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Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The phase III PRODIGY study demonstrated that neoadjuvant chemotherapy with docetaxel, oxaliplatin, and S-1 (DOS) followed by surgery and adjuvant S-1 chemotherapy (CSC) improved progression-free survival (PFS) compared with surgery followed by adjuvant S-1 (SC) for patients with resectable locally advanced gastric cancer (LAGC) with clinical T2-3N+ or T4Nany disease. The primary end point was PFS. Overall survival (OS) was the secondary end point. We herein report the long-term follow-up outcomes, including OS, from this trial. A total of 238 and 246 patients were randomly assigned to the CSC and SC arms, respectively, and were treated (full analysis set). As of the data cutoff (September 2022), the median follow-up duration of the surviving patients was 99.5 months. Compared with SC, CSC significantly increased the OS (adjusted hazard ratio [HR], 0.72; stratified log-rank P = .027) with an 8-year OS rate of 63.0% and 55.1% for the CSC and SC arms, respectively. CSC also significantly improved the PFS (HR, 0.70; stratified log-rank P = .016). In conclusion, neoadjuvant DOS chemotherapy, as part of perioperative chemotherapy, prolonged the OS of Asian patients with LAGC relative to patients treated with surgery and adjuvant S-1. It should be considered one of the standard treatment options for patients with LAGC in Asia.
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Protocolos de Quimioterapia Combinada Antineoplásica , Docetaxel , Combinação de Medicamentos , Terapia Neoadjuvante , Oxaliplatina , Ácido Oxônico , Neoplasias Gástricas , Tegafur , Humanos , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Tegafur/administração & dosagem , Tegafur/uso terapêutico , Docetaxel/administração & dosagem , Docetaxel/uso terapêutico , Oxaliplatina/administração & dosagem , Oxaliplatina/uso terapêutico , Ácido Oxônico/uso terapêutico , Ácido Oxônico/administração & dosagem , Terapia Neoadjuvante/mortalidade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Masculino , Feminino , Pessoa de Meia-Idade , Quimioterapia Adjuvante , Idoso , Adulto , GastrectomiaRESUMO
PURPOSE: Adjuvant chemotherapy after D2 gastrectomy is standard for resectable locally advanced gastric cancer (LAGC) in Asia. Based on positive findings for perioperative chemotherapy in European phase III studies, the phase III PRODIGY study (ClinicalTrials.gov identifier: NCT01515748) investigated whether neoadjuvant docetaxel, oxaliplatin, and S-1 (DOS) followed by surgery and adjuvant S-1 could improve outcomes versus standard treatment in Korean patients with resectable LAGC. PATIENTS AND METHODS: Patients 20-75 years of age, with Eastern Cooperative Oncology Group performance status 0-1, and with histologically confirmed primary gastric or gastroesophageal junction adenocarcinoma (clinical TNM staging: T2-3N+ or T4Nany) were randomly assigned to D2 surgery followed by adjuvant S-1 (40-60 mg orally twice a day, days 1-28 every 6 weeks for eight cycles; SC group) or neoadjuvant DOS (docetaxel 50 mg/m2, oxaliplatin 100 mg/m2 intravenously day 1, S-1 40 mg/m2 orally twice a day, days 1-14 every 3 weeks for three cycles) before D2 surgery, followed by adjuvant S-1 (CSC group). The primary objective was progression-free survival (PFS) with CSC versus SC. Two sensitivity analyses were performed: intent-to-treat and landmark PFS analysis. RESULTS: Between January 18, 2012, and January 2, 2017, 266 patients were randomly assigned to CSC and 264 to SC at 18 Korean study sites; 238 and 246 patients, respectively, were treated (full analysis set). Follow-up was ongoing in 176 patients at data cutoff (January 21, 2019; median follow-up 38.6 months [interquartile range, 23.5-62.1]). CSC improved PFS versus SC (adjusted hazard ratio, 0.70; 95% CI, 0.52 to 0.95; stratified log-rank P = .023). Sensitivity analyses confirmed these findings. Treatments were well tolerated. Two grade 5 adverse events (febrile neutropenia and dyspnea) occurred during neoadjuvant treatment. CONCLUSION: PRODIGY showed that neoadjuvant DOS chemotherapy, as part of perioperative chemotherapy, is effective and tolerable in Korean patients with LAGC.
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Adenocarcinoma/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Docetaxel/uso terapêutico , Junção Esofagogástrica/efeitos dos fármacos , Junção Esofagogástrica/cirurgia , Gastrectomia , Terapia Neoadjuvante , Oxaliplatina/uso terapêutico , Ácido Oxônico/uso terapêutico , Neoplasias Gástricas/terapia , Tegafur/uso terapêutico , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimioterapia Adjuvante , Docetaxel/efeitos adversos , Combinação de Medicamentos , Junção Esofagogástrica/patologia , Feminino , Gastrectomia/efeitos adversos , Gastrectomia/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante/efeitos adversos , Terapia Neoadjuvante/mortalidade , Estadiamento de Neoplasias , Oxaliplatina/efeitos adversos , Ácido Oxônico/efeitos adversos , Intervalo Livre de Progressão , República da Coreia , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Tegafur/efeitos adversos , Fatores de Tempo , Adulto JovemRESUMO
Autophagy plays an important role in the survival of cancer cells under stressful conditions, such as nutrient or oxygen deficiency. Therefore, autophagy inhibition is being considered as a novel therapeutic strategy for cancer. Decursin is a natural compound derived from Angelica gigas; it has been used in the treatment of various diseases, including cancer. However, the mechanism by which decursin regulates autophagy in gastric cancer and other carcinomas remains unclear. Here, we demonstrated that decursin reduced the growth and induced cell cycle arrest in gastric cancer cells in vitro. Decursin blocked autophagic flux by reducing the expression of lysosomal protein cathepsin C (CTSC) and attenuating its activity, thereby causing autophagic dysregulation (i.e., accumulation of LC3 and SQSTM1). Decursin also inhibited cell proliferation and cell cycle progression by inhibiting CTSC and E2F3, both of which were linked to gastric cancer aggressiveness. The antitumor effects of decursin were confirmed in vivo. We established spheroid and patient-derived organoid models and found that decursin decreased the growth of spheroids and patient-derived gastric organoids, as well as modulated the expression of CTSC and autophagy-related proteins. Hence, our findings uncovered a previously unknown mechanism by which decursin regulates cell growth and autophagy and suggests that decursin may act as a potential therapeutic agent that simultaneously inhibits cell growth and autophagy.
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BACKGROUND/AIMS: Pheochromocytoma and paraganglioma (PPGL) are catecholamine-producing tumors that can cause blood pressure (BP) elevation and cardiovascular complications. Clinical presentation of these tumors may be changed through widespread use of imaging studies, which enables detection of PPGLs before onset of symptoms. We investigated clinical profiles of patients with surgically resected PPGLs. METHODS: From 2005 to 2017, 111 consecutive patients with surgically resected PPGLs in two tertiary hospitals in Korea were studied. RESULTS: Mean age was 52 ± 16 years, 57 patients (51.4%) were male and 54 (48.6%) were hypertensive. Twenty-nine PPGLs (26.1%) were extra-adrenal paragangliomas. Sixteen (14.4%) and seven patients (6.3%) (Group 1, n = 23) were diagnosed during work-up of hypertension and transient cardiomyopathy respectively, and the remainder (Group 2, n = 88) were incidentalomas detected during routine abdominal imaging. Patients in the Group 1 were younger and more frequently symptomatic, and had higher BPs, heart rates and levels of urinary catecholamines than those in the Group 2. Paragangliomas were less frequent and secretion of epinephrine and metanephrine was more predominant in the Group 1 than in Group 2. After the surgical resections, 18.2% of patients still needed antihypertensive medications. CONCLUSION: Out of 111 patients with surgically resected PPGLs, 88 (79.3%) were diagnosed as incidentalomas. Seven patients presented with transient cardiomyopathy and 16 with hypertension. Tumor location and secretion of catecholamine may vary depending on the presence of symptoms.
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Neoplasias das Glândulas Suprarrenais , Paraganglioma , Feocromocitoma , Neoplasias das Glândulas Suprarrenais/diagnóstico por imagem , Neoplasias das Glândulas Suprarrenais/cirurgia , Adulto , Idoso , Humanos , Masculino , Metanefrina , Pessoa de Meia-Idade , Paraganglioma/diagnóstico por imagem , Paraganglioma/cirurgia , Feocromocitoma/diagnóstico por imagem , Feocromocitoma/cirurgia , República da CoreiaRESUMO
Purpose: The port site hernia (PSH) is a specific type of incisional hernia related to the trocar sites of laparoscopic surgery. Diastasis recti of the abdominis muscle (DR) is the separation of the rectus muscle by a certain distance. The present study aims to present our experience with umbilical PSH and concomitant DR and to raise awareness of DR as one of the risk factors of umbilical PSH. Methods: Eighteen patients with umbilical PSH after laparoscopic abdominal surgery, was retrospectively reviewed. Preoperative CT was analyzed to measure the Inter-recti distance (IRD) for all patients. Other factors, such as trocar size, wound infection, obesity (BMI), port extension, suture materials, and pre-existing co-morbidities, were recorded and analyzed. Results: Extension of the port incision was associated with umbilical PSH. Ten out of eighteen umbilical PSH patients (56%) had DR before they had first laparoscopic surgery. Nine (50%) patients showed sarcopenia. Moreover, four out of five recurrences had DR. More than two recurrences were all associated with DR. Conclusion: Port extension and sarcopenia were risk factors of umbilical PSH. Also, DR might be a possible risk factor of umbilical PSH occurrence and recurrence. Surgeons should be aware of the presence of DR before the planning of the laparoscopic surgery by diagnostic imaging. If DR is associated with umbilical PSH, we need to consider the correction of both pathologies at the same time.
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Honokiol, a natural biphenolic compound, exerts anticancer effects through a variety of mechanisms on multiple types of cancer with relatively low toxicity. Adenosine 5'phosphateactivated protein kinase (AMPK), an essential regulator of cellular homeostasis, may control cancer progression. The present study aimed to investigate whether the anticancer activities of honokiol in ovarian cancer cells were mediated through the activation of AMPK. Honokiol decreased cell viability of 2 ovarian cancer cell lines, with an halfmaximal inhibitory concentration value of 48.71±11.31 µM for SKOV3 cells and 46.42±5.37 µM for Caov3 cells. Honokiol induced apoptosis via activation of caspase3, caspase7 and caspase9, and cleavage of poly(adenosine 5'diphosphateribose) polymerase. Apoptosis induced by honokiol was weakened by compound C, an AMPK inhibitor, suggesting that honokiolinduced apoptosis was dependent on the AMPK/mechanistic target of rapamycin signaling pathway. Additionally, honokiol inhibited the migration and invasion of ovarian cancer cells. The combined treatment of honokiol with compound C reversed the activities of honokiol in wound healing and Matrigel invasion assays. These results indicated that honokiol may have therapeutic potential in ovarian cancer by targeting AMPK activation.
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Proteínas Quinases Ativadas por AMP/metabolismo , Apoptose/efeitos dos fármacos , Compostos de Bifenilo/farmacologia , Movimento Celular/efeitos dos fármacos , Lignanas/farmacologia , Neoplasias Ovarianas/patologia , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Feminino , Humanos , Camundongos , Modelos Biológicos , Células NIH 3T3 , Invasividade Neoplásica , Neoplasias Ovarianas/enzimologia , Ensaio Tumoral de Célula-TroncoRESUMO
In this study, we evaluate the usefulness of preoperative endoscopic clipping for early gastric cancer (EGC) localization in laparoscopic distal gastrectomy.We retrospectively screened all consecutive patients who underwent laparoscopic distal gastrectomy for EGC by 1 surgeon at Chungnam National University Hospital between January 2014 and December 2016. Patients who underwent combined surgery and patients who had tumors at the lower third of the stomach were excluded. Endoscopic clipping was performed prior to surgery by specialized endoscopists. During the operation, endoscopic metal clips were found using surgical devices, and laparoscopic vessel clips were attached on the presumed site; thereafter, intraoperative radiographs were obtained for confirmation.We analyzed a total of 196 patients; of them, 101 were classified into the clipping group (CG) and 95 into the non clipping group (NCG). The 2 groups were comparable regarding their demographic characteristics. The CG showed less additional resection (2 of 101 patients [2.0%] vs 9 of 95 patients [9.4%], P = .021) and better outcomes in terms of the operation time (Pâ=â.000), duration of hospital stay (Pâ=â.036), and postoperative atelectasis (Pâ=â.001) than the NCG.Preoperative endoscopic clipping was helpful in determining the exact resection margin in laparoscopic distal gastrectomy for EGC.
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Gastrectomia/métodos , Laparoscopia/métodos , Neoplasias Gástricas/cirurgia , Idoso , Feminino , Humanos , Tempo de Internação/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Duração da Cirurgia , Complicações Pós-Operatórias/epidemiologia , Cuidados Pré-Operatórios/efeitos adversos , Cuidados Pré-Operatórios/métodos , Estudos Retrospectivos , Estômago/patologia , Estômago/cirurgia , Instrumentos Cirúrgicos/efeitos adversos , Resultado do TratamentoRESUMO
Pristimerin, a quinonemethide triterpenoid, has demonstrated anticancer activity against a number of types of cancer, including breast cancer. However, its mechanism of action remains unclear. The present study investigated the autophagyinduced anticancer efficacy of pristimerin on MDAMB231 human breast cancer cells. Pristimerin inhibited the growth of these cells in a concentrationdependent manner. Treatment with pristimerin dosedependently induced an increase of light chain 3B (LC3II), whereas autophagy inhibitor 3methyladenine (3MA) inhibited pristimerininduced LC3II accumulation and cytotoxic effects. Autophagy was also activated by paclitaxel as observed by an elevated LC3II level. Although 24 µM paclitaxel induced autophagy without cytotoxicity, combined with pristimerin it additively induced cell growth inhibition and autophagy induction. Autophagy induction was measured with an autophagy detection kit and LC3II levels were monitored by western blot analysis. Treatment with 3MA inhibited LC3II accumulation and cell death induced by a combination of paclitaxel and pristimerin. Pristimerin and paclitaxel inhibited extracellular signalregulated kinase (ERK)1/2/p90RSK signaling, consistent with autophagy indicators, namely p62 degradation and beclin 1 expression. In addition, ERK activator ceramide C6 treatment suppressed the LC3II levels induced by a combination of paclitaxel and pristimerin. These results suggested that exposure to pristimerin induced autophagic cell death, whereas a combination treatment of pristimerin and paclitaxel resulted in an additive effect on ERKdependent autophagic cell death.
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Autofagia/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Paclitaxel/farmacologia , Triterpenos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Feminino , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Triterpenos PentacíclicosRESUMO
Ovarian cancer is one of the most common causes of female mortalities from gynecological tumors. An entkaurane diterpenoid compound CRT1 (ent18acetoxy7ßhydroxy kaur15oxo16ene), mainly isolated from the Vietnamese herb Croton tonkinesis has been used in folk medicine in Vietnam for cancer treatment. However, the effect of this compound on human ovarian cancer cells has not yet been reported. The objective of the present study was to determine the effect of CRT1 on the cell viability, apoptosis and metastasis of SKOV3 human ovarian cancer cells using a Cell Counting Kit8 assay, flow cytometric analysis of Annexin Vfluorescein isothiocyanate/propidium iodide staining, western blot analysis, soft agar colony forming assay, wound healing assay and Matrigel invasion assay. The results revealed that CRT1 possessed significant antiproliferative effects on SKOV3 cells. CRT1 treatment at 25 and 50 µM induced apoptosis, enhanced the percentage of Annexin Vpositive cells, increased the expression of proapoptotic protein Bcell lymphoma 2 (Bcl2)associated X protein, cytochrome c release from the mitochondria to the cytosol, cleaved caspase3, caspase7, caspase9, and poly (adenosine diphosphateribose) polymerase. However, it decreased the expression of Bcl2 in a dosedependent manner. The percentage of necrotic cells increased following CRT1 treatment at <10 µM. CRT1 at 50 µM significantly induced the phosphorylation of extracellular signalregulated kinase (ERK). Growth inhibition and the apoptotic effects of CRT1 could be reversed by PD98059, an ERK inhibitor. Additionally, CRT1 inhibited cell migration and invasion via ERK1/2 activation in SKOV3 cells. These results indicated that CRT1, an entkaurane diterpenoid, may be a potential inhibitor of ovarian cancer by the activating ERK1/2/p90 ribosomal S6 kinase signaling pathway.
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Movimento Celular/efeitos dos fármacos , Diterpenos do Tipo Caurano/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Neoplasias Ovarianas/patologia , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Invasividade Neoplásica , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Ensaio Tumoral de Célula-TroncoRESUMO
5Fluorouracil (5FU) is one of the most commonly used chemotherapeutic agents for gastric cancer. Resistance to 5FUbased chemotherapy remains the major obstacle in the treatment of gastric cancer. A growing body of evidence has suggested that adenosine monophosphateactivated protein kinase (AMPK) is pivotal for chemoresistance. However, the mechanism by which AMPK regulates the chemosensitivity of gastric cancer remains unclear. In the present study, how corosolic acid enhanced the chemosensitivity of gastric cancer cells to 5FU via AMPK activation was investigated. A 5FUresistant gastric cancer cell line (SNU620/5FUR) was established, which had a marked increase in thymidine synthase (TS) expression but reduced AMPK phosphorylation when compared with the parental cell line, SNU620. AMPK regulation by 5aminoimidazole4carboxamide ribonucleotide or compound c was revealed to be markedly associated with TS expression and 5FUresistant cell viability. In addition, corosolic acid activated AMPK, and decreased TS expression and the phosphorylation of mammalian target of rapamycin/4Ebinding protein 1 in a dosedependent manner. Corosolic acid treatment significantly reduced cell viability while compound c reversed corosolic acidinduced cell growth inhibition. The 5FUresistance sensitization effect of corosolic acid was determined by the synergistic reduction of TS expression and inhibition of cell viability in the presence of 5FU. The corosolic acidinduced AMPK activation was markedly increased by additional 5FU treatment, while compound c reversed AMPK phosphorylation. In addition, compound c treatment reversed corosolic acidinduced apoptotic markers such as capase3 and PARP cleavage, and cytochrome c translocation to cytosol, in the presence of 5FU. Corosolic acid treatment in the presence of 5FU induced an increase in the apoptotic cell population based on flow cytometry analysis. This increase was abolished by compound c. In conclusion, these results implied that corosolic acid may have therapeutic potential to sensitize the resistance of gastric cancer to 5FU by activating AMPK.
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Proteínas Quinases Ativadas por AMP/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Fluoruracila/farmacologia , Triterpenos/farmacologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Antineoplásicos/farmacologia , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Fosfoproteínas/metabolismo , Fosforilação/efeitos dos fármacos , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Serina-Treonina Quinases TOR/metabolismo , Triterpenos/química , Regulação para Cima/efeitos dos fármacosRESUMO
Gastric remnant necrosis after a subtotal gastrectomy is an extremely uncommon complication due to the rich vascular supply of the stomach. Despite its rareness, it must be carefully addressed considering the significant mortality rate associated with this condition. Patients vulnerable to ischemic vascular disease in particular need closer attention and should be treated more cautiously. When gastric remnant necrosis is suspected, an urgent endoscopic examination must be performed. We report a case of gastric remnant necrosis following a subtotal gastrectomy and discuss possible risk factors associated with this complication.
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Fatty acid synthase (FASN) is a key anabolic enzyme for de novo fatty acid synthesis, which is important in the development of colon carcinoma. The high expression of FASN is considered a promising molecular target for colon cancer therapy. Emodin, a naturally occurring anthraquinone, exhibits an anticancer effect in various types of human cancer, including colon cancer; however, the molecular mechanisms remain to be fully elucidated. Cell viability was evaluated using a Cell Counting Kit8 assay. The apoptosis rate of cells was quantified via flow cytometry following Annexin V/propidium iodide staining. FASN activity was measured by monitoring oxidation of nicotinamide adenine dinucleotide phosphate at a wavelength of 340 nm, and intracellular free fatty acid levels were detected using a Free Fatty Acid Quantification kit. Western blot analysis and reverse transcriptionpolymerase chain reaction were used to detect target gene and protein expression. The present study was performed to investigate whether the gene expression of FASN and its enzymatic activity are regulated by emodin in a human colon cancer cell line. Emodin markedly inhibited the proliferation of HCT116 cells and a higher protein level of FASN was expressed, compared with that in SW480, SNU-C2A or SNUC5 cells. Emodin significantly downregulated the protein expression of FASN in HCT116 cells, which was caused by protein degradation due to elevated protein ubiquitination. Emodin also inhibited intracellular FASN enzymatic activity and reduced the levels of intracellular free fatty acids. Emodin enhanced antiproliferation and apoptosis in a dose and timedependent manner. The combined treatment of emodin and cerulenin, a commercial FASN inhibitor, had an additive effect on these activities. Palmitate, the final product of the FASN reaction, rescued emodininduced viability and apoptosis. In addition, emodin altered FASNinvolved signaling pathways, including phosphatidylinositol 3-kinase/Akt and mitogenactivated protein kinases/extracellular signal-regulated kinases 1/2. These results suggested that emodin-regulated cell growth and apoptosis were mediated by inhibiting FASN and provide a molecular basis for colon cancer therapy.
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Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Emodina/farmacologia , Ácido Graxo Sintases/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Ciclo Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Colo/efeitos dos fármacos , Colo/metabolismo , Colo/patologia , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Ácido Graxo Sintases/metabolismo , Células HCT116 , HumanosRESUMO
OBJECTIVE: The aim of this study was to investigate the feasibility of sentinel node mapping using a fluorescent dye and visible light in patients with gastric cancer. BACKGROUND: Recently, fluorescent imaging technology offers improved visibility with the possibility of better sensitivity or accuracy in sentinel node mapping. METHODS: Twenty patients with early gastric cancer, for whom laparoscopic distal gastrectomy with standard lymphadenectomy had been planned, were enrolled in this study. Before lymphadenectomy, the patients received a gastrofiberoscopic peritumoral injection of fluorescein solution. The sentinel basin was investigated via laparoscopic fluorescent imaging under blue light (wavelength of 440-490 nm) emitted from an LED curing light. The detection rate and lymph node status were analyzed in the enrolled patients. In addition, short-term clinical outcomes were also investigated. RESULTS: No hypersensitivity to the dye was identified in any enrolled patients. Sentinel nodes were detected in 19 of 20 enrolled patients (95.0%), and metastatic lymph nodes were found in 2 patients. The latter lymph nodes belonged to the sentinel basin of each patient. Meanwhile, 1 patient (5.0%) experienced a postoperative complication that was unrelated to sentinel node mapping. No mortality was recorded among enrolled cases. CONCLUSIONS: Sentinel node mapping with visible light fluorescence was a feasible method for visualizing sentinel nodes in patients with early gastric cancer. In addition, this method is advantageous in terms of visualizing the concrete relationship between the sentinel nodes and surrounding structures.
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Corantes Fluorescentes/farmacologia , Gastrectomia/métodos , Gastroscopia/métodos , Biópsia de Linfonodo Sentinela/métodos , Linfonodo Sentinela/patologia , Neoplasias Gástricas/patologia , Adulto , Idoso , Intervalo Livre de Doença , Detecção Precoce de Câncer/métodos , Feminino , Gastrectomia/mortalidade , Gastroscopia/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Prognóstico , Estudos Prospectivos , República da Coreia , Medição de Risco , Neoplasias Gástricas/cirurgia , Taxa de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND/AIMS: In gastric cancer, the rate of recurrence and metastasis following radical resection is high, necessitating improvement in survival and cure rates. Neoadjuvant chemotherapy (NAC) has potential benefits for locally advanced gastric cancer; however, the surgical benefits and effects on survival are unclear. This study evaluates the effectiveness of NAC in locally advanced gastric cancer and compares clinical outcomes of doublet and triplet regimens. METHODS: We reviewed patient medical records of 383 patients who underwent NAC (n=41) or surgery only (n=342) for treatment of locally advanced gastric cancer. The baseline characteristics and clinical outcomes were compared between the groups. Chemotherapy patients were classified according to regimen, doublet (n=28) and triplet (n=13), and NAC-related clinical response, safety, and toxicity were analyzed. RESULTS: The baseline characteristics did not differ significantly between groups. After NAC, the tumor downstage rate was 51.2% (21/41); however, overall survival (p=0.205) and disease-free survival (p=0.415) were not significantly different between the groups. On subgroup analysis, no significant differences in drug toxicity (p=0.604) or clinical response (p=0.374) were found between outcomes of doublet and triplet chemotherapy regimens. CONCLUSIONS: In patients with locally advanced gastric cancer, NAC showed tolerable drug toxicity and increased tumor downstage, but NAC failed to increase the survival rate, which may be caused by a high D2-lymphadenectomy rate. Therefore, NAC was found to be a therapeutic option for select gastric cancer patients.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Razão de Chances , Estudos Retrospectivos , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Resultado do TratamentoRESUMO
5Fluorouracil (5FU), one of the oldest anticancer therapeutic agents, is increasingly being administered in cancer chemotherapy. In the present study, the anticancer effects of 5FU combined with corosolic acid (CRA) were determined in SNU620 human gastric carcinoma cells and the underlying mechanisms were examined. A combination treatment of 5FU and CRA inhibited the viability of cells additively. Furthermore, apoptotic activity following combination treatment was found to be stronger than that of the single treatments, as observed using an Annexin V/propidium iodide assay. The protein level of Bcl2 was decreased significantly by the combination treatment, whereas the protein level of Bim was increased. The release of mitochondrial cytochrome c was increased as a result of the combination treatment, however, the combination treatment additively increased caspase3 and poly(ADPribose) polymerase cleavages. Additionally, the mammalian target of rapamycin (mTOR) signaling pathway, which is highly activated in gastric cancer, was regulated by 5FU and CRA, and additive mTOR/eukaryotic translation initiation factor 4Ebinding protein 1 (4EBP1) inhibition was observed with the combination treatment. Additional rapamycin treatment along with the combination treatment of 5FU and CRA showed a more marked inhibition of mTOR/4EBP1 in the cells, as well as increased apoptosis and antiproliferation. Thus, these data indicate that CRA enhances the anticancer activities of 5FU via mTOR inhibition in SNU620 human gastric carcinoma cells.
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Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Fluoruracila/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Triterpenos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Humanos , Transdução de Sinais , Neoplasias Gástricas , Serina-Treonina Quinases TOR/metabolismoRESUMO
PURPOSE: Laparoscopy-assisted distal gastrectomy for early gastric cancer has gained acceptance and popularity worldwide. However, laparoscopy-assisted distal gastrectomy for advanced gastric cancer is still controversial. Therefore, we propose this prospective randomized controlled multi-center trial in order to evaluate the safety and feasibility of laparoscopy assisted D2-gastrectomy for advanced stage gastric cancer. MATERIALS AND METHODS: Patients undergoing distal gastrectomy for advanced gastric cancer staged cT2/3/4 cN0/1/2/3a cM0 by endoscopy and computed tomography are eligible for enrollment after giving their informed consent. Patients will be randomized either to laparoscopy-assisted distal gastrectomy or open distal gastrectomy. Sample size calculation revealed that 102 patients are to be included per treatment arm. The primary endpoint is the non-compliance rate of D2 dissection; relevant secondary endpoints are three-year disease free survival, surgical and postoperative complications, hospital stay and unanimity rate of D2 dissection evaluated by reviewing the intraoperative video documentation. DISCUSSION: Oncologic safety is the major concern regarding laparoscopy-assisted distal gastrectomy for advanced gastric cancer. Therefore, the non-compliance rate of clearing the N2 area was chosen as the most important parameter for the technical feasibility of the laparoscopic procedure. Furthermore, surgical quality will be carefully reviewed, that is, three independent experts will review the video records and score with a check list. For a long-term result, disease free survival is considered a secondary endpoint for this trial. This study will offer promising evidence of the feasibility and safety of Laparoscopy-assisted distal gastrectomy for advanced gastric cancer. TRIAL REGISTRATION: NCT01088204 (international), NCCCTS-09-448 (Korea).
RESUMO
Fatty acid synthase (FASN) is a potential therapeutic target for treatment of cancer and obesity, and is highly elevated in 30% of HER2-overexpressing breast cancers. Considerable interest has developed in searching for novel FASN inhibitors as therapeutic agents in treatment of HER2-overexpressing breast cancers. Amentoflavone was found to be effective in suppressing FASN expression in HER2-positive SKBR3 cells. Pharmacological inhibition of FASN by amentoflavone specifically down-regulated HER2 protein and mRNA, and caused an up-regulation of PEA3, a transcriptional repressor of HER2. In addition, pharmacological blockade of FASN by amentoflavone preferentially decreased cell viability and induced cell death in SKBR3 cells. Palmitate reduced the cytotoxic effect of amentoflavone, as the percentage of viable cells was increased after the addition of exogenous palmitate. Amentoflavone-induced FASN inhibition inhibited the translocation of SREBP-1 in SKBR3 cells. Amentoflavone inhibited phosphorylation of AKT, mTOR, and JNK. The use of pharmacological inhibitors revealed that the modulation of AKT, mTOR, and JNK phosphorylation required synergistic amentoflavone-induced FASN inhibition and HER2 activation in SKBR3 cells. These results suggest that amentoflavone modulated FASN expression by regulation of HER2-pathways, and induced cell death to enhance chemopreventive or chemotherapeutic activity in HER2-positive breast cancers.
Assuntos
Antineoplásicos/farmacologia , Biflavonoides/farmacologia , Neoplasias da Mama/metabolismo , Ácido Graxo Sintases/antagonistas & inibidores , Receptor ErbB-2/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Fosforilação , Receptor ErbB-2/genéticaRESUMO
Colon cancer is the third most common malignancy around the world. Surgery, chemotherapy, and radiotherapy are generally used to treat colon cancer, but no effective therapy for advanced colon carcinoma is available. Therefore, there is a need to identify other therapeutic agents against this disease. Magnolol, a hydroxylated biphenyl compound present in Magnolia officinalis, exerts anticancer potential and low toxicity. Emerging evidence has suggested that activation of AMP-activated protein kinase (AMPK), a potential cancer therapeutic target is involved in apoptosis in colon cancer cells. However, the effects of magnolol on human colon cancer through activation of AMPK remain unexplored. In this study, we explored whether magnolol exerts an antiproliferative effect, and induces apoptosis in HCT-116 human colon cancer cells. Magnolol displayed several apoptotic features, including propidium iodide labeling, DNA fragmentation, and caspase-3 and poly(ADP-ribose) polymerase cleavages. We showed that magnolol induced the phosphorylation of AMPK in dose- and time-dependent manners. The selective AMPK inhibitor compound C abrogated the effect of magnolol on AMPK activation, suppression of proliferation, and caspase-3 cleavage. Magnolol downregulated expression of the antiapoptotic protein Bcl2, upregulated expression of pro-apoptotic protein p53 and Bax, and caused the release of mitochondrial cytochrome c. Magnolol-induced p53 and Bcl2 expression was abolished in the presence of compound C. Magnolol inhibited migration and invasion of HCT-116 cells through AMPK activation. These findings demonstrate that AMPK mediates the anticancer effects of magnolol through apoptosis in HCT-116 cells.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Antineoplásicos Fitogênicos/uso terapêutico , Apoptose/efeitos dos fármacos , Compostos de Bifenilo/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Lignanas/uso terapêutico , Magnolia/química , Fitoterapia , Antineoplásicos Fitogênicos/farmacologia , Compostos de Bifenilo/farmacologia , Caspase 3/metabolismo , Movimento Celular/efeitos dos fármacos , Neoplasias do Colo/metabolismo , Citocromos c/metabolismo , Fragmentação do DNA , Relação Dose-Resposta a Droga , Células HCT116 , Humanos , Lignanas/farmacologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Fosforilação , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Poli(ADP-Ribose) Polimerases/metabolismo , Propídio/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transdução de Sinais , Proteína Supressora de Tumor p53/metabolismo , Proteína X Associada a bcl-2/metabolismoRESUMO
BACKGROUND: Excessive catecholamine release in pheochromocytoma is known to cause transient reversible left ventricular (LV) dysfunction, such as in the case of pheochromocytoma-associated catecholamine cardiomyopathy. We investigated patterns of clinical presentation and incidence of LV dysfunction in patients with pheochromocytoma. METHODS: From January 2004 to April 2011, consecutive patients with pheochromocytoma were retrospectively studied with clinical symptoms, serum catecholamine profiles, and radiologic findings. Patterns of electrocardiography and echocardiography were also analyzed. RESULTS: During the study period, a total of 36 patients (21 males, 49.8 ± 15.8 years, range 14-81 years) with pheochromocytoma were included. In the electrocardiographic examinations, normal findings were the most common findings (19, 52.8%). LV hypertrophy in 12 cases (33.3%), sinus tachycardia in 3 (8.3%), ischemic pattern in 1 (2.8%) and supraventricular tachycardia in 1 (2.8%). Echocardiographic exam was done in 29 patients (80.6%). Eighteen patients (62.1%) showed normal finding, 8 (27.6%) revealed concentric LV hypertrophy with normal LV systolic function, and 3 (10.3%) demonstrate LV systolic dysfunction (LV ejection fraction < 50%). Three showed transient LV dysfunction (2 with inverted Takotsubo-type cardiomyopathy and 1 with a diffuse hypokinesia pattern). Common presenting symptoms in the 3 cases were new onset chest discomfort and dyspnea which were not common in the other patients. Their echocardiographic abnormalities were normalized with conventional treatment within 3 days. CONCLUSION: Out of total 36 patients with pheochromocytoma, 3 showed transient LV systolic dysfunction (catecholamine cardiomyopathy). Pheochromocytoma should be included as one of possible causes of transient LV systolic dysfunction.