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1.
Anticancer Res ; 41(9): 4505-4513, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34475076

RESUMO

BACKGROUND: The tumor vascular microenvironment has an important role in tumor progression and metastasis. The objective of this study was to assess the significance of metastatic hepatic tumor vascular microenvironment in relation to the response to systemic fluorouracil-based chemotherapy [folinic acid/fluorouracil/oxaliplatin (FOLFOX) or folinic acid/fluorouracil/irinotecan (FOLFIRI)]. PATIENTS AND METHODS: A total of 48 consecutive patients with colorectal cancer (CRC) with hepatic metastasis were retrospectively reviewed, and factors such as metastatic tumor vascular microenvironment, chemotherapy response and hepatic resection, were analyzed. Tumor angiogenesis was microscopically evaluated by microvessel density (MVD) in sections stained immunochemically with antibody to CD34 in patients with hepatic resection. Angiogenesis in the tumor microenvironment in association with ring enhancement (RE) on computed tomography (CT) was also examined. RESULTS: Microscopic examination revealed that peripheral RE on CT of the metastatic tumor was associated with tumor angiogenesis by MVD. The overall response rate after six courses of first-line chemotherapy for liver metastasis with RE on CT was 64% (23/36), whereas the response rate for those without RE was 25% (3/12), which was significantly lower, although the survival of patients with RE-positive and RE-negative tumors did not differ significantly. CONCLUSION: Peripheral RE of metastatic hepatic tumor on CT was associated with angiogenesis in the tumor microenvironment and higher chemotherapy response.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD34/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Camptotecina/análogos & derivados , Camptotecina/farmacologia , Camptotecina/uso terapêutico , Neoplasias Colorretais/diagnóstico por imagem , Neoplasias Colorretais/metabolismo , Angiografia por Tomografia Computadorizada , Feminino , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Humanos , Leucovorina/farmacologia , Leucovorina/uso terapêutico , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/metabolismo , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/farmacologia , Compostos Organoplatínicos/uso terapêutico , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento , Microambiente Tumoral/efeitos dos fármacos
2.
Anticancer Res ; 41(9): 4637-4644, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34475092

RESUMO

BACKGROUND/AIM: The aim of this study was to investigate frailty as a prognostic factor in patients with colorectal liver metastasis undergoing hepatectomy. PATIENTS AND METHODS: Eighty-seven patients who underwent hepatectomy at our institution were enrolled. Frailty was defined as a score of ≥4 on a clinical frailty scale. Patients were divided into frailty (n=29) and non-frailty (n=58) groups. RESULTS: Overall and cancer-specific survival rates were significantly worse in the frailty group compared with the non-frailty group, and multivariate analysis revealed frailty as an independent prognostic factor. Disease-free survival tended to be worse in the frailty group. Fifty-eight patients relapsed after the first hepatectomy. Twenty-one of 58 recurrent patients were allocated to the frailty group. After recurrence, chemotherapy was significantly more frequently performed in the non-frailty group compared with the frailty group. CONCLUSION: Frailty can predict the prognosis of patients with colorectal liver metastasis undergoing hepatectomy.


Assuntos
Neoplasias Colorretais/cirurgia , Fragilidade/epidemiologia , Hepatectomia/métodos , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/cirurgia , Recidiva Local de Neoplasia/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/tratamento farmacológico , Tratamento Farmacológico , Feminino , Fragilidade/complicações , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento
3.
Commun Biol ; 4(1): 950, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34376784

RESUMO

Colorectal cancer liver metastasis (CRCLM) has two major histopathological growth patterns: angiogenic desmoplastic and non-angiogenic replacement. The replacement lesions obtain their blood supply through vessel co-option, wherein the cancer cells hijack pre-existing blood vessels of the surrounding liver tissue. Consequentially, anti-angiogenic therapies are less efficacious in CRCLM patients with replacement lesions. However, the mechanisms which drive vessel co-option in the replacement lesions are unknown. Here, we show that Runt Related Transcription Factor-1 (RUNX1) overexpression in the cancer cells of the replacement lesions drives cancer cell motility via ARP2/3 to achieve vessel co-option. Furthermore, overexpression of RUNX1 in the cancer cells is mediated by Transforming Growth Factor Beta-1 (TGFß1) and thrombospondin 1 (TSP1). Importantly, RUNX1 knockdown impaired the metastatic capability of colorectal cancer cells in vivo and induced the development of angiogenic lesions in liver. Our results confirm that RUNX1 may be a potential target to overcome vessel co-option in CRCLM.


Assuntos
Neoplasias Colorretais/patologia , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/genética , Metástase Neoplásica/patologia , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Células HT29 , Humanos , Neoplasias Hepáticas/secundário
4.
Medicine (Baltimore) ; 100(34): e27070, 2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34449503

RESUMO

ABSTRACT: The objective of the current study is to analyze the clinical and demographic characteristics of patients with bone metastasis of small cell lung cancer (SCLC) and explore their survival predictors.We retrospectively extracted patients with bone metastasis of SCLC from the Surveillance, Epidemiology, and End Results database. We applied Cox regression analyses to identify independent survival predictor of overall survival (OS) and cancer-specific survival (CSS). Only significant predictors from univariable analysis were included for multivariable Cox analysis. Kaplan-Meier method was used to evaluate survival differences between groups by the log-rank test.A total of 5120 patients with bone metastasis of SCLC were identified and included for survival analysis. The 1-year OS and CSS rates of bone metastasis of SCLC were 19.8% and 21.4%, respectively. On multivariable analysis, gender, age, radiotherapy, chemotherapy, liver metastasis, brain metastasis, insurance status, and marital status independently predicted OS and CSS. There was no significant difference of OS and CSS in terms of race and tumor size.Independent predictors of survival were identified among patients with bone metastasis of SCLC, which could be valuable to clinicians in treatment decision. Patients with bone metastasis of SCLC may benefit from radiotherapy and chemotherapy.


Assuntos
Neoplasias Ósseas/secundário , Carcinoma de Pequenas Células do Pulmão/mortalidade , Carcinoma de Pequenas Células do Pulmão/patologia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/secundário , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Programa de SEER , Fatores Sexuais , Carcinoma de Pequenas Células do Pulmão/terapia , Fatores Socioeconômicos , Análise de Sobrevida , Carga Tumoral
5.
FASEB J ; 35(9): e21834, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34403553

RESUMO

Two distinct genetic mutational pathways characterized by either chromosomal instability or high-frequency microsatellite instability (MSI-H) are recognized in the pathogenesis of colorectal cancer (CRC). Recently, it has been shown that patients with primary CRC that displays MSI-H have a significant, stage-independent, multivariate survival advantage. Biological properties of CMS1 (MSI-H type) can affect therapeutic efficiencies of agents used in the treatment of CRC, and therefore become a new predictive factor of the treatment. But, the predictive impact of MSI-H status for adjuvant chemotherapy remains controversial. This study will assess whether there is any unnecessary or inappropriate use of treatment agents recommended for adjuvant therapy of stage 2 and 3 of disease and for palliative or curative treatment of liver metastatic disease in microsatellite instability high group, a molecular subtype of colon cancer. Within this scope, the efficiencies of fluorouracil- and oxaliplatin-based chemotherapeutic agents will be shown on stage 3 microsatellite instability high colon tumor cell lines first, and then a microfluidic model will be created, imitating the metastasis of colon cancer to the liver. In the microfluidic chip model, we will create in liver tissue, where the metastasis of microsatellite instability high colon cancer will be simulated; the effectiveness of chemotherapeutic agents, immunotherapy agents, and targeted agents on tumor cells as well as drug response will be assessed according to cell viability through released biomarkers from the cells. The proposed hypothesis study includes the modeling and treatment of patient-derived post-metastatic liver cancer in microfluidics which has priority at the global and our region and consequently develop personal medication.


Assuntos
Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Dispositivos Lab-On-A-Chip , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Instabilidade de Microssatélites , Metástase Neoplásica/tratamento farmacológico , Metástase Neoplásica/genética , Antineoplásicos/uso terapêutico , Quimioterapia Adjuvante , Neoplasias do Colo/patologia , Ensaios de Seleção de Medicamentos Antitumorais , Fluoruracila/uso terapêutico , Humanos , Fígado/efeitos dos fármacos , Fígado/imunologia , Fígado/patologia , Neoplasias Hepáticas/secundário , Modelos Biológicos , Metástase Neoplásica/patologia , Especificidade de Órgãos , Oxaliplatina/uso terapêutico
6.
JSLS ; 25(2)2021.
Artigo em Inglês | MEDLINE | ID: mdl-34248343

RESUMO

Introduction: Simultaneous robot assisted colon and liver resections are being performed more frequently at present due to the expanded adoption of the robotic platform for surgical management of metastatic colon cancer. However, this approach has not been studied in detail with only case series available in the literature. The aim of this systematic review was to evaluate the current body of evidence on the feasibility of performing simultaneous robotic colon and liver resections. Methods: A systematic review was performed through PubMed to identify relevant articles describing simultaneous colon and liver resections for metastatic colon cancer. Results: A total of 28 patients underwent simultaneous resections robotically with an average operative time of 420.3 minutes and average blood loss of 275.6 ml. Postoperative stay was 8.6 days on average with all cases achieving negative surgical margins. Conclusions: Robotic simultaneous resection of colorectal cancer with liver metastases is technically feasible and seems oncologically equivalent to open or laparoscopic surgery. Further studies are urgently needed to assess benefits of robotic surgery in the patient population.


Assuntos
Colectomia/métodos , Neoplasias do Colo/cirurgia , Hepatectomia/métodos , Neoplasias Hepáticas/cirurgia , Procedimentos Cirúrgicos Robóticos/métodos , Adulto , Idoso , Neoplasias do Colo/patologia , Terapia Combinada , Humanos , Laparoscopia/métodos , Neoplasias Hepáticas/secundário , Masculino , Margens de Excisão , Pessoa de Meia-Idade , Duração da Cirurgia
7.
J Surg Oncol ; 124(5): 791-800, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34196000

RESUMO

BACKGROUND: Oligometastasis, the presence of a small number of resectable metastatic tumors, usually has favorable outcomes. Here we examined whether the novel oligometastatic score (OLGS), which divides the number of colorectal liver metastases (CRLMs) by the time from colorectal resection to liver recurrence, better predicts CRLM patient survival than the commonly used clinical risk score. METHODS: A total of 143 patients who underwent curative hepatectomy for CRLMs between 2007 and 2018 were analyzed. We investigated their clinical characteristics and outcomes using OLGS. RESULTS: Of the 143 CRLM patients, 70 had synchronous CRLMs and 73 had metachronous CRLMs. Patients with metachronous CRLMs were divided into OLGS-low (n = 59) and OLGS-high (n = 14) subgroups. The 5-year overall survival (OS) rates after hepatectomy differed significantly between the subgroups (p < .001). In the multivariate Cox model, a high OLGS was an independent predictor of 5-year OS (p < .001), and the hazard ratio (HR) of the OLGS-high group (HR = 7.171) was higher than that of the high clinical risk score group (HR = 4.337). CONCLUSION: The OLGS, a simple and handy scoring system, better predicts the 5-year OS of patients with CRLMs after hepatectomy and warrants prospective validation.


Assuntos
Neoplasias Colorretais/mortalidade , Hepatectomia/mortalidade , Neoplasias Hepáticas/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/patologia , Neoplasias Colorretais/cirurgia , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Software , Taxa de Sobrevida
8.
J Cancer Res Clin Oncol ; 147(10): 2993-3002, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34302208

RESUMO

OBJECTIVE: This study aimed to evaluate the efficacy and safety of regorafenib plus drug-eluting beads-transarterial chemoembolization (DEB-TACE) versus regorafenib monotherapy in colorectal cancer liver metastases (CRLM) patients who failed standard treatment regimens. METHODS: Totally, 76 eligible CRLM patients were analyzed, among which 42 patients received regorafenib monotherapy (as regorafenib group) and 34 patients received regorafenib plus DEB-TACE (as regorafenib plus DEB-TACE group). RESULTS: Objective response rate (35.3% versus 7.1%, P = 0.002) and disease control rate (76.5% versus 47.6%, P = 0.011) were both increased in regorafenib plus DEB-TACE group compared with regorafenib group; meanwhile, negative conversion rate of carcinoembryonic antigen (66.7% versus 28.6%, P = 0.008) after treatment was elevated in regorafenib plus DEB-TACE group compared with regorafenib group. Notably, progression-free survival (PFS) (median value: 7.6 versus 4.1 months, P < 0.001) and overall survival (OS) (median value: 15.7 versus 9.2 months, P < 0.001) were both higher in regorafenib plus DEB-TACE group compared with regorafenib group. Furthermore, liver function indexes (alanine transaminase, aspartate aminotransferase, and cholinesterase levels) after treatment were all similar between the two groups (all P > 0.05). In addition, the occurrences of upper abdominal distending pain (P < 0.001), nausea and vomiting (P = 0.002) and fever (P = 0.002) were higher in regorafenib plus DEB-TACE group compared with regorafenib group, while the majority of these adverse events were mild and tolerable. CONCLUSIONS: Regorafenib plus DEB-TACE is superior to regorafenib monotherapy regarding treatment response, PFS and OS, while induces tolerable post-embolization syndrome in CRLM patients who fail standard treatment regimens.


Assuntos
Quimioembolização Terapêutica/mortalidade , Neoplasias Colorretais/terapia , Sistemas de Liberação de Medicamentos , Neoplasias Hepáticas/terapia , Compostos de Fenilureia/uso terapêutico , Piridinas/uso terapêutico , Terapia de Salvação , Neoplasias Colorretais/patologia , Terapia Combinada , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/secundário , Masculino , Microesferas , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida
9.
Anticancer Res ; 41(8): 3933-3940, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34281856

RESUMO

BACKGROUND: Oligometastatic cancer (OM) is possibly associated with relatively better survival outcomes. We attempted to identify cases in line with this OM concept. PATIENTS AND METHODS: A total of 130 cases with unresectable metastatic pancreatic cancer underwent non-curative surgery from April 2001 to December 2019. Sites of metastasis, clinicopathological information, and surgical outcomes were collected to formulate a better definition of OM. RESULTS: OM criteria were defined as having metastasis to a single organ, few countable lesions and low serum cancer antigen 19-9 level. The median overall survival after non-curative surgery of OM cases was 13.0 months and was significantly better than that of non-OM cases (8.4 months, p=0.003). CONCLUSION: We propose single-organ metastasis of limited tumor volume (H1 or P1/2 by the Japanese Society of Cancer of the Colon and Rectum classification) and low serum cancer antigen 19-9 level (<2,000 U/ml) as new criteria for defining OM pancreatic cancer.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Idoso , Antígeno CA-19-9/sangue , Carcinoma Ductal Pancreático/sangue , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/terapia , Feminino , Humanos , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/terapia , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/terapia , Masculino , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/terapia , Neoplasias Peritoneais/sangue , Neoplasias Peritoneais/mortalidade , Neoplasias Peritoneais/secundário , Neoplasias Peritoneais/terapia , Carga Tumoral
10.
Nutrients ; 13(6)2021 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-34199311

RESUMO

Despite multimodal treatment strategies, clinical outcomes of advanced stage colorectal cancer (CRC) patients remain poor. Neoadjuvant/adjuvant chemotherapy efficacy is limited due to chemoresistance, toxicity, and negative side effects. Since both melatonin and glycine have anti-cancer activities without relevant side effects, this study was designed to investigate their combined effects in experimental CRC liver metastases. CRC metastasis with CC531 cells were induced in male Wistar rats. Melatonin and glycine alone or their combination were supplemented for 14 days (n = 100). Blood parameters, a micro-computed tomography scan (tumor volume over time), and immunohistochemistry for Ki67 and CD31 expression in tumor tissue were compared between groups. Melatonin and glycine alone significantly reduced the tumor volume by 63.2% (p = 0.002) and 43% (p = 0.044) over time, respectively, while tumor volume increased by 8.7% in the controls. Moreover, treatment with melatonin and glycine alone reduced the tumor proliferation index. Most interestingly, the combination therapy did not have any influence on the above-mentioned tumor parameters. The leukocyte count was significantly increased with melatonin at the end of the experiment (p = 0.012) which was due to a high lymphocytes count. Tumor microvascular density was significantly reduced in all treatment groups. The results of this study suggest an inhibitory function for melatonin and glycine alone in the case of CRC liver metastasis growth by acting as natural antiangiogenic molecules, followed by angiogenesis-dependent cancer proliferation and immunomodulation.


Assuntos
Inibidores da Angiogênese/administração & dosagem , Neoplasias Colorretais/patologia , Glicina/administração & dosagem , Neoplasias Hepáticas/dietoterapia , Neoplasias Hepáticas/secundário , Melatonina/administração & dosagem , Animais , Linhagem Celular Tumoral , Dieta , Contagem de Leucócitos , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/patologia , Masculino , Microvasos , Transplante de Neoplasias , Ratos , Ratos Wistar , Carga Tumoral
11.
Medicine (Baltimore) ; 100(25): e26496, 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34160464

RESUMO

ABSTRACT: Esophageal cancer (EC) is relatively common; at the time of diagnosis, 50% of cases present with distant metastases, and most patients are men. This study aimed to examine and compare the clinicopathological characteristics and metastatic patterns of male EC (MEC) and female EC (FEC). In addition, risk factors associated with MEC prognosis were evaluated.The present study population was extracted from the Surveillance Epidemiology and End Results database. MEC characteristics and factors associated with prognosis were evaluated using descriptive analysis, the Kaplan-Meier method, and the Cox regression model.A total of 12,558 MEC cases were included; among them, 3454 cases had distant organ metastases. Overall, 27.5% of the entire cohort were patients with distant organ metastases. Compared with patients with non-metastatic MEC, patients with metastatic MEC were more likely to be aged ≤60 years, of Black and White race, have a primary lesion in the overlapping esophagus segments, and have a diagnosis of adenocarcinoma of poorly differentiated and undifferentiated grade that was treated with radiotherapy and chemotherapy rather than surgery; moreover, they were also more likely to be married and insured. In addition, patients with MEC were more likely to be aged ≤60 years, White race, and diagnosed with a primary lesion in the lower third of the esophagus and overlapping esophagus segments, and treated without chemotherapy, compared with those with FEC. Patients in the former group were also more likely than those in the latter group to be unmarried and have bone metastasis only and lung metastasis only. Liver, lung, and bone metastases separately, and simultaneous liver and lung metastases were associated with poor survival in MEC patients.Metastatic MEC is associated with clinicopathological characteristics and metastatic patterns different from those associated with non-metastatic MEC and metastatic FEC. Metastatic MEC and FEC patients may have similar prognoses. Distant organ metastasis may be associated with poor prognosis in patients with MEC and FEC.


Assuntos
Neoplasias Ósseas/epidemiologia , Neoplasias Encefálicas/epidemiologia , Neoplasias Esofágicas/patologia , Neoplasias Hepáticas/epidemiologia , Neoplasias Pulmonares/epidemiologia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Neoplasias Ósseas/secundário , Neoplasias Ósseas/terapia , Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/terapia , Quimiorradioterapia/estatística & dados numéricos , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/secundário , Neoplasias Esofágicas/terapia , Esofagectomia/estatística & dados numéricos , Esôfago , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/terapia , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/terapia , Masculino , Estado Civil/estatística & dados numéricos , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Programa de SEER/estatística & dados numéricos , Fatores Sexuais , Adulto Jovem
12.
Aging (Albany NY) ; 13(11): 14968-14988, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-34081622

RESUMO

Liver metastasis is a leading cause of death in patients with colorectal cancer (CRC). Increasing evidence demonstrates that competing endogenous RNA (ceRNA) networks play important roles in malignant cancers. The purpose of this study was to identify molecular markers and build a ceRNA network as a significant predictor of colorectal liver metastases (CRLM). By integrated bioinformatics analysis, we found that apolipoprotein C1 (APOC1) was upregulated in CRLM and associated with prognosis in patients with CRC and thereby established an APOC1-dependent ceRNA network. By survival analysis, expression analysis, and correlation analysis of each element in the ceRNA network, we identified that ZEB1-AS1, miR-335-5p and APOC1 regulated each other. We further experimentally confirmed that ZEB1-AS1 promoted a CRC progression via regulating the expression of miR-335-5p that controlled the expression of APOC1. Our findings indicate that the ZEB1-AS1-miR-335-5p-APOC1 ceRNA regulatory network is significantly valuable for better prognosis of patients with CRC and as a new therapeutic target for the treatment of CRLM.


Assuntos
Neoplasias Colorretais/patologia , Redes Reguladoras de Genes , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundário , MicroRNAs/genética , RNA Longo não Codificante/genética , Apolipoproteína C-I/metabolismo , Sequência de Bases , Linhagem Celular Tumoral , Movimento Celular/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Ontologia Genética , Humanos , MicroRNAs/metabolismo , Invasividade Neoplásica , Prognóstico , RNA Longo não Codificante/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Análise de Sobrevida
13.
Theranostics ; 11(14): 7018-7028, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093868

RESUMO

Rationale: Hepatectomy and adjuvant chemotherapy after resection of colorectal liver metastases (CRLM) may improve survival, however, patients which may benefit cannot currently be identified. Postoperative circulating tumor DNA (ctDNA) analysis can detect minimal residual disease (MRD) and predict the prognosis and efficacy of adjuvant chemotherapy. Our study aims to determine the impact of serial ctDNA analysis to predict the outcome among patients undergoing resection of CRLM. Methods: Between May 2018 and October 2019, 91 CRLM patients were prospectively enrolled. Whole exome sequencing was performed in 50 primary and 48 metastatic liver tissues. Targeted sequencing of 451 cancer relevant genes was performed in 50 baseline plasma to determine plasma-tissue concordance. We prospectively investigated changes in the amount and constitution of ctDNA in 271 serial plasma samples taken at different time points (baseline, pre-operation, post-operation, post-operative adjuvant chemotherapy (post-ACT) and recurrence) during the treatment of CRLM. Results: Detected molecular alterations were highly consistent among baseline ctDNA, primary and liver metastases tissue. Patients with a higher variant allele frequency (VAF) level at baseline ctDNA represent a higher tumor burden, and decreased ctDNA during pre-operative chemotherapy predicted better tumor response. Patients with detectable post-operative and post-ACT ctDNA were associated with significantly shorter recurrence-free survival (RFS). ROC analysis showed that post-ACT ctDNA status was superior to post-operative ctDNA status in predicting RFS with an AUROC of 0.79. A significant difference in overall recurrence rate was observed in patients with detectable vs undetectable levels of ctDNA after resection of CRLM (79.4% vs 41.7%) and after completion of adjuvant chemotherapy (77.3% vs 40.7%). During adjuvant chemotherapy, patients with decreased ctDNA VAF after adjuvant chemotherapy had a recurrence rate of 63.6%, compared to 92.3% in patients with increased ctDNA VAF. Conclusions: We envision that dynamic ctDNA analysis, especially in a post-ACT setting, might be used to not only reflect MRD but also to determine rational personalized adjuvant therapy after the resection of CRLM.


Assuntos
Quimioterapia Adjuvante , DNA Tumoral Circulante/sangue , Neoplasias Colorretais/sangue , Neoplasias Hepáticas/sangue , Recidiva Local de Neoplasia/sangue , Alelos , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , DNA Tumoral Circulante/genética , DNA Tumoral Circulante/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Correlação de Dados , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Hepatectomia , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Mutação , Recidiva Local de Neoplasia/genética , Neoplasia Residual , Prognóstico , Curva ROC , Sequenciamento Completo do Exoma
14.
Cancer Sci ; 112(9): 3744-3755, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34125460

RESUMO

MicroRNAs (miRNAs) are involved in the progression of many cancers through largely unelucidated mechanisms. The results of our present study identified a gene cluster, miR-221/222, that is constitutively upregulated in serum exosome samples of patients with colorectal carcinoma (CRC) with liver metastasis (LM); this upregulation predicts a poor overall survival rate. Using an in vitro cell coculture model, we demonstrated that CRC exosomes harboring miR-221/222 activate liver hepatocyte growth factor (HGF) by suppressing SPINT1 expression. Importantly, miR-221/222 plays a key role in forming a favorable premetastatic niche (PMN) that leads to the aggressive nature of CRC, which was further shown through in vivo studies. Overall, our results show that exosomal miR-221/222 promotes CRC progression and may serve as a novel prognostic marker and therapeutic target for CRC with LM.


Assuntos
Neoplasias Colorretais/patologia , Exossomos/metabolismo , Neoplasias Hepáticas/secundário , MicroRNAs/genética , Proteínas Secretadas Inibidoras de Proteinases/metabolismo , Animais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Progressão da Doença , Feminino , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , MicroRNAs/metabolismo , Família Multigênica , Prognóstico , Taxa de Sobrevida , Transfecção , Carga Tumoral , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Nat Commun ; 12(1): 3807, 2021 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-34155211

RESUMO

Hypoxia is prominent in solid tumors and a recognized driver of malignancy. Thus far, targeting tumor hypoxia has remained unsuccessful. Myo-inositol trispyrophosphate (ITPP) is a re-oxygenating compound without apparent toxicity. In preclinical models, ITPP potentiates the efficacy of subsequent chemotherapy through vascular normalization. Here, we report the results of an unrandomized, open-labeled, 3 + 3 dose-escalation phase Ib study (NCT02528526) including 28 patients with advanced primary hepatopancreatobiliary malignancies and liver metastases of colorectal cancer receiving nine 8h-infusions of ITPP over three weeks across eight dose levels (1'866-14'500 mg/m2/dose), followed by standard chemotherapy. Primary objectives are assessment of the safety and tolerability and establishment of the maximum tolerated dose, while secondary objectives include assessment of pharmacokinetics, antitumor activity via radiological evaluation and assessment of circulatory tumor-specific and angiogenic markers. The maximum tolerated dose is 12,390 mg/m2, and ITPP treatment results in 32 treatment-related toxicities (mostly hypercalcemia) that require little or no intervention. 52% of patients have morphological disease stabilization under ITPP monotherapy. Following subsequent chemotherapy, 10% show partial responses while 60% have stable disease. Decreases in angiogenic markers are noted in ∼60% of patients after ITPP and tend to correlate with responses and survival after chemotherapy.


Assuntos
Neoplasias do Sistema Digestório/tratamento farmacológico , Hipóxia/tratamento farmacológico , Fosfatos de Inositol/uso terapêutico , Administração Intravenosa , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/sangue , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Neoplasias do Sistema Digestório/patologia , Feminino , Humanos , Fosfatos de Inositol/farmacocinética , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão
16.
J Surg Oncol ; 124(4): 598-606, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34061356

RESUMO

BACKGROUND: Phosphorylated mammalian target of rapamycin (p-mTOR) plays a crucial role in the process of cancer progression. Common gene mutations of colorectal cancer lead to the activation of the PI3k/Akt/mTOR pathway. In this study, we determined whether p-mTOR expression in colorectal liver metastases is a predictive marker of prognosis following liver resection. METHODS: Eighty-one patients with colorectal liver metastases who had undergone curative resection were evaluated using immunohistochemistry of p-mTOR. Data regarding clinicopathological features and patient survival were analyzed. RESULTS: The p-mTOR expression in colorectal liver metastases was detected in 55 (67.9%) patients. Patients whose metastases had high p-mTOR expression showed a significantly lower overall survival rate after resection as compared to patients with low p-mTOR expression (p = 0.016), while there was no significant difference in the disease-free survival between the two groups. Repeat resection for recurrence was performed more frequently in patients with p-mTOR positive than others (p = 0.024). Multivariate analysis showed that p-mTOR expression was an independent prognostic factor of overall survival after liver resection (p = 0.019). CONCLUSIONS: mTOR was frequently activated in colorectal liver metastases, and the p-mTOR expression was a biological marker for predicting the overall survival of patients with colorectal liver metastases following liver resection.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/mortalidade , Regulação Neoplásica da Expressão Gênica , Hepatectomia/mortalidade , Neoplasias Hepáticas/mortalidade , Recidiva Local de Neoplasia/mortalidade , Serina-Treonina Quinases TOR/metabolismo , Biomarcadores Tumorais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Neoplasias Colorretais/cirurgia , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia , Fosforilação , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Serina-Treonina Quinases TOR/genética
17.
J Surg Oncol ; 124(4): 619-626, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34081792

RESUMO

BACKGROUND: Surgical margin status remains a controversial factor in predicting the outcome of colorectal liver metastases (CRLM) resection. Our study aims to evaluate the effects of surgical margins on oncologic outcomes with regard to the genetic and morphological evaluation (GAME) score. METHODS: R1 resection was defined as having a less than 1 mm margin width. Patients who underwent surgery for CRLM from January 2005 to December 2018 were recruited. The patients were divided into two risk subgroups, namely, the low or medium risk (GAME 0-3) and high-risk (GAME score 4 or more) groups. The effects of margin status on overall survival (OS) and recurrence-free survival rate (RFS) were examined. RESULTS: In total, 661 patients were recruited, among which 159 (24.1%) had R1 resection. Before hepatectomy, 514 patients showed a low or medium risk (R1 resection: n = 124), while 147 patients demonstrated a high risk (R1 resection: n = 35). In the whole cohort, multivariable analysis did show that R1 resection was associated with worse RFS and OS. While further research only found that in the low or medium risk group, R1 resection was related to poor OS and RFS. Meanwhile, in the high risk group, no significant difference was found in the median OS and RFS among patients with R0 or R1 resection. CONCLUSION: The prognostic role of margin status varied according to the GAME score. Margin clearance only improved survival rates in patients with low or medium GAME score. In contrast, R1 resection demonstrated similar oncologic outcomes with R0 resection in patients with high GAME score.


Assuntos
Neoplasias Colorretais/patologia , Hepatectomia/mortalidade , Neoplasias Hepáticas/secundário , Margens de Excisão , Recidiva Local de Neoplasia/patologia , Idoso , Neoplasias Colorretais/genética , Neoplasias Colorretais/cirurgia , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/cirurgia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
18.
J Cancer Res Clin Oncol ; 147(9): 2609-2619, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34115241

RESUMO

BACKGROUND: Intra-abdominal infection after curative surgery for colorectal cancer is a serious complication associated with an increased risk of recurrence. Lipopolysaccharides (LPS)-an essential component of the cell wall of Gram-negative bacteria-were found to exert a protumorigenic effect by stimulating the inflammatory pathology and formation of neutrophil extracellular traps (NETs). This study was conducted to test whether LPS-induced formation of NETs promotes the development of cancer and metastasis. METHODS: The clinical characteristics, incidence of relapse, and serum myeloperoxidase-DNA complexes of 40 patients with infection and 40 patients without infection after curative surgery were analyzed. The effects of LPS on the induction of NETs were evaluated in a mouse model of colorectal cancer and liver metastasis. The toll-like receptor 9 (TLR9)-a DNA receptor-was knocked down to assess its effect on the mitogen-activated protein kinase pathway and activities implicated in the formation of NETs. RESULTS: Analysis of the clinical data obtained from these patients showed the significant relation of the formation of NETs and incidence of metastasis and survival rates. Subsequent in vitro experiments revealed an increased level of citrullinated-histone H3 and myeloperoxidase-DNA in LPS-injected mice with colorectal cancer. In the mimic metastatic model, injection of LPS enhanced the metastatic capacity, which was then attenuated by DNase I. This suggested that the formation of NETs was activated by LPS. Injection of TLR9-knockdown HCT116 cells in mice, followed by induction through LPS, mitigated the level of citrullinated-histone H3 and myeloperoxidase-DNA. This finding implied that the formation of NETs was suppressed. CONCLUSION: These findings shed light on the mechanism underlying the relationship between the elevated rate of colorectal cancer recurrence in patients who underwent surgery and the incidence of infection. This mechanism involves the protumorigenic activities of LPS-induced formation of NETs. The NETs which could be mediated by the TLR9 and the mitogen-activated protein kinase signaling pathway.


Assuntos
Neoplasias Colorretais/patologia , Modelos Animais de Doenças , Armadilhas Extracelulares , Lipopolissacarídeos/efeitos adversos , Neoplasias Hepáticas/secundário , Recidiva Local de Neoplasia/patologia , Neutrófilos/imunologia , Idoso , Animais , Apoptose , Estudos de Casos e Controles , Movimento Celular , Proliferação de Células , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/cirurgia , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/cirurgia , Masculino , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/cirurgia , Prognóstico , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Clin Nucl Med ; 46(8): e424-e427, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-34186543

RESUMO

ABSTRACT: A 52-year-old woman previously treated for a stage IIIc high-grade ovarian serous carcinoma presented right upper quadrant abdominal pain, 3 years after extended surgery and chemotherapy. Abdominal CT, MRI, and 18F-FDG PET/CT showed a right hepatic mass, consistent for lone recurrence nearby the hepatic lateral fissure. Preoperative and histologic examination identified a peritoneal lateral fissure lesion. The patient underwent atypic segment 5 segmentectomy. She has been disease-free for 3 years now. Advanced ovarian cancer can be responsible for perihepatic sulcus lesions, such as this right fissure lesion. They should not be mistaken for inoperable parenchyma metastases.


Assuntos
Neoplasias Hepáticas/secundário , Neoplasias Ovarianas/patologia , Neoplasias Peritoneais/secundário , Diagnóstico Diferencial , Feminino , Fluordesoxiglucose F18 , Humanos , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada
20.
Turkiye Parazitol Derg ; 45(2): 146-148, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34103293

RESUMO

A 65-year-old man, with signs of acute colon obstruction, was diagnosed with rectal tumour and liver hydatid cyst. Additionally, a focal liver lesion in segment 1 was detected. Moreover, physical examination revealed hepatomegaly and abdominal distension. Thus, rectal resection and small liver lesion biopsy was performed. Serological and pathohistological analyses showed concomitant presence of hydatid cyst and colorectal metastasis in the liver. Hence, the cyst was treated with anthelmintic therapy, and patient lived another year after the diagnosis. To the best of our knowledge, cases of concomitant hydatid cyst and colorectal liver metastasis has never been reported; thus, this article addresses a unique case of coexistence between these two serious liver diseases.


Assuntos
Neoplasias Colorretais/patologia , Equinococose Hepática/complicações , Neoplasias Hepáticas/secundário , Idoso , Animais , Anti-Helmínticos/uso terapêutico , Neoplasias Colorretais/complicações , Neoplasias Colorretais/cirurgia , Equinococose Hepática/diagnóstico , Equinococose Hepática/terapia , Echinococcus/isolamento & purificação , Humanos , Fígado/parasitologia , Fígado/patologia , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/terapia , Masculino
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