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1.
Crit Rev Oncol Hematol ; 149: 102940, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32252001

RESUMO

BACKGROUND: The role of adjuvant chemotherapy in biliary tract cancer is controversial. We performed a systematic review and meta-analysis to assess the effect of adjuvant chemotherapy in biliary tract cancer patients. METHODS: A literature search was performed to identify randomized controlled trials (RCTs) comparing adjuvant chemotherapy versus observation, and a pooled analysis was conducted using the random-effect model. RESULTS: Three RCTs (N = 866) were included. No difference was observed between chemotherapy and observation in terms of OS (HR 0.91; 95 %CI, 0.75-1.09; p = 0.295), whereas a significant improvement in RFS was shown (HR 0.83; 95 %CI, 0.69-0.99; p = 0.040). No subgroup that benefited most from adjuvant chemotherapy was identified, although a trend was observed in N+ patients (HR 0.83; 95 %CI, 0.65-1.08; p = 0.165). DISCUSSION: Adjuvant chemotherapy yields a significant RFS benefit in biliary tract cancer patients and should be considered for those who are able to tolerate additional treatment after surgery.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Biliar/tratamento farmacológico , Quimioterapia Adjuvante , Neoplasias do Sistema Biliar/patologia , Intervalo Livre de Doença , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto
2.
PLoS One ; 15(1): e0227454, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31914150

RESUMO

Cholangiocarcinoma (CCA), a malignant tumor originating in the biliary tract, is well known to be associated with adverse clinical outcomes and high mortality rates due to the lack of effective therapy. Evasion of apoptosis is considered a key contributor to therapeutic success and chemotherapy resistance in CCA, highlighting the need for novel therapeutic strategies. In this study, we demonstrated that the induction of necroptosis, a novel regulated form of necrosis, could potentially serve as a novel therapeutic approach for CCA patients. The RNA sequencing data in The Cancer Genome Atlas (TCGA) database were analyzed and revealed that both receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL), two essential mediators of necroptosis, were upregulated in CCA tissues when compared with the levels in normal bile ducts. We demonstrated in a panel of CCA cell lines that RIPK3 was differentially expressed in CCA cell lines, while MLKL was more highly expressed in CCA cell lines than in nontumor cholangiocytes. We therefore showed that treatment with both tumor necrosis factor-α (TNF-α) and Smac mimetic, an inhibitor of apoptosis protein (IAP) antagonist, induced RIPK1/RIPK3/MLKL-dependent necroptosis in CCA cells when caspases were blocked. The necroptotic induction in a panel of CCA cells was correlated with RIPK3 expression. Intriguingly, we demonstrated that Smac mimetic sensitized CCA cells to a low dose of standard chemotherapy, gemcitabine, and induced necroptosis in an RIPK1/RIPK3/MLKL-dependent manner upon caspase inhibition but not in nontumor cholangiocytes. We further demonstrated that Smac mimetic and gemcitabine synergistically induced an increase in TNF-α mRNA levels and that Smac mimetic reversed gemcitabine-induced cell cycle arrest, leading to cell killing. Collectively, our present study demonstrated that TNF-α and gemcitabine induced RIPK1/RIPK3/MLKL-dependent necroptosis upon IAP depletion and caspase inhibition; therefore, our findings have pivotal implications for designing a novel necroptosis-based therapeutic strategy for CCA patients.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Desoxicitidina/análogos & derivados , Necroptose/efeitos dos fármacos , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Triazóis/farmacologia , Fator de Necrose Tumoral alfa/farmacologia , Neoplasias do Sistema Biliar/metabolismo , Neoplasias do Sistema Biliar/patologia , Inibidores de Caspase/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patologia , Desoxicitidina/farmacologia , Sinergismo Farmacológico , Humanos , Proteínas Quinases/química , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
3.
Bull Cancer ; 107(1): 48-53, 2020 Jan.
Artigo em Francês | MEDLINE | ID: mdl-31980143

RESUMO

The adjuvant treatment of biliary tract cancers has long been poorly defined. In recent years, randomized trial data have been used to define treatment references. The French Prodige 12 and Japanese BCAT trials have not demonstrated any benefit of adjuvant chemotherapy. The English BILCAP trial tested adjuvant capecitabine for six months at the usual dose in a randomized, controlled-only trial involving nearly 450 patients. Although the results in intention to treat were borderline significant on the primary endpoint, overall survival (P=0.097), sensitivity analyzes adjusted for prognostic factors and relapse-free survival analyses are clearly positive. The absolute benefit of +5%/+10% overall survival, combined with low and known toxicity profile, leads to recommending treatment for any cancer of the resected bile ducts (with the exception of gallbladder cancer pT1N0).


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias do Sistema Biliar/tratamento farmacológico , Colangiocarcinoma/tratamento farmacológico , Neoplasias do Sistema Biliar/patologia , Capecitabina/administração & dosagem , Quimioterapia Adjuvante , Colangiocarcinoma/patologia , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Neoplasias da Vesícula Biliar/tratamento farmacológico , Humanos , Análise de Intenção de Tratamento , Radioterapia Adjuvante , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
4.
World J Gastroenterol ; 25(40): 6116-6128, 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31686767

RESUMO

BACKGROUND: For periampullary adenocarcinoma, the histological subtype is a better prognostic predictor than the site of tumor origin. Intestinal-type periampullary adenocarcinoma (IPAC) is reported to have a better prognosis than the pan-creatobiliary-type periampullary adenocarcinoma (PPAC). However, the classification of histological subtypes is difficult to determine before surgery. Apparent diffusion coefficient (ADC) histogram analysis is a noninvasive, non-enhanced method with high reproducibility that could help differentiate the two subtypes. AIM: To investigate whether volumetric ADC histogram analysis is helpful for distinguishing IPAC from PPAC. METHODS: Between January 2015 and October 2018, 476 consecutive patients who were suspected of having a periampullary tumor and underwent magnetic resonance imaging (MRI) were reviewed in this retrospective study. Only patients who underwent MRI at 3.0 T with different diffusion-weighted images (b-values = 800 and 1000 s/mm2) and who were confirmed with a periampullary adenocarcinoma were further analyzed. Then, the mean, 5th, 10th, 25th, 50th, 75th, 90th, and 95th percentiles of ADC values and ADCmin, ADCmax, kurtosis, skewness, and entropy were obtained from the volumetric histogram analysis. Comparisons were made by an independent Student's t-test or Mann-Whitney U test. Multiple-class receiver operating characteristic curve analysis was performed to determine and compare the diagnostic value of each significant parameter. RESULTS: In total, 40 patients with histopathologically confirmed IPAC (n = 17) or PPAC (n = 23) were enrolled. The mean, 5th, 25th, 50th, 75th, 90th, and 95th percentiles and ADCmax derived from ADC1000 were significantly lower in the PPAC group than in the IPAC group (P < 0.05). However, values derived from ADC800 showed no significant difference between the two groups. The 75th percentile of ADC1000 values achieved the highest area under the curve (AUC) for differentiating IPAC from PPAC (AUC = 0.781; sensitivity, 91%; specificity, 59%; cut-off value, 1.50 × 10-3 mm2/s). CONCLUSION: Volumetric ADC histogram analysis at a b-value of 1000 s/mm2 might be helpful for differentiating the histological subtypes of periampullary adenocarcinoma before surgery.


Assuntos
Adenocarcinoma/diagnóstico , Neoplasias do Sistema Biliar/diagnóstico , Imagem de Difusão por Ressonância Magnética/métodos , Neoplasias Duodenais/diagnóstico , Neoplasias Pancreáticas/diagnóstico , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Adulto , Idoso , Ampola Hepatopancreática/diagnóstico por imagem , Ampola Hepatopancreática/patologia , Ampola Hepatopancreática/cirurgia , Neoplasias do Sistema Biliar/patologia , Neoplasias do Sistema Biliar/cirurgia , Diagnóstico Diferencial , Neoplasias Duodenais/patologia , Neoplasias Duodenais/cirurgia , Feminino , Humanos , Interpretação de Imagem Assistida por Computador , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Pancreaticoduodenectomia , Prognóstico , Curva ROC , Reprodutibilidade dos Testes , Estudos Retrospectivos
5.
BMC Cancer ; 19(1): 945, 2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31610788

RESUMO

BACKGROUND: Biliary rhabdomyosarcoma (RMS) is the most common biliary tumor in children. The management of affected patients contains unique challenges because of the rarity of this tumor entity and its critical location at the porta hepatis, which can make achievement of a radical resection very difficult. METHODS: In a retrospective chart analysis we analysed children suffering from biliary RMS who were registered in three different CWS trials (CWS-96, CWS-2002P, and SoTiSaR registry). RESULTS: Seventeen patients (12 female, 5 male) with a median age of 4.3 years were assessed. The median follow-up was 42.2 months (10.7-202.5). The 5-year overall (OS) and event free survival (EFS) rates were 58% (45-71) and 47% (34-50), respectively. Patients > 10 years of age and those with alveolar histology had the worst prognosis (OS 0%). Patients with botryoid histology had an excellent survival (OS 100%) compared to those with non-botryoid histology (OS 38%, 22-54, p = 0.047). Microscopic complete tumor resection was achieved in almost all patients who received initial tumor biopsy followed by chemotherapy and delayed surgery. CONCLUSION: Positive predictive factors for survival of children with biliary RMS are age ≤ 10 years and botryoid tumor histology. Primary surgery with intention of tumor resection should be avoided.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Biliar/tratamento farmacológico , Neoplasias do Sistema Biliar/cirurgia , Rabdomiossarcoma/tratamento farmacológico , Rabdomiossarcoma/cirurgia , Adolescente , Sistema Biliar/patologia , Neoplasias do Sistema Biliar/patologia , Neoplasias do Sistema Biliar/radioterapia , Biópsia , Criança , Pré-Escolar , Terapia Combinada , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Lactente , Estimativa de Kaplan-Meier , Masculino , Complicações Pós-Operatórias , Recidiva , Estudos Retrospectivos , Rabdomiossarcoma/patologia , Rabdomiossarcoma/radioterapia
6.
BMC Cancer ; 19(1): 990, 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31646981

RESUMO

BACKGROUND: Biliary tract cancer (BTC) has a high mortality. Primary diagnosis is frequently delayed due to mostly unspecific symptoms, resulting in a high number of advanced cases at the time of diagnosis. Advanced BTCs are in principle chemotherapy sensitive as determined by improved disease control, survival and quality of life (QoL). However, median OS does not exceed 11.7 months with the current standard of care gemcitabine plus cisplatin. Thereby, novel drug formulations like nanoliposomal-irinotecan (nal-IRI) in combination with 5- fluorouracil (5-FU)/leucovorin may have the potential to improve therapeutic outcomes in this disease. METHODS: NIFE is an interventional, prospective, randomized, controlled, open label, two-sided phase II study. Within the study, 2 × 46 patients with locally advanced, non-resectable or metastatic BTC are to be enrolled by two stage design of Simon. Data analysis will be done unconnected for both arms. Patients are allocated in two arms: Arm A (experimental intervention) nal-IRI mg/m2, 46 h infusion)/5-FU (2400 mg/m2, 46 h infusion)/leucovorin (400 mg/m2, 0.5 h infusion) d1 on 14 day-cycles; Arm B (standard of care) cisplatin (25 mg/m2, 1 h infusion)/gemcitabine (1000 mg/m2, 0.5 h infusion) d1 and d8 on 21 day-cycles. The randomization (1:1) is stratified for tumor site (intrahepatic vs. extrahepatic biliary tract), disease stage (advanced vs. metastatic), age (≤70 vs. > 70 years), sex (male vs. female) and WHO performance score (ECOG 0 vs. ECOG 1). Primary endpoint of the study is the progression free survival (PFS) rate at 4 months after randomization by an intention-to-treat analysis in each of the groups. Secondary endpoints are the overall PFS rate, the 3-year overall survival rate, the disease control rate after 2 months, safety and patient related outcome with quality of life. The initial assessment of tumor resectability for locally advanced BTCs is planned to be reviewed retrospectively by a central surgical board. Exploratory objectives aim at establishing novel biomarkers and molecular signatures to predict response. The study was initiated January 2018 in Germany. DISCUSSION: The NIFE trial evaluates the potential of a nanoliposomal-irinotecan/5-FU/leucovorin combination in the first line therapy of advanced BTCs and additionally offers a unique chance for translational research. TRIAL REGISTRATION: Clinicaltrials.gov NCT03044587. Registration Date February 7th 2017.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Biliar/tratamento farmacológico , Fluoruracila/uso terapêutico , Irinotecano/uso terapêutico , Leucovorina/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias do Sistema Biliar/patologia , Cisplatino/administração & dosagem , Cisplatino/uso terapêutico , Ensaios Clínicos Fase II como Assunto , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Humanos , Irinotecano/administração & dosagem , Irinotecano/efeitos adversos , Irinotecano/química , Leucovorina/administração & dosagem , Masculino , Fosfolipídeos/química , Intervalo Livre de Progressão , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto
7.
Expert Opin Pharmacother ; 20(17): 2121-2137, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31550186

RESUMO

Introduction: Biliary tract cancer (BTC), which comprises gallbladder cancer, ampullary cancer, and cholangiocarcinoma, is a rare and heterogeneous entity, with limited approved therapeutic options. However, interest in this disease has grown exponentially in recent years, as a mounting body of evidence has shed light on the complex molecular and microenvironmental background of BTC, and clinical investigations have explored a variety of new agents and combinations, with promising results.Areas covered: This review describes the standard of care in advanced BTC and summarizes the most recent evidence available on the pharmacological treatment of resected and advanced disease, focusing on chemotherapy, targeted therapy, and immunotherapy.Expert opinion: The therapeutic armamentarium of BTC has made radical progress after almost a decade of very few positive results. Phase-III evidence now supports the use of adjuvant capecitabine after resection of localized disease, while investigations into improved regimens in the advanced setting are underway, exploring alternative options to the standard gemcitabine-cisplatin doublet. The first positive phase-III trial supports the use of the mFOLFOX6 regimen as a second-line chemotherapy. Targeted therapy against specific genomic alterations can combine with chemotherapy in specific subsets of patients. Despite recent advancements, conducting clinical trials for BTC is still a real challenge.


Assuntos
Neoplasias do Sistema Biliar/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Biliar/patologia , Cisplatino/uso terapêutico , Ensaios Clínicos como Assunto , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Humanos , Imunoterapia , Estadiamento de Neoplasias , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo
8.
Chin Clin Oncol ; 8(4): 42, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31431036

RESUMO

Biliary tract cancer (BTC) is comprised of intrahepatic cholangiocarcinoma (ICC), extrahepatic cholangiocarcinoma (EHC) and gallbladder cancer (GBC). These tumors arise in the biliary epithelium, share histological characteristics and are associated with grim prognosis even when diagnosed at early stages. Moreover, its relatively low incidence in developed countries has precluded the development of clinical trials addressing specific differences among BTC subgroups in terms of their biology, treatment response and clinical outcomes. In this scenario, the development of effective treatment strategies for patients has been rather modest. To date, the combination of cisplatin plus gemcitabine remains as the standard first line therapy in advanced disease and after progression to this regimen there are limited treatment options. Next generation sequencing (NGS) studies have assessed the distribution of driver genes and potentially actionable genomic alterations among ICC, EHC and GBC. Here, we outline genomic differences among these subsets and describe key milestones in order to develop novel targeted drugs against BTCs. Although the early results of several studies are promising, international collaboration is critical to conduct adequately-powered trials, enrolling patients from high-incidence countries.


Assuntos
Neoplasias do Sistema Biliar/genética , Genômica/métodos , Neoplasias do Sistema Biliar/patologia , Humanos , Prognóstico , Resultado do Tratamento
9.
Discov Med ; 28(151): 17-28, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31465722

RESUMO

Hepatobiliary cancers have poor prognosis due to their high level of invasiveness, distant metastasis, and chemotherapy resistance. Hepatocellular carcinoma is the most common type of hepatobiliary cancers representing the fourth leading cause of cancer death worldwide. There is an urgent need to identify the molecular drivers of hepatobiliary cancers to improve the therapeutic outcomes and patient prognosis. Histone modification is an important biological process that is critical in the regulation of epigenetic maintenance and modifications which in turn exert critical impacts on gene expression and chromatin structure stability. Histones may undergo a series of enzyme-catalyzed post-translational modifications such as acetylation, methylation, phosphorylation, ubiquitination, SUMOylating, crotonylation, and 2-hydroxyisobutyrylation. Dysregulation of histone-modifying enzyme may cause multiple diseases including cancers. As such, histone-modifying enzymes constitute a group of potential therapeutic targets. The aim of this review is to summarize the current understanding of the role of histone modification enzymes in regulating epigenetic alterations, cancer development, and their potential as therapeutic targets for hepatobiliary cancers.


Assuntos
Neoplasias do Sistema Biliar , Código das Histonas , Histonas , Proteínas de Neoplasias , Processamento de Proteína Pós-Traducional , Neoplasias do Sistema Biliar/genética , Neoplasias do Sistema Biliar/metabolismo , Neoplasias do Sistema Biliar/patologia , Neoplasias do Sistema Biliar/terapia , Histonas/genética , Histonas/metabolismo , Humanos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo
10.
World J Gastroenterol ; 25(26): 3334-3343, 2019 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-31341359

RESUMO

Choledochal cysts (CCs) are rare bile duct dilatations, intra-and/or extrahepatic, and have higher prevalence in the Asian population compared to Western populations. Most of the current literature on CC disease originates from Asia where these entities are most prevalent. They are thought to arise from an anomalous pancreaticobiliary junction, which are congenital anomalies between pancreatic and bile ducts. Some similarities in presentation between Eastern and Western patients exist such as female predominance, however, contemporary studies suggest that Asian patients may be more symptomatic on presentation. Even though CC disease presents with an increased malignant risk reported to be more than 10% after the second decade of life in Asian patients, this risk may be overstated in Western populations. Despite this difference in cancer risk, management guidelines for all patients with CC are based predominantly on observations reported from Asia where it is recommended that all CCs should be excised out of concern for the presence or development of biliary tract cancer.


Assuntos
Neoplasias do Sistema Biliar/prevenção & controle , Colangiopancreatografia Retrógrada Endoscópica/normas , Cisto do Colédoco/epidemiologia , Grupo com Ancestrais do Continente Asiático/estatística & dados numéricos , Neoplasias do Sistema Biliar/patologia , Cisto do Colédoco/patologia , Cisto do Colédoco/cirurgia , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Feminino , Gastroenterologia/normas , Humanos , Masculino , Guias de Prática Clínica como Assunto , Prevalência , Fatores Sexuais , Resultado do Tratamento
11.
J Chemother ; 31(5): 284-289, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31179889

RESUMO

Objective: Gemcitabine and cisplatin (GC) combination chemotherapy is the current standard of care for patients with advanced biliary tract cancer (BTC). Recently, a randomized controlled trial showed the non-inferiority in overall survival of gemcitabine and S-1 (GS) compared to GC. Because leucovorin is known to enhance the activity of S-1, we conducted this study to evaluate the feasibility of combination therapy of gemcitabine, S-1 and leucovorin (GSL). Methods: Advanced BTC patients without prior treatment other than surgery or adjuvant chemotherapy were eligible to this study. Gemcitabine was administered at a dose of 1000 mg/m2 on day 1, and oral S-1 at a dose of 40 mg/m2 and oral leucovorin at a dose of 25 mg twice daily on days 1-7, every 2 weeks. The primary endpoint was PFS and the secondary endpoints included OS, objective tumour response and the safety. Results: Between June 2013 and December 2015, 20 patients with advanced BTC (12 gallbladder, 4 extrahepatic, 2 intrahepatic, 2 ampulla) including 16 unresectable disease and 4 recurrent disease were enroled. The median PFS and OS were 5.5 (95% confidence interval [CI], 1.8 - not reached) and 16.0 (95% CI, 6.4-20.8) months, respectively. A partial response was achieved in 3 (15%) and stable disease in 8 (40%), giving a disease control rate of 55%. Major grade 3/4 toxicities included neutropenia (30%), anaemia (5%), stomatitis (15%), diarrhoea (15%) and anorexia (10%). There were no treatment-related deaths. Conclusions: This study showed the feasibility and potential efficacy of GSL as a first-line treatment in patients with advanced BTC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Biliar/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Peritoneais/tratamento farmacológico , Idoso , Neoplasias do Sistema Biliar/patologia , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Combinação de Medicamentos , Estudos de Viabilidade , Feminino , Seguimentos , Humanos , Leucovorina/administração & dosagem , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/secundário , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Ácido Oxônico/administração & dosagem , Neoplasias Peritoneais/secundário , Prognóstico , Taxa de Sobrevida , Tegafur/administração & dosagem
12.
Eur J Radiol ; 116: 1-7, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31153550

RESUMO

OBJECTIVES: To prospectively investigate the diagnostic potential of lymph node (LN) magnetic resonance (MR) imaging features. METHODS: A radiologist determined the maximum diameters in the short and long axes, shape, signal intensities on T1- and T2-weighted imaging, pattern of enhancement, and apparent diffusion coefficient (ADC) on diffusion-weighted MR images of LNs and annotated measurable (≥5 mm in short-axis diameter) LNs. Surgically harvested LNs were correlated with the pathologic findings. Univariable and multivariable generalized estimating equation analyses were performed to evaluate predictive power. RESULTS: Of 80 LNs, 29 (36.3%) were positive and 51 (63.7%) negative for metastasis. The mean short-axis diameter of metastatic LNs (10.59 ± 4.30 mm) was larger than that of benign LNs (7.96 ± 2.10 mm). The ADC was significantly (P < 0.001) lower in metastatic than non-metastatic LNs. The area under the curve (AUC) of a univariable model using only the mean ADC was 0.845 (95% confidence interval [CI], 0.743-0.927), and the mean-ADC cutoff value for predicting LN metastasis was 0.901 × 10-3 mm2/s. The AUC of a multivariable model including round shape, heterogeneous enhancement, and the mean ADC was 0.917 (95% CI, 0.845-0.972), with a sensitivity, specificity, overall accuracy, and positive and negative predictive values of 89.7%, 82.4%, 85.0%, 74.3%, and 93.3%, respectively. CONCLUSION: The short-axis diameter and ADC were different between benign and metastatic LNs in pancreatobiliary cancer. However, round shape, heterogeneous enhancement, and a low ADC value (<0.901 × 10-3 mm2/s) may be the most reliable diagnostic features of multiple metastatic LNs.


Assuntos
Neoplasias do Sistema Biliar/patologia , Metástase Linfática/diagnóstico por imagem , Imagem por Ressonância Magnética/métodos , Neoplasias Pancreáticas/patologia , Adulto , Idoso , Área Sob a Curva , Estudos de Coortes , Feminino , Humanos , Linfonodos/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
13.
Crit Rev Oncol Hematol ; 139: 134-142, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30979533

RESUMO

AIM: Gemcitabine-based chemotherapy regimens remain the standard first-line treatment for advanced biliary tract cancers (BTCs) patients with no second-line treatments established yet. The preset meta-analysis aims to comprehensively evaluate the role of second-line treatment for advanced BTCs in terms of response, overall survival and toxicities. MATERIALS AND METHODS: Eligible studies were identified using Medline, Pubmed, and meeting abstracts. Searches were last updated on April 30, 2018. Eligible studies reported survival and/or response data for refractory BTCs patients receiving second-line therapy. Primary outcomes of interest were objective response rate (ORR), disease controlled rate (DCR), 1-year overall survival (OS), and progression free survival (PFS). RESULTS: A total of 38 cohorts from 32 studies were eligible for analysis: 23 prospective phase II trials and 9 retrospective studies. In total, data from 1391 patients were reported with median number of patients included in each cohort of 28.5 (range: 9-255). The weighted median PFS and OS for refractory BTCs received second-line therapy were 2.6 months and 6.5 months, respectively. Fluoropyrimidine-based, gemcitabine-based, or Taxanes-based chemotherapy was not superior to single targeted/toxic agent in terms of ORR. In addition, the pooled disease control rate (DCR) and 1-year overall survival (OS) of fluoropyrimidine-based chemotherapy was inferior to single targeted/toxic agent (DCR: 47% versus 60%, RR 0.78, 95%CI: 0.61-1.00, p = 0.03; 1-year OS: 15% versus 29.6%, RR 0.90, 95%CI: 0.29-0.87, p = 0.006), but not for GEM-based or taxanes-based chemotherapy. In addition, correlation analysis indicates that the best correlations were between median OS and median PFS for all cohorts (r=0.57; P = 0.003). CONCLUSION: Combined second-line treatment is not superior to single targeted/toxic agent as salvage treatment for advanced BTCs in terms of ORR, DCR and 1-year OS, and fluoropyrimidine-based chemotherapy seems to be inferior to other second-line regimens. With available evidence from published data, we could not clearly recommend a preferred second-line regimen for advanced BTCs. Further prospective randomized studies are needed to confirm our findings and investigate more efficient second-line therapy in this setting.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Biliar/tratamento farmacológico , Terapia de Salvação , Neoplasias do Sistema Biliar/patologia , Humanos , Resultado do Tratamento
15.
Ann Surg Oncol ; 26(6): 1858, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30887372

RESUMO

INTRODUCTION: In patients with liver lesions with ductal extension, the corresponding Glissonean pedicle should be divided at its origin to achieve a negative ductal margin; however, during laparoscopic hepatectomy, it is difficult to precisely transect the liver and divide the Glissonean pedicle as planned. METHODS: We present a video of a laparoscopic left lateral sectionectomy using the extrahepatic Glissonean approach for a lesion with ductal extension. RESULTS: A 76-year-old woman presented with a cystic neoplasm in the liver segment 3 bile duct (B3). The preoperative workup suggested biliary extension of the lesion towards the origin of B3. A decision was made to perform laparoscopic left lateral sectionectomy with division of the segment 3 Glissonean pedicle (G3) at its origin, and, additionally, left hepatectomy if the B3 ductal margin turned out to be positive. During the procedure, prior to parenchymal transection, the Arantius' ligament was dissected, and G2 and G3 were extrahepatically taped. The ischemic border was visualized by clamping the isolated pedicle, and was also clearly demonstrated by indocyanine green fluorescence. After transecting the liver towards the tape, G3 was divided at its origin, and the frozen section of the ductal margin was negative for tumors. CONCLUSION: The extrahepatic Glissonean approach can help to obtain a maximal ductal margin for liver lesions with possible biliary extension, although the technique potentially poses the risk of bleeding and/or biliary injury, and requires expertise in hepatobiliary surgery. Further studies with larger sample sizes are warranted to validate the feasibility and efficacy of this strategy.


Assuntos
Neoplasias do Sistema Biliar/cirurgia , Cistadenocarcinoma/cirurgia , Ducto Hepático Comum/cirurgia , Neoplasias Hepáticas/cirurgia , Idoso , Neoplasias do Sistema Biliar/patologia , Cistadenocarcinoma/patologia , Feminino , Ducto Hepático Comum/patologia , Humanos , Neoplasias Hepáticas/patologia , Prognóstico
16.
Surg Today ; 49(9): 762-768, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30859309

RESUMO

OBJECTIVES: Surgical indications for pulmonary metastasis from hepatopancreatobiliary (HPB) carcinomas remain controversial. METHODS: Between 2000 and 2015, 25 patients with pulmonary metastasis from HPB carcinomas and 145 with that from colorectal carcinomas underwent metastasectomies in our institution. The primary diseases were hepatocellular carcinoma (HCC) in 8 patients, pancreatic carcinoma (PC) in 12 and biliary tract carcinoma (BTC) in 5. All patients had a sufficient pulmonary reserve, controlled primary disease and no evidence of other metastatic disease. Perioperative factors were investigated retrospectively to analyze the overall survival (OS), pulmonary metastasis-free survival (PmFS) after pulmonary metastasectomy and disease-free interval between surgery for primary disease and the development of pulmonary metastasis (DFI). RESULTS: Complete resection was performed in all patients with lobectomy in 3, segmentectomy in 5 and partial resection in 17. The respective 1-, 2- and 5-year OS rates after metastasectomy were 82.6%, 69.8% and 69.8% in HPB patients and 98.3%, 92.4% and 78.0% in colorectal carcinoma patients (p = 0.351). The 2-year PmFS of HPB patients was 80.0%, versus 60.6% for colorectal carcinoma patients (p = 0.265). The DFI was 41.4 months for HPB patients and 34.5 months for colorectal carcinoma patients (p = 0.273). CONCLUSIONS: Metastasectomy for pulmonary metastasis from HPB may be performed in carefully selected patients.


Assuntos
Neoplasias do Sistema Biliar/patologia , Carcinoma Hepatocelular/patologia , Neoplasias Colorretais/terapia , Neoplasias Hepáticas/patologia , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/cirurgia , Neoplasias Pancreáticas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pneumonectomia , Resultado do Tratamento
17.
Surg Clin North Am ; 99(2): 301-314, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30846036

RESUMO

Although the most common presentation of biliary disorder in North America is secondary to gallstone disease, an awareness of benign biliary cystic neoplasms is important because of the risk of malignant transformation. The incidence of premalignant cystic neoplasms of the bile duct is not well characterized and they often are detected incidentally for suspicion of other abdominal disorders. This article describes the 4 most common premalignant biliary cystic neoplasms: biliary mucinous cystic neoplasms, intraductal papillary mucinous neoplasms of the bile duct, intraductal tubular papillary neoplasms of the bile duct, and choledochal cysts.


Assuntos
Neoplasias do Sistema Biliar/patologia , Lesões Pré-Cancerosas/patologia , Neoplasias do Sistema Biliar/terapia , Humanos , Lesões Pré-Cancerosas/terapia
18.
J Clin Oncol ; 37(8): 658-667, 2019 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-30707660

RESUMO

PURPOSE: No standard adjuvant treatment currently is recommended in localized biliary tract cancer (BTC) after surgical resection. We aimed to assess whether gemcitabine and oxaliplatin chemotherapy (GEMOX) would increase relapse-free survival (RFS) while maintaining health-related quality of life (HRQOL) in patients who undergo resection. PATIENTS AND METHODS: We performed a multicenter, open-label, randomized phase III trial in 33 centers. Patients were randomly assigned (1:1) within 3 months after R0 or R1 resection of a localized BTC to receive either GEMOX (gemcitabine 1,000 mg/m2 on day 1 and oxaliplatin 85 mg/m2 infused on day 2 of a 2-week cycle) for 12 cycles (experimental arm A) or surveillance (standard arm B). Primary end points were RFS and HRQOL. RESULTS: Between July 2009 and February 2014, 196 patients were included. Baseline characteristics were balanced between the two arms. After a median follow-up of 46.5 months (95% CI, 42.6 to 49.3 months), 126 RFS events and 82 deaths were recorded. There was no significant difference in RFS between the two arms (median, 30.4 months in arm A v 18.5 months in arm B; hazard ratio [HR], 0.88; 95% CI, 0.62 to 1.25; P = .48). There was no difference in time to definitive deterioration of global HRQOL (median, 31.8 months in arm A v 32.1 months in arm B; HR, 1.28; 95% CI, 0.73 to 2.26; log-rank P = .39). Overall survival was not different (median, 75.8 months in arm A v 50.8 months in arm B; HR, 1.08; 95% CI, 0.70 to 1.66; log-rank P = .74). Maximal adverse events were grade 3 in 62% (arm A) versus 18% (arm B) and grade 4 in 11% versus 3% ( P < .001). CONCLUSION: There was no benefit of adjuvant GEMOX in resected BTC despite adequate tolerance and delivery of the regimen.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Biliar/tratamento farmacológico , Neoplasias do Sistema Biliar/cirurgia , Procedimentos Cirúrgicos do Sistema Biliar , Desoxicitidina/análogos & derivados , Oxaliplatina/administração & dosagem , Conduta Expectante , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias do Sistema Biliar/mortalidade , Neoplasias do Sistema Biliar/patologia , Procedimentos Cirúrgicos do Sistema Biliar/efeitos adversos , Procedimentos Cirúrgicos do Sistema Biliar/mortalidade , Quimioterapia Adjuvante , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Feminino , França , Humanos , Masculino , Pessoa de Meia-Idade , Oxaliplatina/efeitos adversos , Intervalo Livre de Progressão , Qualidade de Vida , Fatores de Tempo
19.
Hepatobiliary Pancreat Dis Int ; 18(1): 62-66, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30612929

RESUMO

BACKGROUND: Sodium meta-arsenite (NaAsO2, KML001) is a potential oral anticancer agent acting on telomerase and telomere length. This prospective study evaluated its safety, tolerability, and effectiveness as salvage chemotherapy in patients with advanced biliary tract cancer (BTC) resistant to gemcitabine-based chemotherapy. METHODS: Forty-four patients (21 women and 23 men) with advanced BTC and failure history of gemcitabine-based chemotherapy, performance status (PS) 0-2, normal cardiac, hepatic, and renal function were enrolled. Daily dose of KML001 (7.5 mg. p.o.) was administered to eligible subjects for 24 weeks divided into six treatment cycles. Response was evaluated bimonthly using CT. RESULTS: After an average of 1.5 months of treatment (range: 0.5-10.0), 3 patients (6.8%) obtained progression-free status, 23 patients (52.3%) had disease progression, and 18 patients (40.9%) dropped out before evaluation. One patient (2.3%) completed six treatment cycles without progression. During the treatment, morphine dosage kept the same or decreased in 20 patients (47.6%). Nine patients (20.5%) experienced grade-3 adverse events (AEs), while no patient experienced grade-4 AEs. The most common AEs were liver enzyme elevation (11/44, 25%) and anemia (10/44, 22.7%). KML001 was discontinued in six patients (13.6%) due to AEs, including liver toxicity (n = 3), QTc prolongation (n = 2), and abdominal pain (n = 1). CONCLUSIONS: KML001 did not have enough anticancer effect on patients with advanced BTC resistant to gemcitabine. However, KML001 was safe and well-tolerable in terms of AEs and pain control when used as salvage therapy. Further studies are needed to establish arsenic agents as a reliable treatment option in patients with BTC.


Assuntos
Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Arsenitos/administração & dosagem , Neoplasias do Sistema Biliar/tratamento farmacológico , Terapia de Salvação , Compostos de Sódio/administração & dosagem , Administração Oral , Idoso , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Arsenitos/efeitos adversos , Neoplasias do Sistema Biliar/diagnóstico por imagem , Neoplasias do Sistema Biliar/mortalidade , Neoplasias do Sistema Biliar/patologia , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Esquema de Medicação , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Estudos Prospectivos , Compostos de Sódio/efeitos adversos , Fatores de Tempo , Tomografia Computadorizada por Raios X
20.
BMC Cancer ; 19(1): 55, 2019 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-30634942

RESUMO

BACKGROUND: To date, the cornerstone of treatment in patients with advanced or metastatic cholangiocarcinoma (CCA) is systemic chemotherapy based on a combination of gemcitabine and a platinum derivative. Other therapeutic approaches including targeted agents and tyrosine kinase inhibitors (TKI) have demonstrated disappointing results, highlighting the complexity of CCA. Recently, drugs aiming at the inhibition of HER-receptors have shown first therapeutic benefit in patients with late stage disease. The aim of this phase I study was to test the dose level toxicities (DLTs), safety and efficacy of afatinib, a highly specific panErbB family receptor TKI, in chemotherapy naive patients with advanced CCA in conjunction with an extensive biomarker program. METHODS: Afatinib was administered continuously p. o. as add-on in patients with advanced CCA who received conventional chemotherapy with gemcitabine/cisplatin. A classical 3 + 3 phase I study was employed, while the maximum tolerated dose (MTD) of oral afatinib was determined in a 2 step dose escalation. Safety, overall survival (OS) and progression free survival (PFS) were evaluated for all patients. Finally, a translational biomarker analysis was conducted for the EGFR and VEGF signalling cascades. RESULTS: Overall, 9 patients were enrolled. Further recruitment was discontinued due to lack of efficacy results of the tested drug in other indications. 30 mg afatinib could be safely administered as add-on to 80% of standard dose gemcitabine/cisplatin. The mOS and mPFS were 7.7 and 6.0 months, respectively. Diarrhoea and haematological disorders were the most common observed AEs. Almost all patients overexpressed EGFR on their tumour tissues, whereas none of them expressed mutations in Exons 18, 19 and 21. Non-responders showed a higher variation of VEGF-C, -D, leptin and sEGFR in their sera. CONCLUSIONS: Afatinib failed to show survival benefits in combination with gemcitabine/cisplatin in patients with advanced CCA. Mutational analysis of EGFR and pathways associated with VEGF-C, -D and leptin might show promising results in future studies. CLINICAL TRIALS REGISTRATION: NCT01679405 August, 2012.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Biliar/tratamento farmacológico , Neoplasias do Sistema Biliar/patologia , Adulto , Afatinib/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias do Sistema Biliar/metabolismo , Neoplasias do Sistema Biliar/mortalidade , Biomarcadores , Cisplatino/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Transdução de Sinais , Pesquisa Médica Translacional , Resultado do Tratamento
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