & purificación , ADN Viral/sangre , ADN Viral/genética , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Primarias Desconocidas/sangre , Neoplasias Primarias Desconocidas/epidemiología , Neoplasias Primarias Desconocidas/virología , Neoplasias Orofaríngeas/sangre , Neoplasias Orofaríngeas/epidemiología , Neoplasias Orofaríngeas/virología , Infecciones por Papillomavirus/virología , Pronóstico , Estudios Prospectivos , ARN Mensajero/sangre , ARN Viral/sangre , ARN Viral/genéticaRESUMEN
Positron emission tomography and computed tomography (PET-CT) is widely used to assess the response to radiotherapy. However, the ability of PET-CT to predict treatment failure in human papillomavirus (HPV)-related squamous cell carcinoma of the head and neck (HNSCC) is unsatisfactory. We quantified circulating tumor HPV type16 DNA (ctHPV16DNA) using optimized droplet digital PCR in 35 patients with HPV16-related HNSCC, who received radiotherapy with or without chemotherapy, and prospectively correlated ctHPV16DNA and metabolic response with treatment failure. After a median follow-up of 21 months, ctHPV16DNA and PET-CT had similar negative predictive values (89.7% vs 84.0%), whereas the positive predictive value was much higher in ctHPV16DNA than in PET-CT (100% vs 50.0%). Notably, six patients who had detectable posttreatment ctHPV16DNA all had treatment failure irrespective of metabolic response, whereas none of five patients who had partial metabolic response without detectable posttreatment ctHPV16DNA had treatment failure. The risk of treatment failure was high in patients who had incomplete metabolic response with detectable posttreatment ctHPV16DNA (hazard ratio [HR], 138.8; 95% confidence interval [CI], 15.5-3366.4; P < .0001) and intermediate in patients who had discordant results between metabolic response and posttreatment ctHPV16DNA (HR, 4.7; 95% CI, 0.8-36.2, P = .09) as compared with patients who had complete metabolic response without detectable posttreatment ctHPV16DNA. One-year event-free survival rates of each risk group were 0%, 88% (95% CI, 46-98) and 95% (95% CI, 72-99), respectively (P < .0001). In conclusion, posttreatment ctHPV16DNA complements PET-CT and helps guide decisions managing patients with HPV16-related HNSCC after radiotherapy.
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Carcinoma de Células Escamosas/genética , ADN Tumoral Circulante/genética , Neoplasias de Cabeza y Cuello/genética , Papillomavirus Humano 16/genética , Infecciones por Papillomavirus/genética , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/diagnóstico por imagen , Carcinoma de Células Escamosas/terapia , Quimioradioterapia , ADN Tumoral Circulante/sangre , Femenino , Fluorodesoxiglucosa F18 , Neoplasias de Cabeza y Cuello/diagnóstico por imagen , Neoplasias de Cabeza y Cuello/terapia , Papillomavirus Humano 16/fisiología , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud , Infecciones por Papillomavirus/diagnóstico por imagen , Infecciones por Papillomavirus/terapia , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodosRESUMEN
BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is one of the most frequently diagnosed cancers worldwide. LOXL2 demonstrates alternative splicing events in patients with human papillomavirus (HPV)-negative HNSCC. The current study explored the role of a dominant LOXL2 variant in HPV-negative HNSCC. METHODS: Expression of the LOXL2 variant was analyzed using The Cancer Genome Atlas cohorts and validated using quantitative reverse transcriptase-polymerase chain reaction in a separate primary tumor set. The authors defined the effect of LOXL2 splice variants in assays for cell proliferation using a cell viability assay and colony formation assay. Cell migration and invasion were examined using a cell scratch assay and transwell cell migration and invasion assay in LOXL2 splice variant gain and loss of expression cells. Western blot analysis and gene set enrichment analysis were used to explore the potential mechanism of the LOXL2 splice variant in HPV-negative HNSCC. RESULTS: Expression of a novel LOXL2 variant was found to be upregulated in The Cancer Genome Atlas HPV-negative HNSCC, and confirmed in the separate primary tumor validation set. Analyses of loss and gain of function demonstrated that this LOXL2 variant enhanced proliferation, migration, and invasion in HPV-negative HNSCC cells and activated the FAK/AKT pathway. A total of 837 upregulated and 820 downregulated genes and 526 upregulated and 124 downregulated pathways associated with LOXL2 variant expression were identified using gene set enrichment analysis, which helped in developing a better understanding of the networks activated by this LOXL2 variant in patients with HPV-negative HNSCC. CONCLUSIONS: The novel LOXL2 variant can promote the progression of HPV-negative HNSCC, in part through FAK/AKT pathway activation, which may provide a new potential therapeutic target among patients with HPV-negative HNSCC.
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Aminoácido Oxidorreductasas/genética , Carcinoma de Células Escamosas/genética , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica , Neoplasias de Cabeza y Cuello/genética , Empalme Alternativo , Aminoácido Oxidorreductasas/metabolismo , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Supervivencia Celular/genética , Progresión de la Enfermedad , Neoplasias de Cabeza y Cuello/metabolismo , Neoplasias de Cabeza y Cuello/patología , Humanos , Papillomaviridae/fisiología , Interferencia de ARN , Transducción de Señal/genéticaRESUMEN
BACKGROUND: Human papillomavirus (HPV)-associated oropharyngeal cancer is a disease clinically and biologically distinct from smoking-related head and neck squamous cell carcinoma (HNSCC). Despite its rapidly increasing incidence, the mutational landscape of HPV+ oropharyngeal squamous cell carcinoma (OPSCC) remains understudied. METHODS: This article presents the first mutational analysis of the 46 HPV+ OPSCC tumors within the newly expanded cohort of 530 HNSCC tumors from The Cancer Genome Atlas. A separate exome sequencing analysis was also performed for 46 HPV+ OPSCCs matched to their normal lymphocyte controls from the Johns Hopkins University cohort. RESULTS: There was a strikingly high 33% frequency of mutations within genes associated with chromatin regulation, including mutations in lysine methyltransferase 2C (KMT2C), lysine methyltransferase 2D (KMT2D), nuclear receptor binding SET domain protein 1 (NSD1), CREB binding protein (CREBBP), E1A-associated protein p300 (EP300), and CCCTC-binding factor (CTCF). In addition, the commonly altered genes phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA) and fibroblast growth factor receptor 3 (FGFR3) showed distinct domain-specific hotspot mutations in comparison with their HPV- counterparts. PIK3CA showed a uniquely high rate of mutations within the helicase domain, and FGFR3 contained a predominance of hotspot S249C alterations that were not found in HPV- HNSCC. CONCLUSIONS: This analysis represents one of the largest studies to date of HPV+ OPSCC and lends novel insight into the genetic landscape of this biologically distinct disease, including a high rate of mutations in histone- and chromatin-modifying genes, which may offer novel therapeutic targets.
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Ensamble y Desensamble de Cromatina/genética , Papillomavirus Humano 16/inmunología , Mutación , Neoplasias Orofaríngeas/genética , Neoplasias Orofaríngeas/virología , Infecciones por Papillomavirus/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/virología , Adulto , Anciano , Fosfatidilinositol 3-Quinasa Clase I/genética , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Orofaríngeas/patología , Infecciones por Papillomavirus/patología , Infecciones por Papillomavirus/virología , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Secuenciación del ExomaRESUMEN
Human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) exhibits a different composition of epigenetic alterations. In this study, we identified differentially methylated regions (DMRs) with potential utility in screening for HPV-positive OPSCC. Genome wide DNA methylation was measured using methyl-CpG binding domain protein-enriched genome sequencing (MBD-seq) in 50 HPV-positive OPSCC tissues and 25 normal tissues. Fifty-one DMRs were defined with maximal methylation specificity to cancer samples. The Cancer Genome Atlas (TCGA) methylation array data was used to evaluate the performance of the proposed candidates. Supervised hierarchical clustering of 51 DMRs found that HPV-positive OPSCC had significantly higher DNA methylation levels compared to normal samples, and non-HPV-related head and neck squamous cell carcinoma (HNSCC). The methylation levels of all top 20 DNA methylation biomarkers in HPV-positive OPSCC were significantly higher than those in normal samples. Further confirmation using quantitative methylation specific PCR (QMSP) in an independent set of 24 HPV-related OPSCCs and 22 controls showed that 16 of the 20 candidates had significant higher methylation levels in HPV-positive OPSCC samples compared with controls. One candidate, OR6S1, had a sensitivity of 100%, while 17 candidates (KCNA3, EMBP1, CCDC181, DPP4, ITGA4, BEND4, ELMO1, SFMBT2, C1QL3, MIR129-2, NID2, HOXB4, ZNF439, ZNF93, VSTM2B, ZNF137P and ZNF773) had specificities of 100%. The prediction accuracy of the 20 candidates rang from 56.2% to 99.8% by receiver operating characteristic analysis. We have defined 20 highly specific DMRs in HPV-related OPSCC, which can potentially be applied to molecular-based detection tests and improve disease management.
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Metilación de ADN , Neoplasias Orofaríngeas/genética , Neoplasias Orofaríngeas/virología , Infecciones por Papillomavirus/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/virología , Biomarcadores de Tumor/genética , Estudios de Casos y Controles , Estudios de Cohortes , Epigénesis Genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Orofaríngeas/patología , Papillomaviridae/aislamiento & purificación , Infecciones por Papillomavirus/patología , Carcinoma de Células Escamosas de Cabeza y Cuello/patologíaRESUMEN
BACKGROUND: Lactate dehydrogenase (LDH) is involved in the Warburg effect. Elevated serum LDH is a prognostic marker for metastatic solid cancer. AIM: To investigate the prognostic impact of serum LDH in patients with head and neck squamous cell carcinoma treated with immune checkpoint inhibitors (ICIs). MATERIALS AND METHODS: This retrospective study included 129 patients treated with ICIs between 2017 and 2023. The effects of pretreatment LDH, LDH at 3 months, and change in LDH during the first 3 months (ΔLDH) on overall survival (OS) and progression-free survival (PFS) were analyzed using the Kaplan-Meier method and Cox regression model. RESULTS: The 1-year PFS and OS rates for high and low groups were 6.0% and 30.1% for pretreatment LDH (p = 0.044), 25.7% and 38.3% for on-treatment LDH (p = 0.079), and 14.3% and 38.7% for ΔLDH (p = 0.008), as well as 42.1% and 60.9% for pretreatment LDH (p = 0.109), 56.0% and 80.5% (p < 0.001) for on-treatment LDH, and 31.0% and 81.0% for ΔLDH (p < 0.001), respectively. ΔLDH was an independent prognostic factor for both PFS and OS. CONCLUSIONS AND SIGNIFICANCE: ΔLDH can be used to predict ICI treatment outcomes and as a marker in deciding to continue ICI therapy.
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Circulating tumor DNA (ctDNA), which circulates in the blood after being shed from cancer cells in the body, has recently gained attention as an excellent tumor marker. The purpose of this study was to evaluate whether ct human papillomavirus (HPV) 16 DNA (ctHPV16DNA) levels were associated with quantitative PET parameters in patients with HPV-positive head and neck (HN) squamous cell carcinoma (SCC). Fifty patients with oropharyngeal SCC (OPSCC) and 5 with SCC of unknown primary (SCCUP) before treatment were included. They all underwent blood sampling to test ctHPV16DNA levels and FDG PET-CT examinations. Quantitative PET parameters included SUVmax, metabolic tumor volume (MTV), MTV of whole-body lesions (wbMTV), and 56 texture features. ctHPV16DNA levels were compared to texture features of primary tumors in OPSCC patients (Group A) or the largest primary or metastatic lymph node lesions in OPSCC and SCCUP patients (Group B) and to other PET parameters. Spearman rank correlation test and multiple regression analysis were used to confirm the associations between ctHPV16DNA levels and PET parameters. ctHPV16DNA levels moderately correlated with wbMTV, but not with SUVmax or MTV in Groups A and B. ctHPV16DNA levels exhibited a weak negative correlation with low gray-level zone emphasis in Groups A and B. Multiple regression analysis revealed that wbMTV and high gray-level zone emphasis were the significant factors for ctHPV16DNA levels in Group B. These results were not observed in Group A. This study demonstrated that ctHPV16DNA levels correlated with the whole-body tumor burden and tumor heterogeneity visualized on FDG PET-CT in patients with HPV-positive HNSCC.
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Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Infecciones por Papillomavirus , Humanos , Carcinoma de Células Escamosas de Cabeza y Cuello/diagnóstico por imagen , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Fluorodesoxiglucosa F18/metabolismo , Carcinoma de Células Escamosas/patología , Neoplasias de Cabeza y Cuello/diagnóstico por imagen , RadiofármacosRESUMEN
Purpose: Radiation therapy is widely used to treat head and neck squamous cell carcinoma (HNSCC). This study evaluated the association between circulating plasma programmed death-ligand 1 (PD-L1) and the outcomes of patients with HNSCC after radiation therapy. Methods and Materials: In this retrospective observational study, plasma samples of 76 patients with HNSCC who underwent radiation therapy from June 2019 to August 2021 were analyzed. These plasma samples were obtained before radiation therapy. The median follow-up was 32.5 months. Total and exosomal PD-L1 was measured by enzyme-linked immunosorbent assay and retrospectively analyzed for association with overall survival (OS), progression-free survival (PFS), and local control (LC). Prognostic factors among patients' characteristics and circulating PD-L1 in plasma were evaluated by univariate (log-rank test) and multivariate (Cox proportional hazards model) analyses. Results: The median concentration of total PD-L1 in plasma was 115.1 pg/mL (95% CI, 114.7-137.9 pg/mL), and the median concentration of exosomal PD-L1 was 2.8 pg/mL (95% CI, 6.0-13.0 pg/mL). Univariate and multivariate analyses showed exosomal PD-L1 as a prognostic factor for PFS and LC. Patients with high exosomal PD-L1 in plasma had poor PFS and LC compared with those with low exosomal PD-L1, indicating that 1-year PFS was 79.2% versus 33.3% (P < .001) and 1-year LC was 87.3% versus 50.0% (P < .001) in patients with high and low exosomal PD-L1, respectively. However, exosomal PD-L1 in plasma had no significant effect on OS. Total PD-L1 in plasma did not correlate with PFS, LC, and OS. Conclusions: The pretreatment circulating exosomal PD-L1 in plasma of patients with HNSCC was a prognostic factor after radiation therapy.
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Background: In view of improving biomarkers predicting the efficacy of immunotherapy for head and neck squamous cell carcinoma (R/M HNSCC), this multicenter retrospective study aimed to identify clinical, tumor microenvironmental, and genomic factors that are related to therapeutic response to the anti- Programmed cell death protein 1 (PD-1) antibody, nivolumab, in patients with R/M HNSCC. Methods: The study compared 53 responders and 47 non-responders, analyzing formalin-fixed paraffin-embedded samples using 14-marker multiplex immunohistochemistry and targeted gene sequencing. Results: Of 100 patients included, responders had significantly lower smoking and alcohol index, higher incidence of immune related adverse events, and higher PD-1 ligand (PD-L1) expression in immune cells as well as PD-L1 combined positive score (CPS) than non-responders. The frequency of natural killer cells was associated with nivolumab response in patients with prior cetuximab use, but not in cetuximab-naïve status. Age-stratified analysis showed nivolumab response was linked to high CPS and lymphoid-inflamed profiles in patients aged ≥ 65. In contrast, lower NLR in peripheral blood counts was associated with response in patients aged < 65. Notably, TP53 mutation-positive group had lower CPS and T cell densities, suggesting an immune-excluded microenvironment. Patients with altered tumor suppressor gene pathways, including TP53, CDKN2A, and SMAD4 mutations, had lower CPS, higher smoking index, and were associated with poor responses. Conclusion: Nivolumab treatment efficacy in HNSCC is influenced by a combination of clinical factors, age, prior treatment, immune environmental characteristics, and gene mutation profiles.
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Neoplasias de Cabeza y Cuello , Nivolumab , Carcinoma de Células Escamosas de Cabeza y Cuello , Microambiente Tumoral , Humanos , Microambiente Tumoral/inmunología , Nivolumab/uso terapéutico , Nivolumab/efectos adversos , Masculino , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Carcinoma de Células Escamosas de Cabeza y Cuello/inmunología , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Femenino , Anciano , Persona de Mediana Edad , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/inmunología , Neoplasias de Cabeza y Cuello/genética , Estudios Retrospectivos , Biomarcadores de Tumor/genética , Antineoplásicos Inmunológicos/uso terapéutico , Antineoplásicos Inmunológicos/efectos adversos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Resultado del Tratamiento , Adulto , Antígeno B7-H1/genética , Anciano de 80 o más Años , Mutación , Genómica/métodosRESUMEN
Adipose tissue-derived mesenchymal stem cells (ADSCs) are multipotent and can differentiate into various cell types, including osteocytes, adipocytes, neural cells, vascular endothelial cells, cardiomyocytes, pancreatic ß-cells, and hepatocytes. Compared with the extraction of other stem cells such as bone marrow-derived mesenchymal stem cells (BMSCs), that of ADSCs requires minimally invasive techniques. In the field of regenerative medicine, the use of autologous cells is preferable to embryonic stem cells or induced pluripotent stem cells. Therefore, ADSCs are a useful resource for drug screening and regenerative medicine. Here we present the methods and mechanisms underlying the induction of multilineage cells from ADSCs.
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Tejido Adiposo/citología , Células Madre Mesenquimatosas/citología , Medicina Regenerativa/métodos , Animales , Células de la Médula Ósea/citología , HumanosRESUMEN
It is considered that cancer stem cells have the same characteristics as normal stem cells, such as drug-resistance, self-renewal, differentiation, and tissue-formation. Normal stem cells depend on their surroundings, a niche. Cancer stem cells may also depend on their own niche. Because cancer stem cells are resistant to present remedies, it is important to find a remedy targeting cancer stem cells. The remedy must not only target cancer stem cells themselves but also target the niche surrounding the cancer stem cells.
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Células Madre Neoplásicas/fisiología , HumanosRESUMEN
Nasal squamous cell carcinoma (SCC) is rare and aggressive. It often requires combination treatment. Precise post-treatment disease assessment is vital for determining the subsequent management and prognosis. We present the intriguing case of a 52-year-old man with T4bN0M0 stage IVB SCC. Post-treatment fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET-CT) findings indicated a complete response; however, microscopic remnants of the cancer were detected during endoscopic sinus surgery. This report underscores the limitations of post-treatment assessment using FDG PET-CT and outpatient endoscopy alone due to these modalities' potential inability to detect microscopic residual disease. Endoscopic sinus surgery should be incorporated into routine post-treatment assessments of nasal SCC to improve disease detection and guide further treatment. Further large-scale studies are required to confirm these findings.
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BACKGROUND: Although patients with head and neck squamous cell cancer (HNSCC) often show malnutrition, its effects on immune checkpoint inhibitor (ICI) treatment outcomes in these patients are unclear. OBJECTIVES: To investigate the prognostic influence of nutritional indices in patients with HNSCC treated with ICIs and determine the optimal indices. METHODS: This retrospective study included 106 patients with HNSCC treated with ICIs between 2017 and 2022. The prognostic influences of body mass index (BMI), geriatric nutritional risk index (GNRI), and prognostic nutritional index (PNI) on overall survival (OS) and progression-free survival (PFS) were analysed using the Kaplan-Meier method and Cox-regression models. RESULTS: The 1-year PFS rates in the groups with high and low BMI, GNRI, and PNI were, respectively, 24.2% and 28.4% (p = .731), 29.7% and 14.4% (p = .024), and 30.3% and 13.9% (p = .015). PNI was an independent prognostic factor for both PFS (hazard ratio (HR) = 1.89; 95% confidence interval (CI), 1.08-3.29) and OS (HR = 3.26; 95% CI, 1.66-6.40). CONCLUSIONS: PNI can predict ICI outcomes and should be assessed when ICI treatment is considered.
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Neoplasias de Cabeza y Cuello , Evaluación Nutricional , Humanos , Anciano , Pronóstico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Estudios Retrospectivos , Neoplasias de Cabeza y Cuello/complicaciones , Neoplasias de Cabeza y Cuello/tratamiento farmacológicoRESUMEN
PURPOSE: This study aimed to examine whether circulating tumor human papillomavirus type 16 (HPV16) DNA (ctHPV16DNA) can help identify patients with locally advanced HPV16-related oropharyngeal squamous cell carcinoma who may benefit from deintensified treatment. MATERIALS AND METHODS: We serially collected blood samples before, during, and after treatment from 22 patients who received 70 Gy radiotherapy alone and longitudinally quantified ctHPV16DNA using droplet digital polymerase chain reaction. We correlated the clearance profile of ctHPV16DNA with clinical outcomes. RESULTS: The percentage of patients with detectable ctHPV16DNA decreased after every 10 Gy of radiotherapy. By contrast, the percentage of patients who later developed treatment failure among patients with detectable ctHPV16DNA gradually increased as radiotherapy proceeded, reaching 100% after 60 Gy of radiotherapy. We defined patients with and without detectable ctHPV16DNA after receiving 40 Gy as having slow and rapid clearance profiles, respectively. All 12 patients with a rapid clearance profile remained disease-free after radiotherapy. Of the 10 patients with a slow clearance profile, three had persistent or progressive disease at response evaluation after radiotherapy and one developed distant metastasis during follow-up (ie, four patients experienced treatment failure). The median follow-up for surviving patients was 38.6 months, and the 3-year failure-free survival rates of patients with rapid and slow clearance profiles were 100% and 58%, respectively (P = .02). Neither baseline ctHPV16DNA levels nor metabolic tumor volume was an independent predictor of the pattern of the clearance profile. CONCLUSION: In patients with HPV16-related oropharyngeal squamous cell carcinoma receiving radiotherapy, a slow ctHPV16DNA clearance profile could prelude unfavorable outcomes. Monitoring ctHPV16DNA is essential for determining the clearance profile, which might help optimize treatment intensity individually.
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Neoplasias de Cabeza y Cuello , Neoplasias Orofaríngeas , Infecciones por Papillomavirus , Humanos , Virus del Papiloma Humano , Carcinoma de Células Escamosas de Cabeza y Cuello/radioterapia , Neoplasias Orofaríngeas/radioterapia , Neoplasias Orofaríngeas/patología , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/radioterapia , Infecciones por Papillomavirus/patología , ADN/uso terapéuticoRESUMEN
Cell reprogramming reverts cells to multipotent, preprogrammed states by re-establishing epigenetic markers. It can also induce considerable malignant phenotype modification. Because key events in cancer relapse and metastasis, including epithelial-mesenchymal transition phenotypes, are regulated primarily by reversible and transient epigenetic modifications rather than the accumulation of irreversible and stable genetic abnormalities, studying dynamic mechanisms regulating these biological processes is important. Transcription factors for induced pluripotent stem cells and non-coding microRNAs allow pluripotent phenotype induction. We present the current knowledge of the possible applications of cell reprogramming in reducing aggressive phenotype expression, which can induce tumor cell hibernation and maintain appropriate phenotypes, thereby minimizing relapse and metastasis after surgical resection of gastrointestinal cancer.
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Diferenciación Celular/genética , Transformación Celular Neoplásica/genética , Epigénesis Genética/genética , Transición Epitelial-Mesenquimal/genética , Neoplasias Gastrointestinales/genética , Animales , Transformación Celular Neoplásica/patología , Neoplasias Gastrointestinales/patología , Humanos , Células Madre Pluripotentes Inducidas/patología , Células Madre Neoplásicas/patologíaRESUMEN
BACKGROUND/AIM: To retrospectively evaluate the efficacy and safety of modified TPEx (docetaxel 60 mg/m2 on day 1, cisplatin 60 mg/m2 on day 1, and weekly cetuximab 250 mg/m2 with loading dose of 400 mg/m2) followed by maintenance cetuximab as first-line treatment for inoperable recurrent and/or metastatic squamous cell carcinoma of the head and neck. PATIENTS AND METHODS: We analyzed 22 Japanese patients receiving modified TPEx every 21 days for four cycles with or without prophylactic granulocyte colony-stimulating factor (G-CSF). RESULTS: The best overall response rate was 55% [95% confidence interval (CI)=35-73]. The median progression-free survival and overall survival were 8.9 months (95%CI=3.9-10.2) and 14.3 months (95%CI=10.1-28.2), respectively. Without prophylactic G-CSF, Grade 3/4 neutropenia and febrile neutropenia was common (94% versus 20%; p=0.003 and 41% versus 0%; p=0.11, respectively). CONCLUSION: The modified TPEx is effective, while prophylactic G-CSF is essential.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Cetuximab/administración & dosificación , Cisplatino/administración & dosificación , Docetaxel/administración & dosificación , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Adulto , Anciano , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/patología , Cetuximab/efectos adversos , Cisplatino/efectos adversos , Docetaxel/efectos adversos , Esquema de Medicación , Femenino , Neoplasias de Cabeza y Cuello/mortalidad , Neoplasias de Cabeza y Cuello/patología , Humanos , Japón/epidemiología , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante/métodos , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Several comprehensive studies have demonstrated that the NOTCH pathway is altered in a bimodal manner in head and neck squamous cell carcinoma (HNSCC). In a previous study, it was found that the NOTCH4/HEY1 pathway was specifically upregulated in HNSCC and promoted epithelialmesenchymal transition (EMT), and that HEY1 activation supported SOX2 expression. However, the interactions in this pathway have not yet been fully elucidated. The present study investigated the NOTCH4/HEY1/SOX2 axis in HNSCC using in vitro models and the Cancer Genome Atlas (TCGA) database. To explore the association, reporter and ChIP RTqPCR assays using SOX2overexpressing (SOX2OE) cells were performed. The association between NOTCH4 and HEY1 was examined in the same manner using HEY1overexpressing (HEY1OE) cells. The results of the in vitro experiments indicated that HEY1 promoted EMT in the HNSCC cells. Furthermore, the overexpression of HEY1 also promoted sphere formation and increased murine xenograft tumorigenicity. Reporter assays and ChIP RTqPCR experiments indicated that SOX2 regulated HEY1 expression via direct binding of the HEY1 promoter. HEY1 expression significantly correlated with SOX2 expression in primary lung SCC and other SCCs using the TCGA database. HEY1 also regulated NOTCH4 expression to create a positive reciprocal feedback loop. On the whole, the present study demonstrates that HEY1 expression in HNSCC is regulated via the promotion of SOX2 and promotes EMT. The NOTCH4/HEY1 pathway is specifically upregulated via a positive reciprocal feedback loop mediated by the HEY1medaited regulation of NOTCH4 transcription, and SOX2 correlates with HEY1 expression in SCC from other primary sites.
Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Proteínas de Ciclo Celular/genética , Transición Epitelial-Mesenquimal/genética , Receptor Notch4/genética , Factores de Transcripción SOXB1/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Transformación Celular Neoplásica/genética , Conjuntos de Datos como Asunto , Retroalimentación Fisiológica , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones , Receptor Notch4/metabolismo , Transducción de Señal/genética , Esferoides Celulares , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Regulación hacia Arriba , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: An optimal approach to imaging assessment of neck after chemoradiotherapy must be established to avoid unnecessary neck dissection. METHODS: We retrospectively examined 101 patients and compared between Response evaluation criteria in solid tumors (RECIST), PET response criteria in solid tumors (PERCIST), and positron emission tomography/computed tomography (PET/CT) qualitative assessment. RESULTS: PERCIST was superior to RECIST in positive predictive value (PPV; 47% vs. 36%), with equivalent negative predictive value (NPV; 78%). Only 3 of 15 patients with incomplete responses on either RECIST or PERCIST alone had regional treatment failure, and the combination of RECIST and PERCIST improved PPV (55%) without reducing NPV. This combination yielded the highest hazard ratio of regional treatment failure. The combination of RECIST and PET/CT qualitative assessment also improved PPV (50%). In human papillomavirus (HPV)-related oropharyngeal cancer, NPV was 100% across the imaging assessments, while PPV was poor (14%-33%). CONCLUSIONS: Combining RECIST and PERCIST might optimize decision making in neck management after chemoradiotherapy. HPV status would affect the accuracy of response evaluation.
Asunto(s)
Neoplasias de Cabeza y Cuello , Tomografía Computarizada por Tomografía de Emisión de Positrones , Quimioradioterapia , Fluorodesoxiglucosa F18 , Neoplasias de Cabeza y Cuello/diagnóstico por imagen , Neoplasias de Cabeza y Cuello/terapia , Humanos , Tomografía de Emisión de Positrones , Criterios de Evaluación de Respuesta en Tumores Sólidos , Estudios Retrospectivos , Carcinoma de Células Escamosas de Cabeza y Cuello/diagnóstico por imagen , Carcinoma de Células Escamosas de Cabeza y Cuello/terapiaRESUMEN
PURPOSE: Human papillomavirus (HPV)-related squamous cell carcinoma of the oropharynx (OPSCC) is extremely radiosensitive. Radiation therapy plus high-dose cisplatin remains the standard of care but causes long-term toxicity. Treatment deintensification approaches that reduce toxicity while maintaining survival are desirable for HPV-related OPSCC. METHODS AND MATERIALS: We conducted a single-arm, multicenter, phase 2 trial. Patients with newly diagnosed, biopsy-proven, American Joint Committee on Cancer (seventh edition) stage III or IV OPSCC positive for both p16 and HPV DNA were eligible. Patients with T4, N3, or T1N1 disease were excluded. Smoking history was not included in eligibility criteria. Patients received intensity modulated radiation therapy (IMRT) of 70 Gy in 35 fractions or 70.4 Gy in 32 fractions without chemotherapy. The primary endpoint was complete response or complete metabolic response 10 weeks after IMRT completion. RESULTS: Between September 13, 2013, and November 15, 2016, 39 patients were enrolled according to a 2-stage Simon design. Twenty-three patients (59%) had smoked for more than10 pack-years. Thirty-six patients (92%) had tumors genotyped as HPV16. Thirty-seven patients (95%) received full-dose radiation therapy and 35 (90%) had complete response or complete metabolic response. Median follow-up was 51 months (interquartile range, 41-63 months). One patient (3%) had regional recurrence and 3 (8%) had distant metastasis. One patient died of disease. The 2-year progression-free survival rate was 94% (95% CI, 81%-99%), and the 2-year overall survival rate was 100%. Common grade 3 adverse events during IMRT included mucositis in 10 patients (26%) and dysphagia in 7 patients (18%). No patients were dependent on a feeding tube at 1 month after IMRT completion. No grade 3 or 4 late adverse events were observed. CONCLUSIONS: IMRT alone is associated with excellent response as well as reduced toxicity and could be a treatment option for carefully selected patients with locally advanced "true" HPV-related OPSCC. Further studies are warranted.