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BACKGROUND: Nivolumab plus ipilimumab demonstrated promising clinical activity and durable responses in sorafenib-treated patients with advanced hepatocellular carcinoma (HCC) in the CheckMate 040 study at 30.7-month median follow-up. Here, we present 5-year results from this cohort. PATIENTS AND METHODS: Patients were randomized 1 : 1 : 1 to arm A [nivolumab 1 mg/kg plus ipilimumab 3 mg/kg Q3W (four doses)] or arm B [nivolumab 3 mg/kg plus ipilimumab 1 mg/kg Q3W (four doses)], each followed by nivolumab 240 mg Q2W, or arm C (nivolumab 3 mg/kg Q2W plus ipilimumab 1 mg/kg Q6W). The primary objectives were safety, tolerability, investigator-assessed objective response rate (ORR), and duration of response (DOR) per RECIST version 1.1. RESULTS: A total of 148 patients were randomized across treatment arms. At 60-month minimum follow-up (62.6-month median follow-up), the ORR was 34% (n = 17), 27% (n = 13), and 29% (n = 14) in arms A, B, and C, respectively. The median DOR was 51.2 months [95% confidence interval (CI) 12.6 months-not estimable (NE)], 15.2 months (95% CI 7.1 months-NE), and 21.7 months (95% CI 4.2 months-NE), respectively. The median overall survival (OS) was 22.2 months (34/50; 95% CI 9.4-54.8 months) in arm A, 12.5 months (38/49; 95% CI 7.6-16.4 months) in arm B, and 12.7 months (40/49; 95% CI 7.4-30.5 months) in arm C; 60-month OS rates were 29%, 19%, and 21%, respectively. In an exploratory analysis of OS by response (6-month landmark), the median OS was meaningfully longer for responders versus nonresponders for all arms. No new safety signals were identified with longer follow-up. There were no new discontinuations due to immune-mediated adverse events since the primary analysis. CONCLUSIONS: Consistent with the primary analysis, the arm A regimen of nivolumab plus ipilimumab continued to demonstrate clinically meaningful responses and long-term survival benefit, with no new safety signals in patients with advanced HCC following sorafenib treatment, further supporting its use as a second-line treatment in these patients.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Hepatocelular , Ipilimumab , Neoplasias Hepáticas , Nivolumabe , Sorafenibe , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/mortalidade , Seguimentos , Ipilimumab/administração & dosagem , Ipilimumab/efeitos adversos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/mortalidade , Nivolumabe/administração & dosagem , Nivolumabe/efeitos adversos , Sorafenibe/administração & dosagem , Sorafenibe/efeitos adversos , Sorafenibe/uso terapêuticoRESUMO
BACKGROUND: Patients with advanced hepatocellular carcinoma (aHCC) have a poor prognosis and high mortality. Nivolumab monotherapy demonstrated clinical benefit with an acceptable safety profile in patients with aHCC in the CheckMate 040 study. Five-year follow-up of the sorafenib-naive and sorafenib-experienced groups of CheckMate 040 is presented here. PATIENTS AND METHODS: Patients received nivolumab monotherapy at dose levels of 0.1-10.0 mg/kg (dose-escalation phase) or 3 mg/kg (dose-expansion phase) every 2 weeks until disease progression or unacceptable toxicity. Primary endpoints were safety and tolerability (dose escalation), and objective response rate (ORR) by blinded independent central review (BICR) and by investigator as per RECIST version 1.1 (dose expansion). RESULTS: Eighty sorafenib-naive and 154 sorafenib-experienced patients were treated. Minimum follow-up in both groups was 60 months. ORR as per BICR was 20% [95% confidence interval (CI) 12% to 30%] and 14% (95% CI 9% to 21%) in the sorafenib-naive and sorafenib-experienced groups, respectively. Responses occurred regardless of HCC etiology or baseline tumor cell programmed death-ligand 1 (PD-L1) expression levels. Median overall survival (OS) was 26.6 months (95% CI 16.6-30.6 months) and 15.1 months (95% CI 13.0-18.2 months) in sorafenib-naive and sorafenib-experienced patients, respectively. The 3-year OS rates were 28% in the sorafenib-naive and 20% in the sorafenib-experienced groups; 5-year OS rates were 14% and 12%, respectively. No new safety signals were identified; grade 3/4 treatment-related adverse events were observed in 33% and 21% of patients in the sorafenib-naive and sorafenib-experienced groups, respectively. Biomarker analyses showed that baseline PD-L1 expression ≥1% was associated with higher ORR and longer OS compared with PD-L1 <1%. In the sorafenib-naive group, patients with OS ≥3 years exhibited higher baseline CD8 T-cell density compared with those with OS <1 year. CONCLUSION: With 5 years of follow-up, nivolumab monotherapy continued to provide durable clinical benefit with manageable safety in sorafenib-naive and sorafenib-experienced patients with aHCC.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Nivolumabe/efeitos adversos , Carcinoma Hepatocelular/tratamento farmacológico , Sorafenibe/uso terapêutico , Antígeno B7-H1/metabolismo , Seguimentos , Neoplasias Hepáticas/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ipilimumab/uso terapêuticoRESUMO
OBJECTIVE: To estimate the surveillance incidence of first-time diagnosis of narrow phenotype bipolar I disorder (NPBDI) in young people under 16 years by consultants in child and adolescent psychiatry (CCAP) in the British Isles and describe symptoms, comorbidity, associated factors, management strategies and clinical outcomes at 1-year follow-up. METHOD: Active prospective surveillance epidemiology was utilised to ask 730 CCAP to report cases of NPBDI using the child and adolescent psychiatry surveillance system. RESULTS: Of the 151 cases of NPBDI reported, 33 (age range 10-15.11 years) met the DSM-IV analytical case definition with 60% having had previously undiagnosed mood episodes. The minimum 12-month incidence of NPBDI in the British Isles was 0.59/100 000 (95% CI 0.41-0.84). Irritability was reported in 72% cases and comorbid conditions in 51.5% cases with 48.5% cases requiring admission to hospital. Relapses occurred in 56.67% cases during the 1-year follow-up. CONCLUSIONS: These rates suggest that the first-time diagnosis of NPBDI in young people <16 years of age by CCAP in the British Isles is infrequent; however, the rates of relapse and admission to hospital warrant close monitoring.
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Transtorno Bipolar/epidemiologia , Hospitalização/estatística & dados numéricos , Humor Irritável , Adolescente , Transtorno Bipolar/fisiopatologia , Criança , Comorbidade , Monitoramento Epidemiológico , Feminino , Seguimentos , Humanos , Incidência , Masculino , Fenótipo , Recidiva , Reino UnidoRESUMO
PURPOSE: Day case knee arthroscopy is frequently performed on dedicated lists designed to optimise the throughput of patients. This could affect patient recall of clinical information with clinical, ethical and medicolegal consequences. The purpose of this study was to assess patient recall after knee arthroscopy and identify potential contributory factors. METHODS: Seventy-two patients undergoing day case knee arthroscopy were provided with information about their surgery post-operatively and tested for recall of the information prior to discharge. All patients underwent cognitive assessment when information was delivered and again when tested. Patient recall was correlated with demographic and anaesthetic factors and a multivariate regression model was used to identify risk factors for reduced recall. RESULTS: Recall overall was poor. Significant independent risk factors for reduced recall were reduced cognitive state at the time of information delivery and a shorter time between surgery and information delivery. Duration of anaesthesia, use of sedatives and use of opiate analgesia were not significantly correlated with recall. CONCLUSIONS: Information recall after day case knee athroscopy may be suboptimal. Allowing more time between surgery and information delivery may improve recall. However, this may be difficult during the course of a busy list and surgeons should consider using additional techniques to improve patient recall after surgery to reduce the risk of patient anxiety or non-compliance. LEVEL OF EVIDENCE: IV.
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Procedimentos Cirúrgicos Ambulatórios/psicologia , Artroscopia/psicologia , Articulação do Joelho/cirurgia , Rememoração Mental , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medição da Dor , Estudos Prospectivos , Fatores de Risco , Inquéritos e Questionários , Resultado do TratamentoRESUMO
This is a case report of a 53-yr-old female who experienced sudden sensorineural hearing loss (SSNHL) accompanied by roaring tinnitus in her right ear. The patient's hearing partially improved in the low frequencies in response to intratympanic injections. Given that her hearing loss did not improve further, the patient was fitted with a hearing aid to mask the tinnitus and restore a sense of balance between the two ears. Approximately 9 mo postonset of the SSNHL, a complete spontaneous recovery of hearing occurred. Such a delayed and complete recovery is highly unusual. This case highlights that the spontaneous recovery in hearing indicates that the pathological cause for the SSNHL involved a process that was capable of repair or regeneration, thus ruling out pathologies related to cochlear hair cell destruction or nerve fiber loss. This leaves a possibility that the event causing the onset of the SSNHL resulted in a disruption of the ion homeostatic properties of the cochlea via the production of the endocochlear potential.
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Dexametasona/administração & dosagem , Perda Auditiva Neurossensorial/tratamento farmacológico , Perda Auditiva Neurossensorial/fisiopatologia , Perda Auditiva Súbita/tratamento farmacológico , Perda Auditiva Súbita/fisiopatologia , Feminino , Glucocorticoides/administração & dosagem , Auxiliares de Audição , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Súbita/diagnóstico , Humanos , Pessoa de Meia-Idade , Recuperação de Função Fisiológica/fisiologia , Remissão Espontânea , Zumbido/tratamento farmacológico , Zumbido/fisiopatologiaRESUMO
This case report describes a 44-yr-old female referred by an outside facility who presented with progressive hearing loss in her left ear. Magnetic resonance imaging (MRI) results were normal, but a battery of audiological tests suggested neural hearing loss in the left ear. Following diagnosis of left neural hearing loss, the patient was successfully fit with a hearing aid on the left ear. This case report underlines the importance of using a battery of medical, radiologic, and audiological tests in the accurate determination of hearing loss site of lesion. Obvious retrocochlear dysfunction was revealed via auditory brainstem response (ABR) testing. MRI did not reveal underlying structural abnormality. Without the addition of the ABR to the diagnostic test battery, a cochlear hearing loss site of lesion would most likely have been diagnosed. Accurate diagnosis of hearing loss site of lesion is critical for patient counseling and treatment as well as for patient follow-up and monitoring.
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Potenciais Evocados Auditivos do Tronco Encefálico/fisiologia , Perda Auditiva/diagnóstico , Perda Auditiva/fisiopatologia , Percepção da Fala/fisiologia , Teste do Limiar de Recepção da Fala , Adulto , Diagnóstico Diferencial , Feminino , Auxiliares de Audição , Perda Auditiva/terapia , Humanos , Imageamento por Ressonância Magnética , Emissões Otoacústicas Espontâneas/fisiologiaRESUMO
This case study describes a 45-yr-old female with bilateral, profound sensorineural hearing loss due to Ménière's disease. She received her first cochlear implant in the right ear in 2008 and the second cochlear implant in the left ear in 2010. The case study examines the enhancement to speech recognition, particularly in noise, provided by bilateral cochlear implants. Speech recognition tests were administered prior to obtaining the second implant and at a number of test intervals following activation of the second device. Speech recognition in quiet and noise as well as localization abilities were assessed in several conditions to determine bilateral benefit and performance differences between ears. The results of the speech recognition testing indicated a substantial improvement in the patient's ability to understand speech in noise and her ability to localize sound when using bilateral cochlear implants compared to using a unilateral implant or an implant and a hearing aid. In addition, the patient reported considerable improvement in her ability to communicate in daily life when using bilateral implants versus a unilateral implant. This case suggests that cochlear implantation is a viable option for patients who have lost their hearing to Ménière's disease even when a number of medical treatments and surgical interventions have been performed to control vertigo. In the case presented, bilateral cochlear implantation was necessary for this patient to communicate successfully at home and at work.
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Implante Coclear/métodos , Perda Auditiva Bilateral/cirurgia , Perda Auditiva Neurossensorial/cirurgia , Doença de Meniere/cirurgia , Adulto , Saco Endolinfático/cirurgia , Feminino , Perda Auditiva Bilateral/etiologia , Perda Auditiva Neurossensorial/etiologia , Humanos , Doença de Meniere/complicações , Percepção da Fala , Vertigem/etiologia , Vertigem/cirurgiaRESUMO
AIM: According to the revised Bethesda Guidelines, colorectal cancer (CRC) occurring under age 50 years should be screened to exclude Lynch syndrome. However, in current practice in East Anglia, tumour screening is initiated only after genetics referral, reserved for those with a strong pedigree. This study aimed to determine how many patients with young-onset CRC undergo tumour screening in hospitals in East Anglia. METHOD: A retrospective case notes review over 5 years in four hospitals was undertaken to determine what proportion of those with young-onset CRC underwent referral for tumour screening and to assess local practices in terms of patient counselling and management. RESULTS: One hundred and twenty-two patients were included. There was an average yearly caseload of 6-9 patients per hospital. Documented family history was rare, as was counselling concerning metachronous and extra-colonic tumour risk and CRC risk in relatives. The rate of referral for genetic testing varied from 44% to 65%. Postoperative colonoscopic surveillance was inconsistent. CONCLUSION: Many patients with young-onset CRC are managed as sporadic cancers, without Lynch syndrome having been excluded. This may have implications for survival of patients and any affected relatives. A streamlined management algorithm for tumour screening and genetics referral is recommended.
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Adenocarcinoma/genética , Adenocarcinoma/patologia , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Vigilância da População , Adenocarcinoma/diagnóstico , Adenocarcinoma/terapia , Adulto , Idade de Início , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/terapia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Feminino , Aconselhamento Genético , Testes Genéticos/estatística & dados numéricos , Fidelidade a Diretrizes , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Guias de Prática Clínica como Assunto , Encaminhamento e Consulta/estatística & dados numéricos , Estudos Retrospectivos , Reino Unido , Adulto JovemRESUMO
Sib-pair analysis of 170 individuals from 11 Amish families revealed evidence for linkage of five markers in chromosome 5q31.1 with a gene controlling total serum immunoglobulin E (IgE) concentration. No linkage was found between these markers and specific IgE antibody concentrations. Analysis of total IgE within a subset of 128 IgE antibody-negative sib pairs confirmed evidence for linkage to 5q31.1, especially to the interleukin-4 gene (IL4). A combination of segregation and maximum likelihood analyses provided further evidence for this linkage. These analyses suggest that IL4 or a nearby gene in 5q31.1 regulates IgE production in a nonantigen-specific (noncognate) fashion.
Assuntos
Cromossomos Humanos Par 5 , Ligação Genética , Imunoglobulina E/sangue , Interleucina-4/genética , Adolescente , Adulto , Idoso , Alérgenos/imunologia , Sequência de Bases , Criança , Pré-Escolar , Feminino , Genes MHC da Classe II , Marcadores Genéticos , Humanos , Hipersensibilidade Imediata/genética , Funções Verossimilhança , Escore Lod , Masculino , Pessoa de Meia-Idade , Dados de Sequência MolecularRESUMO
OBJECTIVE: In a busy practice, time is a commodity in rare supply, and keeping abreast of the relevant medical literature is a daunting task. Even after reading an article carefully, important information may be lost because of undue attention to the methodological minutia. METHOD: Fundamental to reducing a complex article into a well-organized and consistent format is the technique of quantitatively diagramming the principal components in the design and findings of the study. This approach allows a coherent brief summary statement of the article, and a platform for a focused scientific discussion and analysis of the clinical applicability of the findings. CONCLUSIONS: The technique of diagramming an article is a tool that the senior author has used for years and has found it valuable in capturing the scientific fundamentals of a manuscript. Once prepared, the diagram has proven to be useful in clarifying presentations during journal club, preparing the background and significance sections of grant applications, reviewing articles as a journal editor and as a journal reviewer, and easily retrieving documents to support evidence-based practice efforts.
Assuntos
Publicações Periódicas como Assunto , RedaçãoRESUMO
The 95 percent confidence interval about the mean demarcates the range of values in which the mean would fall if many samples from the universal parent population were taken. In other words, if the same observation, experiment, or trial were done over and over with a different sample of subjects, but with the same characteristics as the original sample, 95 percent of the means from those repeated measures would fall within this range. This gives a measure of how confident we are in the original mean. It tells us not only whether the results are statistically significant because the CI falls totally on one side or the other of the no difference marker (0 if continuous variables; 1 if proportions), but also the actual values so that we might determine if the data seem clinically important. In contrast, the P value tells us only whether the results are statistically significant, without translating that information into values relative to the variable that was measured. Consequently, the CI is a better choice to describe the results of observations, experiments, or trials.
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Intervalos de Confiança , Interpretação Estatística de Dados , Humanos , OtolaringologiaRESUMO
Case reports have been vital to the advancement of medicine, providing a mechanism for scholarly education and for sharing new discovery and rare observations. However, journals are increasingly reluctant to publish this type of manuscript. Additionally, case reports and limited case series are infrequently cited, potentially interfering with the impact factor of a journal. The increasing emphasis on evidence-based medicine may have artificially decreased the value of case reports. This article describes the value of case reports to medicine, citing 3 examples that have significantly improved the practice of medicine. We also provide criteria for effective reporting, which include the elements of both surprise and closure. In summary, we offer support for the contention that case reports are fundamental to the scholarly practice of medicine and enhance the intent of a quality medical journal.
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Coleta de Dados , Publicações Periódicas como Assunto , Autoria , Coleta de Dados/normas , Medicina Baseada em Evidências , Humanos , Redação/normasRESUMO
OBJECTIVE: To evaluate hearing outcomes and effects of stimulation rate on performance with the Nucleus Freedom cochlear implant (Cochlear Americas, Denver, CO). STUDY DESIGN AND SETTING: Randomized, controlled, prospective, single-blind clinical study using single-subject repeated measures (A-B-A-B) design at 14 academic centers in the United States and Canada and comparison with outcomes of a prior device by the same manufacturer. PATIENTS: Seventy-one severely/profoundly hearing impaired adults. RESULTS: Seventy-one adult recipients were randomly programmed in two different sets of rate: ACE or higher rate ACE RE. Mean scores for Consonant Nucleus Consonant words is 57%, Hearing in Noise Test (HINT) sentences in quiet 78%, and HINT sentences in noise 64%. Sixty-seven percent of subjects preferred slower rates of stimulation, and performance did not improve with higher rates of stimulation using this device. CONCLUSIONS: Subjects performed well, and there was no advantage to higher stimulation rates with this device. SIGNIFICANCE: Higher stimulation rates do not necessarily result in improved performance.
Assuntos
Implantes Cocleares , Surdez/cirurgia , Estimulação Acústica/instrumentação , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Ruído/efeitos adversos , Cuidados Pré-Operatórios , Estudos Prospectivos , Desenho de Prótese , Índice de Gravidade de Doença , Método Simples-Cego , Percepção da Fala , Resultado do TratamentoRESUMO
OBJECTIVES: A new technique for determining the position of each electrode in the cochlea is described and applied to spiral computed tomography data from 15 patients implanted with Advanced Bionics HiFocus I, Ij, or Helix arrays. METHODS: ANALYZE imaging software was used to register 3-dimensional image volumes from patients' preoperative and postoperative scans and from a single body donor whose unimplanted ears were scanned clinically, with micro computed tomography and with orthogonal-plane fluorescence optical sectioning (OPFOS) microscopy. By use of this registration, we compared the atlas of OPFOS images of soft tissue within the body donor's cochlea with the bone and fluid/ tissue boundary available in patient scan data to choose the midmodiolar axis position and judge the electrode position in the scala tympani or scala vestibuli, including the distance to the medial and lateral scalar walls. The angular rotation 0 degrees start point is a line joining the midmodiolar axis and the middle of the cochlear canal entry from the vestibule. RESULTS: The group mean array insertion depth was 477 degrees (range, 286 degrees to 655 degrees). The word scores were negatively correlated (r = -0.59; p = .028) with the number of electrodes in the scala vestibuli. CONCLUSIONS: Although the individual variability in all measures was large, repeated patterns of suboptimal electrode placement were observed across subjects, underscoring the applicability of this technique.
Assuntos
Cóclea/diagnóstico por imagem , Cóclea/patologia , Implante Coclear/métodos , Implantes Cocleares , Perda Auditiva/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Perda Auditiva/diagnóstico por imagem , Perda Auditiva/patologia , Humanos , Imageamento Tridimensional , Masculino , Microscopia de Fluorescência , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
There is a lack of reporting effect sizes and confidence intervals in the current biomedical literature. The objective of this article is to present a discussion of the recent paradigm shift encouraging the use of reporting effect sizes and confidence intervals. Although P values help to inform us about whether an effect exists due to chance, effect sizes inform us about the magnitude of the effect (clinical significance), and confidence intervals inform us about the range of plausible estimates for the general population mean (precision). Reporting effect sizes and confidence intervals is a necessary addition to the biomedical literature, and these concepts are reviewed in this article.
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Intervalos de Confiança , Interpretação Estatística de Dados , Otolaringologia , Probabilidade , Humanos , Reprodutibilidade dos Testes , Projetos de PesquisaRESUMO
beta-Adrenergic receptors were demonstrated in membrane preparations from 6 human Ewing's sarcomas and compared to those from 46 other pediatric cancers with the use of the beta-adrenergic antagonist (-)-(3H)dihydroalprenolol [(-)[3H]DHA]. In contrast to the high numbers of receptor sites found in Ewing's sarcomas (55-640 fmol x mg-1 protein; dissociation constant Kd, 1-2 nM), other childhood cancers (neuroblastoma, rhabdomyosarcoma, brain tumors, lymphoma, osteosarcoma, hepatoblastoma, yolk sac, and Wilms' tumor) contained in general fewer beta-adrenergic receptor sites. Characteristics of (-)-[3H]DHA binding were therefore more fully characterized in the Ewing's tumors. Competition of (-)-[3H]DHA binding by classical catecholamine agonists, as well as by subtype selective agents metoprolol and zinterol, demonstrated the presence of a homogeneous population of beta 1-adrenergic sites in several Ewing's tumors. Adenylate cyclase activity in all Ewing's sarcomas was enhanced by GTP and NaF. However, in spite of high numbers of beta-adrenergic receptors, (-)-isoproterenol was not very effective in the activation of adenylate cyclase activity in several of the Ewing's tumors tested. Neither guanyl-5'-yl-imidophosphate nor GTP altered agonist potency for the receptor site in these catecholamine-insensitive tumors. Hill coefficients obtained from the competition experiments with (-)-isoproterenol (in the presence or absence of guanine nucleotide) were approximately 1.0. These uncoupled receptors were resistant to N-ethylmaleimide denaturation and were densensitized only 50% during culture in the presence of (-)-isoproterenol. Thus Ewing's sarcomas are relatively rich in beta-adrenergic sites, and several tumors appear to have a coupling lesion involving guanine nucleotide-dependent regulatory protein interaction with beta-adrenergic receptors and adenylate cyclase, similar in phenotype to that described in the (unc) variant of S49 mouse lymphoma.
Assuntos
Neoplasias Ósseas/metabolismo , Receptores Adrenérgicos beta/análise , Sarcoma de Ewing/metabolismo , Adenilil Ciclases/metabolismo , Antagonistas Adrenérgicos beta , Animais , Ligação Competitiva , Linhagem Celular , Criança , Di-Hidroalprenolol/farmacologia , Etanolaminas/farmacologia , Humanos , Metoprolol/farmacologia , Camundongos , Camundongos Nus , Neuroblastoma , OsteossarcomaRESUMO
5-Fluoro-2'-deoxyuridine (FdUrd) lowered the dTTP levels in rapidly frozen 12-day W rat embryos and in a human neuroblastoma grown in nude N:NIH(S) mice to about 20% of control values. This effect was associated with greatly increased dCTP levels and reduction of dGTP levels essentially to zero. Elimination of the dGTP pool correlated temporally with the cytotoxicity of FdUrd. Extremely rapid fixation of tissue was required to avoid artifactually high deoxyribonucleoside triphosphate values.
Assuntos
Desoxirribonucleotídeos/metabolismo , Floxuridina/farmacologia , Neuroblastoma/metabolismo , Animais , Técnicas de Cultura/métodos , Embrião de Mamíferos/metabolismo , Feminino , Humanos , Troca Materno-Fetal , Camundongos , Camundongos Nus , Neoplasias Experimentais/metabolismo , Gravidez , RatosRESUMO
The antibody 3F8, an IgG3 murine monoclonal antibody (MoAb) against disialoganglioside GD2, could target iodine-131 (131I) to established subcutaneous human neuroblastoma (NB) xenografts in BALB/c nude mice. 131I-radiolabeled MoAb (0.125-1 mCi) was injected iv. Tumor radioactivity over time was calculated from scintigraphy, and radiation dose to individual tumors was calculated. Tumor shrinkage occurred only with 131I-labeled 3F8, but not with nonradioactive 3F8 or radiolabeled irrelevant antibody. While the tumor of the control mice enlarged by tenfold, the treated tumor showed over 95% shrinkage by 12 days. Both the rate of shrinkage and duration of tumor response were dose dependent. Calculated doses of more than 10,000 rad could be achieved. Only those tumors that received more than 4,200 rad were completely ablated without recurrence. Recurrent tumors were not antigen negative or radioresistant. These results confirmed the prediction based on imaging studies that human NB xenografts could be effectively eradicated with the use of 131I-labeled MoAb 3F8 with tolerable toxicities.