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1.
Anticancer Res ; 39(8): 4561-4568, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366560

RESUMO

BACKGROUND/AIM: Neoplastic spindle cells (NSCs) are believed to play a role in cancer invasion and metastasis, as well as in poor prognosis. The clinicopathological characteristics and prognostic relevance of NSCs was investigated in gallbladder cancer. MATERIALS AND METHODS: Specimens were obtained from 62 patients with gallbladder cancer who underwent surgery. The emergence of NSCs and their correlation with clinicopathological factors, prognosis, and EMT markers was evaluated. RESULTS: The NSC grade correlated with tumor size, preoperative CA19-9, surgical margin, the degree of differentiation, the depth of invasion, lymph node metastasis, lymphatic invasion, vascular invasion, and perineural invasion. Multivariate analysis of overall survival showed that NSCs were an independent prognostic factor. A correlation between NSCs and EMT was also suggested. CONCLUSION: NSCs are an independent prognostic factor for patients with postoperative gallbladder cancer, which also suggests a correlation between NSCs and EMT.


Assuntos
Biomarcadores Tumorais/sangue , Neoplasias da Vesícula Biliar/patologia , Invasividade Neoplásica/patologia , Prognóstico , Adulto , Idoso , Antígeno CA-19-9/sangue , Células Epiteliais/patologia , Transição Epitelial-Mesenquimal/genética , Feminino , Neoplasias da Vesícula Biliar/sangue , Neoplasias da Vesícula Biliar/genética , Neoplasias da Vesícula Biliar/cirurgia , Humanos , Estimativa de Kaplan-Meier , Metástase Linfática , Masculino , Margens de Excisão , Pessoa de Meia-Idade , Invasividade Neoplásica/genética
2.
J Surg Oncol ; 120(4): 603-610, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31292970

RESUMO

BACKGROUND: Gallbladder adenocarcinoma is often incidentally identified following cholecystectomy. We hypothesized that intraoperative bile spillage would be a negative prognostic factor. METHODS: A retrospective review of patients treated at a cancer center with histologically confirmed gallbladder adenocarcinoma, 2009-2017, was performed. Patient, disease, and treatment factors were analyzed in terms of progression-free survival (PFS) and overall survival (OS). RESULTS: Sixty-six patients were identified. Tumor stage was T1 (n = 8, 12%), T2 (n = 23, 35%), T3 (n = 35, 53%). Node stage was N0 (n = 22, 33%), N1+ (n = 26, 39%), Nx (n = 18, 27%). Operations included cholecystectomy alone (n = 27, 36%), cholecystectomy and partial hepatectomy (n = 30, 45%), or hepaticojejunostomy (n = 9, 14%). Median PFS was 7 months (interquartile range [IQR], 2-19); median OS was 16 months (IQR, 10-31). Subset multivariate proportional hazards regression of 41 patients who underwent initial cholecystectomy showed decreased PFS was associated with intraoperative spillage (n = 12, 29%; hazard ratio [HR], 5.5; P = .0014); decreased OS was associated with drain placement (n = 21, 51%; HR, 8.1; P = .006). CONCLUSIONS: Intraoperative bile spillage and surgical drain placement at initial cholecystectomy are negatively associated with PFS and OS in gallbladder adenocarcinoma. Explicit documentation of spillage and drain placement rationale is critical, possibly indicating locally advanced disease and prompting stronger consideration of systemic therapy before definitive resection.


Assuntos
Adenocarcinoma/mortalidade , Bile , Colecistectomia/mortalidade , Neoplasias da Vesícula Biliar/mortalidade , Vesícula Biliar/lesões , Complicações Intraoperatórias/mortalidade , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Idoso , Feminino , Seguimentos , Neoplasias da Vesícula Biliar/patologia , Neoplasias da Vesícula Biliar/cirurgia , Humanos , Achados Incidentais , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
3.
Am Surg ; 85(6): 671-675, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31267910

RESUMO

This study aims to provide some experience in diagnosis and treatment of unexpected gallbladder cancer (UGBC) and find the major risk factors. Retrospective data were collected and analyzed on 22 patients who were diagnosed with UGBC during or after laparoscopic cholecystectomy from January 2013 to January 2018 at our hospital. Average age of the patients was (60.2 ± 12.8) years (range, 42-83 years). Among them, there were 6 men and 16 women. Gallbladder stones, atrophic gallbladder, uneven thickened wall of the gallbladder, and choledocholithiasis were found to be the major risk factors. Eight patients (36.4%) were diagnosed intraoperatively. Seven cases (31.8%) were at the T1 stage; of these, three were treated with laparoscopic cholecystectomy; two were converted to cholecystectomy; and two underwent cholecystectomy, lymph node dissection, and liver resection. Eight (36.4%) T2 patients, five (22.7%) T3 patients, and one T4 patient had radical cholecystectomy. Partial cholecystectomy and cholecystotomy were carried out in another T4 patient. T1 patients did not receive chemotherapy or radiotherapy. Eleven had chemotherapy and four received chemoradiotherapy. The follow-up period ranged from six months to five years. The one-year survival rate for T1 to T4 patients was 100 per cent, 75 per cent, 40 per cent, and 0 per cent, respectively. A high index of clinical suspicion of UGBC is needed if one patient suffered from both gallbladder stones and choledocholithiasis with atrophic gallbladder or uneven thickened wall of the gallbladder preoperatively. To avoid more UGBC and reoperation, imaging examinations combined with tumor marker tests and intraoperative histopathologic examination are highly recommended.


Assuntos
Causas de Morte , Colecistectomia Laparoscópica/métodos , Colelitíase/cirurgia , Neoplasias da Vesícula Biliar/patologia , Neoplasias da Vesícula Biliar/cirurgia , Achados Incidentais , Adulto , Fatores Etários , Idoso , Colecistectomia Laparoscópica/efeitos adversos , Colelitíase/diagnóstico por imagem , Bases de Dados Factuais , Feminino , Neoplasias da Vesícula Biliar/diagnóstico por imagem , Neoplasias da Vesícula Biliar/mortalidade , Humanos , Incidência , Complicações Intraoperatórias/patologia , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/cirurgia , Prognóstico , Reoperação/métodos , Estudos Retrospectivos , Medição de Risco , Índice de Gravidade de Doença , Fatores Sexuais , Análise de Sobrevida
4.
Cancer Sci ; 110(8): 2493-2506, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31215139

RESUMO

Gallbladder cancer (GBC) is the most common malignancy of the bile duct and has a high mortality rate. Here, we demonstrated that BRD4 inhibitor JQ1 and histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) synergistically inhibited the GBC cells in vitro and in vivo. Our results showed that cotreatment with JQ1 and SAHA significantly inhibited proliferation, cell viability and metastasis, and induced apoptosis and G2/M arrest in GBC cells, with only minor effects in benign cells. In vivo, tumor volumes and weights of GBC xenograft models were significantly decreased after treatment with JQ1 or SAHA; meanwhile, the cotreatment showed the strongest effect. Further study indicated that the above anticancer effects was associated with the downregulation of BRD4 and suppression of PI3K/AKT and MAPK/ERK pathways. These findings highlight JQ1 and SAHA as potential therapeutic agents and their combination as a promising therapeutic strategy for GBC.


Assuntos
Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Neoplasias da Vesícula Biliar/tratamento farmacológico , Inibidores de Histona Desacetilases/farmacologia , Proteínas Nucleares/antagonistas & inibidores , Fatores de Transcrição/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Fase G2/efeitos dos fármacos , Neoplasias da Vesícula Biliar/patologia , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Nus , Metástase Neoplásica/tratamento farmacológico , Metástase Neoplásica/patologia , Vorinostat/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
5.
Yonsei Med J ; 60(7): 604-610, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31250573

RESUMO

PURPOSE: This study aimed to determine the prognostic value of new quantitative parameters of ¹8F-fluorodeoxyglucose positron emission tomography/computed tomography (¹8F-FDG PET/CT), including metabolic tumor volume (MTV), in patients with locally advanced and metastatic gallbladder cancer (GBC). MATERIALS AND METHODS: In total, 83 patients initially diagnosed with locally advanced and metastatic GBC and who underwent ¹8F-FDG PET/CT at the time of initial diagnosis were retrospectively reviewed. The metabolic volume-based PET parameters of primary tumors and metastatic lesions were measured, including maximum and average standardized uptake values (SUV), MTV, and total lesion glycolysis. An overall survival (OS) analysis was performed using the Kaplan-Meier method with PET and clinical parameters. A Cox proportional hazards regression analysis was performed to determine independent prognostic factors. RESULTS: In univariate analysis, pathologic differentiation (p<0.001), performance status (PS; p=0.003), C-reactive protein (CRP) level (p=0.009), and PET-related SUVmt max (the highest SUV among the metastatic lesions) (p=0.040) and MTVtotal (the sum of the MTVs of both the primary and metastatic lesions) (p=0.031), were significant for OS. In multivariate analysis, MTVtotal (hazard ratio: 2.07; 95% confidence interval: 1.23-3.48; p=0.006) remained significant for the prediction of OS, as did differentiation (p=0.001), PS (p=0.001), and CRP (p=0.039). CONCLUSION: In locally advanced and metastatic GBC, volume-based PET/CT parameters of the total tumor burden of malignancy, such as MTVtotal, were found to be useful for the identification of patients with poor prognosis.


Assuntos
Fluordesoxiglucose F18 , Neoplasias da Vesícula Biliar/metabolismo , Neoplasias da Vesícula Biliar/patologia , Glicólise , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Carga Tumoral , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Neoplasias da Vesícula Biliar/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos
6.
Virchows Arch ; 475(1): 59-66, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31177317

RESUMO

Sarcomatoid carcinomas recently came into the spotlight through genetic profiling studies and also as a distinct model of epithelial-mesenchymal transition. The literature on sarcomatoid carcinomas of gallbladder is limited. In this study, 656 gallbladder carcinomas (GBC) were reviewed. Eleven (1.7%) with a sarcomatoid component were identified and analyzed in comparison with ordinary GBC (O-GBC). Patients included 9 females and 2 males (F/M = 4.5 vs. 3.9) with a mean age-at-diagnosis of 71 (vs. 64). The median tumor size was 4.6 cm (vs. 2.5; P = 0.01). Nine patients (84%) presented with advanced stage (pT3/4) tumor (vs. 48%). An adenocarcinoma component constituting 1-75% of the tumor was present in nine, and eight had surface dysplasia/CIS; either in situ or invasive carcinoma was present in all cases. An intracholecystic papillary-tubular neoplasm was identified in one. Seven showed pleomorphic-sarcomatoid pattern, and four showed subtle/bland elongated spindle cells. Three had an angiosarcomatoid pattern. Two had heterologous elements. One showed few osteoclast-like giant cells, only adjacent to osteoid. Immunohistochemically, vimentin, was positive in six of six; P53 expression was > 60% in six of six, keratins in six of seven, and p63 in two of six. Actin, desmin, and S100 were negative. The median Ki67 index was 40%. In the follow-up, one died peri-operatively, eight died of disease within 3 to 8 months (vs. 26 months median survival for O-GBC), and two were alive at 9 and 15 months. The behavior overall was worse than ordinary adenocarcinomas in general but was not different when grade and stage were matched. In summary, sarcomatoid component is identified in < 2% of GBC. Unlike sarcomatoid carcinomas in the remainder of pancreatobiliary tract, these are seldom of the "osteoclastic" type and patients present with large/advanced stage tumors. Limited data suggests that these tumors are aggressive with rapid mortality unlike pancreatic osteoclastic ones which often have indolent behavior.


Assuntos
Adenocarcinoma/patologia , Biomarcadores Tumorais/análise , Carcinoma in Situ/patologia , Neoplasias da Vesícula Biliar/patologia , Neoplasias Complexas Mistas/patologia , Sarcoma/patologia , Adenocarcinoma/química , Adenocarcinoma/mortalidade , Adenocarcinoma/cirurgia , Idoso , Carcinoma in Situ/química , Carcinoma in Situ/mortalidade , Carcinoma in Situ/cirurgia , Feminino , Neoplasias da Vesícula Biliar/química , Neoplasias da Vesícula Biliar/mortalidade , Neoplasias da Vesícula Biliar/cirurgia , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Neoplasias Complexas Mistas/química , Neoplasias Complexas Mistas/mortalidade , Neoplasias Complexas Mistas/cirurgia , Sarcoma/química , Sarcoma/mortalidade , Sarcoma/cirurgia , Fatores de Tempo , Resultado do Tratamento
7.
Anticancer Res ; 39(6): 3095-3100, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31177154

RESUMO

BACKGROUND/AIM: To retrospectively evaluate the outcome of patients with unresectable biliary cholangiocarcinoma (CC) treated with radiotherapy (RT) plus/minus chemotherapy (CHT). MATERIALS AND METHODS: Data of patients with intrahepatic CC (ICC), Klatskin's tumor (KT), distal extrahepatic CC (ECC), and gallbladder cancer (GBC) diagnosed from 1991 to 2017 were retrospectively analyzed. The treatment was mainly based on RT plus concurrent CHT +/- brachytherapy (BRT) boost. The Kaplan-Meier method was used to calculate survival curves that were compared using the log-rank test. RESULTS: Seventy-six patients were included in this analysis (males: 59%; females: 41%; median age: 66.5 years). A minority of patients (7.9%) were treated for disease recurrence after surgery. According to TNM, 78.5% of patients had T stage >3 and 77.6% of patients were treated with concurrent CHT-RT while 22.3% received RT followed by sequential CHT. Median RT dose was 50 Gy (range: 16-75 Gy) delivered with conventional fractionation. CHT was based on Gemcitabine or 5-fluorouracil. BRT was prescribed to 51.3% of patient with a median dose of 14 Gy. Reported Grade ≥3 acute GI and hematological toxicity were 13.2% and 8.1%, respectively. No other severe acute toxicities were reported. One- and 2-year overall survival (OS) were 58.1% and 25.8%, respectively (median: 13.5 months), while 1- and 2-year progression-free survival (PFS) were 43.4% and 9.4%, respectively. None of the following variables had a significant impact on OS and PFS: BRT boost, tumor site, concurrent CHT, and the drugs used in concurrent CHT. In contrast, patients receiving RT with 2D technique showed a PFS significantly higher compared to patients treated with the 3D technique (median: 15.5 vs. 8.5 months; p=0.02). CONCLUSION: Combined modality treatment (RT+CHT±BRT) in unresectable biliary cancer was associated with acceptable toxicity and OS comparable to the actual standard treatment (CHT). The significantly improved PFS in patients undergoing 2D-RT raises doubts regarding the adequacy of target delineation in these neoplasms.


Assuntos
Neoplasias dos Ductos Biliares/terapia , Braquiterapia , Quimiorradioterapia , Colangiocarcinoma/terapia , Neoplasias da Vesícula Biliar/terapia , Tumor de Klatskin/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/administração & dosagem , Neoplasias dos Ductos Biliares/mortalidade , Neoplasias dos Ductos Biliares/patologia , Braquiterapia/efeitos adversos , Braquiterapia/mortalidade , Quimiorradioterapia/efeitos adversos , Quimiorradioterapia/mortalidade , Colangiocarcinoma/mortalidade , Colangiocarcinoma/patologia , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Fracionamento da Dose de Radiação , Feminino , Fluoruracila/administração & dosagem , Neoplasias da Vesícula Biliar/mortalidade , Neoplasias da Vesícula Biliar/patologia , Humanos , Tumor de Klatskin/mortalidade , Tumor de Klatskin/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Intervalo Livre de Progressão , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo
8.
BMC Neurol ; 19(1): 95, 2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-31077150

RESUMO

BACKGROUND: Gall bladder cancer (GBC) is associated with abdominal pain, lump, nausea, vomiting, and jaundice due to either gall bladder mass or the involved adjacent peritoneal structures. Gall bladder cancer presenting as refractory epilepsy is rare. Here we report a young female GBC patient who presented with an atypical and refractory frontal lobe seizures as the first manifestation of gall bladder cancer. CASE PRESENTATION: A 46 years young female presented first time to the hospital with uncontrolled seizures and headache in 5 months duration. Seizures were very atypical in semiology with ptosis and mydriasis to either side along with ipsilateral ocular deviation. The episodes were bilateral but right eyelid ptosis, mydriasis and right horizontal conjugate deviation were frequent. MRI brain showed encephalomalacia in the left frontal region on axial T2 and coronal T1 weighted images without any enhancement on gadolinium contrast. CECT abdomen revealed a heterogeneously enhancing gall bladder mass with the evidence of lung metastasis from chest CT scan. CSF for malignant cytology was negative. Seizures were refractory to the treatment. CONCLUSION: Though CNS involvement is uncommon but it can be the only presentation in gall bladder cancer.


Assuntos
Neoplasias Encefálicas/secundário , Neoplasias da Vesícula Biliar/patologia , Convulsões/etiologia , Feminino , Lobo Frontal/patologia , Humanos , Imagem por Ressonância Magnética , Pessoa de Meia-Idade
9.
Biomed Res Int ; 2019: 9205851, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31019975

RESUMO

The effects of standard clinical therapies including surgery and chemotherapy are poor in advanced gallbladder cancer (GBC). There are a few reported cases of human epidermal growth factor receptor 2 (HER2)-positive GBC that responded well to trastuzumab. But trastuzumab has not yet been used to treat HER2-negative GBC. In this study, we investigated the cytotoxic effects of different combined therapies with trastuzumab and gemcitabine and/or 5-fluorouracil on HER2-negative GBC cell lines in vitro and in vivo. Trastuzumab alone showed almost no cytotoxicity to GBC cells with originally low HER2 gene amplification. Sequential therapy with chemotherapy followed by trastuzumab showed superiority over reverse sequential chemotherapy (P<0.05), concurrent combined chemotherapy (P<0.05), chemotherapy alone (P<0.05), and trastuzumab alone (P<0.05) in terms of cytotoxicity. Sequential therapy with chemotherapy followed by trastuzumab nearly completely inhibited cell viability in HER2-negative GBC cells. Similar results were observed with regard to apoptosis. Western blot analysis showed that gemcitabine/5-fluorouracil increased the expressions of total and phosphorylated forms of HER2, thus enhancing the cytotoxicity of trastuzumab. In vivo study verified the results of in vitro study by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling assay and immunohistochemical analysis. Moreover, not only the lightest tumor bearing but also the best survival state was detected in sequential therapy with chemotherapy followed by trastuzumab group compared with other groups. Our in vivo and in vitro data suggest that sequential therapy with gemcitabine/5-fluorouracil followed by trastuzumab represents a novel and promising therapeutic strategy against HER2-negative GBC. The upregulation of phosphorylated HER2 and phosphorylated-AKT induced by gemcitabine/5-fluorouracil treatment shows that HER2/AKT pathway is triggered.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias da Vesícula Biliar , Animais , Apoptose/efeitos dos fármacos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Feminino , Fluoruracila/farmacologia , Neoplasias da Vesícula Biliar/tratamento farmacológico , Neoplasias da Vesícula Biliar/metabolismo , Neoplasias da Vesícula Biliar/patologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Receptor ErbB-2/metabolismo , Trastuzumab/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Harefuah ; 158(4): 233-236, 2019 Apr.
Artigo em Hebraico | MEDLINE | ID: mdl-31032554

RESUMO

INTRODUCTION: The clinicopathologic characterization of tumoral intra-epithelial neoplasms of the gallbladder is fairly limited compared to that of similar tumors of the pancreatobiliary system. Until recently, pre-malignant lesions of the gallbladder were mostly reported as adenomas, which were microscopic and therefore regarded as benign and clinically inconsequential, whereas papillary lesions have been largely regarded as a papillary subtype of gallbladder invasive adenocarcinoma. In an attempt to create a unified terminology for these tumors, the term Intracholecystic papillary-tubular neoplasm (ICPN) was proposed to include all exophytic intra-epithelial tumors of the gallbladder measuring ≥1 cm under one category. A few studies which have retrospectively analyzed tumors fulfilling this category found them to be remarkable analogous to the more well-characterized intra-epithelial tumors of the pancreato-biliary system such as IPMN of the pancreas and IPNB of the bile ducts and as such they also represent an 'adenoma-carcinoma' sequence in the gallbladder. Since then a number of case series have been published which attempted to characterize the clinical and pathological features of these tumors and their relationship with invasive carcinoma. In this paper we report three cases of ICPN which represent different stages of the 'adenoma-carcinoma' sequence.


Assuntos
Adenocarcinoma , Adenoma , Neoplasias da Vesícula Biliar , Adenocarcinoma/patologia , Adenoma/patologia , Neoplasias da Vesícula Biliar/patologia , Humanos , Invasividade Neoplásica , Estudos Retrospectivos
12.
Mol Cancer ; 18(1): 82, 2019 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-30953511

RESUMO

BACKGROUND: Gallbladder cancer is the most common biliary tract malignancy and not sensitive to chemotherapy. Autophagy is an important factor prolonging the survival of cancer cells under chemotherapeutic stress. We aimed to investigate the role of long non-coding RNAs (lncRNAs) in autophagy and chemoresistance of gallbladder cancer cells. METHODS: We established doxorubicin (Dox)-resistant gallbladder cancer cells and used microarray analysis to compare the expression profiles of lncRNAs in Dox-resistant gallbladder cancer cells and their parental cells. Knockdown or exogenous expression of lncRNA combined with in vitro and in vivo assays were performed to prove the functional significance of lncRNA. The effects of lncRNA on autophagy were assessed by stubRFP-sensGFP-LC3 and western blot. We used RNA pull-down and mass spectrometry analysis to identify the target proteins of lncRNA. RESULTS: The drug-resistant property of gallbladder cancer cells is related to their enhanced autophagic activity. And we found a lncRNA ENST00000425894 termed gallbladder cancer drug resistance-associated lncRNA1 (GBCDRlnc1) that serves as a critical regulator in gallbladder cancer chemoresistance. Furthermore, we discovered that GBCDRlnc1 is upregulated in gallbladder cancer tissues. Knockdown of GBCDRlnc1, via inhibiting autophagy at initial stage, enhanced the sensitivity of Dox-resistant gallbladder cancer cells to Dox in vitro and in vivo. Mechanically, we identified that GBCDRlnc1 interacts with phosphoglycerate kinase 1 and inhibits its ubiquitination in Dox-resistant gallbladder cancer cells, which leads to the down-regulation of autophagy initiator ATG5-ATG12 conjugate. CONCLUSIONS: Our findings established that the chemoresistant driver GBCDRlnc1 might be a candidate therapeutic target for the treatment of advanced gallbladder cancer.


Assuntos
Autofagia/genética , Neoplasias da Vesícula Biliar/genética , Regulação Neoplásica da Expressão Gênica , Fosfoglicerato Quinase/genética , RNA Longo não Codificante/genética , Idoso , Animais , Antibióticos Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Proteína 12 Relacionada à Autofagia/genética , Proteína 12 Relacionada à Autofagia/metabolismo , Proteína 5 Relacionada à Autofagia/genética , Proteína 5 Relacionada à Autofagia/metabolismo , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Neoplasias da Vesícula Biliar/tratamento farmacológico , Neoplasias da Vesícula Biliar/metabolismo , Neoplasias da Vesícula Biliar/patologia , Humanos , Masculino , Camundongos , Camundongos Nus , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Pessoa de Meia-Idade , Oligorribonucleotídeos/genética , Oligorribonucleotídeos/metabolismo , Fosfoglicerato Quinase/metabolismo , RNA Longo não Codificante/agonistas , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Ubiquitinação/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Surg Technol Int ; 34: 101-106, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30888678

RESUMO

Neuroendocrine carcinoma (NEC) of the gallbladder is highly aggressive and has a poor prognosis even after curative resection. The purpose of this study was to collate and analyze published data to clarify the surgical outcome of NEC of the gallbladder and the relationships between potential prognostic factors and survival after surgery. We surveyed worldwide literature from 1981 to 2018 and obtained clinicopathological data for 65 patients who had undergone surgical resection for NEC of the gallbladder. The relationships between potential prognostic factors and survival rates were examined by the Kaplan-Meier method and the log-rank test. The 1-, 3-, and 5-year disease-specific survival rates after surgery were 70.2%, 39.3%, and 29.5%, respectively. A multivariate analysis revealed that the factors that were independently associated with poor outcomes after surgery in patients with NEC of the gallbladder were older age, higher pathologic T stage, and positive lymph node metastasis. The major sites of recurrence were the liver, lung, lymph node, and local recurrence. The median time to the event for recurrence was 4.0 months. Even when curative resection was achieved, 36.9% of patients exhibited recurrence within 12 months after curative resection of gallbladder NEC. Although NEC of the gallbladder remains a rare disease worldwide, its poor prognosis, even after curative resection, demands further epidemiological and pathological studies that could lead to the development of new management strategies.


Assuntos
Carcinoma Neuroendócrino/patologia , Carcinoma Neuroendócrino/cirurgia , Neoplasias da Vesícula Biliar/patologia , Neoplasias da Vesícula Biliar/cirurgia , Recidiva Local de Neoplasia/mortalidade , Carcinoma Neuroendócrino/mortalidade , Neoplasias da Vesícula Biliar/mortalidade , Humanos , Prognóstico , Estudos Retrospectivos , Resultado do Tratamento
14.
J Cancer Res Ther ; 15(1): 153-156, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30880772

RESUMO

Context: Gallbladder carcinoma (GBCA) is the fifth most common types of gastrointestinal malignancy and is the most common malignancy of the biliary tract. Cholelithiasis, gallbladder polyps, porcelain gall, and choledochal cysts are common known associations with GBCA. Because of the better understanding of the etiopathogenesis, the traditional nihilistic attitude toward the prognosis has, over the years, given way to greater interest and hope for treating the disease. Long-term survival has been reported in patients with resectable lesions in the hands of expert hepatobiliary surgeons. Objective: This prospective observational study was conducted at a tertiary referral hospital of Eastern India on patients with the diagnosis of GBCA. The main objective was to assess the incidence of gallstones in patients with GBCA, and the relationship, if any, between the size and number of stones and GBCA in our patient cohort. Materials and Methods: This prospective observational study was conducted, over a period of 2 years, at a tertiary referral hospital of Eastern India which caters to patients from all the neighboring districts. A total of 54 patients with the diagnosis of GBCA were included in the study. Data on their demographic and clinical profile, the incidence of associated gallstones, their size (<3 or ≥3cm), and number (solitary or multiple) were collected. Known predisposing factors of GBCA, if any, in those presenting without stones were noted. Results: GBCA was found to afflict females 2.4 times as frequently as males. Patients, irrespective of their sex, were mostly in their sixth decade. Approximately three-fourth of the cases had associated cholelithiasis. The number of stones had no correlation with the disease. However, contrary to available published data, stones <3 cm were significantly more common in our study cohort. Conclusion: The results of this study reaffirm that cholelithiasis is a strong predisposing factor for GBCA and females with gallstones in their sixth decade, are more at risk. Although number of stones was not found to be an independent risk factor, patients with stones <3 cm (mostly multiple) were found to be more at risk in our study.


Assuntos
Carcinoma/etiologia , Neoplasias da Vesícula Biliar/etiologia , Cálculos Biliares/complicações , Adulto , Fatores Etários , Idoso , Carcinoma/patologia , Carcinoma/cirurgia , Colecistostomia , Feminino , Vesícula Biliar/diagnóstico por imagem , Vesícula Biliar/patologia , Neoplasias da Vesícula Biliar/patologia , Neoplasias da Vesícula Biliar/cirurgia , Cálculos Biliares/diagnóstico por imagem , Cálculos Biliares/epidemiologia , Humanos , Incidência , Índia/epidemiologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Fatores de Risco , Fatores Sexuais , Centros de Atenção Terciária/estatística & dados numéricos
15.
J Surg Oncol ; 119(8): 1099-1107, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30864246

RESUMO

BACKGROUND: The aim of the current study was to identify the minimum number and the optimal range of lymph nodes (LNs) to be examined among patients with gallbladder cancer (GBC). METHODS: Between January 1, 2004, and December 31, 2015, patients with a diagnosis of GBC were identified in the National Cancer Database. A machine-based learning approach was used to identify the minimum number and range of LNs to evaluate relative to long-term outcomes. RESULTS: Among 6531 patients with GBC, median number of LNs evaluated was 2 (IQR:1-5); only 21.1% (n = 1376) of patients had 6 or more LNs evaluated. The median number of metastatic LNs was 0 (IQR: 0-1). On multivariable analysis, evaluation of < 4 LNs was associated with a higher hazard of death (referent 4-7 LNs: < 4 LNs, HR = 1.27, 95% CI, 1.16-1.40; P < 0.001), whereas, patients who had 4 to 7 LNs and > 7 LNs evaluated had comparable long-term mortality risk (HR = 1.10, 95%CI, 0.98-1.24; P = 0.11). There was no difference in the proportion of patients who had at least one metastatic LN identified per T category based on total number of nodes resected (all P > 0.05). CONCLUSION: The overwhelming majority of patients did not have the American Joint Committee on Cancer (AJCC) recommended 6 total LN count . A machine-based learning approach identified evaluation of 4 to 7 LNs as the LN number associated with optimal staging and survival. While obtaining 6 LNs may be challenging, evaluation of at least 4 LNs may be a more appropriate threshold as this cut-off value was associated with optimal patient outcomes and staging.


Assuntos
Neoplasias da Vesícula Biliar/mortalidade , Neoplasias da Vesícula Biliar/cirurgia , Linfonodos/patologia , Linfonodos/cirurgia , Idoso , Bases de Dados Factuais , Feminino , Neoplasias da Vesícula Biliar/patologia , Humanos , Estimativa de Kaplan-Meier , Excisão de Linfonodo/métodos , Excisão de Linfonodo/normas , Metástase Linfática , Aprendizado de Máquina , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estados Unidos/epidemiologia
16.
World J Surg Oncol ; 17(1): 55, 2019 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-30902091

RESUMO

BACKGROUND: Mixed neuroendocrine-non-neuroendocrine tumors (MINEN) of the gallbladder are extremely rare; indeed, the English expert literature reports a mere handful of case reports and case series on this topic. According to the WHO classification of 2010, MINEN are considered to be tumors consisting of two major components, neuroendocrine and non-neuroendocrine, each of which hosts at least 30% of the total cellular population. To date, the etiology and pathogenesis of MINEN have not been precisely determined and the non-specific symptoms generally result in late diagnosis (mainly in the terminal stages of the condition) and contribute to the generally poor prognosis. As far as the management of the disease is concerned, radical surgery plays a crucial role; however, the significance of surgical debulking and biological therapy applying somatostatin analogues has not yet been determined. CASE PRESENTATION: A 56-year-old female was referred to our department for a rapidly progressing tumor in the subhepatic area along with the infiltration of S5 and S6 liver segments. With regard to preoperative findings, the tumor appeared as operable, although, during the surgery, an extensive involvement of the hepatoduodenal ligament by the tumor through the lymph nodes was revealed. Due to acute perioperative bleeding from the necrotic tumor, we decided to perform modified resection. Histologically, the tumor was confirmed as MINEN of gallbladder, where the neuroendocrine component was dominant over the non-neuroendocrine component. Six weeks after the discharge, the patient underwent a follow-up CT revealing large recurrence of the disease. Thereafter, the patient was started on systemic therapy with etoposide and carboplatin in combination with somatostatin analogues. Thirteen months after the surgery, the patient is in good clinical condition, and while a recently performed PET/MRI scan revealed a hepatic lesion and hilar lymphadenopathy in full regression, there was a spread of small peritoneal and pleural metastases. The patient remains in the follow-up care. CONCLUSIONS: The occurrence of mixed neuroendocrine-non-neuroendocrine neoplasms is extremely rare. Radical surgery remains the only potentially effective approach to the cure of this disease. The role of biological therapy and debulking in the management of the disease has not yet been precisely defined. In our experience, both of these methods have the potential to positively influence overall survival rates and the postoperational quality of life of patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Neuroendócrino/terapia , Colecistectomia/métodos , Neoplasias da Vesícula Biliar/terapia , Tumor Misto Maligno/terapia , Recidiva Local de Neoplasia/terapia , Carcinoma Neuroendócrino/diagnóstico , Carcinoma Neuroendócrino/patologia , Feminino , Vesícula Biliar/diagnóstico por imagem , Vesícula Biliar/patologia , Vesícula Biliar/cirurgia , Neoplasias da Vesícula Biliar/diagnóstico , Neoplasias da Vesícula Biliar/patologia , Humanos , Pessoa de Meia-Idade , Tumor Misto Maligno/diagnóstico , Tumor Misto Maligno/patologia , Recidiva Local de Neoplasia/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Resultado do Tratamento
17.
BMC Gastroenterol ; 19(1): 42, 2019 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-30885181

RESUMO

BACKGROUND: The aim of our study was to investigate the prevalence and natural long-term progression of gallbladder polyps in a random sample of the general population. METHODS: Four hundred and thirteen subjects (190 women, 223 men; aged 29-75 years) were studied first in 2002 and again eleven years later in 2013. All subjects were interviewed using a standardised questionnaire, anthropometric data were recorded, and an abdominal ultrasound scan was carried out. RESULTS: The prevalence of gallbladder polyps was 6.1% (115/1880) in the 2002 study and 12.1% (50/413) in the 2013 follow-up study. After eleven years, 36 subjects (8.7%, 36/413) had developed new polyps, thirteen subjects (48.1%, 13/27) no longer had gallbladder polyps, and 14 subjects (51.9%, 14/27) still had polyps. The number of polyps had increased in six of these subjects (43%, 6/14), decreased in a further six (43%, 6/14), and remained unchanged in two (14%, 2/14). The mean polyp size was 4.7 mm (± 2.2 mm, range 2-20 mm) in 2002 and 4.0 mm (± 1.9 mm, range 0.5-11 mm) at follow-up. A decrease in polyp size was noted in seven (50%) of the 14 subjects, an increase in size in five subjects (35.7%), and no change in two subjects (14.3%). The shape of the polyps had changed from pedunculated to sessile in two subjects (14.3%, 2/14) and from sessile to pedunculated in one subject (7.1%, 1/14). CONCLUSIONS: In long-term follow-up, the prevalence of gallbladder polyps increased, with new lesions developing in 8.7% of the population. Polyps persisted in 51.9% of the subjects who had them in the original study and disappeared in the other 48.1%.


Assuntos
Progressão da Doença , Neoplasias da Vesícula Biliar/epidemiologia , Neoplasias da Vesícula Biliar/patologia , Pólipos/epidemiologia , Pólipos/patologia , Adulto , Idoso , Feminino , Seguimentos , Neoplasias da Vesícula Biliar/diagnóstico por imagem , Alemanha/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Pólipos/diagnóstico por imagem , Prevalência , Ultrassonografia
18.
Mol Cancer ; 18(1): 33, 2019 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-30825877

RESUMO

BACKGROUND: The long non-coding RNA PVT1 (lncRNA PVT1) has been reported to act as an oncogenic regulator of several cancers. However, its expression and function in gallbladder cancer (GBC) remain largely unknown. METHODS: In situ hybridization (ISH) and quantitative real-time PCR (qPCR) were performed to detect the expression of PVT1 and miR-143 in GBC tissues and cell lines. Immunohistochemistry (IHC) assays were performed to assess the expression of the hexokinase 2 (HK2) protein. The relationships among PVT1, miR-143 and HK2 were evaluated using dual-luciferase reporter, RNA immunoprecipitation (RIP) and biotin pull-down assays. The biological functions of PVT1, miR-143 and HK2 in GBC cells were explored with cell counting kit 8 (CCK-8), 5-ethynyl-20-deoxyuridine (EdU), colony formation, transwell, wound healing and glucose metabolism assays in vitro. For in vivo experiments, a xenograft model was used to investigate the effects of PVT1 and HK2 on GBC. RESULTS: PVT1 was upregulated in GBC tissues and cells and was positively associated with malignancies and worse overall survival. PVT1 knockdown inhibited cell proliferation, migration, and invasion in vitro and restrained tumor growth in vivo. Further studies demonstrated that PVT1 positively regulated HK2 expression via its competing endogenous RNA (ceRNA) activity on miR-143. Additionally, HK2 expression and function were positively correlated with PVT1. Furthermore, we observed that the PVT1/miR-143/HK2 axis promoted cell proliferation and metastasis by regulating aerobic glucose metabolism in GBC cells. CONCLUSIONS: The results of our study reveal a potential ceRNA regulatory pathway in which PVT1 modulates HK2 expression by competitively binding to endogenous miR-143 in GBC cells, which may provide new insights into novel molecular therapeutic targets for GBC.


Assuntos
Carcinoma/genética , Neoplasias da Vesícula Biliar/genética , Regulação Neoplásica da Expressão Gênica , Hexoquinase/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , Adolescente , Adulto , Animais , Carcinoma/metabolismo , Carcinoma/mortalidade , Carcinoma/patologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Neoplasias da Vesícula Biliar/metabolismo , Neoplasias da Vesícula Biliar/mortalidade , Neoplasias da Vesícula Biliar/patologia , Glucose/metabolismo , Glicólise/genética , Hexoquinase/metabolismo , Humanos , Metástase Linfática , Masculino , Camundongos , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Estadiamento de Neoplasias , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Análise de Sobrevida , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Eur J Med Res ; 24(1): 8, 2019 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-30717775

RESUMO

BACKGROUND: Neuroendocrine carcinoma (NEC) of gallbladder is a rare tumor. The clinical manifestation, treatment, and prognosis of gallbladder NEC are rarely reported. CASE PRESENTATION: Eight gallbladder NEC patients were admitted into our hospital. The major complaint was right upper quadrant pain. Two patients underwent a radical resection of gallbladder and liver quadrate lobe. One of them underwent chemotherapies and had no recurrence of NEC during a 25-month followed-up period. The other patient did not undergo chemotherapies, and the NEC recurred in the patient 15 months afterwards. Two patients underwent a radical resection of gallbladder. One of them underwent chemotherapies and had an NEC recurrence 12 months afterwards. The other patient did not undergo chemotherapies and died due to the NEC recurrence 5 months after surgery. Three patients underwent a laparoscopic cholecystectomy and pathologic result showed gallbladder NEC. They did not undergo further treatment and no NEC recurrence was found. One patient underwent tumor biopsy and died due to obstructive jaundice 3 months afterwards. Pathologic results showed that all cases had positive chromogranin A and synaptophysin staining. CONCLUSIONS: Gallbladder NEC showed no noticeably specific features, and the diagnosis relied on the pathological and immunohistochemistrical results. For T1N0M0 gallbladder NEC, cholecystectomy might be enough. For patients in a late stage, the management of combined therapies might be optimal.


Assuntos
Carcinoma Neuroendócrino/patologia , Carcinoma Neuroendócrino/terapia , Neoplasias da Vesícula Biliar/patologia , Neoplasias da Vesícula Biliar/terapia , Idoso , Antineoplásicos/uso terapêutico , Colecistectomia/métodos , Terapia Combinada/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/epidemiologia
20.
Trop Doct ; 49(2): 136-138, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30782095

RESUMO

Gall bladder tuberculosis (TB) is a rare entity and differentiation of gall bladder TB from gall bladder malignancy is difficult. We hereby present an unusual case of incidental diagnosis of gall bladder TB during the evaluation of a gall bladder with suspicion of gall bladder cancer in a 49-year-old woman. The diagnosis of gall bladder TB was made with fine needle aspiration cytology (FNAC) from the gall bladder mass as the disease was found unresectable after cross-sectional imaging. Even with the advancement of cross-sectional imaging, the differentiation of gall bladder TB from gall bladder malignancy is not possible without tissue diagnosis.


Assuntos
Doenças da Vesícula Biliar/diagnóstico , Doenças da Vesícula Biliar/patologia , Vesícula Biliar/microbiologia , Tuberculose/diagnóstico , Tuberculose/patologia , Antituberculosos/uso terapêutico , Diagnóstico Diferencial , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico , Feminino , Vesícula Biliar/diagnóstico por imagem , Vesícula Biliar/patologia , Doenças da Vesícula Biliar/tratamento farmacológico , Doenças da Vesícula Biliar/microbiologia , Neoplasias da Vesícula Biliar/diagnóstico , Neoplasias da Vesícula Biliar/patologia , Humanos , Pessoa de Meia-Idade , Tuberculose/tratamento farmacológico , Tuberculose/microbiologia
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