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About 105 consecutive acute myeloid leukemia (AML) patients treated with the same induction-consolidation program between 2004 and 2013 were retrospectively analyzed. Median age was 47 years. The first induction course included fludarabine (Flu) and high-dose cytarabine (Ara-C) plus idarubicin (Ida), with or without gemtuzumab-ozogamicin (GO) 3 mg/m(2) (FLAI-5). Patients achieving complete remission (CR) received a second course without fludarabine but with higher dose of idarubicin. Patients not achieving CR received an intensified second course. Patients not scheduled for early allogeneic bone marrow transplantation (HSCT) where planned to receive at least two courses of consolidation therapy with Ara-C. Our double induction strategy significantly differs from described fludarabine-containing regimens, as patients achieving CR receive a second course without fludarabine, to avoid excess toxicity, and Ara-C consolidation is administrated at the reduced cumulative dose of 8 g/m(2) per cycle. Toxicity is a major concern in fludarabine containing induction, including the recent Medical Research Council AML15 fludarabine, cytarabine, idaraubicin and G-CSF (FLAG-Ida) arm, and, despite higher anti-leukemic efficacy, only a minority of patients is able to complete the full planned program. In this article, we show that our therapeutic program is generally well tolerated, as most patients were able to receive subsequent therapy at full dose and in a timely manner, with a 30-day mortality of 4.8%. The omission of fludarabine in the second course did not reduce efficacy, as a CR rate of 83% was achieved and 3-year disease-free survival and overall survival (OS) were 49.6% and 50.9%, respectively. Our experience shows that FLAI-5/Ara-C + Ida double induction followed by risk-oriented consolidation therapy can result in good overall outcome with acceptable toxicity. Am. J. Hematol. 91:755-762, 2016. © 2016 Wiley Periodicals, Inc.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia de Consolidação/métodos , Quimioterapia de Indução/métodos , Leucemia Mieloide Aguda/tratamento farmacológico , Adolescente , Adulto , Idoso , Aminoglicosídeos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Criança , Citarabina/administração & dosagem , Feminino , Gemtuzumab , Humanos , Idarubicina/administração & dosagem , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Análise de Sobrevida , Taxa de Sobrevida , Resultado do Tratamento , Vidarabina/administração & dosagem , Vidarabina/análogos & derivados , Vidarabina/toxicidade , Adulto JovemRESUMO
This work focuses on the clinical-organizational model implemented in an Italian region (Liguria) to streamline the access procedures to galenic cannabis preparations. The competent local health care authority that takes care of tracing a virtuous path to obtain common, uniform and shared protocols and ensure high standards of care is A.Li.Sa. (Azienda Ligure Sanitaria), a public organization with the function of coordination, direction and governance of the health care in the regional hospitals and health facilities. To this purpose, different working groups and a board meeting have been set up with the main role to define and develop technical standards to be applied to the prescription, preparation and dispensing of pharmaceutical forms based on therapeutic cannabis. In particular, the galenic preparations provided by the Italian Ministry of Health, described in detail in the regional standard operating protocols, are described and discussed. Moreover, the most significant data monitored from 2018 to 2020 and collected by hospitals and the evaluation of those derived from local pharmacies and health facilities are presented, discussed and compared in regards to their adherence and coherence with the Italian Institute of Health (ISS) data.
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Monoclonal antibodies, such as bamlanivimab and etesevimab combination (BEC), have been proposed for patients with mild or moderate coronavirus disease 2019 (COVID-19). However, few studies have assessed the factors associated with the early administration of BEC or the impact of early BEC treatment on the clinical evolution of the patients. We conducted a retrospective cohort study of all adults with COVID-19 who received BEC at three institutions in the Liguria region. The primary endpoint was to investigate the clinical variables associated with early BEC infusion. Secondary endpoints were 30-day overall mortality and the composite endpoint of requirement of hospital admission or need for supplemental oxygen during the 30-day follow-up period. A total of 127 patients (median age 70 years; 56.7% males) received BEC. Of those, 93 (73.2%) received BEC within 5 days from symptoms onset (early BEC). Patients with a higher Charlson comorbidity index were more likely to receive early treatment (odds ratio (OR) 1.60, 95% confidence interval (CI) 1.04-2.45; p = 0.03) in contrast to those reporting fever at presentation (OR 0.26, 0.08-0.82; p = 0.02). Early BEC was associated with lower likelihood of hospital admission or need for supplemental oxygen (OR 0.19, 0.06-0.65; p = 0.008). Five patients who received early BEC died during the follow-up period, but only one of them due to COVID-19-related causes. Early bamlanivimab and etesevimab combination was more frequently administered to patients with a high Charlson comorbidity index. Despite this, early BEC was associated with a lower rate of hospital admission or need for any supplementary oxygen compared to late administration. These results suggest that efforts should focus on encouraging early BEC use in patients with mild-moderate COVID-19 at risk for complications.
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OBJECTIVES: Candida spp. are the most important non-bacterial pathogens in critically ill patients. The aim of this study was to evaluate trends in the incidence of candidaemia and the distribution of Candida albicans and non-albicans over a 9 year period (1999-2007), and to assess their relationship with fluconazole use. METHODS: This was an interventional cross-over study. Patients admitted to the intensive care unit (ICU) who developed a clinically and microbiologically documented candidaemia were analysed. Fluconazole was used as prophylaxis in critically ill patients until 2002; from January 2003 infectious disease consultants strongly discouraged its use. Fluconazole use, measured as defined daily dose per 1000 patient-days, was calculated. The main outcome of the study is the evaluation of the restriction policy in terms of change in fluconazole use and in incidence of candidaemia. RESULTS: During the 108 month period (January 1999-December 2007), a total of 213 episodes of candidaemia (average incidence 1.42 episodes/10 000 patient-days/year, range 0.36-3.02 episodes) were recorded in a mixed medical and surgical ICU in Italy. C. albicans was the most prevalent isolated species (n = 98, 46%); non-albicans (n = 115, 54%) were mainly represented by Candida parapsilosis (n = 46, 22%) and by Candida glabrata (n = 28, 13%). Segmented regression analysis of the interrupted time series showed that a change in the fluconazole prophylactic strategy resulted in a significant reduction in fluconazole use from the second semester of 2002. A dramatic decrease in the incidence of fungaemia due to C. non-albicans was observed from the second semester of 2003 (intervention effect in the second semester of 2007: -2.31/10 000 patient-days); minor changes in the incidence of C. albicans fungaemia emerged (intervention effect in the second semester of 2007: -0.23/10 000 patient-days). CONCLUSIONS: The study showed a clear correlation between fluconazole use control and decreasing incidence of non-albicans candidaemia. Even if fluconazole remains a first-line treatment option in several cases of invasive candidiasis, its prophylactic use should be carefully evaluated.
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Antifúngicos/uso terapêutico , Candida/classificação , Candidíase/epidemiologia , Quimioprevenção/métodos , Fluconazol/uso terapêutico , Fungemia/epidemiologia , Adulto , Idoso , Candida/isolamento & purificação , Candidíase/microbiologia , Estudos Cross-Over , Uso de Medicamentos/tendências , Feminino , Fungemia/microbiologia , Humanos , Incidência , Unidades de Terapia Intensiva , Itália , Masculino , Pessoa de Meia-IdadeRESUMO
Mesenchymal stromal cells (MSC) present in the tumor microenvironment [usually named tumor-associated fibroblasts (TAF)] can exert immunosuppressive effects on T and natural killer (NK) lymphocytes, favoring tumor immune escape. We have analyzed this mechanism in colorectal carcinoma (CRC) and found that co-culture of NK cells with TAF can prevent the IL-2-mediated NKG2D upregulation. This leads to the impairment of NKG2D-mediated recognition of CRC cells, sparing the NK cell activation through DNAM1 or FcγRIIIA (CD16). In situ, TAF express detectable levels of epidermal growth factor receptor (EGFR); thus, the therapeutic anti-EGFR humanized antibody cetuximab can trigger the antibody-dependent cellular cytotoxicity of TAF, through the engagement of FcγRIIIA on NK cells. Importantly, in the tumor, we found a lymphoid infiltrate containing NKp46+CD3- NK cells, enriched in CD16+ cells. This population, sorted and cultured with IL-2, could be triggered via CD16 and via NKG2D. Of note, ex vivo NKp46+CD3- cells were able to kill autologous TAF; in vivo, this might represent a control mechanism to reduce TAF-mediated regulatory effect on NK cell function. Altogether, these findings suggest that MSC from the neoplastic mucosa (TAF) of CRC patients can downregulate the immune cell recognition of CRC tumor cells. This immunosuppression can be relieved by the anti-EGFR antibody used in CRC immunotherapy.
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Fibroblastos Associados a Câncer/metabolismo , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/metabolismo , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Antineoplásicos Imunológicos , Comunicação Celular , Linhagem Celular Tumoral , Cetuximab/farmacologia , Técnicas de Cocultura , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Citotoxicidade Imunológica , Receptores ErbB/genética , Humanos , Linfocinas/metabolismoRESUMO
PURPOSE: Medication errors in oncology may cause severe damage to patients, professionals, and the environment. The Italian Ministry of Health issued Raccomandazione 14 to provide guidelines for prevention of errors while using antineoplastic drugs. This work aimed at analyzing Raccomandazione 14 through the different viewpoints of the hospital pharmacist, the nurse, the oncologist, and the hospital director. METHODS: Twenty-seven Italian healthcare organizations participated in a self-assessment survey evaluating compliance with Raccomandazione 14 within the oncology, hematology, and pharmacy departments. RESULTS: The self-assessment results showed a general acknowledgement of the need for centralized management of anticancer agents. The specific responsibility of the pharmacist on the centralized management of anticancer drugs from preparation to disposal emerged as a critical point. The nurse, beyond the skills in drug administration and prevention of extravasation, also plays a fundamental role in educating and supporting the patient. The physicians, who are attentive to scientific, clinical, and regulatory criteria in prescribing and monitoring the therapies, are called upon to improve awareness on the importance of sharing standardized procedures with other professionals, to minimize medication error occurrence. The implementation of a complete computerized management from prescribing to drug administration and follow-up was highlighted. Multidisciplinary groups were constituted across the nation by professionals dedicated to the implementation of electronic health records and drug history and medical reconciliation processes. CONCLUSIONS: Our analysis of the Ministerial Raccomandazione 14 urges implementation of the resources for ensuring quality and safety during prescription, preparation, and administration of anticancer drugs.
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BACKGROUND: Insulin-like growth factor-1 (IGF-1) promotes the survival of cardiomyocytes by activating type 1 IGF receptor (IGF-1R). Within the myocardium, IGF-1 action is modulated by IGF binding protein-3 (IGFBP-3), which sequesters IGF-1 away from IGF-1R. Since cardiomyocyte apoptosis is implicated in anthracycline cardiotoxicity, we investigated the effects of the anthracycline, doxorubicin, on the IGF-1 system in H9c2 cardiomyocytes. METHODS AND RESULTS: Besides inducing apoptosis, concentrations of doxorubicin comparable to those observed in patients after bolus infusion (0.1-1 µM) caused a progressive decrease in IGF-1R and increase in IGFBP-3 expression. Exogenous IGF-1 was capable to rescue cardiomyocytes from apoptosis triggered by 0.1 and 0.5 µM, but not 1 µM doxorubicin. The loss of response to IGF-1 was paralleled by a significant reduction in IGF-1 availability and signaling, as assessed by free hormone levels in conditioned media and Akt phosphorylation in cell lysates, respectively. Doxorubicin also dose-dependently induced p53, which is known to repress the transcription of IGF1R and induce that of IGFBP3. Pre-treatment with the p53 inhibitor, pifithrin-α, prevented apoptosis and the changes in IGF-1R and IGFBP-3 elicited by doxorubicin. The decrease in IGF-1R and increase in IGFBP-3, as well as apoptosis, were also antagonized by pre-treatment with the antioxidant agents, N-acetylcysteine, dexrazoxane, and carvedilol. CONCLUSIONS: Doxorubicin down-regulates IGF-1R and up-regulates IGFBP-3 via p53 and oxidative stress in H9c2 cells. This leads to resistance to IGF-1 that may contribute to doxorubicin-initiated apoptosis. Further studies are needed to confirm these findings in human cardiomyocytes and explore the possibility of manipulating the IGF-1 axis to protect against anthracycline cardiotoxicity.