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1.
Br J Surg ; 107(5): 586-594, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32162301

RESUMO

BACKGROUND: Japan Clinical Oncology Group (JCOG) 0212 (ClinicalTrials.gov NCT00190541) was a non-inferiority phase III trial of patients with clinical stage II-III rectal cancer without lateral pelvic lymph node enlargement. The trial compared mesorectal excision (ME) with ME and lateral lymph node dissection (LLND), with a primary endpoint of recurrence-free survival (RFS). The planned primary analysis at 5 years failed to confirm the non-inferiority of ME alone compared with ME and LLND. The present study aimed to compare ME alone and ME with LLND using long-term follow-up data from JCOG0212. METHODS: Patients with clinical stage II-III rectal cancer below the peritoneal reflection and no lateral pelvic lymph node enlargement were included in this study. After surgeons confirmed R0 resection by ME, patients were randomized to receive ME alone or ME with LLND. The primary endpoint was RFS. RESULTS: A total of 701 patients from 33 institutions were assigned to ME with LLND (351) or ME alone (350) between June 2003 and August 2010. The 7-year RFS rate was 71.1 per cent for ME with LLND and 70·7 per cent for ME alone (hazard ratio (HR) 1·09, 95 per cent c.i. 0·84 to 1·42; non-inferiority P = 0·064). Subgroup analysis showed improved RFS among patients with clinical stage III disease who underwent ME with LLND compared with ME alone (HR 1·49, 1·02 to 2·17). CONCLUSION: Long-term follow-up data did not support the non-inferiority of ME alone compared with ME and LLND. ME with LLND is recommended for patients with clinical stage III disease, whereas LLND could be omitted in those with clinical stage II tumours.


ANTECEDENTES: El JCOG0212 (ClinicalTrials.gov: NCT00190541) fue un ensayo fase III de no inferioridad en pacientes con cáncer de recto en estadio clínico II/III sin ganglios linfáticos aumentados de tamaño en la pared pélvica lateral. El ensayo comparó la escisión del mesorrecto (mesorectal excision, ME) con la ME con disección de los ganglios linfáticos laterales (lateral lymph node dissection, LLND), siendo el criterio de valoración principal la supervivencia libre de recidiva (recurrence free survival, RFS). El análisis primario planificado a los 5 años de seguimiento no pudo confirmar la no inferioridad de la ME frente a la ME con LLND. Este estudio tuvo como objetivo comparar la ME como procedimiento único y la ME con LLND utilizando datos de seguimiento a largo plazo del ensayo JCOG0212. MÉTODOS: En este estudio se incluyeron pacientes con cáncer de recto en estadio clínico II/III por debajo de la reflexión peritoneal sin ganglios linfáticos aumentados de tamaño en la pared pélvica lateral. Después de que los cirujanos confirmaran la resección R0 mediante la ME, los pacientes fueron asignados al azar al brazo de ME sola o al brazo de ME con LLND. El criterio de valoración principal fue la supervivencia libre de recidiva (RFS). RESULTADOS: Un total de 701 pacientes de 33 instituciones fueron asignados al azar para ser tratados mediante una ME con LLND (n = 351) o EM sola (n = 350) entre junio de 2003 y agosto de 2010. Las tasas de RFS a 7 años fueron del 71,1% para ME con LLND y 70,7 % para ME sola (cociente de riesgos instantáneos, hazard ratio, HR: 1,09 (i.c. del 95% 0,84-1,42), no inferioridad P = 0,064)). El análisis de subgrupos mostró una mejor RFS entre los pacientes en estadio clínico III que se sometieron a ME con LLND en comparación con ME sola (HR: 1,49 (i.c. del 95%: 1,02-2,17)). CONCLUSIÓN: Los datos de seguimiento a largo plazo no justificaron la no inferioridad de la ME en comparación con la ME con LLND. Se recomienda la ME con LLND para pacientes en estadio clínico III, mientras que LLND podría omitirse para pacientes en estadio clínico II.


Assuntos
Excisão de Linfonodo , Protectomia/métodos , Neoplasias Retais/cirurgia , Intervalo Livre de Doença , Estudos de Equivalência como Asunto , Seguimentos , Humanos , Linfonodos/patologia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Neoplasias Retais/patologia
2.
Clin Radiol ; 74(10): 816.e1-816.e8, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31400805

RESUMO

AIM: To evaluate the diagnostic feasibility of probabilistic analysis using voxel-based morphometry (VBM) in differentiating primary central nervous system lymphoma (PCNSL) from glioblastoma (GBM). MATERIALS AND METHODS: In total, 118 patients with GBM (57 males, 61 females; mean [± standard deviation] age, 56.9±19.3 years; median, 61 years) and 52 patients with PCNSL (37 males, 15 females; mean age, 62±13.3 years, median, 66 years) were studied retrospectively. Each patient underwent preoperative contrast-enhanced T1-weighted imaging (CE-T1WI) using a 1.5 or 3 T magnetic resonance imaging (MRI) system. To assess preferential occurrence sites, images from CE-T1WI were co-registered and spatially normalised using the MNI152 T1 template. Subsequently, a region of interest (ROI) was placed in the centre of the enhancing tumour in normalised images with 1-mm isotropic resolution. The same ROI between normalised and T1 template images was set up using an ROI manager function in ImageJ software. A spherical volume of interest (VOI) with a radius of 10 mm was determined. A probability map was created by overlaying each image with the VOI. Each VOI was removed from T1 template images for VBM analysis. VBM analysis was performed using statistical parametric mapping (SPM) 12 software under default settings. RESULTS: VBM analysis showed significantly higher frequency in the splenium of the corpus callosum among PCNSL patients than among GBM patients (p<0.05; family-wise error correction). CONCLUSION: Topographic analysis using VBM provides useful information for differentiating PCNSL from GBM.


Assuntos
Mapeamento Encefálico , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias do Sistema Nervoso Central/diagnóstico por imagem , Glioblastoma/diagnóstico por imagem , Linfoma/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Meios de Contraste , Diagnóstico Diferencial , Estudos de Viabilidade , Feminino , Substância Cinzenta/diagnóstico por imagem , Humanos , Processamento de Imagem Assistida por Computador/métodos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
3.
Transplant Proc ; 50(5): 1457-1460, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29880370

RESUMO

BACKGROUND: Some literature has reported on endovascular treatment for very early hepatic artery stenosis (HAS; within 2 weeks after liver transplantation, and has deemed endovascular treatment to be a contraindication because out of serious complications associated with the procedure. We report on 2 cases of very early HAS successfully treated with endovascular treatment after living-donor liver transplantation (LDLT). CASE 1: A 54-year-old woman underwent LDLT with a left liver graft. The native right gastric artery and left hepatic artery (LHA) of the donor were anastomosed. On postoperative day (POD) 13, HAS was suspected and multidetector computerized tomographic angiography (MDCTA) was performed, which revealed 90% stenosis of the arterial anastomosis and 50% stenosis of the LHA in the graft. We performed percutaneous balloon arterioplasty (PBA) without any complications. The artery was patent with a postoperative follow-up of 60 months without the need for repeat intervention. CASE 2: A 67-year-old woman with a history of repeated transarterial chemoembolization for hepatocellular carcinoma underwent LDLT with a left liver graft. The native A4 and LHA of the donor were anastomosed. We performed MDCTA on POD 11, which revealed 70% stenosis of the native hepatic artery. We performed PBA followed by stent placement on POD 11 without complication. The artery was patent with a postoperative follow-up of 40 months without the need for repeated intervention. CONCLUSIONS: Endovascular treatment has the potential to avoid the need for repeated surgical interventions or retransplantation, and it can be safely performed in carefully selected patients.


Assuntos
Procedimentos Endovasculares/métodos , Artéria Hepática/patologia , Artéria Hepática/cirurgia , Transplante de Fígado/efeitos adversos , Complicações Pós-Operatórias/cirurgia , Idoso , Constrição Patológica/cirurgia , Feminino , Humanos , Transplante de Fígado/métodos , Doadores Vivos , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento
4.
Eur J Surg Oncol ; 42(2): 184-9, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26683263

RESUMO

BACKGROUND/AIM: The Kyushu Study Group of Clinical Cancer (KSCC) previously reported the safety and efficacy of neoadjuvant chemotherapy with mFOLFOX6 + bevacizumab for H2/H3 liver metastases of colorectal cancer. The aim of the current study was to evaluate the resectability of these metastases before and after chemotherapy as determined by independent liver surgeons. METHODS: Between May 2008 and April 2010, 40 patients were registered in a multicenter phase 2 trial of neoadjuvant chemotherapy (KSCC 0802). In Study 1, 5 independent liver surgeons from five different KSCC centers evaluated the resectability of liver metastases of colorectal cancer based on imaging studies performed before and after chemotherapy. Each surgeon was blinded to the other surgeons' evaluations. In addition, no information about the patients' characteristics was provided. In Study 2, 3 surgeons evaluated the resectability of these lesions based on imaging studies with discussion with each other, with the surgeons being provided with information on the patients' characteristics. RESULTS: In Study 1, 13 patients (36.1%) were evaluated to be resectable at baseline, whereas 17 patients (47.2%) were evaluated to be resectable after chemotherapy. In Study 2, 4 patients (11.1%) were evaluated to be resectable at baseline, compared to 23 patients (63.9%) after chemotherapy. CONCLUSION: Neoadjuvant chemotherapy with mFOLFOX6 + bevacizumab was confirmed to increase the resectability of non-resectable liver metastases of colorectal cancer according to the independent assessments of surgeons.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/cirurgia , Seleção de Pacientes , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bevacizumab/administração & dosagem , Quimioterapia Adjuvante , Comportamento Cooperativo , Feminino , Fluoruracila/administração & dosagem , Humanos , Relações Interprofissionais , Leucovorina/administração & dosagem , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/secundário , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Compostos Organoplatínicos/administração & dosagem , Método Simples-Cego , Tomografia Computadorizada por Raios X
5.
Breast Cancer Res Treat ; 153(2): 337-44, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26267663

RESUMO

A new sensitive fluorescence imaging system was developed for the real-time identification of sentinel lymph nodes (SLNs) in patients with early breast cancer. The purpose of this study was to evaluate the utility of a color charge-coupled device camera system for the intraoperative detection of SLNs and to determine its clinical efficacy and sensitivity in patients with operable breast cancer. We assessed a total of 168 patients diagnosed with or suspected of having early-stage breast cancer without metastasis in SLNs. The intraoperative detection of SLNs was performed using the conventional Indigo Carmine dye (indigotindisulfonate sodium) technique combined with a new Indocyanine green (ICG) imaging system (HyperEye Medical System: HEMS, MIZUHO IKAKOGYO, Japan) to map SLNs, in which the lymphatic vessels and SLNs were visualized transcutaneously with illuminating ICG fluorescence. Between January 2012 and May 2013, SLNs were successfully identified in all 168 patients (detection rate: 100%). By histopathology, the sensitivity was 93.8% for the detection of the metastatic involvement of SLNs (15 of 16 nodal-positive patients). After a median follow-up of 30.5 months, none of the patients presented with axillary recurrence. These results suggest that the HEMS imaging system is a feasible and effective method for the detection of SLNs in breast cancer. Furthermore, the HEMS device permitted the transcutaneous visualization of lymphatic vessels under light conditions, thus facilitating the identification and detection of SLNs without affecting the surgical procedure, together with a high sensitivity and specificity.


Assuntos
Neoplasias da Mama/diagnóstico , Neoplasias da Mama/cirurgia , Verde de Indocianina , Cuidados Intraoperatórios , Imagem Óptica/métodos , Biópsia de Linfonodo Sentinela , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Mastectomia/métodos , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Sensibilidade e Especificidade , Carga Tumoral
6.
Eur J Surg Oncol ; 40(5): 559-566, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24388740

RESUMO

AIMS: The aim of this study was to investigate the relationship between the use of bevacizumab (Bmab) in addition to oxaliplatin (OX), the development of sinusoidal obstruction syndrome (SOS) and the changes in splenic volume as an indicator of the protective effect of Bmab against OX-induced SOS. METHODS: Seventy-nine patients who received OX-based chemotherapy with (OX + Bmab group: n = 48) or without Bmab (OX group: n = 31) for colorectal liver metastases were included in this study. The changes in splenic volume after chemotherapy were evaluated in the two groups. Furthermore, the relationship between the changes in splenic volume and SOS were analyzed in the 55 patients who underwent hepatectomy. RESULTS: A significant increase in the splenic volume was observed in the OX group, but not in the OX + Bmab group. The increase in the splenic volume relative to baseline was significantly higher in the OX group than in the OX + Bmab group (39.1% vs. 2.3%, p < 0.0001). The incidence of moderate or severe SOS was significantly higher in the OX group than in the OX + Bmab group (50.0% vs. 16.0%, p = 0.0068), and the increase in the splenic volume was significantly higher in the patients with SOS than in those without SOS (42.9% vs. 9.9%, p = 0.0001). A multivariate analysis identified the increase in the splenic volume as an independent predictor of the development of SOS. CONCLUSIONS: This study demonstrated that the inhibition of splenic volume enlargement might be a useful indicator of the protective effect of Bmab against OX-induced SOS.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/patologia , Hepatopatia Veno-Oclusiva/prevenção & controle , Neoplasias Hepáticas/tratamento farmacológico , Compostos Organoplatínicos/efeitos adversos , Baço/diagnóstico por imagem , Idoso , Bevacizumab , Feminino , Fluoruracila/uso terapêutico , Hepatopatia Veno-Oclusiva/induzido quimicamente , Humanos , Leucovorina/uso terapêutico , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão , Compostos Organoplatínicos/uso terapêutico , Oxaliplatina , Radiografia , Estudos Retrospectivos , Resultado do Tratamento
7.
Med Phys ; 39(6Part18): 3833-3834, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28518504

RESUMO

PURPOSE: The purpose of this planning study was to evaluate the dosimetric effect of dose escalation for intracranial stereotactic radiotherapy by volumetric modulated arc therapy (RapidArc) with simultaneous integrated boost (SIB-VMAT). METHODS: Dynamic conformal arc therapy (DCA), VMAT, and SIB-VMAT plans using Novalis Tx (Varian/BrainLAB) were performed for twenty target volumes in patients with intracranial metastases with median PTV of 16.0 cm3 (range 2.4-35.2 cm3 ). PTV was created with 2 mm expansion from GTV. All plans were generated with a prescribed dose of 35 Gy in 5 fractions to the PTV (D95 = 95%), and dose escalation up to 40 Gy (SIB-VMAT40) and 45 Gy (SIB-VMAT45) was performed only to the PTV-boost (PTV shrunk by 5 mm) for SIB-VMAT. Each plan was compared using conformity parameters. RESULTS: The average Paddick conformity index (CI) was 0.78, 0.90, 0.91, and 0.89 for DCA, VMAT, SIB-VMAT40, and SIB-VMAT45, respectively. The average healthy tissue overdosage factor (HTOF), suggested by SALT was 0.118, 0.006, 0.007, and 0.011 for DCA, VMAT, SIB-VMAT40, and SIB-VMAT45, respectively. The average V30, V20, and V10 of normal brain for VMAT and SIB-VMAT decreased by 3.0 cm3 (range 0.1-8.2 cm3 ), 3.0 cm3 (range 0.1-8.7 cm@@@3@@), and 7.5 cm@@@3@@ (range 0.3-26.2 cm@@@3@@), respectively, compared to DCA depending on the target volume. CONCLUSIONS: SIB-VMAT improved dose conformity to the PTV for intracranial stereotactic radiotherapy, and decreased high and low dose volume of normal brain compared to DCA. SIB-VMAT offers the ability of dose escalation due to high conformity of high dose regions inside the target volume.

8.
Br J Ophthalmol ; 93(8): 1081-4, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19429582

RESUMO

BACKGROUND: Peroxiredoxin 6 (Prdx6), a new family of antioxidants, regulates gene expression and function by controlling reactive oxygen species, delays hereditary cataracts in rats and protects epithelial cells in the lens against oxidative stresses. AIM: To investigate the correlation between Prdx6 expression, age and the severity of lens opacity at the time of cataract surgery. METHODS: 88 cataractous eyes were examined at Fukui University Hospital, Fukui, Japan, between March 2007 and October 2007. The patient age at the time of surgery, and the subtype and severity of cataract as classified according to the modified version of the Lens Opacities Classification System version III (LOCSIII) were recorded, as well as the expression level of Prdx6 mRNA in their lenses. RESULTS: The expression of Prdx6 was found to be significantly negatively associated with age at the time of cataract surgery (p<0.047). A significant correlation was also found between a higher nuclear or cortical cataract score and lower expression of Prdx6 in patients under 70 years old. CONCLUSION: These findings suggest that oxidative stress contributes to nuclear cataract formation and that a local decrease in Prdx6 in cataractous lenses may indicate the initiation of age-related cataract formation.


Assuntos
Catarata/enzimologia , Peroxirredoxina VI/biossíntese , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Proteínas do Olho/metabolismo , Humanos , Cristalino/enzimologia , Pessoa de Meia-Idade , Estresse Oxidativo , Peroxirredoxina VI/genética , Estudos Prospectivos , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Índice de Gravidade de Doença
9.
J Clin Pathol ; 62(4): 364-9, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19052026

RESUMO

AIMS: 5-Fluorouracil (5-FU) is one of the most widely used anticancer drugs; however, the activity of 5-FU is determined by the presence of several enzymes that limit its activation or degradation, and these include dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyl transferase (OPRT), thymidylate synthase (TS), thymidine kinase (TK), thymidine phosphorylase (TP) and deoxyuridine triphosphatase (dUTPase). The aim of this study was to compare the expression levels of these enzymes between the primary colorectal cancer of patients with and without distant metastases. Furthermore, there was a comparison of these expression levels between the primary tumour and the corresponding metastasis. METHODS: Of 55 patients with colorectal cancer, 20 had no metastasis and the other 35 had distant metastasis. A strong expression was classified as positive, while weak to moderate or no expression was negative by immunohistochemistry. RESULTS: Of the six 5-FU-related enzymes, the numbers of patients with expression of dUTPase (54% versus 15%; p = 0.005), TK (26% versus 0%; p = 0.019) and DPD (17% versus 45%; p = 0.033) were significantly different in those with primary tumours with metastasis compared with those with non-metastasis, respectively. The altered expression of OPRT (34.3%), TS (40.0%) and dUTPase (42.9%) was significantly greater from primary to metastasis among the 35 patients with metastasis. By contrast, the expression of OPRT, TS and dUTPase was decreased in 6, 5 and 7 patients, respectively, in metastatic sites. CONCLUSIONS: From this comparative study of the six 5-FU-related enzymes in colorectal cancer, the expression of dUTPase was most significantly different between primary tumours and their corresponding metastatic tumour. It is suggested that dUTPase may be a predictive biomarker for the metastatic potential of colorectal cancer.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/enzimologia , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/secundário , Pirofosfatases/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/metabolismo , Neoplasias Colorretais/patologia , Neoplasias Colorretais/cirurgia , Feminino , Fluoruracila/metabolismo , Humanos , Mucosa Intestinal/enzimologia , Neoplasias Hepáticas/enzimologia , Neoplasias Pulmonares/enzimologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Adulto Jovem
10.
Eye (Lond) ; 22(11): 1442-5, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18535585

RESUMO

AIM: To elucidate the putative role of human papillomavirus (HPV) infection in pterygium and conjunctival papilloma. METHODS: Hybrid capture II (HC-II) and polymerase chain reaction (PCR) assays were performed to detect HPV in pterygium (42 samples obtained from 40 patients) and conjunctival papilloma (8 samples from 6 patients). The amount of HPV DNA was evaluated by measurement of relative light units (RLUs) on a luminometer. RESULTS: All papilloma samples were positive for HPV DNA by PCR and HC-II. The RLU values for specimens of recurrent and re-recurrent papilloma were markedly higher than those for specimens of primary lesions. HPV was detected by PCR in 2 of 42 (4.8%) beta-globin-positive pterygium specimens, whereas HC-II showed that HPV was negative in all pterygium samples. CONCLUSIONS: Our results support the hypothesis that HPV DNA is associated with the pathogenesis of conjunctival papilloma, but not pterygium. RLU measurement by HC-II may serve as a marker for evaluating the activity of HPV in conjunctival tumours.


Assuntos
DNA Viral/análise , Papiloma/diagnóstico , Infecções por Papillomavirus/diagnóstico , Pterígio/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Túnica Conjuntiva/virologia , Neoplasias da Túnica Conjuntiva/diagnóstico , Neoplasias da Túnica Conjuntiva/virologia , Feminino , Humanos , Hibridização In Situ , Masculino , Pessoa de Meia-Idade , Papiloma/virologia , Infecções por Papillomavirus/virologia , Reação em Cadeia da Polimerase , Pterígio/virologia , Reprodutibilidade dos Testes , Globinas beta/análise
11.
Exp Eye Res ; 84(2): 246-53, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17141219

RESUMO

P-glycoprotein (P-gp), a plasma membrane protein, is thought to function in the export of cytotoxic drugs and to act as a modulator of chloride channels that regulate cell volume in many cell types. P-gp has been shown to play a role in lens volume regulation and initiation of osmotic cataract. We investigated the lenticular expression levels of P-gp in galactose-fed rats, an experimental model of sugar cataract. P-gp was overexpressed in lenses from galactose-fed rats with cortical sugar cataract, and in rat lens epithelial cells cultured in high-glucose medium. However, application of aldose reductase (AR) inhibitor was able to reverse the changes in P-gp levels in the lenses of galactose-fed rats, confirming the role of AR and involvement of the polyol pathway in cataract formation. Our findings suggest that P-gp may be induced by AR over-expression and/or osmotic stress, thus playing a regulatory role in maintaining lenticular osmotic balance in sugar cataract.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/biossíntese , Catarata/metabolismo , Proteínas do Olho/biossíntese , Regulação para Cima , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Aldeído Redutase/metabolismo , Animais , Catarata/induzido quimicamente , Catarata/fisiopatologia , Células Cultivadas , Proteínas do Olho/genética , Feminino , Galactose , Cristalino/metabolismo , Osmose , Reação em Cadeia da Polimerase/métodos , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley
12.
J Exp Clin Cancer Res ; 26(4): 475-82, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18365541

RESUMO

This study was designed to evaluate the antitumor efficacy and feasibility of postoperative adjuvant metronomic chemotherapy using weekly low-dosage CPT-11 and UFT in colorectal cancer at high risk to recurrence. A total of 49 patients (24 stage IIIb and 25 distant metastasis) who underwent a R0 operation were enrolled in this prospective study. Forty mg/m2 of CPT-11 were administered on day 1, day 8, and on day 15 in 28-day cycles. A dosage of 335 mg/m2/day of UFT was given perorally on daily schedule. Cycles were repeated for 6 months, and were followed by UFT alone for further 6 months. One or more adverse effects were seen in 43 of the 49 patients. However, most of these effects were mild at grade 1 or 2: with only nausea in 3 patients, vomiting in 2, leucopenia in 2 and neutropenia in 2 at grade 3. The overall survival rates were favorable both in the stage IIIb group (5-year: 73%) and in the distant metastases group (5-year: 62%). Postoperative adjuvant metronomic chemotherapy using weekly low-dosage CPT-11 and UFT might be safe and feasible and prolong survival time in colorectal cancer at high risk to recurrence.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Camptotecina/análogos & derivados , Neoplasias Colorretais/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Terapia Combinada , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Humanos , Irinotecano , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida , Tegafur/administração & dosagem , Tegafur/efeitos adversos , Uracila/administração & dosagem , Uracila/efeitos adversos
13.
Arch Ophthalmol ; 124(11): 1586-90, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17102006

RESUMO

OBJECTIVE: To investigate the relationship between axial length, myopia of the eye, and the severity of lens opacity at the time of cataract surgery. METHODS: We retrospectively reviewed a consecutive series of 198 eyes of patients aged older than 50 years at Fukui University Hospital (Fukui, Japan) from June 2004 to December 2005. Patient age at the time of surgery, axial length, spherical equivalent, and the subtypes and severity of cataract (as classified according to the modification of the Lens Opacities Classification System, version III) were recorded. RESULTS: Axial length was significantly associated with age at the time of cataract surgery (P<.001). Regarding the severity of nuclear cataract, a significant correlation was seen between a higher score of nuclear cataract and longer axial length (P<.001). The relationship between the severity of nuclear cataract and spherical equivalent at the time of surgery showed a significant association between grading nuclear color and nuclear opalescence 4-6 and higher myopia (P<.001). CONCLUSION: An increase in axial length or myopia of the eye was associated with a lower mean age at the time of surgery and higher grade of nuclear cataract.


Assuntos
Envelhecimento/fisiologia , Antropometria , Extração de Catarata , Catarata/fisiopatologia , Olho/fisiopatologia , Miopia/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Catarata/classificação , Olho/diagnóstico por imagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Ultrassonografia
14.
Diabetologia ; 48(4): 790-8, 2005 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15761720

RESUMO

AIMS/HYPOTHESIS: Osmotic and oxidative stress is associated with the progression and advancement of diabetic cataract. In the present study, we used a cDNA microarray method to analyse gene expression patterns in streptozotocin-induced diabetic rats and galactose-fed cataractous lenses. In addition, we investigated the regulation and interaction(s) of anti-oxidant protein 2 and lens epithelium-derived growth factor in these models. METHODS: To identify differential gene expression patterns, one group of Sprague-Dawley rats was made diabetic with streptozotocin and a second group was made galactosaemic. Total RNA was extracted from the lenses of both groups and their controls. Labelled cDNA was hybridised to Atlas Rat Arrays. Changes in gene expression level were analysed. Real-time PCR and western analysis were used to validate the microarray results. RESULTS: The expression of 31 genes was significantly modulated in hyperglycaemic lenses compared with galactosaemic lenses. Notably, transcript and protein levels of B-cell leukaemia/lymphoma protein 2 and nuclear factor-kappaB were significantly elevated in rat lenses at 4 weeks after injection of streptozotocin. At a later stage, mRNA and protein levels of TGF-beta were elevated. However, levels of mRNA for IGF-1, lens epithelium-derived growth factor and anti-oxidant protein 2 were diminished in streptozotocin-induced diabetic cataract. CONCLUSIONS/INTERPRETATIONS: These results provide evidence that progression of sugar cataract involves oxidative- and TGF-beta-mediated signalling. These pathways may promote abnormal gene expression in the hyperglycaemic and galactosaemic states and thus may contribute to the symptoms associated with these conditions. Since oxidative stress seems to be a major event in cataract formation, supply of anti-oxidant may postpone the progression of such disorders.


Assuntos
Catarata/genética , Diabetes Mellitus Experimental/complicações , Galactosemias/complicações , Perfilação da Expressão Gênica , Análise de Sequência com Séries de Oligonucleotídeos , Animais , Apoptose/genética , Catarata/metabolismo , Catarata/patologia , DNA Complementar/genética , Diabetes Mellitus Experimental/induzido quimicamente , Regulação para Baixo/genética , Galactose/farmacologia , Galactosemias/induzido quimicamente , Fator de Crescimento Insulin-Like I/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Cristalino/química , Cristalino/metabolismo , Cristalino/patologia , NF-kappa B/genética , Peroxidases/metabolismo , Peroxirredoxinas , Reação em Cadeia da Polimerase , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/isolamento & purificação , Ratos , Ratos Sprague-Dawley , Fator de Crescimento Transformador beta/genética , Regulação para Cima/genética , Proteína X Associada a bcl-2
15.
Biochem Biophys Res Commun ; 314(4): 1050-6, 2004 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-14751239

RESUMO

Aldose reductase (AR) has been implicated as a major contributor to the pathogenesis of diabetic cataracts. AR activation generates osmotic and oxidative stresses via the polyol pathway and induces cell death signals. Antioxidant protein 2 (AOP2) protects cells from oxidative stress. We investigated the effect of AR overexpression on polyol accumulation and on hyperglycemic oxidative stress and osmotic stress, as well as the effects of these stresses on human lens epithelial cell (hLEC) survival. hLECs overexpressing the AR became apoptotic during hyperglycemia and showed elevated levels of intracellular polyols. Glutathione and AOP2 levels were significantly decreased in these cells. Interestingly, supply of AOP2 and/or the AR inhibitor fidarestat protected the cells against hyperglycemia-induced death. Overexpression of AR increased osmotic and oxidative stresses, resulting in increased apoptosis in hLECs. Because AOP2 protects hyperglycemia-induced hLEC apoptosis, this molecule may have the potential to prevent hyperglycemia-mediated complications in diabetes.


Assuntos
Aldeído Redutase/metabolismo , Apoptose/fisiologia , Cristalino/citologia , Pressão Osmótica , Estresse Oxidativo , Polímeros/metabolismo , Aldeído Redutase/química , Aldeído Redutase/fisiologia , Sequência de Aminoácidos , Células Cultivadas , Células Epiteliais/citologia , Células Epiteliais/enzimologia , Humanos , Cristalino/enzimologia , Dados de Sequência Molecular , Proteínas Recombinantes de Fusão/metabolismo
16.
Br J Ophthalmol ; 86(12): 1363-6, 2002 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-12446366

RESUMO

AIM: To examine the relation between aldose reductase (AR) and the development and progression of diabetic retinopathy by comparing the erythrocyte AR levels with the prevalence of diabetic retinopathy in NIDDM patients. METHODS: A clinic based cross sectional study was used. 611 NIDDM patients and 73 controls were enrolled. Erythrocyte AR levels were determined by ELISA. These AR levels were then correlated with patient age, duration of diabetes, and HbA(1c) levels. AR levels were also correlated with the prevalence of diabetic retinopathy in the entire NIDDM patient group and in three subgroups formed by separating the NIDDM patients by their duration of diabetes. The prevalence of diabetic retinopathy significantly increased with increased erythrocyte AR levels in patients with duration of diabetes of less than 10 years. A similar, but non-significant correlation between the prevalence of retinopathy and increased erythrocyte AR levels was observed in patients with diabetes duration of 10-20 and >/=20 years. RESULTS: The prevalence of diabetic retinopathy increased with increased erythrocyte AR levels in NIDDM patients with a duration of diabetes of less than 10 years. CONCLUSION: It was suggested that the inhibition of AR in patients with early NIDDM might be beneficial in reducing the development of diabetic retinopathy.


Assuntos
Aldeído Redutase/análise , Diabetes Mellitus Tipo 2/enzimologia , Retinopatia Diabética/enzimologia , Eritrócitos/enzimologia , Adulto , Fatores Etários , Biomarcadores/análise , Estudos Transversais , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Retinopatia Diabética/sangue , Retinopatia Diabética/complicações , Ensaio de Imunoadsorção Enzimática , Feminino , Hemoglobina A/análise , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo
17.
J Diabetes Complications ; 16(5): 363-70, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-12200082

RESUMO

Galactose-fed dogs develop retinal capillary changes similar to diabetic retinopathy with pericyte degeneration as the initial lesion. This is followed by the formation of microaneurysms, hemorrhages, and some areas of acellularity. To investigate the mechanisms for selective pericyte degeneration, retinal capillary pericytes and endothelial cells isolated from beagle dog retina were cultured for 2 weeks in Dulbecco's modified Eagle's medium (DMEM) containing 50 mM D-galactose. Apoptosis was detected in pericytes but not endothelial cells by in situ terminal deoxynucleotidyl transferase (TdT)-mediated biotin-dUTP nick end labelling (TUNEL) staining and the DNA fragmentation assay on agarose gel electrophoresis. This apoptosis was prevented by the addition of the aldose reductase inhibitor AL 1576 to the culture medium containing galactose. Apoptosis was not observed when pericytes were similarly cultured in control DMEM medium. These data support the premise that the selective degeneration of retinal capillary pericytes observed in galactose-fed dogs is linked to increased aldose reductase activity in these cells.


Assuntos
Aldeído Redutase/genética , Apoptose/efeitos dos fármacos , Capilares/patologia , Galactitol/metabolismo , Galactose/toxicidade , Pericitos/patologia , Vasos Retinianos/efeitos dos fármacos , Animais , Capilares/efeitos dos fármacos , Células Cultivadas , Cães , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Masculino , Pericitos/efeitos dos fármacos , Pericitos/metabolismo , Vasos Retinianos/patologia
18.
J Mol Biol ; 320(5): 1053-63, 2002 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-12126624

RESUMO

Human involucrin (hINV), first appears in the cytosol of keratinocytes and ultimately cross-linked to membrane proteins via transglutaminase and forms a protective barrier as an insoluble envelope beneath the plasma membrane. Although the function and evolution of involucrin is known, the regulation of its gene expression is not well understood. An analysis of the hINV gene sequence, upstream of the transcription start site (-534 to +1 nt) revealed the presence of potential sites for binding of lens epithelium-derived growth factor (LEDGF); stress response element (STRE; A/TGGGGA/T) and heat shock element (HSE; nGAAn). We reported earlier that LEDGF activates stress-associated genes by binding to these elements and elevates cellular resistance to various stresses. Here, gel-shift and super-shift assays confirm the binding of LEDGF to the DNA fragments containing HSEs and STREs that are present in the involucrin gene promoter. Furthermore, hINV promoter linked to CAT reporter gene, cotransfected in human corneal simian virus 40-transformed keratinocytes (HCK), was transactivated by LEDGF significantly. In contrast, the activity of hINV promoter bearing mutations at the WT1 (containing HSE and STRE), WT2 (containing STRE) and WT3 (containing STRE) binding sites was diminished. In addition, in HCK cell over-expressing LEDGF, the levels of hINV mRNA and hINV protein are increased by four to five-fold. LEDGF is inducible to oxidants. Cells treated with 12-O-tetradecanoyl-phorbol-13-acetate (TPA), known to stimulate production of H(2)O(2), showed higher levels of LEDGF mRNA. Furthermore, our immunohistochemical studies revealed that hINV protein is found in the cytoplasm of HCK cells over-expressing LEDGF, but not detectable in the normal HCK cells or HCK cells transfected with vector. This regulation appears to be physiologically important, as over-expression of HCK with LEDGF increases the expression of the endogenous hINV gene and may provide new insight to understand the molecular mechanism of transcriptional regulation of this gene. LEDGF may play an important role in establishing an important barrier in corneal keratinocytes by maintaining epidermal turn-over rate, and protecting HCKs against stress.


Assuntos
Substâncias de Crescimento/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular , Proteínas de Membrana/genética , Regiões Promotoras Genéticas , Precursores de Proteínas/genética , Ativação Transcricional , Animais , Sequência de Bases , Sítios de Ligação , Biomarcadores , Células COS , Diferenciação Celular , Linhagem Celular Transformada , Chlorocebus aethiops , Sequência Consenso , Citoplasma , DNA Complementar , Regulação para Baixo , Proteínas de Fluorescência Verde , Substâncias de Crescimento/genética , Humanos , Queratinócitos , Proteínas Luminescentes/genética , Dados de Sequência Molecular , Acetato de Tetradecanoilforbol/farmacologia , Transfecção
19.
Gene Ther ; 9(8): 495-502, 2002 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11948374

RESUMO

The phenotypic alteration of interstitial fibroblasts into 'myofibroblasts', acquiring characteristics of both fibroblasts and smooth muscle cells is a key event in the formation of tubulointerstitial fibrosis. The up-regulation of the early growth response gene 1 (Egr-1) preceded the increased interstitial expression of alpha-smooth muscle actin (alphaSMA), a marker of phenotypic changes, in obstructed kidney, a model of interstitial fibrosis. To target Egr-1 expression in the interstitium of obstructed kidneys, we introduced a DNA enzyme for Egr-1 (ED5) or scrambled DNA (SCR) into interstitial fibroblasts by electroporation-mediated gene transfer. Northern blot analysis confirmed an increase in the cortical mRNA expression of Egr-1 in the obstructed kidneys from untreated or SCR-treated rats, while ED5 transfection blocked Egr-1 expression with a concomitant reduction in TGF-beta, alphaSMA and type I collagen mRNA expression. Consequently, ED5 inhibited interstitial fibrosis. In conclusion, electroporation-mediated retrograde gene transfer can be an ideal vehicle into interstitial fibroblasts, and molecular intervention of Egr-1 in the interstitium may become a new therapeutic strategy for interstitial fibrosis.


Assuntos
DNA de Cadeia Simples/genética , Proteínas de Ligação a DNA/genética , Terapia Genética/métodos , Proteínas Imediatamente Precoces , Rim/metabolismo , Fatores de Transcrição/genética , Obstrução Ureteral/terapia , Actinas/genética , Animais , Linhagem Celular , Colágeno Tipo I/genética , Proteína 1 de Resposta de Crescimento Precoce , Eletroporação , Fibrose , Expressão Gênica , RNA Mensageiro/metabolismo , Ratos , Fator de Crescimento Transformador beta/genética
20.
Oncol Rep ; 9(1): 65-8, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-11748457

RESUMO

The p53 tumor suppressor gene plays an important role in protecting cells from developing undesirable proliferation. The mutant p53 gene or malfunctioning p53 protein found in more than 50% of cancer cells impedes DNA repair or apoptosis induction. This may be why some cancers gain resistance to chemotherapy and radiation and become more resistant after frequent cancer treatments. A non-toxic p53 gene activator would induce cancer cell apoptosis and help damaged cancer cells to recover. Therefore, the combination use of chemotherapeutics or radiation with a non-toxic p53 gene activator will be crucial in cancer therapy, damaging DNA with chemotherapeutics or radiation on the one hand and promoting apoptosis induction with p53 gene activator on the other. This strategy would be most efficient for remission induction and maintenance in cancer therapy. Antineoplastons are naturally occurring peptides and amino acid derivatives that control neoplastic growth. Antineoplaston A10 and AS2-1 are chemically identified and synthesized antineoplastons proven to inhibit cancer cell growth by arresting the cell cycle in the G1 phase and inhibiting tumor growth by reducing mitosis. These agents are thought to be good candidates for clinically easily applicable non-toxic p53 gene activators. Our cases of advanced cancer responded well to combination treatment using chemotherapeutics and irradiation with antineoplaston A10 and AS2-1 in clinical trials being conducted in Kurume University Hospital. We describe herein the clinical cases and discuss the possible mechanism of action of this combination therapy.


Assuntos
Benzenoacetamidas , Neoplasias do Colo/tratamento farmacológico , Terapia Genética/métodos , Glutamina/análogos & derivados , Glutamina/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Fenilacetatos/uso terapêutico , Piperidonas/uso terapêutico , Adulto , Antineoplásicos/uso terapêutico , Apoptose , Ciclo Celular , Neoplasias do Colo/diagnóstico por imagem , Neoplasias do Colo/patologia , Terapia Combinada , Combinação de Medicamentos , Expressão Gênica , Genes Supressores de Tumor , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Indução de Remissão , Tomografia Computadorizada por Raios X , Proteína Supressora de Tumor p53/metabolismo
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