Intellectual outcome in children and adolescents with acute lymphoblastic leukaemia treated with chemotherapy alone: age- and sex-related differences.

One of the most relevant concerns in long-term survivors of paediatric acute lymphoblastic leukaemia (ALL) is the development of neuropsychological sequelae. The majority of the published studies report on patients treated with chemotherapy and prophylactic central nervous system (CNS) irradiation, little is known about the outcome of patients treated with chemotherapy-only regimens. Using the standardised clinical and neuropsychological instruments of the SPOG Late Effects Study, the intellectual performance of 132 paediatric ALL patients treated with chemotherapy only was compared to that of 100 control patients surviving from diverse non-CNS solid tumours. As a group, ALL and solid tumour survivors showed normal and comparable intellectual performances (mean global IQ 104.6 in both groups). The percentage of patients in the borderline range (global IQ between 70 and 85) was comparable and not higher as expected (10% cases and 13% controls, expected 16%). Only 2 (2%) of the former ALL and 1 (1%) of the solid tumour patients were in the range of mental retardation (global IQ<70). Former known risk factors described in children treated with prophylactic CNS irradiation, like a younger age at diagnosis of ALL and female gender, remained valid in chemotherapy-only treated patients. The abandonment of prophylactic CNS irradiation and its replacement by a more intensive systemic and intrathecal chemotherapy led to a reduction, but not the disappearance of late neuropsychological sequelae.

Angiotensin II receptor blockade prevents acute renal sodium retention induced by low levels of orthostatic stress.

BACKGROUND: Depending on its magnitude, lower body negative pressure (LBNP) has been shown to induce a progressive activation of neurohormonal, renal tubular, and renal hemodynamic responses, thereby mimicking the renal responses observed in clinical conditions characterized by a low effective arterial volume such as congestive heart failure. Our objective was to evaluate the impact of angiotensin II receptor blockade with candesartan on the renal hemodynamic and urinary excretory responses to a progressive orthostatic stress in normal subjects. METHODS: Twenty healthy men were submitted to three levels of LBNP (0, -10, and -20 mbar or 0, -7.5, and -15 mm Hg) for 1 hour according to a crossover design with a minimum of 2 days between each level of LBNP. Ten subjects were randomly allocated to receive a placebo and ten others were treated with candesartan 16 mg orally for 10 days before and during the three levels of LBNP. Systemic and renal hemodynamics, renal sodium excretions, and the hormonal response were measured hourly before, during, and for 2 hours after LBNP. RESULTS: During placebo, LBNP induced no change in systemic and renal hemodynamics, but sodium excretion decreased dose dependently with higher levels of LBNP. At -20 mbar, cumulative 3-hour sodium balance was negative at -2.3 +/- 2.3 mmol (mean +/- SEM). With candesartan, mean blood pressure decreased (76 +/- 1 mm Hg vs. 83 +/- 3 mm Hg, candesartan vs. placebo, P < 0.05) and renal plasma flow increased (858 +/- 52 mL/min vs. 639 +/- 36 mL/min, candesartan vs. placebo, P < 0.05). Glomerular filtration rate (GFR) was not significantly higher with candesartan (127 +/- 7 mL/min in placebo vs. 144 +/- 12 mL/min in candesartan). No significant decrease in sodium and water excretion was found during LBNP in candesartan-treated subjects. At -20 mbar, the 3-hour cumulative sodium excretion was + 4.6 +/- 1.4 mmol in the candesartan group (P= 0.02 vs. placebo). CONCLUSION: Selective blockade of angiotensin II type 1 (AT1) receptors with candesartan increases renal blood flow and prevents the antinatriuresis during sustained lower body negative pressure despite a modest decrease in blood pressure. These results thus provide interesting insights into potential benefits of AT1 receptor blockade in sodium-retaining states such as congestive heart failure.

Withholding antimalarials in febrile children who have a negative result for a rapid diagnostic test.

BACKGROUND: The availability of a rapid diagnostic test for malaria (RDTm) allows accurate diagnosis at all levels of health facilities. The objective of the present study was to evaluate the safety of withholding antimalarials in febrile children who have a negative test result. METHODS: We conducted a prospective 2-arm longitudinal study in areas of Tanzania that are moderately and highly endemic for malaria. Children with a history of fever were managed routinely by resident clinicians of 2 health facilities, except that no antimalarials were prescribed if the RDTm result was negative. Children were followed up at home on day 7. The main outcome was the occurrence of complications in children with negative RDTm results; children with positive RDTm results were followed up for the same outcomes for indirect comparison. RESULTS: One thousand children (median age, 24 months) were recruited. Six hundred three children (60%) had a negative RDTm result. Five hundred seventy-three (97%) of these children were cured on day 7. Forty-nine (8%) of the children with negative RDTm results spontaneously visited the dispensary before day 7, compared with 10 (3%) of the children with positive RDTm results. All children who had negative initial results had negative results again when they were tested either at spontaneous attendance or on day 7 because they were not cured clinically, except for 3 who gave positive results on days 2, 4, and 7 respectively but who did not experience any complication. Four children who had negative initial results were admitted to the hospital subsequently, all with negative results for malaria tests upon admission. Two of them died, of causes other than malaria. CONCLUSIONS: Not giving antimalarial drugs in febrile children who had a negative RDTm result was safe, even in an area highly endemic for malaria. Our study provides evidence for treatment recommendations based on parasitological diagnosis in children <5 years old.

Successful treatment of trilateral retinoblastoma with conventional and high-dose chemotherapy plus radiotherapy: a case report.

Trilateral retinoblastoma (TRB) is a rare condition characterized by an intracranial neuroblastic tumor associated with bilateral or unilateral retinoblastoma (RB). The outcome is almost always fatal. An 18-month-old patient with familial bilateral RB was referred for a pineal lesion detected on a screening by magnetic resonance imaging. The child, considered inoperable by 2 different neurosurgical teams, was treated with conventional chemotherapy (methotrexate, vincristine, vepeside, cyclophosphamide, and carboplatin) plus tandem transplantation (vepeside/carboplatin and thiotepa/mephalan) followed by local radiotherapy. At 80 months from the diagnosis of TRB, the patient is alive and in complete remission, with no neuropsychologic consequences. An early and aggressive treatment may improve the prognosis of TRB.

Brucellosis hip abscess without risk factor.

Brucellosis has become a rare entity in many industrialised countries, because of animal vaccination programs. We report a first case in the literature of Brucella abscess in the hip region observed in Switzerland in a subject without any clear risk factor, leading us to conclude that abscess formation can be a rare manifestation of brucellosis. Because it can present in many different forms and locations without having characteristic clinics, a high index of suspicion is needed for the diagnosis even if the patient is a healthy athlete with no clear way of obvious route for contamination, and this even more if all the common causes of athletic hip pain have been ruled out.

ESCMID* guideline for the diagnosis and management of Candida diseases 2012: prevention and management of invasive infections in neonates and children caused by Candida spp.

Invasive candidiasis (IC) is a relatively common syndrome in neonates and children and is associated with significant morbidity and mortality. These guidelines provide recommendations for the prevention and treatment of IC in neonates and children. Appropriate agents for the prevention of IC in neonates at high risk include fluconazole (A-I), nystatin (B-II) or lactoferrin ± Lactobacillus (B-II). The treatment of IC in neonates is complicated by the high likelihood of disseminated disease, including the possibility of infection within the central nervous system. Amphotericin B deoxycholate (B-II), liposomal amphotericin B (B-II), amphotericin B lipid complex (ABLC) (C-II), fluconazole (B-II), micafungin (B-II) and caspofungin (C-II) can all be potentially used. Recommendations for the prevention of IC in children are largely extrapolated from studies performed in adults with concomitant pharmacokinetic data and models in children. For allogeneic HSCT recipients, fluconazole (A-I), voriconazole (A-I), micafungin (A-I), itraconazole (B-II) and posaconazole (B-II) can all be used. Similar recommendations are made for the prevention of IC in children in other risk groups. With several exceptions, recommendations for the treatment of IC in children are extrapolated from adult studies, with concomitant pharmacokinetic studies. Amphotericin B deoxycholate (C-I), liposomal amphotericin B (A-I), ABLC (B-II), micafungin (A-I), caspofungin (A-I), anidulafungin (B-II), fluconazole (B-I) and voriconazole (B-I) can all be used.

Reduction of small infrarenal abdominal aortic aneurysm expansion rate by statins.

BACKGROUND: To evaluate the effect of statins on the annual expansion rate (ER) of small infrarenal abdominal aortic aneurysms (AAA). PATIENTS AND METHODS: All patients under regular surveillance for small AAA between January 2000 and September 2007, in the Department of Angiology, Lausanne University Hospital, were included. Inclusion criteria were baseline abdominal aortic diameter between 25 and 55 mm, at least two measurements of AAA diameter and a minimum follow up of 6 months. Patients with Marfan disease, infectious or inflammatory AAA, and patients with prior AAA repair were excluded. The influence of statin use and other factors on ER were examined by bivariate and multivariate analysis. RESULTS: Among 589 patients who underwent an abdominal aorta evaluation, 94 patients (89 % men, mean age 69.1 years) were finally included in the analysis. Baseline AAA size was 39.9 ± 7.7 mm (mean±SE) and 48.7 ± 8.4 mm at end of follow-up. Patients had a regular aneurysm size assessment during 38.5 ± 27.7 months. Mean ER was 3.59 mm/y (± 2.81). The 50 patients who were treated with statin during the study period had a lower ER compared to the 44 controls (2.91 vs 4.37 mm/year, p = 0.01). CONCLUSIONS: This study confirms the considerable individual variations in the AAA expansion rate, and emphasizes the need for regular aortic diameter assessments. In this study, patients treated with statin demonstrate a significant decrease in the ER compared to controls. This finding need to be evaluated in prospective interventional studies powered to demonstrate the potential benefit of statin treatment.

Quand référer aux urgences un patient présentant une elévation sévère de la pression artérielle [When should a patient with severe hypertension be referred to the emergency ward?].

When a severe elevation of blood pressure occurs in conjunction with failure of a target organ, immediate referral of the patient to hospital is an easy decision for the primary care physician. However, when severe elevation of blood pressure is observed in the absence of any significant symptom, it is a much more difficult decision to take. Indeed, if some clinical situations require an immediate and aggressive anti-hypertensive therapy, such a treatment can be clearly deleterious for a number of other cases. This paper attempts to clarify in which situations the primary care physician should refer hypertensive crisis to the emergency department.

Expression of a functional single chain antibody on the surface of extracellular enveloped vaccinia virus as a step towards selective tumour cell targeting.

Recombinant vaccinia virus with tumour cell specificity may provide a versatile tool either for direct lysis of cancer cells or for the targeted transfer of genes encoding immunomodulatory molecules. We report the expression of a single chain antibody on the surface of extracellular enveloped vaccinia virus. The wild-type haemagglutinin, an envelope glycoprotein which is not required for viral infection and replication, was replaced by haemagglutinin fusion molecules carrying a single chain antibody directed against the tumour-associated antigen ErbB2. ErbB2 is an epidermal growth factor receptor-related tyrosine kinase overexpressed in a high percentage of human adenocarcinomas. Two fusion proteins carrying the single chain antibody at different NH2-terminal positions were expressed and exposed at the envelope of the corresponding recombinant viruses. The construct containing the antibody at the site of the immunoglobulin-like loop of the haemagglutinin was able to bind solubilized ErbB2. This is the first report of replacement of a vaccinia virus envelope protein by a specific recognition structure and represents a first step towards modifying the host cell tropism of the virus.

Peptabody-EGF: a novel apoptosis inducer targeting ErbB1 receptor overexpressing cancer cells.

The epidermal growth factor receptor (EGFR) plays a central role in cell life by controlling processes such as growth or proliferation. This receptor is commonly overexpressed in a number of epithelial malignancies and its upregulation is often associated with an aggressive phenotype of the tumor. Thus, targeting of EGFR represents a very promising challenge in oncology, and antibodies raised against this receptor have been investigated as potential antitumor agents. Various putative mechanisms of action were proposed for such antibodies, including decreased proliferation, induction of apoptosis, stimulation of the immunological response against targeted cancer cells or combinations thereof. We report here the development of an alternative high affinity molecule that is directed against EGFR. Production of this pentameric protein, named peptabody-EGF, includes expression in a bacterial expression system and subsequent refolding and multimerization of peptabody monomers. The protein complex contains 5 human EGF ligand domains, which confer specific binding towards the extracellular portion of EGFR. Receptor binding of the peptabody-EGF had a strong antiproliferative effect on different cancer cell lines overexpressing EGFR. However, cells expressing constitutive levels of the target receptor were barely affected. Peptabody-EGF treated cancer cells exhibited typical characteristics of apoptosis, which was found to be induced within 30 min after the addition of the peptabody-EGF. In vitro experiments demonstrated a significantly higher binding activity for peptabody-EGF than for the therapeutic monoclonal EGFR antibody Mab-425. Furthermore, the antitumor action provoked by the peptabody-EGF was greatly superior than antibody mediated effects when tested on EGFR overexpressing cancer cell lines. These findings suggest a potential application of this high affinity molecule as a novel tool for anti-EGFR therapy.

The impact of carotid plaque screening on motivation for smoking cessation.

Showing smokers their own atherosclerotic plaques might increase motivation for smoking cessation, since they underestimate their own risk for smoking-related diseases. To assess the feasibility and optimal processes of studying the impact of carotid atherosclerotic plaque screening in smokers, we enrolled 30 daily cigarette smokers, aged 40-70 years, in an observational pre-post pilot study. All smokers underwent smoking cessation counseling, nicotine replacement therapy, a carotid ultrasound, an educational tutorial on atherosclerosis, baseline and 2-month motivation to change assessment, and assessment of smoking cessation at 2 months. Participants had a mean smoking duration of 34 years (SD = 7). Carotid plaques were present in 22 smokers (73%). Between baseline and 2 months after plaque screening, motivation for smoking cessation increased from 7.4 to 8.4 out of 10 (p = .02), particularly in those with plaques (7.2 to 8.7, p = .008). At 2 months, the smoking quit rate was 63%, with a quit rate of 73% in those with plaques vs. 38% in those without plaques (p = .10). Perceived stress, anxiety, and depression did not increase after screening. 96% of respondents answered correctly at least 80% of questions regarding atherosclerosis knowledge at baseline and after 2 months. In conclusion, studying the process of screening for carotid plaques for the purpose of increasing motivation for smoking cessation, in addition to counseling and drug therapy for smoking cessation in long-term smokers, appears feasible. The impact of carotid plaque screening on smoking cessation should be examined in larger randomized controlled trials with sufficient power to assess the impact on long-term smoking cessation rates.

Efficacy of trovafloxacin in treatment of experimental staphylococcal or streptococcal endocarditis.

The efficacy of trovafloxacin against Staphylococcus aureus and viridans group streptococci was investigated in vitro and in an experimental model of endocarditis. The MICs at which trovafloxacin and ciprofloxacin inhibited 90% of clinical isolates of such bacteria (MIC90s) were (i) 0.03 and 2 mg/liter, respectively, for 30 ciprofloxacin-susceptible S. aureus isolates, (ii) 32 and 128 mg/liter, respectively, for 20 ciprofloxacin-resistant S. aureus isolates, and (iii) 0.25 and 8 mg/liter, respectively, for 28 viridans group streptococci. Rats with aortic vegetations were infected with either of two ciprofloxacin-susceptible but methicillin-resistant S. aureus strains (strains COL and P8), one penicillin-susceptible Streptococcus sanguis strain, or one penicillin-resistant Streptococcus mitis strain. Rats were treated for 3 or 5 days with doses that resulted in kinetics that simulated those achieved in humans with trovafloxacin (200 mg orally once a day), ciprofloxacin (750 mg orally twice a day), vancomycin (1 g intravenously twice a day), or ceftriaxone (2 g intravenously once a day). Against the staphylococci, the activities of both trovafloxacin and ciprofloxacin were equivalent to that of vancomycin, and treatment of endocarditis with these drugs was successful (P &lt; 0.05). However, ciprofloxacin selected for resistant derivatives in vitro and in vivo, whereas trovafloxacin was 10 to 100 times less prone than ciprofloxacin to select for resistance in vitro and did not select for resistance in vivo. Against the two streptococcal isolates, trovafloxacin significantly (P &lt; 0.05) decreased bacterial counts in the vegetations but was less effective than the control drug, ceftriaxone. Thus, a simulated oral dose of trovafloxacin (200 mg per day) was effective against ciprofloxacin-susceptible staphylococci and was less likely than ciprofloxacin to select for resistance. The simulated oral dose of trovafloxacin also had some activity against streptococcal endocarditis, but optimal treatment of infections caused by such organisms might require higher doses of the drug.

Colloidal systems for the delivery of cyclosporin A to the anterior segment of the eye.

Due to the eye's specific anatomical and physiological conformation, the treatment of eye diseases is a real challenge for pharmaceutical therapy. The presence of efficient protective barriers (i.e., the conjunctival and corneal membranes) and protective mechanisms (i.e., blinking and nasolachrymal drainage) makes this organ particularly impervious to local drug therapy. To overcome these issues, numerous strategies have been envisioned using pharmaceutical technology. Many formulations currently on the market or still under development are emulsions or colloidal systems intended to enhance precorneal residence time and corneal penetration, causing a consequent increase in drug bioavailability after instillation. After a review of some recent developments in the field of cyclosporin A formulations for the eye, a novel micellar formulation of cyclosporine A based on a diblock methoxy-poly(ethylene glycol)-hexysubstituted poly(lactides) (MPEG-hexPLA) is described.

Adalimumab in acute sciatica reduces the long-term need for surgery: a 3-year follow-up of a randomised double-blind placebo-controlled trial.

INTRODUCTION: Two subcutaneous injections of adalimumab in severe acute sciatica significantly reduced the number of back operations in a short-term randomised controlled clinical trial. OBJECTIVE: To determine in a 3-year follow-up study whether the short-term benefit of adalimumab in sciatica is sustained over a longer period of time. METHODS: The primary outcome of this analysis was incident discectomy. Three years after randomisation, information on surgery could be retrieved in 56/61 patients (92%).A multivariate Cox proportional hazard models, adjusted for potential confounders, was used to determine factors predisposing to surgery. RESULTS: Twenty-three (41%) patients had back surgery within 3 years, 8/29 (28%) in the adalimumab group and 15/27 (56%) in the placebo group, p=0.04. Adalimumab injections reduced the need for back surgery by 61% (HR)=0.39 (95% CI 0.17 to 0.92). In a multivariate model, treatment with a tumour necrosis factor-α antagonist remained the strongest protective factor (HR=0.17, p=0.002). Other significant predictors of surgery were a good correlation between symptoms and MRI findings (HR=11.6, p=0.04), baseline intensity of leg pain (HR=1.3, p=0.06), intensity of back pain (HR=1.4, p=0.03) and duration of sickness leave (HR=1.01 per day, p=0.03). CONCLUSION: A short course of adalimumab in patients with severe acute sciatica significantly reduces the need for back surgery.