RESUMEN
BACKGROUND: This study aimed to establish a consensus on the delineation of target volumes for neoadjuvant radiation therapy (nRT) in esophageal squamous cell carcinoma (ESCC) within China. METHODS: From February 2020 to June 2021, nine ESCC patients who received nRT were retrospectively selected from Sun Yat-sen University Cancer Center and Shandong Cancer Hospital. A panel from eight cancer radiotherapy centers performed two rounds of nRT target volume delineation for these patients: the first round for cases 1-6 and the second for cases 7-9. Online meetings were held after each delineation round to discuss findings. The consistency of delineations across centers was compared using mean undirected Hausdorff distances (Hmean), dice similarity coefficients (DSC), and total volumes, analyzed with the Mann-Whitney U test. RESULTS: The second round of delineations showed improved consistency across centers (total clinical target volume (CTVtotal): mean DSC = 0.76-0.81; mean Hmean = 2.11-3.14 cm) compared to the first round (CTVtotal: mean DSC = 0.63-0.64; mean Hmean = 5.66-7.34 cm; DSC and Hmean: P < 0.050 between rounds), leading to the formation of a consensus and an atlas for ESCC nRT target volume delineation. A proposal was reached through evaluating target volume delineations, analyzing questionnaire survey outcomes, and reviewing pertinent literature. CONCLUSIONS: We have developed guidelines and an atlas for target volume delineation in nRT therapy for ESCC in China. These resources are designed to facilitate more consistent delineation of target volumes in both clinical practice and clinical trials.
Asunto(s)
Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Terapia Neoadyuvante , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , China , Neoplasias Esofágicas/radioterapia , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/radioterapia , Carcinoma de Células Escamosas de Esófago/patología , Terapia Neoadyuvante/métodos , Planificación de la Radioterapia Asistida por Computador/métodos , Estudios RetrospectivosRESUMEN
BACKGROUND: Genome instability (GI) is a hallmark of esophageal squamous cell carcinoma (ESCC) while factors affecting GI remain unclear. METHODS: Here, we aimed to characterize genomic events representing specific mechanisms of GI based on 201 ESCC samples and validated our findings at the patient, single-cell and cancer cell-line levels, including a newly generated multi-omics dataset of the trial NCT04006041. RESULTS: A two-gene (AHNAK and AHNAK2) mutation signature was identified to define the "AHNAK1/2-mutant" cancer subtype. Single-cell-assisted multi-omics analysis showed that this subtype had a higher neoantigen load, active antigen presentation, and proficient CD8 + T cell infiltrations, which were validated at pan-cancer levels. Mechanistically, AHNAK1/2-mutant ESCC was characterized by impaired response of TGF-ß and the inefficient alternative end-join repair (Alt-EJ) that might promote GI. Knockdown of AHNAK in ESCC cell lines resulted in more Alt-EJ events and increased sensitivities to cisplatin. Furthermore, this two-gene signature accurately predicted better responses to DNA-damaging therapy in various clinical settings (HR ≈ 0.25). The two-gene signature predicted higher pCR rates in ESCCs receiving neoadjuvant immunotherapy-involved treatment. Finally, a molecular classification scheme was built and outperformed established molecular typing models in the prognosis stratification of ESCC patients. CONCLUSION: Our study extended our understanding of the AHNAK family in promoting GI and selecting treatment responders of ESCC.
Asunto(s)
Neoplasias Esofágicas , Inmunoterapia , Proteínas de la Membrana , Proteínas de Neoplasias , Factor de Crecimiento Transformador beta , Animales , Femenino , Humanos , Masculino , Ratones , Línea Celular Tumoral , Proteínas del Citoesqueleto , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/inmunología , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/terapia , Carcinoma de Células Escamosas de Esófago/inmunología , Carcinoma de Células Escamosas de Esófago/patología , Inmunoterapia/métodos , Proteínas de la Membrana/genética , Mutación , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/inmunología , Pronóstico , Transducción de Señal , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
OBJECTIVE: To investigate the impact of vasculogenic mimicry (VM) and postoperative adjuvant therapy on the prognosis and survival of patients with esophageal squamous cell carcinoma (ESCC), as well as to assess whether VM affects the clinical benefit of postoperative adjuvant therapy. METHODS: This single-center retrospective analysis included patients who underwent radical surgery for ESCC, which was documented in the medical record system. The presence or absence of VM in surgical specimens was determined using double staining with PAS/CD31. Stratification was applied based on adjuvant therapy and VM status. Survival curves and COX modeling were used to analyze the impact of the presence or absence of VM on the benefit of adjuvant therapy and the survival prognosis of patients. RESULTS: VM-positive patients were more prone to postoperative recurrence and metastasis. VM was identified as an independent risk factor for progression-free survival (PFS) (p < 0.001, 95% CI:1.809-3.852) and overall survival (OS) (p < 0.001, 95% CI:1.603-2.786) in postoperative ESCC. Postoperative adjuvant therapy significantly prolonged PFS (p = 0.008) and OS time (p < 0.001) in patients with stage II and III ESCC, with concurrent chemoradiotherapy being the most effective. However, the presence of VM significantly reduced the benefits of postoperative adjuvant therapy (p < 0.001). CONCLUSION: VM negatively impacts the prognosis of postoperative ESCC patients and reduces the efficacy of postoperative adjuvant therapy.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Recurrencia Local de Neoplasia , Humanos , Masculino , Femenino , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/mortalidad , Persona de Mediana Edad , Estudios Retrospectivos , Carcinoma de Células Escamosas de Esófago/patología , Carcinoma de Células Escamosas de Esófago/terapia , Carcinoma de Células Escamosas de Esófago/cirugía , Carcinoma de Células Escamosas de Esófago/mortalidad , Pronóstico , Anciano , Neovascularización Patológica , Quimioterapia Adyuvante/métodos , Esofagectomía , Resistencia a Antineoplásicos , Estadificación de NeoplasiasRESUMEN
BACKGROUND: Stromal fibrosis is highly associated with therapeutic resistance and poor survival in esophageal squamous cell carcinoma (ESCC) patients. Low expression of plasma gelsolin (pGSN), a serum abundant protein, has been found to correlate with inflammation and fibrosis. Here, we evaluated pGSN expression in patients with different stages of cancer and therapeutic responses, and delineated the molecular mechanisms involved to gain insight into therapeutic strategies for ESCC. METHODS: Circulating pGSN level in ESCC patients was determined by enzyme-linked immunosorbent assay analysis, and the tissue microarray of tumors was analyzed by immunohistochemistry staining. Cell-based studies were performed to investigate cancer behaviors and molecular mechanisms, and mouse models were used to examine the pGSN-induced tumor suppressive effects in vivo. RESULTS: Circulating pGSN expression is distinctively decreased during ESCC progression, and low pGSN expression correlates with poor therapeutic responses and poor survival. Methylation-specific PCR analysis confirmed that decreased pGSN expression is partly attributed to the hypermethylation of the GSN promoter, the gene encoding pGSN. Importantly, cell-based immunoprecipitation and protein stability assays demonstrated that pGSN competes with oncogenic tenascin-C (TNC) for the binding and degradation of integrin αvß3, revealing that decreased pGSN expression leads to the promotion of oncogenic signaling transduction in cancer cells and fibroblasts. Furthermore, overexpression of pGSN caused the attenuation of TNC expression and inactivation of cancer-associated fibroblast (CAF), thereby leading to tumor growth inhibition in mice. CONCLUSIONS: Our results demonstrated that GSN methylation causes decreased secretion of pGSN, leading to integrin dysregulation, oncogenic TNC activation, and CAF formation. These findings highlight the role of pGSN in therapeutic resistance and the fibrotic tumor microenvironment of ESCC.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Gelsolina , Microambiente Tumoral , Humanos , Carcinoma de Células Escamosas de Esófago/metabolismo , Gelsolina/genética , Gelsolina/metabolismo , Ratones , Neoplasias Esofágicas/metabolismo , Animales , Masculino , Femenino , Quimioradioterapia/métodos , Persona de Mediana Edad , Línea Celular Tumoral , Resistencia a Antineoplásicos , FibrosisRESUMEN
BACKGROUND: Tumor cells (TC) participate in tumor progression by altering the immune responses in the tumor microenvironment. However, the clinical relevance and prognostic effect of PD-L1 expression and tumor-infiltrating lymphocytes (TILs) in esophageal squamous cell carcinoma (ESCC) are unknown. The purpose of this study was to investigate the interactions and clinical significance of PD-L1 expression and TILs in ESCC. METHODS: Tissue specimens were collected from 126 patients with ESCC who underwent curative esophagectomy. Immunohistochemical analysis and multiplex immunofluorescence for CD4, CD8, CD25, FOXP3, and PD-L1 in the tumor were used to identify multiple tumor-infiltrating immune cells (TIIC), Tregs, and TC. RESULTS: PD-L1 was expressed in tumor cells (PD-L1 TC). PD-L1 TIIC and PD-L1 TC affected the biological behavior of TC. The positive expression rate of PD-L1 TC and CD8+ TILs was 27.8% (35/126) and 31.7% (40/126), respectively. Kaplan-Meier analysis showed that overall survival (OS) was significantly associated with decreased CD8+ TILs and PD-L1 TC-positive expression, which promote ESCC progression and metastasis. CONCLUSION: Tumor depth, CD8, and PD-L1 TC were independent prognostic factors in ESCC, and a predictive nomogram with these three risk factors improved the accuracy of predicting OS in patients with ESCC after surgical resection. The conjoint analysis of multiple immune-related factors is beneficial for stratifying patient survival risk.
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Antígeno B7-H1 , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Linfocitos Infiltrantes de Tumor , Microambiente Tumoral , Humanos , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Antígeno B7-H1/metabolismo , Masculino , Femenino , Carcinoma de Células Escamosas de Esófago/patología , Carcinoma de Células Escamosas de Esófago/cirugía , Carcinoma de Células Escamosas de Esófago/metabolismo , Carcinoma de Células Escamosas de Esófago/mortalidad , Carcinoma de Células Escamosas de Esófago/inmunología , Pronóstico , Persona de Mediana Edad , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/cirugía , Neoplasias Esofágicas/inmunología , Anciano , Microambiente Tumoral/inmunología , Biomarcadores de Tumor/metabolismo , Estimación de Kaplan-Meier , Adulto , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , EsofagectomíaRESUMEN
BACKGROUND: Pembrolizumab plus cisplatin and 5-fluorouracil administered as first-line therapy for advanced esophageal cancer patients has shown a better objective response and survival than conventional chemotherapy with less severe hematological adverse events. The safety and efficacy of this regimen were evaluated in patients with T4b esophageal squamous cell carcinoma (ESCC). METHODS: Eight consecutive patients with T4b ESCC received this regimen according to KEYNOTE-590 as induction, and they were evaluated after 1-3 courses. The programmed death-ligand 1 (PD-L1) combined positive score (CPS) was also evaluated before chemotherapy. Efficacy for the primary lesion was evaluated by our original formula for the tumor reduction rate. RESULTS: The numbers of patients with partial response (PR), stable disease, and progressive disease (PD) were 5, 1, and 2, respectively. The tumor reduction rate ranged from 69 to 87% in PR patients, and all PR patients had relief from T4b. Two patients underwent conversion surgery with R0 resection. PD-L1 CPS was over 90 in 2 PR patients, but under 10 in 2 other PR patients. PD-L1 CPS was under 10 in PD patients. One patient had hyperprogression, resulting in an esophago-pulmonary fistula. Greater than grade 3 adverse events were bleeding gastric ulcer in one patient (12.5%), neutropenia without G-CSF in 3 patients (37.5%), and hypopotassemia in 1 patient (12.5%). No patient had febrile neutropenia. CONCLUSIONS: Marked tumor reduction was confirmed in 62.5% of patients with pembrolizumab plus cisplatin and 5-fluorouracil with less adverse events. This regimen could be administered as induction chemotherapy for patients with T4b ESCC.
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Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Cisplatino , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Fluorouracilo , Humanos , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Cisplatino/uso terapéutico , Fluorouracilo/administración & dosificación , Fluorouracilo/uso terapéutico , Fluorouracilo/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Masculino , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/patología , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Persona de Mediana Edad , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/patología , Femenino , Anciano , Antígeno B7-H1 , Resultado del Tratamiento , Estadificación de Neoplasias , Progresión de la EnfermedadRESUMEN
OBJECTIVES: Esophageal squamous cell carcinoma (ESCC) is a malignant tumor with high incidence and mortality rates worldwide. This study aimed to investigate the correlation between LINC-PINT polymorphisms and ESCC risk in the Hainan Han population. METHODS: A total of 391 patients with ESCC and 452 healthy controls were enrolled to evaluate the effect of LINC-PINT SNPs (single nucleotide polymorphisms) on ESCC susceptibility. Associations were evaluated by calculating odds ratios (OR) and 95% confidence intervals (CIs). Multifactor dimensionality reduction analysis was performed to explore the association between SNP-SNP interactions and ESCC susceptibility. We further determined the correlation between clinical indicators and SNP in patients with ESCC. RESULTS: Our study showed that rs157916 (OR 0.63, p = 0.011) and rs157928 (OR 0.80, p = 0.021) were associated with a decreased risk of ESCC. Stratified analysis indicated that rs157916 could decrease the risk of ESCC in people aged >64 years, in males, and non-drinkers (OR 0.58, p = 0.042; OR 0.58, p = 0.010; OR 0.62, p = 0.025, respectively). Rs16873842 was related to a decreased risk of ESCC in males (OR 0.70, p = 0.015). Rs7801029 was associated with ESCC risk in females (OR 0.39, p = 0.033) and non-drinkers (OR 0.68, p = 0.040). Rs7781295 decreased the ESCC risk in smokers (OR 0.58, p = 0.046) and drinkers (OR 0.58, p = 0.046). In addition, rs157928 played a protective role in ESCC risk in females (OR 0.39, p = 0.033) and non-smokers (OR 0.32, p = 0.006). Additionally, the best predictive model for ESCC was a combination of rs157916, rs16873842, rs7801029, rs7781295, rs28662387, and rs157928. CONCLUSION: Our study revealed that LINC-PINT polymorphisms were associated with ESCC risk.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , ARN Largo no Codificante , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios de Casos y Controles , China/epidemiología , Neoplasias Esofágicas/etnología , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas de Esófago/etnología , Carcinoma de Células Escamosas de Esófago/genética , Factores de Riesgo , ARN Largo no Codificante/genética , Pueblos del Este de Asia/genética , Etnicidad/genéticaRESUMEN
BACKGROUND: Programmed cell death-1 (PD-1) blockade improves survival in patients with advanced esophageal squamous cell carcinoma (ESCC). However, the efficacy of taxanes after exposure to PD-1 blockade remains unclear in patients with advanced ESCC. METHODS: We retrospectively analyzed the clinical outcomes of advanced ESCC patients treated with taxanes (paclitaxel or docetaxel) with/without prior exposure to PD-1 blockade (Exposed /Naïve group) at National Cancer Center Hospital from June 2016 to December 2020. RESULTS: Ninety-nine patients (Exposed group, n = 32; Naïve group, n = 67) were included. The objective response rate (ORR) of the Exposed group was significantly higher than that of the Naïve group (37.5% vs. 13.4%, p = 0.009). The median progression-free survival was similar between the Exposed and Naïve groups (3.8 vs. 2.8 months, HR 1.12, 95% CI 0.65-1.86, p = 0.66). PD-1 blockade exposure independently predicated higher ORR to taxanes in multivariate analysis. Grade ≥ 3 adverse events were comparable between the Exposed and Naïve groups (45.8% vs. 40.3%, p = 0.64). CONCLUSIONS: Taxanes following PD-1 blockade in advanced ESCC showed a higher ORR but similar PFS compared to taxanes without prior PD-1 exposure.
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Docetaxel , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Paclitaxel , Humanos , Masculino , Femenino , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Estudios Retrospectivos , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/patología , Persona de Mediana Edad , Anciano , Docetaxel/uso terapéutico , Docetaxel/efectos adversos , Docetaxel/administración & dosificación , Paclitaxel/uso terapéutico , Paclitaxel/efectos adversos , Paclitaxel/administración & dosificación , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Taxoides/efectos adversos , Taxoides/uso terapéutico , Supervivencia sin Progresión , Resultado del Tratamiento , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
BACKGROUND: Despite the recognized therapeutic potential of programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors in advanced esophageal squamous cell carcinoma (ESCC), their role in neoadjuvant therapy and reliable efficacy biomarkers remain elusive. MATERIALS AND METHODS: We retrospectively analyzed locally advanced ESCC patients who underwent surgery following a 2-cycle platinum and paclitaxel-based treatment, with or without PD-1 inhibitors (January 2020-March 2023). We assessed peripheral blood indexes and tertiary lymphoid structures (TLS) density to evaluate their impact on pathological response and prognosis, leading to a clinical prediction model for treatment efficacy and survival. RESULTS: Of the 157 patients recruited, 106 received immunochemotherapy (ICT) and 51 received chemotherapy (CT) alone. The ICT group demonstrated a superior pathological response rate (PRR) (47.2% vs. 29.4%, p = 0.034) with comparable adverse events and postoperative complications. The ICT group also showed a median disease-free survival (DFS) of 39.8 months, unattained by the CT group. The 1-year DFS and overall survival (OS) rates were 73% and 91% for the ICT group, and 68% and 81% for the CT group, respectively. We found higher baseline activated T cells, lower baseline Treg cells, and a decreased posttreatment total lymphocyte and CD4+/CD8+ ratio predicted an enhanced PRR. Reduced posttreatment CD4+/CD8+ ratio and increased NK cells were associated with prolonged survival, while higher TLS density indicated poorer prognosis. Among ICT group, a lower posttreatment CD4+/CD8+ ratio indicated longer DFS and reduced posttreatment B cells indicated longer OS. A nomogram integrating these predictors was developed to forecast treatment efficacy and survival. CONCLUSION: The combination of PD-1 inhibitors and chemotherapy appears promising for locally advanced ESCC. Evaluating the differentiation status and dynamic changes of peripheral blood immune cells may provide valuable predictive insights into treatment efficacy and prognosis.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Terapia Neoadyuvante , Humanos , Masculino , Carcinoma de Células Escamosas de Esófago/terapia , Carcinoma de Células Escamosas de Esófago/mortalidad , Carcinoma de Células Escamosas de Esófago/inmunología , Carcinoma de Células Escamosas de Esófago/patología , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Femenino , Terapia Neoadyuvante/métodos , Estudios Retrospectivos , Persona de Mediana Edad , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/inmunología , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/tratamiento farmacológico , Anciano , Inmunoterapia/métodos , Subgrupos Linfocitarios/inmunología , Pronóstico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resultado del Tratamiento , Paclitaxel/administración & dosificación , Paclitaxel/uso terapéutico , Adulto , EsofagectomíaRESUMEN
Immunotherapy has revolutionized the treatment landscape of esophageal squamous cell carcinoma. He et al. present the final results of the randomized phase 3 ESCORT-1st trial, confirming positive survival outcomes when adding the anti-PD1 inhibitor camrelizumab to first-line chemotherapy treatment in Chinese patients with esophageal squamous cell cancer.1.
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Anticuerpos Monoclonales Humanizados , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Inhibidores de Puntos de Control Inmunológico , Humanos , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/inmunología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/patología , Carcinoma de Células Escamosas de Esófago/inmunología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
N6-methyladenosine (m6A) methylation, as a new regulatory mechanism, has been reported to be involved in diverse biological processes in recent years. Wilms tumor 1-associated protein (WTAP), as the key member of m6A methylation, has been proven to participate in tumorigenesis. Here, we studied the expression of WTAP and its potential mechanism involved in the development of esophageal squamous cell carcinoma (ESCC). We detected the expression of WTAP and its correlation with clinicopathological features, and we determined the function of WTAP on ESCC cells by MTS assay, colony formation, scratch wound healing assay, Transwell assay, and subcutaneous xenograft assay. We used mRNA sequencing technology to screen candidate downstream targets for WTAP and investigated the underlying mechanism of CCND1 in ESCC promotion through a series of rescue assays. An elevated expression of WTAP in ESCC malignancy indicated a worse prognosis. WTAP promoted the proliferation and metastasis of ESCC cells, and CCND1 was identified as the potential downstream effecter of WTAP. Moreover, WTAP modulated ESCC progression through a MAPK pathway-dependent pattern. Our research suggested that WTAP promoted both proliferation and metastasis of ESCC by accelerating the expression of CCND1 via the MAPK signaling pathway, indicating that WTAP may be a candidate prognostic biomarker for ESCC and also will be a promising strategy for ESCC cancer therapy.
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Proliferación Celular , Ciclina D1 , Progresión de la Enfermedad , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Sistema de Señalización de MAP Quinasas , Humanos , Ciclina D1/metabolismo , Ciclina D1/genética , Carcinoma de Células Escamosas de Esófago/patología , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/metabolismo , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Animales , Línea Celular Tumoral , Ratones , Masculino , Regulación Neoplásica de la Expresión Génica , Pronóstico , Femenino , Factores de Empalme de ARN/genética , Factores de Empalme de ARN/metabolismo , Movimiento Celular , Ratones Desnudos , Persona de Mediana Edad , Proteínas de Ciclo CelularRESUMEN
The average five-year survival rate for esophageal cancer, a common malignant tumor of the digestive system, is barely 20%. The majority of esophageal squamous cell carcinoma (ESCC) patients had already progressed to a locally advanced or even advanced stage at initial diagnosis, making routine surgery ineffective. Chemotherapy and immunotherapy are important neoadjuvant treatments for ESCC, however, it remains unknown how treatment will affect the immunological microenvironment, especially at the spatial level. Here, we presented the TME characters of ESCC from the temporal and spatial dimensions using scRNA-seq and ST, investigated the changes of immune cell clusters in the TME under neoadjuvant chemotherapy and preoperative immunotherapy, and explored the potential mechanisms. It was found that compared with chemotherapy, immunotherapy combined with chemotherapy increased the level of T cell proliferation, partially restored the function of exhausted T cells, induced the expansion of specific exhausted CD8 T cells, increased the production of dendritic cells (DCs), and supported the immune hot microenvironment of the tumor. We also found that CD52 and ID3 have potential as biomarkers of ESCC. Particularly, CD52 may be served as a predictor of the efficacy to screen the advantaged population of different regimens. Through multiple pathways, CAF2 and CAF5's antigen-presenting role affected the other fibroblast clusters, resulting in malignant transformation. We analyzed the immune microenvironment differences between the two regimens to provide a more thorough description of the ESCC microenvironment profile and serve as a foundation for customized neoadjuvant treatment of ESCC.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Inmunoterapia , Terapia Neoadyuvante , Microambiente Tumoral , Humanos , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/inmunología , Carcinoma de Células Escamosas de Esófago/inmunología , Carcinoma de Células Escamosas de Esófago/terapia , Carcinoma de Células Escamosas de Esófago/patología , Inmunoterapia/métodos , Masculino , FemeninoRESUMEN
BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is often diagnosed at advanced stages due to the inherent limitations of current screening methodologies. Central to evaluating tumor invasion and prognostic assessment in ESCC is the integrity of the basement membrane (BM). However, current research on the implications of BM-related genes (BMRGs) in diagnosing ESCC remains sparse. METHODS: We performed a comprehensive analysis using single-cell RNA-sequencing (scRNA-seq) data from the Gene Expression Omnibus (GEO) database, alongside gene expression profiles acquired from GEO and The Cancer Genome Atlas (TCGA) databases. This identified differentially expressed BMRGs in ESCC. Employing LASSO, RF, and SVM-RFE, we selected potential BM biomarkers and crafted a diagnostic nomogram for ESCC, validated by ROC curves and AUC values. We also explored immune infiltration and biological mechanisms through consensus clustering and GSVA, and utilized single cell trajectory analysis and GSCALite to study gene distributions and pathways. In vitro experiments further elucidated the role of these genes in ESCC carcinogenesis. RESULTS: Here, we discovered that ESCC cell types exhibited markedly elevated BM-related scores. Our analysis pinpointed seven BM genes upregulated and linked to immune infiltration, showcasing unique gene expression profiles and varying immune cell densities across the BM-related subtypes. Furthermore, a robust positive correlation was observed between these genes expression and EMT activity. The knockdown of BGN significantly suppressed cell proliferation, migration, invasion, while also augmenting cell viability following chemotherapy drug treatment. CONCLUSION: Our study identified seven key BMRGs (BGN, LAMB3, SPARC, MMP1, LUM, COL4A1, and NELL2) and established a diagnostic nomogram for ESCC. Of noteworthy significance is the discovery of BGN as a promising drug target, indicating a novel strategy for future clinical combination therapies in ESCC.
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Membrana Basal , Biomarcadores de Tumor , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Genómica , Humanos , Carcinoma de Células Escamosas de Esófago/genética , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/diagnóstico , Biomarcadores de Tumor/genética , Membrana Basal/metabolismo , Genómica/métodos , Línea Celular Tumoral , Regulación Neoplásica de la Expresión GénicaRESUMEN
OBJECTIVES: Surgery is the mainstream treatment for early-stage esophageal squamous cell carcinoma (ESCC) and occult recurrent laryngeal nerve lymph node metastasis (RLNM) is not uncommon among those with R0 resection. The clinical value of postoperative radiotherapy (PORT) in patients with RLNM only is still controversial. METHODS: Consecutive patients with early-stage ESCC treated with R0 resection and pathologically confirmed RLNM only from June 2012 to July 2022 were retrospectively reviewed. PORT, covering the supraclavicular and superior mediastinum area (small T-field) at a dose of 50.4 Gy for 28 fractions, was performed in some patients. Propensity score matching (PSM) was performed to balance the baseline characteristics between patients with or without PORT. Pattern of failure, disease-free survival (DFS), and overall survival (OS) were compared. RESULTS: Among the 189 patients identified, 69 (35.5%) received PORT and the other 120 (63.5%) did not. After PSM, 154 patients were included in the matched cohort, including 62 in the PORT group and 92 in the non-PORT group. With a median follow-up of 48 (95% CI: 40.3-55.7) months, 69 patients developed their initial disease recurrence in the whole population and PORT significantly decreased the frequency of local recurrence (61.2% vs 21.4%) among those with recurrent disease. Additionally, in the PSM matched cohort, PORT significantly prolonged patients' DFS (HR 0.393, P = 0.002) and OS (HR 0.462, P = 0.020). Moreover, PORT remained as the independent factor associated with improved DFS (HR 0.360, P = 0.001) and OS (HR 0.451, P = 0.021) after multivariate Cox analyses. In addition, tumor location and pathological TNM stage were found to be independent prognostic factors associated with survival outcomes. CONCLUSION: PORT is associated with improved DFS and OS in ESCC patients with R0 resection and RLNM only, which warrants future validation.
Asunto(s)
Carcinoma de Células Escamosas de Esófago , Metástasis Linfática , Nervio Laríngeo Recurrente , Humanos , Masculino , Femenino , Persona de Mediana Edad , Carcinoma de Células Escamosas de Esófago/cirugía , Carcinoma de Células Escamosas de Esófago/radioterapia , Carcinoma de Células Escamosas de Esófago/patología , Nervio Laríngeo Recurrente/patología , Estudios Retrospectivos , Anciano , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/radioterapia , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/cirugía , Ganglios Linfáticos/patología , Radioterapia Adyuvante/métodos , Recurrencia Local de Neoplasia/patología , Supervivencia sin EnfermedadRESUMEN
BACKGROUND AND OBJECTIVE: To investigate the oncologic outcomes of patients with esophageal squamous cell carcinoma (ESCC) who have achieved a pathologic complete response (pCR) of the primary tumor (ypT0) after neoadjuvant chemoradiotherapy (NCRT). METHODS: Patients with thoracic ESCC who underwent scheduled NCRT followed by surgery at our hospital between January 2010 and December 2022 were retrospectively analyzed. Only patients with ypT0 disease were enrolled in this study. RESULTS: A total of 118 patients were ultimately enrolled in this study. Ninety-two patients achieved pCR in the primary tumor and lymph nodes (ypT0N0), while 26 patients had residual metastatic disease in 52 lymph nodes (ypT0N+). Forty-five of the 52 lymph nodes with residual tumors were abdominal lymph nodes. Positive lymph nodes were more often observed in patients with tumors located in the lower third of the esophagus. The 1-, 3-, and 5-year overall survival (OS) rates for the entire study group were 96.5%, 79.5%, and 77.1%, and the 1-, 3-, and 5-year disease-free survival (DFS) rates were 90.5%, 76.8%, and 69.0%, respectively. According to multivariate analyses, pN classification was an independent predictor of both OS and DFS (P < 0.05), while sex and cT classification were also found to be independent prognostic factors for DFS (P < 0.05). CONCLUSIONS: Residual nodal metastatic disease in patients with ypT0 ESCC after NCRT was more often found in the abdominal lymph nodes. pN classification was an independent predictor of both OS and DFS for ypT0 ESCC patients after NCRT.
Asunto(s)
Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Terapia Neoadyuvante , Humanos , Masculino , Femenino , Persona de Mediana Edad , Terapia Neoadyuvante/métodos , Carcinoma de Células Escamosas de Esófago/terapia , Carcinoma de Células Escamosas de Esófago/patología , Carcinoma de Células Escamosas de Esófago/mortalidad , Estudios Retrospectivos , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/mortalidad , Anciano , Quimioradioterapia/métodos , Adulto , Resultado del Tratamiento , Metástasis Linfática , Estadificación de Neoplasias , Supervivencia sin Enfermedad , Esofagectomía , Tasa de SupervivenciaRESUMEN
CASE PRESENTATION: A 70-year-old man was diagnosed with mid-thoracic esophageal squamous cell carcinoma (distance from incisors, 27-30 cm) because of progressive dysphagia and underwent thoracic laparoscopic esophagectomy at a local hospital. He was transferred from the ICU 4 days after surgery; however, a large amount of purulent fluid exuded from the neck incision after oral drinking, which was consistent with cervical anastomotic leakage. Later, the patient experienced difficulty breathing and expelling sputum; he was then transferred back to the ICU for treatment. A CT scan showed massive fluid collection in the mediastinum and left pleural cavity. Thoracentesis yielded yellowish fluid, and the patient's general condition gradually improved after placement of a closed chest drainage system. The patient's cervical anastomotic fistula persisted and did not heal, and he was subsequently transferred to our medical center with the closed chest drainage system left in place.
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Neoplasias Esofágicas , Tomografía Computarizada por Rayos X , Humanos , Masculino , Anciano , Neoplasias Esofágicas/cirugía , Neoplasias Esofágicas/diagnóstico , Drenaje/métodos , Esofagectomía/métodos , Fuga Anastomótica/diagnóstico , Fuga Anastomótica/cirugía , Toracocentesis/métodos , Carcinoma de Células Escamosas de Esófago/cirugía , Carcinoma de Células Escamosas de Esófago/diagnósticoRESUMEN
BACKGROUND: Adjuvant nivolumab reduces recurrence in patients with locoregional esophageal cancer who had pathological residual disease after neoadjuvant chemoradiotherapy and R0 resection. However, the efficacy of adjuvant anti-PD-1 therapy in patients at higher risk of recurrence remains unclear. METHODS: This phase II trial (ClinicalTrials.gov identifier: NCT03322267) enrolled patients with locally advanced esophageal squamous cell carcinoma (ESCC) received neoadjuvant chemoradiotherapy plus esophagectomy but still had various risk factors for recurrence, such as involved or close margins (≤ 1 mm), extranodal extension of the involved lymph nodes, and the ypN2-3 stage. Patients received adjuvant therapy composed of a course of cisplatin-based chemoradiotherapy and pembrolizumab (200 mg, IV every 3 weeks) for 18 cycles. The primary endpoint was 1-year relapse-free survival (RFS) rate. RESULTS: Twenty-five patients were enrolled. The risk factors were tumor margins of ≤ 1 mm (18 patients), extranodal extension of the involved lymph nodes (9 patients), and the ypN2-3 stage (9 patients). The median follow-up duration was 21.6 months (95% CI: 18.7-33.2). The rate of 1-year RFS was 60.0%. The median duration of RFS and overall survival was 14.3 (95% CI: 9.0-19.5) and 21.6 (95% CI: 0.0-45.5) months, respectively. Treatment-emergent adverse events of any grade and those of ≥ 3 grade occurred in 56% and 8% of all patients receiving cisplatin-based chemoradiotherapy and in 79.2% and 12.5% of those receiving pembrolizumab. CONCLUSIONS: Adjuvant chemoradiotherapy followed by pembrolizumab is feasible and may be associated with improved 1-year RFS rate in patients at high risk of recurrence after trimodality therapy for locally advanced ESCC. Trial registration number ClinicalTrials.gov (No. NCT03322267).
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Anticuerpos Monoclonales Humanizados , Quimioradioterapia Adyuvante , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Terapia Neoadyuvante , Recurrencia Local de Neoplasia , Humanos , Masculino , Persona de Mediana Edad , Femenino , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Carcinoma de Células Escamosas de Esófago/terapia , Carcinoma de Células Escamosas de Esófago/mortalidad , Carcinoma de Células Escamosas de Esófago/patología , Anciano , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/patología , Recurrencia Local de Neoplasia/terapia , Terapia Neoadyuvante/métodos , Quimioradioterapia Adyuvante/métodos , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , EsofagectomíaRESUMEN
OBJECTIVE: Explore the efficacy and safety of involved-field irradiation (IFI) combined with S-1 as definitive concurrent chemoradiotherapy (dCRT) for locally advanced elderly esophageal squamous cell carcinoma (ESCC), under the premise of intensity-modulated radiotherapy (IMRT). METHODS: We designed a prospective single-arm phase II study. The study enrolled 91 patients aged 75 to 92 years. Eligible participants had histologically confirmed squamous cell carcinoma, stage II to IV disease based on the 8th edition of the American Joint Committee on Cancer (AJCC). All elderly patients (EPs) received dCRT with S-1. which was administered orally twice daily for 28 days. The radiotherapy dose was 61.2 Gy delivered in 34 fractions or 50.4 Gy delivered in 28 fractions. The primary endpoint was 2-year overall survival (OS), and the secondary endpoints were progression-free survival (PFS), local control rate (LCR), and safety. RESULTS: From July 2017 to July 2021, we enrolled EPs with ESCC who were treated at the Jiangsu Cancer hospital. As of August 1, 2023, the median follow-up of surviving EPs was 31.4 months (IQR: 25.2 to 72.6 months). 83 patients (91.2%) completed the whole course of treatment. The 2-year OS rate was 59.2%, and the PFS rate was 43.7%. The most common grade 1 to 2 adverse effects (AEs) were radiation esophagitis (79.1%), and then were radiation pneumonia (46.2%). Anemia (41.8%) was the most common of grade 1 to 2 hematologic toxicity. The incidence of grade 3 or above AEs was 24.2%, and the incidence of leukopenia was the highest (11.0%). There was not one death due to treatment-related toxicity. In a subgroup analysis of radiotherapy doses, we found no statistically significant differences in PFS (P = 0.465) and OS (P = 0.345) in EPs with ESCC who received 50.4 Gy and 61.2 Gy, and that patients in the 50.4 Gy group had lower dermatitis (P = 0.045) and anemia (P = 0.004). CONCLUSIONS: IF-IMRT combined with S-1 is a promising regimen for elderly ESCC. And the radiotherapy dose of 50.4 Gy remains the standard dose for EPs with ESCC undergoing CCRT.
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Quimioradioterapia , Combinación de Medicamentos , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Ácido Oxónico , Tegafur , Humanos , Tegafur/uso terapéutico , Anciano , Ácido Oxónico/uso terapéutico , Ácido Oxónico/administración & dosificación , Masculino , Femenino , Anciano de 80 o más Años , Carcinoma de Células Escamosas de Esófago/radioterapia , Carcinoma de Células Escamosas de Esófago/patología , Carcinoma de Células Escamosas de Esófago/mortalidad , Neoplasias Esofágicas/radioterapia , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/mortalidad , Estudios Prospectivos , Radioterapia de Intensidad Modulada/efectos adversos , Radioterapia de Intensidad Modulada/métodos , Tasa de Supervivencia , Antimetabolitos Antineoplásicos/uso terapéuticoRESUMEN
Single-cell RNA sequencing (scRNA-Seq) technology provides the scope to gain insight into the interplay between intrinsic cellular processes as well as transcriptional and behavioral changes in gene-gene interactions across varying conditions. The high level of scarcity of scRNA-seq data, however, poses a significant challenge for analysis. We propose a complete differential co-expression (DCE) analysis framework for scRNA-Seq data to extract network modules and identify hub-genes. The performance of our method has been shown to be satisfactory after validation using an scRNA-Seq esophageal squamous cell carcinoma (ESCC) dataset. From comparison with four other existing hub-gene finding methods, it has been observed that our method performs better in the majority of cases and has the ability to identify unique potential biomarkers that were not detected by the other methods. The potential biomarker genes identified by our framework, differential co-expression analysis method for single-cell RNA sequencing data (scDiffCoAM), have been validated both statistically and biologically.
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Biomarcadores de Tumor , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Regulación Neoplásica de la Expresión Génica , Análisis de Secuencia de ARN , Análisis de la Célula Individual , Humanos , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/patología , Análisis de la Célula Individual/métodos , Biomarcadores de Tumor/genética , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patología , Análisis de Secuencia de ARN/métodos , Perfilación de la Expresión Génica/métodos , Redes Reguladoras de Genes/genética , RNA-Seq/métodos , Análisis de Expresión Génica de una Sola CélulaRESUMEN
Introduction: Alcohol flushing syndrome (AFS) is experienced by up to 46% of East Asians. This study aimed to review the risk of cancers in AFS patients, elucidate an exposure-response relationship, and understand risk associated with alcohol intake and cancer. Method: An electronic database search of PubMed, Embase, Scopus and Cochrane Library was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines. Observational studies on AFS' effects and all cancers risk were included. Studies including patients with existing malignancy were excluded. Dichotomous variables were pooled using the Mantel-Haenszel method with a random effects model. Sensitivity and subgroup analyses were performed. PROSPERO (CRD42023392916) protocol was followed. Results: A total of 18 articles were included in the final analysis with a total of 387,521 participants. AFS was associated with an increased risk of all cancers (odds ratio [OR] 1.19, 95% confidence interval [CI] 1.06-1.34), esophageal squamous cell carcinoma (OR 1.47, 95% CI 1.05-2.05) and gastric adenocarci-noma (OR 1.40, 95% CI 1.14-1.72). Men with AFS exhibited an increased risk of all cancers (OR 1.34, 95% CI 1.13-1.59). However, this was not observed in women. All cancers risk was associated with AFS in those who consumed drink (i.e. consumed alcohol) more than 200 g of pure ethanol/week (OR 1.68, 95% CI 1.20-2.37) but not those who consumed less than 200 g of pure ethanol/week (OR 1.27, 95% CI 0.90-1.79) or non-drinkers (OR 0.99, 95% CI 0.67-1.47). Conclusion: AFS is associated with an increased risk of all cancers, particularly esophageal squamous cell carcinoma and gastric adenocarcinoma.