RESUMEN
Detecting microevolutionary responses to natural selection by observing temporal changes in individual breeding values is challenging. The collection of suitable datasets can take many years and disentangling the contributions of the environment and genetics to phenotypic change is not trivial. Furthermore, pedigree-based methods of obtaining individual breeding values have known biases. Here, we apply a genomic prediction approach to estimate breeding values of adult weight in a 35-year dataset of Soay sheep (Ovis aries). Comparisons are made with a traditional pedigree-based approach. During the study period, adult body weight decreased, but the underlying genetic component of body weight increased, at a rate that is unlikely to be attributable to genetic drift. Thus cryptic microevolution of greater adult body weight has probably occurred. Genomic and pedigree-based approaches gave largely consistent results. Thus, using genomic prediction to study microevolution in wild populations can remove the requirement for pedigree data, potentially opening up new study systems for similar research.
Asunto(s)
Genoma , Genómica , Animales , Peso Corporal , Genotipo , Modelos Genéticos , Linaje , Fenotipo , OvinosRESUMEN
We review novel, in vivo and tissue-based imaging technologies that monitor and optimize cancer therapeutics. Recent advances in cancer treatment centre around the development of targeted therapies and personalisation of treatment regimes to individual tumour characteristics. However, clinical outcomes have not improved as expected. Further development of the use of molecular imaging to predict or assess treatment response must address spatial heterogeneity of cancer within the body. A combination of different imaging modalities should be used to relate the effect of the drug to dosing regimen or effective drug concentration at the local site of action. Molecular imaging provides a functional and dynamic read-out of cancer therapeutics, from nanometre to whole body scale. At the whole body scale, an increase in the sensitivity and specificity of the imaging probe is required to localise (micro)metastatic foci and/or residual disease that are currently below the limit of detection. The use of image-guided endoscopic biopsy can produce tumour cells or tissues for nanoscopic analysis in a relatively patient-compliant manner, thereby linking clinical imaging to a more precise assessment of molecular mechanisms. This multimodality imaging approach (in combination with genetics/genomic information) could be used to bridge the gap between our knowledge of mechanisms underlying the processes of metastasis, tumour dormancy and routine clinical practice. Treatment regimes could therefore be individually tailored both at diagnosis and throughout treatment, through monitoring of drug pharmacodynamics providing an early read-out of response or resistance.
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Biomarcadores de Tumor/análisis , Imagen Molecular/métodos , Proteínas de Neoplasias/análisis , Neoplasias/diagnóstico , Neoplasias/terapia , Humanos , Neoplasias/metabolismo , Integración de SistemasRESUMEN
BACKGROUND: The Lung Cancer Cetuximab Study is an open-label, randomized phase II pilot study of cisplatin and vinorelbine combined with the epidermal growth factor receptor (EGFR)-targeted monoclonal antibody cetuximab versus cisplatin and vinorelbine alone, in patients with advanced EGFR-expressing, non-small-cell lung cancer (NSCLC). End points of the study are activity, safety and pharmacokinetics. PATIENTS AND METHODS: Following randomization, for a maximum of eight cycles, patients received three-weekly cycles of cisplatin (80 mg/m(2), day 1) and vinorelbine (25 mg/m(2) on days 1 and 8) alone or following cetuximab treatment (initial dose 400 mg/m(2), followed by 250 mg/m(2) weekly thereafter). RESULTS: Eighty-six patients were randomly allocated to the study (43 per arm). Confirmed response rates were 28% in the cisplatin/vinorelbine arm (A) and 35% in the cetuximab plus cisplatin/vinorelbine arm (B). Median progression-free survival (PFS) was 4.6 months in arm A and 5.0 months in arm B, with PFS rates at 12 months of 0% and 15%, respectively. Median survival was 7.3 months in arm A and 8.3 months in arm B. The 24-month survival rates were 0% and 16%, respectively. The cetuximab combination was well tolerated. CONCLUSION: In the first-line treatment of advanced NSCLC, the combination of cetuximab plus cisplatin/vinorelbine demonstrated an acceptable safety profile and the potential to improve activity over cisplatin/vinorelbine alone.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/mortalidad , Invasividad Neoplásica/patología , Adulto , Anciano , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/patología , Cetuximab , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Intervalos de Confianza , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/patología , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Estadificación de Neoplasias , Probabilidad , Valores de Referencia , Medición de Riesgo , Análisis de Supervivencia , Resultado del Tratamiento , Vinblastina/administración & dosificación , Vinblastina/efectos adversos , Vinblastina/análogos & derivados , VinorelbinaRESUMEN
BACKGROUND: The management of women who have breast cancers diagnosed whilst they are pregnant is challenging. The aim is to give optimal treatment to the mother to maximise the chances of survival, whilst minimising the risks of harm to the fetus. However, few breast surgeons or oncologists develop expertise in this area owing to the rarity of the association. DESIGN: In this review we evaluate and summarise the current literature regarding the diagnosis, management and prognosis of pregnancy-associated breast cancer. Data were identified by searches of Medline, PubMed and references from relevant articles for the period from 1966 to 2004. Papers were selected based on their size and adequacy of design. RESULTS: There is a lack of controlled data concerning the management of pregnancy-associated breast cancer. The data available suggest that diagnosis and surgery may be carried out as for the non-pregnant patient, with some limitations on staging investigations. Radiotherapy is contraindicated during pregnancy although, in terms of immediate complications, chemotherapy can be used after the first trimester. CONCLUSIONS: Data from prospective databases that are currently recruiting will provide further important information concerning the management of this condition, and in particular the long-term sequelae for mother and fetus.
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Neoplasias de la Mama/terapia , Complicaciones Neoplásicas del Embarazo/etiología , Complicaciones Neoplásicas del Embarazo/terapia , Resultado del Embarazo , Femenino , Humanos , EmbarazoRESUMEN
Patients undergoing primary chemotherapy for invasive breast cancer consented to a core biopsy of the invasive breast primary pre- and 24 h postchemotherapy. The resulting tissue was analysed for apoptosis, Ki67, ER and HER-2 using immunohistochemical techniques. These data were then used to evaluate the relationship between these biological markers and response to chemotherapy and overall survival. Response rate to chemotherapy in this group was 86%, 16 patients (25%) achieved a clinical complete response and 41 (63%) a partial response. Prechemotherapy there was a significant correlation between Ki67 and apoptotic index (AI), r=0.6, (P<0.001). A significant rise in AI (P<0.001), and fall in Ki67 (P=0.002) was seen 24 h following chemotherapy. No relationship was seen between pretreatment AI and clinical response, but higher Ki67 and growth index (Ki67/AI ratio, GI) did correlate with clinical response (both r=0.31, P<0.025). No correlation was seen between the change in AI or Ki67 at 24 h and clinical response or survival. Significant changes in apoptosis and proliferation can be demonstrated 24 h following chemotherapy, but these changes do not relate to clinical response or outcome in this study. Pretreatment proliferation and GI are however predictive of response to chemotherapy in breast cancer.
Asunto(s)
Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/tratamiento farmacológico , Carcinoma Ductal de Mama/tratamiento farmacológico , Carcinoma Lobular/tratamiento farmacológico , Adulto , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patología , Carcinoma Lobular/metabolismo , Carcinoma Lobular/patología , División Celular/efectos de los fármacos , Femenino , Humanos , Técnicas para Inmunoenzimas , Antígeno Ki-67/metabolismo , Persona de Mediana Edad , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: Granulocyte colony-stimulating factor (G-CSF) allows cycles of conventional bolus chemotherapy to be accelerated with reduction in treatment time and a boost in dose intensity. Theoretically, this approach could be hazardous with infusional 5-fluorouracil (5-FU) chemotherapy, since G-CSF-stimulated neutrophil proliferation would be occurring in the face of continuous S-phase active 5-FU. We performed this phase II randomised study to compare the safety, tolerability and efficacy of conventional 3-weekly epirubicin, cyclophosphamide and continuous infusional 5-FU (infusional ECF) to an accelerated 2-weekly schedule with G-CSF support, in patients with advanced breast cancer. PATIENTS AND METHODS: Twenty-seven patients were randomised. with 14 in the accelerated arm. Patients received bolus epirubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 every 3 weeks (conventional arm) or every 2 weeks (accelerated arm) and 5-FU 200 mg/m2/day continuous infusion throughout. G-CSF 300 microg/day s.c. on days 10-12 was given each accelerated cycle. RESULTS: There were no treatment delays secondary to inadequate neutrophil or platelet recovery in either arm, with higher median day 1 neutrophil counts for each cycle in the accelerated arm compared with the conventional arm. Eighty-six per cent of the planned conventional chemotherapy cycles and 82% of the planned accelerated cycles were given. There were no major differences in toxicity between the arms, with the most common grade 3 toxicities being alopecia and stomatitis. Eight patients developed neutropenic sepsis (five in the accelerated arm and three in the conventional arm). Ten patients (77%) responded in the conventional arm and nine (64%) in the accelerated arm. CONCLUSIONS: Accelerated infusional ECF with limited G-CSF support is a feasible and well-tolerated regimen with rapid haematological recovery. A 50% increase in relative dose intensity of epirubicin and cyclophosphamide is achieved, while overall treatment time is reduced by 33%.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Hematopoyesis/efectos de los fármacos , Adulto , Biopsia con Aguja , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/cirugía , Quimioterapia Adyuvante , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Epirrubicina/administración & dosificación , Epirrubicina/efectos adversos , Femenino , Estudios de Seguimiento , Humanos , Infusiones Intravenosas , Dosis Máxima Tolerada , Persona de Mediana Edad , Estadificación de Neoplasias , Valores de Referencia , Análisis de Supervivencia , Resultado del Tratamiento , Reino UnidoRESUMEN
We investigated the prevalence of renal impairment in individuals with known hypertension or diabetes aged 50--75 years in two South London General PRACTICES: We initially interrogated the practice and hospital biochemistry databases for each individual's most recent serum creatinine. Individuals with no result recorded in the previous year were then invited for screening: 189/365 (51.8%) attended. Data were collected on 821 of a total potential population of 997. Taking a serum creatinine of 120 mmol/l as the upper limit of normal, the overall prevalence of renal disease in this population was 8.4%: 6.1% in the hypertensives, 12.6% in the diabetics and 16.9% in those with both. Significant proteinuria (> or =2+) was present in 3.9% of the total population: 2.2% of hypertensives, 8.3% of diabetics and 3.9% of those with both. At screening, 44.5% of individuals had inadequately controlled blood pressure. Renal impairment is common in this population at high risk of renal disease. Screening for renal disease in this population is simple, safe and gives a high yield of positive results.
Asunto(s)
Nefropatías Diabéticas/etiología , Hipertensión/complicaciones , Fallo Renal Crónico/etiología , Anciano , Biomarcadores/sangre , Creatinina/sangre , Nefropatías Diabéticas/sangre , Nefropatías Diabéticas/epidemiología , Inglaterra/epidemiología , Femenino , Glucosuria/epidemiología , Glucosuria/etiología , Humanos , Hipertensión/sangre , Hipertensión/epidemiología , Fallo Renal Crónico/sangre , Fallo Renal Crónico/epidemiología , Masculino , Tamizaje Masivo/métodos , Persona de Mediana Edad , Prevalencia , Proteinuria/epidemiología , Proteinuria/etiología , Juego de Reactivos para DiagnósticoRESUMEN
In the United States, blacks are more frequently diagnosed than whites with end-stage renal failure (ESRF) from primary hypertension or diabetic nephropathy. We performed a validation retrospective case-note study of all blacks with ESRF who started renal replacement therapy (RRT) at three teaching hospitals in London, England, during 1991 to 1995 to investigate and validate the causes of primary renal disease using standard criteria. We identified 144 black patients with a mean age of 52.0 +/- 16.0 (SD) years; 59% were men and 32% had renal histological data. One hundred forty-four whites who were matched for age, sex, and onset of RRT (42% with renal histological data) underwent a similar validation exercise. Before the validation, the principal working diagnosis in the black patients had been diabetic nephropathy in 35% (89%, type 2; 11%, type 1); primary hypertension, 19%; glomerulonephritis (GN), 18%; and uncertain cause, 15%. After validation analysis, this changed to diabetes, 38% (16% biopsy proven); uncertain, 24%; GN, 20%; and primary hypertension, only 10% (28% biopsy proven). Among the uncertain cases (n = 34), 19 patients had hypertension, but this could not be established as the primary disease; 94% of all blacks had hypertension, accelerated in 21%. Among whites, only 3.5% had primary hypertension, and this proportion was not changed by the validation study. Type 2 diabetes is the most common single cause of ESRF in black patients in London, and although hypertension is more common and more severe in blacks, the proportion of renal failure attributed to primary hypertension is overestimated, and the diagnosis is often made using inadequate criteria.
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Negro o Afroamericano , Fallo Renal Crónico/etnología , Terapia de Reemplazo Renal , Población Negra , Nefropatías Diabéticas/complicaciones , Nefropatías Diabéticas/etnología , Femenino , Humanos , Hipertensión/complicaciones , Hipertensión/etnología , Fallo Renal Crónico/etiología , Fallo Renal Crónico/terapia , Londres , Masculino , Persona de Mediana Edad , Nefritis/complicaciones , Nefritis/etnología , Estudios RetrospectivosRESUMEN
Despite the introduction of systemic chemotherapy, inflammatory breast cancer (IBC) remains a disease with a poor prognosis. We performed this phase II study to evaluate the efficacy of infusional chemotherapy as initial treatment in patients with IBC. Fifty-four patients with newly diagnosed IBC were offered infusional chemotherapy and 34 accepted. The schedule consisted of continuous infusional ECF (bolus epirubicin and cisplatin, substituted by carboplatin or cyclophosphamide in some patients) plus continuous 5-FU, given three weekly for six cycles. Following chemotherapy patients went on to have surgery and/or radiotherapy. The chemotherapy was well tolerated and resulted in an overall response rate of 79% with 35% of patients achieving a complete clinical response. The median response duration, time to progression and overall survival were 12 months (4-89+ months), 12 months (4-89+ months) and 23 months (7-89+ months), respectively. Patients had a 5 year disease free and overall survival of 11% and 29%, respectively. Infusional ECF is well tolerated and achieves a high clinical response rate in patients with IBC, but survival results do not appear to be superior to those achieved with conventional bolus chemotherapy schedules.
RESUMEN
The interaction between cell death and cell proliferation determines the growth dynamics of all tissues. Studies are described here which relate the changes in proliferation and apoptosis that occur in human breast cancer during medical therapeutic manoeuvres. Xenograft studies strongly support the involvement of increased apoptosis as well as decreased proliferation after oestrogen withdrawal, and limited studies in clinical samples confirm the involvement of both processes. Cytotoxic chemotherapy induces increases in apoptosis within 24 h of starting treatment. However, after 3 months therapy the residual cell population shows apoptotic and proliferation indices much below pretreatment levels. Further molecular studies of this "dormant" population are important to characterise the mechanism of their resistance to drug therapy. The early changes in proliferation and apoptosis may provide useful intermediate response indices.
Asunto(s)
Apoptosis , Neoplasias de la Mama/patología , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Animales , Antígenos de Neoplasias/análisis , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Antineoplásicos Hormonales/uso terapéutico , Apoptosis/efectos de los fármacos , Biomarcadores , Neoplasias de la Mama/tratamiento farmacológico , División Celular/efectos de los fármacos , Resistencia a Antineoplásicos , Estradiol/análogos & derivados , Estradiol/farmacología , Estradiol/uso terapéutico , Moduladores de los Receptores de Estrógeno/uso terapéutico , Estrógenos , Femenino , Fulvestrant , Humanos , Antígeno Ki-67/análisis , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Neoplasias Hormono-Dependientes/tratamiento farmacológico , Neoplasias Hormono-Dependientes/patología , Embarazo , Tamoxifeno/uso terapéutico , Células Tumorales CultivadasRESUMEN
Numerous recent studies have indicated the central role of apoptosis as a determinant of the growth abnormalities occurring with malignancy and of the effectiveness of a wide range of therapeutic manoeuvres in cancer treatment. However, there has been a relative paucity of studies measuring apoptosis in human solid tumours, because of the low incidence of apoptotic cells, the difficulty of identifying cells undergoing apoptosis, and the ethical and practical restrictions on obtaining repeat biopsies from patients during therapy. Fine-needle aspirates (FNAs) may be obtained from breast carcinomas as a minimally invasive technique allowing repeat sampling. We describe an approach in which the in situ end labelling (TUNEL) assay is applied to cells in FNAs prior to their analysis by flow cytometry, which allows many thousands of cells to be analysed automatically by objective criteria. Cells that were discriminated as apoptotic on flow cytometric analysis were sorted onto microscope slides and found to show nuclear morphology typical of apoptotic cells. A statistically significant relationship was found between the flow cytometric analysis and the conventional application of TUNEL on histological sections (P = 0.03). Repeat analyses of FNAs from 12 carcinomas showed a median 2.05% apoptotic cells and an overall coefficient of variation of 34.9%. Of the total variability in 12 tumours, 80% was attributed to variation between tumours, 12% between batches, and 8% was random. Thus, this technique should be able to detect the major differences in the percentage of apoptotic cells that occur between different tumours (range 0.3-11.3% by flow cytometry) and between different phases of treatment, and should provide a useful tool for further research on this process in solid tumours.
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Apoptosis , Neoplasias de la Mama/patología , Carcinoma/patología , Adulto , Anciano , Apoptosis/genética , Biopsia con Aguja , Neoplasias de la Mama/genética , Carcinoma/genética , Separación Celular/métodos , Fragmentación del ADN , ADN de Neoplasias/análisis , Citometría de Flujo/métodos , Humanos , Persona de Mediana Edad , Fase SRESUMEN
BACKGROUND: Apoptosis has a role in many cellular processes including development, normal tissue homeostasis, and malignancy. This aspect of research is relatively new with distinct methods of analysing disparate biochemical and genetic events to measure apoptotic cells. The use of biotinylated nucleotides to identify DNA strand breaks is a commonly reported method of estimating cells numbers undergoing apoptosis; however, investigators report inconsistent results for a variety of reasons. AIMS AND METHOD: To compare two in situ techniques of measuring apoptosis: in situ nick translation (ISNT) and TdT mediated dUTP-biotin nick end labelling (TUNEL); and to assess DNA cleavage in 20 paired paraffin wax embedded breast cancer tissues from patients; one group who had received no prior treatment and one group who had received chemohormonal treatment. RESULTS AND CONCLUSIONS: Apoptotic scores obtained from paraffin wax embedded human breast cancer after using ISNT and TUNEL methods were not significantly different (p = 0.11). A strong correlation between scores obtained from the two techniques was found (r = 0.758, p < 0.0001). Optimisation of both techniques is crucial to ensure maximal assay performance in breast cancer tissue.
Asunto(s)
Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/patología , Fragmentación del ADN , ADN de Neoplasias , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Apoptosis , Biotinilación , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Carcinoma Ductal de Mama/tratamiento farmacológico , Carcinoma Ductal de Mama/genética , Desoxiuridina , Femenino , Humanos , Técnicas para Inmunoenzimas , Adhesión en ParafinaRESUMEN
Experimental laboratory data suggest that tumour growth is a balance between apoptosis and proliferation and that suppression of drug-induced apoptosis by oncogenes such as bcl-2 may be an important cause of intrinsic chemoresistance. The aims of this study were to assess the in vivo relationship of apoptosis to proliferation and Bcl-2 protein in human breast tumours both prior to chemotherapy and in the residual resistant cell population at the completion of treatment. We examined apoptotic index (AI), Ki67 and Bcl-2 protein expression in the tissue of 40 patients with operable breast cancer immediately before ECF preoperative chemotherapy, and in 20 of these patients with residual tumour, at the completion of treatment. There was a significant positive association between AI and Ki67 both before and after chemotherapy, and in their percentage change with treatment. In the residual specimens AI and Ki67 were significantly reduced compared with pre-treatment biopsies, while Bcl-2 expression showed a significant increase. No differences were seen in the pre-treatment levels of any of the variables measured between patients obtaining pathological complete response and those who did not, although numbers were small. These data suggest that apoptosis and proliferation are closely related in vivo. It is possible that the phenotype of reduced apoptosis and proliferation, and increased Bcl-2 may be associated with breast cancer cells resistant to cytotoxic chemotherapy, although this can only be proven by assessing larger numbers of patients in relation to pathological response.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Carcinoma Ductal de Mama/tratamiento farmacológico , Carcinoma Lobular/tratamiento farmacológico , Antígeno Ki-67/análisis , Proteínas Proto-Oncogénicas c-bcl-2/análisis , Adulto , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/metabolismo , Carcinoma Lobular/metabolismo , División Celular/efectos de los fármacos , Resistencia a Antineoplásicos , Femenino , Humanos , Inmunohistoquímica , Persona de Mediana EdadRESUMEN
PURPOSE: We previously developed an inpatient regimen that consisted of infusional fluorouracil (5-FU), epirubicin, and cisplatin (ECisF), with a response rate of 86% in advanced breast cancer. The current phase II 2:1 randomized study investigated whether cyclophosphamide can be substituted for cisplatin (ECycloF) to reduce toxicity and allow the regimen to be administered on an outpatient basis without loss of efficacy. PATIENTS AND METHODS: Ninety-six women (median age, 49 years; range, 28 to 73) with breast cancer (59 metastatic, 37 locally advanced) received continuous infusional 5-FU (200 mg/m2/d via Hickman line) and six cycles of epirubicin (60 mg/m2 every 21 days) with either cyclophosphamide 600 mg/m2 every 21 days (38 metastatic, 24 locally advanced) or cisplatin 60 mg/m2 every 21 days (21 metastatic, 13 locally advanced). There were no significant differences in patient characteristics between these groups. RESULTS: ECycloF was better tolerated than ECisF in terms of lethargy (P = .005), stomatitis (P = .008), plantar palmar erythema (P = .02), constipation (P < .001), thrombosis (P = .0014), and nausea and vomiting (P = .05). Although there was a trend toward more anemia and leukopenia with ECisF (P =. 1), there was no significant difference in the rates of infection. Efficacy was comparable in terms of overall response (69% v 68%), complete response (CR; 13% v 15%), and median progression-free survival (9 v 8 months). CONCLUSION: ECycloF is an outpatient regimen with a lower incidence of severe nonhematologic toxicity than inpatient ECisF; it has comparable efficacy and is considerably more economical.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Adulto , Anciano , Antibióticos Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/secundario , Cisplatino/administración & dosificación , Ciclofosfamida/administración & dosificación , Epirrubicina/administración & dosificación , Femenino , Fluorouracilo/administración & dosificación , Humanos , Infusiones Intravenosas , Persona de Mediana Edad , Análisis de SupervivenciaRESUMEN
We studied all new patients accepted for renal replacement therapy (RRT) in one unit from 1/1/96 to 31/12/97 (n = 198), to establish time from nephrology referral to RRT, evidence of renal disease prior to referral and the adequacy of renal management prior to referral. Sixty four (32.3%, late referral group) required RRT within 12 weeks of referral. Fifty-nine (29.8%) had recognizable signs of chronic renal failure > 26 weeks prior to referral. Patients starting RRT soon after referral were hospitalized for significantly longer on starting RRT (RRT within 12 weeks of referral, median hospitalization 25.0 days (n = 64); RRT > 12 weeks after referral, median 9.7 days (n = 126), (p < 0.001)). Observed survival at 1 year was 68.3% overall, with 1-year survival of the late referral and early referral groups being 60.5% and 72.5%, respectively (p = NS). Hypertension was found in 159 patients (80.3%): 46 (28.9%) were started on antihypertensive medication following referral, while a further 28 (17.6%) were started on additional antihypertensives. Of the diabetic population (n = 78), only 26 (33.3%) were on an angiotensin-converting-enzyme inhibitor (ACEI) at referral. Many patients are referred late for dialysis despite early signs of renal failure, and the pre-referral management of many of the patients, as evidenced by the treatment of hypertension and use of ACEI in diabetics, is less than optimal.
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Fallo Renal Crónico/terapia , Terapia de Reemplazo Renal/estadística & datos numéricos , Adulto , Anciano , Anciano de 80 o más Años , Antihipertensivos/uso terapéutico , Estudios de Cohortes , Creatinina/sangre , Femenino , Hospitalización , Humanos , Hipertensión/tratamiento farmacológico , Fallo Renal Crónico/sangre , Fallo Renal Crónico/etiología , Masculino , Persona de Mediana Edad , Derivación y Consulta/estadística & datos numéricos , Diálisis Renal , Factores de Tiempo , Resultado del TratamientoRESUMEN
Hormonal breast cancer therapies have traditionally been considered cytostatic, but recent pre-clinical data suggest that anti-oestrogens can induce apoptosis. The aim of this study was to assess whether tamoxifen (TAM) and ICI 182780 (ICI) could induce apoptosis in human breast cancer, and whether this was related to oestrogen receptor status. We measured apoptosis in primary breast cancer patients before and after pre-surgical treatment with 20 mg/day TAM (study 1) or 6 or 18 mg/day ICI (study 2). In each study there was a randomised non-treatment (NT) control group. TAM significantly increased apoptotic index (AI) in ER+ but not in ER- tumours. There was a significant increase in AI following treatment with ICI. Insufficient pairs of samples were available to determine whether this change was confined to ER+ tumours, but in a cross-sectional analysis AI was significantly higher in excision biopsies for ICI-treated than NT patients for ER+ but not ER- tumours. Our results provide clinical evidence that apoptosis may be induced in ER+ primary breast cancer by both non-steroidal and steroidal anti-oestrogens.
Asunto(s)
Antineoplásicos Hormonales/uso terapéutico , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Estradiol/análogos & derivados , Antagonistas de Estrógenos/uso terapéutico , Tamoxifeno/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Biopsia , Neoplasias de la Mama/cirugía , Terapia Combinada , Estradiol/uso terapéutico , Femenino , Fulvestrant , Humanos , Estudios Longitudinales , Persona de Mediana Edad , Adhesión en Parafina , Placebos , Receptores de Estrógenos/análisisRESUMEN
A qualitative study was conducted to examine the processes nurses used to make decisions in actual practice settings. Nurse participants (n = 17) practicing in acute care settings were observed and interviewed to determine the covert cognitive processes that occurred while they were making decisions. Data were analyzed using a constant comparative method. Two decision-making categories emerged: goal-directed process and rule-out process. The goal-directed process was used to reach a goal. The rule-out process involved the development and elimination of hypotheses until only one remained. This process was used to determine what problems existed, the cause of a problem, or the action needed.
Asunto(s)
Enfermedad Aguda/enfermería , Competencia Clínica , Toma de Decisiones , Proceso de Enfermería , Adulto , Objetivos , Humanos , Investigación Metodológica en Enfermería , Solución de ProblemasRESUMEN
Afro-caribbean patients are more frequently diagnosed than caucasians as having end-stage renal failure (ESRF) from primary hypertension or diabetic nephropathy. We performed a retrospective study to investigate the diagnostic criteria and to validate the causes of primary renal disease in all new cases of afro-caribbean patients with ESRF who commenced RRT at 3 inner city Hospitals (1991-1995). We collected clinical-pathological data using a standard proforma. Three of us validated the diagnoses. We have identified 142 afro-caribbean patients for inclusion in this study:mean age of 52.3 (15.50, 52.3 percent were male. Renal biopsy was performed in 32 percent of the patients. Before the validation ,the working diagnosis (including that submitted to EDTA) had been diabetic nephropathy 35.2 percent; primary hypertension 18.3 percent; "uncertain" cause 15.5 percent and primary glomerulonephritis 11.3 percent. Following the analysis we ascribed the underlying cause of ESRF to be: diabetic nephropathy 38.7percent (18.2 percent biopsy proven);"uncertain" 21.8 percent; primary glomerulonephritis 10.6 percent (100 percent bx proven); secondary glomerulonephritis 10.6 percent (66.6 percent bx proven); primary hypertension 10.6 percent (40 percent bx proven); pyelonephritis 3.5 percent; polycystic kidneys 2.8 percent. Among the "uncertain" (n=31): twenty four (17 percent) were related to long-standing hypertension but could not be proven as primary disease. Among the diabetic ESRF patients (n=55), only 6 had IDDM while 49 had NIDDM. Twenty percent (28/142) of all patients had accelerated hypertension while 95 percent (134/142) had hypertension at some time during their disease. This study shows that in afro-caribbean patients NIDDM is the main cause of ESRF, whilst the evidence of primary hypertension is over-estimated, the diagnosis is often made on inadequate criteria. Nevertheless primary hypertension plays an important role in progression to ESRF. (AU)
Asunto(s)
Humanos , Insuficiencia Renal Crónica/diagnóstico , Negro o Afroamericano , Hipertensión , Nefropatías DiabéticasAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Mama/patología , Biopsia , Neoplasias de la Mama/cirugía , Femenino , Humanos , Cuidados PreoperatoriosRESUMEN
The p53 tumour-suppressor gene is important in the regulation of cell growth and apoptosis, and loss of functional wild-type activity may be associated with tumour formation and resistance to therapy. Differentiation of functionally normal wild-type protein from mutant or abnormal protein remains difficult using either immunohistochemical assays or mutational DNA sequencing. p21(WAF1/CIP1) (p21) is induced by wild type p53 and plays an important role in promoting cell cycle arrest. To test the hypothesis that p21 protein expression may act as a downstream marker of tumours from patients with locally advanced breast cancer before treatment with doxorubicin, pretreatment p53 status had been characterized in 63 tumours by p53 protein immunostaining and DNA mutational analysis. There was a significant association between immunostaining for p53 and the presence of p53 mutations (P = 0.01). Of 56 patients available for determination of p21, 31 (55%) expressed p21 protein. Twenty-eight out of 31 patients (90%) positive for p21 had low negative p53 protein expression, whereas only 3 of 13 patients (23%) with high p53 expressed p21 (P = 0.009). No association was seen between p21 protein expression and p53 mutations (P = 0.24). The combination of p53 and p21 immunostaining results improved the specificity of the immunostaining but at a cost of significant reduction in sensitivity. Immunohistochemical assessment of p21 protein expression is inversely associated with abnormal p53 protein in human breast cancer. The detection of p21 protein expression in combination with p53 protein expression did not improve the ability of immunohistochemistry (IHC) to differentiate between normal and mutant p53 protein.