RESUMO
BACKGROUND.: Prolonged invasive mechanical ventilation (IMV) is a frequent challenge, and an increasing number of patients are transferred from intensive care units to long-term acute care hospitals or specialized weaning units. There are few published data for discharge home rates, use of noninvasive ventilation (NIV), or long-term survival. METHODS.: A case-note and database review was conducted of patients admitted to a UK national specialized weaning unit for weaning from IMV between 1992 and 2012. Patients were grouped into diagnostic categories according to the predominant cause of weaning failure. Weaning outcomes and long-term survival were assessed according to diagnostic group and mode of ventilation on discharge. RESULTS.: Four hundred and fifty-eight patients were transferred for weaning from IMV. Four hundred and seventeen (91%) survived to hospital discharge, of whom at least 343 (82%) were ultimately discharged to their own home. Three hundred and thirty (72%) weaned from IMV, of whom 142 weaned from all ventilation and 188 weaned to nocturnal NIV. Weaning success was highest for patients with chronic obstructive pulmonary disease and chest wall disorders. Median survival from unit discharge was 25 months (interquartile range 5-74), with the longest survival seen for patients discharged with nocturnal NIV [37 (12-81) months]. CONCLUSIONS.: These results confirm successful weaning outcomes for patients transferred to a specialized weaning and long-term ventilation service. In contrast to other service models, most patients achieved discharge to their own home.
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Unidades Hospitalares/organização & administração , Desmame do Respirador/métodos , Idoso , Bases de Dados Factuais , Feminino , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Ventilação não Invasiva/efeitos adversos , Ventilação não Invasiva/mortalidade , Alta do Paciente , Encaminhamento e Consulta , Respiração Artificial/métodos , Análise de Sobrevida , Resultado do Tratamento , Desmame do Respirador/mortalidade , Desmame do Respirador/estatística & dados numéricosRESUMO
AIMS: To determine whether IHC4 score assessed on pre-treatment core biopsies (i) predicts response to neo-adjuvant chemotherapy in ER-positive (ER+) breast cancer; (ii) provides more predictive information than Ki67 alone. METHODS: 113 patients with ER+ primary breast cancer treated with neo-adjuvant chemotherapy at the Royal Marsden Hospital between 2002 and 2010 were included in the study. Pathologic assessment of the excision specimen was made for residual disease. IHC4 was determined on pre-treatment core biopsies, blinded to clinical outcome, by immunohistochemistry using quantitative scoring of ER (H-score), PgR (%) and Ki67 (%). Determination of HER2 status was made by immunohistochemistry and fluorescent in situ hybridization for 2+ cases. IHC4 and Ki67 scores were tested for their association with pathological complete response (pCR) rate and residual cancer burden (RCB) score. RESULTS: 18 (16%) of the 113 patients and 8 (9%) of the 88 HER2-ve cases achieved pCR. Ki67 and IHC4 score were both positively associated with achievement of pCR (P < 10-7 and P < 10-9, respectively) and RCB0+1 (P < 10-5 and P < 10-9, respectively) following neo-adjuvant chemotherapy in all patients. Rates of pCR+RCB1 were 45 and 66% in the highest quartiles of Ki67 and IHC4 scores, respectively. In ER+HER2-ve cases, pCR+RCB1 rates were 35% and in the highest quartile of both Ki67 and IHC4. There were no pCRs in the lower half of IHC4 or Ki67 scores. CONCLUSIONS: IHC4 was strongly predictive of pCR or near pCR in ER+ breast cancers following neo-adjuvant chemotherapy. Ki67 was an important component of this predictive ability, but was not as predictive as IHC4.
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Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Receptores de Estrogênio/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Feminino , Humanos , Antígeno Ki-67/metabolismo , Pessoa de Meia-Idade , Terapia Neoadjuvante , Receptor ErbB-2/metabolismo , Receptores de Progesterona/metabolismo , Análise de Sobrevida , Resultado do TratamentoRESUMO
New research questions emerge as medical needs continue to evolve and as we improve our understanding of cancer biology and treatment of malignancies. Although significant advances have been made in some areas of breast cancer research resulting in improvements in therapies and outcomes over the last few decades, other areas have not benefited to the same degree and we continue to have many gaps in our knowledge. This article summarizes the 12 short and medium-term clinical research needs in breast cancer deemed as priorities in 2016 by a panel of experts, in an attempt to focus and accelerate future research in the most needed areas: (i) de-escalate breast cancer therapies in early breast cancer without sacrificing outcomes; (ii) explore optimal adjuvant treatment durations; (iii) develop better tools and strategies to identify patients with genetic predisposition; (iv) improve care in young patients with breast cancer; (v) develop tools to speed up drug development in biomarker-defined populations; (vi) identify and validate targets that mediate resistance to chemotherapy, endocrine therapy and anti-HER2 therapies; (vii) evaluate the efficacy of local-regional treatments for metastatic disease; (viii) better define the optimal sequence of treatments in the metastatic setting; (ix) evaluate the clinical impact of intra-patient heterogeneity (intra-tumor, inter-tumor and inter-lesion heterogeneity); (x) better understand the biology and identify new targets in triple-negative breast cancer; (xi) better understand immune surveillance in breast cancer and further develop immunotherapies; and (xii) increase survivorship research efforts including supportive care and quality of life.
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Neoplasias da Mama/tratamento farmacológico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/metabolismo , Pesquisa Biomédica , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/metabolismo , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Terapia de Alvo Molecular , Melhoria de Qualidade , Resultado do TratamentoRESUMO
The development of trastuzumab and other targeted systemic therapies has transformed the management of HER-2 positive breast cancers. However, as patients live longer and systemic therapies may not cross the blood brain barrier a rising number of patients are developing leptomeningeal metastases and brain metastases as a sanctuary site of disease. Intrathecal trastuzumab has been reported to treat these. We describe a breast cancer patient with HER-2 positive leptomeningeal disease in the spinal cord successfully treated with intrathecal trastuzumab and methotrexate, alongside systemic anti-HER-2 therapy and radiotherapy. We also review the literature to date on the efficacy and safety of intrathecal trastuzumab, and recent evidence suggesting that intrathecal trastuzumab passes via the blood brain barrier into the serum to achieve intravenous concentrations similar to that seen with systemic therapy alone. Overall, intrathecal trastuzumab appears to be a safe and often effective treatment for leptomeningeal metastases in HER-2 positive breast cancer. Ongoing phase I and II studies are required to determine optimum dosing schedules, validate CSF and CSF-to-serum pharmacokinetics, determine efficacy, and to assess the added benefits or disadvantages of prior radiotherapy and concomitant systemic therapy.
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Antineoplásicos/administração & dosagem , Neoplasias da Mama/patologia , Neoplasias Meníngeas/tratamento farmacológico , Receptor ErbB-2 , Neoplasias da Medula Espinal/tratamento farmacológico , Trastuzumab/administração & dosagem , Neoplasias da Mama/química , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos , Injeções Espinhais , Neoplasias Meníngeas/secundário , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Receptor ErbB-2/análise , Receptor ErbB-2/antagonistas & inibidores , Neoplasias da Medula Espinal/secundárioRESUMO
Knowledge of sediment movement throughout a catchment environment is essential due to its influence on the character and form of our landscape relating to agricultural productivity and ecological health. Sediment fingerprinting is a well-used tool for evaluating sediment sources within a fluvial catchment but still faces areas of uncertainty for applications to large catchments that have a complex arrangement of sources. Sediment fingerprinting was applied to the Manawatu River Catchment to differentiate 8 geological and geomorphological sources. The source categories were Mudstone, Hill Subsurface, Hill Surface, Channel Bank, Mountain Range, Gravel Terrace, Loess and Limestone. Geochemical analysis was conducted using XRF and LA-ICP-MS. Geochemical concentrations were analysed using Discriminant Function Analysis and sediment un-mixing models. Two mixing models were used in conjunction with GRG non-linear and Evolutionary optimization methods for comparison. Discriminant Function Analysis required 16 variables to correctly classify 92.6% of sediment sources. Geological explanations were achieved for some of the variables selected, although there is a need for mineralogical information to confirm causes for the geochemical signatures. Consistent source estimates were achieved between models with optimization techniques providing globally optimal solutions for sediment quantification. Sediment sources was attributed primarily to Mudstone, ≈38-46%; followed by the Mountain Range, ≈15-18%; Hill Surface, ≈12-16%; Hill Subsurface, ≈9-11%; Loess, ≈9-15%; Gravel Terrace, ≈0-4%; Channel Bank, ≈0-5%; and Limestone, ≈0%. Sediment source apportionment fits with the conceptual understanding of the catchment which has recognized soft sedimentary mudstone to be highly susceptible to erosion. Inference of the processes responsible for sediment generation can be made for processes where there is a clear relationship with the geomorphology, but is problematic for processes which occur within multiple terrains.
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BACKGROUND: Trastuzumab has changed the natural history of metastatic HER2 positive breast cancer. Some patients remain well and in remission for many years. There is currently no established duration after which trastuzumab in the advanced setting can be safely discontinued. This study aims to evaluate long-term efficacy and cardiac safety of trastuzumab when used as first-line treatment for patients with metastatic HER2 positive breast cancer. PATIENT AND METHODS: We retrospectively identified 215 patients with HER2 positive, locally advanced or metastatic breast cancer who commenced first line trastuzumab-containing therapy for metastatic disease between 2001 and 2010 at The Royal Marsden Hospital. RESULTS: The median progression free survival for all patients was 12 months (95%CI: 10.3-14.6 months); 103 (48%) patients remained in remission beyond one year, 59 (27%) beyond two years and 25 (12%) beyond five years. The median overall survival was 2.6 years (95% confidence interval (CI): 2.2-3.3). The objective response rate (ORR) was 65% with 17 (8%) complete responses and 120 (57%) partial responses. Trastuzumab was well tolerated. Twenty eight (13%) patients recorded any grade of left ventricular dysfunction. There was no significant difference in cardiac toxicity between those patients on less than or more than one year of trastuzumab. CONCLUSION: Trastuzumab is associated with long-term remissions in a significant proportion of patients with metastatic HER2 positive disease when used in the first-line advanced setting.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Receptor ErbB-2/análise , Trastuzumab/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/química , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Metástase Linfática , Pessoa de Meia-Idade , Estudos Retrospectivos , Tempo , Resultado do TratamentoRESUMO
BACKGROUND: The purpose of this study was (i) to test the hypothesis that combining Ki67 with residual cancer burden (RCB) following neoadjuvant chemotherapy, as the residual proliferative cancer burden (RPCB), provides significantly more prognostic information than either alone; (ii) to determine whether also integrating information on ER and grade improves prognostic power. PATIENTS AND METHODS: A total of 220 patients treated with neoadjuvant chemotherapy for primary breast cancer were included in the study. Analyses employed a Cox proportional hazard model. Prognostic indices (PIs) were created adding in Ki67, grade and ER to RCB. Leave-one-out cross-validation was used to reduce bias. The overall change in χ(2) of the best model for each index was used to compare the prognostic ability of the different indices. RESULTS: All PIs provided significant prognostic information for patients with residual disease following neoadjuvant chemotherapy. RPCB (χ(2) = 61.4) was significantly more prognostic than either RCB (χ(2) = 38.1) or Ki67 (χ(2) = 53.8) alone P < 0.001. A PI incorporating RCB, Ki67 grade and ER provided the most prognostic information overall and gave χ(2) = 73.8. CONCLUSIONS: This study provides proof of principle that the addition of post-treatment Ki67 to RCB improves the prediction of long-term outcome. Prediction may be further improved by addition of post-treatment grade and ER and warrants further investigation for estimating post-neoadjuvant risk of recurrence. These indices may have utility in stratifying patients for novel therapeutic interventions after neoadjuvant chemotherapy.
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Neoplasias da Mama/tratamento farmacológico , Antígeno Ki-67/análise , Terapia Neoadjuvante , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasia Residual/tratamento farmacológico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais , Neoplasias da Mama/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Receptores de Estrogênio/metabolismo , Resultado do TratamentoRESUMO
BACKGROUND: The purpose of this study was to identify any differences in key biomarkers associated with estrogen action between biopsies taken at diagnosis and at recurrence or progression during treatment with an aromatase inhibitor (AI). PATIENTS AND METHODS: Patients were retrospectively identified from a clinical database as having relapsed or progressed during AI treatment. Immunohistochemistry was carried out against estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2), insulin-like growth factor type-1 receptor (IGF1R), insulin receptor substrate-1 (IRS-1), stathmin, phosphatase and tensin homolog and Ki67. RESULTS: Fifty-five pairs of samples were identified with ER- and/or PgR-positive diseases. Four (7%) patients were ER-negative at progression. Overall, PgR levels were lower in the recurrence sample, but 35% of cases remained positive. IGF1R levels decreased significantly. There were no substantial changes in HER2, IRS-1 or stathmin levels to indicate a role in resistance. Higher Ki67 levels at resistance indicate more proliferative disease. CONCLUSIONS: The phenotype of AI-recurrent lesions shows high between-tumour heterogeneity. There is evidence of an increase in Ki67, a reduction in IGF1R and a loss of ER expression in some individuals and some activation of growth factor signalling pathways that may explain resistance in individuals and merit treatment targeted to those pathways. Biopsy at recurrence will be necessary to identify the relevant target for individuals.
Assuntos
Inibidores da Aromatase/uso terapêutico , Biomarcadores Tumorais/análise , Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Receptores de Estrogênio/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Anastrozol , Androstadienos/uso terapêutico , Neoplasias da Mama/mortalidade , Feminino , Humanos , Proteínas Substratos do Receptor de Insulina/metabolismo , Antígeno Ki-67/metabolismo , Letrozol , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Nitrilas/uso terapêutico , PTEN Fosfo-Hidrolase/metabolismo , Receptor ErbB-2/metabolismo , Receptor IGF Tipo 1/metabolismo , Receptores de Progesterona/metabolismo , Estudos Retrospectivos , Estatmina/metabolismo , Tamoxifeno/uso terapêutico , Triazóis/uso terapêuticoRESUMO
BACKGROUND: Premature ovarian failure and infertility following chemotherapy in early breast cancer (EBC) are major concerns for young women. The role of gonadotrophin-releasing hormone (GnRH) agonists with chemotherapy in EBC in reducing the incidence of chemotherapy-induced early menopause remains uncertain, and long-term data on the recovery of fertility are sparse. We report an audit of our experience with the GnRH agonist, goserelin (Zoladex®), used with chemotherapy to preserve ovarian function and maintain fertility. PATIENTS AND METHODS: Pre-menopausal women were given goserelin subcutaneously every 28 days during chemotherapy, starting 0-14 days before treatment. The main clinical end point was recovery of menstruation after chemotherapy. The other end points were rate of successful conception and median time to recovery of menses. RESULTS: About 84% of 125 women recovered menstruation with the median time to recovery of 6 months (1-43 months), including 76% of 71 patients aged over 35. Of the 42 patients who attempted pregnancy, 71% (n=30) managed to achieve pregnancies. At the time of analysis, there were 42 pregnancies and 30 healthy deliveries. CONCLUSIONS: The GnRH agonist, goserelin, given with chemotherapy for EBC is associated with a low risk of long-term chemotherapy-induced amenorrhoea and a high chance of pregnancy. Further randomised trials are needed.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Gosserrelina/uso terapêutico , Menstruação , Ovário/fisiopatologia , Resultado da Gravidez , Pré-Menopausa , Adulto , Neoplasias da Mama/fisiopatologia , Feminino , Humanos , Pessoa de Meia-Idade , GravidezRESUMO
Although there have been major improvements in the management of breast cancer, with a rapidly falling death rate despite an increasing incidence of the disease, metastatic breast cancer remains common and the cause of death in nearly 12 000 women annually in the UK. Numerous treatment options are available that either target the tumour or reduce the complications of the disease. Clinical decision making depends on knowledge of the extent and biology of the disease and available drug options, an understanding of the functional status, and also the wishes and expectations of the individual patient. In addition, the organisation of services and support of the patient are essential components of high-quality care. The National Institute for Health and Clinical Excellence (NICE) has produced guidelines for the treatment of advanced breast cancer, which in some areas have perhaps failed to appreciate the complexity of patient management. This guidance document aims to provide succinct practical advice on the treatment of metastatic breast cancer, highlight some limitations of the NICE guidelines, and provide suggestions for management where available data are limited.
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Neoplasias Ósseas/terapia , Neoplasias Encefálicas/terapia , Neoplasias da Mama/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Inibidores da Aromatase/uso terapêutico , Neoplasias Ósseas/secundário , Neoplasias Encefálicas/secundário , Neoplasias da Mama/patologia , Terapia Combinada , Tomada de Decisões , Feminino , Gosserrelina/uso terapêutico , Humanos , Ovariectomia , Equipe de Assistência ao Paciente , Pós-Menopausa , Pré-Menopausa , Radioterapia , Tamoxifeno/uso terapêutico , Reino UnidoRESUMO
BACKGROUND: Surprisingly few data are published on the relevance of even commonly used biomarkers of response to aromatase inhibitors (AIs) in advanced breast cancer. Here, we aim to determine the effectiveness of AIs in that setting according to quantitative levels of estrogen receptor (ER), progesterone receptor (PgR) and Ki67 or human epithelial growth factor receptor-2 (HER-2) status. PATIENTS AND METHODS: ER, PgR, HER-2 and Ki67 protein expressions were centrally assessed in 177 archival formalin-fixed paraffin-embedded primary or locally recurrent breast tumours from women who subsequently received AI treatment of advanced disease. RESULTS: Among ER-positive patients (n = 146), higher PgR, but not ER, levels were associated with increased time to AI treatment failure (TTF). Higher Ki67 staining was associated with decreased TTF. ER-positive/HER-2-positive patients showed a non-significant trend for decreased TTF compared with ER-positive/HER-2-negative patients. PgR level, but not Ki67, remained a significant predictor of TTF in multivariate analysis of ER-positive patients. CONCLUSIONS: Higher PgR and Ki67 levels are significantly associated with increased and decreased TTF, respectively, in ER-positive patients receiving AI treatment of advanced disease. The higher proliferation seen in PgR-negative tumours does not explain the poorer clinical responsiveness of this subgroup.
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Inibidores da Aromatase/uso terapêutico , Biomarcadores Farmacológicos/metabolismo , Neoplasias da Mama/tratamento farmacológico , Antígeno Ki-67/metabolismo , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Pós-Menopausa , Análise Serial de Tecidos , Falha de Tratamento , Resultado do TratamentoRESUMO
BACKGROUND: First-line bevacizumab combined with chemotherapy significantly improves efficacy versus chemotherapy alone in human epidermal growth factor receptor 2 (HER2)-negative locally recurrent or metastatic breast cancer (LR/mBC). This large, open-label study further assesses first-line bevacizumab with taxane-based chemotherapy in routine oncology practice. PATIENTS AND METHODS: Patients with HER2-negative LR/mBC, Eastern Cooperative Oncology Group (ECOG) performance status (PS) of zero to two and no prior chemotherapy for LR/mBC received bevacizumab 10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks plus taxane-based chemotherapy (or other non-anthracycline chemotherapy) until disease progression, unacceptable toxicity or patient withdrawal. The primary end point was safety; time to progression (TtP) was a secondary end point. RESULTS: Median follow-up in 2251 treated patients was 12.7 months. Median age was 53 years and 94% of patients had ECOG PS of zero or one. Bevacizumab was most commonly administered with single-agent paclitaxel (35%), single-agent docetaxel (33%) or taxane-based combination therapy (10%). The most frequent grade ≥3 adverse event (AE) was neutropenia (5.4%). Grade ≥3 AEs previously associated with bevacizumab included hypertension (4.4%), arterial/venous thromboembolism (3.2%), proteinuria (1.7%) and bleeding (1.4%). No new bevacizumab safety signals were observed. Median TtP was 9.5 months (95% confidence interval 9.1-9.9). CONCLUSIONS: The study population in ATHENA was more representative of general oncology practice than populations enrolled into randomised trials, although there may have been some bias towards younger, fitter patients. The safety and efficacy of bevacizumab-taxane therapy in this large study were consistent with results from randomised first-line trials.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/secundário , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/secundário , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Hidrocarbonetos Aromáticos com Pontes/administração & dosagem , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Masculino , Pessoa de Meia-Idade , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Taxoides/administração & dosagem , Resultado do Tratamento , Adulto JovemRESUMO
Major changes are occurring in the approach to the management of early breast cancer. Although the incidence is rising steadily, nevertheless mortality is falling significantly in the United Kingdom and throughout the Western world. To a considerable extent this is because of the use of adjuvant medical therapies along with local treatments for early breast cancer. These include the traditional approaches of endocrine therapy and chemotherapy along with newer approaches including so-called targeted biological therapies including trastuzumab (Herceptin). The challenge now is to select which patients benefit best from each of these treatments. It is clear that breast cancer is no longer one disease but a heterogeneous group of subtypes, each with their own biology and pattern of clinical behaviour.
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Neoplasias da Mama/tratamento farmacológico , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Neoplasias da Mama/química , Difosfonatos/uso terapêutico , Feminino , Humanos , Imuno-Histoquímica , Inibidores de Poli(ADP-Ribose) Polimerases , TrastuzumabRESUMO
Single agent capecitabine is effective and well tolerated in metastatic breast cancer (MBC). We have retrospectively analysed capecitabine outcome as 1st, 2nd or 3rd line chemotherapy in 89 elderly patients ≥70 years with locally advanced or MBC treated in our Unit, 55 (62%) as 1st line and 34 (38%) as 2nd or 3rd line. Starting dose was 1000 mg/m(2) twice daily, days 1-14 every 3 weeks, but 36 (41%) started on a 25% dose reduction because of frailty and 12 (13%) reduced dose after the 1st or the 2nd cycle. Overall response rate (ORR) was 45% (95% CI: 35-55%). A further 19 (21%) achieved stable disease (SD) for ≥6 months. Median time to progression (TTP) and overall survival (OS) were 30 (95% CI: 23-37) and 61 (95% CI: 44-77) weeks, respectively. The ORR for 1st line treatment was 51% compared with 35% for 2nd and 3rd line treatment (p = 0.03). No significant difference in efficacy was seen between patients receiving the full versus reduced dose. Capecitabine was well tolerated, although 35% had treatment delays and 57% required dose reduction. Grade 3-4 toxicities were hand-foot syndrome in 11%, lethargy 9% and diarrhoea 2%. Capecitabine is an effective and well-tolerated drug in elderly patients with MBC including for 1st line treatment. Dose reduction is frequently required but does not appear to affect outcome.
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Antimetabólitos Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Desoxicitidina/análogos & derivados , Fluoruracila/análogos & derivados , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/uso terapêutico , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Capecitabina , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/uso terapêutico , Progressão da Doença , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Fluoruracila/uso terapêutico , Humanos , Estimativa de Kaplan-Meier , Metástase Neoplásica , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Rapid eye movement (REM) sleep behaviour disorder (RBD) is a common sleep disorder that can be associated with a number of neurodegenerative conditions as well as with narcolepsy. Current diagnostic criteria require overnight polysomnography, and there are no other biomarkers available. The control of REM sleep is complex with a putative on/off switch within the brainstem activated, amongst other things, by hypocretinergic pathways from the lateral hypothalamus. METHODS: Cerebrospinal fluid hypocretin levels were measured in five patients with idiopathic RBD. RESULTS: Hypocretin levels were between 254 and 450 pg/ml and therefore within the normal range of >100 pg/ml. CONCLUSION: Hypocretin levels in patients with idiopathic RBD are normal.
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Peptídeos e Proteínas de Sinalização Intracelular/líquido cefalorraquidiano , Neuropeptídeos/líquido cefalorraquidiano , Transtorno do Comportamento do Sono REM/líquido cefalorraquidiano , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , OrexinasRESUMO
BACKGROUND: The epirubicin with cisplatin and infusional 5-fluorouracil (5-FU) (ECisF) regimen was found to be highly active in the treatment of metastatic breast cancer and as neoadjuvant therapy. The UK TRAFIC (trial of adjuvant 5-FU infusional chemotherapy) trial (CRUK/95/007) compared this schedule with 5-FU, epirubicin and cyclophosphamide (FEC60) as adjuvant therapy in patients with early breast cancer. METHODS: In this multicentre, open-label, phase III randomised controlled trial, 349 women were randomly assigned to receive i.v. ECisF [epirubicin 60 mg/m(2), day 1, cisplatin 60 mg/m(2), day 1 and 5-FU 200 mg/m(2) by daily 24-h infusion (n = 172)] or FEC [5-FU 600 mg/m(2), day 1, epirubicin 60 mg/m(2), day 1 and cyclophosphamide 600 mg/m(2), day 1 (n = 177)]. Both treatments were delivered every 3 weeks for six cycles. The primary end point was relapse-free interval (RFI). TRAFIC is registered as an International Standard Randomised Controlled Trial (ISRCTN 83324925). RESULTS: All randomised patients were included in the intent-to-treat population. With a median follow-up of 112 months, there was no significant difference in RFI between the treatment groups [hazard ratio 0.84 (95% confidence interval 0.60-1.19); P = 0.33]. Toxic effects were more frequent in patients allocated to ECisF. CONCLUSIONS: While limited by size, TRAFIC has long follow-up. No evidence of a clinically worthwhile benefit for the infusional treatment compared with standard treatment was observed which would justify further investigation or widespread use.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimioterapia Adjuvante , Cisplatino/administração & dosagem , Ciclofosfamida/administração & dosagem , Epirubicina/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Humanos , Análise de SobrevidaRESUMO
BACKGROUND: Recent data suggest that capecitabine may have little efficacy in women with metastatic triple negative breast cancer (TNT). We have therefore retrospectively analysed capecitabine outcome in the TN subgroup of patients with locally advanced or metastatic breast cancer treated in our unit. PATIENTS AND METHODS: All TNT patients on our prospectively maintained database with locally advanced or metastatic breast cancer who were given capecitabine as 1st-, 2nd- or 3rd-line chemotherapy were assessed for response and outcome. RESULTS: In total, 363 patients with locally advanced or metastatic breast cancer treated with capecitabine were identified. Eighty-nine (24.5%) patients had TNT and of these, 47 (53%) patients received capecitabine as 1st-line treatment and 42 (47%) as 2nd- or 3rd-line treatment. The overall response rate was 21% (95% CI: 13-31%), including 1 (1%) complete response (CR) and 18 (20%) partial responses (PR). Another 11 (12%) patients maintained stable disease (SD) for 6 months. An overall disease control (CR + PR + SD) was, therefore, achieved in 30 (33%) patients. The median time to disease progression was 11 weeks (95% CI: 9-13) and the median overall survival was 39 weeks (95% CI: 33-45). Median response duration was 22 weeks (95% CI: 18-25). No significant difference in efficacy was seen between 1st- and 2nd-/3rd-line treatment. CONCLUSION: Capecitabine is a treatment option for patients with TN tumours in advanced disease including 1st line and 2nd/3rd line.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Desoxicitidina/análogos & derivados , Fluoruracila/análogos & derivados , Receptores de Estrogênio/análise , Receptores de Progesterona/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/química , Capecitabina , Desoxicitidina/uso terapêutico , Feminino , Fluoruracila/uso terapêutico , Humanos , Pessoa de Meia-Idade , Resultado do TratamentoAssuntos
Anticorpos Monoclonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Quimioterapia Adjuvante/métodos , Receptor ErbB-2/efeitos dos fármacos , Antraciclinas/uso terapêutico , Anticorpos Monoclonais Humanizados , Feminino , Humanos , Receptor ErbB-2/antagonistas & inibidores , TrastuzumabRESUMO
BACKGROUND: Analysis of estrogen receptor (ER), progesterone receptor (PgR) and HER2 status in early breast cancer (EBC) is increasingly being conducted in core needle biopsies (CNBs) taken at diagnosis but the concordance with the excisional biopsy (EB) is poorly documented. PATIENTS AND METHODS: Patients with EBC presenting to The Royal Marsden Hospital from June 2005 to September 2007 who had CNB and subsequent EB were included. ER and PgR were determined by immunohistochemistry (IHC) and graded from 0 to 8 (Allred score). HER2 was determined by IHC and scored from 0 to 3+. FISH analysis was carried out in HER2 2+ cases and in discordant cases. RESULTS: In all, 336 pairs of samples were compared. ER was positive in 253 CNBs (75%) for 255 EBs (76%) and was discordant in six patients (1.8%). PgR was positive in 221 CNBs (66%) and 227 (67.6%) EBs being discordant in 52 cases (15%). HER2 was positive in 41 (12.4%) of the 331 CNBs in which it was determined compared with 44 (13.3%) EBs and discordant in four cases (1.2%). CONCLUSIONS: CNB can be used with confidence for ER and HER2 determination. For PgR, due to a substantial discordance between CNB and EB, results from CNB should be used with caution.
Assuntos
Biópsia por Agulha/métodos , Biópsia/métodos , Neoplasias da Mama/diagnóstico , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Diagnóstico Precoce , Feminino , Humanos , Reprodutibilidade dos TestesRESUMO
Accelerated (dose-dense) chemotherapy, in which the frequency of administration is increased without changing total dose or duration, may increase the efficacy of cancer chemotherapy. We performed a randomised Phase II study to assess the safety and relative toxicity of AC (doxorubicin; cyclophosphamide) vs E(epirubicin)C given by conventional or accelerated schedules as neoadjuvant or adjuvant chemotherapy for early breast cancer. Furthermore, the relative toxicity of doxorubicin and epirubicin remains uncertain. Patients were randomised to one of four arms; four courses of standard 3 weekly cyclophosphamide 600 mg m(-2) in combination with doxorubicin 60 mg m(-2) (AC) vs epirubicin 90 mg m(-2) (EC) 3 weekly vs the same regimens administered every 2 weeks with pegfilgrastim (G-CSF). A total of 126 patients were treated, 42 with standard AC, 42 with accelerated AC, 19 with standard EC and 23 with accelerated EC. Significantly more grade 3/4 day one neutropenia was seen with standard (6/61, 10%) compared to accelerated (0/65,) regimens (P=0.01). A trend towards more neutropenic sepsis was seen in the combined standard and accelerated AC arms (12/84, 14%) compared to the combined EC arms (1/42, 2%), P=0.06. Falls in left ventricular ejection fraction were not increased with accelerated treatment. Accelerated AC and EC with pegfilgrastim are safe and feasible regimens in the treatment of early breast cancer with less neutropenia than conventional 3 weekly schedules.