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ABSTRACT: Glucocorticoids are key components of the standard-of-care treatment regimens for B-cell malignancy. However, systemic glucocorticoid treatment is associated with several adverse events. ABBV-319 is a CD19-targeting antibody-drug conjugate engineered to reduce glucocorticoid-associated toxicities while possessing 3 distinct mechanisms of action (MOA) to increase therapeutic efficacy: (1) antibody-mediated delivery of a glucocorticoid receptor modulator (GRM) payload to activate apoptosis, (2) inhibition of CD19 signaling, and (3) enhanced fragment crystallizable (Fc)-mediated effector function via afucosylation of the antibody backbone. ABBV-319 elicited potent GRM-driven antitumor activity against multiple malignant B-cell lines in vitro, as well as in cell line-derived xenografts and patient-derived xenografts (PDXs) in vivo. Remarkably, a single dose of ABBV-319 induced sustained tumor regression and enhanced antitumor activity compared with repeated dosing of systemic prednisolone at the maximum tolerated dose in mice. The unconjugated CD19 monoclonal antibody (mAb) also displayed antiproliferative activity in a subset of B-cell lymphoma cell lines through the inhibition of phosphoinositide 3-kinase signaling. Moreover, afucosylation of CD19 mAb enhanced Fc-mediated antibody-dependent cellular cytotoxicity. Notably, ABBV-319 displayed superior efficacy compared with afucosylated CD19 mAb in human CD34+ peripheral blood mononuclear cell-engrafted NSG-Tg(Hu-IL15) transgenic mice, demonstrating enhanced antitumor activity when multiple MOAs are enabled. ABBV-319 also showed durable antitumor activity across multiple B-cell lymphoma PDX models, including nongerminal center B-cell diffuse large B-cell lymphoma and relapsed lymphoma after R-CHOP treatment. Collectively, these data support the ongoing evaluation of ABBV-319 in a phase 1 clinical trial.
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Antígenos CD19 , Inmunoconjugados , Receptores de Glucocorticoides , Ensayos Antitumor por Modelo de Xenoinjerto , Humanos , Animales , Antígenos CD19/inmunología , Ratones , Inmunoconjugados/farmacología , Inmunoconjugados/uso terapéutico , Receptores de Glucocorticoides/antagonistas & inhibidores , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Linfoma de Células B/tratamiento farmacológico , Linfoma de Células B/patología , Línea Celular Tumoral , Ratones SCID , Femenino , Maitansina/análogos & derivadosRESUMEN
OBJECTIVE: Studies in hospital settings demonstrate that there is greater guideline adherence when care is delivered by a respiratory specialist, however, this has not been explored in primary care. The aim of this study is to determine the impact integrating respiratory specialists into primary care has on the delivery of guideline adherent chronic obstructive pulmonary disease (COPD) care. METHODS: 18 general practitioner (GP) practices were randomised to provide either usual or specialist-led COPD care. Patients at participating practices were included if they had an existing diagnosis of COPD. Outcomes were measured at the individual patient level. The primary outcome was guideline adherence, assessed as achieving four or more items of the COPD care bundle. Secondary outcome measures included quality of life, number of exacerbations, number of COPD-related hospitalisations and respiratory outpatient attendances. RESULTS: 586 patients from 10 practices randomised to the intervention and 656 patients from 8 practices randomised to the control arm of the study were included. The integration of respiratory specialists into GP practices led to a statistically significant (p<0.001) improvement in the provision of guideline adherent care when compared with usual care in this cohort (92.7% vs 70.1%) (OR 4.14, 95% CI 2.14 to 8.03). CONCLUSION: This is the first study to demonstrate that guideline adherence is improved through the integration of respiratory specialists into GP practices to deliver annual COPD reviews. To facilitate changes in current healthcare practice and policy, the findings of this paper need to be viewed in combination with qualitative research exploring the acceptability of specialist integration. TRIAL REGISTRATION NUMBER: NCT03482700.
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Medicina General , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Atención a la Salud , Calidad de VidaRESUMEN
BACKGROUND: Adjuvant chemotherapy for patients with early breast cancer improves outcomes but its toxicity affects patients' quality of life (QOL). The UK TACT2 trial investigated whether accelerated epirubicin improves time to recurrence and if oral capecitabine is non-inferior to cyclophosphamide, methotrexate, and fluorouracil (CMF) for efficacy with less toxicity. Results showed no benefit for accelerated epirubicin and capecitabine was non-inferior. As part of the QOL substudy, we aimed to assess the effect of chemotherapies on psychological distress, physical symptoms, and functional domains. METHODS: TACT2 was a multicentre, phase 3, open-label, parallel-group, randomised, controlled trial done in 129 UK centres. Participants were aged 18 years or older with histologically confirmed node-positive or high-risk node-negative invasive primary breast cancer, who had undergone complete excision, and due to receive adjuvant chemotherapy. Patients were randomly assigned (1:1:1:1) to four cycles of 100 mg/m2 epirubicin either every 3 weeks (standard epirubicin) or every 2 weeks with 6 mg pegfilgrastim on day 2 of each cycle (accelerated epirubicin), followed by four 4-week cycles of either CMF (600 mg/m2 cyclophosphamide intravenously on days 1 and 8 or 100 mg/m2 orally on days 1-14; 40 mg/m2 methotrexate intravenously on days 1 and 8; and 600 mg/m2 fluorouracil intravenously on days 1 and 8 of each cycle) or four 3-week cycles of 2500 mg/m2 capecitabine (1250 mg/m2 given twice daily on days 1-14 of each cycle). The randomisation schedule was computer generated in random permuted blocks, stratified by centre, number of nodes involved (none vs 1-3 vs ≥4), age (≤50 years vs >50 years), and planned endocrine treatment (yes vs no). QOL was one of the secondary outcomes and is reported here. All patients from a subset of 44 centres were invited to complete QOL questionnaires (Hospital Anxiety and Depression Scale [HADS] and European Organisation for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire 30-item core module [QLQ-C30] and Quality of Life Questionnaire breast module [QLQ-BR23]) at baseline, end of standard or accelerated epirubicin, end of CMF or capecitabine, and at 12 and 24 months after randomisation. The QOL substudy prespecified two coprimary QOL outcomes assessed in the intention-to-treat population: overall QOL (reported elsewhere) and HADS total score. Prespecified secondary QOL outcomes were EORTC QLQ-C30 subscales of physical function, role function, and fatigue and EORTC QLQ-BR23 subscales of sexual function and systemic therapy side-effects. This trial is registered with ISRCTN, ISRCTN68068041, and ClinicalTrials.gov, NCT00301925. FINDINGS: From Dec 16, 2005, to Dec 5, 2008, 4391 patients (20 [0·5%] of whom were male) were enrolled in TACT2; 1281 (85·8%) of 1493 eligible patients were included in the QOL substudy. Eight (0·6%) participants in the QOL substudy were male and 1273 (99·4%) were female. Median follow-up was 85·6 months (IQR 80·6-95·9). Analysis was performed on the complete QOL dataset (as of Sept 15, 2011) when all participants had passed the 24-month timepoint. Prerandomisation questionnaires were completed by 1172 (91·5%) patients and 1179 (92·0%) completed at least one postrandomisation questionnaire. End-of-treatment HADS depression score (p=0·0048) and HADS total change score (p=0·0093) were worse for CMF versus capecitabine. Accelerated epirubicin led to worse physical function (p=0·0065), role function (p<0·0001), fatigue (p=0·0002), and systemic side-effects (p=0·0001), but not sexual function (p=0·36), compared with standard epirubicin during treatment, but the effect did not persist. Worse physical function (p=0·0048), sexual function (p=0·0053), fatigue (p<0·0001), and systemic side-effects (p<0·0001), but not role functioning (p=0·013), were seen for CMF versus capecitabine at end of treatment; these differences persisted at 12 months and 24 months. INTERPRETATION: Accelerated epirubicin was associated with worse QOL than was standard epirubicin but only during treatment. These findings will help patients and clinicians make an informed choice about accelerated chemotherapy. CMF had worse QOL effects than did capecitabine, which were persistent for 24 months. The favourable capecitabine QOL compared with CMF supports its use as an adjuvant option after neoadjuvant chemotherapy in patients with triple-negative breast cancer. FUNDING: Cancer Research UK, Amgen, Pfizer, and Roche.
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Neoplasias de la Mama , Humanos , Masculino , Femenino , Neoplasias de la Mama/patología , Capecitabina , Epirrubicina/efectos adversos , Metotrexato/efectos adversos , Calidad de Vida , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Fluorouracilo , Ciclofosfamida , Quimioterapia Adyuvante/métodos , Fatiga/inducido químicamente , Reino UnidoRESUMEN
OBJECTIVE: Alpha-1 antitrypsin deficiency (AATD) is a common, potentially lethal inborn disorder caused by mutations in alpha-1 antitrypsin (AAT). Homozygosity for the 'Pi*Z' variant of AAT (Pi*ZZ genotype) causes lung and liver disease, whereas heterozygous 'Pi*Z' carriage (Pi*MZ genotype) predisposes to gallstones and liver fibrosis. The clinical significance of the more common 'Pi*S' variant remains largely undefined and no robust data exist on the prevalence of liver tumours in AATD. DESIGN: Baseline phenotypes of AATD individuals and non-carriers were analysed in 482 380 participants in the UK Biobank. 1104 participants of a multinational cohort (586 Pi*ZZ, 239 Pi*SZ, 279 non-carriers) underwent a comprehensive clinical assessment. Associations were adjusted for age, sex, body mass index, diabetes and alcohol consumption. RESULTS: Among UK Biobank participants, Pi*ZZ individuals displayed the highest liver enzyme values, the highest occurrence of liver fibrosis/cirrhosis (adjusted OR (aOR)=21.7 (8.8-53.7)) and primary liver cancer (aOR=44.5 (10.8-183.6)). Subjects with Pi*MZ genotype had slightly elevated liver enzymes and moderately increased odds for liver fibrosis/cirrhosis (aOR=1.7 (1.2-2.2)) and cholelithiasis (aOR=1.3 (1.2-1.4)). Individuals with homozygous Pi*S mutation (Pi*SS genotype) harboured minimally elevated alanine aminotransferase values, but no other hepatobiliary abnormalities. Pi*SZ participants displayed higher liver enzymes, more frequent liver fibrosis/cirrhosis (aOR=3.1 (1.1-8.2)) and primary liver cancer (aOR=6.6 (1.6-26.9)). The higher fibrosis burden was confirmed in a multinational cohort. Male sex, age ≥50 years, obesity and the presence of diabetes were associated with significant liver fibrosis. CONCLUSION: Our study defines the hepatobiliary phenotype of individuals with the most relevant AATD genotypes including their predisposition to liver tumours, thereby allowing evidence-based advice and individualised hepatological surveillance.
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Colelitiasis/epidemiología , Cirrosis Hepática/epidemiología , Neoplasias Hepáticas/epidemiología , Deficiencia de alfa 1-Antitripsina/complicaciones , Adulto , Anciano , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Prevalencia , Reino UnidoRESUMEN
BACKGROUND: In the phase 3 MARIANNE trial, trastuzumab emtansine (T-DM1) with or without pertuzumab showed noninferior progression-free survival and better tolerability than trastuzumab plus a taxane (HT) for the first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer. This article reports the final descriptive overall survival (OS) analysis, updated safety data, and additional patient-reported outcomes and biomarker analyses. METHODS: OS was assessed in 1095 patients with HER2-positive breast cancer and no prior therapy for advanced disease who had been randomized to HT, T-DM1 plus a placebo (hereafter T-DM1), or T-DM1 plus pertuzumab (T-DM1+pertuzumab). A post hoc exploratory landmark analysis of OS, baseline patient and disease characteristics, and tumor biomarkers in patients with and without an objective tumor response (OR) according to the Response Evaluation Criteria in Solid Tumors within 6.5 months of randomization was conducted. RESULTS: The median OS was similar across groups (50.9, 53.7, and 51.8 months for the HT, T-DM1, and T-DM1+pertuzumab groups, respectively). Among patients with an OR, the median OS was longer with T-DM1 (64.4 months) and T-DM1+pertuzumab (not reached) versus HT (56.3 months). No baseline characteristics or biomarkers were strongly associated with OR. The incidence of grade 3 or higher adverse events was greater with HT (55.8%) than T-DM1 (47.1%) or T-DM1+pertuzumab (48.6%). The median time to clinically meaningful deterioration (a 3-point or greater change) in neurotoxicity symptoms was shorter with HT (2.1 months) and T-DM1+pertuzumab (4.2 months) than T-DM1 (6.2 months). Fewer patients reported alopecia and diarrhea and were bothered by treatment side effects in the T-DM1 arm. CONCLUSIONS: These results support T-DM1 as a first-line treatment for patients with HER2-positive metastatic breast cancer who are deemed unsuitable for taxane-based therapy.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biomarcadores de Tumor , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Hidrocarburos Aromáticos con Puentes/administración & dosificación , Femenino , Humanos , Estimación de Kaplan-Meier , Metástasis de la Neoplasia , Estadificación de Neoplasias , Oportunidad Relativa , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Taxoides/administración & dosificación , Trastuzumab/administración & dosificación , Resultado del TratamientoRESUMEN
BACKGROUND: The phase III EMILIA and TH3RESA trials demonstrated clinical benefits of trastuzumab emtansine (T-DM1) therapy in patients with previously treated HER2-positive metastatic breast cancer (MBC). Data from these and other trials showed that T-DM1-associated survival benefits were observed across biomarker subgroups tested in these trials. Prespecified, exploratory analyses of the phase III MARIANNE study examined the effects of HER2-related biomarkers on PFS in patients administered T-DM1 in the first-line MBC setting. METHODS: In MARIANNE, patients with previously untreated HER2-positive MBC were randomized (1:1:1) to trastuzumab plus taxane, T-DM1 plus placebo, or T-DM1 plus pertuzumab. Biomarker subgroups included HER2 and HER3 mRNA expression levels (≤median vs. >median), HER2 staining intensity (IHC 3+ vs. 2+ vs. 0/1+), PIK3CA status (mutated vs. non-mutated), PTEN H-score (≤median vs. >median), and PTEN protein expression level (0 vs. 1+ vs. 2+ vs. 3+ vs. 4+). PFS was analyzed descriptively for each subgroup using Kaplan-Meier methodology. Additional exploratory post-hoc analyses evaluated the effects of HER2 heterogeneity. Multivariate analyses were also performed. RESULTS: Median PFS was numerically longer for patients with HER2 mRNA levels >median versus ≤median across treatment arms. In general, there were no predictive biomarkers of benefit for either T-DM1 treatment arm; most hazard ratios were close to 1 with wide confidence intervals that included the value 1. Focal HER2 expression (IHC 3+ or IHC 2+) was present in 3.8% of patients and was associated with numerically shorter PFS in the T-DM1-containing treatment arms versus trastuzumab plus taxane. Compared with non-mutated PIK3CA, mutated PIK3CA was associated with numerically shorter median PFS across treatment groups. Post-hoc multivariate analysis showed HER2 mRNA expression and mutated PIK3CA were prognostic for PFS (P ≤ 0.001 for both biomarkers). CONCLUSIONS: In MARIANNE, biomarkers related to the HER2 pathway did not have predictive value for PFS when comparing T-DM1 (with or without pertuzumab) with trastuzumab plus taxane. However, HER2 mRNA level and PIK3CA mutation status showed prognostic value. Evaluation of other potential biomarkers, including immune markers, is ongoing. TRIAL REGISTRATION: Registration number: NCT01120184 . Date of registration: April 28, 2010 (registered prospectively).
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Receptor ErbB-2/metabolismo , Receptor ErbB-3/metabolismo , Ado-Trastuzumab Emtansina , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/patología , Hidrocarburos Aromáticos con Puentes/uso terapéutico , Fosfatidilinositol 3-Quinasa Clase I/genética , Fosfatidilinositol 3-Quinasa Clase I/metabolismo , Femenino , Humanos , Maitansina/análogos & derivados , Maitansina/uso terapéutico , Proteínas de la Membrana/metabolismo , Mutación , Fosfohidrolasa PTEN/metabolismo , Pronóstico , ARN Mensajero/metabolismo , Receptor ErbB-2/genética , Receptor ErbB-3/genética , Análisis de Supervivencia , Taxoides/uso terapéutico , Trastuzumab/uso terapéuticoRESUMEN
Following publication of the original article [1], the authors reported the following errors in the article.
RESUMEN
BACKGROUND: Adjuvant chemotherapy for early breast cancer has improved outcomes but causes toxicity. The UK TACT2 trial used a 2×2 factorial design to test two hypotheses: whether use of accelerated epirubicin would improve time to tumour recurrence (TTR); and whether use of oral capecitabine instead of cyclophosphamide would be non-inferior in terms of patients' outcomes and would improve toxicity, quality of life, or both. METHODS: In this multicentre, phase 3, randomised, controlled trial, we enrolled patients aged 18 years or older from 129 UK centres who had histologically confirmed node-positive or high-risk node-negative operable breast cancer, had undergone complete excision, and were due to receive adjuvant chemotherapy. Patients were randomly assigned to receive four cycles of 100 mg/m2 epirubicin either every 3 weeks (standard epirubicin) or every 2 weeks with 6 mg pegfilgrastim on day 2 of each cycle (accelerated epirubicin), followed by four 4-week cycles of either classic cyclophosphamide, methotrexate, and fluorouracil (CMF; 600 mg/m2 cyclophosphamide intravenously on days 1 and 8 or 100 mg/m2 orally on days 1-14; 40 mg/m2 methotrexate intravenously on days 1 and 8; and 600 mg/m2 fluorouracil intravenously on days 1 and 8 of each cycle) or four 3-week cycles of 2500 mg/m2 capecitabine (1250 mg/m2 given twice daily on days 1-14 of each cycle). The randomisation schedule was computer generated in random permuted blocks, stratified by centre, number of nodes involved (none vs one to three vs four or more), age (≤50 years vs >50 years), and planned endocrine treatment (yes vs no). The primary endpoint was TTR, defined as time from randomisation to first invasive relapse or breast cancer death, with intention-to-treat analysis of standard versus accelerated epirubicin and per-protocol analysis of CMF versus capecitabine. This trial is registered with ISRCTN, number 68068041, and with ClinicalTrials.gov, number NCT00301925. FINDINGS: From Dec 16, 2005, to Dec 5, 2008, 4391 patients (4371 women and 20 men) were recruited. At a median follow-up of 85·6 months (IQR 80·6-95·9) no significant difference was seen in the proportions of patients free from TTR events between the accelerated and standard epirubicin groups (overall hazard ratio [HR] 0·94, 95% CI 0·81-1·09; stratified p=0·42). At 5 years, 85·9% (95% CI 84·3-87·3) of patients receiving standard epirubicin and 87·1% (85·6-88·4) of those receiving accelerated epirubicin were free from TTR events. 4358 patients were included in the per-protocol analysis, and no difference was seen in the proportions of patients free from TTR events between the CMF and capecitabine groups (HR 0·98, 95% CI 0·85-1.14; stratified p=0·00092 for non-inferiority). Compared with baseline, significantly more patients taking CMF than those taking capecitabine had clinically relevant worsening of quality of life at end of treatment (255 [58%] of 441 vs 235 [50%] of 475; p=0·011) and at 12 months (114 [34%] of 334 vs 89 [22%] of 401; p<0·001 at 12 months) and had worse quality of life over time (p<0·0001). Detailed toxicity and quality-of-life data were collected from 2115 (48%) of treated patients. The most common grade 3 or higher adverse events in cycles 1-4 were neutropenia (175 [16%]) and fatigue (56 [5%]) of the 1070 patients treated with standard epirubicin, and fatigue (63 [6%]) and infection (34 [3%]) of the 1045 patients treated with accelerated epirubicin. In cycles 5-8, the most common grade 3 or higher adverse events were neutropenia (321 [31%]) and fatigue (109 [11%]) in the patients treated with CMF, and hand-foot syndrome (129 [12%]) and diarrhoea (67 [6%]) in the 1044 patients treated with capcitabine. INTERPRETATION: We found no benefit from increasing the dose density of the anthracycline component of chemotherapy. However, capecitabine could be used in place of CMF without significant loss of efficacy and with improved quality of life. FUNDING: Cancer Research UK, Amgen, Pfizer, and Roche.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Carcinoma/tratamiento farmacológico , Epirrubicina/administración & dosificación , Recurrencia Local de Neoplasia , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/patología , Neoplasias de la Mama/cirugía , Neoplasias de la Mama Masculina/tratamiento farmacológico , Neoplasias de la Mama Masculina/cirugía , Capecitabina/administración & dosificación , Capecitabina/efectos adversos , Carcinoma/secundario , Carcinoma/cirugía , Quimioterapia Adyuvante/métodos , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Diarrea/inducido químicamente , Supervivencia sin Enfermedad , Epirrubicina/efectos adversos , Fatiga/inducido químicamente , Femenino , Filgrastim , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Estudios de Seguimiento , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Síndrome Mano-Pie/etiología , Humanos , Infecciones/inducido químicamente , Masculino , Metotrexato/administración & dosificación , Metotrexato/efectos adversos , Persona de Mediana Edad , Recurrencia Local de Neoplasia/diagnóstico , Neutropenia/inducido químicamente , Polietilenglicoles , Calidad de Vida , Proteínas Recombinantes/administración & dosificación , Tasa de Supervivencia , Factores de TiempoRESUMEN
OBJECTIVES: To identify clinical and organizational factors associated with delays in antimicrobial therapy for septic shock. DESIGN: In a retrospective cohort of critically ill patients with septic shock. SETTING: Twenty-four ICUs. PATIENTS: A total of 6,720 patients with septic shock. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Higher Acute Physiology Score (+24 min per 5 Acute Physiology Score points; p < 0.0001); older age (+16 min per 10 yr; p < 0.0001); presence of comorbidities (+35 min; p < 0.0001); hospital length of stay before hypotension: less than 3 days (+50 min; p < 0.0001), between 3 and 7 days (+121 min; p < 0.0001), and longer than 7 days (+130 min; p < 0.0001); and a diagnosis of pneumonia (+45 min; p < 0.01) were associated with longer times to antimicrobial therapy. Two variables were associated with shorter times to antimicrobial therapy: community-acquired infections (-53 min; p < 0.001) and higher temperature (-15 min per 1°C; p < 0.0001). After adjusting for confounders, admissions to academic hospitals (+52 min; p< 0.05), and transfers from medical wards (medical vs surgical ward admission; +39 min; p < 0.05) had longer times to antimicrobial therapy. Admissions from the emergency department (emergency department vs surgical ward admission, -47 min; p< 0.001) had shorter times to antimicrobial therapy. CONCLUSIONS: We identified clinical and organizational factors that can serve as evidence-based targets for future quality-improvement initiatives on antimicrobial timing. The observation that academic hospitals are more likely to delay antimicrobials should be further explored in future trials.
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Antiinfecciosos/uso terapéutico , Choque Séptico/tratamiento farmacológico , Femenino , Humanos , Unidades de Cuidados Intensivos/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Mejoramiento de la Calidad/organización & administración , Estudios Retrospectivos , Factores de Riesgo , Factores de TiempoRESUMEN
Breast cancer heterogeneity demands that prognostic models must be biologically driven and recent clinical evidence indicates that future prognostic signatures need evaluation in the context of early compared with late metastatic risk prediction. In pre-clinical studies, we and others have shown that various protein-protein interactions, pertaining to the actin microfilament-associated proteins, ezrin and cofilin, mediate breast cancer cell migration, a prerequisite for cancer metastasis. Moreover, as a direct substrate for protein kinase Cα, ezrin has been shown to be a determinant of cancer metastasis for a variety of tumour types, besides breast cancer; and has been described as a pivotal regulator of metastasis by linking the plasma membrane to the actin cytoskeleton. In the present article, we demonstrate that our tissue imaging-derived parameters that pertain to or are a consequence of the PKC-ezrin interaction can be used for breast cancer prognostication, with inter-cohort reproducibility. The application of fluorescence lifetime imaging microscopy (FLIM) in formalin-fixed paraffin-embedded patient samples to probe protein proximity within the typically <10 nm range to address the oncological challenge of tumour heterogeneity, is discussed.
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Neoplasias de la Mama/patología , Proteína Quinasa C-alfa/metabolismo , Factores Despolimerizantes de la Actina/metabolismo , Neoplasias de la Mama/enzimología , Neoplasias de la Mama/metabolismo , Proteínas del Citoesqueleto/metabolismo , Femenino , Transferencia Resonante de Energía de Fluorescencia , Humanos , Metástasis de la Neoplasia , Fosforilación , Fracciones Subcelulares/metabolismo , Especificidad por Sustrato , Resultado del TratamientoRESUMEN
A study of the microbiological quality of cooked, sliced vacuum-packed meat was undertaken. Three hundred and eighty-one samples were taken (127 sets of three samples) from 55 commercial premises that produced packets of sliced, cooked, vacuum-packed meat for retail sale. The set of three samples consisted of one from the unsliced, cooked meat, one from the sliced product immediately after slicing, and one sliced packet for end of shelf-life testing. Samples were examined for aerobic colony count (ACC), Enterobacteriaceae, Escherichia coli, Listeria, and Salmonella. When compared to current UK guidelines for the quality of ready to eat food, samples were found to be unsatisfactory for ACC, Enterobacteriaceae, and E. coli. Unsatisfactory rates increased at the end of shelf-life compared to the unsliced meat sample results. No samples were positive for Listeria monocytogenes or Salmonella. This data is important for producers setting the shelf-life of their products.
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Análisis de los Alimentos/métodos , Contaminación de Alimentos/análisis , Microbiología de Alimentos/normas , Embalaje de Alimentos/métodos , Productos de la Carne , Vacio , Bacterias/crecimiento & desarrollo , Seguridad de Productos para el Consumidor , Análisis de los Alimentos/normas , Contaminación de Alimentos/prevención & control , Embalaje de Alimentos/normas , Guías como Asunto , Productos de la Carne/microbiología , Productos de la Carne/normas , Factores de Tiempo , GalesRESUMEN
BACKGROUND: The optimum endocrine treatment for postmenopausal women with advanced hormone-receptor-positive breast cancer that has progressed on non-steroidal aromatase inhibitors (NSAIs) is unclear. The aim of the SoFEA trial was to assess a maximum double endocrine targeting approach with the steroidal anti-oestrogen fulvestrant in combination with continued oestrogen deprivation. METHODS: In a composite, multicentre, phase 3 randomised controlled trial done in the UK and South Korea, postmenopausal women with hormone-receptor-positive breast cancer (oestrogen receptor [ER] positive, progesterone receptor [PR] positive, or both) were eligible if they had relapsed or progressed with locally advanced or metastatic disease on an NSAI (given as adjuvant for at least 12 months or as first-line treatment for at least 6 months). Additionally, patients had to have adequate organ function and a WHO performance status of 0-2. Participants were randomly assigned (1:1:1) to receive fulvestrant (500 mg intramuscular injection on day 1, followed by 250 mg doses on days 15 and 29, and then every 28 days) plus daily oral anastrozole (1 mg); fulvestrant plus anastrozole-matched placebo; or daily oral exemestane (25 mg). Randomisation was done with computer-generated permuted blocks, and stratification was by centre and previous use of an NSAI as adjuvant treatment or for locally advanced or metastatic disease. Participants and investigators were aware of assignment to fulvestrant or exemestane, but not of assignment to anastrozole or placebo. The primary endpoint was progression-free survival (PFS). Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, numbers NCT00253422 (UK) and NCT00944918 (South Korea). FINDINGS: Between March 26, 2004, and Aug 6, 2010, 723 patients underwent randomisation: 243 were assigned to receive fulvestrant plus anastrozole, 231 to fulvestrant plus placebo, and 249 to exemestane. Median PFS was 4·4 months (95% CI 3·4-5·4) in patients assigned to fulvestrant plus anastrozole, 4·8 months (3·6-5·5) in those assigned to fulvestrant plus placebo, and 3·4 months (3·0-4·6) in those assigned to exemestane. No difference was recorded between the patients assigned to fulvestrant plus anastrozole and fulvestrant plus placebo (hazard ratio 1·00, 95% CI 0·83-1·21; log-rank p=0·98), or between those assigned to fulvestrant plus placebo and exemestane (0·95, 0·79-1·14; log-rank p=0·56). 87 serious adverse events were reported: 36 in patients assigned to fulvestrant plus anastrozole, 22 in those assigned to fulvestrant plus placebo, and 29 in those assigned to exemestane. Grade 3-4 adverse events were rare; the most frequent were arthralgia (three in the group assigned to fulvestrant plus anastrozole; seven in that assigned to fulvestrant plus placebo; eight in that assigned to exemestane), lethargy (three; 11; 11), and nausea or vomiting (five; two; eight). INTERPRETATION: After loss of response to NSAIs in postmenopausal women with hormone-receptor-positive advanced breast cancer, maximum double endocrine treatment with 250 mg fulvestrant combined with oestrogen deprivation is no better than either fulvestrant alone or exemestane.
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Androstadienos/uso terapéutico , Antineoplásicos/uso terapéutico , Inhibidores de la Aromatasa/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Estradiol/análogos & derivados , Antagonistas de Estrógenos/administración & dosificación , Nitrilos/administración & dosificación , Triazoles/administración & dosificación , Anastrozol , Androstadienos/efectos adversos , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Estradiol/administración & dosificación , Estradiol/efectos adversos , Femenino , Fulvestrant , Humanos , Metástasis de la Neoplasia , Nitrilos/efectos adversos , Posmenopausia , Receptores de Estrógenos/análisis , Triazoles/efectos adversosRESUMEN
Introduction: Bronchiectasis occurs in patients with alpha-1 antitrypsin deficiency (AATD), but it is unknown whether an association exists independently of chronic obstructive pulmonary disease (COPD). We assessed whether bronchiectasis was associated with COPD in our cohort, and whether it has clinical significance for lung function decline, exacerbation rate, or symptoms. Study Design and Methods: PiZZ, PiSZ and PiMZ patients from the Birmingham AATD Research Database were studied. Demographics were recorded, along with the outcomes of symptoms, FEV1, TLCO, KCO, and annualised exacerbation rate. Lung function decline was calculated for those with ≥3 measurements. Multivariate regression analyses were conducted to assess for associations of bronchiectasis with each outcome. A further binomial logistic regression model assessed for predictors of bronchiectasis diagnosis, including COPD. Those with alternative bronchiectasis causes were excluded from statistical models. Results: 1290 patients were eligible. PiZZ patients with bronchiectasis were older at presentation (54 vs 49 years, p<0.001), less likely to have smoked (65 vs 76.1%, p = 0.001), and had higher mMRC scores (mMRC 2 vs 0 OR 1.97, 95% CI 1.20 - 3.25, p = 0.008; mMRC 3 vs 0 OR 2.58 95% CI 1.59 - 4.19, p<0.001; mMRC 4 vs 0 OR 2.2 95% CI 1.23 - 3.92; p=0.008) than those without. The odds ratio of bronchiectasis diagnosis was not associated with COPD diagnosis in any phenotype. Bronchiectasis was associated with lower serum alpha-1 antitrypsin levels in PiZZ patients (p = 0.012). Bronchiectasis was not associated with a difference in FEV1 pp/year decline, KCO pp/year, TLCO pp/year decline, or exacerbation rate in multivariate analysis. Conclusion: Bronchiectasis exists in a significant minority of AATD patients independently of COPD, and is associated with more severe shortness of breath. Appropriate treatment of bronchiectasis in AATD is essential.
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Aim: Alpha-1 antitrypsin deficiency is an autosomal co-dominant condition that predisposes individuals to early-onset emphysema. As with COPD, AATD-COPD is associated with pulmonary exacerbations, which impacts on overall mortality and quality of life. Though there is evidence that COPD is associated with a higher prevalence of cardiovascular disease and major adverse cardiovascular events (MACE), it is unclear if this is true for patients with AATD-COPD. Methods: Prevalence of cardiovascular disease was determined in two separate severe AATD cohorts: AlphaNet, USA and the Birmingham AATD registry, UK. All patients had preexisting lung disease. Cardiovascular disease was defined as presence of any of the following: heart failure, ischaemic heart disease, atrial fibrillation, stroke, and myocardial infarction. A Cox proportional hazards model was used to assess the impact of prior cardiovascular disease and frequent exacerbator phenotype on risk of future MACE. Results: Out of 3493 patients with severe AATD, 14.7% had prior cardiovascular disease, including stroke (2.3%), myocardial infarction (2.2%), and heart failure (2.5%). Frequent exacerbators were more likely to have preexisting cardiovascular disease compared with those with one or no exacerbations in the preceding year (63% vs 44.8%, p = 0.001). There was increased risk of future MACE in frequent exacerbators (HR 1.85, 95% CI 1.24 to 2.75), former and current smokers (HR 1.80, 95% CI 1.07 to 3.02, p = 0.026, and HR 4.04, 95% CI 1.44 to 11.32, p = 0.008, respectively), and those with prior cardiovascular disease (HR 3.81, 95% CI 2.60 to 5.58, p < 0.001). Conclusion: In severe AATD-COPD, MACE are associated with an increased exacerbation frequency, previous cardiovascular disease, and a history of smoking.
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Enfermedades Cardiovasculares , Insuficiencia Cardíaca , Infarto del Miocardio , Enfermedad Pulmonar Obstructiva Crónica , Accidente Cerebrovascular , Deficiencia de alfa 1-Antitripsina , Humanos , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/epidemiología , Prevalencia , Calidad de Vida , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Deficiencia de alfa 1-Antitripsina/diagnóstico , Deficiencia de alfa 1-Antitripsina/epidemiología , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/epidemiología , Infarto del Miocardio/diagnóstico , Infarto del Miocardio/epidemiología , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/epidemiologíaRESUMEN
BACKGROUND: Pulmonary exacerbations in alpha-1 antitrypsin deficiency (AATD) related lung disease are a significant contributor to disease burden, as with usual COPD. Separating the early stages of an exacerbation from the day-to-day variation in stable COPD is central to the concerns of both clinicians and patients and has been identified as a research priority by NIHR. Clinical tools that distinguish baseline symptoms from those of an exacerbation could allow early and appropriate treatment of AECOPD to reduce the impact and potentially may slow disease progression thereby improving survival and quality of life. Candidate tools include symptom diaries and biomarkers of infection and acute inflammation. Urinary biomarkers of AECOPD have yet to be explored in AATD related COPD. METHODS: 55 patients with AATD related lung disease with a history of 2 or more AECOPD in the preceding year were prospectively followed for 18 months. Each patient recorded symptom scores daily via an electronic symptom diary (eDiary) based on Bronkotest. Urinary biomarkers for AAT, NE, CRP, TIMP1 and desmosine were measured weekly using a home urinary lateral flow device. During self-reported AECOPD patients were asked to perform urine analysis on the first 7 consecutive days. RESULTS: Type I Anthonisen exacerbations and episodes occurring in autumn/winter lasted longer than Type II/III exacerbations and spring/summer episodes respectively. Median urinary CRP concentration across all study participants increased during Type I AECOPD. eDiary adherence was 68% over a median of 17.8 months (IQR 15.7 to 18.5). CONCLUSIONS: Use of an eDiary and urinary biomarkers to detect and characterise AECOPD remotely in AATD related lung disease is feasible over a prolonged period and paves the way for precision detection of exacerbations.
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Enfermedad Pulmonar Obstructiva Crónica , Deficiencia de alfa 1-Antitripsina , Humanos , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Calidad de Vida , Pulmón , Deficiencia de alfa 1-Antitripsina/complicaciones , Deficiencia de alfa 1-Antitripsina/diagnóstico , Deficiencia de alfa 1-Antitripsina/tratamiento farmacológico , Progresión de la Enfermedad , Biomarcadores , alfa 1-AntitripsinaRESUMEN
Results from the NSABP B-28 trial suggest AKT activation may predict reduced benefit from taxanes following standard anthracycline therapy. Pre-clinical data support a link between PI3 K/AKT signalling and taxane resistance. Using the UK taxotere as adjuvant chemotherapy trial (TACT), we tested the hypothesis that activation of AKT or downstream markers, p70S6K or p90RSK, identifies patients with reduced benefit from taxane chemotherapy. TACT is a multi-centre open-label phase III trial comparing four cycles of standard FEC (fluorouracil, epirubicin, cyclophosphamide) followed by four cycles of docetaxel versus eight cycles of anthracycline-based chemotherapy. Samples from 3,596 patients were available for the current study. We performed immunohistochemical analysis of activation of AKT, p70S6 K and p90RSK. Using a training set with multiple cut-offs for predictive values (10 % increments in expression), we found no evidence for a treatment by marker interaction for pAKT473, pS6 or p90RSK. pAKT473, pS6 and p90RSK expression levels were weakly correlated. A robust, preplanned statistical analysis in the TACT trial found no evidence that pAKT473, pS6 or p90RSK identifies patients deriving reduced benefit from adjuvant docetaxel. This result is consistent with the recent NASBP B28 study where the pAKT473 effect is not statistically significant for the treatment interaction test. Therefore, neither TACT nor NASBP-B28 provides statistically robust evidence of a treatment by marker interaction between pAKT473 and taxane treatment. Alternative methods for selecting patients benefitting from taxanes should be explored.
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Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Taxoides/uso terapéutico , Adulto , Antraciclinas/uso terapéutico , Biomarcadores/metabolismo , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Supervivencia sin Enfermedad , Docetaxel , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Humanos , Persona de Mediana Edad , Fosforilación , Valor Predictivo de las Pruebas , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo , Proteínas Quinasas S6 Ribosómicas 90-kDa/metabolismo , Resultado del TratamientoRESUMEN
PIK3CA mutations are reported to be present in approximately 25% of breast cancer (BC), particularly the estrogen receptor-positive (ER+) and HER2-overexpressing (HER2+) subtypes, making them one of the most common genetic aberrations in BC. In experimental models, these mutations have been shown to activate AKT and induce oncogenic transformation, and hence these lesions have been hypothesized to render tumors highly sensitive to therapeutic PI3K/mTOR inhibition. By analyzing gene expression and protein data from nearly 1,800 human BCs, we report that a PIK3CA mutation-associated gene signature (PIK3CA-GS) derived from exon 20 (kinase domain) mutations was able to predict PIK3CA mutation status in two independent datasets, strongly suggesting a characteristic set of gene expression-induced changes. However, in ER+/HER2- BC despite pathway activation, PIK3CA mutations were associated with a phenotype of relatively low mTORC1 signaling and a good prognosis with tamoxifen monotherapy. The relationship between clinical outcome and the PIK3CA-GS was also assessed. Although the PIK3CA-GS was not associated with prognosis in ER- and HER2+ BC, it could identify better clinical outcomes in ER+/HER2- disease. In ER+ BC cell lines, PIK3CA mutations were also associated with sensitivity to tamoxifen. These findings could have important implications for the treatment of PIK3CA-mutant BCs and the development of PI3K/mTOR inhibitors.
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Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Mutación , Neoplasias Hormono-Dependientes/genética , Neoplasias Hormono-Dependientes/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Receptores de Estrógenos/metabolismo , Factores de Transcripción/metabolismo , Antibióticos Antineoplásicos/uso terapéutico , Antineoplásicos Hormonales/uso terapéutico , Secuencia de Bases , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Fosfatidilinositol 3-Quinasa Clase I , Cartilla de ADN/genética , Femenino , Perfilación de la Expresión Génica , Humanos , Diana Mecanicista del Complejo 1 de la Rapamicina , Complejos Multiproteicos , Neoplasias Hormono-Dependientes/tratamiento farmacológico , Análisis de Secuencia por Matrices de Oligonucleótidos , Pronóstico , Proteínas , Proteínas Proto-Oncogénicas c-akt/genética , Receptor ErbB-2/metabolismo , Transducción de Señal , Sirolimus/uso terapéutico , Serina-Treonina Quinasas TOR , Tamoxifeno/uso terapéuticoRESUMEN
Introduction: Determinants of long-term mortality following acute hypercapnic respiratory failure have been extensively studied in patients with chronic obstructive pulmonary disease. However, respiratory failure due to obesity has not been studied to the same extent. This retrospective survey aims to identify whether admission pH is associated with long-term mortality in patients requiring acute noninvasive ventilation (NIV) for obesity-related respiratory failure (ORRF). Methods: Records from April 2013 to March 2020 were accessed from a NIV quality database at an acute teaching hospital. Adults with hypercapnic ORRF requiring acute NIV were included. pH data were grouped by threshold (pH≤ and >7.25) and correlated with time from presentation to death; multivariable analysis was performed using Cox proportional hazards. Results: A total of 277 acute NIV episodes were included. Two-year mortality was similar for patients in both pH categories. Univariable analysis identified pH ≤ 7.25 to increase risk of two-year mortality by 43%. However, multivariable analysis identified that pH was not a significant determinant of long-term mortality, although male sex, older age, and higher admission pCO2 increased the risk of death at two years by 76%, 3% per year of age, and 16% per 1 kPa of pCO2 increase, respectively. Conclusion: Severity of hypercapnia on admission, male sex, and older age are associated with worse two-year mortality in patients requiring acute NIV for ORRF. There is scope for further analyses including investigating the role of domiciliary NIV in ORRF patients.