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BACKGROUND: We developed a 13-mer locked nucleic acid (LNA) inhibitor of miR-221 (LNA-i-miR-221) with a full phosphorothioate (PS)-modified backbone. This agent downregulated miR-221, demonstrated anti-tumor activity against human xenografts in mice, and favorable toxicokinetics in rats and monkeys. Allometric interspecies scaling allowed us to define the first-in-class LNA-i-miR-221 safe starting dose for the clinical translation. METHODS: In this first-in-human, open-label, dose-escalation phase 1 trial, we enrolled progressive cancer patients (aged ≥ 18 years) with ECOG 0-2 into 5 cohorts. The treatment cycle was based on a 30-min IV infusion of LNA-i-miR-221 on 4 consecutive days. Three patients within the first cohort were treated with 2 cycles (8 infusions), while 14 patients were treated with a single course (4 infusions); all patients were evaluated for phase 1 primary endpoint. The study was approved by the Ethics Committee and Regulatory Authorities (EudraCT 2017-002615-33). RESULTS: Seventeen patients received the investigational treatment, and 16 were evaluable for response. LNA-i-miR-221 was well tolerated, with no grade 3-4 toxicity, and the MTD was not reached. We recorded stable disease (SD) in 8 (50.0%) patients and partial response (PR) in 1 (6.3%) colorectal cancer case (total SD + PR: 56.3%). Pharmacokinetics indicated non-linear drug concentration increase across the dose range. Pharmacodynamics demonstrated concentration-dependent downregulation of miR-221 and upregulation of its CDKN1B/p27 and PTEN canonical targets. Five mg/kg was defined as the recommended phase II dose. CONCLUSIONS: The excellent safety profile, the promising bio-modulator, and the anti-tumor activity offer the rationale for further clinical investigation of LNA-i-miR-221 (ClinTrials.Gov: NCT04811898).
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MicroRNAs , Neoplasias , Humanos , MicroRNAs/genética , MicroRNAs/uso terapêutico , Neoplasias/tratamento farmacológico , Oligonucleotídeos/uso terapêuticoRESUMO
BACKGROUND: In actuality, it is difficult to obtain an early prognostic stratification for patients with acute respiratory failure treated with noninvasive ventilation (NIV). We tested whether an early evaluation through a predictive scoring system could identify subjects at risk of in-hospital mortality or NIV failure. METHODS: This was a retrospective study, which included all the subjects with acute respiratory failure who required NIV admitted to an emergency department-high-dependence observation unit between January 2014 and December 2017. The HACOR (heart rate, acidosis [by using pH], consciousness [by using the Glasgow coma scale], oxygenation [by using [Formula: see text]/[Formula: see text]], respiratory rate) score was calculated before the NIV initiation (T0) and after 1 h (T1) and 24 h (T24) of treatment. The primary outcomes were in-hospital mortality and NIV failure, defined as the need for invasive ventilation. RESULTS: The study population included 644 subjects, 463 with hypercapnic respiratory failure and an overall in-hospital mortality of 23%. Thirty-six percent of all the subjects had NIV as the "ceiling" treatment. At all the evaluations, nonsurvivors had a higher mean ± SD HACOR score than did the survivors (T0, 8.2 ± 4.9 vs 6.1 ± 4.0; T1, 6.6 ± 4.8 vs 3.8 ± 3.4; T24, 5.3 ± 4.5 vs 2.0 ± 2.3 [all P < .001]). These data were confirmed after the exclusion of the subjects who underwent NIV as the ceiling treatment (T0, 8.2 ± 4.9 vs 6.1 ± 4.0 [P = .002]; T1, 6.6 ± 4.8 vs 3.8 ± 3.4; T24, 5.3 ± 4.5 vs 2.0 ± 3.2 [all P < .001]). At T24, an HACOR score > 5 (Relative Risk [RR] 2.39, 95% CI 1.60-3.56) was associated with an increased mortality rate, independent of age and the Sequential Organ Failure Assessment score. CONCLUSIONS: Among the subjects treated with NIV for acute respiratory failure, the HACOR score seemed to be a useful tool to identify those at risk of in-hospital mortality.
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Ventilação não Invasiva , Síndrome do Desconforto Respiratório , Insuficiência Respiratória , Doença Aguda , Mortalidade Hospitalar , Humanos , Insuficiência Respiratória/terapia , Estudos RetrospectivosRESUMO
OBJECTIVES: The current gold-standard for the first-line treatment in IIIb/IV stages of epithelial ovarian cancer (EOC) is the combination of carboplatin and paclitaxel plus bevacizumab in some countries. In the era of personalized medicine, there is still uncertainty on the impact of several molecularly targeted agents, which have been investigated for the management of this disease. To shed light on the actual role of targeted therapy in EOC, a systematic review and meta-analysis was performed. METHODS: Clinical trials were selected by searching "Pubmed" database and abstracts from major cancer meetings within the time-frame of January 2004-June 2015. The endpoints were survival outcome and response rate (RR). Hazard ratios (HRs) of survival outcomes, with confidence intervals and odds-ratios (ORs) of RR, were extracted from retrieved studies and used for current analysis. Meta-analysis was carried out by random effect model. RESULTS: 30 randomized trials for a total of 10,530 patients were selected and included in the final analysis. A benefit in terms of OS (pooled HR 0.915; 95%CI 0.840-0.997; p=0.043), particularly for anti-angiogenetic agents (HR 0.872; 95%CI 0.761-1.000; p=0.049), has been demonstrated for targeted therapy. Moreover, a significant advantage in platinum-resistant subgroup in term of PFS (HR 0.755; 95%CI 0.624-0.912; p=0.004) was found. CONCLUSIONS: This systematic review and meta-analysis provide the first evidence that targeted therapy is potentially able to translate into improved survival of EOC patients, with a major role played by anti-angiogenetic drugs. The role of target therapy is underlined in the platinum-resistant setting that represents the "pain in the neck" in EOC management.
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Inibidores da Angiogênese/uso terapêutico , Biomarcadores Tumorais/metabolismo , Terapia de Alvo Molecular/métodos , Neoplasias Ovarianas/tratamento farmacológico , Biomarcadores Tumorais/genética , Progressão da Doença , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Razão de Chances , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/mortalidade , Seleção de Pacientes , Medicina de Precisão , Fatores de Risco , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Pneumoperitoneum is a rare cause of abdominal pain characterized by a high mortality. Ultrasonography (US) can detect free intraperitoneal air; however, its accuracy remains unclear. The aims of this pilot study were to define the diagnostic performance and the reliability of abdominal US for the diagnosis of pneumoperitoneum. METHODS: This was a prospective observational study. Four senior and two junior physicians were shown, in an unpaired randomized order, abdominal US videos from 11 patients with and 11 patients without pneumoperitoneum. Abdominal US videos were obtained from consecutive patients presenting to ED complaining abdominal pain with the diagnosis of pneumoperitoneum established by CT. Abdominal US was performed according to a standardized protocol that included the following scans: epigastrium, right and left hypochondrium, umbilical area and right hypochondrium with the patient lying on the left flank. We evaluated accuracy, intra- and inter-observer agreement of abdominal US when reviewed by senior physicians. Furthermore, we compared the accuracy of a "2 scan-fast exam" (epigastrium and right hypochondrium) vs the full US examination and the accuracy of physicians expert in US vs nonexpert ones. Finally, accuracy of US was compared with abdominal radiography in patients with available images. RESULTS: Considering senior revision, accuracy of abdominal US was 88.6 % (95 % CI 79.4-92.4 %) with a sensitivity of 95.5 % (95 % CI 86.3-99.2 %) and a specificity of 81.8 % (95 % CI 72.6-85.5 %). Inter- and intra-observer agreement (k) were 0.64 and 0.95, respectively. Accuracy of a "2 scan-fast exam" (87.5 %, 95 % CI 77.9-92.4 %) was similar to global exam. Sensitivity of abdominal radiography (72.2 %, 95 % CI 54.8-85.7 %) was lower than that of abdominal US, while specificity (92.5 %, 95 % CI 79.5-98.3 %) was higher. Accuracy (68.2 %, 95 % CI 51.4-80.9 %) of junior reviewers evaluating US was lower than senior reviewers. CONCLUSIONS: Senior physicians can recognize US signs of pneumoperitoneum with a good accuracy and reliability; sensitivity of US could be superior to abdominal radiography and a 2 fast-scan exam seems as accurate as full abdominal examination. US could be a useful bedside screening test for pneumoperitoneum. Trial registry ClinicalTrials.gov; No.: NCT02004925; URL: http://www.clinicaltrials.gov.
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It is still uncertain if targeted therapy-based regimens in advanced gastric cancer actually produce survival benefit. To shed light on this important question, we performed a systematic review and meta-analyses on each relevant targeted-pathway. By searching literature databases and proceedings of major cancer meetings in the time-frame 2005-2014, 22 randomized clinical trials exploring targeted therapy for a total of 7022 advanced gastric cancer patients were selected and included in the final analysis. Benefit was demonstrated for antiangiogenic agents in terms of overall survival (HR 0.759; 95%CI 0.655-0.880; p < 0.001). Conversely no benefit was found for EGFR pathway (HR 1.077; 95%CI 0.847-1.370; p = 0.543). Meta-analysis of HER-2 pathway confirmed improvement in terms of survival outcome, already known for this class of drugs (HR 0.823; 95%CI 0.722-0.939; p = 0.004). Pooled analysis demonstrated a significant survival benefit (OS: HR 0.823; PFS: HR 0.762) with acceptable tolerability profile for targeted-based therapies as compared to conventional treatments. This finding conflicts with the outcome of most individual studies, probably due to poor trial design or patients selection. In conclusion, our findings demonstrate a significant survival benefit for targeted therapy in its whole, which can be ascribed to anti-angiogenic and anti-HER2 agents.
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Terapia de Alvo Molecular/métodos , Neoplasias Gástricas/tratamento farmacológico , Inibidores da Angiogênese/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Receptores ErbB/antagonistas & inibidores , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptor ErbB-2/antagonistas & inibidores , Neoplasias Gástricas/epidemiologia , Neoplasias Gástricas/mortalidade , Análise de SobrevidaRESUMO
Nanoparticle albumin bound paclitaxel (nab-paclitaxel) represents the first nanotechnology-based drug in cancer treatment. We discuss the development of this innovative compound and report the recent changing-practice results in breast and pancreatic cancer. A ground-breaking finding is the demonstration that nab-paclitaxel can not only enhance the activity and reduce the toxicity of chromophore-diluted compound, but also exert activity in diseases considered refractory to taxane-based treatment. This is the first clinical demonstration of major activity of nanotechnologically modified drugs in the treatment of human neoplasms.
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BACKGROUND: Ovarian cancer (OC) is the sixth most common cancer in women. Currently, carboplatin/paclitaxel ± bevacizumab is the cornerstone of front-line treatment. Conversely, the therapeutic options for recurrent or progressive disease are not well defined. For platinum-sensitive patients the best therapeutic approach is still a re-challenge with a platinum-based regimen. Pegylated liposomal doxorubicin (PLD), is considered one of the most active therapeutic options for recurrent or progressive OC. In this retrospective mono-institutional analysis, we evaluated the impact of PLD on the outcome of OC patients. PATIENTS AND METHODS: We performed the retrospective study on a cohort of 108 patients with histologically confirmed serous papillary OC, followed at our Institution between 2001 and 2011. 80 patients were in stage III/IV and 55 of them received a second-line treatment. Thirty patients were treated with PLD. Both groups (PLD-treated versus PLD-untreated) underwent a median of 3 treatment lines and were prognostically balanced. The median follow-up was 60 months. Survival endpoints, toxicity and correlations between patients' baseline characteristics and treatment efficacy were evaluated. RESULTS: Patients who had undergone PLD treatment (PLD group) showed a median overall survival (OS) of 45 months as compared to 65 months of patients not treated with PLD (PLD-free group) (HR 2.50 [0.95-6.67; p = 0.06]). Moreover, the median progression-free survival was 6 months in the PLD group versus 10 months in the PLD-free group (HR 1.75 [0.94-3.34; p = 0.07]). The overall objective response rate in II line treatment was 43% (13% in PLD group versus 57% in PLD-free group). Furthermore, we investigated survival endpoints in platinum-refractory patients who received PLD at least once during the course of disease. No OS advantage was achieved by PLD administration when compared to other therapeutic options (30 versus 32 months; HR 1.16 [0.31-4.34; p = 0.81]). No difference in term of toxicity was observed among different groups. CONCLUSIONS: No evidence of superiority if PLD was compared to alternative agents was found in this analysis, particularly in the platinum-refractory setting. Our findings indicate a modest therapeutic activity of PLD in OC. Analysis of cost/benefit of PLD in OC is eagerly awaited.