An X-ray chimney extending hundreds of parsecs above and below the Galactic Centre.

Evidence has mounted in recent decades that outflows of matter and energy from the central few parsecs of our Galaxy have shaped the observed structure of the Milky Way on a variety of larger scales1. On scales of 15 parsecs, the Galactic Centre has bipolar lobes that can be seen in both the X-ray and radio parts of the spectrum2,3, indicating broadly collimated outflows from the centre, directed perpendicular to the Galactic plane. On larger scales, approaching the size of the Galaxy itself, γ-ray observations have revealed the so-called 'Fermi bubble' features4, implying that our Galactic Centre has had a period of active energy release leading to the production of relativistic particles that now populate huge cavities on both sides of the Galactic plane. The X-ray maps from the ROSAT all-sky survey show that the edges of these cavities close to the Galactic plane are bright in X-rays4-6. At intermediate scales (about 150 parsecs), radio astronomers have observed the Galactic Centre lobe, an apparent bubble of emission seen only at positive Galactic latitudes7,8, but again indicative of energy injection from near the Galactic Centre. Here we report prominent X-ray structures on these intermediate scales (hundreds of parsecs) above and below the plane, which appear to connect the Galactic Centre region to the Fermi bubbles. We propose that these structures, which we term the Galactic Centre 'chimneys', constitute exhaust channels through which energy and mass, injected by a quasi-continuous train of episodic events at the Galactic Centre, are transported from the central few parsecs to the base of the Fermi bubbles4.

OIE twinning programme for veterinary education.

Building capacity is synonymous with sustaining development. Both are required to fuel progress and propel efforts towards heightening health and security. The urgency to build capacity has been catalysed by an increasing number of sanitary crises, threats, and disease outbreaks that have spanned countries, regions and continents. Education has often bridged the gaps in learning, but it has also divided the ways in which learning is practised. Differing cultural, religious and political beliefs, together with alternate economic priorities, have meant that countries have been advocating for education to meet their own specific needs, and not necessarily those of the international community. The varying contents of veterinary curricula around the world do not always demonstrate that the initial education of veterinary students provides them with the necessary skill sets to fulfil their responsibilities as key actors in the private and public sectors of national Veterinary Services. This has resulted in discrepancies in the competencies acquired by veterinarians and their capacities to uphold good veterinary governance and practices. To address this educational imbalance, the World Organisation for Animal Health (OIE) has drafted recommendations and guidelines to assist Veterinary Education Establishments worldwide with improving the breadth and depth of their veterinary curricula in order to strengthen their national Veterinary Services. The OIE has, furthermore, developed a twinning programme for Veterinary Education Establishments, under which learning opportunities for teaching staff and students are created and shared. Twinning has, to date, proved to be an effective and powerful mechanism through which developments in veterinary education through mutual capacity and confidence-building can be sustained.

Le renforcement des capacités est synonyme de développement durable. L'un comme l'autre sont indispensables pour alimenter le progrès et canaliser les efforts vers un niveau optimal de santé et de sécurité. Le renforcement des capacités est devenu une nécessité urgente du fait du nombre croissant de crises sanitaires, de menaces et de foyers de maladies qui se propagent dans différents pays, régions et continents. L'offre éducative permet souvent de remédier à des savoirs lacunaires mais elle peut aussi créer des fractures quant aux manières d'apprendre. Les différentes croyances culturelles, religieuses et politiques mais aussi les priorités économiques successives ont souvent induit des politiques éducatives qui visent à répondre aux besoins spécifiques d'un pays plutôt qu'à satisfaire ceux de la communauté internationale. Les variations de contenu des programmes d'enseignement de la médecine vétérinaire dans le monde ne permettent pas toujours de garantir que la formation initiale des jeunes diplômés les dote des compétences requises pour exercer pleinement leurs responsabilités en tant qu'acteurs essentiels des composantes tant privées que publiques des Services vétérinaires. Cela se traduit par un écart entre les compétences acquises par les vétérinaires et les capacités requises pour soutenir une bonne gouvernance et des bonnes pratiques vétérinaires. Afin de remédier à cette disparité des contenus d'enseignement, l'Organisation mondiale de la santé animale (OIE) a préparé des projets de recommandations et de lignes directrices visant à aider les établissements d'enseignement de la médecine vétérinaire dans le monde à dispenser une formation plus étendue et approfondie, dans le but de renforcer les Services vétérinaires nationaux. En outre, le programme de jumelages entre établissements d'enseignement de la médecine vétérinaire mis en place par l'OIE offre de nouvelles perspectives pédagogiques, tant aux enseignants qu'aux étudiants. Le jumelage s'est révélé jusqu'à présent un mécanisme efficace et performant : par le renforcement mutuel des capacités et de la confiance qu'il induit, il pérennise dans les pays participants les effets de la modernisation de l'enseignement vétérinaire.

Refuerzo de capacidades es sinónimo de desarrollo sostenible. Ambos elementos son necesarios para alimentar el progreso e impulsar una labor que permita mejorar los niveles de salud y seguridad. El creciente número de crisis o amenazas sanitarias y de brotes infecciosos que se han extendido por países, regiones y continentes ha puesto de manifiesto que urge dotarse de más sólidos medios de acción. La enseñanza ha servido a menudo para aportar al alumno conocimientos que le faltaban, pero a la vez ha consagrado diferentes maneras de aprender. El distinto bagaje cultural, religioso y político y las dispares prioridades económicas de los países han llevado a una situación en que cada país apuesta por un tipo de enseñanza adaptado a sus propias necesidades específicas, y no necesariamente a las de la comunidad internacional. Los heterogéneos programas de estudios veterinarios que se siguen en el mundo no siempre sirven para que el estudiante de veterinaria salga de la facultad provisto del conjunto de aptitudes necesarias para cumplir la función que le incumbe como pieza básica de los Servicios Veterinarios nacionales, ya sea desde el sector privado o desde el público. Ello da lugar a una gran disparidad en cuanto a las competencias que adquieren los veterinarios y a su capacidad para secundar las buenas prácticas y el buen gobierno veterinarios. Con el objetivo de resolver estas discordancias en la enseñanza, la Organización Mundial de Sanidad Animal (OIE) ha elaborado recomendaciones y directrices que ayudan a establecimientos de formación veterinaria de todo el mundo a conferir más amplitud y profundidad a sus programas de estudios y, con ello, a fortalecer los Servicios Veterinarios de su país. La OIE, además, tiene formulado un programa de hermanamiento dirigido a dichos establecimientos, que ofrecen así a profesores y alumnos la posibilidad de formarse o de hacer intercambios. Por lo observado hasta la fecha, el hermanamiento constituye un potente y eficaz mecanismo con el que respaldar el desarrollo de la formación veterinaria, gracias a la creación de lazos de confianza y al refuerzo recíproco de capacidades.

Autotaxin interacts with lipoprotein(a) and oxidized phospholipids in predicting the risk of calcific aortic valve stenosis in patients with coronary artery disease.

BACKGROUND: Studies have shown that lipoprotein(a) [Lp(a)], an important carrier of oxidized phospholipids, is causally related to calcific aortic valve stenosis (CAVS). Recently, we found that Lp(a) mediates the development of CAVS through autotaxin (ATX). OBJECTIVE: To determine the predictive value of circulating ATX mass and activity for CAVS. METHODS: We performed a case-control study in 300 patients with coronary artery disease (CAD). Patients with CAVS plus CAD (cases, n = 150) were age- and gender-matched (1 : 1) to patients with CAD without aortic valve disease (controls, n = 150). ATX mass and enzymatic activity and levels of Lp(a) and oxidized phospholipids on apolipoprotein B-100 (OxPL-apoB) were determined in fasting plasma samples. RESULTS: Compared to patients with CAD alone, ATX mass (P < 0.0001), ATX activity (P = 0.05), Lp(a) (P = 0.003) and OxPL-apoB (P < 0.0001) levels were elevated in those with CAVS. After adjustment, we found that ATX mass (OR 1.06, 95% CI 1.03-1.10 per 10 ng mL-1 , P = 0.001) and ATX activity (OR 1.57, 95% CI 1.14-2.17 per 10 RFU min-1 , P = 0.005) were independently associated with CAVS. ATX activity interacted with Lp(a) (P = 0.004) and OxPL-apoB (P = 0.001) on CAVS risk. After adjustment, compared to patients with low ATX activity (dichotomized at the median value) and low Lp(a) (<50 mg dL-1 ) or OxPL-apoB (<2.02 nmol L-1 , median) levels (referent), patients with both higher ATX activity (≥84 RFU min-1 ) and Lp(a) (≥50 mg dL-1 ) (OR 3.46, 95% CI 1.40-8.58, P = 0.007) or OxPL-apoB (≥2.02 nmol L-1 , median) (OR 5.48, 95% CI 2.45-12.27, P < 0.0001) had an elevated risk of CAVS. CONCLUSION: Autotaxin is a novel and independent predictor of CAVS in patients with CAD.

Venlafaxine's therapeutic reference range in the treatment of depression revised: a systematic review and meta-analysis.

INTRODUCTION: The selective serotonin and norepinephrine reuptake inhibitor venlafaxine is among the most prescribed antidepressant drugs worldwide and, according to guidelines, its dose titration should be guided by drug-level monitoring of its active moiety (AM) which consists of venlafaxine (VEN) plus active metabolite O-desmethylvenlafaxine (ODV). This indication of therapeutic drug monitoring (TDM), however, assumes a clear concentration/effect relationship for a drug, which for VEN has not been systematically explored yet. OBJECTIVES: We performed a systematic review and meta-analysis to investigate the relationship between blood levels, efficacy, and adverse reactions in order to suggest an optimal target concentration range for VEN oral formulations for the treatment of depression. METHODS: Four databases (MEDLINE (PubMed), PsycINFO, Web of Science Core Collection, and Cochrane Library) were systematically searched in March 2022 for relevant articles according to a previously published protocol. Reviewers independently screened references and performed data extraction and critical appraisal. RESULTS: High-quality randomized controlled trials investigating concentration/efficacy relationships and studies using a placebo lead-in phase were not found. Sixty-eight articles, consisting mostly of naturalistic TDM studies or small noncontrolled studies, met the eligibility criteria. Of them, five cohort studies reported a positive correlation between blood levels and antidepressant effects after VEN treatment. Our meta-analyses showed (i) higher AM and (ii) higher ODV concentrations in patients responding to VEN treatment when compared to non-responders (n = 360, k = 5). AM concentration-dependent occurrence of tremor was reported in one study. We found a linear relationship between daily dose and AM concentration within guideline recommended doses (75-225 mg/day). The population-based concentration ranges (25-75% interquartile) among 11 studies (n = 3200) using flexible dosing were (i) 225-450 ng/ml for the AM and (ii) 144-302 ng/ml for ODV. One PET study reported an occupancy of 80% serotonin transporters for ODV serum levels above 85 ng/ml. Based on our findings, we propose a therapeutic reference range for AM of 140-600 ng/ml. CONCLUSION: VEN TDM within a range of 140 to 600 ng/ml (AM) will increase the probability of response in nonresponders. A titration within the proposed reference range is recommended in case of non-response at lower drug concentrations as a consequence of VEN's dual mechanism of action via combined serotonin and norepinephrine reuptake inhibition. Drug titration towards higher concentrations will, however, increase the risk for ADRs, in particular with supratherapeutic drug concentrations.

Optimisation of pharmacotherapy in psychiatry through therapeutic drug monitoring, molecular brain imaging and pharmacogenetic tests: focus on antipsychotics.

BACKGROUND: For psychotic disorders (i.e. schizophrenia), pharmacotherapy plays a key role in controlling acute and long-term symptoms. To find the optimal individual dose and dosage strategy, specialized tools are used. Three tools have been proven useful to personalize drug treatments: therapeutic drug monitoring (TDM) of drug levels, pharmacogenetic testing (PG), and molecular neuroimaging. METHODS: In these Guidelines, we provide an in-depth review of pharmacokinetics, pharmacodynamics, and pharmacogenetics for 50 antipsychotics. Over 30 international experts in psychiatry selected studies that have measured drug concentrations in the blood (TDM), gene polymorphisms of enzymes involved in drug metabolism, or receptor/transporter occupancies in the brain (positron emission tomography (PET)). RESULTS: Study results strongly support the use of TDM and the cytochrome P450 (CYP) genotyping and/or phenotyping to guide drug therapies. Evidence-based target ranges are available for titrating drug doses that are often supported by PET findings. CONCLUSION: All three tools discussed in these Guidelines are essential for drug treatment. TDM goes well beyond typical indications such as unclear compliance and polypharmacy. Despite its enormous potential to optimize treatment effects, minimize side effects and ultimately reduce the global burden of diseases, personalized drug treatment has not yet become the standard of care in psychiatry.

Comparison between transcatheter and surgical prosthetic valve implantation in patients with severe aortic stenosis and reduced left ventricular ejection fraction.

BACKGROUND: Patients with severe aortic stenosis and reduced left ventricular ejection fraction (LVEF) have a poor prognosis with conservative therapy but a high operative mortality when treated surgically. Recently, transcatheter aortic valve implantation (TAVI) has emerged as an alternative to surgical aortic valve replacement (SAVR) for patients considered at high or prohibitive operative risk. The objective of this study was to compare TAVI and SAVR with respect to postoperative recovery of LVEF in patients with severe aortic stenosis and reduced LV systolic function. METHODS AND RESULTS: Echocardiographic data were prospectively collected before and after the procedure in 200 patients undergoing SAVR and 83 patients undergoing TAVI for severe aortic stenosis (aortic valve area ≤1 cm(2)) with reduced LV systolic function (LVEF ≤50%). TAVI patients were significantly older (81±8 versus 70±10 years; P<0.0001) and had more comorbidities compared with SAVR patients. Despite similar baseline LVEF (34±11% versus 34±10%), TAVI patients had better recovery of LVEF compared with SAVR patients (ΔLVEF, 14±15% versus 7±11%; P=0.005). At the 1-year follow-up, 58% of TAVI patients had a normalization of LVEF (>50%) as opposed to 20% in the SAVR group. On multivariable analysis, female gender (P=0.004), lower LVEF at baseline (P=0.005), absence of atrial fibrillation (P=0.01), TAVI (P=0.007), and larger increase in aortic valve area after the procedure (P=0.01) were independently associated with better recovery of LVEF. CONCLUSION: In patients with severe aortic stenosis and depressed LV systolic function, TAVI is associated with better LVEF recovery compared with SAVR. TAVI may provide an interesting alternative to SAVR in patients with depressed LV systolic function considered at high surgical risk.

Linezolid plus rifampin as a salvage therapy in prosthetic joint infections treated without removing the implant.

The aim of this study is to describe our experience with linezolid plus rifampin as a salvage therapy in prosthetic joint infections (PJIs) when other antibiotic regimens failed or were not tolerated. A total of 161 patients with a documented prosthetic joint infection were diagnosed with a PJI and prospectively followed up from January 2000 to April 2007. Clinical characteristics, inflammatory markers, microbiological and radiological data, and antibiotic treatment were recorded. After a 2-year follow-up, patients were classified as cured when the prosthesis was not removed, symptoms of infection disappeared, and inflammatory parameters were within the normal range. Any other outcome was considered a failure. The mean age of the entire cohort (n = 161) was 67 years. Ninety-five episodes were on a knee prosthesis (59%), and 66 were on a hip prosthesis (41%). A total of 49 patients received linezolid plus rifampin: 45 due to failure of the previous antibiotic regimen and 4 due to an adverse event associated with the prior antibiotics. In no case was the implant removed. The mean (standard deviation) duration of treatment was 80.2 (29.7) days. The success rate after 24 months of follow-up was 69.4% (34/49 patients). Three patients developed thrombocytopenia and 3 developed anemia; however, it was not necessary to stop linezolid. Linezolid plus rifampin is an alternative salvage therapy when the implant is not removed.

Construction and content validation of a measurement tool to evaluate person-centered therapeutic relationships in physiotherapy services.

OBJECTIVES: This study sought to develop a tool for evaluating person-centered therapeutic relationships within physiotherapy services, and to examine the content validity of the same. METHODS: A mixed qualitative and quantitative study was performed in three distinct phases: 1) the items were generated based on a literature review and a content analysis of focus groups of patients and physiotherapists; 2) an e-Delphi survey process was performed based on three rounds to select and refine the proposed questionnaire; 3) two rounds of cognitive interviews were conducted to evaluate the comprehension of items, the clarity of language and the appropriateness and relevance of content. RESULTS: Thirty-one items were generated based on the seven domains identified after the analysis of four focus groups of physiotherapists and four patient focus groups. Nine experts participated in the e-Delphi survey. Fifty-five patients participated in the two rounds of the cognitive pre-tests. Participating patients were from public and private physical therapy services. Based on the participants' suggestions, four items were removed, and four were added, whereas 16 were reworded. CONCLUSIONS: The final tool comprised 31 items divided into seven domains. The response format was based on a 5-point Likert frequency scale. The response options ranged from "strongly agree" to "strongly disagree".

Fatal-stroke syndrome revealing fungal cerebral vasculitis due to Arthrographis kalrae in an immunocompetent patient.

We report an uncommon clinical presentation of a unique case of fatal invasive fungal cerebral vasculitis due to Arthrographis kalrae in a nonimmunocompromised host. The identity of the fungus was determined by morphological characteristics and by analysis of internal transcribed spacer 1 sequences and was confirmed by postmortem examination of the brain tissues. Establishing rapidly the link between the clinical syndromes and the fungal infection of the central nervous system is essential to improve the outcome. As our case has shown, it is more challenging to make a diagnosis of fungal infection when there are no risk factors of immunodeficiency and when the clinical presentation seems uncommon.

Clinical phase I and pharmacology study of gemcitabine (2', 2'-difluorodeoxycytidine) administered in a two-weekly schedule.

Gemcitabine (dFdC) was tested in a Phase I trial at 14 doses (40-5700 mg/m(2)), administered every 2 weeks as a (1/2) -h infusion to 52 patients with refractory solid cancer. Gemcitabine and its deaminated metabolite difluorodeoxyuridine (dFdU), measured with HPLC, reached plasma peak levels of 2-3 microM at 40 mg/m(2) which increased to 512 microM at 5700 mg/m(2). Gemcitabine was eliminated rapidly with a t(1/2) beta of 2.3-15.8 min in the 40-5700 mg/m(2) dose range, with one exception of 38 min at 4500 mg/m(2) . dFdU was still present at a plateau of +/- 20 microM from 4-24 h at doses >960 mg/m(2). Up to 3650 mg/m(2) linear pharmacokinetics were observed for gemcitabine, while those for dFdU were linear over the whole range. Gemcitabine clearance varied between 1.5-12.6 l/min and was 1.5-fold higher in males than in females (p= 0.024); its volume of distribution was 45.2-248 l. In lymphocytes peak levels of the active metabolite dFdCTP were 100-380 pmol/10( 6 )cells in the first course. Apparently a plateau was reached which was confirmed by incubation of white blood cells with increasing gemcitabine concentrations up to 500 microM, reaching a plateau of about 350 pmol/10(6 )cells; in contrast in cancer cells this concentration dependence did not exist and accumulation reached about 1590 pmol/10( 6 )cells. In tumors isolated from patients treated with gemcitabine dFdCTP reached about 70 pmol/g wet weight. Gemcitabine itself was eliminated only to a limited extent in the urine, but dFdU was eliminated almost completely in the urine in the first 24 h (51-92%). In conclusion, dFdC was rapidly eliminated in contrast to dFdU, which was present for at least 18 h, as well as dFdCTP in lymphocytes.

Bariatric surgery at the extremes of age.

The safety and efficacy of bariatric surgery in adolescents and especially in Medicare population have been challenged. Our aim was to determine short-term (30-day) and long-term outcomes of bariatric surgery in patients>or=60 years and or=60 years and 12 patientsor=60 years and all 12 adolescents returned the questionnaire (92%) at a mean of 5 years (range 1-19 years). For patients>or=60 years, 30-day mortality was 0.7%, serious morbidity delaying discharge was 14%, and 5-year mortality was 5%. At a mean of 5 years, body mass index (BMI in kg/m2) decreased from a mean (+/-SEM) of 46+/-1 to 33+/-1 with a 51% resolution of weight-related comorbidities and an 89% subjective overall satisfaction rate. In patients

Phase I and pharmacokinetic study of Taxotere (RP 56976; NSC 628503) given as a short intravenous infusion.

Taxotere (N-debenzoyl-N-tert-butoxycarbonyl-10-deacetyl Taxol; RP 56976; NSC 628503) is a semisynthetic analogue of Taxol. It is twice as active in inhibiting tubuline depolymerization and has a better in vivo activity on B16 melanoma, with responses in advanced colon 38 and PO3 adenocarcinoma. Sixty-five patients (49 women, 16 men), with a median age of 57 years, received 248 courses of Taxotere given as a 1-2-h i.v. infusion every 2 or 3 weeks. Ten distinct dose levels from 5 to 115 mg/m2 were studied. Dose-dependent, reversible neutropenia was the limiting toxicity. Delayed and cumulative skin reactions occurred beyond 70 mg/m2. Alopecia was observed in the majority of patients beyond 70 mg/m2. Four partial responses were achieved in patients with ovarian carcinoma, breast carcinoma, small cell lung cancer, and carcinoma with unknown primary. The pharmacokinetics of Taxotere, determined in 23 patients receiving 20 to 115 mg/m2, was linear. At the highest doses, the Taxotere plasma profile was typically triphasic, with a terminal half-life of 13.5 +/- 7.5 (SD) h, a plasma clearance of 21.1 +/- 5.3 liters/h/m2, and a distribution volume of 72 +/- 40 liters/m2. AUC correlated with the percentage decrease of neutrophils in a sigmoid Emax model. The renal excretion of unchanged Taxotere was very low (< 5% of the dose). The recommended dose for phase II trials with this schedule is 100 mg/m2 every 3 weeks.

Molecular quantification of bacteria from respiratory samples in patients with suspected ventilator-associated pneumonia.

Ventilator-associated pneumonia (VAP) is the most common infection in critically ill patients. Initial antibiotic therapy is often broad spectrum, which promotes antibiotic resistance so new techniques are under investigation to obtain early microbiological identification and quantification. This trial compares the performance of a new real-time quantitative molecular-based method with conventional culture in patients with suspected VAP. Patients with suspected VAP who were ventilated for at least 48 h were eligible. An endotracheal aspirate (ETA) and a bronchoalveolar lavage (BAL) were performed at each suspected VAP episode. Both samples were analysed by conventional culture and molecular analysis. For the latter, bacterial DNA was extracted from each sample and real-time PCR were run. In all, 120 patients were finally included; 76% (91) were men; median age was 65 years, and clinical pulmonary infection score was ≥6 for 73.5% (86) of patients. A total of 120 BAL and 103 ETA could be processed and culture results above the agreed threshold were obtained for 75.0% (90/120) of BAL and 60.2% (62/103) of ETA. The main isolated bacteria were Staphylococcus aureus, Pseudomonas aeruginosa and Haemophilus influenzae. Performance was 89.2% (83.2%-93.6%) sensitivity and 97.1% (96.1%-97.9%) specificity for BAL samples and 71.8% (61.0%-81.0%) sensitivity and 96.6% (95.4%-97.5%) specificity for ETA samples when the molecular biology method was compared with conventional culture method (chosen as reference standard). This new molecular method can provide reliable quantitative microbiological data and is highly specific with good sensitivity for common pathogens involved in VAP.

Neurally adjusted ventilatory assist as an alternative to pressure support ventilation in adults: a French multicentre randomized trial.

PURPOSE: Neurally adjusted ventilatory assist (NAVA) is a ventilatory mode that tailors the level of assistance delivered by the ventilator to the electromyographic activity of the diaphragm. The objective of this study was to compare NAVA and pressure support ventilation (PSV) in the early phase of weaning from mechanical ventilation. METHODS: A multicentre randomized controlled trial of 128 intubated adults recovering from acute respiratory failure was conducted in 11 intensive care units. Patients were randomly assigned to NAVA or PSV. The primary outcome was the probability of remaining in a partial ventilatory mode (either NAVA or PSV) throughout the first 48 h without any return to assist-control ventilation. Secondary outcomes included asynchrony index, ventilator-free days and mortality. RESULTS: In the NAVA and PSV groups respectively, the proportion of patients remaining in partial ventilatory mode throughout the first 48 h was 67.2 vs. 63.3 % (P = 0.66), the asynchrony index was 14.7 vs. 26.7 % (P < 0.001), the ventilator-free days at day 7 were 1.0 day [1.0-4.0] vs. 0.0 days [0.0-1.0] (P < 0.01), the ventilator-free days at day 28 were 21 days [4-25] vs. 17 days [0-23] (P = 0.12), the day-28 mortality rate was 15.0 vs. 22.7 % (P = 0.21) and the rate of use of post-extubation noninvasive mechanical ventilation was 43.5 vs. 66.6 % (P < 0.01). CONCLUSIONS: NAVA is safe and feasible over a prolonged period of time but does not increase the probability of remaining in a partial ventilatory mode. However, NAVA decreases patient-ventilator asynchrony and is associated with less frequent application of post-extubation noninvasive mechanical ventilation. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02018666.

Intensification of adjuvant chemotherapy: 5-year results of a randomized trial comparing conventional doxorubicin and cyclophosphamide with high-dose mitoxantrone and cyclophosphamide with filgrastim in operable breast cancer with 10 or more involved axillary nodes.

PURPOSE: To determine whether intensifying the dose of adjuvant chemotherapy improves the outcome of women with primary breast cancer and 10 or more involved axillary nodes. PATIENTS AND METHODS: Patients (n = 150) were randomized to receive either four cycles of standard doxorubicin 60 mg/m(2) plus cyclophosphamide 600 mg/m(2) every 3 weeks (arm A) or four courses of intensified mitoxantrone 23 mg/m(2) plus cyclophosphamide 600 mg/m(2), with filgrastim 5 g/kg/d from days 2 to 15, every 3 weeks (arm B). Disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS) were determined using life-table estimates. RESULTS: There were no significant differences in DFS (P =.44), DDFS (P =.67), or OS (P =.99) between the two groups at 5 years; DDFS was 45% (arm A) versus 50% (arm B), and DFS was 41% versus 49%, respectively. Five-year survival was similar in both arms (61% v 60%, respectively). Failure to note an intergroup difference in outcome was unrelated to relative dose-intensity. Analysis of patients with 15 or more positive nodes revealed a significant difference in 5-year DDFS (19% v 49% in arm B; P =.01). Toxicity was generally mild in both groups, with no toxic death. The incidence of febrile neutropenia was low (0.3% v 3%). Alopecia was less frequent in arm B (P <.001). CONCLUSION: This randomized trial confirms the feasibility of administering mitoxantrone 23 mg/m(2) with cyclophosphamide and filgrastim. Although there was no significant difference between conventional and intensified arms at 5 years, according to subgroup analysis, intensified treatment may decrease the risk of relapse in patients with 15 or more positive nodes compared with doxorubicin an cyclophosphamide.

Randomized phase III trial of edatrexate versus methotrexate in patients with metastatic and/or recurrent squamous cell carcinoma of the head and neck: a European Organization for Research and Treatment of Cancer Head and Neck Cancer Cooperative Group study.

PURPOSE: To compared the response rates and the toxicity of the new antifolate edatrexate (EDX) with that of methotrexate (MTX) in a randomized trial in patients with metastatic or recurrent squamous cell cancer of the head and neck (SCC) and to compare the durations of response and survival. PATIENTS AND METHODS: Two hundred seventy-three patients with SCC were randomized to receive either EDX or MTX as a weekly intravenous (IV) bolus injection. Doses of EDX were initially 80 mg/m2/wk, but because of the toxicity, this was later reduced to 70 mg/m2/wk. MTX was administered at a dose of 40 mg/m2/wk throughout. In both arms, two dose increments of 10% were scheduled in case of no toxicity. RESULTS: Of 264 eligible patients, 131 were treated with EDX and 133 with MTX. There were five treatment-related deaths: four on EDX and one on MTX. Overall, toxicity was similar in both arms; however, stomatitis, skin toxicity, and hair loss were more pronounced on the EDX arm. The overall response rate was 21% (six complete responses [CRs] and 21 partial responses [PRs]) for EDX and 16% (nine CRs and 12 PRs) for MTX (P = .392). Responses were mainly seen in patients with locoregional disease. Tumors that originated from the hypopharynx responded poorly in comparison to tumors from other sites. The median duration of response was 6.1 months for EDX and 6.4 months for MTX (log-rank P = .262). There was no difference in overall or progression-free survival. The median survival duration was 6 months on both treatment groups. CONCLUSIONS: Both EDX and MTX are moderately active against SCC. In this large phase III study, response rates, time to treatment failure, and overall survival appeared to be similar for both antifolates. However, EDX had more side effects than MTX and therefore cannot be recommended for routine palliative treatment of patients with SCC.

Granulocyte-macrophage colony-stimulating factor allows safe escalation of dose-intensity of chemotherapy in metastatic adult soft tissue sarcomas: a study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group.

PURPOSE: This study was designed to test the feasibility of administering doxorubicin at an optimal dose-intensity (> 70 mg/m2 per 21 days) in combination with ifosfamide under recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) cover in patients with metastatic soft tissue sarcomas. PATIENTS AND METHODS: One hundred four eligible patients (of 111 entered) in 16 centers received doxorubicin 75 mg/m2 plus ifosfamide 5 g/m2 every 3 weeks for up to seven cycles. rhGM-CSF (250 micrograms/m2) was administered once or twice daily by subcutaneous injections for up to 14 days between cycles of chemotherapy. RESULTS: Full protocol dose-intensity of chemotherapy was administered to the majority of patients with only 15 of 293 cycles being complicated by febrile episodes that required hospitalization. There were two treatment-related deaths: one from septicemia and one from cardiac failure. The main toxicities attributed to rhGM-CSF were pruritus and rash. A 45% response rate (10% complete remission [CR]) was seen, with a median response duration of 9 months and median survival of 15 months. CONCLUSION: This high-dose regimen of chemotherapy was feasible under rhGM-CSF cover and produced a higher response rate and median survival than previously seen by the European Organization for Research and Treatment of Cancer (EORTC) Soft Tissue Sarcoma Group. A randomized phase III study is now underway comparing this regimen with conventional-dose doxorubicin/ifosfamide to test the dose-response relationship.

Alkaline phosphatase and bone calcium parameters.

Effects of cadmium, an alkaline phosphatase inhibitor, on the calcium content of rat bone were investigated in vivo by a radioisotopic method. Disturbance of bone metabolism is observed in both the superficial (delta) and slow exchanges (Ve), which are also significantly decreased. The crystallized calcium bone compartment (E) is also strongly affected. It appears that changes in the superficial calcium exchanges cause the observed decrease in the crystallized calcium mass. The slowing of osteogenesis is confirmed by the decrease of serum alkaline phosphatase activity. A statistical examination of the correlation coefficient reveals a close link (P less than 0.01) between serum alkaline phosphatase activity and the influx of superficial calcium (Vo+) and, as a result, the crystallized bone calcium parameters. These results show that cadmium can be used to study the relationship between alkaline phosphatase and calcification. The present observations allow us to consider the possibility that alkaline phosphatase may play a role in determining the calcium content of the crystallized phases in deep bone through its action on the tissue surface.

Breast cancer: chemotherapy in the treatment of advanced disease.

Chemotherapy in patients with advanced breast cancer remains palliative. Although the majority of patients will experience an initial response or stabilisation of the disease, the survival is only modestly improved. The search for new drugs and more effective combinations must therefore continue. High-dose chemotherapy with or without autologous bone marrow transplant (ABMT) is an enthusiastic perspective of progress but the available data do not permit conclusions about the effectiveness of high-dose therapy compared with conventional treatment.

Oral ondansetron in the prevention of chemotherapy-induced emesis in breast cancer patients. French Ondansetron Study Group.

A multicentre randomised, double-blind parallel group study has been carried out in order to confirm the antiemetic efficacy of orally administered ondansetron. A total of 259 chemotherapy-naive breast cancer patients treated with a 5-fluorouracil, doxorubicin, cyclophosphamide (FAC) or 5-fluorouracil, epirubicin, cyclophosphamide (FEC) regimen were randomly assigned to ondansetron (OND) 8 mg tablet or alizapride (ALI) 150 mg intravenous (i.v.) injection, prior to chemotherapy. These treatments were then followed by OND 8 mg tablet or ALI 50 mg tablet, respectively, 8 to 12 h later. Oral treatment was then continued twice a day over 3-5 days. The number of emetic episodes (EE = vomits+retches) and the grade of nausea were recorded; quality of life was assessed using a specific questionnaire. Of the 254 patients analysed for efficacy, complete or major control (success: 0-2 EE) over the 24 h following start of chemotherapy was obtained in 81% of the OND group compared with 47% of the ALI group (P < 0.001). A significant difference in favour of OND was also observed for nausea (P < 0.0001). For on days 2 to 4 emesis, the arm containing OND was superior to that with ALI (worst day analysis): 77% success versus 63% (P < 0.002). The overall control of emesis (from day 1 to day 4) was better with OND (64% patients success in the OND group versus 41% in the ALI group; P < 0.0001). At the end of the study the number of patients wishing to receive the same anti-emetic treatment for their next course was 83% for OND compared with 54% for ALI (P < 0.0001). In terms of quality of life in relation to emesis phenomena, OND was significantly superior to ALI (P = 0.04). Both treatments were well tolerated. In the prevention of the prolonged emesis induced by FAC/FEC-type emetogenic chemotherapy, orally administered OND was superior to ALI, given as an i.v. injection and followed by tablets.