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Pancytopenia associated with vitamin B12 and folic acid deficiency has been reported in patients who have undergone total gastrectomy. Therefore, myelosuppression due to chemotherapy following total gastrectomy is considered to be more serious. We encountered three cases of severe thrombocytopenia in patients who received chemotherapy after total gastrectomy. The lowest platelet levels in these patients were 1.7 × 104/mm3, 2.3 × 104/mm3, and 0.9 × 104/mm3, respectively. None of the patients presented with vitamin B12 deficiency, and one patient presented with folic acid deficiency. The association between serum vitamin levels and chemotherapy-related adverse events is controversial. Since folic acid has a shorter half-life (6 hours) and cannot accumulate in the body, unlike vitamin B12 that is stored for a long time in the liver, folic acid deficiency is suspected to be associated with thrombocytopenia induced by post-total gastrectomy chemotherapy. However, serum folic acid levels fluctuate depending on the timing of evaluation and require a few days to evaluate. In conclusion, patients who undergo chemotherapy after total gastrectomy should be monitored for severe thrombocytopenia but serum vitamin B12 levels are not necessarily clinically important. By measuring serum folic acid levels at appropriate times, folic acid deficiency may prove to be a reference for predicting severe thrombocytopenia.
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Trombocitopenia , Deficiência de Vitamina B 12 , Ácido Fólico , Gastrectomia/efeitos adversos , Humanos , Trombocitopenia/induzido quimicamente , Trombocitopenia/diagnóstico , Vitamina B 12 , Deficiência de Vitamina B 12/induzido quimicamente , Deficiência de Vitamina B 12/diagnósticoRESUMO
Dysphonia has been reported with anti-angiogenic chemotherapy agents. Dysphonia in patients with cancer receiving chemotherapy tends to be overlooked in clinical practice since it is non-life-threatening. However, it reduces quality of life. Although inhibition of vascular endothelial growth factor receptor is the reported mechanism of dysphonia, it has not been elucidated. We report 6 cases of patients with dysphonia suspected to be due to panitumumab and nivolumab that have not been reported previously. Peripheral edema, a factor in dysphonia, can be seen with aflibercept, bevacizumab, panitumumab, and nivolumab. Therefore, chemotherapy drugs with peripheral edema may be related to dysphonia.
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Disfonia , Fator A de Crescimento do Endotélio Vascular , Inibidores da Angiogênese/efeitos adversos , Bevacizumab/efeitos adversos , Disfonia/induzido quimicamente , Disfonia/diagnóstico , Humanos , Qualidade de Vida , Ranibizumab , Receptores de Fatores de Crescimento do Endotélio Vascular , Proteínas Recombinantes de FusãoRESUMO
BACKGROUND: Clinical evidence of thiamine-related neuropsychiatric symptoms, including the initial stage, is limited because serum thiamine levels tend to be evaluated only for patients who develop severe neuropsychiatric symptoms suspected to be related to severe thiamine deficiency. This study aimed to evaluate the relationship between thiamine decline and neuropsychiatric symptoms, including initial symptoms, and the effect of chemotherapy on serum thiamine levels in gastrointestinal and hematological cancer patients receiving chemotherapy. METHOD: We retrospectively identified 87 patients who were diagnosed with gastrointestinal and hematological cancers at our hospital. We evaluated the risk factors associated with neuropsychiatric symptoms, including initial symptoms (neuropsychiatric symptoms), the relationship between the presence of neuropsychiatric symptoms and serum thiamine levels, and changes in serum thiamine levels after chemotherapy. RESULTS: Logistic regression analysis identified thiamine decline as a significant factor associated with neuropsychiatric symptoms (p < 0.001, odds ratio = 0.040, 95% confidence interval [CI]: 0.010-0.163). The Mann-Whitney U test showed that patients with neuropsychiatric symptoms had significantly lower serum thiamine levels (19.5 ± 5.4 ng/mL, n = 39) than patients without neuropsychiatric symptoms (31.9 ± 14.2 ng/mL, n = 48) (p = 0.001). In hematological cancer patients, serum thiamine levels gradually declined after chemotherapy, with the lowest levels at 5-8 weeks (23.5 ± 7.6 ng/mL, P = 0.035 vs. 0 weeks, Wilcoxon rank sum test). CONCLUSION: Our study showed that a decrease in serum thiamine levels can be a risk factor for neuropsychiatric symptoms, and chemotherapy can lead to a decrease in serum thiamine levels.
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Antineoplásicos/efeitos adversos , Neoplasias Gastrointestinais/sangue , Neoplasias Hematológicas/sangue , Transtornos Mentais/sangue , Deficiência de Tiamina/sangue , Tiamina/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Feminino , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/epidemiologia , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/epidemiologia , Humanos , Masculino , Transtornos Mentais/epidemiologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Deficiência de Tiamina/epidemiologia , Adulto JovemRESUMO
INTRODUCTION: Primary benign adenomas of the appendix occur rarely. According to appendectomy and autopsy reports, benign adenomas of the appendix are sporadically reported, accounting for ~0.02-0.08% cases. PRESENTATION OF CASE: We report the case of a 58-year-old woman with a segmental polyp protruding into the appendiceal orifice. The polyp was spotted during lower gastrointestinal endoscopy; however, treatment was postponed at the patient's request. During a confirmatory lower gastrointestinal endoscopy for treatment, the polyp was no longer found protruding from the appendiceal orifice and had disappeared. An appendicectomy was performed for diagnostic and therapeutic purposes. Pathological examination showed a low-degree atypical tubular adenoma with no malignant findings. DISCUSSION: Despite the risk of perforation, surgical resection remains the gold standard for treating appendiceal adenoma. Resection can be performed endoscopically if the stem and base of the adenoma can be identified. In the present case, laparoscopy was a good indication from the safety standpoint, and it was radically curative. Furthermore, upon performing an appendectomy, the patient was informed of the risks of cancer-related complications or the need for additional resection. CONCLUSION: This suggestive case proves that appendiceal tumors can disappear endoscopically depending on the timing of examination and treatment.
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OBJECTIVES: FOLFOX is a standard chemotherapy regimen used to treat colorectal cancer. Adverse events associated with FOLFOX treatment include peripheral neuropathy and myelosuppression. This report discusses the case of a 64-year-old man with rectal cancer who developed hyperammonemia and impaired consciousness following initiation of mFOLFOX6 as a postoperative adjuvant therapy. METHODS: This case study reports on the clinical disease progression of the aforementioned patient. RESULTS: Following preoperative chemoradiotherapy, the patient underwent low anterior resection for rectal cancer. mFOLFOX6 was then initiated as postoperative adjuvant therapy. During the 5th cycle of mFOLFOX6 treatment, the patient presented with impaired consciousness and upper extremity convulsions. Blood testing revealed marked hyperammonemia (349 µg/dL (normal range: 12 - 66 µg/dL)). Imaging did not reveal any intracranial lesions that could cause impaired consciousness. The patient recovered within a day after rehydration and BCAA substitution. CONCLUSION: Although impaired consciousness is a rare adverse reaction of FOLFOX, it has a major psychological impact on the patient and his/her family. Hyperammonemia should therefore be considered a potential cause of impaired consciousness during FOLFOX therapy and should be appropriately diagnosed and treated.
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Hiperamonemia , Neoplasias Retais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Estado de Consciência , Feminino , Fluoruracila/efeitos adversos , Humanos , Hiperamonemia/induzido quimicamente , Hiperamonemia/diagnóstico , Hiperamonemia/tratamento farmacológico , Leucovorina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Neoplasias Retais/tratamento farmacológicoRESUMO
PURPOSE: Most patients with Crohn's disease (CD) experience surgical recurrence. In this era of novel therapies, we conducted this study to clarify which treatments effectively decrease the risk of surgical recurrence in patients with CD. METHODS: The subjects of this retrospective study were 37 patients with CD. We created cumulative surgery rate curves and performed univariate and multivariate analyses. RESULTS: Univariate analysis revealed that patients who consumed an elemental diet (ED; ≥ 900 kcal/day), anti-tumor necrosis factor-alpha, and thiopurines had a significantly better prognosis than those who did not (p = 0.011, p = 0.025, and p = 0.0080, respectively). Multivariate analysis revealed that ED therapy and thiopurines were independent significant factors for controlling surgical recurrence (p = 0.046 and p = 0.032, respectively). Additional analyses showed that the most promising ED therapeutic dose was ≥ 1200 kcal/day, while an ED therapeutic dose of ≥ 900 kcal/day was acceptable. CONCLUSIONS: Although univariate analyses revealed that all three treatment strategies had significant effects on surgical recurrence in patients with CD, multivariate analysis revealed that only ED therapy was significantly associated with surgical recurrence rates. Thus, ED therapy plays an important role in the management of CD, even in the era of biological therapies.
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Doença de Crohn/dietoterapia , Doença de Crohn/cirurgia , Alimentos Formulados , Prevenção Secundária , Adulto , Idoso , Análise de Variância , Procedimentos Cirúrgicos do Sistema Digestório/estatística & dados numéricos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Recidiva , Reoperação , Estudos Retrospectivos , Risco , Adulto JovemRESUMO
OBJECTIVES: The aim of this retrospective study was to search for risk factors for neurological adverse events in gastrointestinal cancer patients receiving chemotherapy and analyze the relationship between thiamine serum levels and neurological adverse events. MATERIALS AND METHODS: This is a single-center retrospective observational study. We enrolled patients who were diagnosed with gastrointestinal cancer at our hospital, for whom we measured the thiamine serum levels. We then performed a multivariate analysis (logistic regression) to identify risk factors for the neurological symptoms in our cohort. We then divided the patients into two groups, with and without neurological symptoms, based on their electronic medical records. By using the Mann-Whitney U-test, we performed a comparative analysis of the thiamine serum levels between the two groups. We also used descriptive statistics to examine the presence/absence of neurological symptoms or other potentially related clinical features in patients with decreased thiamine serum levels. RESULTS: The logistic regression analysis detected the decrease in thiamine serum levels as a statistically significant risk factor for neurological symptoms. The analysis of the relationship between the presence/absence of neurological symptoms and thiamine serum levels showed that the thiamine serum levels were significantly lower in the group presenting neurological symptoms. Descriptive statistics showed that all the patients with decreased thiamine serum levels had either cognitive decline, attention decline, or depression symptoms, and most of them were receiving the 5-fluorouracil anticancer drug and showing decreased serum albumin levels. We also observed a slight decrease in serum sodium, vitamin B12, and folate levels. CONCLUSION: When neurological symptoms occur in patients receiving chemotherapy for gastrointestinal cancer, the measurement of thiamine serum levels may become a standard reference for treatment indication.
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Antimetabólitos Antineoplásicos/uso terapêutico , Fluoruracila/uso terapêutico , Neoplasias Gastrointestinais/tratamento farmacológico , Doenças do Sistema Nervoso/etiologia , Deficiência de Tiamina/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Ácido Fólico/sangue , Neoplasias Gastrointestinais/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Sódio/sangue , Tiamina/sangue , Vitamina B 12/sangue , Adulto JovemRESUMO
We describe a case of a patient treated for cognitive dysfunction (CD) with suspected thiamine deficiency (TD). A 74-year-old man with gastric cancer presented with grade 3 diarrhea and grade 1 anorexia. He had been receiving trastuzumab plus tegafur (a chemotherapeutic fluorouracil prodrug), gimeracil, and oteracil (S-1) and oxaliplatin. On admission, cognitive function was assessed with the Hasegawa's Dementia Scale (HDS-R) because he had impaired short-term memory. His thiamine levels increased from 22 to 109 ng/mL after administration of 75 mg of thiamine. Furthermore, the patient's HDS-R score improved from 9 to 22, and cognitive and memory functions improved. TD should be considered in older CD patients receiving oral chemotherapy agents including fluorouracil.
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Disfunção Cognitiva/etiologia , Neoplasias Gástricas/tratamento farmacológico , Deficiência de Tiamina/complicações , Idoso , Humanos , MasculinoRESUMO
INTRODUCTION: Chemotherapy is difficult to administer in patients with poor performance status (PS), advanced metastatic lesion, and unresectable colon cancer. We report herein our experience of a patient who showed complete response to chemotherapy and marked PS improvement. The patient presented with the following adverse factors poor PS, advanced progression of metastatic lesions, advanced unresectable colorectal cancer with severe stricture, and old age. PRESENTATION OF CASE: The patient was an 80-year-old male diagnosed with occlusive cancer of the descending colon with multiple metastases in the liver, Stage â £b (National Comprehensive Cancer Network guidelines version 2. 2018). A 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) + panitumumab (Pmab) regimen was successfully administered and led to decreased tumor marker levels; oral intake also became possible. Additional examinations showed that the primary lesion and distant metastatic lesions had almost disappeared; the patient had achieved a near complete response (CR). Currently, 35 cycles of mFOLFOX6ï¼Pmab have been administered, and his near CR has been maintained for 32 months. DISCUSSION: Best supportive care (BSC) is the recommended option for elderly patients with advanced unresectable colon cancer. This is the first case in which an elderly patient with poor PS and advanced unresectable colorectal cancer was treated with combination chemotherapy of mFOLFOX6 + Pmab. CONCLUSION: Although the use of chemotherapy for elderly with advanced unresectable colorectal cancer or those with poor PS is limited, this case shows that systemic chemotherapy is now an option for such cases previously managed with BSC.
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INTRODUCTION: A mobile cecum is a frequently encountered congenital anomaly. It is important to recognize this atypical position of the cecum as it may interfere with an accurate diagnosis of acute appendicitis. PRESENTATION OF CASE: A 48-year-old man presented with abdominal pain, anorexia, and fever. He had mild lower abdominal discomfort, and rebound tenderness in the suprapubic region, but no guarding or right lower quadrant findings. Laboratory tests identified an elevated white blood cell count (12350â¯cells/mL) and C-reactive protein level (4.56â¯mg/dL). In view of the clinical picture suggestive of localized peritonitis, an abdominal computed tomography (CT) was performed, which revealed a caudally located cecum, lying in the pelvis, along with evidence of an acutely inflamed appendix. An urgent surgical procedure was performed, which confirmed the diagnosis of acute appendicitis accompanying a mobile cecum. DISCUSSION: In the presence of a mobile cecum, the clinical findings of acute appendicitis may be atypical owing to the abnormal position of the appendix. In such cases, there is the possibility of a missed diagnosis. In our case, a CT examination that was performed in view of the clinical diagnosis of mild peritonitis aided in establishing the diagnosis of acute appendicitis and a mobile cecum. CONCLUSION: Anatomical variations of the cecum and the appendix may result in atypical presentation of acute appendicitis. A high index of suspicion, and a CT examination may be helpful in establishing the diagnosis in such cases.
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INTRODUCITON: We report a recent case of strangulated bowel obstruction due to an incarcerated secondary perineal hernia that developed after laparoscopic rectal resection. PRESENTATION OF CASE: A 75-year-old man undergoing treatment for alcoholic cirrhosis underwent laparoscopic abdominoperineal resection of the rectum (APR) for lower rectal cancer after preoperative chemoradiotherapy. Lung metastases were diagnosed 2 months postoperatively. Ten days after chemotherapy initiation, the patient was hospitalized on an emergency basis due to hepatic encephalopathy. Ten days thereafter, we observed perineal skin protrusion. Moreover, the skin disintegrated spontaneously, resulting in ascetic fluid outflow. Pain and fever developed, with inflammatory reactions. Contrast-enhanced computed tomography showed strangulated small bowel obstruction due to perineal hernia. We performed an emergency surgery, during which we found small intestine wall incarcerated in the pelvic dead space, with thickening and edema; no necrosis or perforation was observed. We performed internal fixation by introducing an ileus tube into the ileocecum and fixing its balloon at the cecal terminus. DISCUSSION: Secondary perineal hernia is rare and can develop after APR. Its prevalence is likely to increase in future because of the increasing ubiquity of laparoscopic APR, in which no repair of peritoneal stretching to the pelvic floor is performed. However, only two case of secondary perineal hernia causing strangulated bowel obstruction has been reported in the literature. The follow-up evaluation of our procedures and future accumulation of cases will be important in raising awareness of this clinical entity. CONCLUSION: We suggest that the pelvic floor and the peritoneum should be repaired.
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We investigated the effectiveness of prophylactic FOLFOX after curative resection of synchronous metastases in patients with colorectal cancer (CRC). Clinicopathological information including postoperative chemotherapy, such as a therapeutic regimen, relapse-free survival (RFS), site of recurrence, etc., was retrospectively analyzed in 116 CRC patients with synchronous distant metastases, and 63 patients with metachronous metastases who had received surgery in our hospital between 2000 and 2009. Fifty-three patients (84%) out of 63 without adjuvant chemotherapy, and 38 (83%) out of 46 patients that received oral or intravenous 5-fluorouracil (5-FU) (alone or with leucovorin (LV)or isovorin) developed recurrent tumor(s) afterwards. The median RFSs were 119 and 281 days, respectively. By contrast, a single patient among 6 who underwent FOLFOX (up to 12 therapeutic courses) showed recurrence 476 days after surgery. The RFS of the FOLFOX was significantly higher than that of the 5-FU (+LV) or surgery alone (p=0. 03, p=0. 007, respectively). In conclusion, the FOLFOX regimen is more beneficial for CRC patients with synchronous metastasis as adjuvant chemotherapy than 5-FU (+LV) or other followup strategies.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimioterapia Adjuvante , Neoplasias Colorretais/patologia , Neoplasias Colorretais/cirurgia , Feminino , Fluoruracila/uso terapêutico , Humanos , Leucovorina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica/tratamento farmacológico , Compostos Organoplatínicos/uso terapêutico , Recidiva , Estudos RetrospectivosRESUMO
OBJECTIVES: The prophylactic effect of FOLFOX regimen, a standard regimen for unresectable colorectal cancer (CRC), was investigated in the adjuvant setting of CRC cases with distant metastases. METHODS: The study population included 116 CRC patients with synchronous metastases and 91 patients with metachronous metastases who had undergone curative operation in our hospital between 2000 and 2009. Clinicopathological parameters of CRC, postoperative chemotherapeutic regimen, recurrence rate, and relapse-free survival (RFS) were analyzed retrospectively. RESULTS: After resection of CRC and synchronous metastases, 53 (84%) out of 63 patients without chemotherapy, and 38 (83%) out of 46 that received 5-fluorouracil (5-FU) alone or with leucovorin (LV) developed recurrent tumors. By contrast, only 1 (17%) among 6 patients who underwent FOLFOX treatment showed recurrence. The FOLFOX group exhibited significantly improved RFS as compared to the 5-FU (+ LV) or surgery-alone group (p = 0.03, p = 0.007, respectively). On the other hand, in patients with metachronous metastases, tumor-relapse rate and RFS were not significantly influenced by post-metastasectomy therapies. CONCLUSIONS: In this retrospective analysis, the adjuvant administration of FOLFOX appeared to reduce the risk of relapse in a small group of CRC patients with synchronous metastases. Prospective randomized trials will be required to confirm the benefits of this management strategy.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Recidiva Local de Neoplasia , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimioterapia Adjuvante , Neoplasias Colorretais/cirurgia , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Estimativa de Kaplan-Meier , Leucovorina/administração & dosagem , Leucovorina/efeitos adversos , Modelos Logísticos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/efeitos adversos , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
Id genes (inhibitor of DNA binding/differentiation) play important roles in tumour growth. We have previously described crucial roles of Id gene over-expression in endothelial cells for tumour angiogenesis. Here, we have evaluated direct effects of Id gene down-regulation on tumour cells, namely on cell proliferation, motility, and adhesion to lung microvasculature during haematogenous metastasis. For this purpose, Id genes were stably down-regulated by RNA interference in human colorectal cancer cells. These cells showed delayed proliferation, inhibited motility and decreased expression of integrin alpha6 and consequently reduced adhesion to lung microvasculature in mice. Static adhesion assays and laminar flow assays revealed decreased laminin binding capacity of these cells, and blocking experiments confirmed that it could be attributed to decreased expression of integrin alpha6. The present results indicate important roles of Id genes in tumour cells during early steps of haematogenous metastasis and suggest dual effects from their therapeutic inhibition.
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Neoplasias Colorretais/genética , Neoplasias Hematológicas/etiologia , Proteínas Inibidoras de Diferenciação/genética , Animais , Moléculas de Adesão Celular , Linhagem Celular Tumoral , Transformação Celular Neoplásica , Regulação para Baixo , Feminino , Citometria de Fluxo , Humanos , Laminina/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos NusRESUMO
Endothelial progenitor cells (EPCs) have been recently found to exist circulating in peripheral blood of adults, and home to sites of neovascularization in peripheral tissues. They can also be differentiated from peripheral blood mononuclear cells (PBMNCs). In tumor tissues, EPCs are found in highly vascularized lesions. Few reports exist in the literature concerning the characteristics of EPCs, especially related to their surface antigen expressions, except for endothelial markers. Here, we aimed to investigate the surface expression of differentiation markers, and the functional activities of early-outgrowth of EPCs (EO-EPCs), especially focusing on their antigen-presenting ability. EO-EPCs were generated from PBMNCs, by culture in the presence of angiogenic factors. These EO-EPCs had the morphological and functional features of endothelial cells and, additionally, they shared antigen-presenting ability. They induced the proliferation of allogeneic lymphocytes in a mixed-lymphocyte reaction, and could generate cytotoxic lymphocytes, with the ability to lyze tumor cells in an antigen-specific manner. The antigen-presenting ability of EO-EPCs, however, was weaker than that of monocyte-derived dendritic cells, but stronger than peripheral blood monocytes. Since EO-EPCs play an important role in the development of tumor angiogenesis, targeting EPCs would be an effective anti-angiogenic strategy. Alternatively, due to their antigen-presenting ability, EO-EPCs can be used as the effectors of anti-tumor immunotherapy. Since they share endothelial antigens, the activation of a cellular immunity against angiogenic vessels can be expected. In conclusion, EO-EPCs should be an interesting alternative for the development of new therapeutic strategies to combat cancer, either as the effectors or as the targets of cancer immunotherapy.
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Células Apresentadoras de Antígenos/imunologia , Células Endoteliais/imunologia , Neovascularização Patológica/imunologia , Células-Tronco/imunologia , Células Apresentadoras de Antígenos/citologia , Células Apresentadoras de Antígenos/metabolismo , Antígenos de Diferenciação , Biomarcadores/análise , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Citometria de Fluxo , Humanos , Ativação Linfocitária/imunologia , Teste de Cultura Mista de Linfócitos , Células-Tronco/citologia , Células-Tronco/metabolismo , Linfócitos T/imunologiaRESUMO
Inhibitor of DNA binding (Id) proteins are essential for cell differentiation, proliferation, migration, invasion and angiogenesis. Recently, they have been shown to correlate with less differentiated phenotypes, high malignant potential and poor clinical outcome in various kinds of tumors. In an attempt to develop new strategies for the treatment of peritoneal metastasis of gastric cancer, we prepared an Id1, 3 double-knockdown gastric cancer cell line, MKN45, by RNA interference and investigated its effects on the development of metastatic nodules in the peritoneal cavity. Both cell proliferation and migration capabilities were decreased in Id1, 3 double-knockdown cells, as was their ability to bind to laminin, which could be explained by the decreased expression of integrin alpha6. These are important steps in the metastatic process. In a mouse model, the number of peritoneal metastatic nodules formed by Id1, 3 double-knockdown cells was reduced compared to mock-transfected control cells, as was the size of individual tumors. In this study, we clearly demonstrated that Id1, 3 double-knockdown significantly impaired the ability of gastric cancer cells to form peritoneal metastasis. Id should be considered an ideal target for the treatment and prevention of gastric cancer, and RNA interference is an attractive and promising strategy to achieve it.
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Proteína 1 Inibidora de Diferenciação/genética , Proteína 1 Inibidora de Diferenciação/fisiologia , Proteínas Inibidoras de Diferenciação/genética , Proteínas Inibidoras de Diferenciação/fisiologia , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/fisiologia , Neoplasias Peritoneais/secundário , Neoplasias Gástricas/patologia , Animais , Movimento Celular , Proliferação de Células , Modelos Animais de Doenças , Humanos , Camundongos , Metástase Neoplásica/genética , Metástase Neoplásica/fisiopatologia , Interferência de RNA , Células Tumorais CultivadasRESUMO
We have investigated a potential anti-angiogenic effect of plaunotol, an extract from the leaves of Plau-noi, in an angiogenesis model consisting of human umbilical vein endothelial cells (HUVECs). Plaunotol inhibited the proliferative activity of HUVECs in a dose-dependent manner. In addition, it caused a remarkable decrease of the ability of HUVECs to adhere and spread on gelatin and vitronectin, but not fibronectin. Tube-like formation in Matrigel was also inhibited in a dose-dependent way. These results strongly suggest the specific inhibition of integrin alphavbeta3 to be the main event of plaunotol-induced suppression of angiogenesis. The alphavbeta3 antagonists are known to be potent inhibitors of tumor angiogenesis and plaunotol, by causing the functional inhibition of alphavbeta3, should be considered a promising new anti-angiogenic drug.
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Inibidores da Angiogênese/farmacologia , Proliferação de Células/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Álcoois Graxos/farmacologia , Integrina alfaVbeta3/metabolismo , Adesão Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Colágeno/metabolismo , Diterpenos , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Fibronectinas/metabolismo , Gelatina/metabolismo , Humanos , Laminina/metabolismo , Proteoglicanas/metabolismo , Veias Umbilicais/citologia , Vitronectina/metabolismoRESUMO
High level expression of cyclooxygenase (COX)-2 is reported in 80-90% of colorectal adenocarcinomas. In the recent years, selective inhibitors of COX-2 have been developed, and are shown to effectively protect against cancer development and progression. Colon cancer cells, as well as the epithelial cells in general, are dependent on appropriate interactions with the extracellular matrix (ECM) proteins to achieve a number of important functions, such as proliferation, differentiation, invasion and survival. These interactions are mediated via a family of cell-surface receptors called integrins, which interact with cytoskeletal proteins on the cytoplasmic side of the plasma membrane and thereby provide a link between the ECM and the cytoskeleton. In the present study, a high-COX-2 (high level COX-2 expression) colon cancer cell line, HT-29, and a low-COX-2 (low level COX-2 expression), DLD-1, were used to investigate the anticolon cancer effect of the selective COX-2 inhibitor, JTE-522. Moreover, to clarify its mechanisms of action, we focused especially on the ability to adhere to and to migrate on ECM. We could clearly demonstrate that, in addition to the decrease of the proliferative activity, JTE-522 caused a dose-dependent decrease in both the ability of colon cancer cells to adhere to and to migrate on ECM. These effects were, at least in part, dependent on the down-regulation of beta1-integrin expression, which was evident in HT-29, the high-COX-2 colon cancer cells, but not the low-COX-2, DLD-1. In addition, prostaglandin E2 almost completely reversed the effect of JTE-522, strongly suggesting the involvement of a COX-2-dependent pathway. In conclusion, for the first time, we could demonstrate the down-regulation of beta1 integrin caused by COX-2 inhibition, with consequent impairment of the ability of cancer cells to adhere to and to migrate on ECM, which are crucial steps for cancer metastases to develop.
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Benzenossulfonatos/farmacologia , Integrina beta1/metabolismo , Oxazóis/farmacologia , Benzenossulfonatos/antagonistas & inibidores , Adesão Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Neoplasias do Colo , Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase/farmacologia , Dinoprostona/farmacologia , Relação Dose-Resposta a Droga , Regulação para Baixo , Matriz Extracelular/efeitos dos fármacos , Células HT29 , Humanos , Proteínas de Membrana , Oxazóis/antagonistas & inibidores , Prostaglandina-Endoperóxido Sintases , Células Tumorais CultivadasRESUMO
BACKGROUND: Monocytes are the main effector cells of the immune system, and the regulation of their survival and apoptosis is essential for monocyte-involved immune responses. Green tea polyphenol catechin has been reported to have antiallergic and anti-inflammatory activities, but its effect on monocytes has not yet been explored. OBJECTIVE: To elucidate the mechanisms of the anti-inflammatory effect of catechin, we studied the effect of catechin, especially epigallocatechin gallate (EGCG), on the apoptosis of monocytes. METHODS: Isolated peripheral blood monocytes were incubated without or with catechin, and apoptosis was evaluated by annexin V and propidium iodide double-staining or terminal deoxynucleotidyl assay. The activation of caspases 3, 8, and 9 was also evaluated by flow cytometry. The influence of GM-CSF or LPS, the known monocyte survival factors, on the EGCG-induced apoptosis of monocytes was investigated. RESULTS: Among the 4 catechin derivatives tested, EGCG and epicatechin gallate induced apoptosis of monocytes. Caspases 3, 8, and 9, which play a central role in the apoptotic cascade, were dose-dependently activated by EGCG treatment. The EGCG-induced apoptosis of monocytes was not affected by GM-CSF or LPS. CONCLUSION: Catechin, especially EGCG, by promoting monocytic apoptosis, may be a new promising anti-inflammatory agent, and should be tested in clinical trials.