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BACKGROUND: SERENA-1 (NCT03616587) is a phase I, multi-part, open-label study of camizestrant in pre- and post-menopausal women with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. Parts A and B aim to determine the safety and tolerability of camizestrant monotherapy and define doses for clinical evaluation. PATIENTS AND METHODS: Women aged ≥18 years with metastatic or recurrent ER+, HER2- breast cancer, refractory (or intolerant) to therapy, were assigned 25 mg up to 450 mg once daily (QD; escalation) or 75, 150, or 300 mg QD (expansion). Safety and tolerability, antitumor efficacy, pharmacokinetics, and impact on mutations in the estrogen receptor gene (ESR1m) circulating tumor (ct)DNA levels were assessed. RESULTS: By 9 March 2021, 108 patients received camizestrant monotherapy at 25-450 mg doses. Of these, 93 (86.1%) experienced treatment-related adverse events (TRAEs), 82.4% of which were grade 1 or 2. The most common TRAEs were visual effects (56%), (sinus) bradycardia (44%), fatigue (26%), and nausea (15%). There were no TRAEs grade 3 or higher, or treatment-related serious adverse events at doses ≤150 mg. Median tmax was achieved â¼2-4 h post-dose at all doses investigated, with an estimated half-life of 20-23 h. Efficacy was observed at all doses investigated, including in patients with prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) and/or fulvestrant treatment, with and without baseline ESR1 mutations, and with visceral disease, including liver metastases. CONCLUSIONS: Camizestrant is a next-generation oral selective ER antagonist and degrader (SERD) and pure ER antagonist with a tolerable safety profile. The pharmacokinetics profile supports once-daily dosing, with evidence of pharmacodynamic and clinical efficacy in heavily pre-treated patients, regardless of ESR1m. This study established 75-, 150-, and 300-mg QD doses for phase II testing (SERENA-2, NCT04214288 and SERENA-3, NCT04588298).
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Neoplasias da Mama , Receptor ErbB-2 , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/genética , Pessoa de Meia-Idade , Receptor ErbB-2/genética , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/metabolismo , Idoso , Adulto , Receptores de Estrogênio/metabolismo , Administração Oral , Receptor alfa de Estrogênio/genética , Idoso de 80 Anos ou mais , Dose Máxima Tolerável , Relação Dose-Resposta a Droga , Azetidinas , IsoquinolinasRESUMO
BACKGROUND: Up to 50% of patients with uveal melanoma develop metastases (MUM) with a poor prognosis and median overall survival of approximately 1 year. METHODS: This phase I study evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of the oral protein kinase C inhibitor LXS196 in 68 patients with MUM (NCT02601378). Patients received LXS196 doses ranging from 100-1000 mg once daily (QD; n = 38) and 200-400 mg twice daily (BID; n = 30). RESULTS: First cycle dose-limiting toxicities (DLTs) were observed in 7/38 (18.4%) QD and 2/17 (11.8%) BID patients. Hypotension was the most common DLT, occurring at doses ≥500 mg/day, and manageable with LXS196 interruption and dose reduction. Median duration of exposure to LXS196 was 3.71 months (range: 1.81-15.28) for QD and 4.6 months (range: 0.33-58.32) for BID dosing. Clinical activity was observed in 6/66 (9.1%) evaluable patients achieving response (CR/PR), with a median duration of response of 10.15 months (range: 2.99-41.95); 45/66 had stable disease (SD) per RECIST v1.1. At 300 mg BID, the recommended dose for expansion, 2/18 (11.1%) evaluable patients achieved PR and 12/18 (66.7%) had SD. CONCLUSION: These results suggest manageable toxicity and encouraging clinical activity of single-agent LXS196 in patients with MUM.
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Proteína Quinase C , Inibidores de Proteínas Quinases , HumanosRESUMO
The availability of an unprecedented massive amount of data has provided a magnificent window of opportunity for the development of new drugs. There are currently more drugs in development targeting cancer than any other disease. While this has brought us new waves of drugs, the counterpart is that with these new molecules we have different mechanisms of action, drug kinetics and dynamics, response types and toxicity profiles, which impair classical early clinical trial designs from being effective and efficient. What we once treated as a 'one-size-fits-all' homogeneous disease, has now been uncovered to be a rather heterogeneous condition with multiple targetable mutations. As this generates endless scenarios, it will be impossible to design single 'me-too' trials for every different disease, target, biomarker and agent. To overcome this, we must focus on improving early phase studies, undoubtedly the most critical step from bench to bedside. Goals include decreasing clinical development times, lowering research and development costs and optimizing decisions in advancing through the several phases with a higher degree of certainty in exchange for less failed attempts. We need more informative and, really, transformative early phase designs that seek to obtain the typical late phase objectives in a time continuum and to allow for more robust and efficient go/no-go decisions. With this in mind, different classes of drugs seem to fit with different designs, which present solutions to the different challenges that they pose after finding the maximum tolerated dose/optimum biological dose. This article reviews these concepts and designs and how they can adapt to this new reality in early phase investigation.
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Antineoplásicos/uso terapêutico , Desenvolvimento de Medicamentos/tendências , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Desenho de Fármacos , HumanosRESUMO
OBJECTIVE: To evaluate the reproducibility of a protocol for dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for the pharmacokinetic study of breast tumors. MATERIAL AND METHODS: We carried out this prospective study from October 2009 through December 2009. We studied 12 patients with stage ii-iii invasive breast cancer without prior treatment. Our center's research ethics committee approved the study. The 12 patients underwent on two consecutive days DCE-MRI with a high temporal resolution protocol (21 acquisitions/minute). The data obtained in an ROI traced around the largest diameter of the tumor (ROI 1) and in another ROI traced around the area of the lesion's highest K(trans) intensity (ROI 2) were analyzed separately. We used parametric and nonparametric statistical tests to study the reproducibility and concordance of the principal pharmacokinetic variables (K(trans), Kep, Ve and AUC90). RESULTS: The correlations were very high (r>.80; P<.01) for all the variables for ROI 1 and high (r=.70-.80; P<.01) for all the variables for ROI 2, with the exception of Ve both in ROI 1 (r=.44; P=.07) and in ROI 2 (r=.13; P=.235). There were no statistically significant differences between the two studies in the values obtained for K(trans), Kep and AUC90 (P>.05 for each), but there was a statistically significant difference between the two studies in the values obtained for Ve in ROI 2 (P=.008). CONCLUSIONS: The high temporal resolution protocol for DCE-MRI used at out center is very reproducible for the principal pharmacokinetic constants of breast.
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Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/metabolismo , Meios de Contraste/farmacocinética , Imageamento por Ressonância Magnética , Neoplasias da Mama/patologia , Protocolos Clínicos , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Estadiamento de Neoplasias , Estudos Prospectivos , Reprodutibilidade dos TestesRESUMO
BACKGROUND: To identify whether circulating levels of angiogenesis-related factors may be predictive of bevacizumab efficacy in pre-treated metastatic colorectal cancer (mCRC) patients. METHODS: Pre-treatment serum levels of 24 cytokines were measured using a multiplex bead assay (MBA) in 32 pre-treated mCRC patients treated with irinotecan plus bevacizumab-based salvage therapy. Macrophage-derived chemokine (MDC), interleukins (ILs) 8 and 6 levels were also validated by enzyme-linked immunosorbent assay (ELISA) at different time points during therapy. RESULTS: Higher epidermal growth factor (EGF) and MDC baseline levels (2.2- and 1.4-fold, respectively) and lower IL-10, IL-6 and IL-8 levels (0.2-, 0.6-, and 0.6-fold, respectively, P<0.05) were observed in patients responding to therapy. Baseline levels of these five serum factors compose a risk signature that may define the subset of patients most likely to benefit from bevacizumab-based therapy in terms of response rate and survival times. A positive correlation was found between MBA and ELISA results (P<0.01). Treatment exposure increased MDC and had opposite effects on IL-8 levels, which were decreased (P<0.05). CONCLUSION: This study suggests that a set of inflammatory and angiogenesis-related serum markers may be associated with the efficacy of bevacizumab-containing regimen.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/sangue , Neoplasias Colorretais/sangue , Neoplasias Colorretais/tratamento farmacológico , Anticorpos Monoclonais Humanizados/administração & dosagem , Bevacizumab , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Quimiocina CCL22/metabolismo , Estudos de Coortes , Fator de Crescimento Epidérmico/metabolismo , Feminino , Humanos , Interleucinas/metabolismo , Irinotecano , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Preclinical studies showed a synergistic effect for 5-fluorouracil and lurbinectedin against solid tumors. This phase I trial evaluated a combination of capecitabine plus lurbinectedin in patients with selected advanced solid tumors. Results in patients with relapsed metastatic breast cancer (MBC) are described. PATIENTS AND METHODS: Patients received capecitabine daily on day (D)1-D14 combined with lurbinectedin on D1, D8 or D1 every 3 weeks (q3w) intravenously, following a standard 3 + 3 escalation design and expansion at the recommended dose (RD). RESULTS: Of the 81 enrolled patients, 28 had relapsed MBC: 20 with hormone receptor (HR)-positive tumors and 8 with triple-negative tumors; 3 treated in the D1,D8 schedule and 25 in the D1 schedule. The RD was capecitabine 1650 mg/m2 daily on D1-D14 plus lurbinectedin 2.2 mg/m2 on D1 q3w. Sixteen confirmed responses and two prolonged disease stabilizations (≥6 months) were observed [overall response rate (ORR)/clinical benefit rate (CBR) = 57%/64% at all dose levels; 47%/60% at the RD]. Twelve responses and both prolonged stabilizations occurred in HR-positive tumors (ORR/CBR = 60%/70% at all dose levels, 56%/78% at the RD). Four responses were found in triple-negative tumors (ORR and CBR = 50% at all dose levels; 33% at the RD). Myelotoxicity was reversible and manageable at the RD; most non-hematological toxicities were mild/moderate. No episodes of febrile neutropenia or severe palmar-plantar erythrodysesthesia syndrome occurred. No major pharmacokinetic drug-drug interaction was found between lurbinectedin, capecitabine or capecitabine metabolites. CONCLUSIONS: The capecitabine/lurbinectedin combination showed encouraging clinical activity in relapsed MBC, especially in HR-positive tumors. Toxicity was manageable at the RD. Further development is warranted in relapsed MBC.
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Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/patologia , Capecitabina/farmacologia , Capecitabina/uso terapêutico , Carbolinas/uso terapêutico , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêuticoRESUMO
BACKGROUND: Lurbinectedin, a selective inhibitor of oncogenic transcription, has shown preclinical antitumor activity against homologous recombination repair-deficient models and preliminary clinical activity in BRCA1/2 breast cancer. PATIENTS AND METHODS: This phase II basket multitumor trial (NCT02454972) evaluated lurbinectedin 3.2 mg/m2 1-h intravenous infusion every 3 weeks in a cohort of 21 patients with pretreated germline BRCA1/2 breast cancer. Patients with any hormone receptor and human epidermal growth factor receptor 2 status were enrolled. The primary efficacy endpoint was overall response rate (ORR) according to RECIST v1.1. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety. RESULTS: Confirmed partial response (PR) was observed in six patients [ORR = 28.6%; 95% confidence interval (CI) 11.3% to 52.2%] who had received a median of two prior advanced chemotherapy lines. Lurbinectedin was active in both BRCA mutations: four PRs in 11 patients (36.4%) with BRCA2 and two PRs in 10 patients (20.0%) with BRCA1. Median DoR was 8.6 months, median PFS was 4.1 months and median OS was 16.1 months. Stable disease (SD) was observed in 10 patients (47.6%), including 3 with unconfirmed response in a subsequent tumor assessment [ORR unconfirmed = 42.9% (95% CI 21.8% to 66.0%)]. Clinical benefit rate (PR + SD ≥ 4 months) was 76.2% (95% CI 52.8% to 91.8%). No objective response was observed among patients who had received prior poly (ADP-ribose) polymerase inhibitors. The most common treatment-related adverse events (AEs) were nausea (61.9%), fatigue (38.1%) and vomiting (23.8%). These AEs were mostly grade 1/2. The most common grade 3/4 toxicity was neutropenia (42.9%: grade 4, 23.8%: with no febrile neutropenia). CONCLUSIONS: This phase II study met its primary endpoint and showed activity of lurbinectedin in germline BRCA1/2 breast cancer. Lurbinectedin showed a predictable and manageable safety profile. Considering the exploratory aim of this trial as well as previous results in other phase II studies, further development of lurbinectedin in this indication is warranted.
Assuntos
Neoplasias da Mama , Neutropenia , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Genes BRCA2 , Genes BRCA1 , Ribose/uso terapêutico , Mutação em Linhagem Germinativa , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Células Germinativas/patologia , Neutropenia/tratamento farmacológico , Hormônios/uso terapêutico , Difosfato de Adenosina/uso terapêutico , Proteína BRCA1/genéticaRESUMO
MicroRNAs are non-coding RNAs that can block mRNA translation and influence mRNA stability. Recent evidence indicates that miRNA variations can affect drug resistance, efficacy, and metabolism, opening new avenues of pharmacogenomics research. We investigated associations between polymorphisms in both miRNA-containing genomic regions (primary and precursor miRNA) and in genes related to miRNA biogenesis with clinical outcome in metastatic colorectal cancer (mCRC) patients treated with 5-fluorouracil and irinotecan (CPT-11). Eighteen single-nucleotide polymorphisms (SNPs) were analyzed in 61 patients. A significant association with tumor response and time to progression (TTP) was found for SNP rs7372209 in pri-miR26a-1 (P=0.041 and P=0.017, respectively). The genotypes CC and CT were favorable when compared with the TT variant genotype. In addition, SNP rs1834306, located in the pri-miR-100 gene, significantly correlated with a longer TTP (P=0.04). In the miRNA-biogenesis pathway, a trend was identified between SNP rs11077 in the exportin-5 gene and disease control rate (P=0.076). This study is the first to suggest a relationship between treatment outcome and SNPs in the miRNA-biogenesis machinery, in both primary and precursor miRNAs. Our results suggest that miRNA polymorphic variants might be useful predictors of clinical outcome in mCRC patients treated with 5-fluorouracil and CPT-11 combination.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/genética , MicroRNAs/genética , Metástase Neoplásica , Polimorfismo de Nucleotídeo Único , Idoso , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Progressão da Doença , Feminino , Fluoruracila/administração & dosagem , Genótipo , Humanos , Irinotecano , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: To determine the dose-limiting toxicity (DLT), maximum tolerated dose, recommended dose (RD) and preliminary evidence of activity of escalating doses of irinotecan (CPT-11) fixed-dose-rate infusional gemcitabine (FDR-GMB) and bevacizumab in pretreated metastatic colorectal cancer (mCRC) patients. Pharmacogenomic analysis was performed to investigate the association between VEGF single-nucleotide polymorphisms and clinical outcome. PATIENTS AND METHODS: A total of 89 mCRC patients were recruited in a two-step study design; 28 were included in the dose-finding study and 59 in the pharmacogenomic analysis. The FDR-GMB of 1000 mg m⻲, bevacizumab 5 mg kg⻹ and CPT-11 doses ranging from 100 to 160 mg m⻲ were explored. The VEGF protein serum levels were quantified by EIA. Allelic discrimination was performed to genotype polymorphisms in the VEGF gene. RESULTS: CPT-11 RD was 150 mg m⻲. Diarrhoea and neutropenia were the DLT. After a median follow-up of 42 months, the median time to progression (TTP) and overall survival were 5.2 and 19.9 months, respectively. VEGF levels were significantly correlated with VEGF-2578AA and VEGF-460CC genotypes, and a trend was observed with VEGF+405GG genotype. The presence of any of these genotypes correlated with a longer median TTP (8.8 vs 4.5 months, P=0.04). CONCLUSION: The triplet combination tested in this study is effective and well tolerated. A possible predictive role for VEGF gene polymorphisms and baseline VEGF circulating levels is suggested.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Bevacizumab , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Progressão da Doença , Relação Dose-Resposta a Droga , Genótipo , Humanos , Irinotecano , Metástase Neoplásica , Farmacogenética , Análise de Sobrevida , Fatores de Tempo , Fator A de Crescimento do Endotélio Vascular/genética , GencitabinaRESUMO
MicroRNAs (miRNAs) comprise an abundant class of small non-coding RNAs that act as important post-transcriptional regulators of gene expression. Accumulating evidence shows that aberrantly expressed miRNAs play important roles in human cancers and underscores them as potential targets for therapeutic intervention. Basic research has provided strong evidence about the role of miRNA as oncogenes and as tumor suppressor genes in cancer. In accord with this finding, miRNA-based cancer therapy is a very interesting field of investigation that offers the appeal of targeting multiple gene networks controlled by a single, aberrantly expressed miRNA. A new door in cancer research is opening and it may lead to the modulation of miRNAs.
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Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/terapia , Genes Supressores de Tumor , MicroRNAs/fisiologia , Oncogenes , HumanosRESUMO
The strength of electronic correlation effects in the spin-dependent electronic structure of ferromagnetic bcc Fe(110) has been investigated by means of spin and angle-resolved photoemission spectroscopy. The experimental results are compared to theoretical calculations within the three-body scattering approximation and within the dynamical mean-field theory, together with one-step model calculations of the photoemission process. This comparison indicates that the present state of the art many-body calculations, although improving the description of correlation effects in Fe, give too small mass renormalizations and scattering rates thus demanding more refined many-body theories including nonlocal fluctuations.
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BACKGROUND AND METHODS: The authors report their experience with thrombolytic therapy in seven cases of graft thrombosis managed successfully with low-dose i.v. rt-TPA. In six patients the cause was an anatomical one and so, after the successful lysis, there was enough time to confirm a correct diagnosis and plan the "right" and "less extensive" surgical procedure, obviating it in one case with a "functional" cause of thrombosis. RESULTS: No complication directly attributable to rt-TPA infusion occurred, and no systemic fibrinogenolysis was registered in any cases. Judging from this experience, i.v. rt-TPA appears safe and effective in patients with graft thrombosis, proving to be a good adjunctive therapeutic mode. CONCLUSIONS: Further studies are needed do delineate more clearly safe indication and the validity of this method.
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Fibrinolíticos/uso terapêutico , Oclusão de Enxerto Vascular/tratamento farmacológico , Terapia Trombolítica , Ativador de Plasminogênio Tecidual/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Fibrinolíticos/administração & dosagem , Seguimentos , Oclusão de Enxerto Vascular/sangue , Oclusão de Enxerto Vascular/complicações , Humanos , Infusões Intravenosas , Isquemia/sangue , Isquemia/tratamento farmacológico , Isquemia/etiologia , Perna (Membro)/irrigação sanguínea , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes , Segurança , Ativador de Plasminogênio Tecidual/administração & dosagemRESUMO
The paper reports the study of 35 patients affected by pancreatic and periampullary carcinoma. The authors analyse the results of six patients treated using pancreaticoduodenectomy with pyloric preservation and compare the results to those achieved using Whipple's operation.
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Adenoma de Células das Ilhotas Pancreáticas/cirurgia , Ampola Hepatopancreática , Carcinoma Intraductal não Infiltrante/cirurgia , Neoplasias do Ducto Colédoco/cirurgia , Duodeno/cirurgia , Pâncreas/cirurgia , Neoplasias Pancreáticas/cirurgia , Idoso , Feminino , Humanos , Masculino , Métodos , Pessoa de Meia-Idade , PancreatectomiaRESUMO
The authors report their experience with 9 patients, affected by pancreatic and periampullary carcinoma, treated using pancreaticoduodenectomy with pyloric preservation. They analyse the physiopathology of this technique, by the light of the international reports, and note the advantages that this technique allows about the nutritional status and the quality of life of the patients operated on.
Assuntos
Ampola Hepatopancreática/fisiopatologia , Neoplasias do Ducto Colédoco/fisiopatologia , Neoplasias Duodenais/fisiopatologia , Neoplasias Pancreáticas/fisiopatologia , Pancreaticoduodenectomia/métodos , Idoso , Ampola Hepatopancreática/cirurgia , Neoplasias do Ducto Colédoco/cirurgia , Neoplasias Duodenais/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/cirurgia , Pancreaticoduodenectomia/instrumentação , Qualidade de Vida , Estudos Retrospectivos , Resultado do TratamentoRESUMO
OBJECTIVES: To investigate quantitative methods of tumor proliferation using 3'-[(18)F]fluoro-3'-deoxythymidine ([(18)F]FLT) PET in patients with breast cancer (BC), studied before and after one bevacizumab administration, and to correlate the [(18)F]FLT-PET uptake with the Ki67 index. MATERIAL AND METHODS: Thirty patients with newly diagnosed, untreated BC underwent a [(18)F]FLT-PET before and 14 days after bevacizumab treatment. A dynamic scan centered over the tumor began simultaneously with the injection of [(18)F]FLT (385 ± 56 MBq). Image derived input functions were obtained using regions of interest drawn on the left ventricle (LV) and descending aorta (DA). Metabolite corrected blood curves were used as input functions to obtain the kinetic Ki constant using the Patlak graphical analysis (time interval 10-60 min after injection). Maximum SUV values were derived for the intervals 40-60 min (SUV40) and 50-60 min (SUV50). PET parameters were correlated with the Ki67 index obtained staining tumor biopsies. RESULTS: [(18)F]FLT uptake parameters decreased significantly (p<0.001) after treatment: SUV50=3.09 ± 1.21 vs 2.22 ± 0.96; SUV40=3.00 ± 1.18 vs 2.14 ± 0.95, Ki_LV(10-3)=52[22-116] vs 38[13-80] and Ki_DA(10-3)=49[15-129] vs 33[11-98]. Consistency interclass correlation coefficients within SUV and within Ki were high. Changes of SUV50 and Ki_DA between baseline PET and after one bevacizumab dose PET correlated with changes in Ki67 index (r-Pearson=0.35 and 0.26, p=0.06 and 0.16, respectively). CONCLUSIONS: [(18)F]FLT-PET is useful to demonstrate proliferative changes after a dose of bevacizumab in patients with BC. Quantification of tumor proliferation by means of SUV and Ki has shown similar results, but SUV50 obtained better results. A correlation between [(18)F]FLT changes and Ki67 index was observed.
Assuntos
Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/patologia , Didesoxinucleosídeos , Radioisótopos de Flúor , Tomografia por Emissão de Pósitrons , Adulto , Idoso , Inibidores da Angiogênese/uso terapêutico , Bevacizumab/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Proliferação de Células , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Tomografia por Emissão de Pósitrons/métodos , Estudos ProspectivosRESUMO
BACKGROUND: To investigate whether single nucleotide polymorphisms (SNPs) in gemcitabine (GMB) metabolism genes were associated with clinical outcome in pre-treated metastatic colorectal cancer (mCRC) patients. PATIENTS AND METHODS: SNPs of hCNT1, hENT1, CDA, dCTD and RRM1 genes were evaluated in 95 mCRC patients and detected using TaqMan genotyping assays. Association of genotypes with overall response rate (ORR), time to progression (TTP) and overall survival (OS) was tested by univariate and multivariate analysis. RRM1 -37A>C polymorphism was correlated with GMB IC50 value and with the RRM1 gene expression level in CRC cell lines. RESULTS: The ORR was 38.9%. The median TTP and OS were 4 and 14.3 months, respectively. By multivariate analysis, patients carrying the RRM1 -37CC genotype or the CDA A-76 C-containing allele had a significantly higher likelihood of achieving a tumour response. RRM1 -37A>C polymorphism remained associated with clinical efficacy (TTP). In vitro experiments, in CRC cell lines, showed that the RRM1 A-37C genotype was associated with the levels of RRM1 expression and with GMB IC50 values. Finally, the down-regulation of RRM1 with a specific siRNA strongly influenced GMB sensitivity. CONCLUSION: RRM1 -37A>C polymorphism may represent a useful biomarker to select mCRC patients most likely to benefit from GMB-based salvage therapy.
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Antimetabólitos Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Desoxicitidina/análogos & derivados , Polimorfismo Genético/genética , Proteínas Supressoras de Tumor/genética , Adulto , Idoso , Western Blotting , Desoxicitidina/uso terapêutico , Progressão da Doença , Feminino , Genótipo , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , RNA Interferente Pequeno/genética , Estudos Retrospectivos , Ribonucleosídeo Difosfato Redutase , Células Tumorais Cultivadas , GencitabinaRESUMO
The aim of cystic fibrosis (CF) care is to improve both the life expectancy and quality of life of patients. However, rising costs and limited resources of health services must be taken into account. There are many different antibiotic strategies for therapy of Pseudomonas aeruginosa infection in CF patients. In this 5-year retrospective study we found that the cost of treatment of initial infection is considerably lower than the cost of treating chronic P. aeruginosa infections. The percentage distribution of costs of antibiotic treatment in relationship to the administration route was considerably different between outpatients and inpatients. We observed an increase in antibiotic costs with the age of the patient and the decrease in FEV(1)values. The implementation of early eradication treatment, in addition to decreasing the prevalence of patients chronically infected by P. aeruginosa, might also bring about a notable decrease in costs.
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Antibacterianos/economia , Efeitos Psicossociais da Doença , Fibrose Cística/tratamento farmacológico , Fibrose Cística/economia , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/economia , Adulto , Antibacterianos/uso terapêutico , Ceftazidima/economia , Ceftazidima/uso terapêutico , Pré-Escolar , Doença Crônica , Ciprofloxacina/economia , Ciprofloxacina/uso terapêutico , Ácidos Clavulânicos/economia , Ácidos Clavulânicos/uso terapêutico , Colistina/economia , Colistina/uso terapêutico , Fibrose Cística/complicações , Humanos , Meropeném , Infecções por Pseudomonas/etiologia , Pseudomonas aeruginosa , Estudos Retrospectivos , Tienamicinas/economia , Tienamicinas/uso terapêutico , Ticarcilina/economia , Ticarcilina/uso terapêutico , Tobramicina/economia , Tobramicina/uso terapêuticoRESUMO
Antibiotic strategies against Pseudomonas aeruginosa infection in cystic fibrosis (CF) patients should consider the natural history of the P. aeruginosa infection, ranging from the first isolation of the germ in the airways to isolation at every microbiological culture, and the patient's clinical condition. Antibiotic treatment against P. aeruginosa given at the time of first isolation may prevent or delay chronic infection. The period of intermittent colonization can be considered the time before the development of mucoid P. aeruginosa phenotype. The optimal treatment strategy in this stage remains unclear in terms of agents used and duration of treatment. To treat acute exacerbation, the authors suggest using intravenous administration of two different classes of antibiotics. Maintenance antibiotics are administered to slow the decline in pulmonary function for P. aeruginosa chronic infection. The meaning of maintenance therapy has changed over time, beginning from intravenous quarterly anti-Pseudomonas antibiotics, irrespective of symptoms, to other strategies such as oral macrolides, ciprofloxacin or inhaled antibiotics (tobramycin and colistin). Aerosol delivery can provide a high concentration at the desired site with minimal absorption and therefore low risk of toxicity. There is scientific evidence that antibiotics are clinically effective in CF patients. Antibiotic selection should be based on periodic isolation and identification of pathogens and antimicrobial susceptibility.