Assuntos
Anilidas/efeitos adversos , Carcinoma de Células Renais/tratamento farmacológico , Toxidermias/etiologia , Neoplasias Renais/tratamento farmacológico , Piridinas/efeitos adversos , Vasculite Leucocitoclástica Cutânea/induzido quimicamente , Anilidas/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Piridinas/uso terapêuticoRESUMO
BACKGROUND: In EMBRACA, talazoparib prolonged progression-free survival versus chemotherapy (hazard ratio [HR] 0.542 [95% confidence interval (CI) 0.413-0.711]; P < 0.0001) and improved patient-reported outcomes (PRO) in germline BRCA1/2 (gBRCA1/2)-mutated advanced breast cancer (ABC). We report final overall survival (OS). PATIENTS AND METHODS: This randomized phase III trial enrolled patients with gBRCA1/2-mutated HER2-negative ABC. Patients received talazoparib or physician's choice of chemotherapy. OS was analyzed using stratified HR and log-rank test and prespecified rank-preserving structural failure time model to account for subsequent treatments. RESULTS: A total of 431 patients were entered in a randomized study (287 talazoparib/144 chemotherapy) with 412 patients treated (286 talazoparib/126 chemotherapy). By 30 September 2019, 216 deaths (75.3%) occurred for talazoparib and 108 (75.0%) chemotherapy; median follow-up was 44.9 and 36.8 months, respectively. HR for OS with talazoparib versus chemotherapy was 0.848 (95% CI 0.670-1.073; P = 0.17); median (95% CI) 19.3 months (16.6-22.5 months) versus 19.5 months (17.4-22.4 months). Kaplan-Meier survival percentages (95% CI) for talazoparib versus chemotherapy: month 12, 71% (66% to 76%)/74% (66% to 81%); month 24, 42% (36% to 47%)/38% (30% to 47%); month 36, 27% (22% to 33%)/21% (14% to 29%). Most patients received subsequent treatments: for talazoparib and chemotherapy, 46.3%/41.7% received platinum and 4.5%/32.6% received a poly(ADP-ribose) polymerase (PARP) inhibitor, respectively. Adjusting for subsequent PARP and/or platinum use, HR for OS was 0.756 (95% bootstrap CI 0.503-1.029). Grade 3-4 adverse events occurred in 69.6% (talazoparib) and 64.3% (chemotherapy) patients, consistent with previous reports. Extended follow-up showed significant overall improvement and delay in time to definitive clinically meaningful deterioration in global health status/quality of life and breast symptoms favoring talazoparib versus chemotherapy (P < 0.01 for all), consistent with initial analyses. CONCLUSIONS: In gBRCA1/2-mutated HER2-negative ABC, talazoparib did not significantly improve OS over chemotherapy; subsequent treatments may have impacted analysis. Safety was consistent with previous observations. PRO continued to favor talazoparib.
Assuntos
Neoplasias da Mama , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteína BRCA1/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Células Germinativas , Mutação em Linhagem Germinativa , Humanos , Ftalazinas , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Qualidade de VidaRESUMO
Background: In the EMBRACA phase III trial, talazoparib (1 mg daily, orally) demonstrated a statistically significant improvement in PFS versus physician's choice of chemotherapy (PCT; capecitabine, eribulin, gemcitabine, or vinorelbine) in patients with HER2-negative advanced breast cancer carrying a germline BRCA1/2 mutation; we evaluated patient-reported outcomes (PROs). Patients and methods: Patients were randomized 2 : 1 to receive talazoparib or PCT. PROs were assessed at day 1 (baseline), the start of each treatment cycle (every 3 weeks), and at the end of treatment, using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-30) and its breast cancer module, QLQ-BR23. Prespecified exploratory analyses included a longitudinal mixed-effect model comparing treatment arms and a time to definitive clinically meaningful deterioration (TTD) analysis carried out in the global health status/quality of life (GHS/QoL), and all functional and symptom scales from the EORTC QLQ-C30 and -BR23 questionnaires. Between-arm TTD comparisons were made using a stratified log-rank test and a Cox proportional hazards model. Results: Baseline scores were similar between arms. Statistically significant estimated overall improvement from baseline in GHS/QoL was seen for talazoparib compared with statistically significant deterioration for PCT {3.0 [95% confidence interval (CI) 1.2, 4.8] versus -5.4 [95% CI -8.8, -2.0]; between arms, P < 0.0001}. A statistically significant greater delay was observed in TTD in GHS/QoL, favoring talazoparib over PCT [hazard ratio, 0.38 (95% CI 0.26, 0.55; median, 24.3 versus 6.3 months, respectively; P < 0.0001)]. A statistically significant overall change and a statistically significant delay in TTD, all favoring talazoparib, were also observed in multiple functions and symptoms. Conclusion: Patients who received talazoparib had significant overall improvements and significant delay in TTD in multiple cancer-related and breast cancer-specific symptoms, functions, and GHS/QoL. ClinicalTrials.gov: NCT01945775.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Ftalazinas/efeitos adversos , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Qualidade de Vida , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Feminino , Mutação em Linhagem Germinativa , Humanos , Pessoa de Meia-Idade , Medidas de Resultados Relatados pelo Paciente , Ftalazinas/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Fatores de Tempo , Adulto JovemRESUMO
Background: Different methods have been proposed to analyze adverse events (AEs) associated with targeted therapies. While these AEs lead to dose adjustments for many patients, conventional reporting methods do not take drug administration into consideration. This paper underlines the importance of jointly reporting AEs and drug administration using prevalence, and proposes a complementary approach to reporting. Patients and methods: The prevalence method estimates the probability of progression-free patients being in a particular health state (state 1: AEs with full dose; state 2: AEs with reduced dose; state 3: no AEs with reduced dose) at different time points. To take into account the impact of dose adjustments on efficacy, the weighted prevalence method can be used by assigning utility weights to the different health states. The benefit of these methods was illustrated using data from a phase II trial of regorafenib. Results: Only 4.6% of progression-free patients developed mucositis/stomatitis (grade ≥2) at 3 months. The prevalence of patients not experiencing this AE but whose dose was reduced or treatment interrupted was 58.1%. The weighted prevalence of the regorafenib toxicity profile and dose reduction was higher in the control arm. Conclusion: This case study confirms the importance of jointly analyzing AEs and drug administration. The weighted prevalence approach is an average score that incorporates the dimension of drug administration into AE assessment. This can be helpful for regulatory agencies as well as for clinicians to evaluate the benefit-risk ratio of therapies in their treatment choice. Clinical trial: NCT01900743.
Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Terapia de Alvo Molecular/efeitos adversos , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/efeitos adversos , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Sarcoma/tratamento farmacológico , Método Duplo-Cego , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Seguimentos , França/epidemiologia , Humanos , Mucosite/epidemiologia , Mucosite/etiologia , Prevalência , Prognóstico , Sarcoma/patologia , Estomatite/epidemiologia , Estomatite/etiologia , Taxa de SobrevidaRESUMO
BACKGROUND: In medical oncology, changes in practices are almost always based on randomized trials but medical history shows that it is different in surgical oncology. In the past, many surgical procedures were routinely performed without a rigorous evaluation of the risk-benefit. To highlight the complexity of developing randomized surgical trials, disquisitions on methodology presented in the medical literature. This is particularly true when we consider breast reconstruction after surgical treatment for breast cancer. It is illusory to perform and conduct a randomized clinical trial (RCT) when a surgical procedure is routinely used by most surgeons. METHODS: As a case study, we present the scientific rationale and the design of the MAPAM01 trial which evaluates the security of the nipple sparing mastectomy. Other alternative approaches, such as propensity score and CUSUM, are presented. RESULTS: In this situation, to design surgical trials using alternative methodological approaches present a particularly important challenge both for surgeons and methodologists. Alternative approach to randomized trials can be useful to evaluate surgical procedures routinely used. CONCLUSION: Close collaboration between surgeons and methodologists is needed to propose appropriate and well-designed surgical trials.
Assuntos
Neoplasias da Mama/cirurgia , Mamoplastia/métodos , Mastectomia/métodos , Tratamentos com Preservação do Órgão/métodos , Projetos de Pesquisa/normas , Pesquisadores , Cirurgiões , Adulto , Feminino , França , Humanos , Colaboração Intersetorial , Oncologia/métodos , Oncologia/normas , Mamilos , Estudos Observacionais como Assunto , Melhoria de Qualidade , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND: Little information is currently available concerning young medical students desire to pursue a career in oncology, or their career expectations. METHODS: This project is a cross-sectional epidemiological study. A voluntary and anonymous questionnaire was distributed to all young oncologists studying in France between the 2nd of October 2013 and the 23rd of February 2014. RESULTS: The overall response rate was 75.6%. A total of 505 young oncologists completed the questionnaire. The main determining factors in the decision to practice oncology were the cross-sectional nature of the field (70.8%), the depth and variety of human relations (56.3%) and the multi-disciplinary field of work (50.2%). Most residents would like to complete a rotation outside of their assigned region (59.2%) or abroad (70.2%) in order to acquire additional expertise (67.7%). In addition, most interns would like to undertake a fellowship involving care, teaching and research in order to hone their skills (85.7%) and forge a career in public hospitals (46.4%). Career prospects mainly involve salaried positions in public hospitals. Many young oncologists are concerned about their professional future, due to the shortage of openings (40.8%), the workload (52.8%) and the lack of work-life balance (33.4%). CONCLUSIONS: This investigation provides a comprehensive profile of the reasons young oncologists chose to pursue a career in oncology, and their career prospects.
Assuntos
Escolha da Profissão , Educação de Pós-Graduação em Medicina , Internato e Residência , Oncologia , Especialização , Estudantes de Medicina , Estudos Transversais , Emprego , França , Humanos , Estudantes de Medicina/estatística & dados numéricos , Inquéritos e QuestionáriosRESUMO
PURPOSE: As the incidence of invasive breast cancer will increase with age, the number of elderly patients with a diagnosis metastatic breast cancer will also rise. But the use of cytotoxic drugs in elderly metastatic breast cancer patients is not systematic and is dreaded by medical oncologists. The need for prospective oncologic data from this population seems increasingly obvious. The main objective of this review is to investigate design and characteristics of phase II trials that assess activity and feasibility of chemotherapies in elderly advanced/metastatic breast cancer patients. METHODS: An electronic search in PUBMED allowed us to retrieve articles published in English language on phase II trials in elderly metastatic breast cancer between January 2002 and May 2016. Sixteen publications were finally included in this review. RESULTS: The primary endpoint was a simple, a composite, and a co-primary endpoints in 11, three, and two studies, respectively. Efficacy was the primary objective in 15 studies: simple (n = 10), composite (n = 3), co-primary endpoints (n = 2). Composite or co-primary endpoints combined efficacy and toxicity. Thirteen studies used multistage designs. CONCLUSIONS: Only five studies evaluated the feasibility, i.e., to jointly assess efficacy and tolerance to treatment (toxicity, quality of life, etc) as primary endpoint. Development of elderly specific phase III clinical trials might be challenging, it therefore seems essential to conduct phase II clinical trials evaluating jointly efficacy and toxicity in a well-defined geriatric population. Use of multistage designs that take into account heterogeneity would allow to identify a subpopulation at interim analysis and to reduce the number of patients exposed to an inefficient or a toxic treatment regimen. It is crucial to evaluate new therapies (targeted therapies, immunotherapies) using adequate methodologies (Study design, endpoint).
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Ensaios Clínicos Fase II como Assunto , Feminino , Humanos , Metástase Neoplásica , Estudos Prospectivos , Qualidade de Vida , Projetos de Pesquisa , Resultado do TratamentoRESUMO
PURPOSE: Obesity increases the risk of cardiovascular disease, type 2 diabetes mellitus and cancer development. Autophagy and apoptosis are critical processes for development and homeostasis in multicellular organisms and have been linked to a variety of disorders. We aimed to investigate whether the quantity and quality of dietary fat can influence these processes in the adipose tissue of obese people. METHODS: A randomized, controlled trial within the LIPGENE study assigned 39 obese people with metabolic syndrome to 1 of 4 diets: (a) a high-saturated fatty acid diet, (b) a high-monounsaturated fatty acid (HMUFA) diet, and (c, d) two low-fat, high-complex carbohydrate diets supplemented with long-chain n-3 polyunsaturated fatty acids (LFHCC n-3) or placebo (LFHCC), for 12 weeks each. RESULTS: We found an increase in the expression of autophagy-related BECN1 and ATG7 genes after the long-term consumption of the HMUFA diet (p = 0.001 and p = 0.004, respectively) and an increase in the expression of the apoptosis-related CASP3 gene after the long-term consumption of the LFHCC and LFHCC n-3 diets (p = 0.001 and p = 0.029, respectively). CASP3 and CASP7 gene expression changes correlated with HOMA index. CONCLUSION: Our results suggest that the processes of autophagy and apoptosis in adipose tissue may be modified by diet and that the consumption of a diet rich in monounsaturated fat may contribute to adipose tissue homeostasis by increasing autophagy. They also reinforce the notion that apoptosis in adipose tissue is linked to insulin resistance. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT00429195.
Assuntos
Adipócitos/citologia , Tecido Adiposo/fisiopatologia , Apoptose , Autofagia , Gorduras na Dieta/administração & dosagem , Adulto , Idoso , Proteína 7 Relacionada à Autofagia/genética , Proteína 7 Relacionada à Autofagia/metabolismo , Proteína Beclina-1/genética , Proteína Beclina-1/metabolismo , Glicemia/metabolismo , Caspase 3/genética , Caspase 3/metabolismo , Caspase 7/genética , Caspase 7/metabolismo , Dieta com Restrição de Gorduras , Dieta Hiperlipídica , Ácidos Graxos/administração & dosagem , Ácidos Graxos Monoinsaturados/administração & dosagem , Ácidos Graxos Ômega-3/administração & dosagem , Feminino , Regulação da Expressão Gênica , Homeostase , Humanos , Resistência à Insulina , Masculino , Síndrome Metabólica/fisiopatologia , Pessoa de Meia-Idade , Obesidade/fisiopatologia , Método Simples-CegoRESUMO
BACKGROUND: In the era of personalized medicine, molecularly targeted therapies (MTT) have modified the outcome of some cancer types. The price of tumor control needs to be balanced with toxicity since these new therapies are administered continuously for several months or sometimes for several years. For cytotoxic drugs, the incidence of adverse event (AE) was traditionally reported as frequency and intensity. This simple measure is not sufficient to capture the recurrent nature and duration of AE. This paper presents two methods to better describe the toxicity burden across the time: prevalence and Q-TWiST. PATIENTS AND METHODS: Limitation of worst-grade method and advantages of prevalence and Q-TWiST in the analysis of toxicity were illustrated using data from a phase II trial and a hypothetically simulated clinical trial. RESULTS: Prevalence integrates the recurrent nature of AE. Using prevalence, it is possible to obtain a time profile of AE. Q-TWiST method evaluates the weighted time spent in each health state and also considers the recurrent nature of side-effects in order to assess the 'risk-benefit' ratio of a treatment. When interpreting Q-TWiST results, it is necessary to take into account overall survival and progression-free survival and to define a clinically relevant difference according to the setting. CONCLUSION: The two methods presented here capture different effects. They are helpful for physicians in their treatment choice (balance benefit risk), to counsel patients and to optimize supportive care. In order to ensure consistency and provide critical information required for medical decision-making, it is important to encourage the use of alternative statistical methods in the analysis of toxicities associated with MTT. CLINICAL TRIAL: NCT00541008.
Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Terapia de Alvo Molecular/efeitos adversos , Neoplasias/tratamento farmacológico , Tomada de Decisão Clínica , Ensaios Clínicos Fase II como Assunto , Intervalo Livre de Doença , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Humanos , Masculino , Neoplasias/epidemiologia , Neoplasias/patologia , Medicina de Precisão , Qualidade de VidaRESUMO
We report four patients developing a late form of papulopustular rash induced by epidermal growth factor receptor inhibitors. These patients presented an unusual presentation of acneiform rash, characterized by late development (several months after treatment commenced), localization to the limbs with sparing of the face, and association with severe pruritus and Staphylococcus aureus superinfection in all cases. These clinical symptoms may suggest a distinct mechanism from the early acne-like rash frequently observed with these targeted anticancer therapies. Clinicians should be aware of this delayed adverse event, and we suggest the term 'late acneiform toxicity of EGFR inhibitors (LATE) syndrome' to permit better characterization of this clinical picture.
Assuntos
Cloridrato de Erlotinib/efeitos adversos , Piperidinas/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Quinazolinas/efeitos adversos , Dermatopatias Papuloescamosas/induzido quimicamente , Adulto , Idoso , Receptores ErbB/antagonistas & inibidores , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prurido/induzido quimicamente , Dermatopatias Papuloescamosas/microbiologia , Dermatopatias Papuloescamosas/patologia , Infecções Estafilocócicas/etiologia , Staphylococcus aureus/isolamento & purificaçãoRESUMO
BACKGROUND: Inflammatory breast cancer (IBC) is a rare and aggressive disease requiring a multimodal treatment. We evaluated the benefit of adding docetaxel-5-fluorouracil (D-5FU) regimen after preoperative dose-intense (DI) epirubicin-cyclophosphamide (EC) and locoregional treatment in IBC patients. PATIENTS AND METHODS: PEGASE 07 was a national randomized phase III open-label study involving 14 hospitals in France. Women with nonmetastatic IBC were eligible and randomly assigned to receive either four cycles of DI EC (E 150 mg/m(2) and C 4000 mg/m(2) every 3 weeks with repeated hematopoietic stem cell support), then mastectomy with axillary lymph node dissection, and radiotherapy (arm A) or the same treatment followed by four cycles of D-5FU (D 85 mg/m(2), day 1 and 5FU 750 mg/m(2)/day continuous infusion, days 1-5 every 3 weeks) administered postradiotherapy (arm B). Patients with hormone receptor-positive tumors received hormonal therapy. Disease-free survival (DFS) was the primary end point. Secondary end points included tolerance, pathological complete response (pCR) rate, and overall survival (OS). RESULTS: Between January 2001 and May 2005, 174 patients were enrolled and treated (87 in each arm). Median follow-up was similar in both arms: 59.6 months [95% confidence interval (CI) 58.4-60.3] in arm A and 60.5 months (95% CI 58.3-61.4) in arm B. The estimated 5-year DFS rates were not different: 55% (95% CI 43.9-64.7) in arm A and 55.5% (95% CI 44.3-65.3) in arm B [hazard ratio (HR) = 0.94 (0.61-1.48); P = 0.81]. Identical results were observed for 5-year OS: 70.2% (95% CI 59.1-78.8) in arm A and 70% (95% CI 58.8-78.7) in arm B [HR = 0.93 (0.55-1.60); P = 0.814]. Following DI EC induction, in-breast and global (breast plus nodes) pCR were 28.9% and 20.1%, respectively. Estrogen receptor and pCR status were independently associated with survival. CONCLUSION: The addition of D-5FU after preoperative DI EC and standard local therapy did not improve DFS in IBC. CLINICAL TRIAL NUMBER: ClinicalTrials.gov identifier: NCT02324088.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Lobular/tratamento farmacológico , Neoplasias Inflamatórias Mamárias/tratamento farmacológico , Mastectomia , Terapia Neoadjuvante/métodos , Adulto , Antineoplásicos Hormonais/administração & dosagem , Axila , Quimiorradioterapia Adjuvante/métodos , Quimioterapia Adjuvante/métodos , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Docetaxel , Epirubicina/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Humanos , Neoplasias Inflamatórias Mamárias/metabolismo , Excisão de Linfonodo , Pessoa de Meia-Idade , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Taxoides/administração & dosagemRESUMO
BACKGROUND: Using surrogate end points for overall survival, such as disease-free survival, is increasingly common in randomized controlled trials. However, the definitions of several of these time-to-event (TTE) end points are imprecisely which limits interpretation and cross-trial comparisons. The estimation of treatment effects may be directly affected by the definitions of end points. The DATECAN initiative (Definition for the Assessment of Time-to-event Endpoints in CANcer trials) aims to provide recommendations for definitions of TTE end points. We report guidelines for randomized cancer clinical trials (RCTs) in breast cancer. PATIENTS AND METHODS: A literature review was carried out to identify TTE end points (primary or secondary) reported in publications of randomized trials or guidelines. An international multidisciplinary panel of experts proposed recommendations for the definitions of these end points based on a validated consensus method that formalize the degree of agreement among experts. RESULTS: Recommended guidelines for the definitions of TTE end points commonly used in RCTs for breast cancer are provided for non-metastatic and metastatic settings. CONCLUSION: The use of standardized definitions should facilitate comparisons of trial results and improve the quality of trial design and reporting. These guidelines could be of particular interest to those involved in the design, conducting, reporting, or assessment of RCT.
Assuntos
Neoplasias da Mama/terapia , Determinação de Ponto Final/normas , Ensaios Clínicos Controlados Aleatórios como Assunto/normas , Projetos de Pesquisa/normas , Terminologia como Assunto , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/mortalidade , Consenso , Técnica Delphi , Progressão da Doença , Intervalo Livre de Doença , Determinação de Ponto Final/classificação , Feminino , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto/classificação , Fatores de Tempo , Falha de TratamentoRESUMO
BACKGROUND AND AIMS: Consumption of foods that modulate inflammatory stress in genetically-prone individuals may influence development of cardiometabolic diseases. Isoflavones in soy-derived foods function as phytoestrogens, have antioxidant and anti-inflammatory activity, inhibit protein-tyrosine kinase activity, and may be atheroprotective. We examined the relationship between soy food consumption and inflammatory responses to endotoxemia, postprandial responses to oral lipid tolerance test (OLTT), and insulin sensitivity from frequently sampled intravenous tolerance tests (FSIGTT). METHODS AND RESULTS: We administered low-dose endotoxin (LPS 1 ng/kg) to induce transient endotoxemia in young, healthy volunteers (N = 215) of African (AA), and European (EA) ancestry as part of the GENE Study. We further supported these findings in two independent samples: the MECHE Study and NHANES. Soy food consumption was a significant predictor of peak cytokine response following LPS. Individuals with moderate-high (>1.48 mg/day, N = 65) vs. low-no (<1.48 mg/day, N = 150) isoflavone consumption had significantly higher tumor necrosis factor alpha (TNFα) post-LPS (AUC, P = 0.009). Further, high-isoflavone consumers were protected against inflammation-induced decline in insulin sensitivity (SI) in GENE. We observed significant differences by soy consumption in the interferon gamma (IFNγ) response to OLTT, and the insulin response to OGTT in MECHE, as well as significantly lower fasting insulin, and 2-hour glucose post-OGTT in EA NHANES subjects. CONCLUSION: We demonstrate that soy consumption may influence inflammatory and metabolic responses. In research of nutritional exposures, measuring evoked phenotypes may be more informative than describing resting characteristics. The GENE Study was registered under NCT00953667 and the MECHE Study under NCT01172951, both at clinicaltrials.gov.
Assuntos
Doenças Cardiovasculares/prevenção & controle , Inflamação/prevenção & controle , Isoflavonas/administração & dosagem , Adolescente , Adulto , Negro ou Afro-Americano , Anti-Inflamatórios/administração & dosagem , Antioxidantes/administração & dosagem , Glicemia/metabolismo , Índice de Massa Corporal , Feminino , Voluntários Saudáveis , Homeostase/efeitos dos fármacos , Humanos , Resistência à Insulina , Modelos Lineares , Lipopolissacarídeos/administração & dosagem , Masculino , Pessoa de Meia-Idade , Inquéritos Nutricionais , Fitoestrógenos/administração & dosagem , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismo , Ensaios Clínicos Controlados Aleatórios como Assunto , Alimentos de Soja/análise , Fator de Necrose Tumoral alfa/metabolismo , População Branca , Adulto JovemRESUMO
PURPOSE: Recent improvements in the detection of breast cancer at an early stage have resulted in a rising incidence of breast ductal carcinoma in situ with microinvasion. So far, there is no consensus regarding its optimal management. We hereby report on our 10-year single institutional experience in breast ductal carcinoma in situ with microinvasion including pathological reviewing. PATIENTS AND METHODS: All consecutive patients treated for a ductal carcinoma in situ with microinvasion at the Institut Claudius-Regaud (Toulouse, France) over a 10-year period were included in this study. We reviewed all available histological materials. RESULTS: Sixty-three patients were eligible for this study. Two patients presented with a lymph node invasion at diagnosis. Each patient benefited from initial surgical management, which consisted either in mastectomy (n=25) or conservative resection (n=37). Axillary exploration was performed in 52 patients (82%). After a median follow-up of 61.3 months [46.9;69], the 5-year overall survival and disease free survival were 98.2 (95% CI=[88.2;99.7]) and 89.5% (95% CI=[76.3;95.6]) respectively. Two delayed invasive relapses occurred leading to one specific death. The pathological review highlighted a trend towards a loss of HR and HER2 expression (9%) in the microinvasive component in comparison with its surrounded in situ carcinoma. CONCLUSION: The risk of initial lymph node involvement and delayed invasive local relapse deserve an optimal locoregional management including lymph node evaluation. The non-negligible discrepancy's rate between in situ and microinvasive components justifies HR status and HER2 expression assessment on the microinvasive component.
Assuntos
Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Carcinoma in Situ/patologia , Carcinoma in Situ/terapia , Carcinoma Ductal de Mama/patologia , Carcinoma Ductal de Mama/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Carcinoma in Situ/metabolismo , Carcinoma in Situ/mortalidade , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/mortalidade , Quimioterapia Adjuvante , Feminino , Seguimentos , Humanos , Excisão de Linfonodo , Metástase Linfática , Mastectomia , Mastectomia Segmentar , Pessoa de Meia-Idade , Invasividade Neoplásica , Metástase Neoplásica , Recidiva Local de Neoplasia , Radioterapia Adjuvante , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Estudos RetrospectivosRESUMO
OBJECTIVES: Low-grade chronic inflammation predicts cardiovascular outcomes and is observed in women with polycystic ovary syndrome (PCOS). Whether this is entirely a cause or consequence of insulin resistance (IR) is unknown. METHODS: Seventy pairs of women with and without PCOS, matched for age, body mass index (BMI) and IR (HOMA, QUICKI and Avignon index), were generated from a larger cohort of 103 women with and 104 BMI-matched women without PCOS. Women with PCOS were studied in the follicular phase of the menstrual cycle. White cell count (WCC), high-sensitivity CRP (hsCRP) and a series of 12 cytokines and growth factors were measured. These inflammatory markers were also compared between women with PCOS and 10 normal women studied in the follicular, peri-ovulatory and luteal stages. RESULTS: When all subjects were compared, WCC (6.75 × 10(9) vs 5.60 × 10(9 ) g/l, P < 0.005), hsCRP (4.04 vs 2.90 mg/l, P < 0.05) and IL-6 (1.11 vs 0.72 pg/ml, P < 0.05) were greater in women with PCOS. Pair-matching for IR eliminated between-group differences in hsCRP and cytokines but did not alter the difference in WCC (6.60 × 10(9) vs 5.60 × 10(9 ) g/l, P < 0.005). WCC was greater in PCOS compared to normal women at all stages of the menstrual cycle. CONCLUSIONS: Low-grade inflammation occurs in PCOS. Increased hsCRP and cytokines are associated with IR, but increased WCC is observed even when IR is accounted for. The explanation for this and its clinical significance is unknown.
Assuntos
Resistência à Insulina/fisiologia , Leucocitose/etiologia , Obesidade/sangue , Obesidade/complicações , Síndrome do Ovário Policístico/sangue , Adulto , Índice de Massa Corporal , Estudos Transversais , Feminino , Humanos , Adulto JovemRESUMO
BACKGROUND AND AIMS: CCAAT/enhancer-binding protein alpha (CEBPA) is a transcription factor involved in adipogenesis and energy homeostasis. Caloric restriction reduces CEBPA protein expression in patients with metabolic syndrome (MetS). A previous report linked rs12691 SNP in CEBPA to altered concentration of fasting triglycerides. Our objective was to assess the effects of rs12691 in glucose metabolism in Metabolic Syndrome (MetS) patients. METHODS AND RESULTS: Glucose metabolism was assessed by static (glucose, insulin, adiponectin, leptin and resistin plasma concentrations) and dynamic (disposition index, insulin sensitivity index, HOMA-IR and acute insulin response to glucose) indices, performed at baseline and after 12 weeks of 4 dietary interventions (high saturated fatty acid (SFA), high monounsaturated fatty acid (MUFA), low-fat and low-fat-high-n3 polyunsaturated fatty acid (PUFA)) in 486 subjects with MetS. Carriers of the minor A allele of rs12691 had altered disposition index (p = 0.0003), lower acute insulin response (p = 0.005) and a lower insulin sensitivity index (p = 0.025) indicating a lower insulin sensitivity and a lower insulin secretion, at baseline and at the end of the diets. Furthermore, A allele carriers displayed lower HDL concentration. CONCLUSION: The presence of the A allele of rs12691 influences glucose metabolism of MetS patients.
Assuntos
Glicemia/metabolismo , Proteínas Estimuladoras de Ligação a CCAAT/genética , Suplementos Nutricionais , Síndrome Metabólica/genética , Polimorfismo de Nucleotídeo Único , Adiponectina/sangue , Adulto , Idoso , Alelos , Glicemia/análise , Índice de Massa Corporal , Peso Corporal , DNA/genética , DNA/isolamento & purificação , Gorduras na Dieta/administração & dosagem , Jejum , Ácidos Graxos/administração & dosagem , Ácidos Graxos Monoinsaturados/administração & dosagem , Ácidos Graxos Ômega-3/administração & dosagem , Feminino , Genótipo , Humanos , Insulina/sangue , Insulina/metabolismo , Resistência à Insulina , Secreção de Insulina , Leptina/sangue , Metabolismo dos Lipídeos/genética , Masculino , Síndrome Metabólica/sangue , Pessoa de Meia-Idade , Resistina/sangue , Triglicerídeos/sangueRESUMO
Background The genomic grade index (GGI) completes the prognostic value of histological grade (HG). Other proliferation markers include the mitotic activity index (MAI) and the Ki67 immunohistochemistry (IHC) status. We compared the prognostic value of GGI, HG, MAI, Ki67 IHC and messenger RNA (mRNA) status in node-positive breast cancer (BC) patients treated with adjuvant anthracycline-based chemotherapy in the prospective PACS01 trial. Patients and methods The five proliferation-related parameters (GGI, Ki67 mRNA expression and centrally determined HG, MAI, and Ki67 IHC status) of tumours were available for 204 cases and analysed as continuous values. We compared the correlations of each one with the other proliferation-related parameters and with histoclinical variables including the disease-free survival (DFS). Results Expected correlations were observed between the five parameters and for each parameter with biological features (hormone-receptor and HER2 status, molecular subtypes), but the GGI displayed the strongest correlations. The GGI outperformed the prognostic performance of the four other proliferation-related parameters for the DFS in all 204 patients and in the 95 HG2 patients. In multivariate analysis including the classical prognostic factors, only GGI remained significant. Finally, the GGI outperformed the prognostic performance of MKI67 mRNA expression in a series of 1599 samples and 656 HG2 cases. Conclusions In this small pilot biomarker study ancillary to the PACS01 trial, the GGI outperforms the prognostic performance of centrally determined HG, MAI, Ki67 IHC status and mRNA expression. Further validation is warranted in larger series.
Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Antígeno Ki-67/metabolismo , Índice Mitótico , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/mortalidade , Ensaios Clínicos Fase III como Assunto , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Metástase Linfática , Pessoa de Meia-Idade , Análise Multivariada , Gradação de Tumores , Prognóstico , Modelos de Riscos Proporcionais , Curva ROC , Estudos RetrospectivosRESUMO
OBJECTIVE: To determine the recommended dose (RD) of vinflunine in combination with trastuzumab in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) and to investigate potential pharmacokinetic (PK) interactions. PATIENTS AND METHODS: In the first part of the study, two dose levels of vinflunine given every 3 weeks were explored (280 and 320 mg/m(2)) combined with trastuzumab (4 mg/kg loading dose and 2 mg/kg weekly). For each level of dose, six patients were enrolled to determine the RD for phase 2 studies (RP2S). In the second part of the study, 18 additional patients at RP2S have been evaluated to confirm safety and investigate preliminary antitumor activity. RESULTS: The RD was 320 mg/m(2) according to the dose escalation plan. Eleven of 15 additional patients who received this dose experienced dose-limiting toxicities, leading to a reduction in the RD to 280 mg/m(2). When compared to prior trials when vinflunine was used as a single agent, neither vinflunine total blood clearance nor trastuzumab serum concentrations were modified when the drugs were combined. All patients were evaluable, and the overall response rate was 73.3 % (95 % CI 54.1-87.7). The median progression-free survival was 11.3 months (95 % CI 9.4-21.0). At the dose of 280 mg/m(2), grade 3-4 neutropenia were seen in 4 patients (44.4 %) without febrile neutropenia. Non-hematologic grade 4 toxicities were not reported while grade 3 peripheral sensory neuropathy concerned 2 patients (22.2 %). CONCLUSION: The RD of vinflunine in combination with the standard regimen of trastuzumab is 280 mg/m(2) every 3 weeks. No mutual PK drug-drug interaction was seen. This regimen appears to be active with a favorable safety profile. Its role in HER2-positive MBC treatment needs to be defined in prospective comparative clinical trials.