RESUMO
Background: Neutrophil/lymphocyte ratio (NLR), defined as absolute neutrophils count divided by absolute lymphocytes count, has been reported as poor prognostic factor in several neoplastic diseases but only a few data are available about unresectable metastatic colorectal cancer (mCRC) patients (pts). The aim of our study was to evaluate the prognostic and predictive role of NLR in the TRIBE trial. Patients and methods: Pts enrolled in TRIBE trial were included. TRIBE is a multicentre phase III trial randomizing unresectable and previously untreated mCRC pts to receive FOLFOXIRI or FOLFIRI plus bevacizumab. A cut-off value of 3 was adopted to discriminate pts with low (NLR < 3) versus high (NLR ≥ 3) NLR, as primary analysis. As secondary analysis, NLR was treated as an ordinal variable with three levels based on terciles distribution. Results: NLR at baseline was available for 413 patients. After multiple imputation at univariate analysis, patients with high NLR had significantly shorter progression-free survival (PFS) [hazard ratio (HR) 1.27 (95% CI 1.05-1.55), P = 0.017] and overall survival (OS) [HR 1.56 (95% CI 1.25-1.95), P < 0.001] than patients with low NLR. In the multivariable model, NLR retained a significant association with OS [HR 1.44 (95% CI 1.14-1.82), P = 0.014] but not with PFS [HR 1.18 (95% CI 0.95-1.46), P = 0.375]. No interaction effect between treatment arm and NLR was evident in terms of PFS (P for interaction = 0.536) or OS (P for interaction = 0.831). Patients with low [HR 0.84 (95% CI 0.64-1.08)] and high [HR 0.73 (95% CI 0.54-0.97)] NLR achieved similar PFS benefit from the triplet and consistent results were obtained in terms of OS [HR 0.83 (95% CI 0.62-1.12) for low NLR; HR 0.82 (95% CI 0.59-1.12) for high NLR]. Conclusion: This study confirmed the prognostic role of NLR in mCRC pts treated with bevacizumab plus chemotherapy in the first line, showing the worse prognosis of pts with high NLR. The advantage of the triplet is independent of NLR at baseline.
Assuntos
Neoplasias Colorretais/sangue , Contagem de Linfócitos , Metástase Neoplásica , Neutrófilos/citologia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bevacizumab/administração & dosagem , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Feminino , Fluoruracila/administração & dosagem , Humanos , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Prognóstico , Estudos RetrospectivosRESUMO
BACKGROUND: The combination of bevacizumab with fluorouracil-based chemotherapy is a standard first-line treatment option in metastatic colorectal cancer (mCRC). We studied the efficacy of continuing or reintroducing bevacizumab in combination with second-line chemotherapy after progression to bevacizumab-based first-line therapy. PATIENTS AND METHODS: In this phase III study, patients with mCRC treated with fluoropyrimidine-based first-line chemotherapy plus bevacizumab were randomized to receive in second-line mFOLFOX-6 or FOLFIRI (depending on first-line regimen) with or without bevacizumab. The primary end point was progression-free survival. To detect a hazard ratio (HR) for progression of 0.70 with an α and ß error of 0.05 and 0.20, respectively, 262 patients were required. RESULTS: In consideration of the results of the ML18147 trial, the study was prematurely stopped. Between April 2008 and May 2012, a total of 185 patients were randomized. Bevacizumab-free interval was longer than 3 months in 43% of patients in chemotherapy alone arm and in 50% of patients in the bevacizumab arm. At a median follow-up of 45.3 months, the median progression-free survival was 5.0 months in the chemotherapy group and 6.8 months in the bevacizumab group [adjusted HR = 0.70; 95% confidence interval (CI) 0.52-0.95; stratified log-rank P = 0.010]. Subgroup analyses showed a consistent benefit in all subgroups analyzed and in particular in patients who had continued or reintroduced bevacizumab. An improved overall survival was also observed in the bevacizumab arm (adjusted HR = 0.77; 95% CI 0.56-1.06; stratified log-rank P = 0.043). Responses (RECIST 1.0) were similar in the chemotherapy and bevacizumab groups (17% and 21%; P = 0.573). Toxicity profile was consistent with previously reported data. CONCLUSIONS: This study demonstrates that the continuation or the reintroduction of bevacizumab with second-line chemotherapy beyond first progression improves the outcome and supports the use of this strategy in the treatment of mCRC. ClinicalTrials.gov number: NCT00720512.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Adulto , Idoso , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Progressão da Doença , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estudos Prospectivos , Retratamento , Taxa de SobrevidaRESUMO
BACKGROUND: Surveys carried out in Mediterranean countries demonstrated very low rates of awareness of both diagnosis and prognosis among cancer patients. In our institution, a long-term training program aimed at improving communication skills among all physicians interacting with cancer patients was conducted. We report here the results of an extensive assessment of patients' awareness conducted after the first training period. PATIENTS AND METHODS: In a 2-year period, after every first visit of patients with a histological diagnosis of cancer, oncologists elicited perception of the patients and completed a structured questionnaire focusing on the understanding of the diagnosis and prognosis. Our data are thus a photograph of the results of the informative process conducted during the diagnostic phase. RESULTS: Among the enrolled 649 patients, 79.3% were aware of their diagnosis; factors significantly associated with higher levels of awareness were age younger than 70 and referral from surgery (versus internal medicine). Knowledge about the palliative or curative aims of future treatments (a surrogate sign of prognostic consciousness) was evident in 55.2%. CONCLUSIONS: Compared with historical data, our results show a high level of comprehension of the diagnosis of malignancy, probably due to the extensive training effort together with the method chosen for assessment.
Assuntos
Atitude do Pessoal de Saúde , Conhecimentos, Atitudes e Prática em Saúde , Oncologia/educação , Neoplasias/diagnóstico , Neoplasias/terapia , Educação de Pacientes como Assunto , Relações Médico-Paciente , Revelação da Verdade , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Conscientização , Compreensão , Empatia , Feminino , Pesquisas sobre Atenção à Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Direitos do Paciente , Prognóstico , Avaliação de Programas e Projetos de Saúde , Encaminhamento e Consulta , Inquéritos e Questionários , Recursos Humanos , Adulto JovemRESUMO
Endocrine disrupting chemicals (EDCs) have become a major issue in the field of environmental science due to their ability to interfere with the endocrine system. Recent studies show that surface water is contaminated with EDCs, many released from wastewater treatment plants (WWTP). This pilot study used biological (E-screen assay) and chemical (stir bar sorptive extraction-GC-MS) analyses to quantify estrogenic activity in effluent water samples from a municipal WWTP and in water samples of the recipient river, upstream and downstream of the plant. The E-screen assay was performed on samples after solid phase extraction (SPE) to determine total estrogenic activity; the presence of estrogenic substances can be evaluated by measuring the 17-beta-estradiol equivalency quantity (EEQ). Untreated samples were also assayed with an acute toxicity test (Vibrio fischeri) to study the correlation between toxicity and estrogenic disruption activity. Mean EEQs were 4.7 ng/L (+/-2.7 ng/L) upstream and 4.4 ng/L (+/-3.7 ng/L) downstream of the plant, and 11.1 ng/L (+/-11.7 ng/L) in the effluent. In general the WWTP effluent had little impact on estrogenicity nor on the concentration of EDCs in the river water. The samples upstream and downstream of the plant were non-toxic or weakly toxic (0Assuntos
Disruptores Endócrinos/análise
, Esgotos/química
, Poluentes Químicos da Água/análise
, Aliivibrio fischeri/efeitos dos fármacos
, Linhagem Celular Tumoral
, Disruptores Endócrinos/toxicidade
, Monitoramento Ambiental/métodos
, Cromatografia Gasosa-Espectrometria de Massas
, Humanos
, Projetos Piloto
, Rios
, Extração em Fase Sólida/métodos
, Testes de Toxicidade
, Eliminação de Resíduos Líquidos/métodos
, Poluentes Químicos da Água/toxicidade
RESUMO
Many xenobiotics, widely diffused in the environment, have the potential to disrupt the delicate endocrine system balance of wildlife and humans. Substances showing hormone-like actions in living organisms are defined endocrine-disruptor chemicals and they may mimic, block, or interfere with the synthesis, release, transport, elimination, and binding of natural hormones. Different ecotoxicologic studies were applied to screen for the discharge of estrogenic and toxic substances into the aquatic environment from a small industrial wastewater treatment plant based in Northern Italy. Samples of wastewater (3 L) were taken at three different periods during the year from different points of the plant's process: three phases of treatment, and effluent. Untreated samples (1 L) were assayed with two toxicity tests: Microtox and Daphnia magna. A simplified proliferation test using human estrogen receptor-positive MCF-7 breast cancer cells (E-screen assay) was performed on 2-L samples after solid-phase extraction for the determination of total estrogenic activity; the presence of estrogenic substances was evaluated by measuring the proliferation rate in cells exposed to samples. The results of the Microtox assay employing the marine bacterium Vibrio fischeri were compared with data obtained from whole-effluent toxicity testing methods employing D. magna. Toxicity was found only for the influent point. The proliferative effect of the five points, relative to the positive control 17beta-estradiol (relative proliferation effect), was between 2.4% and 39%, and the 17beta-estradiol equivalent concentrations were between 0.06 and 3.94 ng/L. A first comparison between results from toxicity load and estrogenic activity was performed. At all process points, the effluent samples were considered acceptable (taking only toxicity into account), but we demonstrated that they had estrogenic activity in the river water indicating an input of estrogenic substances by way of the treatment plant.
Assuntos
Daphnia , Eliminação de Resíduos Líquidos , Poluentes Químicos da Água/toxicidade , Xenobióticos/toxicidade , Animais , Neoplasias da Mama/patologia , Dano ao DNA , Monitoramento Ambiental , Feminino , Humanos , Itália , Receptores de Estrogênio/efeitos dos fármacos , Testes de Toxicidade , Células Tumorais Cultivadas , Vibrio/genética , Poluentes Químicos da Água/farmacologia , Xenobióticos/farmacologiaRESUMO
Gastric cancer is often associated with p53 over-expression and Helicobacter pylori (HP) infection. In this study we have investigated the production of the p53 protein and mutation of its gene in precancerous gastric lesions with HP infection. For this purpose 130 patients who underwent endoscopy for dyspepsia were enrolled in the study. To assess p53 production and mutation of the p53 gene we employed an immunoluminometric assay and polymerase chain reaction single strand conformation polymorphism (PCR-SSCP) analysis, respectively. Histologically, 52 of the 130 enrolled patients showed intestinal metaplasia type I (IM) (90.4% of these were also HP positive), 47 had HP-related gastritis and 31 were normal. p53 cytosol levels were significantly higher in patients with IM or HP-related gastritis than in normal patients (p = 0.0137 and p = 0.0411, respectively). All DNAs extracted from gastric mucosa samples with higher p53 values and examined for p53 mutations by PCR-SSCP analysis were characterized by a normal run. Our data indicate, that irreversible genetic changes in the p53 protein has not yet occurred in morphologically non-neoplastic gastric mucosa with IM and HP-related chronic gastritis. In conclusion, the increase in p53 cytosolic levels found in our study is due to an increased production of the wild-type protein probably related to an inflammatory response induced by HP infection.
Assuntos
Antígenos de Bactérias , Mucosa Gástrica/metabolismo , Gastrite/metabolismo , Infecções por Helicobacter/metabolismo , Proteína Supressora de Tumor p53/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas de Bactérias , Doença Crônica , Feminino , Mucosa Gástrica/patologia , Gastrite/microbiologia , Gastrite/patologia , Infecções por Helicobacter/microbiologia , Infecções por Helicobacter/patologia , Helicobacter pylori/isolamento & purificação , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Proteína Supressora de Tumor p53/genéticaRESUMO
Whole diesel exhaust has been classified recently as a probable carcinogen, and several genotoxicity studies have found particulate exhaust to be clearly mutagenic. Moreover, genotoxicity of diesel particulate is greatly influenced by fuel nature and type of combustion. In order to obtain an effective environmental pollution control, combustion processes using alternative fuels are being analyzed presently. The goal of this study is to determine whether the installation of exhaust after treatment-devices on two light-duty, exhaust gas recirculation (EGR) valve-equipped diesel engines (1930 cc and 2500 cc) can reduce the mutagenicity associated with particles collected during U.S.A. and European driving cycles. Another interesting object was to compare the ability of alternative biodiesel and conventional diesel fuels to reduce the mutagenic activity associated with collected particles from two light duty diesel engines (both 1930 cc) during the European driving cycle. SOF mutagenicity was assayed using the Salmonella/microsome test (TA 98 and TA 100 strains, +/- S9 fraction). In the first part of our study, the highest mutagenicity was revealed by TA98 strain without enzymatic activation, suggesting a direct-acting mutagenicity prevalence in diesel particulate. The 2500 cc engine revealed twofold mutagenic activity compared with the 1930 cc engine (both EGR valve equipped), whereas an opposite result was found in particulate matter amount. The use of a noncatalytic ceramic trap produced a decrease of particle mutagenic activity in the 2500 cc car, whereas an enhancement in the 1930 cc engine was found. The catalytic converter and the electrostatic filter installed on the 2500 cc engine yielded a light particle amount and an SOF mutagenicity decrease. A greater engine stress was obtained using European driving cycles, which caused the strongest mutagenicity/km compared with the U.S.A. cycles. In the second part of the investigation, even though a small number of assays were available, exhaust emission generation by biodiesel fuel seemed to yield a smaller environmental impact than that of the referenced diesel fuel. The results point out the usefulness of mutagenicity testing in the research of both newer, more efficient automotive aftertreatment devices and less polluting fuels.