Abstract The new Regulation (EU) No. 536/2014 for clinical trials of medicinal products for human is part of a European regulatory framework in which the European Commission has wished to give a ...strong impetus to scientific research and industrial progress. It is a new regulation that fills a series of regulatory gaps in the Clinical Trials through the creation of a uniform framework for the authorization of clinical trials by all interested Member States with a single assessment of the results. The Regulation thus facilitates cross-border cooperation to make the clinical tests wider and encourage the development of special treatments, for example for rare diseases, but above all streamlines the rules on clinical trials across European Union (EU), introducing simplified rules for experimentation so-called 'low level of intervention', on which much has been discussed and still arouses concern, providing for authorized medicines or used off-label in the presence of scientific evidence published on efficacy and safety and to benefit from they will be mainly the pediatric and oncological therapeutic areas. The applications and any communication will be submitted paperlessly via a new electronic EU portal. The complex processing procedures and shorter time limits are to be stressed in comparison to the previously valid regulations. This is a major challenge for all stakeholders, but on the other hand it should contribute to the future role of the EU in the development of innovative medicines.
Abstract
The occiput posterior (OP) position is one of the most frequent malposition during labor. During the first stage of labor, the fetal head may stay in the OP position in 30% of the cases, but ...of these only 5-7% remains as such at time of delivery. The diagnosis of OP position in the second stage of labor is made difficult by the presence of the caput succedaneum or scalp hair, both of which may give some problem in the identification of fetal head sutures and fontanels and their location in relationship to maternal pelvic landmarks. The capability of diagnosing a fetus in OP position by digital examination has been extremely inaccurate, whereas an ultrasound approach, transabdominal, transperineal and transvaginal, has clearly shown its superior diagnostic accuracy. This is true not only for diagnosis of malpositions, detected in both first and second stage of labor, but also in cases of marked asynclitism.
Although there have been reports in the surgical literature regarding the negative effects of preoperative hyperglycemia on outcome, the impact of elevated preoperative serum glucose levels in trauma ...patients is unknown. Our objectives were to determine whether preoperative hyperglycemia was associated with a greater morbidity and mortality in trauma patients who underwent surgical intervention upon admission. Prospective data was collected on 252 consecutive nondiabetic trauma patients admitted for > or =3 days who went directly to the OR from the resuscitation area. Patients were stratified by preoperative serum glucose level (<200 vs. > or =200 mg/dL) age, gender, Injury Severity Score (ISS), and other preexisting risk factors. Outcome was measured by incidence of infection, hospital (HLOS) and ICU (ILOS) length of stay, and mortality. Multiple linear regression models were used to evaluate serum glucose in relation to other preoperative risk factors. Blunt trauma accounted for the majority (86%) of the injuries. Orthopedic procedures were the most common (36%) followed by neurosurgical (22%), abdominal (22%), and thoracic (6%). Patients with elevated serum glucose had a significantly greater incidence of infection, HLOS, ILOS, and mortality matched per age and ISS. Elevated serum glucose on admission is an accurate predictor of postoperative infection, HLOS, ILOS, and mortality. A randomized prospective trial evaluating the impact of preoperative glucose control is warranted.
Nilotinib is a second-generation tyrosine kinase inhibitor that has been approved for the first-line treatment of chronic-phase chronic myeloid leukemia, based on the results of a prospective ...randomized study of nilotinib versus imatinib (ENESTnd). Apart from this registration study, very few data are currently available on first-line nilotinib treatment. We report here the long-term, 6-year results of the first investigator-sponsored, GIMEMA multicenter phase 2, single-arm trial with nilotinib 400 mg twice daily as first-line treatment in 73 patients with chronic-phase chronic myeloid leukemia. Six-year overall survival and progression-free survival rates were 96%, with one death after progression to blast phase. At 6 years, 75% of the patients were still on nilotinib. The cumulative incidence of major molecular response was 98%; only one patient had a confirmed loss of major molecular response. The cumulative incidence of deep molecular response (MR 4.0) was 76%. Deep molecular response was stable (≥ 2 years) in 34% of these patients. Cardiovascular adverse events, mainly due to arterial thrombosis, occurred in 11/73 patients (15%), after 24 to 76 months of therapy. They were more frequent in elderly patients, and in those with baseline cardiovascular risk factors. None was fatal, although there was a relevant morbidity. This is the study with the longest follow-up of a high dose of nilotinib (400 mg twice daily): it highlights the high efficacy and the cardiovascular toxicity of the drug (CTG.NCT.00481052).
There is a paucity of data evaluating serum albumin on admission as a predictor of outcome in adult trauma patients. Our objectives were to evaluate whether or not hypoalbuminemia on admission is a ...predictor of adverse outcome in trauma patients. Prospective data was collected daily on 1023 patients over a 2-year period. Patients were stratified by serum albumin level on admission, age, gender, injury severity, and comorbid conditions. Outcome was measured by ICU and hospital length of stay, ventilator days, incidence of infection, and mortality. Student t test, χ2, and multilinear regression analysis were used to determine level of significance. Blunt injuries accounted for the majority (78%) of the admissions. The mean age of the study population was 43 ± 21 years with a mean Injury Severity Score (ISS) of 21.4 ± 12. The majority of patients were male (74.5%). The mean albumin level on admission was 2.9 ± 1.8. Five hundred ninety-three (58%) patients were admitted with a serum albumin level of ≥2.6 as compared to 430 patients (42%) with an admission albumin level of <2.6. Patients with a lower serum albumin level were found to have a significantly greater ICU (17.1 vs 14.2 days) and hospital length of stay (17.3 vs 20.1 days, P < 0.05), ventilator days (11.1 vs 13.5 days, P < 0.05), and mortality (P = 0.008) when matched for age and injury severity. The relative risk of infection and mortality increased greater than 2.5-fold in patients with increased age and low serum albumin when analyzed by multilinear regression analysis, P < 0.001. An admission serum albumin level of <2.6 g/dL is a significant independent predictor of morbidity and mortality in trauma patients. The combination of increased age and low albumin level was most predictive of infection and mortality. Early nutrition should be considered in these high-risk patients.
The introduction and the extended clinical use of nilotinib in the first-line treatment of chronic myeloid leukemia have been based on company-sponsored trials. Independent confirmations are ...extremely important. We report an investigator-sponsored study of nilotinib 300 mg twice daily in 130 chronic myeloid leukemia patients in early chronic phase. A deep molecular response was achieved in 46% (MR
) and 17% (MR
) of patients at 2 years; 58% of the enrolled patients achieved a MR
at least once, with a sustained MR
in 52% of them. With a median observation of 29 months (range 24-37 months), 77% of patients were still on treatment with nilotinib. The reasons for permanent discontinuation were: 3% progression, 5% failure or suboptimal response, 8% adverse events, 1% treatment-free remission, and 5% other reasons. Thirteen thrombotic arterial events were reported in 12 patients. A prospective evaluation of metabolic effects showed an increase of fasting glucose without significant variations of glycated hemoglobin, an increase of total cholesterol (both low density lipoprotein and high density lipoprotein fractions) and a decrease of triglycerides. This study confirms a high and rapid efficacy of nilotinib 300 mg twice daily and provides detailed information on the type and incidence of non-hematologic and metabolic adverse events (clinicaltrials.gov identifier: 01535391).
Some trial have demonstrated a benefit of adjuvant fluoropirimidine with or without platinum compounds compared with surgery alone. ITACA-S study was designed to evaluate whether a sequential ...treatment of FOLFIRI irinotecan plus 5-fluorouracil/folinic acid (5-FU/LV) followed by docetaxel plus cisplatin improves disease-free survival in comparison with 5-FU/LV in patients with radically resected gastric cancer.
Patients with resectable adenocarcinoma of the stomach or gastroesophageal junction were randomly assigned to either FOLFIRI (irinotecan 180mg/m2 day 1, LV 100mg/m2 as 2h infusion and 5-FU 400mg/m2 as bolus, days 1 and 2 followed by 600mg/m2/day as 22h continuous infusion, q14 for four cycles) followed by docetaxel 75mg/m2 day 1, cisplatin 75mg/m2 day 1, q21 for three cycles (sequential arm) or De Gramont regimen (5-FU/LV arm).
From February 2005 to August 2009, 1106 patients were enrolled, and 1100 included in the analysis: 562 in the sequential arm and 538 in the 5-FU/LV arm. With a median follow-up of 57.4 months, 581 patients recurred or died (297 sequential arm and 284 5-FU/LV arm), and 483 died (243 and 240, respectively). No statistically significant difference was detected for both disease-free hazard ratio (HR) 1.00; 95% confidence interval (CI): 0.85–1.17; P = 0.974 and overall survival (OS) (HR 0.98; 95% CI: 0.82–1.18; P = 0.865). Five-year disease-free and OS rates were 44.6% and 44.6%, 51.0% and 50.6% in the sequential and 5-FU/LV arm, respectively.
A more intensive regimen failed to show any benefit in disease-free and OS versus monotherapy.
ClinicalTrials.gov Identifier: NCT01640782.
There is a paucity of data describing the incidence of pre‐existing diseases or risk factors and their effects in trauma patients. We conducted a prospective study to determine the incidence of such ...factors in critically ill trauma patients and to evaluate their impact on outcome. The study, performed over a 2‐year period, examined the hospital course of all trauma patients admitted to the ICU. Multiple risk factors were evaluated and analyzed via multivariate regression analysis. Outcome was evaluated by infection rate, hospital length of stay, ventilator days, and mortality matched for age and Injury Severity Score (ISS). A total of 1172 patients (73% blunt injury) were enrolled over the study period. Of these, 873 (74.5%) were male. The mean age was 42.5 years with an ISS of 19.8. Tobacco use (24%) was the most common risk factor identified, followed by hypertension (HTN, 17%), coronary artery disease (9%), chronic obstructive pulmonary disease (COPD)/reactive airway disease (4%), non‐insulin‐dependent diabetes (NIDDM) (4%), insulin‐dependent diabetes (IDDM) (3.2%), cancer (3%), liver disease (2%), and HIV/AIDS (1.4%). Of these risk factors, IDDM was found to be an independent risk factor for infection (0.004) and ventilator days (0.047), increasing age was found to be an independent risk factor for hospital length of stay (0.023) and mortality (<0.001), and HTN was found to be an independent risk factor for increased ventilator days (0.04). In addition, COPD/reactive airway disease was found to be an independent predictor of ventilator days, infection, and ICU days (P < 0.05). Thus, increased age, IDDM, COPD, and HTN are most predictive of outcome in critically ill trauma patients. With our aging population it is becoming increasingly important to identify pre‐existing risk factors on admission in order to minimize their effects on outcome.
Previous studies on oxaliplatin and fluoropyrimidines as adjuvant therapy in older patients with stage III colon cancer (CC) produced conflicting results.
We assessed the impact of age on time to ...tumour recurrence (TTR), disease-free survival (DFS), cancer-specific survival (CSS), and overall survival (OS) in 2360 patients with stage III CC (1667 aged <70 years and 693 ≥ 70 years) randomised to receive 3 or 6 months of FOLFOX or CAPOX within the frame of the phase III, TOSCA study.
Older patients compared with younger ones presented more frequently an Eastern Cooperative Oncology Group performance status equal to 1 (10.5% vs 3.3%, p < 0.001), a greater number of right-sided tumours (40.9% vs 26.6%, p < 0.001), and were at higher clinical risk (37.2% vs 33.2%, p = 0.062). The treatments were almost identical in the two cohorts (p = 0.965). We found a greater proportion of dose reductions (46.7% vs 41.4%, p = 0.018), treatment interruptions (26.1% vs 19.3%, p < 0.001) and a higher proportion of recurrences (24.2% vs 20.3%, p = 0.033) in the older patients. The multivariable analysis of the TTR did not indicate a statistically significant effect of age (hazard ratio HR: 1.19; 95% confidence interval CI: 0.98–1.44; p = 0.082). The HR comparing older with younger patients was 1.34 (95% CI: 1.12–1.59; p = 0.001) for DFS, 1.58 (95% CI: 1.26–1.99; p < 0.001) for OS, and 1.28 (95% CI: 0.96–1.70; p = 0.089) for CSS.
Worse prognostic factors and reduced treatment compliance have a negative impact on the efficacy of oxaliplatin-based adjuvant therapy in older patients.
•The outcome of oxaliplatin as an adjuvant therapy in elderly patients with colon cancer is doubt.•Worse prognostic factors and reduced compliance have a negative impact on its effectiveness.•Fluoropyrimidine monotherapy is an appropriate choice for most elderly patients.•Only fit elderly patients should receive oxaliplatin as an adjuvant therapy.
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