Oral Antibiotics for Fever in Low-Risk Neutropenic Patients With Cancer: A Double-Blind, Randomized, Multicenter Trial Comparing Single Daily Moxifloxacin With Twice Daily Ciprofloxacin Plus Amoxicillin/Clavulanic Acid Combination Therapy--EORTC Infectious Diseases Group Trial XV.

PURPOSE This double-blind, multicenter trial compared the efficacy and safety of a single daily oral dose of moxifloxacin with oral combination therapy in low-risk febrile neutropenic patients with cancer. PATIENTS AND METHODS Inclusion criteria were cancer, febrile neutropenia, low risk of complications as predicted by a Multinational Association for Supportive Care in Cancer (MASCC) score > 20, ability to swallow, and ≤ one single intravenous dose of empiric antibiotic therapy before study drug treatment initiation. Early discharge was encouraged when a set of predefined criteria was met. Patients received either moxifloxacin (400 mg once daily) monotherapy or oral ciprofloxacin (750 mg twice daily) plus amoxicillin/clavulanic acid (1,000 mg twice daily). The trial was designed to show equivalence of the two drug regimens in terms of therapy success, defined as defervescence and improvement in clinical status during study drug treatment (< 10% difference). Results Among the 333 patients evaluated in an intention-to-treat analysis, therapy success was observed in 80% of the patients administered moxifloxacin and in 82% of the patients administered combination therapy (95% CI for the difference, -10% to 8%, consistent with equivalence). Minor differences in tolerability, safety, and reasons for failure were observed. More than 50% of the patients in the two arms were discharged on protocol therapy, with 5% readmissions among those in either arm. Survival was similar (99%) in both arms. CONCLUSION Monotherapy with once daily oral moxifloxacin is efficacious and safe in low-risk febrile neutropenic patients identified with the help of the MASCC scoring system, discharged early, and observed as outpatients.

Therapeutic Drug Monitoring (TDM) of Imatinib: Effectiveness of Bayesian dose adjustment for CML patients enrolled in the Imatinib Concentration Monitoring (I-COME) study

Introduction: As imatinib pharmacokinetics are highly variable, plasma levels differ largely between patients under the same dosage. Retrospective studies in chronic myeloid leukemia (CML) patients showed significant correlations between low levels and suboptimal response, as well as between high levels and poor tolerability. Monitoring of trough plasma levels, targeting 1000 μg/L and above, is thus increasingly advised. Our study was launched to assess prospectively the clinical usefulness of systematic imatinib TDM in CML patients. This preliminary analysis addresses the appropriateness of the dosage adjustment approach applied in this study, which targets the recommended trough level and allows an interval of 4-24 h after last drug intake for blood sampling. Methods: Blood samples from the first 15 patients undergoing 1st TDM were obtained 1.5-25 h after last dose. Imatinib plasma levels were measured by LC-MS/MS and the concentrations were extrapolated to trough based on a Bayesian approach using a population pharmacokinetic model. Trough levels were predicted to differ significantly from the target in 12 patients (10 <750 μg/L; 2 >1500 μg/L along with poor tolerance) and individual dose adjustments were proposed. 8 patients underwent a 2nd TDM cycle. Trough levels of 1st and 2nd TDM were compared, the sample drawn 1.5 h after last dose (during distribution phase) was excluded from the analysis. Results: Individual dose adjustments were applied in 6 patients. Observed concentrations extrapolated to trough ranged from 360 to 1832 μg/L (median 725; mean 810, CV 52%) on 1st TDM and from 720 to 1187 μg/L (median 950; mean 940, CV 18%) on 2nd TDM cycle. Conclusions: These preliminary results suggest that TDM of imatinib using a Bayesian interpretation is able to target the recommended trough level of 1000 μg/L and to reduce the considerable differences in trough level exposure between patients (with CV decreasing from 52% to 18%). While this may simplify blood collection in daily practice, as samples do not have to be drawn exactly at trough, the largest possible interval to last drug intake yet remains preferable to avoid sampling during distribution phase leading to biased extrapolation. This encourages the evaluation of the clinical benefit of a routine TDM intervention in CML patients, which the randomized Swiss I-COME trial aims to.

When "enough" is not enough: new perspectives on optimal methadone maintenance dose.

Some methadone maintenance treatment (MMT) programs prescribe inadequate daily methadone doses. Patients complain of withdrawal symptoms and continue illicit opioid use, yet practitioners are reluctant to increase doses above certain arbitrary thresholds. Serum methadone levels (SMLs) may guide practitioners dosing decisions, especially for those patients who have low SMLs despite higher methadone doses. Such variation is due in part to the complexities of methadone metabolism. The medication itself is a racemic (50:50) mixture of 2 enantiomers: an active "R" form and an essentially inactive "S" form. Methadone is metabolized primarily in the liver, by up to five cytochrome P450 isoforms, and individual differences in enzyme activity help explain wide ranges of active R-enantiomer concentrations in patients given identical doses of racemic methadone. Most clinical research studies have used methadone doses of less than 100 mg/day [d] and have not reported corresponding SMLs. New research suggests that doses ranging from 120 mg/d to more than 700 mg/d, with correspondingly higher SMLs, may be optimal for many patients. Each patient presents a unique clinical challenge, and there is no way of prescribing a single best methadone dose to achieve a specific blood level as a "gold standard" for all patients. Clinical signs and patient-reported symptoms of abstinence syndrome, and continuing illicit opioid use, are effective indicators of dose inadequacy. There does not appear to be a maximum daily dose limit when determining what is adequately "enough" methadone in MMT.

Lymphocyte specificity to protein antigens. III. Capacity of low responder mice to beef cytochrome c to respond to a peptide fragment of the molecule.

Lymph node cells derived from A.TH or A.TL mice primed with beef cytochrome c show striking patterns of reactivity when assayed in vitro for antigen-induced T cell proliferation. Whereas cells from A.TH mice respond specifically to beef cytochrome c or peptides composed of amino acids 1-65 and 81-104, cells from A.TL mice respond neither to beef cytochrome c nor to peptide 1-65, but proliferate following exposure to either peptide 81-104 or to a cytochrome c hybrid molecule in which the N-terminal peptide of beef (1-65) was substituted by a similar peptide obtained from rabbit cytochrome c. Thus, T cells from mice phenotypically unresponsive to beef cytochrome may, in fact, contain populations of lymphocytes capable of responding to a unique peptide, the response to which is totally inhibited when the same fragment is presented in the sequence of the intact protein.

Heterogeneity of t(4;14) in multiple myeloma. Long-term follow-up of 100 cases treated with tandem transplantation in IFM99 trials.

One hundred de novo multiple myeloma patients with t(4;14) treated with double intensive therapy according to IFM99 protocols were retrospectively analyzed. The median overall survival (OS) and event-free survival (EFS) were 41.4 and 21 months, respectively, as compared to 65 and 37 for patients included in the IFM99 trials without t(4;14) (P<10(-7)). We identified a subgroup of patients presenting at diagnosis with both low beta(2)-microglobulin <4 mg/l and high hemoglobin (Hb) >/=10 g/l (46% of the cases) with a median OS of 54.6 months and a median EFS of 26 months, respectively, which benefits from high-dose therapy (HDT); conversely patients with one or both adverse prognostic factor (high beta(2)-microglobulin and/or low Hb) had a poor outcome. The achievement of either complete response or very good partial response after HDT was also a powerful independent prognostic factor for both OS and EFS.

How High Dose(s) of Oral Vitamin D3 Can Correct Insufficiency in a Non Supplemented Rheumatologic Population ?

Introduction: 700 to 1000 UI Vitamin D/day prevent 20% of fall and fracture. Higher dosage could prevent other health problems, such as immune diseases. Adherence to oral daily vitamin D supplementation is low. There is no guideline on how to supplement patients with rheumatic diseases. We evaluated if 1-2 dose(s) of 300'000 UI oral vitamin D3 was enough to reach an optimal level of 25-OH vitamin D in late winter in patients with insufficiency. Methods: During November 2009 (M0) patients attending our Rheumatology Outpatient Clinic had a blood test to measure 25-OH vitamin D. Results were classified as: deficiency <10µg/l, insufficiency 10µg/l to 30µg/l and normal >30µg/l. Patients on daily oral vitamin D3 or who received a single high dose of vitamin D3 in the last 6 months and patients with deficiency or normal results were excluded. Patients included received a single dose of 300'000 IU of oral vitamin D3 and were asked to come back for a blood test for 25-OH vitamin D after 3 (M3) and 6 months (M6). If they were still insufficient at M3, they received a second high dose of 300'000 IU of oral vitamin D3. Results: 292 patients had their level of 25-OH vitamin D determined at M0. 141 patients (70% women) had vitamin D insufficiency (18.5µg/l (10.2-29.1)) and received a prescription for a single dose of 300'000 IU of oral vitamin D3. Men and women were not statistically different in term of age and 25-OH vitamin D level at M0. 124/141 (88%) patients had a blood test at M3. 2/124 (2%) had deficiency (8.1µg/l (7.5-8.7)), 50/124 (40%) normal results (36.7µg/l (30.5-56.5)). 58% (72/124) were insufficient (23.6µg/l (13.8-29.8)) and received a second prescription for 300'000 IU of oral vitamin D3. Of the 50/124 patients who had normal results at M3 and did not receive a second prescription, 36 (72%) had a test at M6. 47% (17/36) had normal results (34.8µg/l (30.3-42.8)), 53% (19/36) were insufficient (25.6µg/l (15.2-29.9)). Out of the 54/72 (75%) patients who received a second prescription, 28/54 (52%) had insufficiency (23.2µg/l (12.8-28.7)) and 26/54 (48%) had normal results (33.8µg/l (30.0-43.7)) at M 6. Discussion: This real life study has shown that one or two oral bolus of 300'000 IU of vitamin D3 in autumn and winter was not enough to completely correct hypovitaminosis D but was a good way of preventing a nadir of 25-OH vitamin D usually observed in spring in a Swiss rheumatologic population.

Antigen affinity and antigen dose exert distinct influences on CD4 T-cell differentiation.

Cumulative T-cell receptor signal strength and ensuing T-cell responses are affected by both antigen affinity and antigen dose. Here we examined the distinct contributions of these parameters to CD4 T-cell differentiation during infection. We found that high antigen affinity positively correlates with T helper (Th)1 differentiation at both high and low doses of antigen. In contrast, follicular helper T cell (TFH) effectors are generated after priming with high, intermediate, and low affinity ligand. Unexpectedly, memory T cells generated after priming with very low affinity antigen remain impaired in their ability to generate secondary Th1 effectors, despite being recalled with high affinity antigen. These data challenge the view that only strongly stimulated CD4 T cells are capable of differentiating into the TFH and memory T-cell compartments and reveal that differential strength of stimulation during primary T-cell activation imprints unique and long lasting T-cell differentiation programs.

Comparison of "Live High-Train Low" in Normobaric versus Hypobaric Hypoxia.

We investigated the changes in both performance and selected physiological parameters following a Live High-Train Low (LHTL) altitude camp in either normobaric hypoxia (NH) or hypobaric hypoxia (HH) replicating current "real" practices of endurance athletes. Well-trained triathletes were split into two groups (NH, n = 14 and HH, n = 13) and completed an 18-d LHTL camp during which they trained at 1100-1200 m and resided at an altitude of 2250 m (PiO2  = 121.7±1.2 vs. 121.4±0.9 mmHg) under either NH (hypoxic chamber; FiO2 15.8±0.8%) or HH (real altitude; barometric pressure 580±23 mmHg) conditions. Oxygen saturations (SpO2) were recorded continuously daily overnight. PiO2 and training loads were matched daily. Before (Pre-) and 1 day after (Post-) LHTL, blood samples, VO2max, and total haemoglobin mass (Hbmass) were measured. A 3-km running test was performed near sea level twice before, and 1, 7, and 21 days following LHTL. During LHTL, hypoxic exposure was lower for the NH group than for the HH group (220 vs. 300 h; P<0.001). Night SpO2 was higher (92.1±0.3 vs. 90.9±0.3%, P<0.001), and breathing frequency was lower in the NH group compared with the HH group (13.9±2.1 vs. 15.5±1.5 breath.min-1, P<0.05). Immediately following LHTL, similar increases in VO2max (6.1±6.8 vs. 5.2±4.8%) and Hbmass (2.6±1.9 vs. 3.4±2.1%) were observed in NH and HH groups, respectively, while 3-km performance was not improved. However, 21 days following the LHTL intervention, 3-km run time was significantly faster in the HH (3.3±3.6%; P<0.05) versus the NH (1.2±2.9%; ns) group. In conclusion, the greater degree of race performance enhancement by day 21 after an 18-d LHTL camp in the HH group was likely induced by a larger hypoxic dose. However, one cannot rule out other factors including differences in sleeping desaturations and breathing patterns, thus suggesting higher hypoxic stimuli in the HH group.

Cell-permeable peptides induce dose- and length-dependent cytotoxic effects.

We have explored the threshold of tolerance of three unrelated cell types to treatments with potential cytoprotective peptides bound to Tat(48-57) and Antp(43-58) cell-permeable peptide carriers. Both Tat(48-57) and Antp(43-58) are well known for their good efficacy at crossing membranes of different cell types, their overall low toxicity, and their absence of leakage once internalised. Here, we show that concentrations of up to 100 microM of Tat(48-57) were essentially harmless in all cells tested, whereas Antp(43-58) was significantly more toxic. Moreover, all peptides bound to Tat(48-57) and Antp(43-58) triggered significant and length-dependent cytotoxicity when used at concentrations above 10 microM in all but one cell types (208F rat fibroblasts), irrespective of the sequence of the cargo. Absence of cytotoxicity in 208F fibroblasts correlated with poor intracellular peptide uptake, as monitored by confocal laser scanning fluorescence microscopy. Our data further suggest that the onset of cytotoxicity correlates with the activation of two intracellular stress signalling pathways, namely those involving JNK, and to a lesser extent p38 mitogen-activated protein kinases. These responses are of particular concern for cells that are especially sensitive to the activation of stress kinases. Collectively, these results indicate that in order to avoid unwanted and unspecific cytotoxicity, effector molecules bound to Tat(48-57) should be designed with the shortest possible sequence and the highest possible affinity for their binding partners or targets, so that concentrations below 10 microM can be successfully applied to cells without harm. Considering that cytotoxicity associated to Tat(48-57)- and Antp(43-58) bound peptide conjugates was not restricted to a particular type of cells, our data provide a general framework for the design of cell-penetrating peptides that may apply to broader uses of intracellular peptide and drug delivery.

Low concentrations of 3-hydroxy glutarate leads to ammonium accumulation and non-apoptotic cell death in developing brain cells

We previously showed in a 3D rat brain cell in vitro model for glutaric aciduria type-I that repeated application of 1mM 3-hydroxy-glutarate (3-OHGA) caused ammonium accumulation, morphologic alterations and induction of non-apoptotic cell death in developing brain cells. Here, we performed a dose-response study with lower concentrations of 3- OHGA.We exposed our cultures to 0.1, 0.33 and 1mM 3-OHGA every 12h over three days at two developmental stages (DIV5-8 and DIV11-14). Ammonium accumulation was observed at both stages starting from 0.1mM 3-OHGA, in parallel with a glutamine decrease. Morphological changes started at 0.33mM with loss of MBP expression and loss of astrocytic processes. Neurons were not substantially affected. At DIV8, release of LDH in the medium and cellular TUNEL staining increased from 0.1mM and 0.33mM 3-OHGA exposure, respectively. No increase in activated caspase-3 was observed. We confirmed ammonium accumulation and non-apoptotic cell death of brain cells in our in vitro model at lower 3-OHGA concentrations thus strongly suggesting that the observed effects are likely to take place in the brain of affected patients. The concomitant glutamine decrease suggests a defect in the astrocyte ammonium buffering system. Ammonium accumulation might be the cause of non-apoptotic cell death.

Adverse drug reactions following nonresponse in a depressed patient with CYP2D6 deficiency and low CYP 3A4/5 activity

A 47-year-old male taxi driver experienced multiple adverse drug reactions during therapy with clomipramine (CMI) and quetiapine for major depressive disorder, after having been unsuccessfully treated with adequate doses of mirtazapine and venlafaxine. Drug serum concentrations of CMI and quetiapine were significantly increased and pharmacogenetic testing showed a poor metabolizer status for CYP2D6, low CYP3A4/5 activity and normal CYP2C19 genotype. After reduction of the CMI dose and discontinuation of quetiapine, all ADR subsided except for the increase in liver enzymes. The latter improved but did not normalize completely, even months later, possibly due to concomitant cholelithiasis.

Changes in the phenolic content of low density lipoprotein after olive oil consumption in men. A randomized crossover controlled trial

Olive oil decreases the risk of CVD. This effect may be due to the fatty acid profile of the oil, but it may also be due to its antioxidant content which differs depending on the type of olive oil. In this study, the concentrations of oleic acid and antioxidants (phenolic compounds and vitamin E) in plasma and LDL were compared after consumption of three similar olive oils, but with differences in their phenolic content. Thirty healthy volunteers participated in a placebo-controlled, double-blind, crossover, randomized supplementation trial. Virgin, common, and refined olive oils were administered during three periods of 3 weeks separated by a 2-week washout period. Participants were requested to ingest a daily dose of 25 ml raw olive oil, distributed over the three meals of the day, during intervention periods. All three olive oils caused an increase in plasma and LDL oleic acid (P,0·05) content. Olive oils rich in phenolic compounds led to an increase in phenolic compounds in LDL (P,0·005). The concentration of phenolic compounds in LDL was directly correlated with the phenolic concentration in the olive oils. The increase in the phenolic content of LDL could account for the increase of the resistance of LDL to oxidation, and the decrease of the in vivo oxidized LDL, observed in the frame of this trial. Our results support the hypothesis that a daily intake of virgin olive oil promotes protective LDL changes ahead of its oxidation.

Prooxidant/Antioxidant Balance in Hypoxia: A Cross-Over Study on Normobaric vs. Hypobaric "Live High-Train Low".

"Live High-Train Low" (LHTL) training can alter oxidative status of athletes. This study compared prooxidant/antioxidant balance responses following two LHTL protocols of the same duration and at the same living altitude of 2250 m in either normobaric (NH) or hypobaric (HH) hypoxia. Twenty-four well-trained triathletes underwent the following two 18-day LHTL protocols in a cross-over and randomized manner: Living altitude (PIO2 = 111.9 ± 0.6 vs. 111.6 ± 0.6 mmHg in NH and HH, respectively); training "natural" altitude (~1000-1100 m) and training loads were precisely matched between both LHTL protocols. Plasma levels of oxidative stress [advanced oxidation protein products (AOPP) and nitrotyrosine] and antioxidant markers [ferric-reducing antioxidant power (FRAP), superoxide dismutase (SOD) and catalase], NO metabolism end-products (NOx) and uric acid (UA) were determined before (Pre) and after (Post) the LHTL. Cumulative hypoxic exposure was lower during the NH (229 ± 6 hrs.) compared to the HH (310 ± 4 hrs.; P<0.01) protocol. Following the LHTL, the concentration of AOPP decreased (-27%; P<0.01) and nitrotyrosine increased (+67%; P<0.05) in HH only. FRAP was decreased (-27%; P<0.05) after the NH while was SOD and UA were only increased following the HH (SOD: +54%; P<0.01 and UA: +15%; P<0.01). Catalase activity was increased in the NH only (+20%; P<0.05). These data suggest that 18-days of LHTL performed in either NH or HH differentially affect oxidative status of athletes. Higher oxidative stress levels following the HH LHTL might be explained by the higher overall hypoxic dose and different physiological responses between the NH and HH.

Available evidence on re-irradiation with stereotactic ablative radiotherapy following high-dose previous thoracic radiotherapy for lung malignancies.

Patients affected with intra-thoracic recurrences of primary or secondary lung malignancies after a first course of definitive radiotherapy have limited therapeutic options, and they are often treated with a palliative intent. Re-irradiation with stereotactic ablative radiotherapy (SABR) represents an appealing approach, due to the optimized dose distribution that allows for high-dose delivery with better sparing of organs at risk. This strategy has the goal of long-term control and even cure. Aim of this review is to report and discuss published data on re-irradiation with SABR in terms of efficacy and toxicity. Results indicate that thoracic re-irradiation may offer satisfactory disease control, however the data on outcome and toxicity are derived from low quality retrospective studies, and results should be cautiously interpreted. As SABR may be associated with serious toxicity, attention should be paid for an accurate patients' selection.

Objective assessment of low contrast detectability in computed tomography with Channelized Hotelling Observer.

PURPOSE: Iterative algorithms introduce new challenges in the field of image quality assessment. The purpose of this study is to use a mathematical model to evaluate objectively the low contrast detectability in CT. MATERIALS AND METHODS: A QRM 401 phantom containing 5 and 8 mm diameter spheres with a contrast level of 10 and 20 HU was used. The images were acquired at 120 kV with CTDIvol equal to 5, 10, 15, 20 mGy and reconstructed using the filtered back-projection (FBP), adaptive statistical iterative reconstruction 50% (ASIR 50%) and model-based iterative reconstruction (MBIR) algorithms. The model observer used is the Channelized Hotelling Observer (CHO). The channels are dense difference of Gaussian channels (D-DOG). The CHO performances were compared to the outcomes of six human observers having performed four alternative forced choice (4-AFC) tests. RESULTS: For the same CTDIvol level and according to CHO model, the MBIR algorithm gives the higher detectability index. The outcomes of human observers and results of CHO are highly correlated whatever the dose levels, the signals considered and the algorithms used when some noise is added to the CHO model. The Pearson coefficient between the human observers and the CHO is 0.93 for FBP and 0.98 for MBIR. CONCLUSION: The human observers' performances can be predicted by the CHO model. This opens the way for proposing, in parallel to the standard dose report, the level of low contrast detectability expected. The introduction of iterative reconstruction requires such an approach to ensure that dose reduction does not impair diagnostics.