Phase II study of imatinib in patients with recurrent gliomas of various histologies: a European Organisation for Research and Treatment of Cancer Brain Tumor Group Study.

PURPOSE: To evaluate the safety and the efficacy of imatinib in recurrent malignant gliomas. PATIENTS: AND METHODS: This was a single-arm, phase II study. Eligible patients had recurrent glioma after prior radiotherapy with an enhancing lesion on magnetic resonance imaging. Three different histologic groups were studied: glioblastomas (GBM), pure/mixed (anaplastic) oligodendrogliomas (OD), and low-grade or anaplastic astrocytomas (A). Imatinib was started at a dose of 600 mg/d with dose escalation to 800 mg in case of no toxicity; during the trial this dose was increased to 800 mg/d with escalation to 1,000 mg/d. Trial design was one-stage Fleming; both an objective response and 6 months of progression-free survival (PFS) were considered a successful outcome to treatment. RESULTS: A total of 112 patients (51 patients with GBM, 25 patients with A, and 36 patients with OD) were enrolled. Imatinib was in general well tolerated. The median number of cycles was 2.0 (range, 1 to 43 cycles). Five patients had an objective partial response, including three patients with GBM; all had 6 months of PFS. The 6-month PFS rate was 16% (95% CI, 8.0% to 34.0%) in GBM, 4.0% (95% CI, 0.3% to 15.0%) in OD, and 9% (95% CI, 2.0% to 25.0%) in A. The exposure to imatinib was significantly lower in patients using enzyme-inducing antiepileptic drugs. The presence of ABCG2 point mutations were not correlated with pharmacokinetic findings. No somatic activating mutations of KIT or platelet-derived growth factor receptor-A or -B were found. CONCLUSION: In the dose range of 600 to 1,000 mg/d, single-agent imatinib is well tolerated but has limited antitumor activity in patients with recurrent gliomas.

Doublecortin-positive cells in the adult primate cerebral cortex and possible role in brain plasticity and development.

We have demonstrated that cortical cell autografts might be a useful therapy in two monkey models of neurological disease: motor cortex lesion and Parkinson's disease. However, the origin of the useful transplanted cells obtained from cortical biopsies is not clear. In this report we describe the expression of doublecortin (DCX) in these cells based on reverse-transcription polymerase chain reaction (RT-PCR) and immunodetection in the adult primate cortex and cell cultures. The results showed that DCX-positive cells were present in the whole primate cerebral cortex and also expressed glial and/or neuronal markers such as glial fibrillary protein (GFAP) or neuronal nuclei (NeuN). We also demonstrated that only DCX/GFAP positive cells were able to proliferate and originate progenitor cells in vitro. We hypothesize that these DCX-positive cells in vivo have a role in cortical plasticity and brain reaction to injury. Moreover, in vitro these DCX-positive cells have the potential to reacquire progenitor characteristics that confirm their potential for brain repair.

Application of the 2008 definitions for invasive fungal diseases to the trial comparing voriconazole versus amphotericin B for therapy of invasive aspergillosis: a collaborative study of the Mycoses Study Group (MSG 05) and the European Organization for Research and Treatment of Cancer Infectious Diseases Group.

BACKGROUND: Strict definition of invasive aspergillosis (IA) cases is required to allow precise conclusions about the efficacy of antifungal therapy. The Global Comparative Aspergillus Study (GCAS) compared voriconazole to amphotericin B (AmB) deoxycholate for the primary therapy of IA. Because predefined definitions used for this trial were substantially different from the consensus definitions proposed by the European Organization for Research and Treatment of Cancer/Mycoses Study Group in 2008, we recategorized the 379 episodes of the GCAS according to the later definitions. METHODS: The objectives were to assess the impact of the current definitions on the classification of the episodes and to provide comparative efficacy for probable/proven and possible IA in patients treated with either voriconazole or AmB. In addition to original data, we integrated the results of baseline galactomannan serum levels obtained from 249 (65.7%) frozen samples. The original response assessment was accepted unchanged. RESULTS: Recategorization allowed 59 proven, 178 probable, and 106 possible IA cases to be identified. A higher favorable 12-week response rate was obtained with voriconazole (54.7%) than with AmB (29.9%) (P < .0001). Survival was higher for voriconazole for mycologically documented (probable/proven) IA (70.2%) than with AmB (54.9%) (P = .010). Higher response rates were obtained in possible IA treated with voriconazole vs AmB with the same magnitude of difference (26.2%; 95% confidence interval [CI], 7.2%-45.3%) as in mycologically documented episodes (24.3%; 95% CI, 11.9%-36.7%), suggesting that possible cases are true IA. CONCLUSIONS: Recategorization resulted in a better identification of the episodes and confirmed the higher efficacy of voriconazole over AmB deoxycholate in mycologically documented IA.

Ethics and creative accounting: Some empirical evidence on accounting for intangibles in Spain

Recent research shows that financial reports are losing relevance. Mainly thisis due to the growing strategic importance of intangible assets in theperformance of a company. A possible solution is to modify accounting standardsso that statements include more self-generated intangible assets, taking intoaccount with their inherent risk and difficulty of valuation. We surveyed loanofficers who were asked to assess the credit-worthiness of a hypotheticalcompany. The only information given was a simplified version of financialstatements. Half the group got statements where research and development costshad been capitalized. The other half got statements in which these costs hadbeen treated as an expense. The findings show that capitalization wassignificantly more likely to attract a positive response to a loan request. Thepaper raises the question of whether accounting for intangibles might providemanagers with one more creative accounting technique and, in consequence, itsethical implications.

R&D cooperation and spillovers: Some empirical evidence

This paper provides some first empirical evidence on the relationshipbetween R&D spillovers and R&D cooperation. The results suggest disentangling different aspects of know-how flows. Firms which rate incoming spillovers more importantly and who can limit outgoing spillovers by a more effective protection of know-how, are more likely to cooperate in R&D. Our analysis also finds that cooperating firms have higher incoming spillovers and higher protection of know-how, indicating that cooperation may serve as a vehicle to manage information flows. Our results thus suggest that on the one hand the information sharing and coordination aspects of incoming spillovers are crucial in understanding cooperation, while on the other hand, protection against outgoing spillovers is important for firms to engage in stable cooperative agreements by reducing free-rider problems. Distinguishing different types of cooperative partners reveals that while managing outgoing spillovers is less critical in alliances with non-commercial research partners than between vertically related partners, the incoming spillovers seem to be more critical in understanding the former type of R&D cooperation.

Complementarity between technology make and buy in innovation strategies: Evidence from Belgiam manufacturing firms

This paper characterizes the innovation strategy of manufacturing firms andexamines the relation between the innovation strategy and importantindustry-, firm- and innovation-specific characteristics using Belgiandata from the Eurostat Community Innovation Survey. In addition to importantsize effects explaining innovation, we find that high perceived risks andcosts and low appropriability of innovations do not discourage innovation,but rather determine how the innovation sourcing strategy is chosen. Withrespect to the determinants of the decision of the innovative firm toproduce technology itself (Make) or to source technology externally (Buy),we find that small firms are more likely restrict their innovation strategyto an exclusive make or buy strategy, while large firms are more likely tocombine both internal and external knowledge acquisition in their innovationstrategy. An interesting result that highlights the complementary nature ofthe Make and Buy decisions, is that, controlled for firm size, companies forwhich internal information is an important source for innovation are morelikely to combine internal and external sources of technology. We find thisto be evidence of the fact that in-house R&D generates the necessaryabsorptive capacity to profit from external knowledge acquisition. Also theeffectiveness of different mechanisms to appropriate the benefits ofinnovations and the internal organizational resistance against change areimportant determinants of the firm's technology sourcing strategy.

Grinder's Group Mastery Theory : scientific research and its application to classroom teaching

Estudi centrat en el paper de la comunicació no verbal com a eina docent per a la gestió de l’aula, prenent com a referència el model de comunicació de Michael Grinder (Pentimento), basat en la Programació Neuro-lingüística (PNL). Aquest model s’analitza i es compara amb altres models i estudis sobre la comunicació no verbal, per establir-ne similituds i diferències. Per tal d’avaluar l’eficàcia de les tècniques de gestió de l’aula a través de la comunicació no verbal proposades per Grinder en un context educatiu real, s’inclouen i s’analitzen enregistraments de la implementació de diferents tècniques en un institut de secundària de Catalunya. Tota la informació recollida i analitzada permet valorar i ressaltar com és de significatiu tot allò que s’expressa més enllà del llenguatge, i per tant, com són d’importants i d’útils les habilitats comunicatives d’un professor en la seva tasca d’ensenyar.

Sagopilone (ZK-EPO, ZK 219477) for recurrent glioblastoma. A phase II multicenter trial by the European Organisation for Research and Treatment of Cancer (EORTC) Brain Tumor Group.

Background: Sagopilone (ZK 219477), a lipophylic and synthetic analog of epothilone B, that crosses the blood-brain barrier has demonstrated preclinical activity in glioma models.Patients and methods: Patients with first recurrence/progression of glioblastoma were eligible for this early phase II and pharmacokinetic study exploring single-agent sagopilone (16 mg/m(2) over 3 h every 21 days). Primary end point was a composite of either tumor response or being alive and progression free at 6 months. Overall survival, toxicity and safety and pharmacokinetics were secondary end points.Results: Thirty-eight (evaluable 37) patients were included. Treatment was well tolerated, and neuropathy occurred in 46% patients [mild (grade 1) : 32%]. No objective responses were seen. The progression-free survival (PFS) rate at 6 months was 6.7% [95% confidence interval (CI) 1.3-18.7], the median PFS was just over 6 weeks, and the median overall survival was 7.6 months (95% CI 5.3-12.3), with a 1-year survival rate of 31.6% (95% CI 17.7-46.4). Maximum plasma concentrations were reached at the end of the 3-h infusion, with rapid declines within 30 min after termination.Conclusions: No evidence of relevant clinical antitumor activity against recurrent glioblastoma could be detected. Sagopilone was well tolerated, and moderate-to-severe peripheral neuropathy was observed in despite prolonged administration.

Vacuole membrane protein 1 is an endoplasmic reticulum protein required for organelle biogenesis, protein secretion, and development

Vacuole membrane protein 1 (Vmp1) is membrane protein of unknown molecular function that has been associated with pancreatitis and cancer. The social amoeba Dictyostelium discoideum has a vmp1-related gene that we identified previously in a functional genomic study. Loss-of-function of this gene leads to a severe phenotype that compromises Dictyostelium growth and development. The expression of mammalian Vmp1 in a vmp1 Dictyostelium mutant complemented the phenotype, suggesting a functional conservation of the protein among evolutionarily distant species and highlights Dictyostelium as a valid experimental system to address the function of this gene. Dictyostelium Vmp1 is an endoplasmic reticulum protein necessary for the integrity of this organelle. Cells deficient in Vmp1 display pleiotropic defects in the secretory pathway and organelle biogenesis. The contractile vacuole, which is necessary to survive under hypoosmotic conditions, is not functional in the mutant. The structure of the Golgi apparatus, the function of the endocytic pathway and conventional protein secretion are also affected in these cells. Transmission electron microscopy of vmp1 cells showed the accumulation of autophagic features that suggests a role of Vmp1 in macroautophagy. In addition to these defects observed at the vegetative stage, the onset of multicellular development and early developmental gene expression are also compromised.

Editorial research and the publication process in biomedicine and health: Report from the Esteve Foundation Discussion Group, December 2012.

Despite the fact that there are more than twenty thousand biomedical journals in the world, research into the work of editors and publication process in biomedical and health care journals is rare. In December 2012, the Esteve Foundation, a non-profit scientific institution that fosters progress in pharmacotherapy by means of scientific communication and discussion organized a discussion group of 7 editors and/or experts in peer review biomedical publishing. They presented findings of past editorial research, discussed the lack of competitive funding schemes and specialized journals for dissemination of editorial research, and reported on the great diversity of misconduct and conflict of interest policies, as well as adherence to reporting guidelines. Furthermore, they reported on the reluctance of editors to investigate allegations of misconduct or increase the level of data sharing in health research. In the end, they concluded that if editors are to remain gatekeepers of scientific knowledge they should reaffirm their focus on the integrity of the scientific record and completeness of the data they publish. Additionally, more research should be undertaken to understand why many journals are not adhering to editorial standards, and what obstacles editors face when engaging in editorial research.