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BACKGROUND: Guidelines for the use of chemotherapy and endocrine therapy recently recommended that estrogen receptor (ER) status be considered positive if ≥1% of tumor cells demonstrate positive nuclear staining by immunohistochemistry. In clinical practice, a range of thresholds are used; a common one is 10% positivity. Data addressing the optimal threshold with regard to the efficacy of endocrine therapy are lacking. In this study, we compared patient, tumor, treatment and survival differences among breast cancer patients using ER-positivity thresholds of 1% and 10%. METHODS: The study population consisted of patients with primary breast carcinoma treated at our center from January 1990 to December 2011 and whose records included complete data on ER status. Patients were separated into three groups: ≥10% positive staining for ER (ER-positive ≥10%), 1%-9% positive staining for ER (ER-positive 1%-9%) and <1% positive staining (ER-negative). RESULTS: Of 9639 patients included, 80.5% had tumors that were ER-positive ≥10%, 2.6% had tumors that were ER-positive 1%-9% and 16.9% had tumors that were ER-negative. Patients with ER-positive 1%-9% tumors were younger with more advanced disease compared with patients with ER-positive ≥10% tumors. At a median follow-up of 5.1 years, patients with ER-positive 1%-9% tumors had worse survival rates than did patients with ER-positive ≥10% tumors, with and without adjustment for clinical stage and grade. Survival rates did not differ significantly between patients with ER-positive 1%-9% and ER-negative tumors. CONCLUSIONS: Patients with tumors that are ER-positive 1%-9% have clinical and pathologic characteristics different from those with tumors that are ER-positive ≥10%. Similar to patients with ER-negative tumors, those with ER-positive 1%-9% disease do not appear to benefit from endocrine therapy; further study of its clinical benefit in this group is warranted. Also, there is a need to better define which patients of this group belong to basal or luminal subtypes.
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Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Carcinoma Intraductal não Infiltrante/metabolismo , Receptores de Estrogênio/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/classificação , Neoplasias da Mama/mortalidade , Neoplasias da Mama/terapia , Carcinoma Ductal de Mama/classificação , Carcinoma Ductal de Mama/mortalidade , Carcinoma Ductal de Mama/terapia , Carcinoma Intraductal não Infiltrante/classificação , Carcinoma Intraductal não Infiltrante/mortalidade , Carcinoma Intraductal não Infiltrante/terapia , Quimioterapia Adjuvante , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Adulto JovemRESUMO
We analyzed the cost-effectiveness of the International Conference on Harmonisation (ICH) E14 guideline that requires a thorough QT/QTc (TQT) study for all drugs under development. We compared two pharmacoeconomic scenarios: the health effects and costs resulting from implementing ICH E14 ("regulation" scenario) vs. not implementing ICH E14 ("no regulation" scenario). We used a dynamic population model to calculate the cost-effectiveness of ICH E14 for a prototype QT-prolonging antipsychotic drug entering the US and European markets. The incremental cost-effectiveness ratios of regulation vs. no regulation were ~2.4 million per sudden cardiac death prevented and ~187,000 per quality-adjusted life year (QALY) gained in users of antipsychotic drugs. The main driver of cost was the requirement for electrocardiogram (ECG) monitoring of users of QTc-prolonging drugs. Even when several of the assumptions in the model were varied, there were no results in favor of regulation. Our study shows that cost-effectiveness analysis of drug regulatory measures is feasible and should be considered before developing such measures.
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Antipsicóticos/economia , Análise Custo-Benefício/estatística & dados numéricos , Controle de Medicamentos e Entorpecentes/economia , Eletrocardiografia/economia , Antipsicóticos/efeitos adversos , Humanos , Modelos EconômicosRESUMO
Non-antiarrhythmic drugs have been reported to prolong the QTc interval and induce potentially fatal ventricular tachyarrhythmias. An increasing number of drugs that are used for treating malignancies are no exception. Therefore, both oncologists and regulators expect sponsors of oncology drugs to evaluate, during the development of the drugs, their effects on the electrocardiogram (ECG), particularly on the QTc interval. In the case of agents that cannot be administered to healthy volunteers, the primary approach is to carry out an intense ECG evaluation, employing robust ECG recordings, during early-phase clinical trials, together with characterization of the concentration-QTc interval relationship, and follow this up with an appropriate intensity of ECG monitoring in the later phases of development. This article describes the broad principles of these approaches, including recommendations for exclusion criteria (relative to baseline QTc interval and to cardiac comorbidity); it also describes methods for conducting ECG monitoring and a proposed scheme for the management of any QTc-related effects that may emerge.
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Antineoplásicos/efeitos adversos , Monitoramento de Medicamentos/métodos , Eletrocardiografia , Síndrome do QT Longo/induzido quimicamente , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Ensaios Clínicos como Assunto/métodos , Relação Dose-Resposta a Droga , Desenho de Fármacos , Humanos , Neoplasias/tratamento farmacológico , Seleção de Pacientes , Fatores de RiscoRESUMO
Stevia rebaudiana Bertoni that conventionally propagated by seed or by cuttings or clump division which has a limitation of quality and quantity seed material. In present study, callus culture technique was tried to achieve rapid plant multiplication for quality seed material. Callus induction and multiplication medium was standardized from nodal as well as leaf sagments. It is possible to maintain callus on Murashige and Skoog medium supplemented with 6-benzyl amino purine and naphthalene acetic acid. Maximum callus induction was obtained on Murashige and Skoog medium incorporated with 6-benzyl amino purine (2.0-3.0 mg/l) and naphthalene acetic acid (2.0 mg/l) treatments. However, Murashige and Skoog medium containing 2.0 mg/l 6-benzyl amino purine+2.0 mg/l naphthalene acetic acid was found to be the best for callus induction. Higher regeneration frequency was noticed with Murashige and Skoog medium supplemented with 2.0 mg/l 6-benzyl amino purine+0.2 mg/l naphthalene acetic acid. Regenerated plants were rooted better on (1/4) Murashige and Skoog strength supplemented with 0.1 mg/l indole-3-butyric acid. The rooted plantlets were hardened successfully in tera care medium with 63 per cent survival rate. The developed protocol can be utilized for mass production of true to type planting material on large scale independent of season, i.e. external environmental conditions.
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A simple, precise, accurate and rapid high performance thin layer chromatographic method has been developed and validated for the simultaneous estimation of valsartan and hydrochlorothiazide in combined dosage forms. The stationary phase used was precoated silica gel 60F(254). The mobile phase used was a mixture of chloroform: methanol: toluene: glacial acetic acid (6:2:1:0.1 v/v/v/v). The detection of spots were carried out at 260 nm. The method was validated in terms of linearity, accuracy, precision and specificity. The calibration curve was found to be linear between 300 to 800 ng/spot for valsartan and 100 to 600 ng/spot for hydrochlorothiazide. The limit of detection and the limit of quantification for the valsartan were found to be 100 and 300 ng/spot respectively and for hydrochlorothiazide 30 and 100 ng/spot respectively. The proposed method can be successfully used to determine the drug content of marketed formulation.
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A simple, precise, accurate and rapid high performance thin layer chromatographic method has been developed and validated for the estimation of sumatriptan in tablet dosage forms. The stationary phase used was precoated silica gel 60F254. The mobile phase used was a mixture of methanol:water:glacial acetic acid (4.0:8.0:0.1, v/v/v). The detection of spots was carried out at 230 nm. The method was validated in terms of linearity, accuracy, precision and specificity. The calibration curve was found to be linear between 200 to 800 ng/spot. The limit of detection and the limit of quantification for the sumatriptan were found to be 63.87 and 193.54 ng/spot, respectively. The proposed method can be successfully used to determine the drug content of marketed formulation.
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INTRODUCTION: Controversy around sub-specialisation in a district general hospital (DGH) has been ongoing for years. AIM: To study the effect of colorectal sub-specialisation on general surgical cases. METHODS: A retrospective audit between October 2002 and September 2003, including all referrals to the outpatient clinics of a single consultant surgeon in a DGH. RESULTS: 1,055 patients were seen in outpatient clinics, of which 53% (563) were seen in rapid access colorectal clinics. Overall, 87% (914) of patients were diagnosed to have colorectal pathology. The majority of the colorectal cases were referred using the designated referral forms. There were 427 urgent, 162 soon and 325 routine referrals with colorectal pathology, and 35 urgent, 22 soon and 84 routine referrals with non-colorectal pathology. Median waiting times for urgent, soon and routine referrals were 12, 61 and 91 days, respectively, for patients with colorectal pathology, in comparison with 44, 75 and 397 days for non-colorectal pathology. CONCLUSION: This audit confirms that colorectal sub-specialisation has resulted in a significant delay in the management of patients with non-colorectal diseases. This has major implications within a DGH setting.
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Neoplasias Colorretais/cirurgia , Procedimentos Cirúrgicos do Sistema Digestório/estatística & dados numéricos , Hospitais Gerais/estatística & dados numéricos , Listas de Espera , Adolescente , Adulto , Idoso , Feminino , Fidelidade a Diretrizes , Humanos , Masculino , Pessoa de Meia-Idade , Encaminhamento e Consulta , Estudos Retrospectivos , Reino UnidoRESUMO
OBJECTIVES: To assess the safety and effectiveness of administering local steroid injections in an operational field hospital environment. METHOD: A prospective study of patients presenting to the physiotherapy department at the British Military Hospital (BMH) Shaibah, Iraq was undertaken from July 2006 - September 2006. Patients with a condition amenable to local steroid injection and who had not improved with conservative therapy were considered for the study. They then underwent local injection with steroid and local anaesthetic. RESULTS: During this period 12 patients were identified that fitted the criteria for local steroid injection. This represented 7% (12/179) of patients who were seen by the physiotherapy department in either an in or out-patient setting. All patients were injected with local anaesthetic and steroid injection with a single dose of intravenous antibiotic as antimicrobial cover. 10/12 (83.3%) were able to return to their unit within this theatre of operation. The only complication was one case of post injection flare of pain, which settled after 48 hours. CONCLUSION: The use of local steroid injection, as an adjunct to physical therapy, can enable service personnel to remain in the theatre of operations. These patients may have otherwise required aero medical evacuation. We consider the use of a local steroid injection to be a safe and effective intervention in certain patients where conservative measures alone do not work. This study highlights the safety of using steroid injections in an operational field hospital setting. Further large scale studies may help corroborate this conclusion.
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Corticosteroides/administração & dosagem , Medicina Militar/métodos , Doenças Musculoesqueléticas/tratamento farmacológico , Doença Aguda , Corticosteroides/efeitos adversos , Corticosteroides/uso terapêutico , Doença Crônica , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Hospitais de Emergência , Humanos , Injeções , Iraque , Modalidades de Fisioterapia , Estudos Prospectivos , Reino UnidoRESUMO
The pattern of growth and regression of ovarian follicles was monitored once daily for one complete estrous cycle in eight individual water buffaloes by ultrasonographic scanning of the ovaries for an entire interovulatory interval of normal cycle length. One-wave follicular growth was observed in five animals and two-wave follicular growth in three buffaloes during the estrous cycle. The first follicular wave of a two-wave cycle emerged significantly earlier (P < 0.05) than the emergence of the solitary wave of a one-wave cycle. One- and two-wave cycles differed significantly (P < 0.05) with respect to the mean interovulatory interval (21.0 +/- 0.54 days versus 22.7 +/- 0.33 days) and the mean interestrus interval (20.8 +/- 0.58 days versus 22.3 +/- 0.66 days). The overall linear growth rate of the ovulatory follicle was significantly greater (P < 0.01) in a two-wave cycle compared to that of a one-wave cycle (1.17 +/- 0.33 mm/day versus 0.32 +/- 0.01 mm/day). In a one-wave pattern, the growth profile of the solitary dominant follicle was atypical, showing three distinct phases, i.e. growth phase, regression phase and regrowth phase culminating in ovulation. The level of plasma progesterone steadily increased from day 0 of estrous cycle, attained peak level on day 14 and declined thereafter. A slower growth rate of the dominant follicle was observed in the presence of higher plasma progesterone concentration. The present study shows that one-wave follicular growth is a normal phenomenon in suckled water buffaloes.
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Búfalos/fisiologia , Estro/fisiologia , Folículo Ovariano/fisiologia , Ovário/diagnóstico por imagem , Progesterona/sangue , Animais , Feminino , Fatores de Tempo , UltrassonografiaRESUMO
The competitive binding of a molecule forming a liquid crystal and a targeted analyte to a common molecular receptor presented at a solid surface possessing nanometer-scale topography is used to trigger an easily visualized surface-driven change in the orientation of a micrometer-thick film of liquid crystal. Diffusion of the targeted analyte from atmosphere to surface-immobilized receptor across the micrometer-thick film of liquid crystal is fast (on the order of seconds), and the competitive interaction of the targeted analyte and liquid crystal with the receptor provides a high level of tolerance to nontargeted species (water, ethanol, acetone, and hexanes). Systems that provide parts-per-billion (by volume) sensitivity to either organoamine or organophosphorus compounds are demonstrated, and their use for imaging of spatial gradients in concentration is reported. This approach does not require complex instrumentation and could provide the basis of wearable personalized sensors for measurement of real-time and cumulative exposure to environmental agents.
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Aminas/análise , Compostos de Bifenilo/química , Exposição Ambiental , Nitrilas/química , Compostos Organofosforados/análise , Aminas/química , Ligação Competitiva , Ácidos Carboxílicos/química , Cobre/química , Cristalização , Equipamentos e Provisões , Ligação de Hidrogênio , Microscopia de Polarização , Compostos Organofosforados/química , Sensibilidade e Especificidade , Propriedades de SuperfícieAssuntos
Legislação de Medicamentos/história , Medicina Estatal/história , Teratogênicos/história , Talidomida/história , Anormalidades Induzidas por Medicamentos/etiologia , Anormalidades Induzidas por Medicamentos/história , História do Século XX , Humanos , Medicina Estatal/legislação & jurisprudência , Talidomida/efeitos adversos , Talidomida/uso terapêutico , Reino UnidoRESUMO
We report the uniform planar anchoring of thermotropic liquid crystals on films of bovine serum albumin (BSA) covalently immobilized on the surface of glass microscope slides and mechanically rubbed using a cloth. The azimuthal orientations of the liquid crystals were measured to be parallel to the direction of rubbing. Following immersion and removal of these rubbed films of BSA from aqueous solutions containing either BSA, fibrinogen, lysozyme, anti-FITC immunoglobulin G (IgG), or antistreptavidin IgG, we measured liquid crystals placed onto these surfaces to largely retain their uniform alignment. In contrast, following immersion of a rubbed film of BSA into an aqueous solution of anti-BSA IgG, we observed liquid crystals on these surfaces to assume nonuniform orientations. We conclude that specific binding of anti-BSA IgG to the film of rubbed BSA erased anisotropy induced within the film of BSA by rubbing. This result suggests that the spatial scale of anisotropy within the rubbed film of BSA is comparable to or smaller than the size of the IgG molecule. Because the anisotropy within a rubbed film of a protein can be erased by specific binding of a second protein, we believe these types of substrates (rubbed films of proteins) have the potential to be useful in a variety of label-free biomolecular assays where specific binding of a target species to its ligand can be imaged through observation of the optical appearance of liquid crystal placed onto the surface.
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Soroalbumina Bovina/química , Adsorção , Anisotropia , Cristalização , Imunoglobulina G/metabolismo , Soroalbumina Bovina/metabolismoRESUMO
In this case report, we present a 50-year- old woman, who presented with severe headache as her only presenting clinical symptom due to nasopharyngeal mass. Histo-pathological evaluation of the biopsy from nasopharyngeal mass revealed clear cell carcinoma. On further evaluation, an asymptomatic mass was detected in the left kidney. The metastatic lesion was treated with palliative radiotherapy. A search of the literature revealed no reports of such unusual metastasis in the nasopharynx from a primary carcinoma of the renal origin.
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The infrahyoid neck is a complex region of anatomy and pathology. The spatial division of the infrahyoid neck into six discrete spaces is accomplished by three layers of the deep cervical fascia. Once understood, the pathologic processes in this region can be better characterized. Additionally, this article includes the anatomy and pathology of the thyroid and parathyroid glands and the brachial plexus.
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Pescoço/anatomia & histologia , Plexo Braquial/anatomia & histologia , Plexo Braquial/diagnóstico por imagem , Humanos , Osso Hioide/anatomia & histologia , Osso Hioide/diagnóstico por imagem , Linfonodos/anatomia & histologia , Linfonodos/diagnóstico por imagem , Imageamento por Ressonância Magnética , Pescoço/diagnóstico por imagem , Glândulas Paratireoides/anatomia & histologia , Glândulas Paratireoides/diagnóstico por imagem , Nervos Periféricos/anatomia & histologia , Nervos Periféricos/diagnóstico por imagem , Glândula Tireoide/anatomia & histologia , Glândula Tireoide/diagnóstico por imagem , Tomografia Computadorizada por Raios XRESUMO
Liver transplantation or the surgical construction of portacaval shunts may radically alter an individual's debrisoquine hydroxylation capacity. Good clinical management should encompass a full awareness of such changing needs and problems in patients who undergo hepatic surgery.
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Debrisoquina/farmacocinética , Transplante de Fígado/efeitos adversos , Derivação Portocava Cirúrgica/efeitos adversos , Adulto , Debrisoquina/análogos & derivados , Debrisoquina/urina , Feminino , Humanos , Hidroxilação , Masculino , Pessoa de Meia-IdadeRESUMO
1. There is an increasing appreciation of the relevance of pharmacokinetics of drugs during evaluation of their safety for human clinical use. Regulatory requirements for clinical pharmacokinetic data have progressively evolved to emphasize and address these safety implications. 2. Historically the dose schedules usually recommended have been too high, often with serious consequences. Therefore, the need to establish reliable dose response (both therapeutic and toxic) relationships must be an important objective. 3. Concurrent developments in our understanding of the pharmacological effects (therapeutic or toxic) of metabolites, the interethnic and interindividual differences in drug responses and the toxicological aspects of drug chirality now provide compelling reasons for the roles of bioactivation, pharmacogenetics and stereochemical factors to be addressed in pharmacokinetic studies during the clinical development of drugs. 4. Apart from the traditional pharmacokinetic studies following single and multiple doses in healthy volunteers, patients and special subgroups, reliable dose-response curves for therapeutic and toxic effects must be established in well-designed controlled studies using a wide range of doses. Often, doses lower than those recommended have a much improved risk/benefit ratio. 5. Secondary pharmacology of the drug and its active metabolites must be defined for assessment of safety (adverse reactions and pharmacokinetic and pharmacodynamic drug-drug interactions) in high dose/concentration situations. 6. The enzyme systems responsible for the metabolism of a drug must be identified followed by rational investigations of drug-drug and drug-disease interactions both from the efficacy and safety viewpoints. Factors responsible for alterations in the functional expression of this enzyme system must be identified and the safety and efficacy implications of these findings at interethnic, inter- and intraindividual levels must be fully explored during all phases of the clinical development of the drug. This should lead to carefully designed patient subgroup-specific dose schedules which maximize the risk/benefit ratio for all patients. 7. Drugs operate in a chiral environment and, not surprisingly, enantiomers of a drug differ significantly in their pharmacokinetics and pharmacodynamics. The possibility of interactions between enantiomers of a drug and of enantioselective interactions should be examined. These should be thoroughly investigated and the decision to market a racemic mixture or one of its enantiomers must be justified. 8. Analysis of population pharmacokinetics offers an approach by which to examine the roles of various factors which are likely to be clinically relevant for the safe and effective use of drugs.(ABSTRACT TRUNCATED AT 400 WORDS)
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Controle de Medicamentos e Entorpecentes , Farmacocinética , Ensaios Clínicos como Assunto , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/metabolismo , Farmacogenética , EstereoisomerismoRESUMO
Apolipoprotein (apo) B48 is produced in the mammalian intestine by a tissue-specific RNA-editing mechanism, which mediates a C to U conversion at position 6666 in apoB mRNA. This generates an inframe translation stop codon (UAA) in place of glutamine (CAA) at position 2153. To establish the sequences required for editing we have used an in vitro conversion assay to monitor the editing of synthetic RNAs by rat intestinal extracts. Transcripts containing 55 nucleotides (positions 6649-6703) or more of human apoB mRNA sequence were edited in vitro. Transcripts containing 42 nucleotides (positions 6648-6689) and 26 nucleotides (positions 6662-6687) were edited at 62 and 24% efficiency, respectively, of the 55-nucleotide sequence. To delineate the precise sequence requirements for editing, mutants were generated where 6-nucleotide sections of the 55-base region were changed to anti-sense sequence. Mutation of the 12-nucleotide region immediately downstream of C-6666 abolished editing, and mutation of 6-base sequences immediately 3' and 5' of this 12-nucleotide region significantly reduced editing. Having identified the key region of interest, a panel of 46 mutant RNAs carrying single base substitutions or deletions between nucleotide positions 6657 and 6685 was constructed. Mutagenesis in the sequence 5'-TGATCAGTATA-3' (positions 6671-6681) downstream of C-6666 had the most dramatic effect, since almost all mutations abolished or greatly reduced conversion in vitro. These results suggest that editing is a highly sequence-specific process. We propose that this downstream region is a recognition and/or binding site for the editing enzyme. A search for this sequence in other genes may help to reveal other RNAs that undergo editing.
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Apolipoproteínas B/metabolismo , Processamento Pós-Transcricional do RNA , Animais , Sequência de Bases , Deleção Cromossômica , DNA , Humanos , Dados de Sequência Molecular , Mutagênese , Conformação de Ácido Nucleico , RNA Mensageiro/química , RNA Mensageiro/metabolismo , Ratos , Ratos EndogâmicosRESUMO
Human intestinal apolipoprotein (apo) B mRNA undergoes a C to U RNA editing at nucleotide 6666 to generate a translation stop at codon 2153, which defines the carboxy-terminal of apo B48. Here we show that two of eleven human intestinal cDNAs spanning residue 6666 were edited from a genomically-encoded C to a T at residue 6802 as well as at residue 6666. This additional editing converts Thr (ACA) codon 2198 to Ile (AUA). Synthetic RNA including the nucleotide 6802 was edited in vitro by intestinal extracts at 10-15% of the editing efficiency of nucleotide 6666. A sequence is identified as important for recognition by the editing activity. No secondary structural homology was identified between the two edited sites. No other sequence in the region between 6411 and 6893 nucleotides of apo B mRNA was found to be edited in vivo or in vitro. Apo B RNA editing extracts from intestine did not edit maize cytochrome oxidase II mRNA.