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Dysregulation of long noncoding RNA (lncRNA) expression plays a pivotal role in the initiation and progression of gastric cancer (GC). However, the regulation of lncRNA SNHG15 in GC has not been well studied. Mechanisms for ferroptosis by SNHG15 have not been revealed. Here, we aimed to explore SNHG15-mediated biological functions and underlying molecular mechanisms in GC. The novel SNHG15 was identified by analyzing RNA-sequencing (RNA-seq) data of GC tissues from our cohort and TCGA dataset, and further validated by qRT-PCR in GC cells and tissues. Gain- and loss-of-function assays were performed to examine the role of SNHG15 on GC both in vitro and in vivo. SNHG15 was highly expressed in GC. The enhanced SNHG15 was positively correlated with malignant stage and poor prognosis in GC patients. Gain- and loss-of-function studies showed that SNHG15 was required to affect GC cell growth, migration and invasion both in vitro and in vivo. Mechanistically, the oncogenic transcription factors E2F1 and MYC could bind to the SNHG15 promoter and enhance its expression. Meanwhile, SNHG15 increased E2F1 and MYC mRNA expression by sponging miR-24-3p. Notably, SNHG15 could also enhance the stability of SLC7A11 in the cytoplasm by competitively binding HNRNPA1. In addition, SNHG15 inhibited ferroptosis through an HNRNPA1-dependent regulation of SLC7A11/GPX4 axis. Our results support a novel model in which E2F1- and MYC-activated SNHG15 regulates ferroptosis via an HNRNPA1-dependent modulation of the SLC7A11/GPX4 axis, which serves as the critical effectors in GC progression, and provides a new therapeutic direction in the treatment of GC.
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Sistema de Transporte de Aminoácidos y+ , Progresión de la Enfermedad , Ferroptosis , Regulación Neoplásica de la Expresión Génica , Ribonucleoproteína Nuclear Heterogénea A1 , Fosfolípido Hidroperóxido Glutatión Peroxidasa , ARN Largo no Codificante , Neoplasias Gástricas , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Neoplasias Gástricas/metabolismo , Humanos , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Ribonucleoproteína Nuclear Heterogénea A1/metabolismo , Ribonucleoproteína Nuclear Heterogénea A1/genética , Animales , Línea Celular Tumoral , Ratones , Ferroptosis/genética , Masculino , Sistema de Transporte de Aminoácidos y+/genética , Sistema de Transporte de Aminoácidos y+/metabolismo , Femenino , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Fosfolípido Hidroperóxido Glutatión Peroxidasa/genética , Proliferación Celular/genética , Factor de Transcripción E2F1/metabolismo , Factor de Transcripción E2F1/genética , Movimiento Celular/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Persona de Mediana Edad , Pronóstico , Ratones Desnudos , Transducción de Señal/genética , Retroalimentación FisiológicaRESUMEN
The aims of this study were to enhance the antitumour immunity in Epstein-Barr virus-associated gastric cancer (EBVaGC). We performed RNA-seq analysis to compare the differential expression genes between EBVaGC and EBV-negative gastric cancer (EBVnGC) patients. The expression levels of CD68, CD163 and CD47 were analyzed by immunohistochemistry. Different subsets of macrophages were investigated by a coincubation model. The effects of CD47 blockade were also detected. The expression levels of CD68, CD163 and CD47 were significantly higher in EBVaGC, and were associated with poor prognoses. Macrophages coincubated with EBV+ AGS cells tended to be immunosuppressed, which could be reversed by CD47 deficiency or blocking CD47. EBV resulted in cGAS-STING pathway activation, which stimulated CD47 expression and inhibited macrophage phagocytosis. Anti-CD47 therapy activated cGAS-STING signaling, which was responsible for production of IFN-ß, resulting in activation of antitumour immunity. Our results provide a promising new strategy for CD47-targeted immunotherapy in EBVaGC.
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Infecciones por Virus de Epstein-Barr , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/terapia , Neoplasias Gástricas/metabolismo , Herpesvirus Humano 4 , Infecciones por Virus de Epstein-Barr/genética , Inmunohistoquímica , Inmunoterapia , Antígeno CD47/genéticaRESUMEN
OBJECTIVE: This study aimed to propose a revised ypN (r-ypN) classification based on lymph node ratio (LNR) and to examine its prognostic value in postneoadjuvant esophageal cancer. BACKGROUND: A new postneoadjuvant pathologic (ypTNM) staging classification has been introduced for esophageal cancer. However, the ypN classification currently defined by the number of positive lymph nodes is influenced by the extent of lymphadenectomy. METHODS: Data on 7195 esophageal cancer patients receiving neoadjuvant chemoradiation were extracted from the National Cancer Database (NCDB). Four r-ypN stages were defined by 3 LNR thresholds (0%, 10%, and 20% using X-tile software). A revised ypTNM (r-ypTNM) classification was developed by solely changing N categories. Kaplan-Meier method and Cox proportional hazards models were used for survival analyses. Akaike information criterion (AIC) and Harrell's concordance index ( C -index) were used to compare the predictive performance of the current and the revised classification. External validation was performed using an independent cohort from the NEOCRTEC5010 clinical trial. RESULTS: Both ypN ( P <0.001) and r-ypN ( P <0.001) were independent prognostic factors of overall survival (OS) for esophageal cancer patients. Kaplan-Meier curves demonstrated a better discrimination with r-ypN than ypN categories. Within each ypN category (except ypN3), OS was significantly different comparing r-ypN strata; however, there were no differences between ypN strata within each r-ypN category (except r-ypN3). r-ypN (AIC: 60752 vs 60782; C -index: 0.591 vs 0.587) and r-ypTNM (AIC: 60623 vs 60628; C -index: 0.613 vs 0.610) showed better predictive performance than the current staging system, with a lower AIC (better calibration) and higher C -index (improved discrimination). This advantage was also confirmed by external validation using the NEOCRTEC5010 cohort. CONCLUSIONS: LNR showed better performance than ypN in predicting OS of esophageal cancer patients after neoadjuvant chemoradiation and may be an improvement on the current staging system.
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Neoplasias Esofágicas , Ganglios Linfáticos , Humanos , Ganglios Linfáticos/patología , Terapia Neoadyuvante/métodos , Índice Ganglionar , Escisión del Ganglio Linfático/métodos , Pronóstico , Estadificación de Neoplasias , Estudios RetrospectivosRESUMEN
OBJECTIVE: To evaluate the outcome following the strategy of endoscopic R0 resection (ER) plus adjuvant treatment (AT) versus esophagectomy for esophageal squamous cell cancer in T1a invading muscularis mucosa (M3)-T1b stage. METHODS: We evaluated the outcomes of 46 esophageal squamous cell cancer (ESCC) patients with T1aM3-T1b stage who underwent ER + AT from the Esophageal Cancer Endoscopic Therapy Consortium (ECETC) and compared these outcomes to 92 patients who underwent esophagectomy. Propensity score matching (1:2) was used, with overall survival (OS) and relapse-free survival (RFS) being compared between the two groups. RESULTS: During a median follow-up of 32 months, there were no statistical differences (P = 0.226) in OS between the two groups. The 1-, 2-, and 3-year overall survival in the esophagectomy group was 95%, 91%, and 84%, respectively. There were no mortalities within three years in the ER + AT group. The RFS between the two groups was also not significantly different (P = 0.938). The 1-, 2-, and 3-year RFS of patients in the esophagectomy group was 90%, 90%, and 83%, respectively, while it was 97%, 94%, and 74% in the ER + AT group, respectively. The local recurrence rates between the two groups were not significantly different (P = 0.277). CONCLUSIONS: This first multicenter analysis showed similar outcomes were found regarding OS and RFS between the two groups in T1aM3-T1b stage patients. ER + AT may be considered in high-risk patients or for those who refuse esophagectomy.
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Neoplasias Esofágicas , Esofagectomía , Neoplasias Esofágicas/cirugía , Humanos , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Esophagectomy is recommended after endoscopic resection (ER) for early esophageal squamous cell carcinoma (ESCC) when histopathological factors indicate a risk of nodal metastasis and incomplete resection. We aimed to analyze the outcomes of surgery management in this clinical setting and evaluate risk factors for residual disease after ER. PATIENTS AND METHODS: We conducted a retrospective review of cT1N0M0 ESCC patients with noncurative ER and additional esophagectomy (2009-2019, eight centers). Noncurative ER was defined as positive resected margins on pathology, lymphovascular invasion (LVI), poor differentiation, or submucosal invasion. The pathology after ER and esophagectomy was analyzed to identify predictors of nodal metastasis and residual tumor. RESULTS: The study enrolled 128 patients. Primary residual tumor and nodal metastasis were confirmed in 25 (19.5%) and 15 (11.7%) patients, respectively. On multivariate analysis, nodal metastasis was independently associated with submucosal invasion [odds ratio (OR), 9.9; 95% CI, 1.1-96.1], LVI (OR, 20.9; 95% CI, 2.9-150.5), and tumor size ≥ 2 cm (OR, 8.1; 95% CI, 1.4-48.2) (all P < 0.05), but not with poor differentiation (P = 0.613). Regarding residual primary tumor, only positive vertical margin was significant factor (OR, 147; 95% CI, 18 to > 999; P < 0.001). CONCLUSIONS: Additional esophagectomy after noncurative ER allowed the resection of residual tumor and nodal metastasis, with favorable outcomes. Close follow-up may be feasible for a positive horizontal margin alone or poor differentiation alone, whereas intensive treatment should be considered for patients with submucosal invasion, LVI, and a positive vertical margin, especially when combined with tumor size ≥ 2 cm. Prospective research is needed to confirm the optimal management after ER.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Neoplasias de Cabeza y Cuello , Neoplasias Esofágicas/cirugía , Carcinoma de Células Escamosas de Esófago/cirugía , Esofagectomía , Humanos , Estudios Prospectivos , Estudios RetrospectivosRESUMEN
BACKGROUND: Neoadjuvant therapy followed by surgery is recommended for locally advanced esophageal cancer. With the inaccuracies of clinical staging particularly for cT1N+ and cT2Nany tumors, some have proposed consideration of surgery followed by adjuvant treatment. Our objective is to evaluate the efficacy of neoadjuvant therapy vs surgery followed by adjuvant therapy, and to identify the ideal sequence of treatment in patients with cT1N+ and cT2Nany tumors. METHODS: We performed an analysis utilizing the National Cancer Database (2006-2015) identifying all patients with cT1N+ and cT2Nany esophageal cancer undergoing esophagectomy. The treatment was stratified as: neoadjuvant therapy (NT), adjuvant therapy (AT) and combination therapy of neoadjuvant and adjuvant (CT) groups and outcomes were analyzed. RESULTS: We identified 2795 patients with 81.9% (n=2289) receiving NT, 10.2% (n=285) AT, and 7.9% (n=221) CT. There were no significant differences noted in survival among AT, NT, and CT group in cT1N+(P=0.376), cT2N-(P=0.436), cT2N+(P=0.261) esophageal cancer by multivariate analysis using Cox regression model. This relationship held true in both squamous cell carcinoma and adenocarcinoma. CONCLUSION: In clinical T1N+, T2Nany patients, there was no evident superiority of NT over AT. Surgery followed by adjuvant therapy can be considered to be an alternative option in these patients. Further prospective studies are needed to validate these findings.
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Adenocarcinoma/terapia , Carcinoma de Células Escamosas/terapia , Neoplasias Esofágicas/terapia , Esofagectomía , Terapia Neoadyuvante/métodos , Adenocarcinoma/patología , Anciano , Carcinoma de Células Escamosas/patología , Quimioterapia Adyuvante , Neoplasias Esofágicas/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Gastric cancer (GC) is one of the most common and lethal malignancies worldwide, and its poor prognosis is mainly due to the rapid tumor progression including tumor invasion, distant metastasis, etc. Understanding the molecular mechanisms regulating GC progression lays the basis for the development of targeted therapeutic agents. Increasing evidence suggests that guanine nucleotide-binding protein subunit beta-4 (GNB4), a key subunit of heterotrimeric G protein, plays a crucial role in the initiation and progression of multiple malignancies. However, whether and how GNB4 promotes GC progression are still unknown. In this study, we found that GNB4 was highly expressed in GC tissues compared to that in non-tumor tissues and was significantly associated with tumor invasion depth, pathological stage and poor survival rate of GC patients. Both gain-of-function and loss-of-function studies revealed that GNB4 significantly enhanced GC cell growth and motility both in vitro and in vivo. Further studies revealed that GNB4 overexpression induced G1-S transition and promoted the process of epithelial-mesenchymal transformation. These tumor promoting effects were mediated by GNB4 which activates the Erk1/2 pathway through upregulating Erk1/2 phosphorylation, as U0126, an Erk1/2 phosphorylation inhibitor, could significantly inhibit GNB4-mediated cell proliferation, migration and invasion. In summary, GNB4 contributes to the proliferation and metastasis of GC cells by activating the Erk1/2 signaling pathway, and it may serve as a potential therapeutic target of GC.
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Movimiento Celular , Fase G1 , Subunidades beta de la Proteína de Unión al GTP/metabolismo , Sistema de Señalización de MAP Quinasas , Proteínas de Neoplasias/metabolismo , Fase S , Neoplasias Gástricas/metabolismo , Animales , Línea Celular Tumoral , Femenino , Subunidades beta de la Proteína de Unión al GTP/genética , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Proteína Quinasa 1 Activada por Mitógenos/genética , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/genética , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Invasividad Neoplásica , Proteínas de Neoplasias/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologíaRESUMEN
Background: Meckel's diverticulum (MD) is the most common congenital defect of the gastrointestinal tract, occurring in about 1% to 2% of population. Most MD are rarely symptomatic, with presenting symptoms including diverticulitis, digestive tract hemorrhage and intestinal obstruction. The semblance of symptoms to enteritis and appendicitis makes preoperative diagnosis challenging. Current diagnosis of MD includes technetium-99m pertechnate scan, laparoscopic or intraoperative findings and examining surgical specimens. Here, we report that a double-balloon enteroscopy (DBE) improves the diagnosis accuracy of MD and presents high clinical application value. Case Description: A 12-year-old male patient was admitted to our hospital due to recurrent abdominal pain and black stools for more than half a year, recurrence for 2 days, accompanied by vomiting. The boy had anemic appearance, with periumbilical tenderness, and no mass was detected upon palpations. Past medical records revealed recurrent abdominal pain episodes thrice. Pre-surgery 99TcmO4-single-photon emission computed tomography/computed tomography (SPECT/CT) imaging was performed but did not reach the condition for diagnosis of MD. DBE was then performed and identified an upper ileum mass. After surgery, it was confirmed that the patient was an inverted MD, and the pathology showed gastric mucosa and pancreatic tissue. The patient recovered well after surgery and was discharged. Conclusions: DBE is not widely used in the diagnosis of MD, but its accuracy is higher than that of radionuclide scanning imaging. In addition, several advantages such as hemostasis treatment, direct detection and observation of the diverticulum, and demarcation of the site and scope of the lesion prior to surgery brings high clinical application value.
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PURPOSE: The incidence of multiple primary malignancies (MPM) involving lung cancer has increased in recent decades. There is an urgent need to clarify the genetic profile of such patients and explore more efficacious therapy for them. EXPERIMENTAL DESIGN: Peripheral blood samples from MPM involving patients with lung cancer were assessed by whole-exome sequencing (WES), and the identified variants were referenced for pathogenicity using the public available database. Pathway enrichment analysis of mutated genes was performed to identify the most relevant pathway. Next, the effects of mutations in relevant pathway on function and response to targeted drugs were verified by in vitro and in vivo experiments. RESULTS: Germline exomes of 71 patients diagnosed with MPM involving lung cancer were sequenced. Pathway enrichment analysis shows that the homologous recombination repair (HRR) pathway has the strongest correlation. Moreover, HRR genes, especially key Holliday junction resolvases (HJR) genes (GEN1, BLM, SXL4, and RMI1), were most frequently mutated, unlike the status in the samples from patients with lung cancer only. Next, we identified a total of seven mutations in HJR genes led to homologous recombination DNA repair deficiency and rendered lung cancer cells sensitive to PARP inhibitor treatment, both in vitro and in vivo. CONCLUSIONS: This is the first study to map the profile of germline mutations in patients with MPM involving lung cancer. This study may shed light on early prevention and novel targeted therapies for MPM involving patients with lung cancer with HJR mutations.
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Antineoplásicos , Neoplasias Pulmonares , Neoplasias Primarias Múltiples , Humanos , Resolvasas de Unión Holliday/metabolismo , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Mutación de Línea Germinal , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Antineoplásicos/uso terapéuticoRESUMEN
Background: Traditional thoracotomy, an invasive surgical procedure, has been the standard approach for extended lobectomy in treating non-small cell lung cancer (NSCLC). However, minimally invasive surgery (MIS) has gained traction with advancements in surgical techniques. Despite this, the outcomes of extended lobectomy via a minimally invasive approach remain largely uncharted. Using the comprehensive National Cancer Database (NCDB), our research aimed to clarify the safety, feasibility, and efficacy of minimally invasive extended lobectomy in patients diagnosed with NSCLC. Methods: Our study encompassed a selection of patients with NSCLC who underwent extended lobectomy (defined as lobectomy or bilobectomy with chest wall, diaphragm or pericardial resection) between 2010 and 2014. Through propensity score matching (PSM), we ensured a balanced comparison between patients who underwent MIS and those who opted for the traditional open extended lobectomy. Both univariate and multivariate analyses were employed to discern whether the surgical approach had any significant impact on the prognosis of patients undergoing this specific procedure. Results: Before PSM, our dataset included 3,934 patients. After 1:2 PSM, the MIS group included 683 cases, while the open group included 1,317 cases. One notable finding was the reduced average postoperative hospital stay for the MIS group at 7.15 days compared to the open group at 8.40 days (P<0.001). Furthermore, the 5-year survival rate was similar, with the MIS group at 53.1% and the open group at 51.3% (P=0.683). Conclusions: The results of our study suggest that MIS for extended lobectomy not only is safe and feasible but also is oncologically effective. However, it is imperative to note that these encouraging findings necessitate further validation through prospective studies to ascertain the full scope of benefits and potential risks associated with MIS.
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OBJECTIVE: This study aimed to develop and validate robust predictive models for patients with oesophageal cancer who achieved a pathological complete response (pCR) and those who did not (non-pCR) after neoadjuvant therapy and oesophagectomy. DESIGN: Clinicopathological data of 6517 primary oesophageal cancer patients who underwent neoadjuvant therapy and oesophagectomy were obtained from the National Cancer Database for the training cohort. An independent cohort of 444 Chinese patients served as the validation set. Two distinct multivariable Cox models of overall survival (OS) were constructed for pCR and non-pCR patients, respectively, and were presented using web-based dynamic nomograms (graphical representation of predicted OS based on the clinical characteristics that a patient could input into the website). The calibration plot, concordance index and decision curve analysis were employed to assess calibration, discrimination and clinical usefulness of the predictive models. RESULTS: In total, 13 and 15 variables were used to predict OS for pCR and non-pCR patients undergoing neoadjuvant therapy followed by oesophagectomy, respectively. Key predictors included demographic characteristics, pretreatment clinical stage, surgical approach, pathological information and postoperative treatments. The predictive models for pCR and non-pCR patients demonstrated good calibration and clinical utility, with acceptable discrimination that surpassed that of the current tumour, node, metastases staging system. CONCLUSIONS: The web-based dynamic nomograms for pCR (https://predict-survival.shinyapps.io/pCR-eso/) and non-pCR patients (https://predict-survival.shinyapps.io/non-pCR-eso/) developed in this study can facilitate the calculation of OS probability for individual patients undergoing neoadjuvant therapy and radical oesophagectomy, aiding clinicians and patients in making personalised treatment decisions.
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Neoplasias Esofágicas , Nomogramas , Humanos , Terapia Neoadyuvante , Esofagectomía , Modelos de Riesgos ProporcionalesRESUMEN
BACKGROUND: Helicobacter pylori (H pylori) infection is the primary cause of gastric cancer (GC). The role of Disabled-2 (DAB2) in GC remains largely unclear. This study aimed to investigate the role of DAB2 in H pylori-mediated gastric tumorigenesis. METHODS: We screened various datasets of GC to analyze DAB2 expression and cell signaling pathways. DAB2 expression was assessed in human GC tissue microarrays. H pylori infection in vivo and in vitro models were further explored. Immunostaining, immunofluorescence, chromatin immunoprecipitation, co-immunoprecipitation, Western blot, quantitative polymerase chain reaction, and luciferase reporter assays were performed in the current study. RESULTS: The bioinformatic analysis verified that DAB2 was 1 of the 8 genes contributed to tumorigenesis and associated with poor prognosis in GC. The median overall survival and disease-free survival rates in DAB2high group were significantly less than those in DAB2low group. These findings demonstrated that H pylori transcriptionally activated DAB2 expression via signal transducer and activator of transcription 3 (STAT3)-dependent pathway. By bioinformatics analysis and knockdown or overexpression of DAB2, we found that DAB2 upregulated Yes-associated protein 1 (YAP1) transcriptional activity. Mechanistically, DAB2 served as a scaffold protein for integrin beta 3 (ITGB3) and SRC proto-oncogene non-receptor tyrosine kinase (SRC), facilitated the phosphorylation of SRC, promoted the small GTPase ras homolog family member A (RHOA) activation and phosphorylation of YAP1, and ultimately enhanced the YAP1 transcriptional activity. CONCLUSIONS: Altogether, these findings indicated that DAB2 is a key mediator in STAT3-regulated translation of YAP1 and plays crucial roles in H pylori-mediated GC development. DAB2 might serve as a novel therapeutic target for GC.
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Background: Postoperative complications tend to result in prolonged hospitalization. The aim of this study was to investigate whether prolonged postoperative length of stay (LOS) can predict patient survival, particularly long-term survival. Methods: All patients undergoing lung cancer surgery between 2004 and 2015 were identified in the National Cancer Database (NCDB). The highest quintile of LOS (more than 8 days) was defined as prolonged length of stay (PLOS). We performed 1:1 propensity score matching (PSM) between the groups with and without PLOS (Non-PLOS). Excluding confounding factors, postoperative LOS was used as a surrogate for postoperative complications. Kaplan-Meier and Cox proportional hazards survival analyses were performed to analyze survival. Results: A total of 88,007 patients were identified. After matching, 18,585 patients were enrolled in the PLOS and Non-PLOS groups, respectively. Before and after matching, 30-day rehospitalization rate and 90-day mortality in the PLOS group were significantly higher than they were in the Non-PLOS group (P<0.001), indicating a potential worse short-term postoperative survival. After matching, the median survival of the PLOS group was significantly lower than that of the Non-PLOS group (53.2 vs. 63.5 months, P<0.0001). Multivariable analysis revealed that PLOS is independent negative predictor of overall survival [OS; hazard ratio (HR) =1.263, 95% confidence interval (CI): 1.227 to 1.301, P<0.001]. In addition, age (<70 or ≥70), gender, race, income, year of diagnosis, surgery type, pathological stage, and neoadjuvant therapy also were independent prognostic factors of postoperative survival for patients with lung cancer (all P<0.001). Conclusions: Postoperative LOS could be taken as the quantitative indicator of postoperative complications of lung cancer in NCDB. In this study, PLOS predicted worse short-term and long-term survival independent of other factors. Avoiding PLOS could be considered to benefit patient survival after lung cancer surgery.
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OBJECTIVES: Oesophagectomy was always recommended after noncurative endoscopic resection (ER). And the optimal time interval from ER to oesophagectomy remains unclear. This study was to explore the effect of interval on pathologic stage and prognosis. METHODS: We included 155 patients who underwent ER for cT1N0M0 oesophageal cancer and then received subsequent oesophagectomy from 2009 to 2019. Overall survival and disease-free survival (DFS) were analysed to find an optimal cut-off of interval from ER to oesophagectomy. In addition, pathologic stage after ER was compared to that of oesophagectomy. Logistic regression model was built to identify risk factors for pathological upstage. RESULTS: The greatest difference of DFS was found in the groups who underwent oesophagectomy before and after 30 days (P = 0.016). Among total 155 patients, 106 (68.39%) received oesophagectomy within 30 days, while 49 (31.61%) had interval over 30 days. Comparing the pathologic stage between ER and oesophagectomy, 26 patients had upstage and thus had worse DFS (hazard ratio = 3.780, P = 0.042). T1b invasion, lymphovascular invasion and interval >30-day group had a higher upstage rate (P = 0.014, P < 0.001 and P < 0.001, respectively). And they were independent risk factors for pathologic upstage (odds ratio = 3.782, 4.522 and 2.844, respectively). CONCLUSIONS: It was the first study exploring the relationship between time interval and prognosis in oesophageal cancer. The longer interval between noncurative ER and additional oesophagectomy was associated with a worse DFS, so oesophagectomy was recommended performed within 1 month after ER. Older age, T1b stage, lymphovascular invasion and interval >30 days were significantly associated with pathologic upstage, which is related to the worse outcome too.
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Adenocarcinoma , Carcinoma de Células Escamosas , Neoplasias Esofágicas , Humanos , Esofagectomía/efectos adversos , Carcinoma de Células Escamosas/patología , Pronóstico , Adenocarcinoma/patología , Estudios RetrospectivosRESUMEN
BACKGROUND: Ovarian metastasis following radical gastrectomy, also known as metachronous ovarian metastasis (MOM), pose a significant threat to the long-term survival of female gastric cancer (GC) patients. However, a mechanism to identify and characterize operated patients at high risk of developing MOM remains unknown. This retrospective study aimed to identify risk factors for the occurrence of MOM based on the profiling of clinicopathological parameters and expression of sex hormone receptors (SHR) of operated GC patients with and without ovarian relapse. METHODS: The clinicopathological data of 1,055 female GC patients from two medical centers who underwent surgery between January 2011 and December 2015 were reviewed. A total of 378 patients with and without the occurrence of MOM met the eligibility criteria, including the availability of medical records, adequacy of lymph node dissection, completeness of clinicopathological data, sufficient follow-up time, and no administration of neoadjuvant chemotherapy were selected for further analysis. Expressions of estrogen receptor alpha (ERα), estrogen receptor beta (ERß), and progesterone receptor (PR) were detected by immunohistochemical staining on the surgical specimens of patients, and retrospective statistical analyses identified independent risk factors for the occurrence of MOM. A risk prediction model in the format of a polygenic hazard score (PHS) for the occurrence of MOM was established by introducing and modifying the previously validated polygenic risk score (PRS)/PHS. RESULTS: A Cox regression-based multivariate analysis identified premenopausal with an HR of 3.15 (95% CI, 1.66-5.98), more advanced pathological T stage with an HR of 3.79 (95% CI, 2.14-6.69), more advanced pathological N stage with an HR of 1.85 (95% CI, 1.35-2.54), and negative expression of ERß with an HR of 0.33 (95% CI, 0.15-0.7) as independent risk factors for the occurrence of MOM (P<0.01). Accordingly, a PHS for the occurrence of MOM was established, with 1-, 2-, and 3-year ovarian relapse rates for the high-risk group estimated at 17.8%, 33.7%, and 46.2%, respectively. CONCLUSIONS: Premenopausal status, depth of tumor invasion, number of positive lymph nodes, and negative expression of ERß were independent factors for the occurrence of MOM. More frequent follow-up examinations are recommended to provide timely diagnosis and medical intervention.
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BACKGROUND: PARP inhibitors (PARPi) benefit only a fraction of breast cancer patients with BRCA mutations, and their efficacy is even more limited in triple-negative breast cancer (TNBC) due to clinical primary and acquired resistance. Here, we found that the efficacy of the PARPi olaparib in TNBC can be improved by combination with the CDK4/6 inhibitor (CDK4/6i) palbociclib. METHODS: We screened primary olaparib-sensitive and olaparib-resistant cell lines from existing BRCAmut/TNBC cell lines and generated cells with acquired olaparib resistance by gradually increasing the concentration. The effects of the PARPi olaparib and the CDK4/6i palbociclib on BRCAmut/TNBC cell lines were examined in both sensitive and resistant cells in vitro and in vivo. Pathway and gene alterations were assessed mechanistically and pharmacologically. RESULTS: We demonstrated for the first time that the combination of olaparib and palbociclib has synergistic effects against BRCAmut/TNBC both in vitro and in vivo. In olaparib-sensitive MDA-MB-436 cells, the single agent olaparib significantly inhibited cell viability and affected cell growth due to severe DNA damage. In olaparib-resistant HCC1937 and SUM149 cells, single-agent olaparib was ineffective due to potential homologous recombination (HR) repair, and the combination of olaparib and palbociclib greatly inhibited HR during the G2 phase, increased DNA damage and inhibited tumour growth. Inadequate DNA damage caused by olaparib activated the Wnt signalling pathway and upregulated MYC. Further experiments indicated that the overexpression of ß-catenin, especially its hyperphosphorylation at the Ser675 site, activated the Wnt signalling pathway and mediated olaparib resistance, which could be strongly inhibited by combined treatment with palbociclib. CONCLUSIONS: Our data provide a rationale for clinical evaluation of the therapeutic synergy of the PARPi olaparib and CDK4/6i palbociclib in BRCAmut/TNBCs with high Wnt signalling activation and high MYC expression that do not respond to PARPi monotherapy.
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Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Femenino , Humanos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Transducción de SeñalRESUMEN
OBJECTIVE: The aim of this study was to construct the immunoscore (IS) to facilitate the prediction of postoperative survival and benefit from adjuvant chemotherapy (ACT) in esophageal squamous cell carcinoma (ESCC). METHODS: A total of 249 patients who received radical esophagectomy at Fudan University Shanghai Cancer Center were divided into training set and testing set. Eighty-nine patients with ESCC from TCGA database were enrolled into the validation set. Myeloid cells in tumor microenvironment were evaluated by immunohistochemistry or CIBERSORT, and then were included into a LASSO Cox regression model to construct the immunoscore. The predictive value of the immunoscore for prognosis after surgery or ACT was analyzed. RESULTS: The immunoscore was constructed by four types of myeloid cells including macrophages, neutrophils, mast cells, and dendritic cells and was demonstrated as IS=2^(0.527719*Mφ -0.2604269*MC-0.4812935*DC-0.4519706*Neu). The overall survival was significantly different between two immunotypes, which were divided according to the immunoscore, in all sets (P<0.001, P=0.005, and P=0.002, respectively). Immunotype A was identified as an independent predictor for survival benefit in all three sets (HR=2.068, P=0.005; HR=2.028, P=0.007; HR=6.474, P=0.007; respectively). In patients who received ACT, immunotype A was significantly related to longer overall survival both in the training set (P<0.001) and in the testing set (P=0.011). The nomogram based on immunotype and other clinicopathological factors showed good efficiency of predicting response to ACT. Finally, several important cytokines and pathways were highly enriched in immunoscore A subgroup. CONCLUSION: The immunoscore was an effective prognostic predictor in ESCC for patients undergoing surgical resection and receiving ACT.
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As a cell proliferation biomarker, Ki-67 is principally used in ER+/HER2- breast cancer. However, the importance and the best cutoff point of Ki-67 in triple-negative breast cancer (TNBC) remains unclear and was evaluated in this study.A total of 1800 patients with early invasive TNBC between 2011 and 2016 at Fudan University Shanghai Cancer Center were consecutively recruited for this study. The optimal cutoff for Ki-67 was assessed by Cutoff Finder. Propensity score matching (PSM, ratio = 1:2) was performed to match the Ki-67low group with the Ki-67high group. Overall survival (OS) and disease-free survival (DFS) were compared between the two groups using the Kaplan-Meier method and Cox regression model. The most relevant cutoff value for Ki-67 for prognosis was 30% (p = 0.008). At the cutoff point of 30%, worse DFS and OS were observed in the Ki-67high group. In multivariate analyses, N-stage (p < 0.001), T-stage (p = 0.038), and Ki-67 at the 30% threshold (p = 0.020) were independently linked to OS. In subgroup analysis, Ki-67 cutoff at 30% had prognostic and predictive potential for DFS with either tumor size ≤2 cm (p = 0.008) or lymph node-negative (N-) (p = 0.038) and especially with T1N0M0 (stage I) TNBCs. For 945 N- TNBC patients, adjuvant chemotherapy (CT) was associated with better OS in the Ki-67high group (p = 0.017) than in the Ki-67low group (p = 0.875). For stage I/Ki-67low patients, adjuvant CT did not affect DFS (p = 0.248). Thus, Ki-67 cutoff at 30% had early independent prognostic and predictive potential for OS and DFS in TNBCs, and Ki-67 > 30% was significantly associated with worse prognosis, especially for stage I patients. For stage I/Ki-67low TNBC patients, the advantage of CT is unclear, providing the basis for future de-escalation therapy.
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Biomarcadores de Tumor/metabolismo , Quimioterapia Adyuvante/mortalidad , Antígeno Ki-67/metabolismo , Neoplasias de la Mama Triple Negativas/patología , Adolescente , Adulto , Anciano , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Pronóstico , Tasa de Supervivencia , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/metabolismo , Adulto JovenRESUMEN
PURPOSE: Early detection and control of lung cancer brain metastases (BMs) are important. However, several guideline recommendations are inconsistent with regard to routine preoperative brain MRI, especially in patients with clinical stage IA lung cancer. Our study evaluated the value of preoperative brain MRI in patients with clinical stage IA lung cancer. METHODS: A retrospective analysis of patients with lung cancer was performed using a prospectively collected database. Clinical data and the results of brain MRI were collected and analyzed. RESULTS: Patients with pathologically proved primary lung cancer who underwent an MRI at initial diagnosis were identified (3392 patients). In total, 170 patients (5.0%) were diagnosed with BMs. The increased frequency of BMs was significantly associated with advanced clinical stage (P = 0.000) and pathological type (P = 0.011). BMs were detected in 11 out of 1595 patients with clinical stage IA lung cancer (0.7%). BMs were more common in patients with clinical stage cT1c lung cancer (1.9%) than those with clinical stage cT1a or cT1b (0.1%, odds ratio = 21.30, 95% confidence interval: 2.7-166.9, P = 0.000). All patients with stage IA lung cancer and BMs had solid lung lesions (P = 0.002). CONCLUSIONS: Preoperative brain MRI might help identify BMs in patients with lung cancer that has progressed beyond stage IA. In patients with clinical stage IA lung cancer, we do not recommend preoperative brain MRI, but it may potentially be beneficial in those with solid T1c cancers.
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Adenocarcinoma/patología , Neoplasias Encefálicas/epidemiología , Neoplasias Encefálicas/secundario , Carcinoma de Células Escamosas/patología , Neoplasias Pulmonares/patología , Imagen por Resonancia Magnética/métodos , Cuidados Preoperatorios , Adenocarcinoma/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Escamosas/cirugía , China/epidemiología , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Neoplasias Pulmonares/cirugía , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Estudios Prospectivos , Estudios Retrospectivos , Adulto JovenRESUMEN
BACKGROUND: It is important to identify patients with esophageal squamous cell carcinoma (ESCC) in T1b stage that are the least likely to metastasize on the lymph nodes, to undergo endoscopic resection, especially for the patients unfit for esophagectomy. The relationship between endoscopic morphology and frequency of nodal metastasis has never been well studied. The aims of the study were to investigate the predictive value of endoscopic morphology for lymphatic metastasis, and to develop a risk stratification model in submucosal (T1b) ESCC. METHODS: Pathologic variables of patients with T1b ESCC who underwent esophagectomy from 2006 through 2016 were collected and divided into training sets (patients between 2006 and 2011) and validation sets (patients between 2012 and 2016). The endoscopic morphology of the tumor was determined by analyzing endoscopic reports according to the Paris classification. The correlation between the clinicopathological factors and nodal metastasis was examined. A prediction model was developed to estimate the risk of metastasis using these predictors. RESULTS: A total of 175 patients were included in this study. A tumor with an endoscopic shape of flat type (0-II type as Paris classification was defined) was significantly related to lower risk of lymphatic metastasis with the frequency of 15.5% (OR: 3.049, 95% CI: 1.363-6.819, P=0.005). The combination of endoscopic morphology with other pathologic characteristics including lymphovascular invasion, length of tumor, depth of tumor invasion into submucosa, and tumor differentiation improved the predictive value of the nodal metastasis. The risk stratification model was developed with a C-index of 0.726 (95% CI: 0.702-0.751), which identified a low risk subgroup with a lymph node rate of 7.2%. CONCLUSIONS: Our results suggest that when a tumor is in flat shape (0-II type) it is related to a less lymphatic metastasis, and the combination of the endoscopic morphology with the other four pathologic variables can yield a more robust approach to predict the risk of lymphatic metastasis in submucosal ESCC.