Unilateral urinary flow impairment at the pelviureteral junction: outcome of renal function with respect to therapeutic strategy.

OBJECTIVES: To evaluate the renal function outcome in children with unilateral hydronephrosis and urinary flow impairment at the pelviureteral junction with respect to the therapeutic strategy. METHODS: We retrospectively selected 45 children with iodine-123-hippuran renography performed at diagnosis and after 3 or more years of follow-up. All children had bilateral nonobstructive pattern findings on diuretic renography at follow-up. Eleven children were treated conservatively, and 34 underwent unilateral pyeloplasty. Split and individual renal function, measured by an accumulation index, was computed from background-corrected renograms for the affected and contralateral kidneys at diagnosis and the follow-up examination. RESULTS: Of 11 children treated conservatively, 9 had normal bilateral function at diagnosis, all had reached normal function at follow-up. Of the 34 operated kidneys, 12 (38%) had initially normal function that remained normal at the follow-up examination, and 22 had impaired function that had normalized at the follow-up examination in 15 (68%). The function of the contralateral kidneys was increased in 5 of 8 children with persistently abnormal affected kidneys. Pyeloplasty was performed in 23 children (68%) and 11 children (32%) younger and older than 1 year, respectively. The function of the affected kidneys increased in both groups, but normalization occurred only in the younger children. CONCLUSIONS: Of the children selected for conservative treatment, 82% had normal bilateral renal function at diagnosis that was normal in all at the follow-up examination. Of the children treated surgically, 65% had initially impaired function of the affected kidney that improved in 87% after pyeloplasty. Normalization of function was observed only in children who were younger than 1 year old at surgery. Persistently low function of the affected kidney was compensated for by the contralateral one regardless of the age at surgery.

RANKL expression, function, and therapeutic targeting in multiple myeloma and chronic lymphocytic leukemia.

Bone destruction is a prominent feature of multiple myeloma, but conflicting data exist on the expression and pathophysiologic involvement of the bone remodeling ligand RANKL in this disease and the potential therapeutic benefits of its targeted inhibition. Here, we show that RANKL is expressed by primary multiple myeloma and chronic lymphocytic leukemia (CLL) cells, whereas release of soluble RANKL was observed exclusively with multiple myeloma cells and was strongly influenced by posttranscriptional/posttranslational regulation. Signaling via RANKL into multiple myeloma and CLL cells induced release of cytokines involved in disease pathophysiology. Both the effects of RANKL on osteoclastogenesis and cytokine production by malignant cells could be blocked by disruption of RANK-RANKL interaction with denosumab. As we aimed to combine neutralization of RANKL with induction of antibody-dependent cellular cytotoxicity of natural killer (NK) cells against RANKL-expressing malignant cells and as denosumab does not stimulate NK reactivity, we generated RANK-Fc fusion proteins with modified Fc moieties. The latter displayed similar capacity compared with denosumab to neutralize the effects of RANKL on osteoclastogenesis in vitro, but also potently stimulated NK cell reactivity against primary RANKL-expressing malignant B cells, which was dependent on their engineered affinity to CD16. Our findings introduce Fc-optimized RANK-Ig fusion proteins as attractive tools to neutralize the detrimental function of RANKL while at the same time potently stimulating NK cell antitumor immunity.

Therapeutic cancer vaccines based on molecularly defined human tumor antigens.

The results of numerous phases I and II clinical trials testing the safety and immunogenicity of various cancer vaccine formulations based on cytolytic T lymphocytes (CTLs)-defined tumor antigens have been reported recently. Specific T cell responses can be detected in only a fraction of immunized patients. A smaller but significant fraction of these patients have objective tumor responses. Efficient therapeutic vaccination should aim at boosting naturally occurring anti-tumor responses and at sustaining a large contingent of tumor antigen-specific and fully functional effector T cells at tumor sites.

Neurological Prognostication after Cardiac Arrest and Therapeutic Hypothermia: a Prospective Validation Study

Introduction: Clinical examination and electroencephalography study (EEG) have been recommended to predict functional recovery in comatose survivors of cardiac arrest (CA), however their prognostic value in patients treated with induced hypothermia (IH) has not been evaluated. Hypothesis: We aimed to validate the prognostic ability of clinical examination and EEG in predicting outcome of patients with coma after CA treated with IH and sought to derive a score with high predictive value for poor functional outcome in this setting. Methods: We prospectively studied 100 consecutive comatose survivors of CA treated with IH. Repeated neurological examination and EEG were performed early after passive rewarming and off sedation. Mortality was assessed at hospital discharge, and functional outcome at 3 to 6 months with Cerebral Performance Categories (CPC), and was dichotomized as good (CPC 1-2) vs. poor (CPC 3-5). Independent predictors of outcome were identified by multivariable logistic regression and used to assess the prognostic value of a Reproducible Electro-clinical Prognosticators of Outcome Score (REPOS). Results: Patients (20/100) with good outcome had all a reactive EEG background. Incomplete recovery of brainstem reflexes, myoclonus, time to return of spontaneous circulation (ROSC) > 25 min, and unreactive EEG background were all independent predictors of death and severe disability, and were added to construct the REPOS. Using a cut-off of 0 or 1 variables for good vs. 2 to 4 for poor outcome, the REPOS had a positive predictive value of 1.00 (95% CI: 0.92-1.00), a negative predictive value of 0.43 (95% CI: 0.29-0.58) and an accuracy of 0.81 for poor functional recovery at 3 to 6 months. Conclusions: In comatose survivors of CA treated with IH, a prognostic score, including clinical and EEG examination, was highly predictive of death and poor functional outcome at 3 to 6 months. Lack of EEG background reactivity strongly predicted poor neurological recovery after CA. Our findings show that clinical and electrophysiological studies are effective in predicting long-term outcome of comatose survivors after CA and IH, and suggest that EEG improves early prognostic assessment in the setting of therapeutic cooling.

Simultaneous quantification of selective serotonin reuptake inhibitors and metabolites in human plasma by liquid chromatography-electrospray mass spectrometry for therapeutic drug monitoring.

A simple and sensitive liquid chromatography-electrospray ionization mass spectrometry method was developed for the simultaneous quantification in human plasma of all selective serotonin reuptake inhibitors (citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline) and their main active metabolites (desmethyl-citalopram and norfluoxetine). A stable isotope-labeled internal standard was used for each analyte to compensate for the global method variability, including extraction and ionization variations. After sample (250μl) pre-treatment with acetonitrile (500μl) to precipitate proteins, a fast solid-phase extraction procedure was performed using mixed mode Oasis MCX 96-well plate. Chromatographic separation was achieved in less than 9.0min on a XBridge C18 column (2.1×100mm; 3.5μm) using a gradient of ammonium acetate (pH 8.1; 50mM) and acetonitrile as mobile phase at a flow rate of 0.3ml/min. The method was fully validated according to Société Française des Sciences et Techniques Pharmaceutiques protocols and the latest Food and Drug Administration guidelines. Six point calibration curves were used to cover a large concentration range of 1-500ng/ml for citalopram, desmethyl-citalopram, paroxetine and sertraline, 1-1000ng/ml for fluoxetine and fluvoxamine, and 2-1000ng/ml for norfluoxetine. Good quantitative performances were achieved in terms of trueness (84.2-109.6%), repeatability (0.9-14.6%) and intermediate precision (1.8-18.0%) in the entire assay range including the lower limit of quantification. Internal standard-normalized matrix effects were lower than 13%. The accuracy profiles (total error) were mainly included in the acceptance limits of ±30% for biological samples. The method was successfully applied for routine therapeutic drug monitoring of more than 1600 patient plasma samples over 9 months. The β-expectation tolerance intervals determined during the validation phase were coherent with the results of quality control samples analyzed during routine use. This method is therefore precise and suitable both for therapeutic drug monitoring and pharmacokinetic studies in most clinical laboratories.

The Dyadic and Triadic Therapeutic Alliance in Cross-cultural Health Care: The case of Hispanic American Patients

This research project conducted in the Psychology Department of the University of Lausanne (Switzerland) evaluated the therapeutic alliance with Hispanic American Patients. From the patient's perspective, the therapeutic alliance was explored in two types of frameworks: the dyadic and the triadic setting. The dyadic setting is the encounter between a therapist (health professional) and a patient who ideally share the same language. The triadic setting is the encounter of a therapist and a patient who speak different languages, but are able to interact using the help of an interpreter. My specific interest focuses on studying the therapeutic alliance in a cross- cultural setting through a mixed methodology. As part of the quantitative phase, non- parametric tests were used to analyze 55 questionnaires of the Therapeutic Alliance for Migrants - Health Professionals' version (QALM-PS). For the qualitative phase, a thematic analysis was used to analyze 20 transcript interviews. While no differences were found concerning the strength of the therapeutic alliance between the triadic and dyadic settings, results showed that the factors that enrich the therapeutic alliance with migrant patients depend more on an emotional alliance (bond) than on a rational alliance (agreements). Indeed, the positive relationship with the interpreter, and especially with the therapist, relies considerably on human qualities and moral values, bringing the conception of humanity as an important need when meeting foreign patients in health care settings. In addition, the quality of communication, which could be attributed to the type of interpreter in the triadic setting, plays an important role in the establishment of a positive therapeutic relationship. Ce projet de recherche mené au Département de psychologie de l'Université de Lausanne (Suisse) a évalué l'alliance thérapeutique avec les patients hispano-américains. Du point de vue du patient, l'alliance thérapeutique a été étudiée dans deux types de dispositifs: le cadre dyadique et triadique. Le cadre dyadique est la rencontre d'un thérapeute (professionnel de la santé) et d'un patient qui, idéalement, partagent la même langue. Le cadre triadique est la rencontre d'un thérapeute et d'un patient qui parlent différentes langues, mais sont capables d'interagir grâce à l'aide d'un interprète. Mon intérêt porte en particulier sur l'étude de l'alliance thérapeutique dans un cadre interculturel au travers d'une méthodologie mixte. Dans la phase quantitative, des tests non paramétriques ont été utilisés pour les analyses des 55 questionnaires de l'alliance thérapeutique pour les migrants, version - professionnels de la santé (QALM-PS). Pour la phase qualitative, une analyse thématique a été utilisée pour l'analyse des 20 entretiens transcrits. Bien qu'aucune différence n'a été constatée en ce qui concerne la force de l'alliance thérapeutique entre les cadres dyadiques et triadiques, les résultats montrent que les facteurs qui enrichissent l'alliance thérapeutique avec les patients migrants dépendent plus de l'alliance émotionnelle (lien) que sur une alliance rationnelle (accords). En effet, la relation positive avec l'interprète, et en particulier avec le thérapeute, repose en grande partie sur des qualités humaines et des valeurs morales, ce qui porte la conception de l'humanité comme un besoin important lors de la rencontre des patients étrangers dans un cadre de santé. En outre, la qualité de la communication, qui pourrait être attribuée au type d'interprète dans le cadre triadique, joue un rôle important dans l'établissement d'une relation thérapeutique positive.

Therapeutic nanoparticles in clinics and under clinical evaluation.

This article reviews nanoparticulate-chemotherapeutic systems that have been developed for human therapy, considering the components of the nanoparticles, the therapeutic agents associated with the nanoparticles and the clinical indications these therapeutic nanoparticles have been developed for. In this evaluation we have put into perspective the types of nanomaterials and their therapeutic indications. We have reviewed the nanoparticulate-chemotherapeutic systems that have been published, approved and marketed and that are currently in clinical use. We have also analyzed the nanoparticulate-chemotherapeutic systems that are in clinical trials and under preclinical development.

Therapeutic drug monitoring of seven psychotropic drugs and four metabolites in human plasma by HPLC-MS.

A simple and sensitive LC-MS method was developed and validated for the simultaneous quantification of aripiprazole (ARI), atomoxetine (ATO), duloxetine (DUL), clozapine (CLO), olanzapine (OLA), sertindole (STN), venlafaxine (VEN) and their active metabolites dehydroaripiprazole (DARI), norclozapine (NCLO), dehydrosertindole (DSTN) and O-desmethylvenlafaxine (OVEN) in human plasma. The above mentioned compounds and the internal standard (remoxipride) were extracted from 0.5 mL plasma by solid-phase extraction (mix mode support). The analytical separation was carried out on a reverse phase liquid chromatography at basic pH (pH 8.1) in gradient mode. All analytes were monitored by MS detection in the single ion monitoring mode and the method was validated covering the corresponding therapeutic range: 2-200 ng/mL for DUL, OLA, and STN, 4-200 ng/mL for DSTN, 5-1000 ng/mL for ARI, DARI and finally 2-1000 ng/mL for ATO, CLO, NCLO, VEN, OVEN. For all investigated compounds, good performance in terms of recoveries, selectivity, stability, repeatability, intermediate precision, trueness and accuracy, was obtained. Real patient plasma samples were then successfully analysed.

Indicators of therapeutic effect in FIT-06, a Phase II trial of a DNA vaccine, GTU(®)-Multi-HIVB, in untreated HIV-1 infected subjects.

BACKGROUND: Combination highly active antiretroviral therapy (HAART) has significantly decreased HIV-1 related morbidity and mortality globally transforming HIV into a controllable condition. HAART has a number of limitations though, including limited access in resource constrained countries, which have driven the search for simpler, affordable HIV-1 treatment modalities. Therapeutic HIV-1 vaccines aim to provide immunological support to slow disease progression and decrease transmission. We evaluated the safety, immunogenicity and clinical effect of a novel recombinant plasmid DNA therapeutic HIV-1 vaccine, GTU(®)-multi-HIVB, containing 6 different genes derived from an HIV-1 subtype B isolate. METHODS: 63 untreated, healthy, HIV-1 infected, adults between 18 and 40 years were enrolled in a single-blinded, placebo-controlled Phase II trial in South Africa. Subjects were HIV-1 subtype C infected, had never received antiretrovirals, with CD4 ≥ 350 cells/mm(3) and pHIV-RNA ≥ 50 copies/mL at screening. Subjects were allocated to vaccine or placebo groups in a 2:1 ratio either administered intradermally (ID) (0.5mg/dose) or intramuscularly (IM) (1mg/dose) at 0, 4 and 12 weeks boosted at 76 and 80 weeks with 1mg/dose (ID) and 2mg/dose (IM), respectively. Safety was assessed by adverse event monitoring and immunogenicity by HIV-1-specific CD4+ and CD8+ T-cells using intracellular cytokine staining (ICS), pHIV-RNA and CD4 counts. RESULTS: Vaccine was safe and well tolerated with no vaccine related serious adverse events. Significant declines in log pHIV-RNA (p=0.012) and increases in CD4+ T cell counts (p=0.066) were observed in the vaccine group compared to placebo, more pronounced after IM administration and in some HLA haplotypes (B*5703) maintained for 17 months after the final immunisation. CONCLUSIONS: The GTU(®)-multi-HIVB plasmid recombinant DNA therapeutic HIV-1 vaccine is safe, well tolerated and favourably affects pHIV-RNA and CD4 counts in untreated HIV-1 infected individuals after IM administration in subjects with HLA B*57, B*8101 and B*5801 haplotypes.

Stratégies thérapeutiques dans les myopathies inflammatoires [Therapeutic strategies in idiopatic inflammatory myopathies]

Idiopathic inflammatory myopathies, such as polymyositis and dermatomyositis, share common clinical features such as progressive, symmetrical muscle weakness prevailing in the lower limbs, associated sometimes with muscle pains. High CK and typical biopsy insure the diagnosis. Possible causes for secondary myopathies and associated diseases should be actively investigated. The search for autoantibodies helps to better classify inflammatory myopathies and to better define the prognosis of the myopathy. Glucocorticoids are the cornerstone of the early phase therapy. Glucocorticoid-sparing agents, such as azathioprine and methotrexate, are second line agents but can be readily prescribed. In case of therapeutic resistance, a rescue treatment (ciclosporine, immunoglobulins, rituximab, cyclophosphamide) could be considered.

Prognostic value of continuous EEG monitoring during therapeutic hypothermia after cardiac arrest.

Introduction: Continuous EEG (cEEG) is increasingly used to monitor brain function in neuro-ICU patients. However, its value in patients with coma after cardiac arrest (CA), particularly in the setting of therapeutic hypothermia (TH), is only beginning to be elucidated. The aim of this study was to examine whether cEEG performed during TH may predict outcome. Methods: From April 2009 to April 2010, we prospectively studied 34 consecutive comatose patients treated with TH after CA who were monitored with cEEG, initiated during hypothermia and maintained after rewarming. EEG background reactivity to painful stimulation was tested. We analyzed the association between cEEG findings and neurologic outcome, assessed at 2 months with the Glasgow-Pittsburgh Cerebral Performance Categories (CPC). Results: Continuous EEG recording was started 12 ± 6 hours after CA and lasted 30 ± 11 hours. Nonreactive cEEG background (12 of 15 (75%) among nonsurvivors versus none of 19 (0) survivors; P < 0.001) and prolonged discontinuous "burst-suppression" activity (11 of 15 (73%) versus none of 19; P < 0.001) were significantly associated with mortality. EEG seizures with absent background reactivity also differed significantly (seven of 15 (47%) versus none of 12 (0); P = 0.001). In patients with nonreactive background or seizures/epileptiform discharges on cEEG, no improvement was seen after TH. Nonreactive cEEG background during TH had a positive predictive value of 100% (95% confidence interval (CI), 74 to 100%) and a false-positive rate of 0 (95% CI, 0 to 18%) for mortality. All survivors had cEEG background reactivity, and the majority of them (14 (74%) of 19) had a favorable outcome (CPC 1 or 2). Conclusions: Continuous EEG monitoring showing a nonreactive or discontinuous background during TH is strongly associated with unfavorable outcome in patients with coma after CA. These data warrant larger studies to confirm the value of continuous EEG monitoring in predicting prognosis after CA and TH.

Therapeutic drug monitoring in cancer - Are we missing a trick?

Therapeutic drug monitoring (TDM) can be defined as the measurement of drug in biological samples to individualise treatment by adapting drug dose to improve efficacy and/or reduce toxicity. The cytotoxic drugs are characterised by steep dose-response relationships and narrow therapeutic windows. Inter-individual pharmacokinetic (PK) variability is often substantial. There are, however, a multitude of reasons why TDM has never been fully implemented in daily oncology practice. These include difficulties in establishing appropriate concentration target, common use of combination chemotherapies and the paucity of published data from pharmacological trials. The situation is different with targeted therapies. The large interindividual PK variability is influenced by the pharmacogenetic background of the patient (e.g. cytochrome P450 and ABC transporters polymorphisms), patient characteristics such as adherence to treatment and environmental factors (drug-drug interactions). Retrospective studies have shown that targeted drug exposure correlates with treatment response in various cancers. Evidence for imatinib currently exists, others are emerging for compounds including nilotinib, dasatinib, erlotinib, sunitinib, sorafenib and mammalian target of rapamycin (mTOR) inhibitors. Applications for TDM during oral targeted therapies may best be reserved for particular situations including lack of therapeutic response, severe or unexpected toxicities, anticipated drug-drug interactions and concerns over adherence treatment. There are still few data with monoclonal antibodies (mAbs) in favour of TDM approaches, even if data showed encouraging results with rituximab and cetuximab. TDM of mAbs is not yet supported by scientific evidence. Considerable effort should be made for targeted therapies to better define concentration-effect relationships and to perform comparative randomised trials of classic dosing versus pharmacokinetically-guided adaptive dosing.

Early change in maladaptive defense style and development of the therapeutic alliance

Résumé Cette étude examine les changements précoces dans le Style Défensif Maladaptatif (SDM), le développement de l'alliance thérapeutique et la relation entre le SDM et l'alliance au cours d'une psychothérapie psychodynamique ultra-brève. Soixante-huit patients ambulatoires du centre de consultation psychiatrique et psychothérapique ont bénéficié d'une intervention psychodynamique en quatre séances. Les mesures des défenses et de l'alliance étaient effectuées à la première et à la dernière séance. Les patients qui ont débuté l'intervention avec une alliance faible et qui l'ont terminée avec une alliance haute (groupe de patients avec une alliance de croissance linéaire) ont diminué leur utilisation de défenses maladaptatives de manière significative au cours de la thérapie, alors que ce n'a pas été le cas pour les patients des groupes à alliances haute-stable et basse-stable. Les résultats ont montré qu'à la fin de l'intervention, le SDM et l'alliance étaient corrélés pour tous les patients. Cette corrélation intéressait plus particulièrement le groupe avec une alliance de croissance linéaire. Ces résultats suggèrent, que le développement de l'alliance thérapeutique reflètent le travail de collaboration entre le patient et son thérapeute alors qu'ils essayent de mieux comprendre les causes de la crise du patient. Cette compréhension peut aider à réduire les défenses initialement activées pour permettre au patient de se défendre de l'anxiété et d'un sentiment de détresse. Abstract This study examined the early change in Maladaptive Defense Style (MDS), the development of the Therapeutic Alliance, and the relationship between MDS and alliance, in a short psychodynamic intervention. Sixty-eight outpatients from a psychiatric clinic completed a four-session psychodynamic intervention. Defense and alliance measures were collected at the intake and the final session. Patients who began the intervention with a poor alliance but ended with a good alliance (linear growth therapeutic alliance group) significantly decreased their use of maladaptive defenses over the course of therapy, while patients in the high and low alliance groups did not. Results showed that at the end of the intervention, MDS and alliance were related across all patients. This relation concerned particularly the linear growth therapeutic alliance profile. These results suggest that the developing therapeutic alliance might reflect the collaborative work between the patient and the therapist as they try to understand the causes of the crisis. This understanding might help reduce maladaptive defenses that were initially activated to ward off anxiety and distress.