RESUMO
BACKGROUND: Grade 3 neuroendocrine neoplasms (NENs) of gastroenteropancreatic (GEP) origin with Ki-67 indices <55% do not respond well to platinum-based chemotherapy. The combination of capecitabine and temozolomide (CAPTEM) has shown favorable responses in grade 1-2 NENs, but has rarely been studied in patients with grade 3 NENs. PATIENTS AND METHODS: This open-label, single-arm phase II trial included patients with unresectable or metastatic grade 3 NENs of GEP origin with Ki-67 indices <55% enrolled between June 2017 and July 2020. Patients received oral capecitabine 750 mg/m2 twice daily on days 1 to 14 and oral temozolomide 200 mg/m2 once daily on days 10 to 14 every 4 weeks. Histologic findings were centrally reviewed after the completion of enrollment. The primary endpoint was overall response rate, and the secondary endpoints were progression-free survival (PFS), overall survival (OS), and adverse events. RESULTS: Of the 30 patients included in the full analysis set, 1 (3.3%) achieved complete response, 8 (26.7%) had partial responses, and 14 (46.7%) had stable disease, making the overall response rate 30.0%. At a median follow-up of 19.2 months, the median PFS was 5.9 months and the median OS was not reached. Patients with well-differentiated NENs showed significantly better median PFS (9.3 months versus 3.5 months, P = 0.005) and median OS (not reached versus 6.2 months, P = 0.004) than patients with poorly differentiated tumors. Expression of O6-methyl-guanine methyltransferase protein did not correlate with clinical outcomes. The most common grade 3-4 adverse events were thrombocytopenia (10%), anemia (6.7%), and nausea (6.7%). CONCLUSIONS: CAPTEM was effective and well tolerated in patients with grade 3 GEP-NENs with Ki-67 indices <55%, with superior efficacy outcomes compared with the historical controls receiving platinum-based chemotherapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Tumores Neuroendócrinos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Capecitabina/efeitos adversos , Humanos , Antígeno Ki-67 , Tumores Neuroendócrinos/tratamento farmacológico , Temozolomida/uso terapêuticoRESUMO
Lysine-specific demethylase 1 (LSD1), which has been considered as a potential therapeutic target in human cancer, has been known to regulate many biological functions through its non-histone substrates. Although LSD1-induced hypoxia-inducible factor alpha (HIF1α) demethylation has recently been proposed, the effect of LSD1 on the relationship between HIF1α post-translational modifications (PTMs) and HIF1α-induced tumor angiogenesis remains to be elucidated. Here, we identify a new methylation site of the HIF1α protein antagonized by LSD1 and the interplay between HIF1α protein methylation and other PTMs in regulating tumor angiogenesis. LSD1 demethylates HIF1α at lysine (K) 391, which protects HIF1α against ubiquitin-mediated protein degradation. LSD1 also directly suppresses PHD2-induced HIF1α hydroxylation, which has a mutually dependent interplay with Set9-mediated HIF1α methylation. Moreover, the HIF1α acetylation that occurs in a HIF1α methylation-dependent manner is inhibited by the LSD1/NuRD complex. HIF1α stabilized by LSD1 cooperates with CBP and MTA1 to enhance vascular endothelial growth factor (VEGF)-induced tumor angiogenesis. Thus, LSD1 is a key regulator of HIF1α/VEGF-mediated tumor angiogenesis by antagonizing the crosstalk between PTMs involving HIF1α protein degradation.
Assuntos
Neoplasias da Mama/irrigação sanguínea , Histona Desmetilases/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Células HEK293 , Xenoenxertos , Histona Desmetilases/genética , Células Endoteliais da Veia Umbilical Humana , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Transcrição Gênica , Transfecção , Ubiquitina/metabolismoRESUMO
The downstream events and target genes of p53 in the process of senescence are not fully understood. Here, we report a novel function of the forkhead transcription factor Foxp3, which is a key player in mediating T-cell inhibitory functions, in p53-mediated cellular senescence. The overexpression of Foxp3 in mouse embryonic fibroblasts (MEFs) accelerates senescence, whereas Foxp3 knockdown leads to escape from p53-mediated senescence in p53-expressing MEFs. Consistent with these results, Foxp3 expression resulted in the induction of senescence in epithelial cancer cells, including MCF7 and HCT116 cells. Foxp3 overexpression also increased the intracellular levels of reactive oxygen species (ROS). The ROS inhibitor N-acetyl-l-cysteine rescued cells from Foxp3-expression-induced senescence. Furthermore, the elevated ROS levels that accompanied Foxp3 overexpression were paralleled by an increase in p21 expression. Knockdown of p21 in Foxp3-expressing MEFs abrogated the Foxp3-dependent increase in ROS levels, indicating that Foxp3 acts through the induction of p21 and the subsequent ROS elevation to trigger senescence. Collectively, these results suggest that Foxp3 is a downstream target of p53 that is sufficient to induce p21 expression, ROS production and p53-mediated senescence.
Assuntos
Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Fibroblastos/citologia , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Linhagem Celular , Senescência Celular , Fibroblastos/metabolismo , Regulação da Expressão Gênica , Células HCT116 , Humanos , Células MCF-7 , Camundongos , Espécies Reativas de Oxigênio/metabolismoRESUMO
PTEN is one of the most frequently mutated or deleted tumor suppressors in human cancers. NEDD4-1 was recently identified as the E3 ubiquitin ligase for PTEN; however, a number of important questions remain regarding the role of ubiquitination in regulating PTEN function and the mechanisms by which PTEN ubiquitination is regulated. In the present study, we demonstrated that p34, which was identified as a binding partner of NEDD4-1, controls PTEN ubiquitination by regulating NEDD4-1 protein stability. p34 interacts with the WW1 domain of NEDD4-1, an interaction that enhances NEDD4-1 stability. Expression of p34 promotes PTEN poly-ubiquitination, leading to PTEN protein degradation, whereas p34 knockdown results in PTEN mono-ubiquitination. Notably, an inverse correlation between PTEN and p34/NEDD4-1 levels was confirmed in tumor samples from colon cancer patients. Thus, p34 acts as a key regulator of the oncogenic behavior of NEDD4-1 and PTEN.
Assuntos
Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Proteínas Nucleares/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Transativadores/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Complexos Endossomais de Distribuição Requeridos para Transporte/antagonistas & inibidores , Complexos Endossomais de Distribuição Requeridos para Transporte/genética , Células HEK293 , Humanos , Células MCF-7 , Ubiquitina-Proteína Ligases Nedd4 , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/genética , PTEN Fosfo-Hidrolase/genética , Estabilidade Proteica , Estrutura Terciária de Proteína , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Transativadores/antagonistas & inibidores , Transativadores/genética , Fatores de Transcrição , Ubiquitina-Proteína Ligases/antagonistas & inibidores , Ubiquitina-Proteína Ligases/genética , UbiquitinaçãoRESUMO
Janus kinase (JAK) is one of the main upstream activators of signal transducers and activators of transcription (STAT) that are constitutively activated in various malignancies and are associated with cell growth, survival, and carcinogenesis. Here, we investigated the role of JAKs in colorectal cancer in order to develop effective therapeutic targets for INCB018424, which is the first JAK1/2 inhibitor to be approved by FDA. After examining the basal expression levels of phospho-JAK1 and phospho-JAK2, we measured the effects of INCB018424 on the phosphorylation of JAK1/2 using western blot analysis. Cell viability was determined using the trypan blue exclusion assay. The cell death mechanism was identified by the activation of caspase 3 using western blot and annexin V staining. The basal levels of phospho-JAK1 and phospho-JAK2 were cancer cell type dependent. Colorectal cancer cell lines that phosphorylate both JAK1 and JAK2 include DLD-1 and RKO. INCB018424 inactivates both JAK1 and JAK2 in DLD-1 cells but inactivates only JAK1 in RKO cells. Cell death was proportional to the inactivation of JAK1 but not JAK2. INCB018424 causes caspase-dependent cell death, which is prevented by treatment with z-VAD. The inhibition of JAK1 phosphorylation seemed sufficient to allow INCB018424-mediated apoptosis. JAK1 is a key molecule that is involved in colon cancer cell survival and the inhibition of JAK1 by INCB01424 results in caspase-dependent apoptosis in colorectal cancer cells. The use of selective JAK1 inhibitors could be an attractive therapy against colorectal cancer, but further clinical investigations are needed to test this possibility.
Assuntos
Apoptose/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Janus Quinase 1/antagonistas & inibidores , Pirazóis/farmacologia , Linhagem Celular Tumoral , Neoplasias do Colo/patologia , Humanos , Janus Quinase 1/metabolismo , Nitrilas , Fosforilação , Pirimidinas , Fatores de Transcrição STAT/fisiologia , Transdução de SinaisRESUMO
BACKGROUND: Surrogate biomarkers for metastatic colorectal cancer (mCRC) are urgently needed to achieve the best outcomes for targeted therapy. METHODS: A clinical association analysis was performed to examine the three single-nucleotide polymorphisms (SNPs) that were previously proposed as markers of chemosensitivity to the cetuximab (124 patients) and bevacizumab regimens (100 patients) in mCRC patients. In addition, biological correlations were examined for the candidate SNPs in terms of their regulatory pathway. RESULTS: For cetuximab regimens, patients homozygous for the wild-type alleles (GG) of LIFR rs3729740 exhibited a 1.9 times greater overall response rate (ORR) and 1.4 months longer progression-free survival (PFS) than those homozygous or heterozygous for the mutant allele (GA and AA; P=0.022 and 0.027, respectively). For bevacizumab regimens, patients homozygous for the minor alleles (TT) of ANXA11 rs1049550 exhibited an ORR twice as high as those homozygous or heterozygous for the ancestral allele (CC and CT; P=0.031). Overall response rate gain was achieved up to 10% in patients with wild-type LIFR rs3729740 patients either with wild-type KRAS or skin toxicity (P=0.001) respectively. Specifically in clones treated with cetuximab and bevacizumab regimens, active p-ERK and MMP-9 expressions were significantly reduced in clones expressing wild-type LIFR rs3729740 (P=0.044) and in those expressing minor-type ANXA11 rs1049550 (P=0.007), respectively. CONCLUSION: LIFR rs3729740 and possibly ANXA11 rs1049550 may be useful as biomarkers for predicting whether mCRC patients are sensitive to relevant target regimens, although further validation in large cohorts is needed.
Assuntos
Anexinas/genética , Neoplasias Colorretais/tratamento farmacológico , Subunidade alfa de Receptor de Fator Inibidor de Leucemia/genética , Terapia de Alvo Molecular , Metástase Neoplásica/tratamento farmacológico , Adulto , Idoso , Inibidores da Angiogênese/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab , Biomarcadores Tumorais/genética , Cetuximab , Neoplasias Colorretais/genética , Intervalo Livre de Doença , MAP Quinases Reguladas por Sinal Extracelular/biossíntese , MAP Quinases Reguladas por Sinal Extracelular/genética , Feminino , Genótipo , Humanos , Masculino , Metaloproteinase 9 da Matriz/biossíntese , Metaloproteinase 9 da Matriz/genética , Pessoa de Meia-Idade , Metástase Neoplásica/genética , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas p21(ras) , Proteínas ras/genéticaRESUMO
The BCR-ABL fusion transcript encodes the BCR-ABL tyrosine kinase (TK), which causes chronic myelogenous leukemia (CML). Although the TK inhibitor imatinib mesylate, which targets the BCR-ABL protein, has been proven to be effective in controlling leukemic growth, imatinib resistance has been observed with disease relapse because of point mutations in the ABL gene that inhibit imatinib efficacy. In this study, we designed oligodeoxyribozymes (DNAzymes) that specifically target and cleave both the junction sequence and the site of the point mutation (T315I), conferring imatinib resistance in BCR-ABL mRNA. DNAzymes significantly induced apoptosis and inhibited proliferation in wild-type and T315I-mutant BCR-ABL-positive cells. Selective cleavage of T315I-mutant ABL mRNA by DNAzyme (T315I Dz) led to cell cycle arrest in G0/G1 phase, with induction of caspase-3/-7 in imatinib-resistant BCR-ABL-positive cells harboring the T315I mutation. Moreover, cotreatment with the DNAzyme targeting the T315I mutation and imatinib resulted in enhanced inhibition of proliferation and induction of apoptosis in T315I leukemic cells as compared with imatinib alone, thereby antagonizing imatinib resistance in CML cells bearing T315I-mutant BCR-ABL. Therefore, cleavage of T315I-mutant ABL mRNA by DNAzyme combined with imatinib treatment may be an alternative approach to overcoming imatinib resistance in leukemic cells.
Assuntos
Apoptose/genética , DNA Catalítico/genética , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Mutação Puntual , Animais , Apoptose/efeitos dos fármacos , Pareamento de Bases , Sequência de Bases , Benzamidas/farmacologia , Catálise , Linhagem Celular Tumoral , Sobrevivência Celular/genética , DNA Catalítico/metabolismo , Proteínas de Fusão bcr-abl/química , Proteínas de Fusão bcr-abl/metabolismo , Regulação Leucêmica da Expressão Gênica , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Camundongos , Piperazinas/farmacologia , Pirimidinas/farmacologia , Transcrição GênicaRESUMO
Non-small cell lung cancer (NSCLC) harboring an activating epidermal growth factor receptor (EGFR) mutation shows good and rapid response to EGFR tyrosine kinase inhibitors (TKIs). We prospectively evaluated the efficacy of EGFR TKI for metastatic brain tumors in NSCLC patients harboring EGFR mutation. This was an open-label, single-institution, phase II study. Patients diagnosed with NSCLC harboring EGFR mutation and measurable metastatic brain tumors were eligible. They received either erlotinib or gefitinib once a day. Out of total 28 patients enrolled, 23 patients (83%) showed a partial response (PR) and 3 patients (11%) did stable disease (SD), giving a disease control rate of 93%. Median progression free survival (PFS) and overall survival (OS) were 6.6 months (95% CI, 3.8-9.3 months) and 15.9 months (95% CI, 7.2-24.6 months), respectively. There was no difference in PFS and OS according to EGFR TKIs used. After discontinuation of the treatment, 14 patients (50%) received local therapy for metastatic brain tumors during their disease course, either whole brain radiotherapy or radiosurgery, giving a local therapy-free interval of 12.6 months (95% CI, 7.6-17.6 months). EGFR TKI therapy might be the treatment of choice for metastatic brain tumors in NSCLC patients harboring an activating EGFR mutation.
Assuntos
Antineoplásicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Quinazolinas/farmacologia , Adulto , Idoso , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/secundário , Intervalo Livre de Doença , Receptores ErbB/antagonistas & inibidores , Cloridrato de Erlotinib , Éxons , Feminino , Gefitinibe , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Mutação Puntual , Quinazolinas/uso terapêutico , Deleção de Sequência , Resultado do TratamentoRESUMO
Despite great potential benefits, there are concerns about the possible harm from medical imaging including the risk of radiation-related cancer. There are particular concerns about computed tomography (CT) scans in children because both radiation dose and sensitivity to radiation for children are typically higher than for adults undergoing equivalent procedures. As direct empirical data on the cancer risks from CT scans are lacking, the authors are conducting a retrospective cohort study of over 240,000 children in the UK who underwent CT scans. The main objective of the study is to quantify the magnitude of the cancer risk in relation to the radiation dose from CT scans. In this paper, the methods used to estimate typical organ-specific doses delivered by CT scans to children are described. An organ dose database from Monte Carlo radiation transport-based computer simulations using a series of computational human phantoms from newborn to adults for both male and female was established. Organ doses vary with patient size and sex, examination types and CT technical settings. Therefore, information on patient age, sex and examination type from electronic radiology information systems and technical settings obtained from two national surveys in the UK were used to estimate radiation dose. Absorbed doses to the brain, thyroid, breast and red bone marrow were calculated for reference male and female individuals with the ages of newborns, 1, 5, 10, 15 and 20 y for a total of 17 different scan types in the pre- and post-2001 time periods. In general, estimated organ doses were slightly higher for females than males which might be attributed to the smaller body size of the females. The younger children received higher doses in pre-2001 period when adult CT settings were typically used for children. Paediatric-specific adjustments were assumed to be used more frequently after 2001, since then radiation doses to children have often been smaller than those to adults. The database here is the first detailed organ-specific paediatric CT scan database for the UK. As well as forming the basis for the UK study, the results and description of the methods will also serve as a key resource for paediatric CT scan studies currently underway in other countries.
Assuntos
Bases de Dados Factuais , Especificidade de Órgãos , Doses de Radiação , Sistema de Registros , Tomografia Computadorizada por Raios X/estatística & dados numéricos , Contagem Corporal Total/estatística & dados numéricos , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Reino Unido/epidemiologia , Adulto JovemRESUMO
AIM: To evaluate the clinical outcome and the survival benefits of transarterial chemoembolization (TACE) for unresectable intrahepatic cholangiocarcinoma (ICC) compared with supportive therapy. MATERIALS AND METHODS: From January 1996 to April 2009, a total of 155 patients with unresectable ICC met the entry criteria and underwent TACE (72 patients) or supportive treatment (83 patients). Their survival was the primary end point. RESULTS: The baseline patients and tumour characteristics were well-balanced in the two groups. The median number of sessions per patient was 2.5 (range 1-17 sessions) in the TACE group. After TACE, the incidence of significant (≥ grade 3) haematological and non-haematological toxicities was 13 and 24%, respectively, and no patients died within 30 days following TACE. The objective tumour regression (≥ partial response) was achieved in 23% of the patients in the TACE group. The Kaplan-Meier survival analysis showed that the survival period was significantly longer in the TACE group (median 12.2 months) than in the symptomatic treatment (median 3.3 months) group (p < 0.001). CONCLUSIONS: TACE is safe and offers greater survival benefits than supportive treatment for the palliative treatment of unresectable ICC.
Assuntos
Ductos Biliares Intra-Hepáticos , Quimioembolização Terapêutica/métodos , Cuidados Paliativos/métodos , Neoplasias dos Ductos Biliares/terapia , Colangiocarcinoma/terapia , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/terapia , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
BACKGROUND: Advanced biliary cancer is often treated with fluoropyrimidine-based chemotherapy. In this study, we evaluated the efficacy and tolerability of a combination of S-1, an oral fluoropyrimidine prodrug, and oxaliplatin in patients with metastatic biliary cancer. METHODS: Patients with histologically confirmed metastatic biliary cancer and no history of radiotherapy or chemotherapy were enrolled. Oxaliplatin was administered intravenously (130 mg m(-2)), followed by 14-day administration of oral S-1 (40 mg m(-2) twice daily) with a subsequent 7-day rest period every 21 days. Pharmacokinetic analysis of S-1 was performed at cycle 1. Patients were genotyped for CYP2A6 polymorphisms ((*)1, (*)4, (*)7, (*)9 or (*)10), and pharmacokinetic and clinical parameters compared according to the CYP2A6 genotype. RESULTS: In total, 49 patients were evaluated, who received a median of four cycles. The overall response rate was 24.5%. Median progression-free and overall survival was 3.7 and 8.7 months, respectively. The most common haematological grade 3 out of 4 toxicity was neutropenia (14%), while non-hematological grade 3 out of 4 toxicities included anorexia (14%), nausea (12%), asthenia (10%), vomiting (10%), and diarrhoea (4%). Biotransformation of S-1 (AUC(0-24 h) of 5-fluorouracil/AUC(0-24 h) of tegafur) was 1.85-fold higher for the *1/*1 group than for the other groups (90% confidence interval 1.37-2.49). Diarrhoea (P=0.0740), neutropenia (P=0.396), and clinical efficacy (response rate, P=0.583; PFS, P=0.916) were not significantly associated with CYP2A6 genotype, despite differences in 5-FU exposure. CONCLUSION: The combination of S-1 and oxaliplatin appears to be active and well tolerated in patients with metastatic biliary cancer, and thus is feasible as a therapeutic modality. CYP2A6 genotypes are associated with differences in the biotransformation of S-1. However, the impact of the CYP2A6 polymorphism on variations in clinical efficacy or toxicity requires further evaluation.
Assuntos
Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Hidrocarboneto de Aril Hidroxilases/genética , Neoplasias do Sistema Biliar/tratamento farmacológico , Neoplasias do Sistema Biliar/genética , Compostos Organoplatínicos/administração & dosagem , Ácido Oxônico/administração & dosagem , Tegafur/administração & dosagem , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Neoplasias do Sistema Biliar/metabolismo , Neoplasias do Sistema Biliar/patologia , Biomarcadores Farmacológicos/análise , Biomarcadores Farmacológicos/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/fisiologia , Citocromo P-450 CYP2A6 , Combinação de Medicamentos , Feminino , Humanos , Inativação Metabólica/genética , Inativação Metabólica/fisiologia , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/efeitos adversos , Compostos Organoplatínicos/farmacocinética , Oxaliplatina , Ácido Oxônico/efeitos adversos , Ácido Oxônico/farmacocinética , Polimorfismo de Nucleotídeo Único/fisiologia , Tegafur/efeitos adversos , Tegafur/farmacocinética , Resultado do Tratamento , Adulto JovemRESUMO
A piezoelectric valve, which has a flow rate of about 463 mbar l/s, has been installed to fuel the Korea Superconducting Tokamak Advanced Research (KSTAR) tokamak. The valve flow rate is in situ calibrated by analyzing the pressure rise curve while fueling the vessel at a constant rate. The calibration method and results are presented. In addition to the flow rate, other vacuum system parameters, such as the pumping speed and the vessel volume, were experimentally obtained. Based on these measurements, a KSTAR vacuum system simulator was developed to calculate the valve drive signal to obtain a programmed pressure trace. An arbitrarily shaped pressure trace was successfully controlled in KSTAR with this hardware and software system.
RESUMO
BACKGROUND AND STUDY AIMS: Magnetic resonance cholangiopancreatography (MRCP) is rapidly replacing diagnostic endoscopic retrograde cholangiopancreatography (ERCP) in various pancreaticobiliary diseases. This study was designed to evaluate the accuracy of MRCP in detection of hepatolithiasis and accompanying biliary strictures. PATIENTS AND METHODS: A prospective study over 2 years was conducted in 66 patients with primary intrahepatic stones. All patients with hepatolithiasis underwent percutaneous transhepatic cholangioscopy (PTC) within 2 weeks of the MRCP examination. The MRCP findings were compared with those of PTC as the reference standard for assessing the location of intrahepatic stones and the presence or absence of accompanying biliary strictures. RESULTS: The sensitivity, specificity, and accuracy of MRCP for detecting and locating intrahepatic stones were 97 %, 99 %, and 98 %, respectively. The sensitivity, specificity, and accuracy of MRCP for detecting and locating intrahepatic bile duct strictures were 93 %, 97 %, and 97 %, respectively. During PTC, six of the 66 patients (9 %) were found on histology to have intraductal cholangiocarcinoma in stone-bearing ducts, which had not been suspected on MRCP. CONCLUSIONS: In this study, MRCP allowed intrahepatic stones and accompanying biliary strictures to be located accurately. MRCP may therefore be able to replace diagnostic ERCP in patients with primary intrahepatic stones. However, MRCP had a limited ability to reveal concurrent intraductal cholangiocarcinoma associated with hepatolithiasis.
Assuntos
Ductos Biliares Intra-Hepáticos/patologia , Colangiopancreatografia por Ressonância Magnética , Litíase/diagnóstico , Hepatopatias/diagnóstico , Colangiopancreatografia Retrógrada Endoscópica , Constrição Patológica/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Sensibilidade e EspecificidadeRESUMO
Secretory phospholipase A2 (PLA2) consists of several 14-kDa isoforms with extensive homology, which makes it difficult to identify a specific isoform. In this study, we have developed and characterized monoclonal antibodies (MAbs) directed specifically against human group V sPLA2 (hVPLA2) derived from cultured hybridomas. These hybridomas were produced from the fusion of BALB/c-derived myeloma s/p20-Ag14 and splenocytes from mice immunized with purified recombinant hVPLA2. Three hybridomas secreting MAbs, MCL-3G1, MCL-2A5, and MCL-1B7, were selected and subcloned on the basis of their specificity to recognize hVPLA2 using solid-phase enzyme-linked immunoadsorbent assay (ELISA). The purified MAbs demonstrated a common pattern of immunoreactivity to hVPLA2, but not to human group IIa isoform (hIIaPLA2). Isotype analysis indicates that these hybridomas are of the IgG1 type. Under reducing conditions, MCL-3G1 sensitively detected hVPLA2 and demonstrated no cross-reactivity to either hIIaPLA2 or group IV cytosolic PLA2. Although specific for hVPLA2, a relatively modest signal was recognized with MCL-1B7 and MCL-2A5. These newly developed MAbs allow for determination of tissue distribution and cell-specific functions of hVPLA2.
Assuntos
Anticorpos Monoclonais/imunologia , Fosfolipases A/imunologia , Animais , Anticorpos Monoclonais/química , Western Blotting , Reações Cruzadas , Ensaio de Imunoadsorção Enzimática , Fosfolipases A2 do Grupo V , Humanos , Hibridomas/química , Imunoglobulina G/análise , Camundongos , Camundongos Endogâmicos BALB C , Fosfolipases A2 , Isoformas de Proteínas/imunologia , Proteínas Recombinantes/imunologiaRESUMO
The medical records of 399 patients who underwent hepatic resection between January 1981 and December 1990 were reviewed. Information regarding the results of the hepatic resection in terms of the operative indication, operative procedure, operative morbidity, and mortality was abstracted. As of the end of 1990, a total of 402 hepatic resections had been completed, including those of 319 primary malignancies, 4 secondary malignancies, 2 gallbladder carcinomas, 42 cases of intrahepatic cholelithiasis, and 35 benign masses. Major hepatic resections were performed on 117 patients (29%), of whom 60 (51%) had histologically proven liver cirrhosis. Minor hepatic resections were performed on the remaining 285 patients (71%). Sepsis was the most frequent complication, which manifested primarily as wound infection (71 cases) or intra-abdominal infection (25 cases). Nonfatal hepatic failure occurred in nine patients with cirrhosis and one patient without cirrhosis. There were 38 operative deaths among the 402 hepatic resections, for an overall operative mortality of 9.4%; 25 of those deaths were due to hepatic failure after the operation, accounting for 66% of the total operative mortality. There was an increasing frequency of hepatic resection during the last 5 years. The indication for resection due to hepatocellular carcinoma increased from 87 to 195 cases. The cumulative data show a decrease in the incidence of complications and the operative mortality rate. In the most recent period, nonlethal postoperative complications occurred in 135 of 286 patients (47%). The overall 1-, 3-, and 5-year survival rates for 172 patients, excluding cases of operative mortality, palliative resection, and re-resection, were 71.0%, 39.8%, and 28.3%, respectively.