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Five-year overall survival of stage III colorectal cancer (CRC) patients treated with standard adjuvant chemotherapy (ACHT) is highly variable. Genomic biomarkers and/or transcriptomic profiles identified lack of adequate validation. Aim of our study was to identify and validate molecular biomarkers predictive of ACHT response in stage III CRC patients by a transcriptomic approach. From a series of CRC patients who received ACHT, two stage III extreme cohorts (unfavorable vs. favorable prognosis) were selected. RNA-sequencing was performed from fresh frozen explants. Tumors were characterized for somatic mutations. Validation was performed in stage III CRC patients extracted from two GEO datasets. According to disease-free survival (DFS), 108 differentially expressed genes (104/4 up/downregulated in the unfavorable prognosis group) were identified. Among 104 upregulated genes, 42 belonged to olfactory signaling pathways, 62 were classified as pseudogenes (n = 17), uncharacterized noncoding RNA (n = 10), immune response genes (n = 4), microRNA (n = 1), cancer-related genes (n = 14) and cancer-unrelated genes (n = 16). Three out of four down-regulated genes were cancer-related. Mutational status (i.e., RAS, BRAF, PIK3CA) did not differ among the cohorts. In the validation cohort, multivariate analysis showed high PNN and KCNQ1OT1 expression predictive of shorter DFS in ACHT treated patients (p = 0.018 and p = 0.014, respectively); no difference was observed in untreated patients. This is the first study that identifies by a transcriptomic approach and validates PNN and KCNQ1OT1 as molecular biomarkers predictive of chemotherapy response in stage III CRC patients. After a further validation in an independent cohort, PNN and KCNQ1OT1 evaluation could be proposed to prospectively identify stage III CRC patients benefiting from ACHT.
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Biomarcadores Tumorais/genética , Moléculas de Adesão Celular/genética , Neoplasias Colorretais/genética , Proteínas Nucleares/genética , Idoso , Quimioterapia Adjuvante/métodos , Classe I de Fosfatidilinositol 3-Quinases/genética , Estudos de Coortes , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Regulação para Baixo/genética , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Estadiamento de Neoplasias/métodos , Canais de Potássio de Abertura Dependente da Tensão da Membrana/genética , Prognóstico , Análise de Sequência de RNA/métodos , Transdução de Sinais/genética , Transcriptoma/genética , Regulação para Cima/genéticaRESUMO
Leiomyosarcomas represent the most common variant of uterine sarcomas, and are also considered to be the least chemosensitive. To date, adriamycin and ifosfamide are believed to be the most effective drugs for its treatment, in addition to docetaxel and gemcitabine. Recently, the introduction of trabectedin has provided clinicians with another treatment option, and the drug may have some benefits for patients as it may allow for long-term treatment. We present the case of a patient who previously failed multiple cycles of chemotherapy and who was subsequently treated with 30 cycles of trabectedin as third-line therapy for multiple metastases of uterine leiomyosarcoma. During the treatment period, the dosage and dose interval of trabectedin were optimized because of the appearance of grade 4 hematological and gastrointestinal toxicity. Dose adjustments led to acceptable tolerability. Trabectedin was associated with a very good partial response, especially at the pulmonary and pancreatic levels, and stable disease was achieved at all metastatic sites. The patient is currently continuing treatment with trabectedin and has clinically stable disease after 2 years of therapy. This case report provides further evidence that trabectedin is a valid and well-tolerated therapeutic option that can be used in the long term in uterine leiomyosarcoma.
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Antineoplásicos Alquilantes/uso terapêutico , Dioxóis/uso terapêutico , Leiomiossarcoma/tratamento farmacológico , Tetra-Hidroisoquinolinas/uso terapêutico , Neoplasias Uterinas/tratamento farmacológico , Idoso , Feminino , Humanos , Leiomiossarcoma/patologia , Metástase Neoplásica , Trabectedina , Neoplasias Uterinas/patologiaRESUMO
Multidrug resistance (MDR) is a major obstacle to the effective treatment of cancer. Cellular overproduction of P-glycoprotein (P-gp), which acts as an efflux pump for various anticancer drugs (e.g. anthracyclines, Vinca alkaloids, taxanes, epipodophyllotoxins, and some of the newer antitumor drugs) is one of the more relevant mechanisms underlying MDR. P-gp belongs to the superfamily of ATP-binding cassette transporters and is encoded by the ABCB1 gene. Its overexpression in cancer cells has become a therapeutic target for circumventing MDR. As an alternative to the classical pharmacological strategy of the coadministration of pump inhibitors and cytotoxic substrates of P-gp and to other approaches applied in experimental tumor models (e.g. P-gp-targeting antibodies, ABCB1 gene silencing strategies, and transcriptional modulators) and in the clinical setting (e.g. incapsulation of P-gp substrate anticancer drugs into liposomes or nanoparticles), a more intriguing strategy for circumventing MDR is represented by the development of new anticancer drugs which are not substrates of P-gp (e.g. epothilones, second- and third-generation taxanes and other microtubule modulators, topoisomerase inhibitors). Some of these drugs have already been tested in clinical trials and, in most of cases, show relevant activity in patients previously treated with anticancer agents which are substrates of P-gp. Of these drugs, ixabepilone, an epothilone, was approved in the United States for the treatment of breast cancer patients pretreated with an anthracycline and a taxane. Another innovative approach is the use of molecules whose activity takes advantage of the overexpression of P-gp. The possibility of overcoming MDR using the latter two approaches is reviewed herein.
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Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/química , HumanosRESUMO
INTRODUCTION: An online survey was conducted to characterize current infection management practices in Italian intensive care units (ICUs), including the antibacterial and antifungal drug regimens prescribed for various types of infections. METHODS: During February and March 2011, all 450 ICUs in public hospitals in Italy were invited to take part in an online survey. The questionnaire focused on ICU characteristics, methods used to prevent, diagnose, and treat infections, and antimicrobials prescribing policies. The frequency of each reported practice was calculated as a percentage of the total number of units answering the question. The overall response rate to the questionnaire was 38.8% (175 of the 450 ICUs contacted) with homogeneous distribution across the country and in terms of unit type. RESULTS: Eighty-eight percent of the responding facilities performed periodical surveillance cultures on all patients. In 71% of patients, cultures were also collected on admission. Endotracheal/bronchial aspirates were the most frequently cultured specimens at both time points. Two-thirds of the responding units had never performed screening cultures for methicillin-resistant Staphylococcus aureus. Around 67% of the ICUs reported the use of antimicrobial de-escalation strategies during the treatment phase. In general, the use of empirical antimicrobial drug regimens was appropriate. Although the rationale for the choice was not always clearly documented, the use of a combination therapy was preferred over antibiotic monotherapy. The preferred first-line agents for invasive candidiasis were fluconazole and an echinocandin (64% and 25%, respectively). Two-thirds of the ICUs monitored vancomycin serum levels and administered it by continuous infusion in 86% of cases. For certain antibiotics, reported doses were too low to ensure effective treatment of severe infections in critically ill patients; conversely, inappropriately high doses were administered for certain antifungal drugs. CONCLUSIONS: Although infection control policies and management practices are generally appropriate in Italian ICUs, certain aspects, such as the extensive use of multidrug empirical regimens and the inappropriate antimicrobial dosing, deserve careful management and closer investigation.
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Infecções/tratamento farmacológico , Unidades de Terapia Intensiva/estatística & dados numéricos , Antibacterianos/administração & dosagem , Antibacterianos/uso terapêutico , Anti-Infecciosos/administração & dosagem , Anti-Infecciosos/uso terapêutico , Antifúngicos/administração & dosagem , Antifúngicos/uso terapêutico , Infecções Bacterianas/diagnóstico , Infecções Bacterianas/tratamento farmacológico , Infecção Hospitalar/diagnóstico , Infecção Hospitalar/tratamento farmacológico , Infecção Hospitalar/prevenção & controle , Esquema de Medicação , Pesquisas sobre Atenção à Saúde , Humanos , Controle de Infecções/métodos , Infecções/diagnóstico , Unidades de Terapia Intensiva/organização & administração , Itália/epidemiologia , Staphylococcus aureus Resistente à Meticilina , Micoses/diagnóstico , Micoses/tratamento farmacológico , Infecções Estafilocócicas/diagnóstico , Infecções Estafilocócicas/tratamento farmacológico , Inquéritos e QuestionáriosRESUMO
Although adjuvant chemotherapy has significantly increased overall survival in resected Stage III colorectal cancer, disease recurrence is still high (30-40%). 20-25% of Stage II patients also develop recurrent disease. Thus, high-risk patients may benefit from chemotherapy. As patient response to standard chemotherapy varies, the study of molecular differences in the expression of pharmacologically relevant genes may help clinicians to understand variability and tailor therapy. The expression of 5-fluorouracil (5-FU) pathway genes in tumors from 53 Stages II-III colorectal cancer patients who underwent 5-FU adjuvant chemotherapy was investigated by reverse transcription quantitative real-time polymerase chain reaction. Patients were dichotomized into high- and low-mRNA expression level groups using median values of gene mRNA levels. Then, a threshold analysis to identify a cut-off distinguishing recurrent- or nonrecurrent-disease was used. A high degree of interpatient variation in relative tumor expression of study genes was observed. Multiple gene correlations were found, which suggest possible coregulation mechanisms. No statistically significant relationship between experimental data and baseline clinical/pathological characteristics or clinical outcome was observed using gene expression median values. Threshold analysis indicated significant inverse relationships between deoxyuridine triphosphatase (DUT), ferrodoxin reductase (FDXR) or tumor protein p53 (TP53) and disease-free survival (DFS) in the entire case series and between DUT or NM23-H1 and DFS in Stage III patients: higher gene expression was associated with shorter DFS. This study provides data on relationships between expression of 5-FU pathway genes and clinical outcome of colorectal cancer patients undergoing 5-FU adjuvant chemotherapy and underscores the predictive role of specific genes. Validation in an independent case series is warranted.
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Adenocarcinoma/genética , Antimetabólitos Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Fluoruracila/uso terapêutico , Recidiva Local de Neoplasia/genética , Farmacogenética , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Quimioterapia Adjuvante , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Nucleosídeo NM23 Difosfato Quinases/genética , Nucleosídeo NM23 Difosfato Quinases/metabolismo , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , Pirofosfatases/genética , Pirofosfatases/metabolismo , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Taxa de Sobrevida , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
BACKGROUND AND OBJECTIVES: Thymidylate synthase (TS) expression levels appear to be related to response to 5-fluorouracil-(5-FU)-based chemotherapy in colorectal cancer (CRC) patients. Three polymorphisms have been proposed as modulators of TS expression: a tandemly repeated sequence (2R/3R) in the 5' UTR, a SNP (G>C) within the 3R allele and a 6bp deletion in the 3' UTR. To evaluate the influence of TS expression and polymorphisms on clinical outcome of 5-FU-treated patients we performed a comprehensive genetic analysis on 63 CRC patients. METHODS: TS expression levels were analyzed in normal and tumor tissues. TS coding sequence and UTR polymorphisms were investigated on DNA from normal tissue. LOH analysis was performed to determine tumor genotype. RESULTS: A difference in disease-free survival (DFS), although not statistically significant, was observed between high and low mRNA expression levels: patients with low levels showed longer DFS. The 2R2R genotype showed significantly lower expression than the 3R3R and 2R3R genotypes in normal tissue. No other TS polymorphism was associated with mRNA expression or clinical outcome. CONCLUSIONS: The results obtained in this pilot study indicate that the number of 5' UTR repeats is the major genetic determinant of TS expression. The lack of association with other polymorphisms might be partially explained by the existence of linkage disequilibrium in the TS gene. Our data support the growing evidence that TS control may require multiple mechanisms acting in close coordination with one another and suggest that TS genotyping alone in tumor samples is not sufficient to accurately predict response to 5-FU.
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Antimetabólitos Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/enzimologia , Fluoruracila/uso terapêutico , Regulação Neoplásica da Expressão Gênica , Timidilato Sintase/genética , Adulto , Idoso , Neoplasias Colorretais/genética , Intervalo Livre de Doença , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
PURPOSE: A large proportion of patients with cancer suffer from breakthrough cancer pain (BTcP). Several unmet clinical needs concerning BTcP treatment, such as optimal opioid dosages, are being investigated. In this analysis the hypothesis, we explore with an unsupervised learning algorithm whether distinct subtypes of BTcP exist and whether they can provide new insights into clinical practice. METHODS: Partitioning around a k-medoids algorithm on a large data set of patients with BTcP, previously collected by the Italian Oncologic Pain Survey group, was used to identify possible subgroups of BTcP. Resulting clusters were analyzed in terms of BTcP therapy satisfaction, clinical features, and use of basal pain and rapid-onset opioids. Opioid dosages were converted to a unique scale and the BTcP opioids-to-basal pain opioids ratio was calculated for each patient. We used polynomial logistic regression to catch nonlinear relationships between therapy satisfaction and opioid use. RESULTS: Our algorithm identified 12 distinct BTcP clusters. Optimal BTcP opioids-to-basal pain opioids ratios differed across the clusters, ranging from 15% to 50%. The majority of clusters were linked to a peculiar association of certain drugs with therapy satisfaction or dissatisfaction. A free online tool was created for new patients' cluster computation to validate these clusters in future studies and provide handy indications for personalized BTcP therapy. CONCLUSION: This work proposes a classification for BTcP and identifies subgroups of patients with unique efficacy of different pain medications. This work supports the theory that the optimal dose of BTcP opioids depends on the dose of basal opioids and identifies novel values that are possibly useful for future trials. These results will allow us to target BTcP therapy on the basis of patient characteristics and to define a precision medicine strategy also for supportive care.
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Pharmacokinetics and pharmacodynamics are significantly altered in critically ill septic patients and the risk of prolonged periods with concentrations below the minimum inhibitory concentration (MIC) and of low area under the serum concentration-time curve/MIC (AUC/MIC) ratios is of concern. We compared the pharmacokinetic/pharmacodynamic (PK/PD) profile of linezolid administered by intermittent or continuous infusion in critically ill septic patients. Patients were divided into two groups: intermittent infusion (Group I) (600mg/12h); or continuous infusion (Group C) (300mg intravenous loading dose +900mg continuous infusion on Day 1, followed by 1200mg/daily from Day 2). Linezolid serum levels were monitored for 72h and microbiological data were collected. The clinical outcome was monitored. Sixteen patients completed the study. MICs of susceptible pathogens were 2mg/L for 80% of the isolates. In Group I, linezolid trough serum levels (C(min)) varied widely and were below the susceptibility breakpoint (4mg/L) during the study period; in 50% of patients C(min) was <1mg/L. In Group C, mean linezolid serum levels were more stable and, starting from 6h, were significantly higher than C(min) levels observed in Group I and were always above the susceptibility breakpoint. Time that the free drug concentration was above the MIC (T(free)>MIC) of>85% was more frequent in Group C than in Group I (P<0.05). Finally, with continuous infusion it was possible to achieve AUC/MIC values of 80-120 more frequently than with intermittent infusion (P<0.05). According to PK/PD parameters, continuous infusion has theoretical advantages over intermittent infusion in this population of patients.
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Acetamidas/farmacologia , Acetamidas/farmacocinética , Antibacterianos/administração & dosagem , Estado Terminal , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Oxazolidinonas/farmacologia , Oxazolidinonas/farmacocinética , Sepse/tratamento farmacológico , Acetamidas/administração & dosagem , Adulto , Idoso , Antibacterianos/farmacocinética , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Esquema de Medicação , Feminino , Bactérias Gram-Negativas/efeitos dos fármacos , Infecções por Bactérias Gram-Negativas/complicações , Infecções por Bactérias Gram-Negativas/microbiologia , Humanos , Infusões Intravenosas , Injeções Intravenosas , Linezolida , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Oxazolidinonas/administração & dosagem , Sepse/etiologiaRESUMO
The pharmacodynamic and pharmacokinetic characteristics of antimicrobial agents are the two fundamental pharmacological components which provide a rationale for the choice of therapy for intraabdominal infections, and especially serious infections. The most important PK-PD parameters are well known which can potentiate therapeutic efficacy. Antimicrobial agents can be subdivided into categories based on whether their activity is dependent on concentration or exposure time. Therefore, a correct dosing regimen for the time-dependent molecules (i.e. beta-lactams, linezolid, tigecycline) should prolong the maximum exposure time to maintain serum levels over the minimum inhibitory concentration (MIC). The concentration-dependent molecules, on the other hand, which include aminoglycosides and fluoroquinolones, should be given in order to reach maximum concentrations, since they are bactericidal in direct proportion to their concentrations and possess a prolonged post-antibiotic effect.
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Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Doenças do Sistema Digestório/tratamento farmacológico , Doenças do Sistema Digestório/microbiologia , Abscesso Abdominal/tratamento farmacológico , Acetamidas/farmacologia , Acetamidas/uso terapêutico , Aminoglicosídeos/farmacologia , Aminoglicosídeos/uso terapêutico , Antibacterianos/farmacocinética , Anti-Infecciosos/farmacologia , Anti-Infecciosos/uso terapêutico , Quimioterapia Combinada , Fluoroquinolonas/farmacologia , Fluoroquinolonas/uso terapêutico , Humanos , Linezolida , Metronidazol/farmacologia , Metronidazol/uso terapêutico , Testes de Sensibilidade Microbiana , Minociclina/análogos & derivados , Minociclina/farmacologia , Minociclina/uso terapêutico , Oxazolidinonas/farmacologia , Oxazolidinonas/uso terapêutico , Peritonite/tratamento farmacológico , Sepse/tratamento farmacológico , Tigeciclina , Resultado do Tratamento , Virginiamicina/farmacologia , Virginiamicina/uso terapêutico , beta-Lactamas/farmacologia , beta-Lactamas/uso terapêuticoRESUMO
The majority of patients with ovarian cancer will experience relapse and thus require second-line therapy. While platinum-based therapies are the primary treatments for refractory disease other options are required, particularly for those with partially platinum-sensitive disease as their response rates are lower. Agents that can resensitize relapsed ovarian cancers to platinum, including trabectedin, are therefore of increasing interest. Trabectedin is a multitarget agent that has a complex, novel mechanism of action and has exhibited promising results in platinum-sensitive ovarian cancer when in combination with pegylated liposomal doxorubicin (PLD). The present study conducted retrospective analysis involving 11 cases (median age 60 years; range 45-75 years) of recurrent ovarian tumors and partial platinum sensitivity undergoing treatment with trabectedin + PLD. The cohort consisted of 7 serous carcinomas, 1 endometrial carcinoma, 2 undifferentiated carcinomas, and 1 mucinous carcinoma. Of the 11 patients, 4 exhibited a complete response, 3 achieved stable disease, and 4 had progression of disease. Mean overall survival was 32.42 months and median progression-free survival was 5.9 months. Trabectedin in combination with PLD was well tolerated in terms of gastrointestinal and hematological toxicity; Grade 3 cutaneous toxicity and grade 3 neutropenia were each observed in 18.2% of patients. There were no grade 4 events. Thus, the present study supports the use of trabectedin + PLD in patients with relapsed ovarian cancer and partial platinum sensitivity, with predictable and manageable toxicity.
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Background: The aim of this study was to identify potential variables influencing the clinical presentation of breakthrough cancer pain (BTP). Methods: Cancer patients with a diagnosis of BTP were enrolled. Demographic and clinical characteristics, as well as background pain and BTP characteristics were collected. Multivariate analyses were conducted to assess the correlation between BTP characteristics and the variables examined. Results: Data of 4016 patients were analysed. Average daily number of BTP episodes was 2.4, mean intensity was 7.5, and a mean duration was 43.3 min. A short onset BTP was observed in 68.9% of patients. In 30.5% of patients BTP was predictable. There were 86.0% of participants who reported a marked interference of BTP with their daily activities. Furthermore, 86.8% of patients were receiving opioids for the management of BTP. The average time to meaningful pain relief was 16.5 min and 70.9% of patients were satisfied with their BTP medications. Age, head and neck cancer, Karnofsky, background pain intensity, predictable and fast onset BTP were independently associated with the number of BTP episodes. BTP pain intensity was independently associated with background pain intensity, fast onset BTP, and Karnofsky. Neuropathic pain mechanism was independently associated with unpredictable BTP. Variables independently associated with a longer duration of BTP were age, place of visit, cancer diagnosis, disease-oriented therapy, background pain intensity and mechanism, and unpredictable BTP. Age, Karnofsky, background pain intensity, fast onset, and long duration of BTP were independently associated with interference with daily activity. Conclusions: BTP has a variable presentation depending on interdependent relationships among its different characteristics.
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Lower respiratory tract infections (LRTIs) cause high morbidity and mortality worldwide. Empiric therapy often base the choice of antibiotic treatment on antibacterial spectrum of the agent rather than on its pharmacological properties or the pathogen resistance profile. Inappropriate prescribing leads to therapeutic failure and antibiotic resistance, with increasing direct and indirect health costs. A consensus on appropriate prescribing in LRTI therapy was appraised by this Delphi exercise, based on a panel of 70 pulmonologists, coordinated by a Scientific Committee of nine experts in respiratory medical care. Full or very high consensus was reached on several issues, including the role of oral cephalosporins in first-line treatments of LRTIs and the appropriateness of cefditoren, with balanced spectrum and high intrinsic activity, in LRTI treatment. Evidence-based medicine approach and a comprehensive process of disease management, from diagnosis to therapy and follow-up, should guide antibiotic prescribing.
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Antibacterianos/uso terapêutico , Infecções Respiratórias/tratamento farmacológico , Cefalosporinas/uso terapêutico , Farmacorresistência Bacteriana/efeitos dos fármacos , Medicina Baseada em Evidências/métodos , Humanos , Prescrição Inadequada/efeitos adversosRESUMO
INTRODUCTION: An ongoing national multicenter survey [Italian Oncologic Pain multiSetting Multicentric Survey (IOPS-MS)] is evaluating the characteristics of breakthrough cancer pain (BTP) in different clinical settings. Preliminary data from the first 1500 cancer patients with BTP enrolled in this study are presented here. METHODS: Thirty-two clinical centers are involved in the survey. A diagnosis of BTP was performed by a standard algorithm. Epidemiological data, Karnofsky index, stage of disease, presence and sites of metastases, ongoing oncologic treatment, and characteristics of background pain and BTP and their treatments were recorded. Background pain and BTP intensity were measured. Patients were also questioned about BTP predictability, BTP onset (≤10 or >10 min), BTP duration, background and BTP medications and their doses, time to meaningful pain relief after BTP medication, and satisfaction with BTP medication. The occurrence of adverse reactions was also assessed, as well as mucosal toxicity. RESULTS: Background pain was well controlled with opioid treatment (numerical rating scale 3.0 ± 1.1). Patients reported 2.5 ± 1.6 BTP episodes/day with a mean intensity of 7.5 ± 1.4 and duration of 43 ± 40 min; 977 patients (65.1%) reported non-predictable BTP, and 1076 patients (71.7%) reported a rapid onset of BTP (≤10 min). Higher patient satisfaction was reported by patients treated with fast onset opioids. CONCLUSIONS: These preliminary data underline that the standard algorithm used is a valid tool for a proper diagnosis of BTP in cancer patients. Moreover, rapid relief of pain is crucial for patients' satisfaction. The final IOPS-MS data are necessary to understand relationships between BTP characteristics and other clinical variables in oncologic patients. FUNDING: Molteni Farmaceutici, Italy.
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Analgésicos Opioides/uso terapêutico , Dor Irruptiva/tratamento farmacológico , Dor do Câncer/tratamento farmacológico , Manejo da Dor/métodos , Adulto , Idoso , Algoritmos , Dor Irruptiva/diagnóstico , Dor Irruptiva/terapia , Dor do Câncer/diagnóstico , Dor do Câncer/epidemiologia , Dor do Câncer/terapia , Feminino , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Medição da Dor , Satisfação do Paciente , Inquéritos e QuestionáriosRESUMO
Uncomplicated urinary tract infections (UTI) are treated with beta-lactams, co-trimoxazole, quinolones and fosfomycin tromethamine. Due to increasing resistance of causative pathogens, antibiotics should be used by considering their pharmacodynamic and pharmacokinetic characteristics. beta-lactams have time-dependent activity and should not be used once-daily. Co-trimoxazole should be restricted due to increasing chemoresistance. Fluoroquinolones play a primary role in the treatment of serious and complicated infections. Fosfomycin tromethamine is active against most urinary tract pathogens. In vitro time-kill kinetics of fosfomycin against Escherichia coli and Proteus mirabilis showed primarily concentration-dependent activity, with a prolonged post-antibiotic effect (3.4 to 4.7h). Based on these results a single 3g dose of fosfomycin guarantees optimal efficacy against common uropathogens with an AUC(urine)/MIC ratio of 500.
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Anti-Infecciosos/farmacologia , Anti-Infecciosos/farmacocinética , Infecções Urinárias/tratamento farmacológico , Infecções Urinárias/metabolismo , Fluoroquinolonas/farmacocinética , Fluoroquinolonas/farmacologia , Fosfomicina/farmacocinética , Fosfomicina/farmacologia , Humanos , Nitrofurantoína/farmacocinética , Nitrofurantoína/farmacologia , Quinolonas/farmacocinética , Quinolonas/farmacologia , Combinação Trimetoprima e Sulfametoxazol/farmacocinética , Combinação Trimetoprima e Sulfametoxazol/farmacologia , beta-Lactamas/farmacocinética , beta-Lactamas/farmacologiaRESUMO
PURPOSE: Recent epidemiological data have confirmed the increasing problem of antimicrobial resistance not only for hospitalized, healthcare-associated patients, but also for outpatients. In particular, the progressive increase in resistance to broad-spectrum antibiotics, such as third-generation cephalosporins, fluoroquinolones or carbapenems in Enterobacteriaceae, is an alarming situation for all urologists and general practitioners. Here, we aimed to review the epidemiological data of multidrug-resistant bacteria in the urological setting, in order to summarize all diagnostic and therapeutic recommendations to use in everyday clinical practice. METHODS: We collected all recent publications from Medline and Cochrane Library from January 2000 to December 2013. Moreover, data from the abstracts presented at the EAU and AUA Congresses during the last 5 years have also been analyzed. All papers were evaluated by an expert panel on urological infections on behalf of the Italian Urological Association (SIU). RESULTS: Fluoroquinolone and other antibiotic-resistant bacteria prevalence is normally very high in the lower urinary tract infection patients. In particular, multidrug-resistant bacteria prevalence in urological practice contributes to infectious morbidity increasing the financial costs to healthcare system. The expert panel on urological infections on behalf of the Italian Urological Association formulated new diagnostic pathway and therapeutic protocol in patients affected by urological tract infections due to multidrug-resistant bacteria. CONCLUSIONS: The recent emergence of multidrug-resistant pathogens is an alarming public health issue also in urological practice with socioeconomic importance. Our practice should be revised on the basis of these new acquisitions.
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Antibacterianos/uso terapêutico , Farmacorresistência Bacteriana Múltipla , Infecções Urinárias/tratamento farmacológico , Infecções Urinárias/microbiologia , Humanos , Guias de Prática Clínica como AssuntoRESUMO
Thymidylate synthase (TS) intratumoural expression may be a prognostic marker and predict outcome of 5-fluorouracil (5-FU)-based chemotherapy in colorectal cancer patients. The TS gene promoter enhancer region contains two different polymorphisms which can influence TS mRNA transcriptional and translational efficiency: a polymorphic tandem repeat sequence (2 or 3 repeats; 2R and 3R) and a single nucleotide polymorphism (SNP), G > C, within the second repeat of the 3R alleles. We studied the relationship between tumoural TS mRNA expression levels and TS gene polymorphisms in the colonic mucosa of 48 colorectal cancer patients. The 3R/3R genotype was characterised by higher TS mRNA levels in the tumour than the 2R/2R-2R/3R genotypes (P = 0.071). Regarding the relationship with the SNP polymorphism, a statistically significant difference in TS gene expression between the 3RG/3RG genotype and 2R/2R-2R/3RC-2R/3RG genotype subset was observed (P = 0.017). No statistically significant correlation was observed between experimental data and baseline clinical-pathological characteristics as well as clinical outcome in the relatively small patient series investigated. This is the first study reporting an association between the TS intra-repeat SNP and gene expression levels in colorectal cancer patients. These results suggest that in 3R/3R patients, the G > C polymorphism may be an important factor in determining TS mRNA expression levels, and warrant further investigation of the role of TS promoter polymorphisms as predictors of sensitivity to 5-FU-based chemotherapy in larger case series.
Assuntos
Neoplasias Colorretais/genética , Polimorfismo Genético/genética , Timidilato Sintase/genética , Adulto , Idoso , Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/cirurgia , Intervalo Livre de Doença , Feminino , Genótipo , Humanos , Mucosa Intestinal/enzimologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/enzimologia , Recidiva Local de Neoplasia/genética , Prognóstico , Regiões Promotoras Genéticas , RNA Neoplásico/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
OBJECTIVE: To evaluate and compare the pharmacokinetic profiles of imipenem and meropenem in a population of critically ill patients with sepsis to find possible differences that may help in selecting the most appropriate drug and/or dosage in order to optimise empiric antimicrobial therapy. PATIENTS AND METHODS: This was a single-centre, randomised, nonblind study of the pharmacokinetics of both intravenous imipenem 1g and meropenem 1g in 20 patients admitted to an intensive care unit with sepsis in whom antimicrobial therapy was indicated on clinical grounds. Patients were divided into two groups: group I received intravenous imipenem 1g plus cilastatin 1g, and group II received intravenous meropenem 1g over 30 minutes. Peripheral blood samples were collected at 0, 0.5 (end of infusion), 0.75, 1, 1.5, 2, 3, 4, 6 and 8 hours after the first dose and were centrifuged for 10 minutes at 4 masculineC. Urine samples were collected during the 8 hours after antimicrobial administration at 2-hour intervals: 0-2, 2-4, 4-6 and 6-8 hours. The total volume of urine was recorded; the serum and urine samples were immediately frozen and stored at -80 masculineC until assayed. Pharmacokinetic analysis was carried out through computerised programs using the least-square regression method and a two-compartment open model. Statistical differences were evaluated by means of one-way ANOVA. RESULTS: The following pharmacokinetic differences between the two drugs were observed: the imipenem mean peak serum concentration was significantly higher than for meropenem (90.1 +/- 50.9 vs 46.6 +/- 14.6 mg/L, p < 0.01); the area under the serum concentration-time curve was significantly higher for imipenem than for meropenem (216.5 +/- 86.3 vs 99.5 +/- 23.9 mg . h/L, p < 0.01), while the mean volume of distribution and mean total clearance were significantly higher for meropenem than for imipenem (25 +/- 4.1 vs 17.4 +/- 4.5L, p < 0.01 and 191 +/- 52.2 vs 116.4 +/- 42.3 mL/min, p < 0.01, respectively). CONCLUSION: The more favourable pharmacokinetic profile of imipenem compared with meropenem in critically ill patients with sepsis might balance the possibly greater potency demonstrated in vitro for meropenem against Gram-negative strains. Hence, the clinical efficacy of the two carbapenems depends mostly on their correct dosage.
Assuntos
Antibacterianos/farmacocinética , Imipenem/farmacocinética , Sepse/tratamento farmacológico , Tienamicinas/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Estado Terminal , Feminino , Humanos , Imipenem/farmacologia , Masculino , Meropeném , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Sepse/metabolismo , Tienamicinas/farmacologiaRESUMO
To provide some insight into molecular mechanisms of 5 fluorouracil (5-FU) clinical resistance in colorectal cancer, we hypothesized that different in vitro exposure schedules of human colorectal cancer cell lines mimicking clinical infusion or bolus regimens could lead to differential gene expression. Resistant HCT-8 colon cancer cell lines (HCT-8/FUI/15R and HCT-8/FUB/2R) were selected from parental sensitive HCT-8 cells by long-term and short-term exposure schedules, respectively. Expression levels of the 437 genes evaluated by the Atlas Select cDNA Expression Human Tumor Array were not substantially different between HCT-8/FUB/2R and HCT-8 cell lines except for three genes downregulated in the resistant subline. Several genes were differentially expressed in HCT-8/FUI/15R cells compared to the parental cell line: 43 genes, including three chemoresistance-related genes, were upregulated, and three genes were downregulated. HCT-8/FUB/2R cells were substantially more resistant to 5-FU in comparison to HCT-8/FUI/15R cells after both 4- and 72-h exposures. No substantial differences were observed among resistant and parental cells in sensitivity to SN-38, the active metabolite of irinotecan, and oxaliplatin. Analysis of the mRNA levels of thymidylate synthase, thymidine phosphorylase, and bcl-2 genes evaluated by reverse transcription and real time PCR (RT-PCR) assay showed comparable results in resistant sublines and sensitive parental cells, whereas expression of the dihydropyrimidine dehydrogenase gene was markedly increased in both resistant cell lines compared to parental cells.
Assuntos
Antineoplásicos/farmacologia , Neoplasias do Colo/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Fluoruracila/farmacologia , Regulação Neoplásica da Expressão Gênica , Antineoplásicos/administração & dosagem , Camptotecina/análogos & derivados , Camptotecina/farmacologia , Carcinoma/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Di-Hidrouracila Desidrogenase (NADP)/biossíntese , Ensaios de Seleção de Medicamentos Antitumorais , Fluoruracila/administração & dosagem , Humanos , Irinotecano , Análise de Sequência com Séries de Oligonucleotídeos , Poli A/química , RNA Mensageiro/metabolismoRESUMO
Gold(III) compounds generally exhibit significant cytotoxic effects on cancer cell lines and are of potential interest as antitumor drugs. We report here on the solution chemistry, the cytotoxicity, and the DNA binding properties of two new bipyridyl gold(III) compounds: [Au(bipy)(OH)(2)][PF(6)] (1) and the organometallic compound [Au(bipy(c)-H)(OH)][PF(6)] (2) (bipy(c) = 6-(1,1-dimethylbenzyl)-2,2'-bipyridine). Both compounds are sufficiently soluble, and stable for hours, within a physiological buffer at 37 degrees C; [Au(bipy)(OH)(2)][PF(6)], at variance with [Au(bipy(c)-H)(OH)][PF(6)], is quickly and quantitatively reduced by ascorbate. Both compounds showed relevant cytotoxic effects toward the A2780S, A2780R, and SKOV3 tumor cell lines; lower effects were detected on the CCRF-CEM/S and CCRF-CEM/R lines. In most cases the mechanisms of resistance to CDDP are only marginally effective against these gold(III) complexes. The interactions of [Au(bipy)(OH)(2)][PF(6)] and [Au(bipy(c)-H)(OH)][PF(6)] with calf thymus DNA were investigated in vitro by various techniques to establish whether DNA represents a primary target for these compounds. Addition of saturating amounts of DNA did not affect appreciably the visible spectra of these gold(III) complexes. Some slight modifications of the CD spectra of calf thymus DNA and of the DNA melting parameters were observed; in any case, ultrafiltration experiments showed that binding of these gold(III) complexes to DNA is weak and reversible. The mechanistic implications of these findings are discussed.
Assuntos
2,2'-Dipiridil/química , 2,2'-Dipiridil/síntese química , Antineoplásicos/síntese química , DNA/química , Ouro , Compostos Organometálicos/síntese química , 2,2'-Dipiridil/análogos & derivados , 2,2'-Dipiridil/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Dicroísmo Circular , Cisplatino/farmacologia , Diálise , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Estabilidade de Medicamentos , Humanos , Espectroscopia de Ressonância Magnética , Compostos Organoáuricos , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Solubilidade , Espectrofotometria Ultravioleta , Células Tumorais CultivadasRESUMO
Leuprorelin acetate is a synthetic agonist analogue of gonadotropin-releasing hormone. Continued leuprorelin administration results in suppression of gonadal steroid synthesis, resulting in pharmacological castration. Since leuprorelin is a peptide, it is orally inactive and generally given subcutaneously or intramuscularly. Sustained release parenteral depot formulations, in which the hydrophilic leuprorelin is entrapped in biodegradable highly lipophilic synthetic polymer microspheres, have been developed to avoid daily injections. The peptide drug is released from these depot formulations at a functionally constant daily rate for 1, 3 or 4 months, depending on the polymer type [polylactic/glycolic acid (PLGA) for a 1-month depot and polylactic acid (PLA) for depot of >2 months], with doses ranging between 3.75 and 30mg. Mean peak plasma leuprorelin concentrations (C(max)) of 13.1, 20.8 to 21.8, 47.4, 54.5 and 53 microg/L occur within 1 to 3 hours of depot subcutaneous administration of 3.75, 7.5, 11.25, 15 and 30 mg, respectively, compared with 32 to 35 microg/L at 36 to 60 min after a subcutaneous injection of 1mg of a non-depot formulation. Sustained drug release from the PLGA microspheres maintains plasma concentrations between 0.4 and 1.4 microg/L over 28 days after single 3.75, 7.5 or 15mg depot injections. Mean areas under the concentration-time curve (AUCs) are similar for subcutaneous or intravenous injection of short-acting leuprorelin 1mg; a significant dose-related increase in the AUC from 0 to 35 days is noted after depot injection of leuprorelin 3.75, 7.5 and 15mg. Mean volume of distribution of leuprorelin is 37L after a single subcutaneous injection of 1mg, and 36, 33 and 27L after depot administration of 3.75, 7.5 and 15mg, respectively. Total body clearance is 9.1 L/h and elimination half-life 3.6 hours after a subcutaneous 1mg injection; corresponding values after intravenous injection are 8.3 L/h and 2.9 hours. A 3-month depot PLA formulation of leuprorelin acetate 11.25mg ensures a C(max) of around 20 microg/L at 3 hours after subcutaneous injection, and continuous drug concentrations of 0.43 to 0.19 microg/L from day 7 until before the next injection. Recently, an implant that delivers leuprorelin for 1 year has been evaluated. Serum leuprorelin concentrations remained at a steady mean of 0.93 microg/L until week 52, suggesting zero-order drug release from the implant. In general, regular or depot leuprorelin treatment is well tolerated. Local reactions are more common after application of the 3- or 4-month depot in comparison with the 1-month depot.