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Pancreatic adenocarcinoma characterized by a mere 10% 5-year survival rate, poses a formidable challenge due to its specific anatomical location, making tumor tissue acquisition difficult. This limitation underscores the critical need for novel biomarkers to stratify this patient population. Accordingly, this study aimed to construct a prognosis prediction model centered on S100 family members. Leveraging six S100 genes and their corresponding coefficients, an S100 score was calculated to predict survival outcomes. The present study provided comprehensive internal and external validation along with power evaluation results, substantiating the efficacy of the proposed model. Additionally, the study explored the S100-driven potential mechanisms underlying malignant progression. By comparing immune cell infiltration proportions in distinct patient groups with varying prognoses, the research identified differences driven by S100 expression. Furthermore, the analysis explored significant ligand-receptor pairs between malignant cells and immune cells influenced by S100 genes, uncovering crucial insights. Notably, the study identified a novel biomarker capable of predicting the sensitivity of neoadjuvant chemotherapy, offering promising avenues for further research and clinical application.
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Adenocarcinoma , Biomarcadores de Tumor , Neoplasias Pancreáticas , Proteínas S100 , Microambiente Tumoral , Humanos , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/genética , Microambiente Tumoral/inmunología , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/inmunología , Pronóstico , Adenocarcinoma/inmunología , Adenocarcinoma/patología , Adenocarcinoma/mortalidad , Adenocarcinoma/genética , Masculino , Femenino , Persona de Mediana Edad , AncianoRESUMEN
In recent years, the incidence of cancers is continuously increasing in young adults. Early-onset cancer (EOC) is usually defined as patients with cancers under the age of 50, and may represent a unique subgroup due to its special disease features. Overall, EOCs often initiate at a young age, present as a better physical performance but high degree of malignancy. EOCs also share common epidemiological and hereditary risk factors. In this review, we discuss several representative EOCs which were well studied previously. By revealing their clinical and molecular similarities and differences, we consider the group of EOCs as a unique subtype compared to ordinary cancers. In consideration of EOC as a rising threat to human health, more researches on molecular mechanisms, and large-scale, prospective clinical trials should be carried out to further translate into improved outcomes.
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Neoplasias , Adulto Joven , Humanos , Estudios Prospectivos , Neoplasias/diagnóstico , Neoplasias/epidemiología , Neoplasias/terapia , Factores de RiesgoRESUMEN
MLN4924 inhibits the proteolytic degradation of Cullin-Ring E3 ligase (CRL) substrates and exhibits antitumor activity toward various malignancies, including pancreatic cancer. MLN4924 suppresses tumor growth by altering various key regulator proteins; however, its impact on gene expression in tumors remains unknown. In this study, the genomic changes caused by MLN4924 in pancreatic cancer were examined by gene chip analysis and ingenuity pathway analysis. Eleven pathways were significantly altered (5 activated and 6 inhibited), 45 functions were significantly changed (21 activated and 24 inhibited), and the most activated upstream factor was predicted to be TNF. Of 691 differentially expressed genes, NAPEPLD knockdown showed synergism with MLN4924, as determined by real-time quantitative PCR and high content screening. NAPEPLD knockdown enhanced the effect of MLN4924 on inhibiting proliferation and inducing apoptosis in vitro. In a pancreatic cancer nude mouse model, MLN4924 inhibited tumor growth more significantly in the NAPEPLD knockdown group than in the control group. NAPEPLD expression was higher in pancreatic cancer tissues than in the normal pancreas but was not associated with prognosis. These findings indicate that MLN4924 causes extensive genomic changes in pancreatic cancer cells, and targeting NAPEPLD may increase the efficacy of MLN4924.
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Neoplasias Pancreáticas , Pirimidinas , Animales , Apoptosis/genética , Línea Celular Tumoral , Ciclopentanos , Perfilación de la Expresión Génica , Ratones , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Pirimidinas/farmacología , Neoplasias PancreáticasRESUMEN
Circular RNAs (circRNAs), the new stars of endogenous non-coding RNAs, are dysregulated in various tumors including pancreatic cancer. Here, we aimed to investigate the biological functions of hsa_circ_0071036 in the tumourigenesis and progression of pancreatic ductal adenocarcinoma (PDAC) and its clinical implications. The differential expression profile of circRNAs in 4 pairs of PDAC tissues was analyzed by microarray assay. Quantitative real-time PCR and fluorescence in situ hybridization (FISH) were utilized to determine the expression patterns and their clinical significance. Functional experiments in vitro and in vivo were performed to explore whether hsa_circ_0071036 functions as an oncogenic circRNA in PDAC. Mechanistically, RT-qPCR, dual luciferase reporter and RNA pull-down assays were conducted to identify the interaction between hsa_circ_0071036 and miR-489 in PDAC. Hsa_circ_0071036 was remarkably overexpressed in PDAC cell lines and tissue samples, which negatively correlated with miR-489 expression. Aberrant expression of hsa_circ_0071036 correlated with poor clinicopathological characteristics and prognoses of PDAC patients. Knockdown of hsa_circ_0071036 suppressed proliferation and invasion and induced apoptosis in vitro. Moreover, the in vivo xenograft model confirmed that silencing of hsa_circ_0071036 attenuated tumor growth. Mechanistic analyses indicated that hsa_circ_0071036 acted as an efficient miRNA sponge for miR-489 in PDAC. In summary, our study revealed that upregulated hsa_circ_0071036 promotes PDAC pathogenesis and progression by directly sponging miR-489, which implies an important role for this circRNA-miRNA functional network.
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Carcinogénesis/metabolismo , MicroARNs/biosíntesis , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/metabolismo , ARN Circular/biosíntesis , Regulación hacia Arriba/fisiología , Anciano , Animales , Carcinogénesis/genética , Carcinogénesis/patología , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , MicroARNs/genética , Persona de Mediana Edad , Neoplasias Pancreáticas/genética , Valor Predictivo de las Pruebas , Pronóstico , ARN Circular/genética , Tasa de Supervivencia/tendencias , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
Pancreatic cancer is a highly malignant tumour of the digestive tract which is difficult to diagnose and treat. Approximately 90% of cases arise from ductal adenocarcinoma of the glandular epithelium. The morbidity and mortality of the disease have increased significantly in recent years. Its 5-year survival rate is <1% and has one of the worst prognoses amongst malignant tumours. Pancreatic cancer has a low rate of early-stage diagnosis, high surgical mortality and low cure rate. Selenium compounds produced by selenoamino acid metabolism may promote a large amount of oxidative stress and subsequent unfolded reactions and endoplasmic reticulum stress by consuming the NADPH in cells, and eventually lead to apoptosis, necrosis or necrotic cell death. In this study, we first identified DIAPH3 as a highly expressed protein in the tissues of patients with pancreatic cancer, and confirmed that DIAPH3 promoted the proliferation, anchorage-independent growth and invasion of pancreatic cancer cells using overexpression and interference experiments. Secondly, bioinformatics data mining showed that the potential proteins interacted with DIAPH3 were involved in selenoamino acid metabolism regulation. Selenium may be incorporated into selenoprotein synthesis such as TrxR1 and GPX4, which direct reduction of hydroperoxides or resist ferroptosis, respectively. Our following validation confirmed that DIAPH3 promoted selenium content and interacted with the selenoprotein RPL6, a ribosome protein subunit involved in selenoamino acid metabolism. In addition, we verified that DIAPH3 could down-regulate cellular ROS level via up-regulating TrxR1 expression. Finally, nude mice xenograft model experimental results demonstrate DIAPH3 knock down could decrease tumour growth and TrxR1 expression and ROS levels in vivo. Collectively, our observations indicate DIAPH3 could promote pancreatic cancer progression by activating selenoprotein TrxR1-mediated antioxidant effects.
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Antioxidantes/metabolismo , Forminas/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Selenoproteínas/metabolismo , Tiorredoxina Reductasa 1/metabolismo , Aminoácidos , Animales , Biomarcadores de Tumor , Línea Celular Tumoral , Biología Computacional/métodos , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Forminas/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , Ratones , Especies Reactivas de Oxígeno/metabolismoRESUMEN
OBJECTIVE: The genetic aberrations that underlie chromatin remodeling in sporadic nonfunctional pancreatic neuroendocrine tumors (NF-pNETs) remain largely unknown. Here, we investigated the dysregulation of the switch/sucrose nonfermentable (SWI/SNF) component ARID1A and its correlation with clinicopathological features and prognosis. METHODS: We sequenced the exomes of sporadic NF-pNETs. Quantitative real-time polymerase chain reaction and immunohistochemistry were used to determine messenger RNA level and protein expression. RESULTS: The sporadic NF-pNETs harbored 264 somatic mutations in 228 different genes, most commonly affecting the SWI/SNF components ARID1B (57.1%) and ARID1A (42.9%). The expression of ARID1A was remarkably downregulated in NF-pNETs and corresponding liver metastases compared with that in normal pancreatic islet tissue. Reduced expression of ARID1A was associated with malignant clinicopathological features (P < 0.05). The loss of ARID1A was related to a high Ki-67 index (P < 0.05). Patients with ARID1A-negative expression had a significantly worse overall survival rate than those with ARID1A-positive expression (P < 0.05). The ARID1A status was an independent predictor of overall survival, and a nomogram integrating ARID1A with clinicopathological features was proposed. CONCLUSIONS: The loss of SWI/SNF components ARID1A may be associated with malignant behaviors and an unfavorable prognosis. Aberrations of ARID1A may contribute to tumorigenesis and metastasis in sporadic NF-pNETs.
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Proteínas de Unión al ADN/genética , Proteínas de Neoplasias/genética , Tumores Neuroendocrinos/genética , Neoplasias Pancreáticas/genética , Factores de Transcripción/genética , Adulto , China/epidemiología , Ensamble y Desensamble de Cromatina/genética , Análisis Mutacional de ADN , Proteínas de Unión al ADN/biosíntesis , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/secundario , Metástasis Linfática , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/biosíntesis , Tumores Neuroendocrinos/mortalidad , Tumores Neuroendocrinos/secundario , Tumores Neuroendocrinos/cirugía , Nomogramas , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/cirugía , Pronóstico , ARN Mensajero/biosíntesis , ARN Mensajero/genética , ARN Neoplásico/biosíntesis , ARN Neoplásico/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Tasa de Supervivencia , Análisis de Matrices Tisulares , Factores de Transcripción/biosíntesis , Secuenciación del ExomaRESUMEN
The authors would like to correct the following panels in Figures.
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BACKGROUND: Protein arginine methyltransferase 1 (PRMT1) is the founding member of the PRMT family of proteins, whose members catalyze methylation of arginine residues in various proteins. Although several studies have reported upregulation of PRMT1 in various cancer types, the expression pattern and the underlying mechanism of PRMT1 action in pancreatic ductal adenocarcinoma (PDAC) are still unclear. METHODS: Immunohistochemistry staining as well as RT-PCR was used to determine the expression pattern of PRMT1 in clinical PDAC samples. Lentivirus packaging and transfection were employed to construct cell lines with PRMT1 overexpression or knockdown. MTT and crystal violet assays were used to determine the proliferation rates of PDAC cells. ß-catenin transcription activity was measured using a TOPFlash assay. PRMT1 binding to the promoter region of CTNNB1 was determined by ChIP-qPCR assay. RESULTS: Elevated PRMT1 expression was found in PDAC tissue samples compared to noncancerous normal tissues in 41 patients using a real-time PCR assay and in 90 patients using a tissue microarray (TMA) in conjunction with immunohistochemistry. Analysis of the PRMT1 expression data and PDAC clinical features revealed that PRMT1 expression was significantly correlated with PDAC tumor size and prognosis in postoperative patients. Additional functional experiments revealed that PRMT1 expression promoted the growth of pancreatic cancer-derived cells, both in vitro and in vivo. Mechanistically, we found that PRMT1 increased the cellular ß-catenin level. We also found that PRMT1 and ß-catenin were co-expressed in TCGA and GTEx datasets containing 370 samples. CONCLUSIONS: Collectively, our study provides novel insight into the expression and function of PRMT1 in PDAC and indicates that PRMT1 may serve as a therapeutic target for treating patients with pancreatic ductal adenocarcinoma.
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Carcinoma Ductal Pancreático/metabolismo , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica/genética , Neoplasias Pancreáticas/metabolismo , Proteína-Arginina N-Metiltransferasas/metabolismo , Proteínas Represoras/metabolismo , Anciano , Animales , Carcinoma Ductal Pancreático/enzimología , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Inmunoprecipitación de Cromatina , Femenino , Humanos , Inmunohistoquímica , Metástasis Linfática , Masculino , Ratones , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Neoplasias Pancreáticas/enzimología , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Pronóstico , Regiones Promotoras Genéticas , Unión Proteica , Proteína-Arginina N-Metiltransferasas/genética , Proteínas Represoras/genética , Análisis de Matrices Tisulares , beta Catenina/genética , beta Catenina/metabolismoRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) remains a refractory disease. Programmed cell death protein-1 (PD-1) monotherapy has shown strong performance in targeting several malignancies. However, the effect and mechanism of intrinsic PD-1 in pancreatic cancer cells is still unknown. In this study, associations between clinicopathological characteristics and stained tissue microarrays of PDAC specimens were analyzed along with profiling and functional analyses. The results showed that cell-intrinsic PD-1 was significantly correlated with overall survival (OS). Independently of adaptive immunity, intrinsic PD-1 promoted tumor growth in PDAC. Concomitantly, the overexpression of intrinsic PD-1 enhanced cancer proliferation and inhibited cell apoptosis in vitro and in vivo. Mechanistically, PD-1 binds to the downstream MOB1, thereby inhibiting its phosphorylation. Moreover, greater synergistic tumor suppression in vitro resulted from combining Hippo inhibitors with anti-PD-1 treatment compared with the suppression achieved by either single agent alone. Additionally, Hippo downstream targets, CYR61 (CCN1) and CTGF (CCN2), were directly affected by PD-1 mediated Hippo signaling activation in concert with survival outcomes. Finally, the formulated nomogram showed superior predictive accuracy for OS in comparison with the TNM stage alone. Therefore, PD-1 immunotherapy in combination with Hippo pathway inhibitors may optimize the anti-tumor efficacy in PDAC patients via targeting cell-intrinsic PD-1.
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Carcinoma Ductal Pancreático/metabolismo , Proliferación Celular , Factor de Crecimiento del Tejido Conjuntivo/metabolismo , Proteína 61 Rica en Cisteína/metabolismo , Neoplasias Pancreáticas/metabolismo , Receptor de Muerte Celular Programada 1/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Animales , Antineoplásicos Inmunológicos/farmacología , Apoptosis , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/inmunología , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Vía de Señalización Hippo , Humanos , Masculino , Ratones Endogámicos NOD , Ratones SCID , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/patología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Transducción de Señal , Carga Tumoral , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
TNF receptor-associated factor 6 (TRAF6), a regulator of NF-κB signaling, has been reported to be associated with the oncogenesis of various tumors including pancreatic cancer, but the underlying mechanisms remain unknown. Here, we found that knocking down the expression of TRAF6 impaired YAP signaling. Moreover, TRAF6 promoted the migration and colony formation of pancreatic cancer cells through YAP. Then, we found that TRAF6 interacted with and promoted the ubiquitination and degradation of MST1, and the expression of TRAF6 and MST1 was negatively correlated in primary human pancreatic cancer samples. Our results reveal that TRAF6 regulates YAP signaling by promoting the ubiquitination and degradation of MST1 in pancreatic cancer, suggesting that TRAF6 could be a possible E3 ligase of MST1 and a potential therapeutic target.
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Proteínas Adaptadoras Transductoras de Señales/metabolismo , Neoplasias Pancreáticas/patología , Fosfoproteínas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteolisis , Transducción de Señal , Factor 6 Asociado a Receptor de TNF/metabolismo , Ubiquitinación , Humanos , Péptidos y Proteínas de Señalización Intracelular , Factores de Transcripción , Proteínas Señalizadoras YAPRESUMEN
BACKGROUND: The prognosis of pancreatic ductal adenocarcinoma (PDAC) remains poor due to the difficulty of disease diagnosis and therapy. Immunotherapy has had robust performance against several malignancies, including PDAC. In this study, we aim to analyze the expression of CD8 and FoxP3 on T lymphocytes and TGF-ß expression in tumor tissues, and then analyze the possible clinical significance of these finding in order to find a novel effective immunotherapy target in PDAC using a murine model. METHODS: A tissue microarray using patient PDAC samples was stained and analyzed for associations with clinicopathological characteristics. A preclinical murine model administrated with various immunotherapies were analyzed by growth inhibitor, flow cytometry, enzyme-linked immuno sorbent assay and immunohistochemistry. RESULTS: The infiltrating FoxP3+ regulatory T cells (Tregs) in tumor tissues were associated with survival, while CD8+ tumor infiltrating lymphocytes (TILs) were not. Considering the drawbacks of these measure alone, the number of CD8+ and FoxP3+ T cells were combined to create a new estimated value-integrated immune ratio (IIR), which showed excellent validity in survival risk stratification. IIR was further verified as an independent prognostic factor according to multivariate analysis as well as TGF-ß expression. Association between TGF-ß expression and infiltrating Tregs was also verified. Then, in our preclinical murine model, CD25 and TGF-ß combination blockade had a higher tumor growth inhibitor value. This combination therapy significantly depleted periphery and intra-tumor FoxP3+ Tregs while increasing intra-tumor CD8+ TILs levels compared to controls or anti-TGF-ß monotherapy (p < 0.05). Anti-CD25 monotherapy alone also had the ability to deplete periphery and intra-tumor Tregs (p < 0.05). The excretion of intra-tumor IL-10, TGF-ß was notably lower but higher IFN-γ excretion in this combination immunotherapy. Such combination immunotherapy was further confirmed to synergize with anti-PD-1 monotherapy to improve tumor growth inhibition and cure rates. CONCLUSIONS: The combination of CD25, TGF-ß and PD-1 blockade plays a potentially effective role in inhibiting tumor formation and progression. Our results also provide a strong rational strategy for use of IIR in future immunotherapy clinical trials.
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Subunidad alfa del Receptor de Interleucina-2/antagonistas & inhibidores , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/patología , Factor de Crecimiento Transformador beta/antagonistas & inhibidores , Adenocarcinoma/inmunología , Adenocarcinoma/patología , Adenocarcinoma/terapia , Adulto , Anciano , Anciano de 80 o más Años , Animales , Antígeno B7-H1/metabolismo , Linfocitos T CD8-positivos/inmunología , Carcinoma Ductal Pancreático/inmunología , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/terapia , Proliferación Celular , Modelos Animales de Enfermedad , Femenino , Factores de Transcripción Forkhead/metabolismo , Humanos , Inmunoterapia , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Linfocitos Infiltrantes de Tumor/inmunología , Masculino , Ratones Endogámicos C57BL , Persona de Mediana Edad , Análisis Multivariante , Neoplasias Pancreáticas/terapia , Pronóstico , Receptor de Muerte Celular Programada 1/metabolismo , Análisis de Supervivencia , Linfocitos T Reguladores/inmunología , Factor de Crecimiento Transformador beta/metabolismo , Carga TumoralRESUMEN
Optimized pancreaticojejunostomy anastomosis was used to investigate the effects on the incidence rate of postoperative complications in pancreaticoduodenectomy. The data of 250 patients who underwent pancreaticoduodenectomy between August 2011 and December 2015 were analyzed; all surgery was performed by a single team. The first 100 surgeries were performed using traditional pancreaticojejunostomy anastomosis, whereas the next 150 patients underwent novel pancreaticojejunostomy anastomosis (the experimental group). General information, disease status and the occurrence rate of postoperative complications [postoperative pancreatic fistula (POPF), biliary leakage, delayed gastric emptying, bleeding and mortality] within 30 days of surgery were observed. In the first group, 56 patients had POPF (56%), the proportion of grades A, B and C was 44% (n=44), 9% (n=9) and 3% (n=3), respectively; in the experimental group, 30 patients had POPF (20%), the proportion of grades A, B and C was 14.67% (n=22), 5.33% (n=8) and 0%, respectively. Furthermore, in the experimental group, none of the patients exhibited postoperative bleeding or succumbed during surgery. The application of the novel embeddedness-like pancreaticojejunostomy anastomosis technique in pancreaticoduodenectomy was safe and effective, and may reduce the incidence of POPF in future.
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OBJECTIVE: To investigate clinicopathological features and prognostic factors of appendiceal neuroendocrine neoplasms(a-NEN). METHODS: Clinical data of 20 patients diagnosed with a-NEN at Zhongshan Hospital of Fudan University between January 2000 and December 2016 were retrospectively analyzed. Pathological diagnosis was based on the WHO classification criteria of digestive system tumors (2010 edition). Based on the mitotic count and Ki-67 index, a-NENs were divided into grade 1 neuroendocrine tumor (NET G1), grade 2(G2) NET G2) and grade 3 (neuroendocrine carcinoma, NEC). Some special types of a-NEN (e.g. goblet cell carcinoid) and mixed adenoneuroendocrine neoplasms were classified as mixed adenoneuroendocrine carcinoma (MANEC). Follow-up was conducted by telephone or return visits. Univariate analysis was carried out using the Kaplan-Meier method, and the log-rank test was used to draw survival curves. RESULTS: Of 20 patients, 14 were male and 6 were female with median age of 54 years. Seventeen cases presented acute right lower quadrant abdominal pain, 1 chronic right lower quadrant abdominal pain, 1 persistent abdominal discomfort with outburst whole abdominal pain and 1 was found during body check without symptoms. Twenty cases comprised 8 G1 patients, 4 G2 patients, 3 G3 patients, and 5 MANEC patients. When diagnosed, there was 1 patient with liver metastasis, 1 patient with abdominal and pelvic metastases, and 2 patients with postoperative pathological findings of lymph node metastasis. Six patients underwent appendectomy, 12 underwent right hemicolectomy, 1 underwent right hemicolectomy plus small intestine resection, and 1 underwent partial hepatectomy plus right hemicolectomy. The follow-up time was 7-187 months(average, 36 months). The total 1- and 3-year survival rates were 94.7% and 60.2%, respectively. Univariate analysis showed that age >50 years (χ2=7.036, P=0.008), pathology grade as MANEC (χ2=5.297, P=0.021), and metastasis (χ2=6.558, P=0.010) indicated lower 5-year survival rate. CONCLUSIONS: Most a-NEN patients have no typical symptoms, and the main complaint at consultation is acute right lower quadrant abdominal pain. Prognosis is poor for patients with age >50 years, MANEC pathology grade and metastasis.
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Neoplasias del Apéndice , Tumores Neuroendocrinos , Neoplasias del Apéndice/complicaciones , Neoplasias del Apéndice/diagnóstico , Neoplasias del Apéndice/cirugía , Carcinoma Neuroendocrino/complicaciones , Carcinoma Neuroendocrino/diagnóstico , Carcinoma Neuroendocrino/terapia , Femenino , Neoplasias Gastrointestinales , Humanos , Masculino , Persona de Mediana Edad , Tumores Neuroendocrinos/complicaciones , Tumores Neuroendocrinos/diagnóstico , Tumores Neuroendocrinos/cirugía , Pronóstico , Estudios RetrospectivosRESUMEN
MLN4924 inhibits the cullin-RING ligases mediated ubiquitin-proteasome system, and has showed antitumor activities in preclinical studies, but its effects and mechanisms on pancreatic cancer (PC) remains elusive. We found that MLN4924 inhibited the proliferation and clonogenicity of PC cells, caused DNA damage, particularly double-strand breaks, and leaded to Chk1 activation and cell-cycle arrest. Chk1 inhibitor SCH 900776 alone exhibited minimal cytotoxicity, and caused no DNA damage on PC cells. But in the combination therapy, SCH 900776 enhanced the cytotoxicity and DNA damage caused by MLN4924, likely by abrogating G2/M arrest and promoting DNA re-replication. In vivo study on a xenograft PC mouse model also showed that SCH 900776 increased the efficacy of MLN4924. We also evaluated the level of NEDD8-activating enzyme (NAE), the direct target of MLN4924, and found that NAE level was elevated in PC tissues compared with normal pancreas, but was irrelevant with prognosis. Our findings provide the preclinical evidence and the rationale of the combination therapy of MLN4924 with SCH 900776 or other Chk1 inhibitors to treat PC.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/antagonistas & inhibidores , Ciclopentanos/uso terapéutico , Neoplasias Pancreáticas/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Animales , Línea Celular Tumoral , Daño del ADN , Replicación del ADN/efectos de los fármacos , Sinergismo Farmacológico , Femenino , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Humanos , Masculino , Ratones Desnudos , Persona de Mediana Edad , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Pronóstico , Enzimas Activadoras de Ubiquitina/metabolismoRESUMEN
Background: The prognosis of pancreatic ductal adenocarcinoma (PDAC) remains poor and the models for survival prediction in PDAC patients after curative resection are still limited. Preoperative alkaline phosphatase-to-albumin ratio (APAR), an original inflammation-based score, has been established to analyze the prognostic significance in PDAC. Therefore, in this study, we aim to formulate a valuable prognostic nomogram for PDAC following curative resection. Methods: A total of 354 patients with PDAC undergoing curative resection were retrospectively enrolled in this study. The prognostic value of APAR was analyzed in primary cohort containing 220 randomly selected PDAC patients with curative resection and prognostic nomogram incorporating APAR into the American Joint Commission on Cancer (AJCC) 8th edition was established to obtain superior discriminatory abilities. The predictive performance of APAR was further validated in another independent cohort of 134 PDAC patients. Results: Patients with higher serum APAR level were probable to sustain poorer overall survival (OS). Significant positive correlations were found between APAR and tumor site, and several serum biochemical indexes, such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), etc. The results of multivariate analysis showed, APAR was also identified as an independent prognostic indicator for OS in both primary and validation cohorts (P=0.004, P=0.038, respectively). Compared with the AJCC 8th edition, the nomogram consisting of APAR, pathological differentiation and the TNM staging system of AJCC 8th edition showed superior predictive accuracy for OS. All these results were further verified in the validation cohort. Conclusions: APAR can be considered as a novel independent prognostic biomarker for PDAC following curative resection. One more accurate and advanced predictive model will be achieved via the incorporation of APAR into nomogram.
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OBJECTIVES: To investigate the antitumor activity of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) plus S-1 in patient-derived pancreatic cancer xenograft mouse models and to explore biomarkers that could predict drug efficacy. METHODS: Ten patient-derived xenograft models were established. The third-generation tumor-bearing mice were randomized into 4 treatment groups: (1) control; (2) S-1; (3) nab-paclitaxel; (4) S-1 plus nab-paclitaxel. Resected tumors were tested by immunohistochemistry for the expression of thymidylate synthase, orotate phosphoribosyltransferase (OPRT), dihydropyrimidine dehydrogenase (DPD), secreted protein that is acidic and rich in cysteine, human epidermal growth factor receptor 2 (HER2), collagen-1, and CD31. RESULTS: Tumor growth inhibition of the S-1 group, nab-paclitaxel group, and combination group was 69.52%, 86.63%, 103.56%, respectively (P < 0.05). The efficacy of S-1 is better in thymidylate synthase-negative, OPRT-positive, and DPD-negative tumors. The efficacy of nab-paclitaxel is better in HER2-positive tumors. Collagen-1 was decreased and CD31 was increased in tumors treated with nab-paclitaxel and S-1 plus nab-paclitaxel compared with control or S-1. CONCLUSIONS: This preclinical study showed that S-1 plus nab-paclitaxel exerted significantly better antitumor activity than S-1 or nab-paclitaxel alone. Thymidylate synthase, OPRT, and DPD were possibly biomarkers of S-1 and HER2 of nab-paclitaxel.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Páncreas/efectos de los fármacos , Neoplasias Pancreáticas/tratamiento farmacológico , Ensayos Antitumor por Modelo de Xenoinjerto , Albúminas/administración & dosificación , Animales , Biomarcadores de Tumor/metabolismo , Colágeno Tipo I/metabolismo , Dihidrouracilo Deshidrogenasa (NADP)/metabolismo , Combinación de Medicamentos , Femenino , Humanos , Inmunohistoquímica , Ratones Desnudos , Orotato Fosforribosiltransferasa/metabolismo , Ácido Oxónico/administración & dosificación , Paclitaxel/administración & dosificación , Páncreas/metabolismo , Páncreas/patología , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo , Distribución Aleatoria , Receptor ErbB-2/metabolismo , Tegafur/administración & dosificación , Timidilato Sintasa/metabolismo , Resultado del TratamientoRESUMEN
A 33-year-old Chinese woman was admitted to our hospital because of an elevated serum alpha-fetoprotein (AFP) level (300 ng/mL) found in a regular medical checkup. Computed tomography imaging of the abdomen revealed a 1.6 × 2.2 cm low-attenuation mass in the head of the pancreas, with no enlarged lymph nodes and no metastatic liver nodules, and a pancreaticoduodenectomy was performed and the tumor was completely removed. The tumor was solid, unencapsulated and poorly demarcated, measuring 2 × 1.4 × 1.8 cm, and the cut surface was grey-yellowish. Histologically, most of the areas of the tumor were composed of small monotonous and round shaped neuroendocrine cells, and approximately 20% of the areas were cells with indistinct cytoplasmic borders, large oval nuclei, prominent nucleoli and abundant eosinophilic cytoplasm, resembling the appearance of HCC. Immunohistochemical stains revealed that the neuroendocrine areas were diffusely positive for chromogranin, and the hepatoid areas showed diffuse and strong positive reaction to AFP. After surgery the AFP level reduced to normal. She received six cycles of postoperative chemotherapy and three years after the surgery was found to have an elevated serum AFP level again which gave rise to the suspicion of tumor recurrence, and a positron emission tomography-computed tomography confirmed the speculation by showing a hypermetabolic lymph node behind the body of the pancreas. She then underwent radiotherapy and the AFP level reduced to normal. Up till now she has survived 46 months since the initial diagnosis. This case and previous cases suggest that the serum AFP could be a useful marker for early detection of the disease, but careful differential diagnosis should be performed, and AFP could also be a marker for evaluation of therapeutic response and recurrence of the AFP-producing hepatoid carcinomas of pancreas.
RESUMEN
BACKGROUND: Gastric neuroendocrine carcinomas (g-NECs) are rare tumors that have aggressive biological behaviors and poor prognosis, but the prognostic factors of postoperative patients with g-NEC are still unclear. Our aim was to study and explore the clinical characteristics and prognostic factors of patients with g-NEC treated with radical surgery. METHODS: The clinical data of 43 g-NEC patients who underwent surgery from January 2002 to January 2011 at the Zhongshan Hospital of Fudan University were analyzed. Follow-up was conducted by telephone, mail, or returning visit survey. RESULTS: The sizes of the 43 neuroendocrine carcinomas (G3) were 1.5 cm × 1.5 cm × 0.5 cm to 7 cm × 8 cm × 1.5 cm. Eight NECs were localized, and 35 had lymph node involvement, of which 1 also had hepatic metastasis. At the end of the follow-up, the follow-up rate was 97.7% (42/43), and the median follow-up time was 22.2 months. The median overall survival of g-NEC patients was 36.5 months, and the 1-, 3-, and 5-year overall survival rates were 86.0%, 51.6%, and 36.7%, respectively. Sex (P < 0.05) and lymph node involvement (P < 0.05) were prognostic factors of postoperative g-NEC patients, among which sex was an independent prognostic factor (P < 0.05), as a survival advantage of female patients over male was observed. CONCLUSIONS: Most of the g-NECs were diagnosed at an advanced stage. The prognosis of g-NECs was related with sex and lymph node involvement, of which sex was an independent prognostic factor, with female patients having a survival advantage.