RESUMO
Importance: There are currently no therapies approved by the US Food and Drug Administration for nasopharyngeal carcinoma (NPC). Gemcitabine-cisplatin is the current standard of care for the first-line treatment of recurrent or metastatic NPC (RM-NPC). Objective: To determine whether toripalimab in combination with gemcitabine-cisplatin will significantly improve progression-free survival and overall survival as first-line treatment for RM-NPC, compared with gemcitabine-cisplatin alone. Design, Setting, and Participants: JUPITER-02 is an international, multicenter, randomized, double-blind phase 3 study conducted in NPC-endemic regions, including mainland China, Taiwan, and Singapore. From November 10, 2018, to October 20, 2019, 289 patients with RM-NPC with no prior systemic chemotherapy in the RM setting were enrolled from 35 participating centers. Interventions: Patients were randomized (1:1) to receive toripalimab (240 mg [n = 146]) or placebo (n = 143) in combination with gemcitabine-cisplatin for up to 6 cycles, followed by maintenance with toripalimab or placebo until disease progression, intolerable toxicity, or completion of 2 years of treatment. Main Outcome: Progression-free survival as assessed by a blinded independent central review. Secondary end points included objective response rate, overall survival, progression-free survival assessed by investigator, duration of response, and safety. Results: Among the 289 patients enrolled (median age, 46 [IQR, 38-53 years; 17% female), at the final progression-free survival analysis, toripalimab treatment had a significantly longer progression-free survival than placebo (median, 21.4 vs 8.2 months; HR, 0.52 [95% CI, 0.37-0.73]). With a median survival follow-up of 36.0 months, a significant improvement in overall survival was identified with toripalimab over placebo (hazard ratio [HR], 0.63 [95% CI, 0.45-0.89]; 2-sided P = .008). The median overall survival was not reached in the toripalimab group, while it was 33.7 months in the placebo group. A consistent effect on overall survival, favoring toripalimab, was found in subgroups with high and low PD-L1 (programmed death-ligand 1) expression. The incidence of all adverse events, grade 3 or greater adverse events, and fatal adverse events were similar between the 2 groups. However, adverse events leading to discontinuation of toripalimab or placebo (11.6% vs 4.9%), immune-related adverse events (54.1% vs 21.7%), and grade 3 or greater immune-related adverse events (9.6% vs 1.4%) were more frequent in the toripalimab group. Conclusions and Relevance: The addition of toripalimab to chemotherapy as first-line treatment for RM-NPC provided statistically significant and clinically meaningful progression-free survival and overall survival benefits compared with chemotherapy alone, with a manageable safety profile. These findings support the use of toripalimab plus gemcitabine-cisplatin as the new standard of care for this patient population. Trial Registration: ClinicalTrials.gov Identifier: NCT03581786.
Assuntos
Anticorpos Monoclonais Humanizados , Antineoplásicos , Cisplatino , Gencitabina , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Cisplatino/uso terapêutico , Método Duplo-Cego , Gencitabina/administração & dosagem , Gencitabina/efeitos adversos , Gencitabina/uso terapêutico , Carcinoma Nasofaríngeo/tratamento farmacológico , Carcinoma Nasofaríngeo/mortalidade , Carcinoma Nasofaríngeo/patologia , Carcinoma Nasofaríngeo/secundário , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/mortalidade , Neoplasias Nasofaríngeas/patologia , Neoplasias Nasofaríngeas/secundário , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Estados Unidos , InternacionalidadeAssuntos
Carcinoma Adenoide Cístico/diagnóstico por imagem , Carcinoma Adenoide Cístico/secundário , Fossa Craniana Média/patologia , Neoplasias Nasofaríngeas/diagnóstico por imagem , Neoplasias Nasofaríngeas/secundário , Idoso , Carcinoma Adenoide Cístico/patologia , Fossa Craniana Média/diagnóstico por imagem , Feminino , Humanos , Imageamento por Ressonância Magnética , Neoplasias Nasofaríngeas/patologia , Nasofaringe/patologiaRESUMO
Nasopharyngeal carcinoma (NPC) originates in the nasopharynx epithelium. Although concurrent chemoradiation therapy followed by chemotherapy is considered as an effective treatment, there is substantial drug resistance in locally advanced NPC patients. One major contributor to the chemoresistance includes aberrant expression of cell adhesion molecules, such as integrin α and ß subunits, giving rise to cell adhesion-mediated drug resistance. Thus, the aim of this study was to investigate the effect of integrin α5 on the development of intrinsic cisplatin resistance in NPC and the associated underlying mechanisms using in vitro three-dimensional (3D) spheroid models, as well as induced cisplatin-resistant NPC (NPCcisR). We demonstrated that established 3D highly- (5-8F) and lowly- (6-10B) metastatic NPC spheroids overexpressed integrin α5 and aggravated their resistance to cisplatin. Besides, enhanced integrin α5 resulted in substantially reduced growth, corresponding to G0/G1 and G2/M cell cycle arrest. In addition, 5-8FcisR and 6-10BcisR cells in 3D forms synergistically strengthened endurance of their spheroids to cisplatin treatment as observed by increased resistance index (RI) and decreased apoptosis. Mechanistically, the aberrantly expressed integrin α5 decreased drug susceptibility in NPC spheroids by inactivating ERK and inhibition of caspase-3 inducing apoptosis. Furthermore, the effect of integrin α5 inducing intrinsic resistance was verified via treatment with ATN-161, a peptide inhibitor for integrin α5ß1. The results showed dramatic reduction in integrin α5 expression, reversal of ERK phosphorylation and caspase-3 cleavage, together with elevated cisplatin sensitivity, indicating regulation of innate drug resistance via integrin α5. Taken together, our findings suggest that integrin α5 could act as a promising target to enhance the chemotherapeutic sensitivity in NPC.
Assuntos
Apoptose , Caspase 3/química , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Integrina alfa5/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/química , Carcinoma Nasofaríngeo/patologia , Esferoides Celulares/patologia , Antineoplásicos/farmacologia , Caspase 3/genética , Caspase 3/metabolismo , Técnicas de Cultura de Células , Pontos de Checagem do Ciclo Celular , Humanos , Integrina alfa5/genética , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Carcinoma Nasofaríngeo/tratamento farmacológico , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/secundário , Fosforilação , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/metabolismoRESUMO
BACKGROUND: This study was performed to investigate whether long-term monitoring of dynamic changes in plasma Epstein-Barr virus (EBV) DNA could improve prognosis prediction of nasopharyngeal carcinoma (NPC). MATERIALS AND METHODS: About 1077 nonmetastatic NPC patients were recruited to retrospectively analyze the prognostic value of plasma EBV DNA load pretreatment and 3, 12, 24, and 36 months posttreatment. We also examined the prognostic value of dynamic changes in plasma EBV DNA at various time points. RESULTS: Patients with plasma EBV DNA load above optimal pre- and posttreatment cut-offs had significantly worse five-year progression-free survival, distant metastasis-free survival, locoregional relapse-free survival, and overall survival (OS) at all-time points, excluding only OS at 36 months posttreatment due to limited mortalities. Patients with persistently undetectable plasma EBV DNA at the first four time points had the best prognosis, followed by those with positive detection pretreatment and consistently negative detection posttreatment, those with negative detection pretreatment and positive detection at one time point posttreatment, and those with positive detection pretreatment and at one time point posttreatment, whereas patients with positive detection at ≥2 time points posttreatment had the worst prognosis. Cox proportional hazard models identified the dynamic change pattern as an independent prognostic factor, and receiver operating characteristic curve analysis demonstrated that the dynamic change at four time point was more valuable than any single time point for predicting disease progression, distant metastasis, locoregional relapse, and mortality. CONCLUSIONS: Dynamic changes in plasma EBV DNA pre- and posttreatment could predict the long-term survival outcome and provide accurate risk stratification in NPC.
Assuntos
DNA Viral/genética , Infecções por Vírus Epstein-Barr/complicações , Herpesvirus Humano 4/genética , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/secundário , Recidiva Local de Neoplasia/patologia , Quimiorradioterapia , DNA Viral/análise , Infecções por Vírus Epstein-Barr/virologia , Feminino , Seguimentos , Herpesvirus Humano 4/isolamento & purificação , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/terapia , Carcinoma Nasofaríngeo/virologia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/terapia , Neoplasias Nasofaríngeas/virologia , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/terapia , Recidiva Local de Neoplasia/virologia , Prognóstico , Curva ROC , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
PURPOSE: The prognosis of nasopharyngeal carcinoma (NPC) patients with parotid lymph node (PLN) metastasis remains unclear. This study was performed to investigate the prognostic significance and optimal staging category of PLN metastasis and develop a nomogram for estimating individual risk. MATERIALS AND METHODS: Clinical data of 7,084 non-metastatic NPC patients were retrospectively reviewed. Overall survival (OS) was the primary endpoint. A nomogram was established based on the Cox proportional hazards regression model. The accuracy and calibration ability of this nomogram was evaluated by C-index and calibration curves with bootstrap validation. RESULTS: Totally, 164/7,084 NPC patients (2.3%) presented with PLNs. Multivariate analyses showed that PLN metastasis was a negative prognostic factor for OS, progression-free survival (PFS), distant metastasis-free survival (DMFS), and locoregional relapse-free survival (LRFS). Patients with PLN metastasis had a worse prognosis than N3 disease. Five independent prognostic factors were included in the nomogram, which showed a C-index of 0.743. The calibration curves for probability of 3- and 5-year OS indicated satisfactory agreement between nomogram-based prediction and actual observation. All results were confirmed in the validation cohort. CONCLUSION: NPC patient with PLN metastasis had poorer survival outcome (OS, PFS, DMFS, and LRFS) than N3 disease. We developed a nomogram to provide individual prediction of OS for patients with PLN metastasis.
Assuntos
Linfonodos/patologia , Carcinoma Nasofaríngeo/mortalidade , Neoplasias Nasofaríngeas/mortalidade , Recidiva Local de Neoplasia/mortalidade , Nomogramas , Neoplasias Parotídeas/mortalidade , Terapia Combinada , Feminino , Seguimentos , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/patologia , Carcinoma Nasofaríngeo/terapia , Neoplasias Nasofaríngeas/secundário , Neoplasias Nasofaríngeas/terapia , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Neoplasias Parotídeas/secundário , Neoplasias Parotídeas/terapia , Prognóstico , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
BACKGROUND/OBJECTIVES: Oral maintenance chemotherapy can effectively prolong overall survival (OS) in many types of metastatic cancer, but its role in metastatic nasopharyngeal carcinoma (mNPC) is unclear. In this study, the efficacy of oral maintenance chemotherapy in mNPC and the effectiveness of circulating tumor EBV-DNA for screening patients were evaluated. METHODS: Between June 2016 and December 2017, 141 patients with mNPC who received platinum-based systemic chemotherapy were included (median follow-up time, 21 months). Patients were classified into two groups according to the administration of oral maintenance chemotherapy. Plasma samples were collected before, during, and after treatment for the measurement of circulating EBV DNA. RESULTS: The 2-year OS was higher for patients who received maintenance chemotherapy than for patients without maintenance chemotherapy (78.9% vs 62.7%, P = .016). Patients with undetectable posttreatment EBV-DNA after 4-6 cycles of systemic chemotherapy (n = 73) had a higher 2-year OS than that of patients with detectable EBV-DNA (n = 68) (82.16% vs 51.45%, P = .001). For patients with undetectable posttreatment EBV-DNA, OS was better for those with maintenance chemotherapy than for those without (86.7% vs 73%, P = .027). For patients with detectable posttreatment EBV-DNA, maintenance chemotherapy did not improve outcomes (49.5% vs 55.4%, P = .824). The most common acute events were hematological toxicity, and all were tolerable and curable. CONCLUSIONS: Oral maintenance chemotherapy with S1 or capecitabine can improve OS in mNPC. Posttreatment EBV-DNA was not only an independent prognosis factor for mNPC but also can screen out beneficiaries of maintenance chemotherapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ácidos Nucleicos Livres/sangue , DNA Viral/sangue , Infecções por Vírus Epstein-Barr/sangue , Herpesvirus Humano 4/genética , Carcinoma Nasofaríngeo/sangue , Neoplasias Nasofaríngeas/sangue , Administração Oral , DNA Viral/genética , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/virologia , Feminino , Seguimentos , Herpesvirus Humano 4/isolamento & purificação , Humanos , Quimioterapia de Manutenção , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/tratamento farmacológico , Carcinoma Nasofaríngeo/patologia , Carcinoma Nasofaríngeo/virologia , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/secundário , Neoplasias Nasofaríngeas/virologia , Prognóstico , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
PURPOSE OF REVIEW: To review, the surgical approaches available on diagnosing a patient with salivary gland malignancy in the infratemporal fossa (ITF). To comment on patient evaluation and method of treatment selection. To identify and report on patient outcome data and make recommendations on future needs. RECENT FINDINGS: There is a need to define the anatomic boundaries contents of the ITF, masticator space, parapharyngeal space (PPS), pterygopalatine fossa, ventral skull base, and paramedian skull base, as evidence from publications. The pathological subtypes identified mainly include adenoid cystic and mucoepidermoid carcinomas. The source of these tumours originates from primary disease in the sinonasal tract and nasopharynx superiorly, and the PPS/deep lobe of parotid inferiorly. Current surgical options available, in suitable selected patient, available in tertiary head and neck cancer hospitals, which have available facilities and staffing is the endoscopic endonasal approach. This approach offers patients a 'complete margin-free surgical excision', minimal complications, shorter hospital stay, and no delay with commencement of any adjuvant treatment compared with the traditional 'open transcutaneous' approach. SUMMARY: The current evidence specifically to the surgical management of salivary gland malignancy involving the ITF is sparse, with great difficult identifying treated patients and their details among a heterogeneous group of patients with many lesions. There is a need for patient data that have specific pathologic conditions to be amalgamated from such centers and publish on outcome events.
Assuntos
Fossa Infratemporal/cirurgia , Recidiva Local de Neoplasia/cirurgia , Seleção de Pacientes , Neoplasias das Glândulas Salivares/cirurgia , Endoscopia/métodos , Humanos , Neoplasias Nasofaríngeas/secundário , Neoplasias Nasofaríngeas/cirurgia , Neoplasias das Glândulas Salivares/patologia , Neoplasias da Base do Crânio/secundário , Neoplasias da Base do Crânio/cirurgiaRESUMO
Nasopharyngeal carcinoma (NPC) is notorious for its aggressiveness and high metastatic potential. NPC patients with distant metastasis have a particularly poor prognosis; however, evaluating metastatic potential by expression profiles of primary tumors is challenging. This study aimed to investigate the association between activation of epidermal growth factor receptor (EGFR) signaling and NPC metastasis and the underlying mechanisms. We found an association between EGFR protein overexpression and intense EGFR immunostaining in NPC samples with advanced tumor node metastasis stage, clinical stage, and distant metastasis in NPC patients. Exogenous EGF stimulates NPC mobility and invasiveness in vitro. Activation of EGFR signaling prompted PKM2 translocation to the nucleus. Silencing either EGFR or PKM2 attenuates NPC cell aggressiveness in vitro and in vivo. Blocking EGFR signaling with cetuximab suppressed NPC cell invasiveness in vitro and metastatic potential in vivo. Comprehensive analyses of transcriptome profiles indicated that the EGFR-PKM2 axis activates a number of novel metastasis promoters, including F3, FOSL1, EPHA2, ANTXR2, and AKR1C2. Finally, we found that the metastasis-promoting function of the EGFR-PKM2 axis is dependent on nuclear PKM2 regulation of the transcription of metastasis-related genes, including FOSL1 and ANTXR2. Our study indicates that EGFR-PKM2 signaling promotes NPC cell invasion and metastasis through induction of FOSL1 and ANTXR2 and identifies EGFR as a promising biomarker for predicting the risk of distant metastasis.
Assuntos
Biomarcadores Tumorais/metabolismo , Proteínas de Transporte/metabolismo , Proteínas de Membrana/metabolismo , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/secundário , Proteínas Proto-Oncogênicas c-fos/metabolismo , Receptores de Peptídeos/metabolismo , Hormônios Tireóideos/metabolismo , Animais , Apoptose , Biomarcadores Tumorais/genética , Proteínas de Transporte/genética , Movimento Celular , Proliferação de Células , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/metabolismo , Invasividade Neoplásica , Prognóstico , Proteínas Proto-Oncogênicas c-fos/genética , Receptores de Peptídeos/genética , Taxa de Sobrevida , Hormônios Tireóideos/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas de Ligação a Hormônio da TireoideRESUMO
BACKGROUND: The study was aimed to evaluate the impact of accumulated oral tegafur-uracil (UFUR) as maintenance chemotherapy on overall survival (OS) and disease-free survival (DFS) rates after concurrent chemoradiotherapy (CCRT) for complete remission (CR) in non-distant metastatic TNM stage IV nasopharyngeal carcinoma (NPC). METHODS: Data were retrospectively analyzed from a database of patients with non-distant metastatic TNM stage IV NPC, composed of those who underwent CCRT for CR from January 2010 through December 2017. RESULTS: Thirty-three patients were treated with CCRT (the non-UFUR group), and the other 37 patients were treated with the same regimen, followed by additional oral UFUR (the UFUR group). Importantly, the 5-year OS rates were 91.89% in the UFUR group and 57.58% in the non-UFUR group (P = .004). CONCLUSIONS: Adding UFUR to CCRT was found to significantly improve the DFS and OS rates of patients with non-distant metastatic TNM stage IV NPC. The authors cautiously suggest UFUR as possible maintenance therapy following CCRT.
Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Carcinoma Nasofaríngeo/terapia , Neoplasias Nasofaríngeas/terapia , Tegafur/administração & dosagem , Uracila/administração & dosagem , Administração Metronômica , Administração Oral , Adulto , Quimiorradioterapia , Intervalo Livre de Doença , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/mortalidade , Carcinoma Nasofaríngeo/secundário , Neoplasias Nasofaríngeas/mortalidade , Neoplasias Nasofaríngeas/secundário , Estadiamento de Neoplasias , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
In the present study a series of dione-thiophenol conjugates was prepared and evaluated against nasopharyngeal carcinoma (NPC) cells. MTT assay showed that compound 4a reduced proliferation of C666-1 and CNE-1â¯cells to 26 and 24%, respectively at 10⯵mol/l concentration. Flow cytometry revealed that increasing the concentration of compound 4a from 2 to 10⯵mol/l increased the proportion of early apoptotic C666-1â¯cells from 2.76 to 69.43%. A significant (Pâ¯<â¯0.001) decrease in the expression of S100P was caused by compound 4a. In compound 4a treated C666-1â¯cells the expression of RAGE, EGFR, CD44, MMP2 and MMP9 was markedly decreased. In summary, compound 4a inhibits nasopharyngeal cancer cell proliferation and induces apoptosis through down-regulation of S100P. Moreover, compound 4a also decreases MMP-2, MMP-9, EGFR, CD44 and RAGE expression in nasopharyngeal cancer cells. Thus, compound 4a can be investigated further as a drug candidate for the treatment of nasopharyngeal cancer.
Assuntos
Antineoplásicos/farmacologia , Proteínas de Ligação ao Cálcio/antagonistas & inibidores , Cicloeptanos/farmacologia , Carcinoma Nasofaríngeo/diagnóstico por imagem , Neoplasias Nasofaríngeas/tratamento farmacológico , Tiofenos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Proliferação de Células/efeitos dos fármacos , Cicloeptanos/química , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Carcinoma Nasofaríngeo/secundário , Neoplasias Nasofaríngeas/secundário , Relação Estrutura-Atividade , Tiofenos/química , Células Tumorais CultivadasRESUMO
RATIONALE: Hepatocellular carcinoma (HCC) is the fifth most common cancer and third leading cause of cancer-related deaths worldwide. Nasopharyngeal metastasis of hepatocellular carcinoma is very rare. This is the first report of posttransplantation nasopharyngeal metastasis. PATIENT CONCERNS: A 45-year-old man with a history of hepatitis B related hepatocellular carcinoma (HCC) in the right segment of the liver received an orthotopic liver transplant. Two year after the transplantation, he suffered from severe headache, and head contrast enhanced CT scans did not show clues for brain or skull metastasis. Then he developed hoarseness and dysphagia. DIAGNOSIS: The nasopharyngeal cancer was confirmed to be metastatic tumor from liver histologically according to biopsy. INTERVENTIONS: This patient underwent radiotherapy (RT) of the metastatic nasopharyngeal tumor, and there was significant symptomatic relief. OUTCOMES: The patient died 3âmonths after nasopharyngeal metastasis was diagnosed. LESSONS: Recurrence of hepatocellular carcinoma with metastasis of nasopharyngeal carcinoma after liver transplantation is rare, but the prognosis is very poor. Close follow-up of patients should be paid attention to prevent the occurrence of such diseases.
Assuntos
Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Neoplasias Nasofaríngeas/secundário , Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/cirurgia , Hepatite B/complicações , Humanos , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/cirurgia , Transplante de Fígado , Masculino , Pessoa de Meia-Idade , Neoplasias Nasofaríngeas/radioterapiaRESUMO
SHROOM2 is a key mediator of RhoA-ROCK pathway that regulates cell motility and actin cytoskeleton organization. However, the functions of SHROOM2 beyond RhoA/ROCK signaling remain poorly understood. Here, we report that SHROOM2 not only participates in RhoA-ROCK-induced stress fiber formation and focal adhesion, but also had an unanticipated role in suppressing epithelial-to-mesenchymal transition (EMT) and tumor metastasis. Depletion of SHROOM2 in nasopharyngeal carcinoma (NPC) cells enhances mesenchymal characteristics and reduces epithelial markers, concomitant with increased motility, enabling the development of invasion and tumor metastasis, which are largely ROCK-independent, as ROCK inhibitor Y-27632 did not cause EMT phenotype; furthermore, combination of ROCK inhibition and SHROOM2 depletion resulted in the most robust increases in cell migration and invasion, indicating that SHROOM2 and ROCK work synergistically rather than epistatic. Analysis of clinical samples suggested that SHROOM2 is downregulated in NPC and the expression of SHROOM2 in metastatic NPC was even lower than in the primary tumors. Our findings uncover a non-canonical role of SHROOM2 as a potent antagonist for EMT and NPC metastasis.
Assuntos
Proteínas de Membrana/metabolismo , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patologia , Quinases Associadas a rho/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo , Amidas/farmacologia , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Transição Epitelial-Mesenquimal/genética , Feminino , Técnicas de Silenciamento de Genes , Células HEK293 , Xenoenxertos , Humanos , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Carcinoma Nasofaríngeo/secundário , Neoplasias Nasofaríngeas/secundário , Invasividade Neoplásica/genética , Piridinas/farmacologia , Transfecção , Carga Tumoral/genética , Quinases Associadas a rho/antagonistas & inibidoresAssuntos
Neovascularização de Coroide/diagnóstico , Angiografia por Tomografia Computadorizada , Lesões por Radiação/diagnóstico , Neovascularização Retiniana/diagnóstico , Tomografia de Coerência Óptica , Adulto , Radioisótopos de Carbono/uso terapêutico , Carcinoma Adenoide Cístico/patologia , Carcinoma Adenoide Cístico/radioterapia , Neovascularização de Coroide/etiologia , Angiografia por Tomografia Computadorizada/métodos , Feminino , Angiofluoresceinografia , Humanos , Neoplasias Nasofaríngeas/radioterapia , Neoplasias Nasofaríngeas/secundário , Neovascularização Retiniana/etiologia , Neoplasias da Base do Crânio/patologia , Neoplasias da Base do Crânio/radioterapia , Tomografia de Coerência Óptica/métodosRESUMO
BACKGROUND: Nasopharyngeal carcinoma (NPC) is a highly invasive and metastatic cancer, with diverse molecular characteristics and clinical outcomes. This study aims to dissect the molecular heterogeneity of NPC, followed by the construction of a microRNA (miRNA)-based prognostic model for prediction of distant metastasis. METHODS: We retrieved two NPC datasets: GSE32960 and GSE70970 as training and validation cohorts, respectively. Consensus clustering was employed for cluster discovery, and support vector machine was used to build a classifier. Finally, Cox regression analysis was applied to constructing a prognostic model for predicting risk of distant metastasis. RESULTS: Three NPC subtypes (immunogenic, classical and mesenchymal) were identified that are molecularly distinct and clinically relevant, of which mesenchymal subtype (~ 36%) is associated with poor prognosis, characterized by suppressing tumor suppressor miRNAs and the activation of epithelial--mesenchymal transition. Out of the 25 most differentially expressed miRNAs in mesenchymal subtype, miR-142, miR-26a, miR-141 and let-7i have significant prognostic power (P < 0.05). CONCLUSIONS: We proposed for the first time that NPC can be stratified into three subtypes. Using a panel of 4 miRNAs, we established a prognostic model that can robustly stratify NPC patients into high- and low- risk groups of distant metastasis.
Assuntos
Carcinoma/genética , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica/genética , MicroRNAs/genética , Neoplasias Nasofaríngeas/genética , Carcinoma/diagnóstico , Carcinoma/secundário , Feminino , Humanos , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Modelos Genéticos , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/diagnóstico , Neoplasias Nasofaríngeas/secundário , PrognósticoRESUMO
OBJECTIVE: Cancers found in the resected branchial cleft cyst are rare clinically but usually impose substantive diagnostic and treatment challenges for clinicians. METHODS: A 31-year-old man presented with a lateral neck mass that was suspected to be an inflammatory branchial cleft cyst. After excision, the pathologic specimen revealed a benign cystic appearance with a focus of undifferentiated carcinoma. Serologic tests for Epstein-Barr virus were negative. A positron emission tomography scan and upper aerodigestive tract endoscopies were negative for any other suspicious lesion. RESULTS: The patient underwent random biopsies of the nasopharynx, tongue base, and hypopharynx and bil tonsillectomy. Pathologic examination of the nasopharyngeal biopsies showed the presence of undifferentiated carcinoma. The cancerous part of the branchial cleft cyst and this nasopharyngeal specimen were positive for the latent membrane protein-1 and EBV-encoded RNAs of Epstein-Barr virus (EBV) and confirmed our diagnosis. CONCLUSION: This is the first report of a NPC metastasizing to a branchial cleft cyst. Molecular diagnostic techniques facilitate the definite diagnosis that enabled us to refine treatment plans and offered the patient a favorable outcome.
Assuntos
Branquioma/secundário , Carcinoma/secundário , Neoplasias Nasofaríngeas/secundário , Adulto , Branquioma/diagnóstico por imagem , Branquioma/metabolismo , Carcinoma/diagnóstico por imagem , Carcinoma/metabolismo , Neoplasias de Cabeça e Pescoço/diagnóstico por imagem , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/secundário , Herpesvirus Humano 4/genética , Humanos , Masculino , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/diagnóstico por imagem , Neoplasias Nasofaríngeas/metabolismo , Metástase Neoplásica , RNA Viral/metabolismo , Tomografia Computadorizada por Raios X , Proteínas da Matriz Viral/metabolismoAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/patologia , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/secundário , Receptor ErbB-2/genética , Anticorpos Monoclonais Humanizados/administração & dosagem , Neoplasias da Mama/cirurgia , Docetaxel/administração & dosagem , Feminino , Seguimentos , Humanos , Mastectomia/métodos , Pessoa de Meia-Idade , Terapia de Alvo Molecular/métodos , Obstrução Nasal/diagnóstico , Obstrução Nasal/etiologia , Neoplasias Nasofaríngeas/diagnóstico por imagem , Doenças Raras , Tomografia Computadorizada por Raios X/métodos , Trastuzumab/administração & dosagem , Resultado do TratamentoRESUMO
Background: Management of metastatic (M1) nasopharyngeal cancer (NPC) is controversial; data suggest high overall survival (OS) rates with definitive chemoradiotherapy (CRT). Herein, we evaluated OS in patients with M1 NPC undergoing chemotherapy alone versus CRT. Methods: The National Cancer Data Base was queried for M1 NPC cases. Patients undergoing no/unknown chemotherapy and/or with unknown/nondefinitive radiotherapy (RT) doses (<60 Gy) were excluded. Logistic regression analysis ascertained clinical factors associated with RT administration. Kaplan-Meier analysis evaluated OS between both cohorts; Cox proportional hazards modeling assessed factors associated with OS. Survival was then evaluated between matched populations using inverse-probability-weighted regression adjustment. OS between groups was also measured in patients surviving ≥1 and ≥3 years to address bias from poor-prognostic subsets (eg, widely disseminated disease), and those receiving CRT ≤30 and ≤60 days of each other (surrogates for concurrent CRT) versus >30 and >60 days (sequential) of each other. Results: Of 555 patients, 296 (53%) received chemotherapy alone and 259 (47%) underwent CRT. Patients undergoing CRT more often had private insurance (P=.001) and lived in areas with higher education levels (P=.028). Median OS in the chemotherapy-only and CRT cohorts were 13.7 and 25.8 months, respectively (P<.001); differences persisted between matched populations (P<.001). On multivariate analysis, receipt of additional RT independently predicted for improved OS (P<.001). OS differences between cohorts remained apparent when evaluating patients surviving for ≥1 (P<.001) and ≥3 (P=.002) years. Patients who received concurrent or sequential CRT displayed improved OS over those receiving chemotherapy alone, for both the 30-day (P<.001) and 60-day cutoffs (P<.001). Conclusions: Patients with M1 NPC undergoing definitive RT and chemotherapy experienced higher survival than those receiving chemotherapy alone. Risk stratification and patient selection for such combined modality interventions is critical.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma/terapia , Quimiorradioterapia/métodos , Neoplasias Nasofaríngeas/terapia , Padrões de Prática Médica/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/economia , Carcinoma/diagnóstico , Carcinoma/mortalidade , Carcinoma/secundário , Quimiorradioterapia/economia , Estudos de Coortes , Feminino , Humanos , Seguro Saúde/estatística & dados numéricos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/diagnóstico , Neoplasias Nasofaríngeas/mortalidade , Neoplasias Nasofaríngeas/patologia , Neoplasias Nasofaríngeas/secundário , Seleção de Pacientes , Padrões de Prática Médica/economia , Medição de Risco , Taxa de Sobrevida , Resultado do Tratamento , Estados Unidos/epidemiologia , Adulto JovemRESUMO
BACKGROUND: A cervical cystic mass is associated with a number of pathologies that present with similar symptoms. These conditions are difficult to differentiate using fine-needle aspiration (FNA), ultrasound (US), computed tomography (CT) and magnetic resonance imaging (MRI). Another dilemma in the differential diagnosis of cervical cystic masses is due to the controversies associated with the existence of branchiogenic carcinoma (BC). BC is an extremely rare disease that must be differentiated from other conditions presenting with cervical cystic masses, especially cystic metastasis from occult primary lesions. CASE PRESENTATION: We present a case report of a right cervical cystic metastasis from a significantly small squamous cell carcinoma primary gingival lesion misdiagnosed as BC by histopathology. A 62-year-old female presented with a painless progressively enlarging cervical mass at the anterior edge of the sternocleidomastoid muscle in the right submandibular region. Preoperative MRI and US revealed a well-defined cystic round mass. Postoperative histological examination indicated BC. Positron emission tomography/computed tomography (PET/CT) revealed high 18F-FDG (18F 2-fluoro-2-deoxy-D-glucose) uptake in surgical regions with a SUV (standard uptake value) max 4.0 and ipsilateral nasopharynx with a SUVmax 4.4, without any distant metastasis. Pathologic results revealed nasopharyngeal lymphadenosis. Considering the low incidence of BC and the limitation of diagnosis in one institution, the patient was referred to another hospital. Physical examination detected a significantly small neoplasm (~3 mm diameter) in the right lower gingiva. Histopathological examination of the neoplasm revealed a well-differentiated squamous cell carcinoma. Surgery, including a partial mandibulectomy and modified neck dissection (neck level I-V and submental lymph nodes) were undertaken. Postoperative histopathological results revealed a well-differentiated squamous cell carcinoma of right lower gingiva and two metastatic lymph nodes in the 18 lymph nodes of level II. A month later, recurrence occurred in the right cervical level II. The patient was placed on postoperative concurrent chemo-radiotherapy and supportive care. The patient suffered from cachexia and survived for only six months after surgery. CONCLUSIONS: In cases of cervical cystic masses that appear after the age of 40, clinicians should bear in mind that occult primary lesions should be excluded and examination of the gingiva should be undertaken. PET/CT has a limited role in identifying small occult primary lesions and a comprehensive physical examination must be carefully performed.
Assuntos
Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/secundário , Neoplasias Gengivais/patologia , Neoplasias Nasofaríngeas/secundário , Branquioma/diagnóstico , Diagnóstico Diferencial , Erros de Diagnóstico , Feminino , Fluordesoxiglucose F18 , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Neoplasias Nasofaríngeas/patologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Compostos RadiofarmacêuticosAssuntos
Biópsia por Agulha Fina , Carcinoma/patologia , Carcinoma/secundário , Técnicas Citológicas/métodos , Testes Diagnósticos de Rotina/métodos , Linfonodos/patologia , Neoplasias Nasofaríngeas/patologia , Neoplasias Nasofaríngeas/secundário , Metástase Neoplásica/diagnóstico , Biomarcadores Tumorais/análise , Carcinoma/diagnóstico , Criança , Feminino , Histocitoquímica , Humanos , Imuno-Histoquímica , Microscopia , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/diagnósticoRESUMO
Nasopharyngeal carcinoma (NPC) is endemic in Southern China, Taiwan, Malaysia, Singapore, North Africa and Alaska. About 30% of NPC patients develop recurrence or metastasis despite initial radical treatment. Palliative chemotherapy is the first-line treatment for inoperable recurrence or distant metastatic disease. However the standard first-line chemotherapeutic regimen is yet to be established until recently gemcitabine and cisplatin has been proven superior to traditional regimen with 5-FU and cisplatin shown in a phase III randomized-controlled trial. Further palliative systemic treatment options including other chemotherapeutic regimens, targeted therapy and more recently immunotherapy have gradually evolved. We provided a comprehensive review on different traditional chemotherapeutic regimens and highlighted the latest chemotherapeutic treatments as well as the latest development of targeted therapies, immune checkpoint inhibitors and other immunotherapeutic options in this setting.