RESUMO
BACKGROUND: Chronic rhinosinusitis (CRS) disease control is a global metric of disease status for CRS. While there is broad acceptance that it is an important treatment goal, there has been inconsistency in the criteria used to define CRS control. The objective of this study was to identify and develop consensus around essential criteria for assessment of CRS disease control. METHODS: Modified Delphi methodology consisting of three rounds to review a list of 24 possible CRS control criteria developed by a 12-person steering committee. The core authorship of the multidisciplinary EPOS 2020 guidelines was invited to participate. RESULTS: Thirty-two individuals accepted the invitation to participate and there was no dropout of participants throughout the entire study (3 rounds). Consensus essential criteria for assessment of CRS control were: overall symptom severity, need for CRS-related systemic corticosteroids in the prior 6 months, severity of nasal obstruction, and patient-reported CRS control. Near-consensus items were: nasal endoscopy findings, severity of smell loss, overall quality of life, impairment of normal activities and severity of nasal discharge. Participantsâ™ comments provided insights into caveats of, and disagreements related to, near-consensus items. CONCLUSIONS: Overall symptom severity, use of CRS-related systemic corticosteroids, severity of nasal obstruction, and patient-reported CRS control are widely agreed upon essential criteria for assessment of CRS disease control. Consideration of near-consensus items to assess CRS control should be implemented with their intrinsic caveats in mind. These identified consensus CRS control criteria, together with evidence-based support, will provide a foundation upon which CRS control criteria with wide-spread acceptance can be developed.
Assuntos
Obstrução Nasal , Pólipos Nasais , Rinite , Sinusite , Humanos , Consenso , Qualidade de Vida , Técnica Delphi , Rinite/diagnóstico , Sinusite/diagnóstico , Sinusite/terapia , Corticosteroides , Doença Crônica , Pólipos Nasais/diagnósticoRESUMO
BACKGROUND: Olfactory dysfunction (OD) associated with chronic rhinosinusitis (CRS) remains quite challenging. Instruments to precisely assess olfactory cleft anatomy and their association with olfaction are needed. METHODS: The olfactory cleft endoscopy scale (OCES) was used to assess the olfactory cleft in healthy control subjects and a cohort of patients with CRS. Psychophysical and psychosocial olfactory function were assessed and correlations with OCES scores were measured. RESULTS: Control subjects and subjects with CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP) were enrol- led. OCES correlated with both psychophysical and psychosocial olfaction, as measured by threshold, discrimination and identi- fication (TDI) scores and Questionnaire on Olfactory Disorders (QOD-NS) scores for all case and control subjects combined. OCES improved in both CRS groups postoperatively with the highest correlation seen in postoperative olfaction in CRSwNP patients. CRS patients who achieve near perfect OCES and sinus endoscopy scores after surgery have olfactory metrics that are indistin- guishable from controls regardless of polyp status. CONCLUSIONS: The OCES is a valid olfactory-specific measure that demonstrates strong validity and provides complimentary infor- mation to traditional sinus endoscopy to aid in our understanding of OD associated with CRS.
Assuntos
Pólipos Nasais , Transtornos do Olfato , Rinite , Sinusite , Doença Crônica , Endoscopia , Humanos , Pólipos Nasais/complicações , Pólipos Nasais/cirurgia , Transtornos do Olfato/etiologia , Rinite/complicações , Sinusite/complicações , Sinusite/cirurgia , OlfatoRESUMO
BACKGROUND: Recent literature suggests that concurrent septoplasty during endoscopic sinus surgery (ESS) improves patient outcomes, however, the underlying indications for performing concurrent septoplasty are unknown. The objective of this study was to investigate the relationship between objective radiologic measures of nasal septal deviation with preoperative patient symptomatology and measures of CRS disease severity. We also sought to understand the association of objective radiologic measurements with surgeon performance of concurrent septoplasty during ESS. METHODOLOGY: Seventy-four patients with CRS undergoing ESS were prospectively enrolled. Angles of septal deviation, intranasal areas and volumes were assessed on preoperative computed tomography (CT) scans and correlated with a robust battery of patient reported outcomes measures (PROMs), objective measures of CRS severity including olfaction scores, radiologic and endoscopic staging, and performance of septoplasty. RESULTS: Intranasal areas and volumes demonstrated only weak linear associations with patient-reported nasal congestion, however, angles of septal deviation alone did not correlate with congestion or any other PROM measure. Meanwhile, radiologic septal-related measurements did not correlate with objective measures of CRS disease severity or the performance of a concurrent septoplasty. CONCLUSIONS: Though prior studies demonstrate improved patient outcomes in the setting of concurrent septoplasty during ESS, this study failed to establish an association between preoperative radiologic septal-related measurements and patient symptomatology or surgeon decision to perform septoplasty. Although objective factors to identify patients most likely to benefit from concurrent septoplasty remain unidentified, the potential improvement of surgical recommendations and patient outcomes makes this an important area of continued investigation.
Assuntos
Obstrução Nasal , Septo Nasal , Rinoplastia , Endoscopia , Feminino , Humanos , Masculino , Obstrução Nasal/cirurgia , Septo Nasal/anatomia & histologia , Resultado do TratamentoRESUMO
The European Position Paper on Rhinosinusitis and Nasal Polyps 2020 is the update of similar evidence based position papers published in 2005 and 2007 and 2012. The core objective of the EPOS2020 guideline is to provide revised, up-to-date and clear evidence-based recommendations and integrated care pathways in ARS and CRS. EPOS2020 provides an update on the literature published and studies undertaken in the eight years since the EPOS2012 position paper was published and addresses areas not extensively covered in EPOS2012 such as paediatric CRS and sinus surgery. EPOS2020 also involves new stakeholders, including pharmacists and patients, and addresses new target users who have become more involved in the management and treatment of rhinosinusitis since the publication of the last EPOS document, including pharmacists, nurses, specialised care givers and indeed patients themselves, who employ increasing self-management of their condition using over the counter treatments. The document provides suggestions for future research in this area and offers updated guidance for definitions and outcome measurements in research in different settings. EPOS2020 contains chapters on definitions and classification where we have defined a large number of terms and indicated preferred terms. A new classification of CRS into primary and secondary CRS and further division into localized and diffuse disease, based on anatomic distribution is proposed. There are extensive chapters on epidemiology and predisposing factors, inflammatory mechanisms, (differential) diagnosis of facial pain, allergic rhinitis, genetics, cystic fibrosis, aspirin exacerbated respiratory disease, immunodeficiencies, allergic fungal rhinosinusitis and the relationship between upper and lower airways. The chapters on paediatric acute and chronic rhinosinusitis are totally rewritten. All available evidence for the management of acute rhinosinusitis and chronic rhinosinusitis with or without nasal polyps in adults and children is systematically reviewed and integrated care pathways based on the evidence are proposed. Despite considerable increases in the amount of quality publications in recent years, a large number of practical clinical questions remain. It was agreed that the best way to address these was to conduct a Delphi exercise . The results have been integrated into the respective sections. Last but not least, advice for patients and pharmacists and a new list of research needs are included. The full document can be downloaded for free on the website of this journal: http://www.rhinologyjournal.com.
Assuntos
Pólipos Nasais , Rinite , Sinusite , Doença Aguda , Adulto , Criança , Doença Crônica , Humanos , Pólipos Nasais/diagnóstico , Pólipos Nasais/terapia , Rinite/diagnóstico , Rinite/terapia , Sinusite/diagnóstico , Sinusite/terapiaRESUMO
Translation of drug candidates into clinical settings requires demonstration of preclinical efficacy and formal toxicology analysis for filling an Investigational New Drug (IND) application with the US Food and Drug Administration (FDA). Here, we investigate the membrane-associated glucose response protein 78 (GRP78) as a therapeutic target in leukemia and lymphoma. We evaluated the efficacy of the GRP78-targeted proapoptotic drug bone metastasis targeting peptidomimetic 78 (BMTP-78), a member of the D(KLAKLAK)2-containing class of agents. BMTP-78 was validated in cells from patients with acute myeloid leukemia and in a panel of human leukemia and lymphoma cell lines, where it induced dose-dependent cytotoxicity in all samples tested. Based on the in vitro efficacy of BMTP-78, we performed formal good laboratory practice toxicology studies in both rodents (mice and rats) and nonhuman primates (cynomolgus and rhesus monkeys). These analyses represent required steps towards an IND application of BMTP-78 for theranostic first-in-human clinical trials.
Assuntos
Avaliação Pré-Clínica de Medicamentos , Proteínas de Choque Térmico/genética , Leucemia/tratamento farmacológico , Linfoma/tratamento farmacológico , Peptidomiméticos/administração & dosagem , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Chaperona BiP do Retículo Endoplasmático , Proteínas de Choque Térmico/antagonistas & inibidores , Humanos , Leucemia/patologia , Linfoma/patologia , Macaca fascicularis , Macaca mulatta , Camundongos , Terapia de Alvo Molecular , Peptidomiméticos/efeitos adversos , Primatas , Ratos , Estados Unidos , United States Food and Drug AdministrationRESUMO
BACKGROUND: Patients with chronic rhinosinusitis (CRS) often have comorbid asthma. Prior studies have not examined the impact of CRS or endoscopic sinus surgery (ESS) upon asthma quality of life (QOL) and asthma control using validated outcome metrics. METHODS: Patients with CRS, both with and without polyps, and comorbid asthma completed the Mini Asthma QOL Questionnaire (miniAQLQ) and Asthma Control Test (ACT) at baseline and 6 months postoperatively as part of a multi-institutional, prospective study. RESULTS: Baseline metrics were available on 86 patients. Patients undergoing ESS reported improved miniAQLQ [0.5 (SD ±1.1), 95% CI: 0.2-0.7; P = 0.002] and ACT scores [1.3 (±4.1), 95% CI: 0.2-2.4; P = 0.025]. Uncontrolled baseline asthma (ACT < 20) was present in 51% of patients undergoing ESS. In uncontrolled patients, ESS resulted in a minimal clinically important difference 57% of the time for miniAQLQ scores (≥0.5 points) and 50% of the time for ACT scores (≥3.0 points). After adjustment with linear regression, baseline miniAQLQ scores were worse in patients with comorbid allergy (P = 0.045) and chronic obstructive pulmonary disease (COPD; P = 0.015). Adjusted baseline ACT scores were worse in patients with COPD (P = 0.004). Covariates associated with changes in miniAQLQ scores after ESS were pre-operative corticosteroid dependency (P = 0.011) and change in total SNOT-22 score (P = 0.010). Covariate associated with significantly less improvement in ACT scores was obstructive sleep apnea (P = 0.016). CONCLUSIONS: Patients with CRS often present with uncontrolled asthma, and ESS improves both miniAQLQ and ACT. Approximately half of patients with uncontrolled asthma improve after ESS, yet there are few CRS-specific factors associated with asthma QOL or control or ESS outcomes.
Assuntos
Asma/epidemiologia , Asma/etiologia , Qualidade de Vida , Rinite/epidemiologia , Sinusite/epidemiologia , Asma/diagnóstico , Asma/prevenção & controle , Doença Crônica , Comorbidade , Feminino , Humanos , Masculino , Avaliação de Resultados da Assistência ao Paciente , Vigilância da População , Complicações Pós-Operatórias , Prognóstico , Rinite/cirurgia , Autorrelato , Índice de Gravidade de Doença , Sinusite/cirurgiaRESUMO
BACKGROUND: The purpose of this investigation was to compare a new psychotherapy for bulimia nervosa (BN), integrative cognitive-affective therapy (ICAT), with an established treatment, 'enhanced' cognitive-behavioral therapy (CBT-E). METHOD: Eighty adults with symptoms of BN were randomized to ICAT or CBT-E for 21 sessions over 19 weeks. Bulimic symptoms, measured by the Eating Disorder Examination (EDE), were assessed at baseline, at the end of treatment (EOT) and at the 4-month follow-up. Treatment outcome, measured by binge eating frequency, purging frequency, global eating disorder severity, emotion regulation, self-oriented cognition, depression, anxiety and self-esteem, was determined using generalized estimating equations (GEEs), logistic regression and a general linear model (intent-to-treat). RESULTS: Both treatments were associated with significant improvement in bulimic symptoms and in all measures of outcome, and no statistically significant differences were observed between the two conditions at EOT or follow-up. Intent-to-treat abstinence rates for ICAT (37.5% at EOT, 32.5% at follow-up) and CBT-E (22.5% at both EOT and follow-up) were not significantly different. CONCLUSIONS: ICAT was associated with significant improvements in bulimic and associated symptoms that did not differ from those obtained with CBT-E. This initial randomized controlled trial of a new individual psychotherapy for BN suggests that targeting emotion and self-oriented cognition in the context of nutritional rehabilitation may be efficacious and worthy of further study.
Assuntos
Adaptação Psicológica , Bulimia Nervosa/terapia , Terapia Cognitivo-Comportamental/métodos , Emoções , Modelos Estatísticos , Autoimagem , Adulto , Ansiedade/complicações , Ansiedade/psicologia , Bulimia/psicologia , Bulimia/terapia , Bulimia Nervosa/complicações , Bulimia Nervosa/psicologia , Depressão/complicações , Depressão/psicologia , Prática Clínica Baseada em Evidências , Feminino , Humanos , Análise de Intenção de Tratamento/estatística & dados numéricos , Relações Interpessoais , Entrevista Psicológica , Masculino , Modelos Psicológicos , Entrevista Motivacional , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Educação de Pacientes como Assunto/métodos , Índice de Gravidade de Doença , Inquéritos e QuestionáriosRESUMO
Five laboratory-acquired brucellosis (LAB) cases that occurred in the United States between 2008 and 2011 are presented. The Centers for Disease Control and Prevention (CDC) reviewed the recommendations published in 2008 and the published literature to identify strategies to further prevent LAB. The improved prevention strategies are described.
Assuntos
Brucelose/diagnóstico , Brucelose/prevenção & controle , Controle de Infecções/métodos , Exposição Ocupacional , Adulto , Criança , Feminino , Pessoal de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Estados UnidosRESUMO
High glycaemic feeds are associated with the development of insulin resistance in horses. However, studies that evaluated the effect of high glycaemic feeds used horses that either ranged in body condition from lean to obese or were fed to increase body condition over a period of months; thus, the ability of high glycaemic feeds to induce insulin resistance in lean horses has not been determined. This study evaluated the insulin sensitivity of 18 lean horses fed a 10% (LO; n = 6), 20% (MED; n = 6) or 60% (HI; n = 6) non-structural carbohydrate complementary feed for 90 days. Although both the MED and HI diets increased insulinaemic responses to concentrate feeding in relation to the LO diet (p > 0.05), neither induced insulin resistance, as assessed by glucose tolerance test, following the 90-day feeding trial. Interestingly, the post-feeding suppression of plasma non-esterified fatty acids was less pronounced in HI-fed horses (p = 0.054) on days 30 and 90 of the study, potentially indicating that insulin-induced suppression of adipose tissue lipolysis was reduced. As insulin-resistant animals often have elevated plasma lipid concentrations, it is possible that altered lipid metabolism is an early event in the development of insulin resistance. The effects of high glycaemic feeds that are fed for a longer duration of time, on glucose and lipid metabolism, should be investigated further.
Assuntos
Adaptação Fisiológica/fisiologia , Ração Animal/análise , Dieta/veterinária , Índice Glicêmico/fisiologia , Cavalos/fisiologia , Metabolismo dos Lipídeos/fisiologia , Fenômenos Fisiológicos da Nutrição Animal , Animais , Glicemia , Peso Corporal , Feminino , Teste de Tolerância a Glucose/veterinária , Resistência à Insulina/fisiologia , Período Pós-Prandial , Fatores de TempoRESUMO
To determine the clinical and biologic relevance of cellular kinetics in leukemia, DNA flow cytometric analysis was performed on bone marrow biopsy specimens from 148 previously untreated adult patients with acute myelogenous leukemia. The proportion of cells in synthesis, second growth, and mitosis (S + G2M) ranged from 4% to 33% with a median of 14%. The overall incidence of complete remission was not affected by the pretreatment cell cycle distribution. As in earlier studies, there was a marked decline in remission rate with advancing age from 73% for patients age less than or equal to 50 yr to 50% for those greater than 50 (P less than 0.01). Although not affecting remission induction overall, an increasing proportion of cells in S + G2M phase was favorable in patients under the age of 50 yr, but was associated with a progressive decline in remission rate in older patients (P = 0.01). This age-related divergent effect of cell cycle kinetics on initial response to therapy was confined to the less favorable subgroup of patients with karyotypic abnormalities, whereas patients with normal diploid cytogenetics had a consistently higher response rate regardless of proliferative activity. A positive correlation was also observed between percent of S + G2M cells and the proportion of diploid metaphases in young patients, contrasting with a negative correlation in the older age group. Our observations strongly suggest that the well-recognized prognostic effect of age on remission induction is not entirely host-mediated, but is at least partly an expression of disease-intrinsic differences between young and older patients.
Assuntos
Leucemia Mieloide Aguda/patologia , Adulto , Fatores Etários , Idoso , Ciclo Celular , Citometria de Fluxo , Humanos , Cariotipagem , Leucemia Mieloide Aguda/genética , Pessoa de Meia-Idade , Mitose , PrognósticoRESUMO
The genomic clones encoding lignin peroxidase isozyme H8 and two closely related genes were isolated from Phanerochaete chrysosporium BKM-1767, and their nucleotide sequences were determined. The positions and approximate lengths of introns were found to be highly conserved in all three clones. Analysis of homokaryotic derivatives indicated that the three clones are not alleles of the same gene(s).
Assuntos
Basidiomycota/genética , Clonagem Molecular , Genes Fúngicos , Isoenzimas/genética , Peroxidases/genética , Sequência de Aminoácidos , Sequência de Bases , Basidiomycota/enzimologia , Southern Blotting , Códon , Dados de Sequência Molecular , Homologia de Sequência do Ácido NucleicoRESUMO
A hybrid vector of adeno-associated virus and phage (termed AAVP) has been introduced as a platform for systemic ligand-directed delivery of transgenes to tumors over the past decade. A series of studies have evaluated the AAVP platform for potential theranostic or purely therapeutic applications in several tumor models. Sufficient ligand-directed tumor targeting consistently resulted in specific molecular-genetic imaging and/or anti-tumor responses to 'suicide' transgene delivery. However, efforts to optimize transduction efficiency are still ongoing. Here, we set out to expand the translational utility of AAVP by combining it with gold (Au) nanoparticles in order to generate a 'transducing matrix' for improved targeted gene delivery in solid phase. Targeted AAVP-based solid-phase transduction is superior to conventional transduction in soluble (aqueous) environments. This transducing matrix is stable and can be further modified with additional attributes (for example, magnetization) for targeted imaging and therapeutic gene delivery. Notably, it spontaneously assembles around cells in vitro to markedly enhance transduction capabilities compared with AAVP alone. This versatile nanoplatform may enable new applications of AAVP for transgene delivery in translational settings including, for example, efforts toward complex tissue patterning.
Assuntos
Bacteriófagos , Terapia Genética/métodos , Vetores Genéticos , Transdução Genética/métodos , Transgenes , Adenoviridae , Linhagem Celular Tumoral , HumanosRESUMO
BACKGROUND: Uncontrolled studies have reported encouraging outcomes for patients with high-risk primary breast cancer treated with high-dose chemotherapy and autologous hematopoietic stem cell support. We conducted a prospective randomized trial to compare standard-dose chemotherapy with the same therapy followed by high-dose chemotherapy. PATIENTS AND METHODS: Patients with 10 or more positive axillary lymph nodes after primary breast surgery or patients with four or more positive lymph nodes after four cycles of primary (neoadjuvant) chemotherapy were eligible. All patients were to receive eight cycles of 5-fluorouracil, doxorubicin (Adriamycin), and cyclophosphamide (FAC). Patients were stratified by stage and randomly assigned to receive two cycles of high-dose cyclophosphamide, etoposide, and cisplatin with autologous hematopoietic stem cell support or no additional chemotherapy. Tamoxifen was planned for postmenopausal patients with estrogen receptor-positive tumors and chest wall radiotherapy was planned for all. All P values are from two-sided tests. RESULTS: Seventy-eight patients (48 after primary surgery and 30 after primary chemotherapy) were registered. Thirty-nine patients were randomly assigned to FAC and 39 to FAC followed by high-dose chemotherapy. After a median follow-up of 6.5 years, there have been 41 relapses. In intention-to-treat analyses, estimated 3-year relapse-free survival rates were 62% and 48% for FAC and FAC/high-dose chemotherapy, respectively (P =.35), and 3-year survival rates were 77% and 58%, respectively (P =.23). Overall, there was greater and more frequent morbidity associated with high-dose chemotherapy than with FAC; there was one septic death associated with high-dose chemotherapy. CONCLUSIONS: No relapse-free or overall survival advantage was associated with the use of high-dose chemotherapy, and morbidity was increased with its use. Thus, high-dose chemotherapy is not indicated outside a clinical trial.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/cirurgia , Transplante de Células-Tronco Hematopoéticas , Adulto , Idoso , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Esquema de Medicação , Feminino , Fluoruracila/administração & dosagem , Seguimentos , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estudos Prospectivos , Radioterapia Adjuvante , Análise de Sobrevida , Transplante Autólogo , Resultado do TratamentoRESUMO
LLC-PK cells grown on media containing normal (480 microM) or reduced magnesium levels (25, 6.3 or 2.5 microM) were used to study the effect of magnesium deficiency on linoleic acid metabolism and cellular membrane fatty acids. The fatty acid composition of the cellular phospholipids showed a significant decrease in 20:4(n-6) and 22:4(n-6) acids and a significant increase in 18:2(n-6), 18:3(n-6) and 20:3(n-6) fatty acids in magnesium-deficient cells compared to magnesium-sufficient cells. When [1-14C]linoleic acid was incubated with control (480 microM Mg2+) or magnesium deficient cells (2.6 microM Mg2+) the rate of tetraenoic acid synthesis (20:4(n-6) + 22:4(n-6) was significantly reduced in magnesium-deficient cells, indicating that the metabolic conversion of 18:2(n-6) to 20:4(n-6) is impaired in magnesium deficiency. This reduction in conversion may be due to the impairment of either the delta(5)- or the delta(6)-desaturase, or both. This study shows that magnesium deficiency perturbs essential fatty acid (EFA) metabolism and decreases the cellular membrane polyunsaturated fatty acid (PUFA) content. These alterations are likely to have adverse effects on cellular membrane properties and functions.
Assuntos
Ácidos Graxos/metabolismo , Ácidos Linoleicos/metabolismo , Deficiência de Magnésio/metabolismo , Fosfolipídeos/metabolismo , Animais , Células Cultivadas , Rim/citologia , Rim/metabolismo , Ácido Linoleico , SuínosRESUMO
Monolayers of porcine kidney cells (LLC-PK) were grown in a series of Nu-Serum-supplemented media containing different Mg(2+) concentrations (480, 250, 25, 6.3 or 2.6 microM) to study the effect of Mg(2+) depletion on cellular phospholipid changes and the consequent effect on the membrane permeability to Ca(2+). Cells grown on 6.3 or 2.6 microM Mg(2+) showed a decrease in PE, PS, Sph, PI and an increase of PC. These changes were attributed mainly to the decreased rate of Sph synthesis through the transfer of phosphocholine from PC to ceramide, or due to the increase of PE N-methylation as found in Mg(2+)-deficient cells. The (45)Ca uptake was increased in cells grown on 25.0 microM Mg(2+), while it was decreased in cells grown on 6.3 or 2.6 microM Mg(2+). These changes in Ca(2+) uptake were related to changes of cellular phospholipids and fatty acids which affect adenylate cyclase activity in the membrane, as well as the membrane fluidity.
Assuntos
Cálcio/metabolismo , Deficiência de Magnésio/metabolismo , Fosfolipídeos/metabolismo , Animais , Células Cultivadas , Colina/metabolismo , Rim/citologia , Rim/metabolismo , Lipídeos/análise , Metilação , Fosfatidilcolinas/biossíntese , SuínosRESUMO
Cholesterol/egg phosphatidylcholine (PC) liposomes (1:1 or 4:1, M/M), in which the absolute amount of PC was adjusted to be the same, were incubated with cultured bovine arterial smooth muscle cells for up to 8 h at 37 degrees C. The effect of increased cellular cholesterol on the accumulation of intracellular calcium in these cells was studied. The results indicate that the intracellular calcium content, measured by Fura-2/AM, was increased 2.3-fold by incubation with 4:1, cholesterol/PC liposomes. Kinetic analysis using 45Ca2+ indicated that the increased calcium influx was due to increase of pool size, not from a change of rate constant. (Ca2+ + Mg2+)-ATPase activity was decreased by 4:1, cholesterol/PC liposomes. The molar ratio of cholesterol/phospholipids in the cell membranes was directly proportional to that in liposomes. No change in phospholipid composition was noted. We suggest that the accumulation of intracellular calcium was a composite result due to the altering effect of inserted cholesterol on surface area, and to direct interactions between cholesterol and the proteins of the Ca2+ channel and (Ca2+ + Mg2+)-ATPase.
Assuntos
Cálcio/metabolismo , Colesterol/metabolismo , Músculo Liso Vascular/metabolismo , Animais , ATPase de Ca(2+) e Mg(2+)/metabolismo , ATPases Transportadoras de Cálcio/metabolismo , Bovinos , Células Cultivadas , Cinética , Lipossomos , Lipídeos de Membrana/metabolismo , Fosfatidilcolinas/metabolismo , Fosfolipídeos/metabolismoRESUMO
Previous investigations have shown that the bile pigment bilirubin can act as peroxyl radicals scavenger and transition metals trap, but also as a peroxidant, to erythrocyte ghost membranes through 1O2-driven photooxidation. In the present study we examined the changes occurring in the lipoprotein particle following bilirubin-sensitized photooxidation of isolated plasma LDL. The oxidative stress resulted in increased TBA reactivity, diene formation, free cholesterol oxidation, apo B fragmentation and enhanced uptake of the modified particle by the mouse macrophage scavenger receptors as well as the decrease binding to the native B, E-receptor on fibroblasts. The marked increase in TBARS production in D2O-enriched medium and the inhibition of lipid peroxidation of azide is consistent with singlet oxygen involvement in the oxidation process. The apo B-bound Cu2+ appears to become redox active during photooxidation since the presence of EDTA in the reaction mixture greatly reduced protein fragmentation. It was also found that BHT inhibited almost completely the lipid peroxidation, as determined by the TBA reaction but could not totally abolish the formation of 5 alpha-hydroxycholesterol, which is the main product formed by the direct attack of 1O2 on cholesterol. The results of this work strongly suggest that, through photooxidation by light-activated bilirubin, the lipoprotein particle may be modified in the blood stream as well, besides being modified in the well known oxidation site within the arterial wall. Our findings provide the rationale for extending these studies to clinical investigations, which aim at developing strategies for minimizing damage to arterial tissue following phototherapy of hyperbilirubinemic newborns or cancer patients after systemic administration of photosensitizers.
Assuntos
Bilirrubina/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Lipoproteínas LDL/metabolismo , Animais , Azidas/farmacologia , Fenômenos Químicos , Química , Colesterol/metabolismo , Cromatografia em Camada Fina , Óxido de Deutério/farmacologia , Eletroforese em Gel de Ágar , Humanos , Luz , Ácido Linoleico , Ácidos Linoleicos/metabolismo , Peróxidos Lipídicos/metabolismo , Lipoproteínas LDL/sangue , Macrófagos , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Receptores de LDL/metabolismo , Azida Sódica , Espectrofotometria , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismoRESUMO
Between June 1973 and November 1980, 1,171 patients with metastatic breast cancer were treated with various doxorubicin-containing regimens at our institution (M.D. Anderson Hospital and Tumor Institute, Houston). Retrospective analysis of all 233 cases (20%) with liver metastases was done to correlate various clinical and biochemical characteristics with response to treatment, survival, and causes of death. A similar analysis was performed for 58 consecutive patients with liver metastases treated at this hospital between December 1955 and December 1957 with hormone therapy or single-agent chemotherapy. Objective responses were observed in 132 of 233 patients (57%) treated with combination chemotherapy. The median survival was 14 months in the 1970s and 5 months in the 1950s. Among patients who had liver metastases at the time of initial diagnosis of breast cancer, survival was longer for the group treated with combination chemotherapy. All cases were classified according to the number of organ sites involved by metastases. Patients with only liver metastases, or liver plus bone lesions had the longest survival. Other clinical and biochemical factors that correlated significantly with longer survival were: no prior chemotherapy, performance status of 1 to 2, absence of ascites, normal bilirubin and lactic dehydrogenase (LDH), SGOT less than or equal to 2 times normal and albumin greater than 4.5 g/dL. The main cause of death was multiorgan failure, with only 20% of patients dying of liver failure. The present study shows that the presence of liver metastases in breast cancer is not by itself an ominous factor. Most patients respond to therapy, and significant palliation with extended survival is possible for several prognostic subgroups. Further improvement in length and quality of survival is expected with earlier diagnosis.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias Hepáticas/secundário , Adulto , Idoso , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Doxorrubicina/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Humanos , Testes de Função Hepática , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Tiotepa/administração & dosagemRESUMO
Three hundred thirty-six patients with stage II or stage III breast cancer were treated on an adjuvant protocol containing fluorouracil, doxorubicin, cyclophosphamide, vincristine, and prednisone (FACVP). Depending on the estrogen-receptor (ER) status, the patients were subdivided to receive maintenance chemotherapy with or without tamoxifen. The administered dose intensity of fluorouracil, doxorubicin, and cyclophosphamide (FAC) (mg/m2/wk) relative to the projected dose intensity (based on planned dose) was computed for each patient. The relative dose intensity of the first six cycles of chemotherapy (RDI6) was compared with disease-free survival (DFS). Of the 299 patients who completed at least six cycles of therapy, 83% received dose intensities within 20% of standard intensity (.8 less than or equal to RDI6 less than or equal to 1.2). The group with the highest dose intensity (RDI6 greater than or equal to 1.13) had the longest DFS, though there was not a clear trend of linear association between dose intensity and DFS after adjustment for prognostic factors (P = .16). The patients who received at least standard dose intensity (RDI6 greater than or equal to 1.0) had longer DFS than those whose therapy did not reach standard intensity (RDI6 less than 1.0). This difference was significant in patients with stage III disease (P = .01). The 37 patients who completed fewer than six cycles of chemotherapy had the shortest DFS (5-year DFS of 48% v 65% in the others). This retrospective analysis, in a heterogeneously treated group of patients, did not show the differences in outcome associated with dose intensity as demonstrated in the earlier studies comparing projected dose intensity of various cyclophosphamide, methotrexate-, and fluorouracil (CMF)-containing adjuvant trials. Improved DFS was noted in the stage III patients receiving higher dose intensity. Our failure to demonstrate the differences in stage II patients may be due to the narrow range of dose intensity in this study or to a difference in the dose-response curves depending on the stage of disease.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Carcinoma/tratamento farmacológico , Doxorrubicina/administração & dosagem , Ciclofosfamida/administração & dosagem , Relação Dose-Resposta a Droga , Esquema de Medicação , Fluoruracila/administração & dosagem , Humanos , Prednisona/administração & dosagem , Análise de Regressão , Estudos Retrospectivos , Análise de Sobrevida , Vincristina/administração & dosagemRESUMO
PURPOSE: Adjuvant chemotherapy for breast cancer has been the routine practice in the past decade. A number of studies have observed an increased incidence of treatment-related leukemias following chemotherapy with alkylating agents and/or topoisomerase II inhibitors. We evaluated the incidence of treatment-related leukemias in breast cancer patients treated in four adjuvant and two neoadjuvant chemotherapy trials at The University of Texas M.D. Anderson Cancer Center. PATIENTS AND METHODS: Between 1974 and 1989, 1,474 patients with stage II or III breast cancer were treated in six prospective trials of adjuvant (n = 4) or neoadjuvant (n = 2) chemotherapy with fluorouracil, doxorubicin, and cyclophosphamide (CTX) (FAC) with or without other drugs. The median observation time was 97 months. In 1,107 patients, FAC chemotherapy was given postoperatively; 367 patients received induction chemotherapy, as well as postoperative chemotherapy. Eight hundred ten patients had surgery followed by radiotherapy and chemotherapy; 664 patients had surgery and chemotherapy only. Patients in two adjuvant and one neoadjuvant study received higher cumulative doses of CTX compared with those in the other studies. RESULTS: Fourteen cases of leukemia were observed. Twelve of these patients had received radiotherapy and chemotherapy, and two had received chemotherapy only. Six of the reported patients with leukemia were treated with a cumulative CTX dose of greater than 6 g/ m2. Five of these patients had received both radiotherapy and chemotherapy. The median latency period in the 14 patients was 66 months (range, 22 to 113). Six of 10 patients with adequate cytogenetic analyses had abnormalities that involved chromosomes 5 and/or 7. The rest of the patients had nonspecific cytogenetic abnormalities or lacked cytogenetic information. The 10-year estimated leukemia rate was 1.5% (95% confidence interval [CI], 0.7% to 2.9%) for all patients treated, 2.5% (95% CI, 1.0% to 5.1%) for the radiotherapy-plus-chemotherapy group, and 0.5% (95% CI, 0.1% to 2.4%) for the chemotherapy-only group; this difference was statistically significant (P = .01). The 10-year estimated leukemia risk for the higher-dose (> 6 g/m2) CTX group was 2% (95% CI, 0.5% to 5.0%) compared with 1.3% (95% CI, 0.4% to 3.0%) for the lower-dose group, a difference that was not statistically significant (P = .53). CONCLUSION: These data illustrate that patients treated with adjuvant FAC chemotherapy plus radiotherapy have a slightly increased risk of leukemia. This information needs to be considered in the treatment plans for patients with breast cancer. However, for most patients, the benefits of adjuvant therapy exceed the risk of treatment-related leukemia.