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1.
Clin Cancer Res ; 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31911545

RESUMO

BACKGROUND: Tumor genomic features have been of particular interest because of their potential impact on the tumor immune microenvironment and response to immunotherapy. Due to the substantial heterogeneity, an integrative approach incorporating diverse molecular features is needed to characterize immunological features underlying primary resistance to immunotherapy and for the establishment of novel predictive biomarkers. METHODS: We developed a pan-cancer deep machine-learning model integrating tumor mutation burden, microsatellite instability and somatic copy number alterations to classify tumors of different types into different genomic clusters, assessed the immune microenvironment in each genomic cluster and the association of each genomic cluster with response to immunotherapy. RESULTS: Our model grouped 8,646 tumors of 29 cancer types from the Cancer Genome Atlas into four genomic clusters. Analysis of RNA-sequencing data revealed distinct immune microenvironment in tumors of each genomic class. Furthermore, applying this model to tumors from two melanoma immunotherapy clinical cohorts demonstrated that patients with melanoma of different genomic classes achieved different benefit from immunotherapy. Interestingly, tumors in cluster 4 demonstrated a cold immune microenvironment and lack of benefit from immunotherapy despite high microsatellite instability burden. CONCLUSION: Our study provides a proof-for-principle that deep learning modeling may have the potential to discover intrinsic statistical cross-modality correlations of multifactorial input data to dissect the molecular mechanisms underlying primary resistance to immunotherapy, which likely involves multiple factors from both the tumor and host at different molecular levels.

2.
Oncologist ; 2019 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-31784489

RESUMO

BACKGROUND: The objective of this study was to develop and validate a nomogram to predict 1-year overall survival (OS) and 2-year OS in patients with high-grade digestive neuroendocrine neoplasms (NENs) as well as to guide selection of subgroups that could benefit from systemic chemotherapy. SUBJECTS, MATERIALS, AND METHODS: We performed a retrospective analysis of 223 patients with NENs of the gut and hepato-biliary-pancreatic system from four centers included in the development cohort. The nomogram was externally validated in a cohort of 90 patients from another one. RESULTS: The final model included lactate dehydrogenase, performance status, stage, Ki67, and site of primary tumor, all of which had a significant effect on OS. The uncorrected C-index was 0.761 for OS, and the bias-corrected C-index was 0.744. Predictions correlated well with observed 1-year and 2-year outcomes (judged by eye). The area under the time-dependent receiver operating characteristic curve at 12 months and 24 months was 0.876 and 0.838, respectively. The nomogram performed well in terms of both discrimination and calibration when applied to the validation cohort, and OS was significantly different between the two groups classified by nomogram score (log-rank p < .001). CONCLUSION: The validated nomogram provided useful prediction of OS, which can be offered for clinicians to improve their abilities to assess patient prognosis, to create clinical risk groups for informing treatment or for patient stratification by disease severity in clinical trials. IMPLICATIONS FOR PRACTICE: The high-grade neuroendocrine neoplasms of the digestive system are rare malignancies with great heterogeneity. An overall survival nomogram was developed and externally validated in this study. Two subgroups were classified by the nomogram score, and platinum-based chemotherapy may not bring clinical benefit for the low-risk patients.

3.
Chronobiol Int ; 36(6): 739-750, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31014124

RESUMO

Circadian clock genes have become a hot topic in cancer research in recent years, and more and more studies are showing that clock genes are involved in regulating cell proliferation cycle and apoptosis of malignant tumors, neuroendocrine and immune function, and other processes. Lung cancer is a malignant tumor with increasing incidence worldwide. The pathogenesis of lung cancer is extremely complicated and includes genetic factors, living environment, and smoking, and the occurrence of lung cancer is related to the regulation of many oncogenes and tumor suppressor genes. But there are few studies on clock genes in lung cancer. Studies on clock genes may help to better understand the mechanism of lung cancer development for an improved treatment. The expressions of all 14 kinds of clock genes in adenocarcinoma (ADC) and squamous cell carcinoma (SCC), two main kinds of non-small-cell lung cancer (NSCLC), were studied based on integration and analysis of data from The Cancer Genome Atlas (TCGA) to show the association between clock gene expression and prognosis of cancer patients. Analysis of TCGA data indicated that overexpression of Cry2, BMAL1, and RORA with underexpression of Timeless and NPAS2 was associated with a favorable prognosis of ADC, and the expression of NPAS2 was associated with the time of patient survival. Additionally, the expression of Cry2 was related to TNM stage. In SCC, high expression of DEC1 was correlated with poor overall survival in patients and the expression of Timeless was associated with the time of patient survival. In NSCLC, circadian clock genes constitute cancer circadian rhythm by interacting with each other, showing that asynchrony with normal tissues, which collectively controlling the occurrence and development of NSCLC.

4.
Dis Markers ; 2018: 9191639, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30416612

RESUMO

Purpose: The objective of this study was to analyze the clinical features and prognosis of gastroenteropancreatic (GEP) neuroendocrine carcinomas (NECs) with liver metastasis and primary hepatic neuroendocrine carcinomas (PHNECs), as these rare hepatic neuroendocrine carcinomas have not been exhaustively studied. Methods: The clinical data of 47 patients with hepatic NECs were retrospectively reviewed and categorized to analyze features and prognosis. Results: The 47 studied cases comprised 13 cases of primary hepatic NECs (primary group) and 34 cases of metastatic hepatic NECs (metastatic group). Male patients were slightly dominant in both groups, while no age predilection was present. PHNECs were mostly single nodules located in the right lobe of the liver. Metastatic hepatic NECs originated mostly from the pancreas and stomach without distinction of the lobes of the liver. Univariate analysis showed that the treatment protocol (radical operation or others) was correlated with the overall survival (OS; p < 0.05) in the primary group, while treatment protocol and cytokeratin 7 (CK7) were associated with OS (p < 0.05) in the metastatic group. Cox proportional hazard regression showed that radical operation was an independent prognostic factor (p < 0.05) for OS in the metastatic group. Conclusions: No significant differences in the clinicopathological features between PHNECs and metastatic hepatic GEP NECs were found, but radical operation was significantly correlated with OS for both carcinomas. Radical operation is the first choice for patients who are eligible for operation.


Assuntos
Carcinoma Neuroendócrino/patologia , Neoplasias Intestinais/patologia , Neoplasias Hepáticas/patologia , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/patologia , Nódulo Pulmonar Solitário/patologia , Neoplasias Gástricas/patologia , Adulto , Idoso , Carcinoma Neuroendócrino/cirurgia , Feminino , Humanos , Neoplasias Intestinais/cirurgia , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/cirurgia , Neoplasias Pancreáticas/cirurgia , Prognóstico , Estudos Retrospectivos , Nódulo Pulmonar Solitário/cirurgia , Neoplasias Gástricas/cirurgia , Análise de Sobrevida
5.
Oncol Lett ; 15(6): 8604-8610, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30065788

RESUMO

Neuroendocrine tumors (NETs) of the gastrointestinal tract often spread to the liver, while primary hepatic NETs (PHNETs), first described by Edmondson in 1958, are very rare. The majority of existing reports regarding PHNETs have small sample sizes, and the clinicopathological characteristics and prognostic factors are still unclear. The aim of the present study was to analyze the clinicopathological features and explore the prognostic factors of PHNETs. From March 2012 to March 2017, 28 cases of PHNETs were retrospectively evaluated to analyze the clinicopathological features and explore the prognostic factors of PHNETs. The 28 PHNETs patients were males (n=15) and females (n=13) aged between 32 and 76 years (mean=53 years). Among them, 16 patients had clinical symptoms. The remaining 12 patients had no obvious clinical symptoms, only hepatoncus was observed during physical examination. Single-factor analysis showed that carbohydrate antigen 125 (CA125), alanine aminotransferase (ALT), aspartate aminotransferase (AST), hemoglobin (HB), Ki-67 positive index (PI), surgical treatment and pathological grading were correlated to PHNET prognosis (P<0.05); multifactor analysis revealed that Ki-67 PI was associated with the prognosis (P<0.05). Thus, the prognosis of PHNETs may be effectively predicted using the indexes of CA125, ALT, AST, HB, Ki-67 PI, pathological grading and surgical treatment. Pathological classification of grade 3, high expression of Ki-67 PI, abnormal elevation of CA125, abnormalities of ALT and AST, anemia and lack of radical operation indicated a poor prognosis. High expression of Ki-67 PI was an independent prognostic factor for PHNETs.

6.
Cell Commun Signal ; 16(1): 16, 2018 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-29661252

RESUMO

BACKGROUND: Gain-of-function mutations and overexpression of KIT are characteristic features of gastrointestinal stromal tumor (GIST). Dysregulation in miRNA expression may lead to KIT overexpression and tumorigenesis. METHODS: miRNA microarray analysis and real-time PCR were used to determine the miRNA expression profiles in a cohort of 69 clinical samples including 50 CD117IHC+/KITmutation GISTs and 19 CD117IHC-/wild-type GISTs. GO enrichment and KEGG pathway analyses were performed to reveal the predicted targets of the dysregulated miRNAs. Of the dysregulated miRNAs whose expression was inversely correlated with that of KIT miRNAs were predicted by bioinformatics analysis and confirmed by luciferase reporter assay. Cell counting kit-8 (CCK-8) and flow cytometry were used to measure the cell proliferation, cycle arrest and apoptosis. Wound healing and transwell assays were used to evaluate migration and invasion. A xenograft BALB/c nude mouse model was applied to investigate the tumorigenesis in vivo. Western blot and qRT-PCR were used to investigate the protein and mRNA levels of KIT and its downstream effectors including ERK, AKT and STAT3. RESULTS: Of the six miRNAs whose expression was inversely correlated with that of KIT, we found that miR-148b-3p was significantly downregulated in the CD117IHC+/KITmutation GIST cohort. This miRNA was subsequently found to inhibit proliferation, migration and invasion of GIST882 cells. Mechanistically, miR-148b-3p was shown to regulate KIT expression through directly binding to the 3'-UTR of the KIT mRNA. Restoration of miR-148b-3p expression in GIST882 cells led to reduced expression of KIT and the downstream effectors proteins ERK, AKT and STAT3. However, overexpression of KIT reversed the inhibitory effect of miR-148b-3p on cell proliferation, migration and invasion. Furthermore, we found that reduced miR-148b-3p expression correlated with poor overall survival (OS) and disease-free survival (DFS) in GIST patients. CONCLUSION: miR-148b-3p functions as an important regulator of KIT expression and a potential prognostic biomarker for GISTs.


Assuntos
Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/patologia , MicroRNAs/metabolismo , Proteínas Proto-Oncogênicas c-kit/metabolismo , Regiões 3' não Traduzidas , Animais , Antagomirs/metabolismo , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Neoplasias Gastrointestinais/metabolismo , Neoplasias Gastrointestinais/mortalidade , Tumores do Estroma Gastrointestinal/metabolismo , Tumores do Estroma Gastrointestinal/mortalidade , Humanos , Mesilato de Imatinib/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-kit/química , Proteínas Proto-Oncogênicas c-kit/genética , Fator de Transcrição STAT3/metabolismo , Taxa de Sobrevida
7.
Clin Chim Acta ; 481: 154-155, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29548922

RESUMO

BACKGROUND: Neuroendocrine tumors (NETs) are uncommon type of cancers, also known as APUD (amine precursor uptake decarboxylation) tumors, which are becoming increasingly prevalent. Alkaline phosphatase (ALP) is a poor prognosis factor in a number of hepatic diseases. However, its distribution and prognostic value in primary hepatic neuroendocrine tumors (PHNETs) are still not clear. In this study, our aim is to investigate the correlations between ALP and clinicopathological features and prognostic factors of PHNETs. METHODS: The clinical data of 22 patients with PHNETs were retrospectively reviewed to investigate whether ALP affects the prognosis of PHNETs. RESULTS: In this study, ALP is correlated to γ-glutamyl transpeptidase (GGT; p = 0.002) and the tumor location in the liver (p = 0.007), and increased levels of ALP had poor effects on overall survival (p = 0.006) and progression-free survival (p = 0.022). CONCLUSION: ALP was identified as an independent prognostic factor for overall survival of PHNETs.


Assuntos
Fosfatase Alcalina/metabolismo , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/enzimologia , gama-Glutamiltransferase/metabolismo , Feminino , Humanos , Masculino , Análise de Sobrevida
8.
Oncotarget ; 7(36): 58148-58161, 2016 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-27531900

RESUMO

Angiosarcoma is a rare malignant mesenchymal tumor with poor prognosis. We aimed to identify malignancy-associated miRNAs and their target genes, and explore biological functions of miRNA and its target in angiosarcoma. By miRNA microarrays and reverse transcription polymerase chain reaction, we identified 1 up-regulated miRNA (miR-222-3p) and 3 down-regulated miRNAs (miR-497-5p, miR-378-3p and miR-483-5p) in human angiosarcomas compared with human capillary hemangiomas. The intermediate-conductance calcium activated potassium channel KCa3.1 was one of the putative target genes of miR-497-5p, and marked up-regulation of KCa3.1 was detected in angiosarcoma biopsy specimens by immunohistochemistry. The inverse correlation of miR-497-5p and KCa3.1 also was observed in the ISO-HAS angiosarcoma cell line at the mRNA and protein levels. The direct targeting of KCa3.1 by miR-497-5p was evidenced by reduced luciferase activity due to complementary binding of miR-497-5p to KCa3.1 mRNA 3' untranslated region. For the functional role of miR-497-5p/KCa3.1 pair, we showed that application of TRAM-34, a specific KCa3.1 channel blocker, or transfection of ISO-HAS cells with KCa3.1 siRNA or miR-497-5p mimics inhibited cell proliferation, cell cycle progression, and invasion by down-regulating cell-cycle related proteins including cyclin D1, surviving and P53 and down-regulating matrix metallopeptidase 9. In an in vivo angiosarcoma xenograft model, TRAM-34 or miR-497-5p mimics both inhibited tumor growth. In conclusion, the tumor suppressor miR-497-5p down-regulates KCa3.1 expression and contributes to the inhibition of angiosarcoma malignancy development. The miR-497-5p or KCa3.1 might be potential new targets for angiosarcoma treatment.


Assuntos
Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Hemangiossarcoma/genética , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/genética , MicroRNAs/metabolismo , Regiões 3' não Traduzidas , Animais , Carcinogênese/genética , Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Regulação para Baixo , Feminino , Hemangiossarcoma/patologia , Humanos , Imuno-Histoquímica , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , Análise em Microsséries , Invasividade Neoplásica/genética , Pirazóis/farmacologia , Interferência de RNA , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , Transfecção , Regulação para Cima
9.
Oncotarget ; 7(28): 44185-44193, 2016 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-27283904

RESUMO

Systemic immune-inflammation index (SII), based on lymphocyte (L), neutrophil (N), and platelet (P) counts, was recently developed and reflects comprehensively the balance of host inflammatory and immune status. We explored its prognostic value in localized gastric cancer (GC) after R0 resection and the potential associations with Thymidine phosphorylase (TYMP), which was reported to increase the migration and invasion of gastric cancer cells. A total of 455 GC patients who received D2 gastrectomy were enrolled. Blood samples were obtained within 1 week before surgery to measure SII (SII = P × N/L). TYMP expression was measured on tumor sections by immunohistochemical analysis. Preoperative high SII indicated worse prognosis (HR: 1.799; 95% CI: 1.174-2.757; p = 0.007) in multivariate analysis and was associated with higher pathological TNM stage, deeper local invasion of tumor and lymph node metastasis (all p < 0.001). SII predicted poor overall survival in pathological TNM stage I subgroup also (p < 0.001). Furthermore we found that in high SII group, positive rate of TYMP expression increased (53.7% vs 42.7%, p = 0.046) and TYMP positive patients had higher SII score (median 405.9 vs. 351.9, p = 0.026). SII, as a noninvasive and low cost prognostic marker, may be helpful to identify higher-risk patients after R0 resection, even for stage I GC patients.


Assuntos
Sistema Imunitário/imunologia , Inflamação/imunologia , Neoplasias Gástricas/cirurgia , Timidina Fosforilase/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Contagem de Células Sanguíneas , Feminino , Gastrectomia/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , /estatística & dados numéricos , Estudos Retrospectivos , Neoplasias Gástricas/enzimologia , Neoplasias Gástricas/imunologia , Análise de Sobrevida , Adulto Jovem
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