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1.
Rev. colomb. cir ; 38(4): 724-731, 20230906. fig, tab
Article in Spanish | LILACS | ID: biblio-1511129

ABSTRACT

Introducción. Un biomarcador se define como una alteración molecular presente en el desarrollo de la patogénesis del cáncer, que puede ser utilizada para el diagnóstico temprano de la enfermedad. La medición del biomarcador se hace por medio de diversas técnicas, como bioquímica, inmunohistoquímica o biología molecular, en diferentes tipos de muestras, como tejido, sangre periférica y orina. El biomarcador ideal será aquel que sea válido y específico a la vez, que sea no invasivo, barato y fácilmente detectable. El uso de biomarcadores para la detección temprana del cáncer debe seguir un desarrollo ordenado y sistemático antes de introducirlos en la práctica clínica. Métodos. Se realizó una búsqueda exhaustiva en las bases de datos de PubMed y Embase, seleccionando los artículos pertinentes para revisarlos acorde a la temática específica de interés. Resultados. Se propone la sistematización del desarrollo de biomarcadores en cinco grandes fases, las cuales tienen la característica de ser ordenadas desde las evidencias más tempranas hasta las fases finales de su estudio. Conclusiones. El correcto desarrollo de biomarcadores hace posible la introducción de intervenciones terapéuticas en el ámbito de la prevención secundaria del cáncer.


Introduction. A biomarker can be defined as a molecular alteration present in the development of cancer pathogenesis which can be used for early diagnosis of the disease. The measurement of the biomarker can be carried out through various techniques such as biochemistry, immunohistochemistry, molecular biology, in different types of samples such as tissue, peripheral blood, and urine. The ideal biomarker will be one that is valid and specific while is non-invasive, cheap, and easily detectable. The use of biomarkers for the early detection of cancer must follow an orderly and systematic development before introducing them into clinical practice. Methods. An exhaustive search was performed in PubMed and Embase databases, selecting the relevant articles according to the specific topic of interest. Results. Systematization of the development of biomarkers in five large phases is proposed, which has the characteristic of being ordered from the earliest evidence to the final phases of their study. Conclusions. The correct development of biomarkers makes possible the introduction of therapeutic interventions in the field of secondary prevention of cancer.


Subject(s)
Humans , Biomarkers, Tumor , Early Diagnosis , Secondary Prevention , Pancreatic Neoplasms , Biliary Tract Neoplasms , Evaluation of Results of Therapeutic Interventions
2.
Rev. cuba. cir ; 62(1)mar. 2023.
Article in Spanish | LILACS, CUMED | ID: biblio-1515253

ABSTRACT

Introducción: El colangiocarcinoma constituye la neoplasia de la vía biliar más frecuente, la cual es responsable de una alta morbimortalidad. Objetivo: Determinar la morbilidad y la mortalidad por colangiocarcinoma extrahepático en el Servicio de Cirugía del Hospital Universitario Manuel Ascunce Domenech. Métodos: Se realizó un estudio descriptivo, prospectivo y observacional de pacientes que ingresaron en el Servicio de Cirugía General con diagnóstico de colangiocarcinoma extrahepático entre septiembre de 2018 y enero del 2022. El universo estuvo conformado por 21 pacientes que cumplieron con los criterios de inclusión. Se utilizaron métodos estadísticos descriptivos y cálculos con valores porcentuales. Resultados: La mayor incidencia de los pacientes fueron del sexo masculino y blancos, con el 71,4 por ciento y el 85,7 por ciento respectivamente. Predominó el adenocarcinoma como variedad histológica con un 85,7 por ciento, así como el colangiocarcinoma proximal y la variante esclerosante de su clasificación. El 71,4 por ciento de los pacientes egresaron vivos y con una cirugía con finalidad curativa. Conclusiones: La mayoría de los pacientes fueron masculinos, de color blanco y de procedencia rural. Los hallazgos más frecuentes fueron la localización proximal y la variante esclerosante. A más de la mitad de los pacientes se les realizó procedimiento de Hess y Whipple con finalidad curativa. La fuga biliar, el adenocarcinoma como tipo histológico y el estado al egreso vivo prevaleció en todos los pacientes(AU)


Introduction: Cholangiocarcinoma is the most frequent biliary tract neoplasm responsible for high morbidity and mortality. Objective: To determine morbidity and mortality due to extrahepatic cholangiocarcinoma in the surgery service of Hospital Universitario Manuel Ascunce Domenech. Methods: A descriptive, prospective and observational study was carried out with patients admitted to the general surgery service with a diagnosis of extrahepatic cholangiocarcinoma between September 2018 and January 2022. The study universe consisted of 21 patients who met the inclusion criteria. Descriptive statistical methods and calculations with percentage values were used. Results: The highest incidence of patients were male and white-skinned, accounting for 71.4 percent and 85.7 percent, respectively. Adenocarcinoma predominated as histological variety, representing 85.7 percent, together with proximal cholangiocarcinoma and the sclerosing variant of its classification. 71.4 percent of the patients were discharged alive and after curative surgery. Conclusions: Most of the patients were male, white-skinned and from rural origin. The most frequent findings were a proximal location and the sclerosing variant. Over half the patients underwent Hess and Whipple procedure with curative purpose. Biliary leakage, adenocarcinoma as histologic type, and the condition of alive at discharge prevailed in all patients(AU)


Subject(s)
Humans , Biliary Tract Neoplasms/etiology , Indicators of Morbidity and Mortality , Cholangiocarcinoma/surgery , Epidemiology, Descriptive , Prospective Studies , Observational Study
3.
Rev. cir. (Impr.) ; 74(3): 248-255, jun. 2022. ilus, tab, graf
Article in Spanish | LILACS | ID: biblio-1407918

ABSTRACT

Resumen Introducción: Si bien actualmente la 8a edición de la clasificación del AJCC para cáncer biliar, recomienda una linfadenectomía con 6 o más GL, su aplicación es escasa. Objetivo: Analizar la aplicabilidad y los resultados de la linfadenectomía en pacientes resecados con fines curativos por cáncer biliar. Materiales y Método: Análisis retrospectivo de pacientes operados por cáncer biliar de 2001 a 2018. Se analizaron variables perioperatorias referidas a la linfadenectomía (número de GL, GL+, morbilidad), comparando supervivencia en pacientes con < 6 y ≥ 6 GL resecados. Resultados: en 72 pacientes resecados por cáncer biliar (46 CaV, 26 CC), se realizaron 66 (91.7%) linfadenectomías N1. En 62.1% (n = 41) se obtuvieron < 6 GL y en el 37.9% (n = 25) ≥ 6 GL. El promedio de GL resecados fue de 5. En 16 (24,2%) linfadenectomías se hallaron GL+ sin diferencias entre ambos grupos. La morbimortalidad global fue de 30,3%, con una mortalidad del 4.5% sin diferencias. Con un seguimiento de 36.9 meses, la supervivencia a 5 años fue 43,7% (n = 17), 7 pacientes con ≥ 6 GL, y 10 pacientes con < 6 GL (p = NS). La supervivencia media en pacientes con GL+ fue 15 meses (6-34 meses). Conclusión: la linfadenectomía ocupa un rol primordial en la cirugía curativa del cáncer biliar, tanto para definir una estadificación y un pronóstico adecuados como para optimizar los resultados de la resección curativa en esta entidad. Su indicación debe ser sistemática con la obtención de un número adecuado de GL acorde a las recomendaciones actuales.


Introduction: Currently the 8th edition of the AJCC classification recommends the resection of 6 or more lymph nodes (LN) in gallbladder cancer and cholangiocarcinoma. However, its implementation is universally scarce. Aim: The goal is to analyze the applicability and results of lymphadenectomy in patients resected with curative purposes in biliary cancer. Materials and Method: a retrospective analysis of patients with biliary cancer (gallbladder carcinoma, intrahepatic and hilar cholangiocarcinoma) treated by curative resection from 2001 to 2018 was performed. Perioperative variables related to lymphadenectomy (LN number, LN positive, related morbidity) were analyzed, comparing survival in patients with < 6 and ≥ 6 resected LN. Results: 72 patients resected for biliary cancer (46 gallbladder cancer, 26 cholangiocarcinoma) were included with 66 (91.7%) N1 lymphadenectomies corresponding to the hepatoduodenal ligament nodes performed. In 62.1% (n = 41) < 6 LN and in 37.9% (n = 25) ≥ 6 LN were resected. Average LN count was 5. In 16 (24.2%) patients positive LN were found, 7 in the group with ≥ 6 LN (28%) vs. 9 in the group with < 6 LN (22%) (p = NS). Overall morbimortality was 30.3% (n = 20). Average follow-up was 36.9 months. Survival at 5 years was 43.7% (n = 17), 7 patients with lymphadenectomy ≥ 6 LN, and 10 patients with < 6 LN (p = NS). Survival mean in patients who had positive LN was 15 months. Conclusión: Lymphadenectomy has a primary role in the radical resection with curative intention for biliary cancer. Systematic indication of lymphadenectomy should be prioritized, with the achievement of an adequately number of LN according to the actual recommendations. Lymphadenectomy is crucial for an adequate staging and prognosis, as well as to optimize the results of curative resection in this entity.


Subject(s)
Humans , Male , Female , Adult , Middle Aged , Aged , Aged, 80 and over , Stomach Neoplasms/surgery , Biliary Tract Neoplasms/surgery , Cholangiocarcinoma , Gastrectomy , Survival Analysis , Retrospective Studies
4.
Rev. colomb. gastroenterol ; 37(1): 99-102, Jan.-Mar. 2022. graf
Article in English, Spanish | LILACS | ID: biblio-1376912

ABSTRACT

Abstract Introduction: We describe the case of a patient with appendiceal metastasis as the first manifestation of a cholangiocarcinoma. Main symptoms: Abdominal pain, jaundice, hyporexia, and choluria. Methods and results: We documented an appendiceal plastron histologically compatible with metastatic appendiceal adenocarcinoma, common hepatic duct stricture, and a suspected cholangiocarcinoma, later corroborated by endoscopic retrograde cholangiopancreatography. Conclusions: Metastatic appendiceal tumors are an infrequent and poorly studied manifestation, whereas those secondary to bile duct neoplasia have rarely been reported in the literature.


Resumen Introducción: se describe el caso de una paciente con una metástasis apendicular como primera manifestación encontrada de un colangiocarcinoma. Síntomas principales: expresado con dolor abdominal, ictericia, hiporexia y coluria. Métodos y resultados: se documentó un plastrón apendicular histológicamente compatible con adenocarcinoma apendicular metastásico, estrechez del conducto hepático común, con alta sospecha de colangiocarcinoma, corroborado luego con la realización de una colangiopancreatografía retrógrada endoscópica. Conclusiones: los tumores apendiculares metastásicos son una presentación infrecuente y poco estudiada, donde los secundarios a neoplasia de vía biliar se han reportados de forma muy escasa en la literatura.


Subject(s)
Appendicitis , Cholangiopancreatography, Endoscopic Retrograde , Cholangiocarcinoma , Signs and Symptoms , Biliary Tract Neoplasms , Abdominal Pain , Jaundice , Neoplasm Metastasis
5.
Chinese Journal of Surgery ; (12): 343-350, 2022.
Article in Chinese | WPRIM | ID: wpr-935609

ABSTRACT

Biliary tract cancer has insidious onset and high degree of malignancy, and radical resection is often impossible when it is diagnosed.Conversion therapy can achieve tumor downgrading, so that patients who were initially unresectable have a chance to achieve R0 resection.However, due to the high heterogeneity and complex immune microenvironment of biliary tract cancer, conversion therapy is still in the stage of active exploration.As a new type of conversion therapy, combination of targeted therapy and immunotherapy is of great significance to effectively improve the efficiency of conversion therapy.Further exploration of combination mechanism and improvement of immune microenvironment are expected to become the future direction of combination of targeted therapy and immunotherapy.


Subject(s)
Humans , Antineoplastic Combined Chemotherapy Protocols , Biliary Tract Neoplasms/surgery , Combined Modality Therapy , Gastrectomy , Immunotherapy , Tumor Microenvironment
6.
Rev. gastroenterol. Perú ; 40(3): 284-287, Jul-Sep 2020. graf
Article in Spanish | LILACS | ID: biblio-1144678

ABSTRACT

RESUMEN El tumor miofibroblástico inflamatorio es una neoplasia mesenquimal infrecuente, realizar el diagnóstico clínico así como el patológico por biopsias es un desafío. Presentamos un caso de un paciente pediátrico con tumor miofibroblástico inflamatorio localizado a nivel de las vías biliares. Se realizaron estudios de laboratorio así como imagenológicos en los cuales se planteó un diagnóstico inexacto, del mismo modo cuando se envió la muestra de la lesión para el análisis intraoperatorio a través de técnicas de congelación, el reporte microscópico también fue incorrecto. Sin embargo cuando se realizó la revisión de las láminas tras la inclusión de la lesión y complementando con estudios de inmunohistoquimica, se concluyó que la lesión correspondió a un tumor miofibroblástico inflamatorio.


ABSTRACT The inflammatory myofibroblastic tumor is an infrequent mesenchymal neoplasm, making the clinical as well as the pathological diagnosis by biopsies is a challenge. We present a case of a pediatric patient with an inflammatory myofibroblastic tumor located at the level of the bile ducts. We sent the lesion sample for intraoperative analysis through freezing techniques, the microscopic report was also incorrect. However, when the plates were reviewed after the inclusion of the lesion and supplemented by immunohistochemical studies, it was concluded that the lesion corresponded to an inflammatory myofibroblastic tumor.


Subject(s)
Child , Humans , Male , Biliary Tract Neoplasms/pathology , Myofibroblasts/pathology
7.
Autops. Case Rep ; 9(2): e2019087, Abr.-Jun. 2019. graf, tab
Article in English | LILACS | ID: biblio-1015059

ABSTRACT

The combination of cisplatin and gemcitabine is the standard first-line treatment of metastatic biliary tract cancer (BTC) patients. The benefit of second-line chemotherapy in these patients is controversial. This study aims to evaluate the activity of FOLFIRI (fluorouracil and irinotecan) after failure to the first-line platinum and gemcitabine-based chemotherapy in metastatic BTC patients. We present a single-institution, retrospective cohort study. Patients with locally advanced or metastatic BTC who progressed after at least one line of chemotherapy, consecutively treated at our Institution between 2007 and 2017 were included. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival (OS), clinical benefit rate (CBR) and safety profile of FOLFIRI. Twelve patients were included in the analysis, with a median follow up of 5 months (95% CI 2.77-7.20). The median number of cycles received was 3 (range 1 to 9). Four grade 3 toxicities were recorded; no grade 4 toxicities and no treatment-related deaths occurred. The median PFS was 1.7 months (95% CI; 0.66-2.67), and median OS was 5 months (95% CI; 2.77-7.20). Two patients presented stable disease, providing a CBR of 17%. We concluded that FOLFIRI presented a favorable toxicity profile and a modest activity in metastatic BTC patients who had progressed to platinum and gemcitabine and may be considered in patients who are able to tolerate additional lines of chemotherapy. Immunotherapy and targeted therapies selected according to the tumoral genomic profile are promising alternatives to improve the outcomes of second-line treatment in BTC.


Subject(s)
Humans , Biliary Tract Neoplasms/drug therapy , Fluorouracil/therapeutic use , Irinotecan/therapeutic use , Neoplasm Metastasis/drug therapy
8.
Radiation Oncology Journal ; : 279-285, 2019.
Article | WPRIM | ID: wpr-786561

ABSTRACT

PURPOSE: This study was conducted to compare the outcome of three-dimensional conformal radiotherapy (3D-CRT) and intensity-modulated radiotherapy (IMRT) for the postoperative treatment of biliary tract cancer.MATERIALS AND METHODS: From February 2008 to June 2016, 57 patients of biliary tract cancer treated with curative surgery followed by postoperative 3D-CRT (n = 27) or IMRT (n = 30) were retrospectively enrolled.RESULTS: Median follow-up time was 23.6 months (range, 5.2 to 97.6 months) for all patients and 38.4 months (range, 27.0 to 89.2 months) for survivors. Two-year recurrence-free survival is higher in IMRT arm than 3D-CRT arm with a marginal significance (25.9% vs. 47.4%; p = 0.088). Locoregional recurrence-free survival (64.3% vs. 81.7%; p = 0.122) and distant metastasis-free survival (40.3% vs. 55.8%; p = 0.234) at two years did not show any statistical difference between two radiation modalities. In the multivariate analysis, extrahepatic cholangiocarcinoma, poorly-differentiated histologic grade, and higher stage were significant poor prognostic factors for survival. Severe treatment-related toxicity was not significantly different between two arms.CONCLUSIONS: IMRT showed comparable results with 3D-CRT in terms of recurrence, and survival, and radiotherapy toxicity for the postoperative treatment of biliary tract cancer.


Subject(s)
Humans , Arm , Biliary Tract Neoplasms , Biliary Tract , Cholangiocarcinoma , Follow-Up Studies , Multivariate Analysis , Radiotherapy , Radiotherapy, Conformal , Radiotherapy, Intensity-Modulated , Recurrence , Retrospective Studies , Survivors
9.
Cancer Research and Treatment ; : 832-840, 2019.
Article in English | WPRIM | ID: wpr-763113

ABSTRACT

PURPOSE: The soluble programmed death-ligand 1 (sPDL1) has immunosuppressive activity and is a candidate biomarker for immuno-oncology drug development. In this study, we measured sPDL1 at pre- and post-chemotherapy and at disease progression to uncover the dynamics of sPDL1 during treatment in biliary tract cancer (BTC) patients. MATERIALS AND METHODS: From 90 BTC patients (training cohort, 53; validation cohort, 37) who were candidates for palliative first-line chemotherapy, blood was collected at pre- and post-chemotherapy (at the time of best response) and at disease progression. The sPDL1 levels were measured using an enzyme-linked immunosorbent assay. Responses to chemotherapy, overall survival (OS), and other prognostic factors including the neutrophil-lymphocyte ratio (NLR) were analyzed. RESULTS: The OS of all patients was 11.5 months (confidence interval [CI], 9.7 to 16.2). The best response was complete response in seven (7.8%), partial response in 20 (22.2%), stable disease in 52 (57.8%), and disease progression (PD) in 11 patients (12.2%). Patients with high pre-chemotherapy sPDL1 (≥ 1.30 ng/mL) showed worse OS than patients with low prechemotherapy sPDL1 (9.1 months vs. 12.5 months, p=0.003). In multivariate analyses, high pre-chemotherapy sPDL1 (hazard ratio [HR], 1.96; 95% CI, 1.2 to 3.9; p=0.011) and high pre-chemotherapy NLR (HR, 1.82; 95% CI, 1.1 to 3.0; p=0.020) were independent poor prognostic factors for OS. At the time of PD, sPDL1 was increased significantly compared with pre-chemotherapy sPDL1 (1.59 ng/mL vs. 0.72 ng/mL, p=0.003). CONCLUSION: The sPDL1 at pre-chemotherapy confers the prognostic value for OS in BTC patients under palliative chemotherapy. The dynamics of sPDL1 during chemotherapy correlate with disease burden and have prognostic value.


Subject(s)
Humans , Biliary Tract Neoplasms , Biomarkers , Cohort Studies , Disease Progression , Drug Therapy , Enzyme-Linked Immunosorbent Assay , Multivariate Analysis , Prognosis
10.
Gut and Liver ; : 104-113, 2019.
Article in English | WPRIM | ID: wpr-719361

ABSTRACT

BACKGROUND/AIMS: There have been no nationwide studies to investigate the trends in incidence and 5-year survival rates of intra- and extrahepatic bile duct cancers and gall-bladder cancer. Therefore, our study aimed to describe the incidence and 5-year survival rates of biliary tract cancers by subsites in South Korea. METHODS: A total of 86,134 patients with biliary tract cancers were selected from the National Health Information Database. Age-standardized incidence rates and annual percentage changes were calculated. Life-table methods and log-rank tests were used to determine the differences in survival rates. Cox-proportional hazard models were used to estimate the hazard ratio of the patients with biliary tract cancers. RESULTS: The incidence rate of intra-hepatic bile duct cancer decreased by 1.3% annually from 8.8 per 100,000 in 2006 to 7.8 per 100,000 in 2015. Extrahepatic bile duct cancer also showed a decreasing trend by 2.2% per year from 8.7 per 100,000 in 2006 to 6.7 per 100,000 in 2015. Gallbladder cancer showed the greatest decline, with an annual percentage change of 2.8% from 6.3 per 100,000 to 5.2 per 100,000 during the same period. The 5-year survival rates were 30.0% in gallbladder cancer, 27.8% in extrahepatic bile duct cancer, and 15.9% in intra-hepatic bile duct cancer. CONCLUSIONS: The overall incidence rates of intrahepatic and extrahepatic bile duct cancer and gallbladder cancer decreased from 2006 to 2015. Among biliary tract cancers, intrahepatic bile duct cancers exhibited the highest incidence rate and the worst survival rate.


Subject(s)
Humans , Bile Duct Neoplasms , Bile Ducts, Extrahepatic , Bile Ducts, Intrahepatic , Biliary Tract Neoplasms , Biliary Tract , Cholangiocarcinoma , Gallbladder Neoplasms , Incidence , Korea , Proportional Hazards Models , Survival Rate
11.
Gut and Liver ; : 471-478, 2019.
Article in English | WPRIM | ID: wpr-763852

ABSTRACT

BACKGROUND/AIMS: Metallic stents designed to relieve malignant biliary obstruction are susceptible to occlusive tumor ingrowth or overgrowth. In a previous report, we described metallic stents covered with paclitaxel-incorporated membrane (MSCPM-I, II) to prevent occlusion from tumor ingrowth via antitumor effect. This new generation paclitaxel-eluting biliary stent is further endowed with sodium caprate (MSCPM-III) for enhanced drug delivery. The purpose of this study is to examine the safety of its drug delivery system in the porcine biliary tract. METHODS: MSCPM-III (10% [wt/vol] paclitaxel) and covered metal stents (CMSs) were endoscopically inserted in porcine bile ducts in vivo. Histologic biliary changes, levels of paclitaxel released, and various serum analytes (albumin, alkaline phosphate, aspartate transaminase, alanine transaminase, total protein, total bilirubin, and direct bilirubin) were assessed. RESULTS: Based on the intensity of reactive inflammation and fibrosis, changes in porcine biliary epithelium secondary to implanted MSCPM-III were deemed acceptable (i.e., safe). Histologic features in the MSCPM-III and CMS groups did not differ significantly. In a related serum analysis, paclitaxel release from MSCPM-III stents was below the limit of detection for 28 days. Biochemical analyses were also similar for the two groups, and no evidence of hepatic or renal toxicity was found in animals receiving MSCPM-III stents. CONCLUSIONS: In a prototypic porcine trial, this newly devised metal biliary stent incorporating both paclitaxel and sodium caprate appears to be safe in the porcine bile duct.


Subject(s)
Animals , Alanine Transaminase , Aspartate Aminotransferases , Bile Ducts , Biliary Tract Neoplasms , Biliary Tract , Bilirubin , Drug Delivery Systems , Drug-Eluting Stents , Epithelium , Fibrosis , Inflammation , Limit of Detection , Membranes , Paclitaxel , Pancreatic Neoplasms , Self Expandable Metallic Stents , Sodium , Stents
12.
Cancer Research and Treatment ; : 886-900, 2019.
Article in English | WPRIM | ID: wpr-763190

ABSTRACT

PURPOSE: Jab1 is a coactivator of c-Jun that enhances the transcriptional function of c-Jun. Jab1 is frequently overexpressed in various cancers and is associatedwith poor prognosis of cancer patients. Thus, Jab1 could be a potential therapeutic target in cancer. However, the role of Jab1 in biliary tract cancer (BTC) has not been studied. MATERIALS AND METHODS: We performed in vitro and in vivo experiments to evaluate the therapeutic potential ofJab1 inhibition in BTC. RESULTS: Among 8 BTC cell lines, many showed higher Jab1 expression levels. In addition, Jab1 silencing by siRNA increased p27 expression levels. SNU478 and HuCCT-1 cells exhibited profound Jab1 knockdown and increased p27 expression by Jab1-specific siRNA transfection. Jab1 silencing induced anti-proliferative and anti-migratory effects and resulted in G1 cell cycle arrest in SNU478 and HuCCT-1 cells. In addition, Jab1 silencing potentiated the anti-proliferative and anti-migratory effects of cisplatin by increasing DNA damage. Interestingly,Jab1 knockdown increased PTEN protein half-life, resulting in increased PTEN expression. In the HuCCT-1 mouse xenograft model, stable knockdown of Jab1 by shRNA also showed anti-proliferative effects in vivo, with decreased Ki-67 expression and AKT phosphorylation and increased Terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling and p27 expression. CONCLUSION: Jab1 knockdown demonstrated anti-proliferative and anti-migratory effects in BTC cells by increasing DNA damage and stabilizing PTEN, resulting in G1 cell cycle arrest. In addition, Jab1 silencing potentiated the anti-proliferative effects of cisplatin. Our data suggest that Jab1 may be a potential therapeutic target in BTC that is worthy of further investigations.


Subject(s)
Animals , Humans , Mice , Biliary Tract Neoplasms , Biliary Tract , Cell Line , Cisplatin , DNA Damage , G1 Phase Cell Cycle Checkpoints , Half-Life , Heterografts , In Vitro Techniques , Phosphorylation , Prognosis , PTEN Phosphohydrolase , RNA, Small Interfering , Transfection
13.
Cancer Research and Treatment ; : 901-909, 2019.
Article in English | WPRIM | ID: wpr-763189

ABSTRACT

PURPOSE: Gemcitabine plus cisplatin (GemCis) is the standard first-line chemotherapy for patients with advanced biliary tract cancer (BTC). In ABC-02 study, the BTC patients received up to 6-8 cycles of 3-weekly GemCis; however, those without progression often receive more than 6-8 cycles. The clinical benefit of maintenance treatment in patients without progression is uncertain. MATERIALS AND METHODS: Advanced BTC patients treated with GemCis between April 2010 and February 2015 at Asan Medical Center, Seoul, Korea, were retrospectively analysed. The patients without progression after 6-8 cycles were stratified according to further treatment i.e., with or without further cycles of GemCis (maintenance vs. observation groups). The primary endpoint was overall survival (OS) and progression-free survival (PFS). RESULTS: Among the 740 BTC patients in the initial screen, 231 cases (31.2%) were eligible for analysis (111 in the observation group, 120 in the maintenance group). The median OS from the GemCis initiation was 20.5 months (95% confidence interval [CI], 15.4 to 25.6) and 22.4 months (95% CI, 17.0 to 27.8) in the observation and maintenance groups, respectively (p=0.162). The median PFS was 10.4 months (95% CI, 7.0 to 13.8) and 13.2 months (95% CI, 11.3 to 15.2), respectively (p=0.320). CONCLUSION: sGemCis maintenance is not associated with an improved survival outcome.


Subject(s)
Humans , Biliary Tract Neoplasms , Biliary Tract , Cholangiocarcinoma , Cisplatin , Disease-Free Survival , Drug Therapy , Korea , Retrospective Studies , Seoul
14.
Cancer Research and Treatment ; : 1167-1179, 2019.
Article in English | WPRIM | ID: wpr-763163

ABSTRACT

PURPOSE: The DNA damage response (DDR) is a multi-complex network of signaling pathways involved in DNA damage repair, cell cycle checkpoints, and apoptosis. In the case of biliary tract cancer (BTC), the strategy of DDR targeting has not been evaluated, even though many patients have DNA repair pathway alterations. The purpose of this study was to test the DDR-targeting strategy in BTC using an ataxia-telangiectasia and Rad3-related (ATR) inhibitor. MATERIALS AND METHODS: A total of nine human BTC cell lines were used for evaluating anti-tumor effect of AZD6738 (ATR inhibitor) alone or combination with cytotoxic chemotherapeutic agents through MTT assay, colony-forming assays, cell cycle analyses, and comet assays. We established SNU478-mouse model for in vivo experiments to confirm our findings. RESULTS: Among nine human BTC cell lines, SNU478 and SNU869 were the most sensitive to AZD6738, and showed low expression of both ataxia-telangiectasia mutated (ATM) and p53. AZD6738 blocked p-Chk1 and p-glycoprotein and increased γH2AX, a marker of DNA damage, in sensitive cells. AZD6738 significantly increased apoptosis, G2/M arrest and p21, and decreased CDC2. Combinations of AZD6738 and cytotoxic chemotherapeutic agents exerted synergistic effects in colony-forming assays, cell cycle analyses, and comet assays. In our mouse models, AZD6738 monotherapy decreased tumor growth and the combination with cisplatin showed more potent effects on growth inhibition, decreased Ki-67, and increased terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling than monotherapy with each drug. CONCLUSION: In BTC, DDR targeting strategy using ATR inhibitor demonstrated promising antitumor activity alone or in combination with cytotoxic chemotherapeutic agents. This supports further clinical development of DDR targeting strategy in BTC.


Subject(s)
Animals , Humans , Mice , Apoptosis , Ataxia Telangiectasia , Biliary Tract Neoplasms , Biliary Tract , Cell Cycle , Cell Cycle Checkpoints , Cell Line , Cisplatin , Comet Assay , DNA Damage , DNA Repair , DNA , ATP Binding Cassette Transporter, Subfamily B, Member 1
15.
Protein & Cell ; (12): 838-847, 2018.
Article in English | WPRIM | ID: wpr-756953

ABSTRACT

This phase I clinical trial (NCT01935843) is to evaluate the safety, feasibility, and activity of chimeric antigen receptor-engineered T cell (CART) immunotherapy targeting human epidermal growth factor receptor 2 (HER2) in patients with advanced biliary tract cancers (BTCs) and pancreatic cancers (PCs). Eligible patients with HER2-positive (>50%) BTCs and PCs were enrolled in the trial. Well cultured CART-HER2 cells were infused following the conditioning treatment composed of nab-paclitaxel (100-200 mg/m) and cyclophosphamide (15-35 mg/kg). CAR transgene copy number in the peripheral blood was serially measured to monitor the expansion and persistence of CART-HER2 cells in vivo. Eleven enrolled patients received 1 to 2-cycle CART-HER2 cell infusion (median CAR T cell 2.1 × 10/kg). The conditioning treatment resulted in mild-to-moderate fatigue, nausea/vomiting, myalgia/arthralgia, and lymphopenia. Except one grade-3 acute febrile syndrome and one abnormal elevation of transaminase (>9 ULN), adverse events related to the infusion of CART-HER2 cells were mild-to-moderate. Post-infusion toxicities included one case of reversible severe upper gastrointestinal hemorrhage which occurred in a patient with gastric antrum invaded by metastasis 11 days after the CART-HER2 cell infusion, and 2 cases of grade 1-2 delayed fever, accompanied by the release of C-reactive protein and interleukin-6. All patients were evaluable for assessment of clinical response, among which 1 obtained a 4.5-months partial response and 5 achieved stable disease. The median progression free survival was 4.8 months (range, 1.5-8.3 months). Finally, data from this study demonstrated the safety and feasibility of CART-HER2 immunotherapy, and showed encouraging signals of clinical activity.


Subject(s)
Aged , Female , Humans , Male , Middle Aged , Biliary Tract Neoplasms , Allergy and Immunology , Therapeutics , Immunotherapy, Adoptive , Pancreatic Neoplasms , Allergy and Immunology , Therapeutics , Receptor, ErbB-2 , Allergy and Immunology , Receptors, Chimeric Antigen , Allergy and Immunology , T-Lymphocytes , Allergy and Immunology
16.
Genomics & Informatics ; : e35-2018.
Article in English | WPRIM | ID: wpr-739678

ABSTRACT

Biliary tract cancer (BTC) is a rare cancer and is associated with a poor prognosis. To understand the genetic characteristics of BTC, we analyzed whole-exome sequencing data and identified somatic mutations in patients with BTC. Tumors and matched blood or normal samples were obtained from seven patients with cholangiocarcinoma who underwent surgical resection. We discovered inactivating mutations of tumor suppressor genes, including APC, TP53, and ARID1A, in three patients. Activating mutations of KRAS and NRAS were also identified. Our analyses identified somatic mutations in Korean patients with BTC


Subject(s)
Humans , Biliary Tract Neoplasms , Biliary Tract , Cholangiocarcinoma , Exome , Genes, Tumor Suppressor , Prognosis
17.
Cancer Research and Treatment ; : 1324-1330, 2018.
Article in English | WPRIM | ID: wpr-717520

ABSTRACT

PURPOSE: Although gemcitabine plus cisplatin has been established as the standard first-line chemotherapy for patients with advanced biliary tract cancer (BTC), overall prognosis remains poor. We investigated the efficacy of a novel triplet combination of oxaliplatin, irinotecan, and S-1 (OIS) for advanced BTC. MATERIALS AND METHODS: Chemotherapy-naive patientswith histologically documented unresectable or metastatic BTC were eligible for this multicenter, single-arm phase II study. Patients received 65 mg/m2 oxaliplatin (day 1), 135 mg/m2 irinotecan (day 1), and 40 mg/m2 S-1 (twice a day, days 1-7) every 2 weeks. Primary endpoint was objective response rate. Targeted exome sequencing for biomarker analysis was performed using archival tissue. RESULTS: In total, 32 patients were enrolled between October 2015 and June 2016. Median age was 64 years (range, 40 to 76 years), with 24 (75%) male patients; 97% patients had metastatic or recurrent disease. Response rate was 50%, and median progression-free survival and overall survival (OS) were 6.8 months (95% confidence interval [CI], 4.8 to 8.8) and 12.5 months (95% CI, 7.0 to 18.0), respectively. The most common grade 3-4 adverse events were neutropenia (32%), diarrhea (6%), and peripheral neuropathy (6%). TP53 and KRAS mutations were the most frequent genomic alterations (42% and 32%, respectively), and KRAS mutations showed a marginal relationship with worse OS (p=0.07). CONCLUSION: OIS combination chemotherapy was feasible and associated with favorable efficacy outcomes as a first-line treatment in patients with advanced BTC. Randomized studies are needed to compare OIS with gemcitabine plus cisplatin.


Subject(s)
Humans , Male , Biliary Tract Neoplasms , Biliary Tract , Cholangiocarcinoma , Cisplatin , Diarrhea , Disease-Free Survival , Drug Therapy , Drug Therapy, Combination , Exome , Neutropenia , Peripheral Nervous System Diseases , Prognosis , Triplets
18.
Korean Journal of Medicine ; : 457-463, 2018.
Article in Korean | WPRIM | ID: wpr-717450

ABSTRACT

BACKGROUND/AIMS: Venous thromboembolic events (VTEs) are common events in patients with advanced cancer. We analyzed the clinical characteristics of VTEs in advanced pancreatic and biliary tract cancer to determine the clinical significance, especially in palliative settings. METHODS: Seventy-nine patients with advanced pancreatic cancer or biliary tract cancer who had thromboembolic events were retrospectively reviewed. We investigated the correlation between clinical course and thromboembolic events, and the laboratory risk factors, such as complete blood count profile. RESULTS: The 79 patients consisted of 40 men (50.6%) and 39 women (49.4%) with a median age of 65 years old (range: 41–80). Forty-three patients (54.4%), had thromboembolic events without any symptoms. Pulmonary thromboembolism occurred in only 31 cases (39.2%), and combined thrombosis at more than two sites occurred in 17 cases (21.5%). Of the 51 patients with active chemotherapy, 45 showed progressive disease. The median survival times were 11.9 weeks in all patients, 15.3 weeks in the treatment group, and 3.4 weeks in the palliative group. There was no difference in survival time between patients treated with dalteparin only and those treated with dalteparin combined with thrombolytic intervention. CONCLUSIONS: VTE can be poor prognostic indicator in pancreatic and biliary tract cacner patients, suggestive of progressive disease and a sign of short life expectancy, requiring hospice and terminal care.


Subject(s)
Female , Humans , Male , Biliary Tract Neoplasms , Biliary Tract , Biomarkers , Blood Cell Count , Dalteparin , Drug Therapy , Hospices , Life Expectancy , Pancreatic Neoplasms , Pulmonary Embolism , Retrospective Studies , Risk Factors , Terminal Care , Thrombosis , Venous Thromboembolism
19.
Gut and Liver ; : 236-245, 2018.
Article in English | WPRIM | ID: wpr-714618

ABSTRACT

Cholangiocarcinoma (CCA) is an aggressive cancer arising from epithelial cells of the bile duct. Most patients with CCA have an unresectable tumor at the time of diagnosis. In Western countries, the risk of CCA increases in patients with primary sclerosing cholangitis, whereas liver fluke infection appears to be the major risk factor for CCA in Asian countries. A diagnosis of liver fluke infection often relies on stool samples, including microscopic examination, polymerase chain reaction-based assays, and fluke antigen detection. Tests of serum, saliva and urine samples are also potentially diagnostic. The presence of liver fluke along with exogenous carcinogens magnifies the risk of CCA in people living in endemic areas. The “liver fluke-cholangiocarcinoma” carcinogenesis pathways consist of mechanical damage to the bile duct epithelium, immunopathologic and cellular reactions to the liver fluke's antigens and excretory/secretory products, liver fluke-induced changes in the biliary tract microbiome and the effects of repeated treatment for liver fluke. A vaccine and novel biomarkers are needed for the primary and secondary prevention of CCA in endemic areas. Importantly, climate change exerts an effect on vector-borne parasitic diseases, and awareness of liver fluke should be enhanced in potentially migrated habitat areas.


Subject(s)
Humans , Asian People , Bile Ducts , Biliary Tract Neoplasms , Biliary Tract , Biomarkers , Carcinogenesis , Carcinogens , Cholangiocarcinoma , Cholangitis, Sclerosing , Climate Change , Clonorchiasis , Diagnosis , Ecosystem , Epithelial Cells , Epithelium , Fasciola hepatica , Liver , Microbiota , Opisthorchiasis , Parasitic Diseases , Risk Factors , Saliva , Secondary Prevention , Trematoda
20.
Dementia and Neurocognitive Disorders ; : 137-147, 2018.
Article in English | WPRIM | ID: wpr-718821

ABSTRACT

BACKGROUND AND PURPOSE: Previous studies have suggested a decreased cancer risk among patients with Alzheimer's disease (AD). There remains a lack of data on the specific types of cancer and risk factors for developing cancer in AD. We evaluated the association between AD and cancer risk, and we examined specific types of cancer. METHODS: A population-based longitudinal study was conducted using the National Health Insurance Service-Senior cohort for 2002–2013. A total of 4,408 AD patients were included in the study, as were 19,150 matched controls. Potential associations between the risk of cancer and AD were analyzed using Cox proportional hazard regressions. RESULTS: Cancer developed in 12.3% of the AD group patients and in 18.5% of control group subjects. AD was associated with a reduced risk of cancer (hazard ratio [HR], 0.70; 95% confidence intervals, 0.64–0.78). The risk of head and neck cancers was significantly reduced (HR, 0.49), as were risks for cancers of the digestive tract, including stomach cancer (HR, 0.42), colorectal cancer (HR, 0.61), liver and biliary tract cancers (HR, 0.68), and pancreatic cancer (HR, 0.55). Lung and prostate cancer risks were also significantly lower for the AD group (HR, 0.52 and HR, 0.72, respectively). CONCLUSIONS: Our results showed an inverse association between AD and cancer. Further research involving a large number of patients in a hospital based-study is needed to address the biological associations between cancer development and dementia, including AD.


Subject(s)
Humans , Alzheimer Disease , Biliary Tract Neoplasms , Cohort Studies , Colorectal Neoplasms , Dementia , Epidemiology , Gastrointestinal Tract , Head , Korea , Liver , Longitudinal Studies , Lung , National Health Programs , Neck , Pancreatic Neoplasms , Prostatic Neoplasms , Risk Factors , Stomach Neoplasms
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