Epirubicin dose and sequential hormonal therapy-Mature results of the HMFEC randomised phase III trial in premenopausal patients with node positive early breast cancer.

Background The hormonal manipulation 5-Fluoro-uracil Epirubicin Cyclophosphamide (HMFEC) trial was developed at a time of uncertainty around the dose intensity of chemotherapy given to premenopausal patients with node positive breast cancer and to the benefits of tailored endocrine therapy in such patients.Patients and methods HMFEC was a multi-centre, phase III, open label, randomised controlled trial with a 2 × 2 factorial design. Eligible patients were premenopausal with node positive early breast cancer; significant cardiac disease or uncontrolled hypertension was exclusion criterion. Patients were allocated to receive either eight cycles of FE50C or FE75C (given 3 weekly) with or without hormone manipulation (HM; tamoxifen or luteinising hormone releasing hormone (LHRH) agonists according to residual hormone levels at the end of chemotherapy) irrespective of ER status. The primary end-point was disease free survival (DFS). Principal analyses were by intention to treat (ITT); however, to reflect contemporary practice, subgroup analyses according to ER status were also conducted. The mature follow-up now available from this modest sized trial enables presentation of definitive results.Results Between 1992 and 2000 a total of 785 patients were randomised into the HMFEC trial (203 FE50C-HM, 191 FE50C+HM, 198 FE75C-HM, 193 FE75C+HM). At a median follow-up of 7.4 years, 245 DFS events have been reported (92 ER-, 153 ER+/unknown). The effects on DFS were not statistically significantly different according to epirubicin dose (hazard ratio [HR] = 0.82, 95% confidence interval [CI] 0.63-1.06; p = 0.13 FE75C versus FE50C); however, FE75C appeared to induce more alopecia and neutropenia. No statistically significant evidence was observed to support an improvement in DFS in patients allocated HM either overall (HR = 0.88, 95% CI 0.68-1.13; p = 0.32) or in patients with ER+/unknown disease (HR = 0.85, 95% CI 0.62-1.17; p = 0.32) although effect sizes are consistent with worthwhile clinical effects. Overall, there was no evidence of a difference in survival between any of the four treatment groups of the trial.Conclusion Higher doses of epirubicin cause more adverse events in the absence of clear improvement in overall survival. Endocrine therapy with either tamoxifen or goserelin provided no significant added benefit to cytotoxic chemotherapy in this group of patients.Trial registration number ISRCTN98335268

Use of antibiotic spacers for knee endoprosthesis infections treatment

OBJCTIVE: The aim of this study is to evaluate the use of cement spacers impregnated with antibiotics for the treatment of infections in the nonconventional endoprostheses of the knee. METHODOLOGY: We have treated seven patients since 2004 (of which six were submitted to surgery in our service and one patient had been submitted to a primary tumor surgery in another removal service) with deep infection in knee tumor prosthesis. All patients were submitted to endoprosthesis removal and reconstructed with antibiotic cement spacer. All patients were monitored both clinically and by lab tests as for monitoring the evolution, being considered able for reviews after 6 (six) months without infections signs. RESULTS: We have noted a small predominance of infectious processes on the prosthesis inserted on proximal tibia as compared with distal femur (57.1% x 42.9%). The mean follow-up time of patients was 68.2 months. During the follow up, one patient died as a result of the root disease. Six patients out of seven were regarded as cured and one persisted with infection signs and symptoms. CONCLUSION: The results obtained up to date have motivated us to continue using this method of treatment.OBJETIVO: O objetivo do estudo é avaliar a utilização dos espaçadores de cimento acrílico com antibiótico no tratamento das infecções em endopróteses não convencionais de joelho. MÉTODO: Desde de 2004 foram tratados sete pacientes (seis pacientes operados no nosso serviço e um paciente que havia sido submetido a cirurgia primária do tumor em outro serviço) com infecção peri-endoprótese não convencional de joelho. Todos pacientes foram submetidos a retirada da endoprótese e reconstrução com espaçador com cimento acrílico com antibiótico. Todos os pacientes foram monitorados clínica e laboratorialmente quanto ao controle da evolução, sendo considerados aptos para a revisão e recolocação de endoprótese após 06 (seis) meses sem sinais infecciosos RESULTADOS: Notamos um discreto predomínio do do processo infeccioso nas próteses realizadas na tíbia proximal em comparação com o fêmur distal (57,1% x 42,9%). O seguimento médio dos pacientes foi 68,2 meses. Durante o seguimento, um paciente faleceu devido a doença de base. Dos sete pacientes, 6 foram considerados curados e um persistiu com sinais e sintomas de infecção. CONCLUSÃO: Os resultados obtidos até o momento tem motivado a continuidade deste método de tratamento.Universidade Federal de São Paulo (UNIFESP) Escola Paulista de Medicina Departamento de Ortopedia e TraumatologiaUNIFESP, EPM, Depto. de Ortopedia e TraumatologiaSciEL

Ubiquitous molecular substrates for associative learning and activity-dependent neuronal facilitation.

Recent evidence suggests that many of the molecular cascades and substrates that contribute to learning-related forms of neuronal plasticity may be conserved across ostensibly disparate model systems. Notably, the facilitation of neuronal excitability and synaptic transmission that contribute to associative learning in Aplysia and Hermissenda, as well as associative LTP in hippocampal CA1 cells, all require (or are enhanced by) the convergence of a transient elevation in intracellular Ca2+ with transmitter binding to metabotropic cell-surface receptors. This temporal convergence of Ca2+ and G-protein-stimulated second-messenger cascades synergistically stimulates several classes of serine/threonine protein kinases, which in turn modulate receptor function or cell excitability through the phosphorylation of ion channels. We present a summary of the biophysical and molecular constituents of neuronal and synaptic facilitation in each of these three model systems. Although specific components of the underlying molecular cascades differ across these three systems, fundamental aspects of these cascades are widely conserved, leading to the conclusion that the conceptual semblance of these superficially disparate systems is far greater than is generally acknowledged. We suggest that the elucidation of mechanistic similarities between different systems will ultimately fulfill the goal of the model systems approach, that is, the description of critical and ubiquitous features of neuronal and synaptic events that contribute to memory induction

Prolonged rote learning produces delayed memory facilitation and metabolic changes in the hippocampus of the ageing human brain

Background: Repeated rehearsal is one method by which verbal material may be transferred from short- to long-term memory. We hypothesised that extended engagement of memory structures through prolonged rehearsal would result in enhanced efficacy of recall and also of brain structures implicated in new learning. Twenty-four normal participants aged 55-70 (mean = 60.1) engaged in six weeks of rote learning, during which they learned 500 words per week every week (prose, poetry etc.). An extensive battery of memory tests was administered on three occasions, each six weeks apart. In addition, proton magnetic resonance spectroscopy (H-1-MRS) was used to measure metabolite levels in seven voxels of interest (VOIs) (including hippocampus) before and after learning.Results: Results indicate a facilitation of new learning that was evident six weeks after rote learning ceased. This facilitation occurred for verbal/episodic material only, and was mirrored by a metabolic change in left posterior hippocampus, specifically an increase in NAA/(Cr+Cho) ratio.Conclusion: Results suggest that repeated activation of memory structures facilitates anamnesis and may promote neuronal plasticity in the ageing brain, and that compliance is a key factor in such facilitation as the effect was confined to those who engaged fully with the training