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1.
Eur J Surg Oncol ; 46(5): 832-838, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-31806519

RESUMEN

BACKGROUND: The clinical implication of lymph node (LN) dissection of intrahepatic cholangiocarcinoma (ICCA) is still controversial, and LN metastasis (LNM) based on tumor site has not been confirmed yet. METHODS: Patients who underwent curative-intent surgery at 10 tertiary referral centers were identified and divided into peripheral (PP) and near second confluence level tumor (NC) groups on the basis of the distance from the second confluence and oncological outcomes were compared. RESULTS: Of 179 patients, 121 patients with LND were divided into the NC (n = 89) and PP groups (n = 32) on the basis of 4.5 cm from the second confluence. NC group showed higher LNM rate than PP group (46.1 vs 21.9%, p = 0.016) and NC was a risk factor for LNM (odds ratio: 4.367; 95% confidence interval: 1.234-15.453, p = 0.022). The 5-year overall survival (OS) rate (38.0% vs. 27.8%, p = 0.777) and recurrence-free survival (RFS) rates (22.8% vs. 25.8%, p = 0.742) showed no differences between the PP and NC groups. In the NC group, N1 patients showed worse 5-year OS (12.7% vs 39.0%, p = 0.004) and RFS (8.8% vs 28.6%, p = 0.004) than the N0 patients. In the PP group, discordant results in 5-year OS (48.9% vs. 50.0%, p = 0.462) and RFS (41.3% vs. 0%, p = 0.056) were found between the N0 and N1 patients. CONCLUSION: The NC group was an independent risk factor for LNM and LNM worsened prognosis in NC group for ICCA. In the PP group, LND should not be omitted because of high LNM rate and insufficient oncologic evidence.


Asunto(s)
Neoplasias de los Conductos Biliares/patología , Conductos Biliares Intrahepáticos , Colangiocarcinoma/patología , Tumor de Klatskin/patología , Ganglios Linfáticos/patología , Anciano , Anastomosis Quirúrgica , Neoplasias de los Conductos Biliares/cirugía , Colangiocarcinoma/cirugía , Supervivencia sin Enfermedad , Femenino , Hepatectomía , Humanos , Yeyuno/cirugía , Estimación de Kaplan-Meier , Tumor de Klatskin/cirugía , Hígado/cirugía , Escisión del Ganglio Linfático , Metástasis Linfática , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Modelos de Riesgos Proporcionales
2.
Langenbecks Arch Surg ; 404(5): 581-588, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31414179

RESUMEN

BACKGROUND: Although the current nodal staging system for gallbladder cancer (GBC) was changed based on the number of positive lymph nodes (PLN), it needs to be evaluated in various situations. METHODS: We reviewed the clinical data for 398 patients with resected GBC and compared nodal staging systems based on the number of PLNs, the positive/retrieved LN ratio (LNR), and the log odds of positive LN (LODDS). Prognostic performance was evaluated using the C-index. RESULTS: Subgroups were formed on the basis of an restricted cubic spline plot as follows: PLN 3 (PLN = 0, 1-2, ≥ 3); PLN 4 (PLN = 0, 1-3, ≥ 4); LNR (LNR = 0, 0-0.269, ≥ 0.27); and LODDS (LODDS < - 0.8, - 0.8-0, ≥ 0). The oncological outcome differed significantly between subgroups in each system. In all patients with GBC, PLN 4 (C-index 0.730) and PLN 3 (C-index 0.734) were the best prognostic discriminators of survival and recurrence, respectively. However, for retrieved LN (RLN) ≥ 6, LODDS was the best discriminator for survival (C-index 0.852). CONCLUSION: The nodal staging system based on PLN was the optimal prognostic discriminator in patients with RLN < 6, whereas the LODDS system is adequate for RLN ≥ 6. The following nodal staging system considers applying different systems according to the RLN.


Asunto(s)
Neoplasias de la Vesícula Biliar/mortalidad , Neoplasias de la Vesícula Biliar/patología , Ganglios Linfáticos/patología , Estadificación de Neoplasias , Anciano , Colecistectomía , Supervivencia sin Enfermedad , Femenino , Neoplasias de la Vesícula Biliar/terapia , Humanos , Escisión del Ganglio Linfático , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Modelos de Riesgos Proporcionales , Reproducibilidad de los Resultados , Estudios Retrospectivos , Tasa de Supervivencia
3.
Oncol Rep ; 38(3): 1867-1876, 2017 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-28731185

RESUMEN

Snail, a zinc-finger transcriptional repressor of E-cadherin expression, is one of the key inducers of epithelial-mesenchymal transition (EMT) in epithelial cancer. In breast cancer, EMT has been associated with malignancies, including metastasis, cancer stem-like properties, and resistance to chemotherapy and radiotherapy. In this study, we analysed the role of Snail in the highly metastatic mesenchymal TUBO­P2J mouse breast cancer cells, by loss of function using short hairpin RNA. Though silencing Snail did not restore the E-cadherin expression or induce morphological changes, Snail silencing significantly ablated in vitro and in vivo metastatic potentials. In addition, Snail silencing also reduced resistance to chemotherapy drugs and cancer stem-like properties, such as CD44 expression, aldehyde dehydrogenase (ALDH) activity, colony formation, and in vivo tumour formation and growth. However, radioresistance was not decreased by silencing Snail. Collectively, this study suggested that Snail is a main regulator of the maintenance of malignancy potentials and is a good target to prevent cancer metastasis and to increase chemotherapy susceptibility.


Asunto(s)
Neoplasias de la Mama/genética , Resistencia a Antineoplásicos/genética , Transición Epitelial-Mesenquimal/genética , Receptores de Hialuranos/genética , Células Madre Neoplásicas/fisiología , Factores de Transcripción de la Familia Snail/genética , Animales , Neoplasias de la Mama/patología , Cadherinas/genética , Línea Celular Tumoral , Movimiento Celular/genética , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Ratones , Ratones Endogámicos BALB C , ARN Mensajero/genética , ARN Interferente Pequeño/genética , Factores de Transcripción/genética
4.
Tumori ; 103(3): 279-285, 2017 May 12.
Artículo en Inglés | MEDLINE | ID: mdl-28085178

RESUMEN

AIMS AND BACKGROUND: The relationship between cancer and metabolism has recently been receiving attention. We investigated the prognostic influence of type 2 diabetes mellitus in patients with hepatocellular carcinoma (HCC) treated with curative resection. METHODS AND STUDY DESIGN: The records of 58 patients who underwent curative resection for HCC pT1-2N0M0 between 2010 and 2014 were reviewed retrospectively. Fourteen patients (24.1%) had diabetes mellitus at diagnosis. Local control (LC) was defined as time to recurrence in the liver. RESULTS: The median follow-up was 23.3 months. Relapses occurred in 20 patients (34.5%) during the follow-up period; 17 of them developed intrahepatic recurrence, which was associated with diabetes mellitus (p = 0.013) and alpha fetoprotein (AFP) levels >500 ng/mL (p = 0.019). Overall relapses (n = 20) were related to T stage (p = 0.044), AFP level (p = 0.005), and diabetes (p = 0.044). The 3-year local control (intrahepatic control), disease-free survival, and overall survival rates were 56.7%, 50.5%, and 84.3%, respectively. LC was affected by diabetes mellitus (p = 0.046), Barcelona Clinic Liver Cancer staging (p<0.001), Milan criteria for transplantation (p = 0.041), serosal invasion (p = 0.032), and microvascular invasion (p = 0.043). Diabetes was also associated with reduced LC in the subgroup with hepatitis B-related HCC (n = 44, p = 0.028). CONCLUSIONS: Diabetes mellitus is correlated with intrahepatic HCC recurrence after surgery. Greater attention should be paid to managing patients with HCC and diabetes mellitus.


Asunto(s)
Carcinoma Hepatocelular/cirugía , Diabetes Mellitus Tipo 2/patología , Hepatitis B/cirugía , Neoplasias Hepáticas/cirugía , Adulto , Anciano , Carcinoma Hepatocelular/complicaciones , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/cirugía , Supervivencia sin Enfermedad , Femenino , Hepatitis B/complicaciones , Hepatitis B/metabolismo , Hepatitis B/patología , Humanos , Hígado/patología , Hígado/cirugía , Neoplasias Hepáticas/complicaciones , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/cirugía , Pronóstico , Factores de Riesgo , Tasa de Supervivencia
5.
Int J Surg ; 34: 161-168, 2016 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-27568651

RESUMEN

PURPOSE: This study examined the safety and facilitative aspects of laparoscopic gastrectomy, with respect to clinicopathologic factors and complications in patients with gastric cancer, in comparison with open gastrectomy. The study also compared the safety of laparoscopic gastrectomy, with respect to the 5-year survival rate and recurrence in terms of the oncologic results, with that of open gastrectomy. METHODS: This retrospective study included 424 patients with gastric cancer who had undergone gastrectomy at Busan Paik Hospital, Inje University, over a 5-year period from January 2010 to December 2014. The gastric cancer database, comprising data collected from the patients' medical records, was examined for the analysis of clinicopathologic factors, complications, survival rates, and recurrence. RESULTS: Of the 424 patients, 146 underwent laparoscopic gastrectomy and 278 underwent open gastrectomy. Differences were observed between laparoscopic and open gastrectomy with respect to clinicopathologic features such as tumor size, number of harvested lymph nodes, differentiation, T stage, N stage, TNM stage, lymphatic invasion, vascular invasion, and perineural invasion. The complication rates of laparoscopic and open gastrectomy were 4.8% and 4.3%, respectively, and the recurrence rates were 3.4% and 11.5%, respectively. The 5-year overall survival rates (OSRs) of laparoscopic and open gastrectomy were 90.5% and 85.9%, respectively, and the 5-year disease-free survival rates (DFSRs) were 90.2% and 75.6%, respectively, with significant differences. The 5-year OSRs of laparoscopic and open gastrectomy for stage I disease were 96.6% and 96.9%, respectively, those for stage II disease were 44.4% and 97.7%, respectively, and those for stage III disease were 75.0% and 61.7%, respectively. The 5-year DFSRs of laparoscopic and open gastrectomy for stage I disease were 95.4% and 96.9%, respectively, those for stage II disease were 60.6% and 84.9%, respectively, and those for stage III disease were 64.3% and 40.1%, respectively, with no significant difference. CONCLUSION: This study showed that laparoscopic gastrectomy is a safe and beneficial modality compared with open gastrectomy in patients with gastric cancer. In terms of the oncologic results, laparoscopic gastrectomy is also considered safe and provides the same results as open gastrectomy.


Asunto(s)
Gastrectomía/mortalidad , Laparoscopía/mortalidad , Neoplasias Gástricas/cirugía , Anciano , Supervivencia sin Enfermedad , Femenino , Gastrectomía/métodos , Humanos , Laparoscopía/métodos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Estudios Retrospectivos , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/patología , Tasa de Supervivencia , Resultado del Tratamiento
6.
Ann Hepatobiliary Pancreat Surg ; 20(4): 201-203, 2016 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-28261701

RESUMEN

This case report presents an unusual case of cholangiocarcinoma arising nearly 35 years after cystoduodenostomy for choledochal cyst. The patient visited our hospital with dyspepsia and studies revealed bezoar within the choledochal cyst caused by bile and food reflux. The patient underwent pancreaticoduodenectomy and a biopsy revealed adenocarcinoma, stage IIB. After 19 months, the patient has no recurrence to date and has recovered well. This case shows that proper surgical management and meticulous, long-term follow-up is imperative for patients with congenital choledochal cyst.

7.
World J Surg Oncol ; 13: 64, 2015 Feb 19.
Artículo en Inglés | MEDLINE | ID: mdl-25889520

RESUMEN

BACKGROUND: FOLFOX-based adjuvant chemotherapy is a benefit for high-risk stage II and stage III colon cancer after curative resection. But, the prognostic factor or predictive marker for the efficacy of FOLFOX remains unclear. This study was aimed to identify the prognostic value and cumulative impact of adjuvant FOLFOX on the stage II and III colon cancer patients. METHODS: A total of 196 stage II and III colon cancer patients were retrospectively enrolled in prospectively collected data. They underwent curative resection followed by FOLFOX4 adjuvant chemotherapy. The oncological outcomes included the 5-year disease-free survival (DFS) rate and 5-year overall survival (OS) rate. Cox-regression analysis was performed to identify the prognostic value, and its cumulative impact was analyzed. RESULTS: The 5-year DFS rate of the patients was 71.94% and the 5-year OS rate was 81.5%. The prognostic values for the 5-year DFS rate and 5-year OS rate were T4 stage and preoperative anemia in a multivariate analysis. Each patient group who had no prognostic value, single, or both factors revealed 95.35%, 69.06%, and 28.57% in the 5-year DFS rate, respectively (p < 0.0001). The 5-year OS rate also showed the significant differences in each group who had no prognostic value, single, or both factors revealed 100%, 79.3%, and 45.92%, respectively (p < 0.0001). CONCLUSION: Our results showed similar efficacy to MOSAIC study in stage II and stage III colon cancer patients treated with adjuvant FOLFOX chemotherapy after curative resection. Patients who had T4 stage and/or preoperative anemia showed worse prognosis than patients without any prognostic value. These findings suggest that FOLFOX could not be effective in the patients with T4 stage colon cancer accompanied by preoperative anemia.


Asunto(s)
Anemia/fisiopatología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/mortalidad , Adenocarcinoma Mucinoso/tratamiento farmacológico , Adenocarcinoma Mucinoso/mortalidad , Adenocarcinoma Mucinoso/patología , Adulto , Anciano , Carcinoma de Células en Anillo de Sello/tratamiento farmacológico , Carcinoma de Células en Anillo de Sello/mortalidad , Carcinoma de Células en Anillo de Sello/patología , Neoplasias del Colon/patología , Femenino , Fluorouracilo/uso terapéutico , Estudios de Seguimiento , Humanos , Leucovorina/uso terapéutico , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Compuestos Organoplatinos/uso terapéutico , Cuidados Preoperatorios , Pronóstico , Estudios Prospectivos , Estudios Retrospectivos , Tasa de Supervivencia
8.
Int J Surg ; 13: 96-101, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25704623

RESUMEN

INTRODUCTION: The prostaglandin (PG) E2 level, which is associated with oncogenesis, progression and metastasis in various types of cancer, is determined by reciprocal regulation of 15-prostaglandin dehydrogenase (15-PGDH) and cyclooxygenase-2. This study investigated 15-PGDH expression in gastric adenocarcinoma, the associations between 15-PGDH expression and clinicopathological factors, and the correlation between 15-PGDH expression and the 5-year gastric-cancer-specific survival rate (5-year GCSS). METHODS: From 175 patients who underwent gastrectomy, we obtained biopsies of gastric adenocarcinoma tissues and adjacent normal tissues for preparation as formalin-fixed, paraffin-embedded specimens and conducted an immunohistochemical analysis. RESULTS: 15-PGDH expression was low in 65.1% of cases. 15-PGDH expression showed no relationship with age or gender, but was significantly correlated with the pathologic type, T stage, N stage, TNM stage, positive lymph node metastasis, metastasis to a larger quantity of lymph nodes, positive lymphatic invasion, positive vascular invasion, positive perineural invasion, and palliative gastrectomy. The 5-year GCSS of the low-expression group was 77.19% and a lower level of 15-PGDH expression correlated to a lower 5-year GCSS. 15-PGDH expression significantly influenced the 5-year GCSS on univariate but not multivariate analysis. CONCLUSION: Our findings indicate that 15-PGDH expression was low in gastric adenocarcinoma and was correlated with the clinicopathological factors associated with prognosis and a more advanced stage of gastric adenocarcinoma. Also, 15-PGDH expression was significantly associated with the 5-year GCSS, but was not an independent prognostic factor thereof.


Asunto(s)
Adenocarcinoma/enzimología , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Hidroxiprostaglandina Deshidrogenasas/análisis , Neoplasias Gástricas/enzimología , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/patología , Adulto , Anciano , Anciano de 80 o más Años , Biopsia , Progresión de la Enfermedad , Femenino , Gastrectomía , Humanos , Ganglios Linfáticos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Invasividad Neoplásica/patología , Pronóstico , Tasa de Supervivencia
9.
Indian J Surg ; 77(Suppl 3): 1252-7, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-27011547

RESUMEN

Adjuvant chemotherapy is benefit for high-risk stage II and stage III colon cancer after curative resection. But, the optimal time between surgical and initiation of adjuvant chemotherapy remains unclear. Moreover, no study of efficacy with different lengths of adjuvant chemotherapy has appeared. This study was aimed to identify association between time (initiation and length) and oncological outcomes of adjuvant chemotherapy on the stages II and III colon cancer patients. A total of 406 high-risk stages II and III colon cancer patients were retrospectively enrolled in prospectively collected data. They were categorized into three groups representing chemotherapy initiation time: less than 4 weeks (group 1), 4 to 6 weeks (group 2), and more than 6 weeks (group 3). They were categorized into two groups representing chemotherapy length time : less than 200 days (group 1a) and more than 200 days (group 2a). The 5-year disease-free survival (DFS) rates were 74.97 % in group 1, 76.94 % in group 2, and 63.97 % in group 3 (p > 0.05). The 5-year DFS rates were 75.49 % in the group that received adjuvant chemotherapy within 6 weeks and 63.97 % in the group that received adjuvant chemotherapy >6 weeks (p = 0.0539). The 5-year DFS rates were 77.21 % in group 1a and 81.82 % in group 2a (p > 0.05). Adjuvant chemotherapy should be safely offered within 6 weeks after surgical excision in patients with colon cancer after considering the patient's general physical condition and hematological factors, even if the chemotherapy length is prolonged.

10.
Drug Metab Dispos ; 42(11): 1803-10, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-25122565

RESUMEN

UDP-glucuronosyltransferase (UGT)-mediated drug-drug interactions are commonly evaluated during drug development. We present a validated method for the simultaneous evaluation of drug-mediated inhibition of six major UGT isoforms, developed in human liver microsomes through the use of pooled specific UGT probe substrates (cocktail assay) and rapid liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. The six probe substrates used in this assay were estradiol (UGT1A1), chenodeoxycholic acid (UGT1A3), trifluoperazine (UGT1A4), 4-hydroxyindole (UGT1A6), propofol (UGT1A9), and naloxone (UGT2B7). In a cocktail incubation, UGT1A1, UGT1A9, and UGT2B7 activities were substantially inhibited by other substrates. This interference could be eliminated by dividing substrates into two incubations: one containing estradiol, trifluoperazine, and 4-hydroxyindole, and the other containing chenodeoxycholic acid, propofol, and naloxone. Incubation mixtures were pooled for the simultaneous analysis of glucuronyl conjugates in a single LC-MS/MS run. The optimized cocktail method was further validated against single-probe substrate assays using compounds known to inhibit UGTs. The degree of inhibition of UGT isoform activities by such known inhibitors in this cocktail assay was not substantially different from that in single-probe assays. This six-isoform cocktail assay may be very useful in assessing the UGT-based drug-interaction potential of candidates in a drug-discovery setting.


Asunto(s)
Cromatografía Liquida/métodos , Glucuronosiltransferasa/metabolismo , Isoenzimas/metabolismo , Microsomas Hepáticos/enzimología , Espectrometría de Masas en Tándem/métodos , Inhibidores Enzimáticos/farmacología , Glucuronosiltransferasa/antagonistas & inhibidores , Humanos , Técnicas In Vitro , Isoenzimas/antagonistas & inhibidores , Especificidad por Sustrato
11.
Ann Surg Treat Res ; 86(6): 302-8, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24949321

RESUMEN

PURPOSE: Prostaglandin E2 (PGE2) is a contributory carcinogen in gastric adenocarcinoma. 15-Hydroxyprostaglandin dehydrogenase (15-PGDH) catabolizes PGE2 by oxidizing its 15(s)-hydroxy group. The aim of this study was to investigate the expression of 15-PGDH in gastric adenocarcinoma tissue and the relationship between 15-PGDH expression and clinicopathologic features of gastric adenocarcinoma. METHODS: Ninety-nine patients who underwent surgical resection for gastric adenocarcinoma between January 2007 and December 2007 were enrolled and evaluated retrospectively. RESULTS: In 62 patients (62.6%), 15-PGDH expression was lower in gastric adenocarcinoma tissue than in nonneoplastic tissue. Regarding the relationship between 15-PGDH expression and clinicopathological features, 15-PGDH expression was significantly lower in tissues with poor differentiation (P = 0.002), advanced T stage (P = 0.0319), a higher number of lymph node metastases (P = 0.045), lymphatic invasion (P = 0.031), and vascular invasion (P = 0.036). CONCLUSION: 15-PGDH expression was associated with a subset of clinicopathologic features such as differentiation grade, T stage, lymphatic invasion, and vascular invasion.

12.
World J Gastrointest Surg ; 6(4): 74-6, 2014 Apr 27.
Artículo en Inglés | MEDLINE | ID: mdl-24829626

RESUMEN

This is a very rare case of the recurrence of gastric cancer in the jejunal stump after radical total gastrectomy with Roux-en-Y reconstruction. In January 2008, a 65-year-old man underwent radical total gastrectomy with Roux-en-Y reconstruction for stage IB gastric cancer of the upper body. At a follow-up in December 2011, the patient had a recurrence of gastric cancer on gastroduodenal fibroscopy. The gastroduodenal fibroscopic biopsy specimens show a well-differentiated tubular adenocarcinoma. Computed tomography showed no lymphadenopathy or hepatic metastases. At laparotomy, there was a tumor in the jejunal stump involving the pancreatic tail and spleen. Therefore, the patient underwent jejunal pouch resection, distal pancreatectomy and splenectomy. The patient was diagnosed with gastric cancer on histopathological examination.

13.
World J Gastrointest Surg ; 6(4): 77-9, 2014 Apr 27.
Artículo en Inglés | MEDLINE | ID: mdl-24829627

RESUMEN

Neuroendocrine carcinoma (NEC) is a rare tumor, comprising < 1% of stomach cancers. A 55-year-old woman was referred to our hospital with biopsy-proven gastric cancer. A shallow ulcerative lesion was detected in the lesser curvature of the lower body. It was suspected to be early gastric cancer IIA + IIC type. Thus, endoscopic submucosal dissection was performed. She was subsequently diagnosed with NEC, which is aggressive and carries a poor prognosis. We conducted a radical resection and a laparoscopic-assisted distal gastrectomy. The tumor had infiltrated the subserosal layer and 6/42 lymph nodes were involved. The mitotic index was 16/10 high power fields and the Ki-67 labeling index was 26%-50%. The final diagnosis of NEC was made according to the World Health Organization 2010 criteria. She was suspected of having jumping metastasis to the proximal margin. The patient was treated with an oral anticancer drug (5-flurouracil based drug) for 2 years. The patient has been followed up for 3 years without recurrence.

14.
Drug Metab Dispos ; 42(1): 141-52, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24170778

RESUMEN

Ticlopidine is a first-generation thienopyridine antiplatelet drug that prevents adenosine 5'-diphosphate (ADP)-induced platelet aggregation. We identified the enzymes responsible for the two-step metabolic bioactivation of ticlopidine in human liver microsomes and plasma. Formation of 2-oxo-ticlopidine, an intermediate metabolite, was NADPH dependent and cytochrome P450 (CYP) 1A2, 2B6, 2C19, and 2D6 were involved in this reaction. Conversion of 2-oxo-ticlopidine to thiol metabolites was observed in both microsomes (M1 and M2) and plasma (M1). These two metabolites were considered as isomers, and mass spectral analysis suggested that M2 was a thiol metabolite bearing an exocyclic double bond, whereas M1 was an isomer in which the double bond was migrated to an endocyclic position in the piperidine ring. The conversion of 2-oxo-ticlopidine to M1 in plasma was significantly increased by the addition of 1 mM CaCl2. In contrast, the activity in microsomes was not changed in the presence of CaCl2. M1 formation in plasma was inhibited by EDTA but not by other esterase inhibitors, whereas this activity in microsomes was substantially inhibited by carboxylesterase (CES) inhibitors such as bis-(p-nitrophenyl)phosphate (BNPP), diisopropylphosphorofluoride (DFP), and clopidogrel. The conversion of 2-oxo-ticlopidine to M1 was further confirmed with recombinant paraoxonase 1 (PON1) and CES1. However, M2 was detected only in NADPH-dependent microsomal incubation, and multiple CYP isoforms were involved in M2 formation with highest contribution of CYP2B6. In vitro platelet aggregation assay demonstrated that M2 was pharmacologically active. These results collectively indicated that the formation of M2 was mediated by CYP isoforms whereas M1, an isomer of M2, was generated either by human PON1 in plasma or by CES1 in the human liver.


Asunto(s)
Arildialquilfosfatasa/metabolismo , Hidrolasas de Éster Carboxílico/metabolismo , Sistema Enzimático del Citocromo P-450/metabolismo , Isoformas de Proteínas/metabolismo , Compuestos de Sulfhidrilo/metabolismo , Ticlopidina/metabolismo , Adulto , Carboxilesterasa/antagonistas & inhibidores , Carboxilesterasa/metabolismo , Clopidogrel , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacología , Esterasas/metabolismo , Humanos , Masculino , Microsomas/enzimología , Microsomas/metabolismo , Microsomas Hepáticos/enzimología , Microsomas Hepáticos/metabolismo , NADP/metabolismo , Inhibidores de Agregación Plaquetaria/metabolismo , Compuestos de Sulfhidrilo/farmacología , Ticlopidina/análogos & derivados , Ticlopidina/farmacología , Adulto Joven
15.
Int J Surg ; 11(9): 944-7, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23820062

RESUMEN

PURPOSE: Extrathyroidal extension (ETE) of papillary thyroid carcinoma (PTC) is a risk factor for tumor recurrence. By TNM Classification (7th edition), differentiated thyroid carcinoma with ETE is designated T3 (minimal invasion), T4a (extended invasion), or T4b (more extensive unresectable invasion), according to the degree of tumor involvement. We subsequently focused our investigation on minimal ETE (MEE), analyzing the clinicopathologic characteristics, recurrence rate, and recurrence-free survival (RFS) in this setting. METHODS: A retrospective study was conducted, based on 332 patients undergoing thyroidectomy for PTC between January 2005 and December 2006. RESULTS: The study population was stratified into two groups: PTC with MEE (103/332; 31.0%) and PTC without MEE (229/332; 69.0%). In patients with PTC, MEE correlated with gender, tumor size, multifocality, lymph node (LN) metastasis, underlying Hashimoto's thyroiditis, and the nature of the surgery. However, no significant intergroup differences were evident with respect to age, recurrence rate, and LN metastasis. In multivariate analysis, LN metastasis (odds ratio = 2.273; 95% confidence interval, 1.280-4.037) was recognized as an independent correlate of mETE (p = 0.005). However, recurrence-free survival did not differ significantly between the groups (p = 0.153), even when further stratified by the presence or absence of LN metastasis. CONCLUSION: In patients with PTC, MEE does not impact RFS. Thus, appropriate surgical intervention and postoperative follow up are mandatory in PTC, regardless of its extent.


Asunto(s)
Carcinoma/patología , Neoplasias de la Tiroides/patología , Adulto , Anciano , Carcinoma/cirugía , Carcinoma Papilar , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Cáncer Papilar Tiroideo , Neoplasias de la Tiroides/cirugía , Adulto Joven
16.
Ann Coloproctol ; 29(3): 115-22, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23862129

RESUMEN

PURPOSE: The serum level of carcinoembryonic antigen (CEA) is a clinical prognostic factor in the follow-up evaluation of patients with colon cancer. We aimed to evaluate the prognostic significance of the rate of decrease of the perioperative serum CEA level in patients with colon cancer after a curative resection. METHODS: A total of 605 patients who underwent a curative resection for colon cancer between January 2000 and December 2007 were enrolled retrospectively. The rate of decrease was calculated using the following equation: ([preoperative CEA - postoperative CEA]/[preoperative CEA] ×100). RESULTS: In the group with a preoperative serum CEA level of >5 ng/mL, the normalized group with a postoperative serum CEA level of ≤5 ng/mL showed a better overall survival (OS) rate and disease-free survival (DFS) rate than those of the non-normalized group (P ≤ 0.0001). The "cutoff values" of the rate of decrease in the perioperative serum CEA that determined the OS and the DFS were 48.9% and 50.8%, respectively. In the multivariate analysis of preoperative serum CEA levels >5 ng/mL, the prognostic factors for the OS and the DFS were the cutoff value (P < 0.0001) and the pN stage (P < 0.0001). CONCLUSION: A rate of decrease of more than 50% in the perioperative serum CEA level, as well as the normalization of the postoperative serum CEA level, may be useful factors for determining a prognosis for colon cancer patients with high preoperative CEA levels.

17.
Drug Metab Pharmacokinet ; 28(6): 462-7, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23629743

RESUMEN

The tyrosine kinase inhibitor nilotinib was examined for its inhibition of cytochrome P450s (CYPs) in human liver microsomes and in human CYPs expressed in a baculovirus-insect cell system. Nilotinib demonstrated preferential inhibition of CYP2C8-mediated paclitaxel 6α-hydroxylation, rosiglitazone hydroxylation and amodiaquine N-deethylation in human liver microsomes, with IC50 values of 0.4, 7.5 and 0.7 µM, respectively. The IC50 value of nilotinib for paclitaxel 6α-hydroxylation was 20-fold lower than that of the other five tyrosine-kinase inhibitors tested. Nilotinib appears to display competitive inhibition against paclitaxel 6α-hydroxylation and amodiaquine N-deethylation, with estimated mean Ki values of 0.90 and 0.15 µM in human liver microsomes and 0.10 and 0.61 µM in recombinant human CYP2C8, respectively. These results are consistent with those of molecular docking simulations, where paclitaxel could not access the CYP2C8 catalytic site in the presence of nilotinib, but the binding of midazolam, a substrate of CYP3A4, to the catalytic site of CYP3A4 was not affected by nilotinib. The demonstrated inhibitory activity of nilotinib against CYP2C8 at concentrations less than those observed in patients who received nilotinib therapy is of potential clinical relevance and further in vivo exploration is warranted.


Asunto(s)
Hidrocarburo de Aril Hidroxilasas/antagonistas & inhibidores , Microsomas Hepáticos/efectos de los fármacos , Pirimidinas/farmacología , Citocromo P-450 CYP2C8 , Humanos , Concentración 50 Inhibidora , Cinética , Simulación del Acoplamiento Molecular , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Pirimidinas/farmacocinética
18.
Int J Colorectal Dis ; 28(8): 1117-25, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23588871

RESUMEN

BACKGROUND: Various types of adhesion barriers are widely used to prevent intra-abdominal adhesion. However, few studies have compared the efficacy of adhesion barriers using the same animal model. The aim of this study was to compare the anti-adhesive effects of various barrier agents using a newly developed, severe adhesion model. METHODS: A severe adhesion model was established by excision of a 1-cm(2) intra-abdominal wall and application of cyanoacrylate in rat. Eighty male Sprague-Dawley rats (10 weeks old; 370 ± 50 g) were divided randomly into four groups (n = 20 each): the untreated control group, G-group using a hyaluronic acid and sodium carboxymethyl cellulose gel (Guardix-sol®), A-group using 4% icodextrin (Adept®), and S-group using a hyaluronate-carboxymethyl cellulose membrane (Seprafilm®). The effect of each adhesion barrier was evaluated by means of the extent and severity of adhesion, difficulty of adhesiolysis scoring systems, and microscopic grade of fibrosis. RESULTS: The G-group showed no difference in adhesion score and fibrosis, the A-group demonstrated only a significantly lower fibrosis, and the S-group exhibited a significantly lower adhesion score and lower fibrosis compared with the control group. The S-group had a significantly lower adhesion score and reduced fibrosis compared with the G-group; however, no significant difference in adhesion score and fibrosis was noted with the A-group. CONCLUSIONS: The membranous barrier Seprafilm® may be effective in the prevention of adhesion in the condition of peritoneal injury combined with foreign material. Adept® showed a tendency of decreasing the severity of adhesion and was effective in the prevention of fibrosis.


Asunto(s)
Abdomen/patología , Materiales Biocompatibles/uso terapéutico , Adherencias Tisulares/tratamiento farmacológico , Adherencias Tisulares/prevención & control , Animales , Modelos Animales de Enfermedad , Masculino , Ratas , Ratas Sprague-Dawley , Adherencias Tisulares/patología
19.
Clin Mol Hepatol ; 19(1): 36-44, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-23593608

RESUMEN

BACKGROUND/AIMS: While gastric variceal bleeding (GVB) is not as prevalent as esophageal variceal bleeding, it is reportedly more serious, with high failure rates of the initial hemostasis (>30%), and has a worse prognosis than esophageal variceal bleeding. However, there is limited information regarding hemostasis and the prognosis for GVB. The aim of this study was to determine retrospectively the clinical outcomes of GVB in a multicenter study in Korea. METHODS: The data of 1,308 episodes of GVB (males:females=1062:246, age=55.0±11.0 years, mean±SD) were collected from 24 referral hospital centers in South Korea between March 2003 and December 2008. The rates of initial hemostasis failure, rebleeding, and mortality within 5 days and 6 weeks of the index bleed were evaluated. RESULTS: The initial hemostasis failed in 6.1% of the patients, and this was associated with the Child-Pugh score [odds ratio (OR)=1.619; P<0.001] and the treatment modality: endoscopic variceal ligation, endoscopic variceal obturation, and balloon-occluded retrograde transvenous obliteration vs. endoscopic sclerotherapy, transjugular intrahepatic portosystemic shunt, and balloon tamponade (OR=0.221, P<0.001). Rebleeding developed in 11.5% of the patients, and was significantly associated with Child-Pugh score (OR=1.159, P<0.001) and treatment modality (OR=0.619, P=0.026). The GVB-associated mortality was 10.3%; mortality in these cases was associated with Child-Pugh score (OR=1.795, P<0.001) and the treatment modality for the initial hemostasis (OR=0.467, P=0.001). CONCLUSIONS: The clinical outcome for GVB was better for the present cohort than in previous reports. Initial hemostasis failure, rebleeding, and mortality due to GVB were universally associated with the severity of liver cirrhosis.


Asunto(s)
Várices Esofágicas y Gástricas/diagnóstico , Hemorragia Gastrointestinal , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Pueblo Asiatico , Endoscopía , Várices Esofágicas y Gástricas/mortalidad , Várices Esofágicas y Gástricas/terapia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Oportunidad Relativa , Pronóstico , República de Corea , Estudios Retrospectivos , Escleroterapia , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Adulto Joven
20.
Ann Coloproctol ; 29(6): 231-7, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24466537

RESUMEN

PURPOSE: To maintain the patient's quality of life, surgeons strive to preserve the sphincter during rectal cancer surgery. This study evaluated the oncologic safety of a sphincter-saving resection with a distal resection margin (DRM) <1 cm without radiotherapy in T3, mid- or low-rectal cancer. METHODS: This retrospective study enrolled 327 patients who underwent a sphincter-saving resection for proven T3 rectal cancer located <10 cm from the anal verge and without radiotherapy between January 1995 and December 2011. The oncologic outcomes included the 5-year cancer-specific survival, the local recurrence, and the systemic recurrence rates. RESULTS: In groups A (DRM ≤1 cm) and B (DRM >1 cm), the 5-year cancer-specific survival rates were 81.57% and 80.03% (P = 0.8543), the 5-year local recurrence rates were 6.69% and 9.52% (P = 0.3981), and the 5-year systemic recurrence rates were 19.46% and 23.11% (P = 0.5750), respectively. CONCLUSION: This study showed that the close DRM itself should not be a contraindication for a sphincter-saving resection for T3 mid- or low-rectal cancer without radiotherapy. However, a prospective randomized controlled trial including the effect of adjuvant therapy will be needed.

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