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1.
J Surg Oncol ; 123(5): 1253-1262, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33524213

RESUMO

BACKGROUND AND OBJECTIVES: In this retrospective study, we examined the CA17 tissue expression and analyzed its clinical significance in cholangiocarcinoma (CCA). MATERIALS AND METHODS: Immunohistochemistry was performed to assess CA17 expression on tissue microarrays in a training cohort enrolling 120 CCA patients and a validation cohort comprising 60 CCA patients. Image pro plus was applied to score the staining intensity and expression level of CA17 marker. Kaplan-Meier analysis, Cox's proportional hazards regression, and nomogram were applied to evaluate the prognostic significance of CA17. RESULTS: CA17 cancer biomarker over-expression was significantly observed in CCA compared to their non-tumor counterparts, and positively correlated with aggressive tumor phenotypes, like lymph node metastasis. Meanwhile, patients with high expression of CA17 correlated with worse postoperative overall survival (OS) and recurrence-free survival. Besides, multivariate analysis identified that CA17 expression was an independent prognostic factor for cholangiocarcinoma patients, which indicated that the CA17 could be more efficient than serum CA19-9 in predicting the OS of CCA patients. Notably, the nomogram integrating CA17 expression had better prognostic performance as compared with current TNM staging systems. CONCLUSION: CA17 was an independent adverse prognostic factor for CCA patients' survival, which may serve as a promising prognostic biomarker for CCA patients.


Assuntos
Neoplasias dos Ductos Biliares/patologia , Biomarcadores Tumorais/metabolismo , Caderinas/metabolismo , Colangiocarcinoma/patologia , Recidiva Local de Neoplasia/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/cirurgia , Colangiocarcinoma/metabolismo , Colangiocarcinoma/cirurgia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/cirurgia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
2.
J Cancer Res Clin Oncol ; 147(4): 1259-1270, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33387039

RESUMO

PURPOSE: Supratentorial extraventricular ependymoma (SEE) is a rare subset of ependymomas located in the supratentorial parenchyma, and little is known regarding its management and prognosis. Our study aimed to reveal the prognostic factors in patients with SEE and the roles of programmed death ligand-1 (PD-L1), programmed cell death protein 1 (PD-1), Ki-67, and neural cell adhesion molecule L1 (L1CAM) in predicting these patients' outcomes. METHODS: We retrospectively studied the clinical features and prognostic factors in 48 patients with SEE admitted to our center from April 2008 to October 2018. Tissue slides were constructed from patient samples, and PD-L1, PD-1, Ki-67, and L1CAM expression levels were evaluated by immunohistochemistry. RESULTS: Patients with gross total resection (GTR) had better progression-free survival than patients with subtotal resection (STR). Moreover, the recurrence hazard ratios in patients with STR at 3, 5, and 10 years were 8.746, 6.866 and 3.962 times those of patients with GTR, respectively. PD-L1 positivity predicted worse progression-free survival, while the recurrence hazard ratios for patients with PD-L1 positivity at 3, 5, and 10 years were 10.445, 5.539, and 3.949 times those of patients with PD-L1 negativity, respectively. Multivariate analysis revealed that PD-L1 expression and GTR could independently predict outcomes in patients with SEE. CONCLUSION: PD-L1 expression was an independent and more readily obtained predictor of outcomes, representing a simple and reliable biological prognostic factor for patients with SEE. Further studies are needed to explore PD-L1 inhibitor treatment for patients with ependymoma. CLINICAL TRIAL REGISTRATION: No clinical trials were performed in the study.


Assuntos
Antígeno B7-H1/metabolismo , Ependimoma/patologia , Recidiva Local de Neoplasia/patologia , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Neoplasias Supratentoriais/patologia , Adolescente , Adulto , Criança , Pré-Escolar , Ependimoma/imunologia , Ependimoma/metabolismo , Ependimoma/cirurgia , Feminino , Seguimentos , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/cirurgia , Prognóstico , Estudos Retrospectivos , Neoplasias Supratentoriais/imunologia , Neoplasias Supratentoriais/metabolismo , Neoplasias Supratentoriais/cirurgia , Taxa de Sobrevida , Adulto Jovem
3.
J Surg Oncol ; 123(4): 1144-1156, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33497473

RESUMO

BACKGROUND: The lungs are the second most common site of metastases in colorectal cancer (CRC). The aim of this study was to investigate prognostic factors, including RNA-binding motif protein 3 (RBM3) expression, in patients with CRC treated with pulmonary metastasectomy (PM). METHODS: The cohort included all patients treated with PM at Skåne University Hospital, Lund, Sweden, from 2000 to 2014. Clinicopathological, treatment, and survival data were collected. Immunohistochemical staining of RBM3 was evaluated on tissue microarrays with samples from all lung metastases and a subset of paired primary tumors. Kaplan-Meier analysis and Cox proportional hazards modeling were applied to examine the associations of investigative factors with overall survival (OS) and recurrence-free survival. RESULTS: In total, 216 patients with a primary tumor in the rectum (57%), left colon (34%), or right colon (9%) underwent PM. The 5-year OS rate was 56%. Age > 60 years, more than one metastasis, size of metastasis > 3 cm, disease-free interval < 24 months, low RBM3 score in the lung metastasis, and no adjuvant chemotherapy following PM were prognostic factors for shorter OS. CONCLUSIONS: Several prognostic factors, including RBM3 expression, may be of aid in selecting CRC patients with lung metastases for PM as well as adjuvant therapy.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Pulmonares/secundário , Metastasectomia/mortalidade , Recidiva Local de Neoplasia/patologia , Neoplasias/patologia , Pneumonectomia/mortalidade , Proteínas de Ligação a RNA/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/cirurgia , Neoplasias/metabolismo , Neoplasias/cirurgia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
4.
Anticancer Res ; 41(2): 885-893, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33517294

RESUMO

BACKGROUND/AIM: Circulating tumor cells (CTCs) may be affected by the environment encountered during blood circulation. We aimed to explore the association between the molecular phenotype of CTCs and systemic inflammatory markers. PATIENTS AND METHODS: CTCs isolated from patients with recurrent/metastatic head and neck squamous cell carcinoma by CD45-negative selection were analyzed for the expression of multiple genes. The correlations between gene expression levels in CTCs and systemic inflammation markers were examined. RESULTS: Thirty-five (83.3%) of the 42 patients were positive for CTCs. No significant differences in systemic inflammatory markers were observed between CTC-positive and CTC-negative patients. Notably, VIM or ZEB2 expression was strongly correlated with that of CD44 or ALDH1. PIK3CA, CD44, ALDH1A1, and PDCD1LG2 expression in CTCs was correlated with lymphocyte- and/or albumin-related systemic inflammatory markers. CONCLUSION: CTCs acquire a survival advantage through phenotypic alterations in the hostile blood environment, and evade circulatory immune surveillance.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias de Cabeça e Pescoço/metabolismo , Recidiva Local de Neoplasia/metabolismo , Células Neoplásicas Circulantes/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Idoso , Idoso de 80 Anos ou mais , Transição Epitelial-Mesenquimal , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Prognóstico , Análise de Sobrevida , Evasão Tumoral , Microambiente Tumoral
5.
Nat Commun ; 12(1): 20, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33397932

RESUMO

Drug resistance and tumor recurrence are major challenges in cancer treatment. Cancer cells often display centrosome amplification. To maintain survival, cancer cells achieve bipolar division by clustering supernumerary centrosomes. Targeting centrosome clustering is therefore considered a promising therapeutic strategy. However, the regulatory mechanisms of centrosome clustering remain unclear. Here we report that KIFC1, a centrosome clustering regulator, is positively associated with tumor recurrence. Under DNA damaging treatments, the ATM and ATR kinases phosphorylate KIFC1 at Ser26 to selectively maintain the survival of cancer cells with amplified centrosomes via centrosome clustering, leading to drug resistance and tumor recurrence. Inhibition of KIFC1 phosphorylation represses centrosome clustering and tumor recurrence. This study identified KIFC1 as a prognostic tumor recurrence marker, and revealed that tumors can acquire therapeutic resistance and recurrence via triggering centrosome clustering under DNA damage stresses, suggesting that blocking KIFC1 phosphorylation may open a new vista for cancer therapy.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Centrossomo/metabolismo , Cinesina/metabolismo , Recidiva Local de Neoplasia/metabolismo , Sequência de Aminoácidos , Animais , Linhagem Celular Tumoral , Instabilidade Cromossômica , Dano ao DNA , Resistencia a Medicamentos Antineoplásicos , Humanos , Cinesina/química , Camundongos , Recidiva Local de Neoplasia/patologia , Fosforilação , Fosfosserina/metabolismo
6.
PLoS One ; 15(12): e0244663, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33370412

RESUMO

The tumour micro-environment (TME) plays a crucial role in the onset and progression of prostate cancer (PCa). Here we studied the potential of a selected panel of TME-markers to predict clinical recurrence (CLR) in PCa. Patient cohorts were matched for the presence or absence of CLR 5 years post-prostatectomy. Tissue micro-arrays (TMA) were composed with both prostate non-tumour (PNT) and PCa tissue and subsequently processed for immunohistochemistry (IHC). The IHC panel included markers for cancer activated fibroblasts (CAFs), blood vessels and steroid hormone receptors ((SHR): androgen receptor (AR), progesterone receptor (PR) and estrogen receptor (ER)). Stained slides were digitalised, selectively annotated and analysed for percentage of marker expression with standardized and validated image analysis algorithms. A univariable analysis identified several TME markers with significant impact on CR: expression of CD31 (vascular marker) in PNT stroma, expression of alpha smooth muscle actin (αSMA) in PCa stroma, and PR expression ratio between PCa stroma and PNT stroma. A multivariable model, which included CD31 expression (vascular marker) in PNT stroma and PR expression ratio between PCa stroma and PNT stroma, could significantly stratify patients for CLR, with the identification of a low risk and high-risk subgroup. If validated and confirmed in an independent prospective series, this subgroup might have clinical potential for PCa patient stratification.


Assuntos
Biomarcadores Tumorais/metabolismo , Recidiva Local de Neoplasia/patologia , Neoplasias da Próstata/patologia , Análise Serial de Tecidos/métodos , Actinas/metabolismo , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/cirurgia , Estadiamento de Neoplasias , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Estudos Prospectivos , Prostatectomia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/cirurgia , Receptores Androgênicos/metabolismo , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo , Microambiente Tumoral
7.
J Cancer Res Ther ; 16(6): 1229-1234, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33342778

RESUMO

Aim: Metaplastic breast cancer (MBC) is a rare subtype with unusual clinical features. We aimed to analyze treatment results and define patients' characteristic features in our large MBC patient series. Materials and Methods: Fifty-six patients with early MBC who received adjuvant radiotherapy (RT) in our center were included in the study. The age, sex, subtypes of MBC, histopathology, hormone and nodal status, tumor size, and types of treatment were retrospectively provided from hospital records. Results: The median tumor size was 4 (1.3-16.5) cm, and triple-negative MBC cases were 38 (67.8%) of all patients. Axillary nodal involvements were present in 25 (44.6%) patients. The median follow-up time was 45.8 (4.9-130) months; the overall survival (OS) and disease-free survival (DFS) for 5 years were 67% and 64%, respectively. While distant metastases were seen in 15 (26.7%) patients, local recurrences were seen in only 4 patients. The median OS and DFS were higher in patients with ≤5.2 cm tumor than >5.2 cm ([130 vs. 49 months, P = 0.01] and [130 vs. 30 months, P = 0.009], respectively). Nodal involvement, hormone receptor status, surgical treatment, and type of RT had no effect on survival. In multivariate analysis, tumor size was not an independent prognostic factor for OS (P = 0.068; hazard ratio [HR]: 3.4, 95% confidence interval [CI] = 0.91-12.8), whereas age >65 years was found an independent poor prognostic factor for OS ([HR: 4.25, 95% CI: 0.23-0.78, P = 0.021] and DFS [HR: 3.1, 95% CI: 0.02-0. 87; P = 0.04], respectively). Conclusions: Distant metastasis is at the forefront rather than local recurrence in MBC patients. More studies are needed to determine the factors that affect survival independently in MBC.


Assuntos
Neoplasias da Mama/patologia , Metaplasia/patologia , Recidiva Local de Neoplasia/patologia , Neoplasias de Mama Triplo Negativas/patologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/metabolismo , Feminino , Humanos , Metaplasia/metabolismo , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia/metabolismo , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/metabolismo , Carga Tumoral
8.
PLoS One ; 15(10): e0237658, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33057328

RESUMO

Breast cancer is the most common invasive cancer and the second leading cause of cancer death in women. and regrettably, this rate is increasing every year. One of the aspects of all cancers, including breast cancer, is the recurrence of the disease, which causes painful consequences to the patients. Moreover, the practical application of data mining in the field of breast cancer can help to provide some necessary information and knowledge required by physicians for accurate prediction of breast cancer recurrence and better decision-making. The main objective of this study is to compare different data mining algorithms to select the most accurate model for predicting breast cancer recurrence. This study is cross-sectional and data gathering of this research performed from June 2018 to June 2019 from the official statistics of Ministry of Health and Medical Education and the Iran Cancer Research Center for patients with breast cancer who had been followed for a minimum of 5 years from February 2014 to April 2019, including 5471 independent records. After initial pre-processing in dataset and variables, seven new and conventional data mining algorithms have been applied that each one represents one kind of data mining approach. Results show that the C5.0 algorithm possibly could be a helpful tool for the prediction of breast cancer recurrence at the stage of distant recurrence and nonrecurrence, especially in the first to third years. also, LN involvement rate, Her2 value, Tumor size, free or closed tumor margin were found to be the most important features in our dataset to predict breast cancer recurrence.


Assuntos
Algoritmos , Neoplasias da Mama/patologia , Mineração de Dados/métodos , Recidiva Local de Neoplasia/patologia , Neoplasias da Mama/metabolismo , Estudos Transversais , Bases de Dados Factuais , Árvores de Decisões , Feminino , Humanos , Bloqueio Interatrial , Irã (Geográfico) , Metástase Linfática/patologia , Modelos Biológicos , Recidiva Local de Neoplasia/etiologia , Recidiva Local de Neoplasia/metabolismo , Redes Neurais de Computação , Receptor ErbB-2/metabolismo , Máquina de Vetores de Suporte
9.
Nat Commun ; 11(1): 4681, 2020 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-32943626

RESUMO

Although advanced lipidomics technology facilitates quantitation of intracellular lipid components, little is known about the regulation of lipid metabolism in cancer cells. Here, we show that disruption of the Gdpd3 gene encoding a lysophospholipase D enzyme significantly decreased self-renewal capacity in murine chronic myelogenous leukaemia (CML) stem cells in vivo. Sophisticated lipidomics analyses revealed that Gdpd3 deficiency reduced levels of certain lysophosphatidic acids (LPAs) and lipid mediators in CML cells. Loss of Gdpd3 also activated AKT/mTORC1 signalling and cell cycle progression while suppressing Foxo3a/ß-catenin interaction within CML stem cell nuclei. Strikingly, CML stem cells carrying a hypomorphic mutation of Lgr4/Gpr48, which encodes a leucine-rich repeat (LRR)-containing G-protein coupled receptor (GPCR) acting downstream of Gdpd3, displayed inadequate disease-initiating capacity in vivo. Our data showing that lysophospholipid metabolism is required for CML stem cell maintenance in vivo establish a new, biologically significant mechanism of cancer recurrence that is independent of oncogene addiction.


Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Diester Fosfórico Hidrolases/metabolismo , Células-Tronco/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Proteína Forkhead Box O3/metabolismo , Lisofosfolipídeos/metabolismo , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação , Recidiva Local de Neoplasia/metabolismo , Diester Fosfórico Hidrolases/genética , Receptores Acoplados a Proteínas-G/genética , Transdução de Sinais , beta Catenina/metabolismo
10.
Zhonghua Fu Chan Ke Za Zhi ; 55(8): 529-534, 2020 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-32854477

RESUMO

Objective: To examine the expression of programmed cell death 1 (PD-1) and its ligand (PD-L1) in epithelial ovarian cancer (EOC) tissues, and investigate the correlation among their expression, clinicopathological features and prognosis. Methods: The specimens of 180 patients with EOC treated in the First Affiliated Hospital of Dalian Medical University from October 2002 to December 2013 were confirmed by pathological examination. The pathological tissue specimens of subtypes ,included 120 cases of serous carcinoma, 30 cases of mucinous carcinoma, 20 cases of endometrioid carcinoma, and 20 cases of clear cell carcinoma. The normal paracancerous tissues of 50 cases randomly selected from the 180 patients as control group. Immunohistochemical SP method was used to detect the expressions of both PD-1 and PD-L1 in epithelial ovarian cancer tissues, and the relationships among their expressions,the clinicopathological parameters and prognosis were respectively analyzed. Results: (1) PD-1 was expressed in lymphocytes infiltrated in EOC tissues, and PD-L1 was expressed in the cell membranes of cancer tissues. In all EOC cases, 33 cases (18.3%, 33/180) of both PD-1 and PD-L1 were highly expressed, and only 1 (2.0%, 1/50) of control group showed high expression. There was statistically significant difference between two groups (P<0.01). (2) Among the four subtypes tissue specimens of EOC, the high expression rate of PD-1 was 25.0% (30/120) for serous carcinoma, 3/15 for endometrioid carcinoma, 0 (0/30) for mucinous carcinoma, and 0 (0/15) for clear cell carcinoma. The high expression rate of PD-L1 was 23.3% (28/120) for serous carcinoma, 3.3% (1/30) for mucinous carcinoma, 2/15 for endometrioid carcinoma, and 2/15 for clear cell carcinoma. Both PD-1 and PD-L1 expressions in the four sub-types of tissue specimens were significantly different (P<0.05). The high expression rate of both PD-1 and PD-L1 was 9.2% (8/87) in the early stage and 26.9% (25/93) in the late stage. There was a statistically significant difference between the two groups (P<0.01). Similarly, the expression of both PD-1 and PD-L1 were significantly higher in the cases of high-grade EOC (type Ⅱ) than those of low-grade (type Ⅰ) and in the cases of EOC distributed bilaterally than that distributed unilaterally, and there were statistically significant differences (P<0.05). (3) The Kaplan-Meier survival analysis showed that the survival time were respectively 35 and 36 months in the cases with high expressions of both PD-1 and PD-L1, and the survival time were the same as 61 months in the cases with low expression of both PD-1 and PD-L1, and the comparison was statistically significant (P<0.05). Conclusions: The expression levels of PD-1 and PD-L1 in EOC tissues are higher than those in adjacent tissues, especially in serous carcinomas. The expression of both PD-1 and PD-L1 is higher in specimens of the patients with advanced stages. The results showed that the high expression of both PD-1 and PD-L1 is an indicator of poor prognosis of patients suffering from EOC.


Assuntos
Antígeno B7-H1/análise , Biomarcadores Tumorais/análise , Carcinoma Epitelial do Ovário/patologia , Cistadenocarcinoma Seroso , Recidiva Local de Neoplasia/patologia , Neoplasias Ovarianas/patologia , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/genética , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Recidiva Local de Neoplasia/metabolismo , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Prognóstico , Receptor de Morte Celular Programada 1 , RNA Mensageiro/genética
11.
Cancer Treat Rev ; 89: 102069, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32717621

RESUMO

BACKGROUND: Salivary duct carcinoma (SDC) is an aggressive subtype of salivary gland cancer. Approximately half of SDC patients will develop recurrences or metastases. Therapeutic palliative therapy is therefore often needed. The majority of SDC tumors expresses the androgen receptor (AR) and one-third expresses human epidermal growth factor receptor 2 (HER2), both are potential therapeutic targets. The aim of this paper is to systematically review and summarize the evidence on systemic palliative therapy for SDC and to provide treatment recommendations. MATERIALS AND METHODS: Electronic libraries were systematically searched with a broad search strategy to identify studies where SDC patients received systemic therapy. Due to the rarity of SDC no restrictions were placed on study designs. RESULTS: The search resulted in 2014 articles of which 153 were full-text analyzed. Forty-five studies were included in the analysis, which included in total 256 SDC patients receiving systemic therapy. Two phase 2 trials primarily including SDC patients were identified. The majority of the studies were case series or case reports, resulting in an overall low quality of available evidence. Based on studies including ≥ 5 SDC patients, objective responses to HER2 targeting agents were observed in 60-70%, to AR pathway agents in 18-53% and to chemotherapy in 10-50%. CONCLUSION: For AR or HER2 positive SDC, agents targeting these pathways are the cornerstone for palliative treatment. Regarding chemotherapy, the combination of carboplatin combined with a taxane is best studied. Regarding other targeted agents and immunotherapy evidence is anecdotal, limiting formulation of treatment recommendations for these antineoplastic agents.


Assuntos
Carcinoma Ductal/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Ductos Salivares/patologia , Neoplasias das Glândulas Salivares/tratamento farmacológico , Carcinoma Ductal/metabolismo , Carcinoma Ductal/patologia , Ensaios Clínicos como Assunto , Humanos , Metástase Neoplásica , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Cuidados Paliativos/métodos , Receptor ErbB-2/metabolismo , Ductos Salivares/metabolismo , Neoplasias das Glândulas Salivares/metabolismo , Neoplasias das Glândulas Salivares/patologia
12.
Prostate ; 80(12): 1024-1037, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32628792

RESUMO

BACKGROUND: Dysregulation of microRNAs has performed vital gene regulatory functions in the genesis, progression, and prognosis of multiple malignant tumors. This study aimed to elucidate the regulatory mechanism of miR-196a in prostate cancer (PCa) and explore its clinical significance. METHODS: Quantitative real-time polymerase chain reaction was implemented to examine miR-196a and p27kip1 messenger RNA expression in PCa. Cell proliferation was evaluated via Cell Counting Kit-8, colony formation, and nude mouse tumorigenicity assays. Luciferase reporter assay was applied to identify target genes. p27kip1 protein expression in PCa was investigated using Western blot analysis and immunohistochemistry. RESULTS: There was a dramatic upregulation of miR-196a in PCa. Upregulated miR-196a was related to worse Gleason score (GS), later pathological stage, and poor biochemical recurrence (BCR)-free survival. In vivo and in vitro experiments exhibited that miR-196a promoted PCa proliferation and expedited G1/S-phase progression through the downregulation of p27kip1 protein. Additionally, p27kip1 protein was distinctly downregulated in PCa. Low p27kip1 protein expression had a strong correlation with increased GS and was an independent predictor of BCR after radical prostatectomy (RP). CONCLUSIONS: Excessive expression of miR-196a and subsequent downregulation of p27kip1 protein play essential roles in promoting PCa proliferation and leading to BCR after RP. miR-196a and its target p27kip1 may become novel molecular biomarkers and therapeutic targets for PCa.


Assuntos
Inibidor de Quinase Dependente de Ciclina p27/metabolismo , MicroRNAs/metabolismo , Neoplasias da Próstata/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Inibidor de Quinase Dependente de Ciclina p27/biossíntese , Inibidor de Quinase Dependente de Ciclina p27/genética , Regulação para Baixo , Células HEK293 , Humanos , Imuno-Histoquímica , Masculino , MicroRNAs/biossíntese , MicroRNAs/genética , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Células PC-3 , Prostatectomia/métodos , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia
13.
Breast Cancer Res ; 22(1): 76, 2020 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-32665033

RESUMO

BACKGROUND: Early luminal breast cancer (BC) represents 70% of newly diagnosed BC cases. Among them, small (under 2 cm) BC without lymph node metastasis (classified as T1N0) have been rarely studied, as their prognosis is generally favorable. Nevertheless, up to 5% of luminal T1N0 BC patients relapse with distant metastases that ultimately prove fatal. The aim of our work was to identify the mechanisms involved in metastatic recurrence in these patients. METHODS: Our study addresses the role that autonomous and non-autonomous tumor cell features play with regard to distant recurrence in early luminal BC patients. We created a cohort of T1N0 luminal BC patients (tumors between 0.5-2 cm without lymph node metastasis) with metastatic recurrence ("cases") and corresponding "controls" (without relapse) matched 1:1 on main prognostic factors: age, grade, and proliferation. We deciphered different characteristics of cancer cells and their tumor micro-environment (TME) by deep analyses using immunohistochemistry. We performed in vitro functional assays and highlighted a new mechanism of cooperation between cancer cells and one particular subset of cancer-associated fibroblasts (CAF). RESULTS: We found that specific TME features are indicative of relapse in early luminal BC. Indeed, quantitative histological analyses reveal that "cases" are characterized by significant accumulation of a particular CAF subset (CAF-S1) and decrease in CD4+ T lymphocytes, without any other association with immune cells. In multivariate analysis, TME features, in particular CAF-S1 enrichment, remain significantly associated with recurrence, thereby demonstrating their clinical relevance. Finally, by performing functional analyses, we demonstrated that CAF-S1 pro-metastatic activity is mediated by the CDH11/osteoblast cadherin, consistent with bones being a major site of metastases in luminal BC patients. CONCLUSIONS: This study shows that distant recurrence in T1N0 BC is strongly associated with the presence of CAF-S1 fibroblasts. Moreover, we identify CDH11 as a key player in CAF-S1-mediated pro-metastatic activity. This is independent of tumor cells and represents a new prognostic factor. These results could assist clinicians in identifying luminal BC patients with high risk of relapse. Targeted therapies against CAF-S1 using anti-FAP antibody or CDH11-targeting compounds might help in preventing relapse for such patients with activated stroma.


Assuntos
Neoplasias da Mama/patologia , Fibroblastos Associados a Câncer/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/imunologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/terapia , Fibroblastos Associados a Câncer/imunologia , Carcinoma Ductal de Mama/imunologia , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Carcinoma Ductal de Mama/terapia , Carcinoma Lobular/imunologia , Carcinoma Lobular/metabolismo , Carcinoma Lobular/patologia , Carcinoma Lobular/terapia , Estudos de Casos e Controles , Terapia Combinada , Feminino , Seguimentos , Humanos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Prognóstico , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo , Taxa de Sobrevida , Microambiente Tumoral/imunologia
14.
Pediatr Blood Cancer ; 67(9): e28426, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32614133

RESUMO

BACKGROUND: Relapse occurs in 50% of pediatric ependymoma cases and has poor prognosis. Few studies have investigated the clinical progress of relapsed disease, and treatment lacks a standardized approach. METHODS AND MATERIALS: We analyzed 302 pediatric ependymoma cases. Tumor, demographic, and treatment variables were investigated for association with relapse risk, time to recurrence, and survival after relapse. DNA methylation profiling was performed for 135/302 cases, and predominant subgroups were EPN_PFA (n = 95) and EPN_RELA (n = 24). Chromosome 1q status was ascertained for 185/302 cases by fluorescent in-situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA), and DNA methylation profiles. RESULTS: Sixty-two percent of cases relapsed, with a median of two recurrences with no difference between posterior fossa and supratentorial locations (66% vs 55% relapse rate). One hundred seventeen (38%) cases relapsed within two years and five (2%) beyond 10 years. The late relapses were clinically heterogeneous. Tumor grade and treatment affected risk and time to relapse variably across subgroups. After relapse, surgery and irradiation delayed disease progression with a minimal impact on survival across the entire cohort. In the EPN_PFA and EPN_RELA groups, 1q gain was independently associated with relapse risk (subhazard ratio [SHR] 4.307, P = 0.027 and SHR 1.982, P = 0.010, respectively) while EPN_PFA had increased relapse risk compared with EPN_RELA (SHR = 0.394, P = 0.018). CONCLUSIONS: Recurrent pediatric ependymoma is an aggressive disease with poor outcomes, for which current treatments are inadequate. We report that chromosome 1q gain increases relapse risk in common molecular subgroups in children but a deeper understanding of the underlying biology at relapse and novel therapeutic approaches are urgently needed.


Assuntos
Neoplasias Encefálicas , Cromossomos Humanos Par 1 , Metilação de DNA , DNA de Neoplasias , Ependimoma , Recidiva Local de Neoplasia , Adolescente , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/terapia , Criança , Pré-Escolar , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 1/metabolismo , DNA de Neoplasias/genética , DNA de Neoplasias/metabolismo , Ependimoma/genética , Ependimoma/metabolismo , Ependimoma/mortalidade , Ependimoma/terapia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/terapia , Estudos Retrospectivos , Fatores de Risco
15.
Oncol Rep ; 44(4): 1758-1770, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32700745

RESUMO

Breast cancer is the leading cause of cancer­-associated deaths in women. Combination immunotherapy attracts great interest as a treatment for breast cancer. However, there are no studies on the use of cytotoxic T­lymphocyte antigen 4 (CTLA­4) monoclonal antibody in combination with the melanoma­associated antigen A family (MAGE­As) co­antigen peptide (p248V9) for treating breast cancer, which should be explored. To this aim, in the present study, the samples of 115 patients with breast cancer were collected, and MAGE­As and CTLA­4 levels in breast cancer and adjacent normal tissues were assessed by immunohistochemical staining. The effect of 5­aza­2'­deoxycytidine (5DC) on the expression of MAGE­As in breast cancer cell lines was assessed by reverse transcription­quantitative PCR and western blot assay. Cytotoxic T cells (CTLs) were induced by MAGE­As co­antigen peptide. The specific lytic rate and IFN­Î³ level were examined by CCK­8 assay and ELISA, respectively. It was found that MAGE­As were highly expressed in breast cancer tissues. 5DC treatment promoted the expression of MAGE­As in breast cancer cells. The upregulation of the expression of MAGE­As specifically enhanced the ability of CTLs to kill breast cancer cells. CTLA­4 was highly expressed in breast cancer tissues and cells, and patients with breast cancer exhibiting high expression of CTLA­4 had low overall survival. CTLA­4 promoted the lytic efficiency of CTLs in breast cancer cells, and the combination of an anti­CTLA­4 antibody and 10 µM 5DC exhibited the highest cell lysis ability of CTLs. The present study demonstrated that MAGE­As co­antigen peptide­specific CTLs in combination with an anti­CTLA­4 monoclonal antibody and 5DC, have potent tumor cell­killing effects. It provides a novel theory for the development of breast cancer therapies.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Antígeno CTLA-4/antagonistas & inibidores , Carcinoma Ductal de Mama/tratamento farmacológico , Antígenos Específicos de Melanoma/metabolismo , Linfócitos T Citotóxicos/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/administração & dosagem , Neoplasias da Mama/imunologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Antígeno CTLA-4/imunologia , Carcinoma Ductal de Mama/imunologia , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Linhagem Celular Tumoral , Decitabina/administração & dosagem , Feminino , Seguimentos , Humanos , Metástase Linfática , Células MCF-7 , Antígenos Específicos de Melanoma/genética , Pessoa de Meia-Idade , Invasividade Neoplásica , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Prognóstico , Taxa de Sobrevida , Linfócitos T Citotóxicos/efeitos dos fármacos
17.
Cancer Immunol Immunother ; 69(10): 2053-2061, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32445029

RESUMO

OBJECTIVE: To explore the programmed death-ligand 1 (PD-L1) expression in varied subtypes of pituitary neuroendocrine tumors with assessment of their clinical behavior at diagnosis and follow-up. METHODS: We conducted a retrospective monocentric study, including all patients operated in the Academic Hospital of Angers (France) for a pituitary neuroendocrine tumor between 2012 and 2018. PDL-1 immunostaining was performed using a European Conformity-In Vitro Diagnostic-labeled anti-PDL1 antibody (clone 22C3). PD-L1 immunostaining was evaluated as the percentage of tumor cells showing positive membrane staining, into four grades: grade 0 = < 1%, grade 1 = 1 to 5%, grade 2 = 6 to 49% and grade 3 = ≥ 50%. PD-L1 expression was compared with tumor features (secretion, proliferation, invasion) and outcome. RESULTS: The study included 139 pituitary neuroendocrine tumors, including 84 (60%) nonfunctioning adenomas. Twenty-five pituitary neuroendocrine tumors were PD-L1 positive (18%), including 3 grade 3, 8 grade 2 and 14 grade 1. PD-L1 expression was not different between functioning and nonfunctioning adenomas (p = 0.26). Among 16 tumors with proliferative markers (Ki-67 ≥ 3% and p53 positive), only one was PD-L1 positive. CONCLUSION: In our series, PD-L1 was expressed in a rather small proportion of PitNET (18%), and this immune marker was not associated with any biological characteristic or behavior of the pituitary tumors. Thus, PD-L1 staining may be necessary before considering PD-L1 blockage in pituitary neuroendocrine tumors, in case of therapeutic impasse.


Assuntos
Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/metabolismo , Recidiva Local de Neoplasia/patologia , Tumores Neuroendócrinos/patologia , Neoplasias Hipofisárias/patologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/metabolismo , Tumores Neuroendócrinos/metabolismo , Neoplasias Hipofisárias/metabolismo , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
18.
BMC Bioinformatics ; 21(1): 196, 2020 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-32429832

RESUMO

BACKGROUND: Compared to the many uses of DNA-level testing in clinical oncology, development of RNA-based diagnostics has been more limited. An exception to this trend is the growing use of mRNA-based methods in early-stage breast cancer. Although DNA and mRNA are used together in breast cancer research, the distinct contribution of mRNA beyond that of DNA in clinical challenges has not yet been directly assessed. We hypothesize that mRNA harbors prognostically useful information independently of genomic variation. To validate this, we use both genomic mutations and gene expression to predict five-year breast cancer recurrence in an integrated test model. This is accomplished first by comparing the feature importance of DNA and mRNA features in a model trained on both, and second, by evaluating the difference in performance of models trained on DNA and mRNA data separately. RESULTS: We find that models trained on DNA and mRNA data give more weight to mRNA features than to DNA features, and models trained only on mRNA outperform models trained on DNA alone. CONCLUSIONS: The evaluation process presented here may serve as a framework for the interpretation of the relative contribution of individual molecular markers. It also suggests that mRNA has a distinct contribution in a diagnostic setting, beyond and independently of DNA mutation data.


Assuntos
Neoplasias da Mama/diagnóstico , Recidiva Local de Neoplasia/diagnóstico , RNA Mensageiro/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Feminino , Expressão Gênica , Genoma Humano , Humanos , Mutação , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/metabolismo , Prognóstico
19.
Cell Mol Life Sci ; 77(22): 4459-4483, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32358622

RESUMO

Redox homeostasis is an essential requirement of the biological systems for performing various normal cellular functions including cellular growth, differentiation, senescence, survival and aging in humans. The changes in the basal levels of reactive oxygen species (ROS) are detrimental to cells and often lead to several disease conditions including cardiovascular, neurological, diabetes and cancer. During the last two decades, substantial research has been done which clearly suggests that ROS are essential for the initiation, progression, angiogenesis as well as metastasis of cancer in several ways. During the last two decades, the potential of dysregulated ROS to enhance tumor formation through the activation of various oncogenic signaling pathways, DNA mutations, immune escape, tumor microenvironment, metastasis, angiogenesis and extension of telomere has been discovered. At present, surgery followed by chemotherapy and/or radiotherapy is the major therapeutic modality for treating patients with either early or advanced stages of cancer. However, the majority of patients relapse or did not respond to initial treatment. One of the reasons for recurrence/relapse is the altered levels of ROS in tumor cells as well as in cancer-initiating stem cells. One of the critical issues is targeting the intracellular/extracellular ROS for significant antitumor response and relapse-free survival. Indeed, a large number of FDA-approved anticancer drugs are efficient to eliminate cancer cells and drug resistance by increasing ROS production. Thus, the modulation of oxidative stress response might represent a potential approach to eradicate cancer in combination with FDA-approved chemotherapies, radiotherapies as well as immunotherapies.


Assuntos
Carcinogênese/metabolismo , Neoplasias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Humanos , Recidiva Local de Neoplasia/metabolismo , Neoplasias/patologia , Oxirredução , Estresse Oxidativo/fisiologia , Transdução de Sinais/fisiologia
20.
Ann Thorac Surg ; 110(4): 1131-1138, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32442617

RESUMO

BACKGROUND: Mutations in the serine/threonine kinase 11 (STK11)/liver kinase B1 (LKB1) have been implicated in mediating resistance to checkpoint blockade among patients with advanced lung adenocarcinoma. We sought to examine the associations between clinicopathologic characteristics, tumor LKB1 expression, features of the immune microenvironment, and postoperative prognosis among patients with early stage lung adenocarcinoma undergoing surgical therapy. METHODS: Formalin-fixed, paraffin-embedded specimens of patients undergoing resection of stage I to III, chemotherapy-naïve adenocarcinomas (1997 to 2008) were analyzed using tissue microarray sectioning. Sublobar resections were excluded. Intratumoral LKB1/STK11 expression was quantified as H-score. In a subset, tumor-associated immune cell populations were quantified using whole tumor sections in peritumoral and intratumoral compartments. RESULTS: In all, 104 patients met inclusion criteria. Expression of LKB1/STK11 (median H-score 102.9) was higher in women (median 123.3) than in men (100, P = .004) and in never-smokers (median 145) than in former/current smokers (100, P = .002). Expression of LKB1/STK11 was positively correlated with intratumoral infiltration of cluster of differentiation (CD) 3+ (r = 0.351, P = .005), CD4+ (r = 0.436, P < .001), and CD8+ (r = 0.263, P = .049) cells. Patients with extrathoracic recurrence had lower tumor expression of LKB1/STK11 than did other patients with recurrent disease. On multivariate analysis, low LKB1/STK11 expression remained independently associated with poor disease-free survival and distant disease-free survival. CONCLUSIONS: Low LKB1/STK11 expression is associated with specific patient characteristics and poor postoperative prognosis in chemotherapy-naïve lung adenocarcinoma. Further investigation is warranted to delineate its clinical significance in the context of evaluating novel therapeutic agents in patients with resectable disease.


Assuntos
Adenocarcinoma de Pulmão/metabolismo , Neoplasias Pulmonares/metabolismo , Recidiva Local de Neoplasia/metabolismo , Estadiamento de Neoplasias , Proteínas Serina-Treonina Quinases/biossíntese , Adenocarcinoma de Pulmão/diagnóstico , Idoso , Biomarcadores Tumorais/metabolismo , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico , Prognóstico , Estudos Retrospectivos
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