Enfermagem baseada na evidência: Atitudes e barreiras em contexto de hemodiálise / Attitudes and barriers to evidence-based nursing in hemodialysis / Enfermería basada en la evidencia: Actitudes y barreras en los centros de hemodiálisis

Resumo Enquadramento: A Prática Baseada na Evidência (PBE) tem impacto positivo na segurança e na qualidade dos cuidados à pessoa com doença renal crónica (DRC) em hemodiálise (HD). Objetivo: Avaliar as atitudes e barreiras à PBE dos enfermeiros nos cuidados prestados à pessoa com DRC em HD. Metodologia: Estudo transversal, exploratório e descritivo. Foi aplicada a versão portuguesa do Questionário de Atitudes e Barreiras face à implementação da Prática Baseada na Evidência (QABPBE-26) a 147 enfermeiros a exercer em unidades de HD. Resultados: Os enfermeiros apresentam atitudes promotoras de PBE, reconhecendo aptidão na pesquisa (76,1%) e na avaliação dos artigos de investigação (78,2%), o que se relaciona com a categoria profissional (p = 0,001; r = -0,278) e habilitações académicas (p = 0,02; r = -0,191). As principais barreiras identificadas relacionam-se com limitações de tempo (66%), falta de formação (68,6%) e falta de partilha de conhecimento por peritos (72,1%). Conclusão: Os enfermeiros reconhecem que a PBE contribui para o desenvolvimento profissional, demonstram atitudes promotoras e identificam barreiras associadas.

Abstract Background: Evidence-based practice (EBP) positively impacts the safety and quality of care for people with chronic kidney disease (CKD) on hemodialysis (HD). Objective: To assess nurses' attitudes toward EBP and the barriers they face in implementing it when caring for people with CKD on HD. Methodology: A cross-sectional, exploratory, and descriptive study was conducted and applied the Portuguese version of the Attitudes to Evidence-Based Practice questionnaire to 147 nurses working in HD. Results: Nurses demonstrated attitudes promoting EBP and perceived aptitude for searching (76.1%) and evaluating evidence (78.2%), which were related to professional group (p = .001; r = -0.278) and academic qualifications (p = .02; r = -0.191). Lack of time (66%), lack of education (68.6%), and lack of experts sharing information (72.1%) were reported as the main barriers. Conclusion: Nurses recognize that EBP contributes to professional development, demonstrate positive attitudes toward EBP, and identify the associated barriers.

Resumen Marco contextual: La práctica basada en la evidencia (PBE) tiene un impacto positivo en la seguridad y la calidad de la atención a las personas con insuficiencia renal crónica (DRC, en portugués) en hemodiálisis (HD). Objetivo: Evaluar las actitudes y barreras del personal de enfermería hacia la PBE en la atención a personas con DRC en HD. Metodología: Estudio transversal, exploratorio y descriptivo. Se aplicó la versión portuguesa del Cuestionario de Actitudes y Barreras para la Implementación de la Práctica Basada en la Evidencia (QABPBE-26) a 147 enfermeros que ejercían en unidades de HD. Resultados: Los enfermeros muestran actitudes que promueven la PBE, reconocen aptitud para la investigación (76,1%) y para la evaluación de artículos de investigación (78,2%), lo que se relaciona con la categoría profesional (p = 0,001; r = -0,278) y las cualificaciones académicas (p = 0,02; r = -0,191). Los principales obstáculos detectados están relacionados con la falta de tiempo (66%), la falta de formación (68,6%) y la falta de intercambio de conocimientos entre expertos (72,1%). Conclusión: Los enfermeros reconocen que la PBE contribuye al desarrollo profesional, demuestran actitudes de apoyo e identifican las barreras asociadas.

Development of a buccal in vitro permeation method - exploring aQbD implementation.

The buccal mucosa is arising within the pharmaceutical landscape as an attractive option for local and systemic drug delivery, mostly due to its high vascularization, inherent permeability and robustness. Still, one of the major challenges in bringing oromucosal preparations to market remains the accurate evaluation of permeability. During pre-clinical drug development, in vitro permeation assessment is essential, and methodologies, based on the selection of a proper membrane in a diffusion cell, have become appealing alternatives to the conventional cell-based models. The development of such methods is being constrained by the number of variables - related to study conditions, setup and formulation - that need to be optimized to accurately estimate buccal permeation. The gap of knowledge over the mentioned variables may lead to long costly developments and poorly accurate methods, especially if the empirical analytical approach is used. In this paper, a systematic risk-based analytical quality by design approach was applied to the development of a buccal in vitro permeation method, ensuring that all sources of variability affecting permeation process were identified, explained and managed by appropriate measures. Researchers are guided through a step by step model, successfully demonstrating with experimental data the impact of critical variables on method's performance.

Oromucosal products - Market landscape and innovative technologies: A review.

Strategies that rely on oral mucosal administration have increased in the last decade and oromucosal products are paving the way to overcome specific challenges, namely improving drug bioavailability when compared with the conventional oral route, due to a reduction of the hepatic first-pass metabolism and pre-systemic degradation. Overall, the advantages of these products make oromucosal route of administration attractive for the development of value-added medicines, which can address more properly the unmet medical needs of specific patients. Generally, such products have an easy and convenient administration since they do not require water for ingestion, which may be particularly relevant for geriatric and pediatric groups, or non-cooperative patients. Usually, the development of these products aims to provide a faster onset of action, critical for acute or emergency treatments. Although oriented to achieve better therapeutic outcomes, today's drug development is primarily focused on patient-centered care, meaning that patients' specific characteristics/needs are an important driving force behind product-development efforts. In accordance, pharmaceutical innovation can rely not only on new drug substances but also on re-formulation of already approved ones or alternative routes of administration, enhancing patient convenience, treatment efficacy and/or safety. Throughout this review, the oromucosal drug products, approved in the last decade, and a retrospective analysis of their critical quality attributes and specifications will be described. Furthermore, trends and opportunities of the latest technologies in this field, as well as the number of ongoing clinical studies, will be presented and discussed.

Guided Bone Regeneration in the Edentulous Atrophic Maxilla Using Deproteinized Bovine Bone Mineral (DBBM) Combined with Platelet-Rich Fibrin (PRF)-A Prospective Study.

BACKGROUND: Bone regeneration procedures represent a major challenge in oral surgery. This study aimed to evaluate a composite PRF/particulate xenograft in guided bone regeneration. METHODS: Edentulous patients with horizontal ridge deficiencies in the anterior maxilla and candidates to an immediate-loading full-arch rehabilitation were included. Horizontal linear measurements indicating bone gain were assessed from computer beam computer tomography (CBCT) scans obtained at pre-surgery, post-surgery, and the 12-month follow-up. Mean bone values were presented as mean ± 95% CI. Non-parametric tests were used as appropriate, and the effect size was calculated with Cohen's d repeated measures. RESULTS: Eighteen patients were rehabilitated with 72 implants. The mean horizontal bone width was 4.47 [4.13-4.80] mm pre-surgically, 9.25 [8.76-9.75] mm post-surgically, and 7.71 [7.28-8.14] mm 12 months after. CONCLUSIONS: PRF associated with a xenograft seems to promote an effective horizontal bone gain. Randomized clinical trials are needed to confirm the benefits of this surgical approach.

Survival Rate of 1008 Short Dental Implants with 21 Months of Average Follow-Up: A Retrospective Study.

This retrospective study evaluated the survival rate of short, sandblasted acid-etched surfaced implants with 6 and 8 mm lengths with at least 120 days of follow-up. Data concerning patient, implant and surgery characteristics were retrieved from clinical records. Sandblasted and acid-etched (SLA)-surfaced tissue-level 6 mm (TL6) or 8 mm (TL8) implants or bone-level tapered 8 mm (BLT8) implants were used. Absolute and relative frequency distributions were calculated for qualitative variables and mean values and standard deviations for quantitative variables. A Cox regression model was performed to verify whether type, length and/or width influence the implant survival. The cumulative implant survival rate was assessed by time-to-event analyses (Kaplan-Meier estimator). In all, 513 patients with a mean age of 58.00 ± 12.44 years received 1008 dental implants with a mean follow-up of 21.57 ± 10.77 months. Most implants (78.17%) presented a 4.1 mm diameter, and the most frequent indication was a partially edentulous arch (44.15%). The most frequent locations were the posterior mandible (53.97%) and the posterior maxilla (31.55%). No significant differences were found in survival rates between groups of type, length and width of implant with the cumulative rate being 97.7% ± 0.5%. Within the limitations of this study, the evaluated short implants are a predictable option with high survival rates during the follow-up without statistical differences between the appraised types, lengths and widths.

Malignant transformation rate of oral leukoplakia-systematic review.

OBJECTIVE: The aim of this study was to perform a systematic review of prevalence studies to determine the rate of malignant transformation of oral leukoplakia and assess the influence of demographic factors (age, gender, and geographic region) on the overall transformation rate. STUDY DESIGN: A search was conducted for publications until July 2019 in 4 electronic databases and peer-reviewed journals. A manual search was performed on the bibliographies of the collected articles, and the authors were contacted for additional information. This study was previously registered with the trial number CRD42019126909 and study quality assessed through established methods. The results were expressed by means of proportions or odds ratios with a 95% confidence interval. Meta-regression was undertaken to evaluate possible sources of heterogeneity, and funnel plot visual analysis was performed to assess publication bias. RESULTS: The 34 observational epidemiologic studies included reported data on 26,209 patients with oral leukoplakia from 18 different countries. Meta-analysis of 32 studies (23,489 patients) presented an estimated overall mean proportion of malignant transformation rate of 9.70% (7.80-11.70) (I2 = 98.66%; τ2 < 0.001; χ2 = 23.18; degrees of freedom [df] = 31). When comparing genders, the odds ratio favored males with 0.622 (0.468-0.826) (I2 = 29.77%; τ2 = 0.089; χ2 = 22.78; df = 16). CONCLUSIONS: Within the limitations of the included studies in this systematic review, the results suggest that the malignant transformation rate was dependent on demographic factors and follow-up time. Future studies should include the development of guidelines to standardize the methodology for long-term follow-up assessment, thus reducing the risk of bias.

Orphan drugs: major development challenges at the clinical stage.

Biotechnology has provided powerful tools to assist in research and development (R&D) for rare diseases. However, orphan drug development presents several major challenges and obstacles, such as low disease prevalence, disease severity, small and heterogeneous patient populations, difficulties in patient recruitment, and limited knowledge of the natural history of disease, among others. Several strategies can be used to plan for and overcome these clinical and regulatory challenges, namely improved clinical trial design, improved patient recruitment, and closer collaboration with the regulatory authorities and with patient associations. As growth in the orphan drug market is expected over the next few years, improving its relevance in the global pharmaceutical market, further challenges might present themselves in the development of orphan drugs.

Avaliação e controlo da dor na pessoa com alterações da comunicação: atitudes, práticas, barreiras e conhecimentos dos enfermeiros / Pain assessment and management in people with communication disorders: nurses' attitudes, practices, barriers and knowledge

Objetivos: Nos vários serviços de internamento dos hospitais, e nos serviços de medicina em particular, a dor faz parte do quotidiano dos doentes e dos profissionais que os cuidam. Nas vivências dos processos complexos de doença, a dor é um dos sintomas quase sempre presente. Do ponto de vista da enfermagem, a avaliação e controlo da dor é objeto de preocupação, contudo nem sempre é fácil avaliar e controlar a dor nos doentes com a comunicação comprometida. Métodos: Este estudo descritivo-correlacional transversal que explorou e descreveu o fenómeno da avaliação da dor no doente com alteração da comunicação, com os objetivos: avaliar as atitudes, práticas, barreiras e conhecimentos dos enfermeiros na avaliação e controlo da dor no doente com alterações da comunicação verbal, no serviço de medicina. Para tal foi aplicado um questionário de avaliação a 64 enfermeiros e foram extraídos dados informatizados de 100 dos doentes com diagnósticos de comunicação ou consciência alterada limitadores à avaliação da dor. Resultados: Os enfermeiros, no geral, apresentaram atitudes positivas em relação à avaliação e controlo da dor. As atitudes menos positivas estão relacionadas com a utilização de opióides. É evidente que existem práticas a melhorar no que concerne à avaliação e controlo da dor. As barreiras identificadas pelos enfermeiros são relativas à avaliação da dor e administração de medicação. Não houve evidência da relação entre a experiência profissional e as atitudes e práticas na avaliação da dor, nem diferenças de acordo com a presença de formação específica. Conclusão: O estudo sugere a revisão e reformulação dos programas de formação dirigidos aos enfermeiros na temática da avaliação e controlo da dor, com abordagem específica das boas práticas nos doentes com alterações da comunicação.

Objectives: In the various inpatient services of hospitals, and in medical services in particular, pain is part of the daily lives of patients and the professionals who care for them. In the experience of complex disease processes, pain is one of the symptoms almost always present. From a nursing point of view, pain assessment and control is a matter of concern, but it is not always easy to assess and control pain in patients with compromised communication. Methods: This descriptive-correlational cross-sectional study explored and described the phenomenon of pain assessment in patients with communication impairment, with the objectives: to evaluate the attitudes, practices, barriers and knowledge of nurses in the assessment and control of pain in patients with verbal communication impairment, in the medical service. To this end, an assessment questionnaire was administered to 64 nurses and computerised data were extracted from 100 of the patients with diagnoses of altered communication or awareness limiting pain assessment. Results: Nurses overall showed positive attitudes towards pain assessment and control. The least positive attitudes were related to the use of opioids. It is evident that there are practices to improve regarding pain assessment and control. The barriers identified by nurses are related to pain assessment and medication administration. There was no evidence of a relationship between professional experience and attitudes and practices in pain assessment, nor differences according to the presence of specific training. Conclusion: The study suggests a review and reformulation of training programmes for nurses in pain assessment and control, with a specific approach to good practice in patients with communication disorders.

The prognostic performance of Adjuvant! Online and Nottingham Prognostic Index in young breast cancer patients.

BACKGROUND: Limited data are available on the prognostic performance of Adjuvant! Online (AOL) and Nottingham Prognostic Index (NPI) in young breast cancer patients. METHODS: This multicentre hospital-based retrospective cohort study included young (⩽40 years) and older (55-60 years) breast cancer patients treated from January 2000 to December 2004 at four large Belgian and Italian institutions. Predicted 10-year overall survival (OS) and disease-free survival (DFS) using AOL and 10-year OS using NPI were calculated for every patient. Tools ability to predict outcomes (i.e., calibration) and their discriminatory accuracy was assessed. RESULTS: The study included 1283 patients, 376 young and 907 older women. Adjuvant! Online accurately predicted 10-year OS (absolute difference: 0.7%; P=0.37) in young cohort, but overestimated 10-year DFS by 7.7% (P=0.003). In older cohort, AOL significantly underestimated both 10-year OS and DFS by 7.2% (P<0.001) and 3.2% (P=0.04), respectively. Nottingham Prognostic Index significantly underestimated 10-year OS in both young (8.5%; P<0.001) and older (4.0%; P<0.001) cohorts. Adjuvant! Online and NPI had comparable discriminatory accuracy. CONCLUSIONS: In young breast cancer patients, AOL is a reliable tool in predicting OS at 10 years but not DFS, whereas the performance of NPI is sub-optimal.

Information perception, wishes, and satisfaction in ambulatory cancer patients under active treatment: patient-reported outcomes with QLQ-INFO25.

BACKGROUND: Information is vital to cancer patients. Physician-patient communication in oncology presents specific challenges. The aim of this study was to evaluate self-reported information of cancer patients in ambulatory care at a comprehensive cancer centre and examine its possible association with patients' demographic and clinical characteristics. PATIENTS AND METHODS: This study included adult patients with solid tumours undergoing chemotherapy at the Institute Jules Bordet's Day Hospital over a ten-day period. EORTC QLQ-C30 and QLQ-INFO25 questionnaires were administered. Demographic and clinical data were collected. Descriptive and inferential statistics were used. RESULTS: 101 (99%) fully completed the questionnaires. They were mostly Belgian (74.3%), female (78.2%), with a mean age of 56.9 ± 12.8 years. The most frequent tumour was breast cancer (58.4%). Patients were well-informed about the disease and treatments, but presented unmet information domains. The Jules Bordet patients desired more information on treatment side effects, long-term outcome, nutrition, and recurrence symptoms. Patients on clinical trials reported having received less information about their disease and less written information than patients outside clinical trials. Higher information levels were associated with higher quality of life (QoL) scores and higher patient satisfaction. CONCLUSION: Patients were satisfied with the information they received and this correlated with higher QoL, but they still expressed unmet information wishes. Additional studies are required to investigate the quality of the information received by patients enrolled in clinical trials.

Cardiotoxicity of systemic agents used in breast cancer.

Several breast cancer therapies can lead to cardiovascular toxicity: drugs such anthracyclines can cause permanent damage, anti-HER2 agents may cause transitory and reversible cardiac dysfunction and others, such as those used in endocrine therapy, primarily disturb lipid metabolism. Considering the seriousness of these complications, trials are now being conducted to address cardiotoxicity associated with new drugs; however, to fully understand their toxicity profiles, longer follow-up is needed. In this review, we compile the information available about cardiac toxicity related to well-established systemic breast cancer treatments, as well as newer drugs, including antiangiogenics, mTOR inhibitors and novel anti-HER2 agents. We also describe current and next generation cardiac biomarkers and functional tests that can optimize treatment and reduce and prevent the incidence of treatment-related cardiotoxicity.

Trastuzumab for patients with HER2 positive breast cancer: delivery, duration and combination therapies.

With the exception of endocrine therapy, no other systemic treatment of patients with breast cancer has reached such a magnitude of beneficial effect as trastuzumab. This targeted agent (monoclonal antibody) is associated with a significant improvement in both disease-free (DFS) and overall survival (OS) in women with HER-2 positive breast cancer when given in combination with or in sequence to adjuvant chemotherapy. This has been confirmed in a recent Cochrane meta-analysis of randomized controlled trials (RCTs), including 6 adjuvant and 2 neoadjuvant studies (NSABP B-31, NCCTG N9831, BCIRG 006, HERA, FinHer, PACS-04, Buzdar and NOAH), with data collection until February 2010. Overall, mortality is reduced by one-third and the risk of relapse by 40%. Concerns regarding cardiac dysfunction are declining, with reports indicating its reversibility in most instances, however truly long term cardiac evaluation is still lacking. Hence, the benefit of trastuzumab could be challenged by cardiac toxicity, in lower-risk patients [T1a,b node-negative (N0) tumors] or those with increased cardiovascular risk (older women and patients with previous significant heart disease/suboptimal left ventricular ejection fraction [LVEF (<55%)], all of whom were largely excluded from the aforementioned adjuvant RCTs. These patient subgroups might warrant a specific approach, such as anti-HER2 treatment combined with just a taxane (avoiding anthracyclines) or with endocrine therapy. Reasonably large phase II trials aimed at exploring these more individualized regimens are underway in the US. The optimal duration of trastuzumab therapy remains unknown since the selection of the one year duration in the pivotal trials was arbitrary. The HERA trial showed that prolonging trastuzumab administration to two years does not confer additional advantage over one year. The PHARE trial compared 6 versus 12 months of trastuzumab and failed to show non-inferiority of the shorter treatment administration. At the present time, one year of adjuvant trastuzumab remains the standard-of-care until results from SOLD, Short-HER and PERSEPHONE consolidate or negate this finding. The route of trastuzumab administration has also been recently challenged. A subcutaneous formulation is being evaluated in several studies. The HannaH phase III trial compared the subcutaneous (SC) to the intravenous (IV) formulation of trastuzumab. The former was proven non-inferior to the latter, although the incidence of serious adverse events was slightly higher in the SC arm. The authors concluded that SC trastuzumab, administered at a fixed dose of 600mg over 5min, is a valid alternative option, with the potential for human and economic savings in clinical practice.

Sexuality and breast cancer: prime time for young patients.

Sexuality and sexual functioning is a cardinal domain of health-related quality of life in breast cancer patients, namely in the younger population. Young women below 40 years of age go through a time in their lives where sexual self-identity has recently matured, their professional obligations are demanding and they bear interpersonal and childbearing expectations, all of which can suffer a devastating turnaround with cancer diagnosis and its physical and psychological aftermath. Although these women's sexuality and directed interventions have remained largely unaddressed so far, concepts are evolving and treatment options are becoming diversified, chiefly on the field of non-hormonal pharmacological therapy of sexual dysfunction. This review will examine the definitions of female sexual dysfunction, the etiology of the disorders in young breast cancer patients, the assessment methods, the non-pharmacological and pharmacological treatment options and the challenges that lie ahead.

How Long is Enough - Optimal Timing of Anti-HER2/neu Therapy in the Adjuvant Setting in Early Breast Cancer.

Trastuzumab administered in combination with various chemotherapy regimens has led to outstanding improvements in both disease-free survival and overall survival. So far, thousands of patients have been treated in this way which has proven to be reasonably safe, with cardiac events being the predominant recognisable toxicity requiring surveillance. Notwithstanding the large cumulative experience of the oncology community in treating early HER2/neu-positive breast cancer with trastuzumab, some uncertainties remain, with key issues being the ideal time of chemotherapy administration and the optimal duration of trastuzumab therapy. This paper discusses these issues in the light of the recent updates of some of the pivotal clinical trials in the adjuvant context.

Development, characterization and in vitro evaluation of single or co-loaded imatinib mesylate liposomal formulations.

Mitoxantrone-based combinations are a standard palliative treatment in hormone-refractory prostate cancer (HRPC) but with no survival benefit. Imatinib has shown preclinical activity against HRPC although minimal clinical therapeutic efficacy. Our previous in vitro studies demonstrated that simultaneous combination of imatinib with mitoxantrone yielded additive growth inhibition effects against PC-3 cell line. The main aim of the work was to develop novel liposomal formulations comprising imatinib co-encapsulated with mitoxantrone, by different loading methods and experimental conditions, in order to achieve the highest drug loading and maximum physical stability. In the optimized formulations, imatinib and mitoxantrone were actively co-loaded by means of a (NH4)2SO4 transmembrane gradient. Encapsulation efficiency, mean size diameter and drug retention in storage and in biological conditions were characterized. Our study presented for the first time an active loading method for imatinib and suggests that the optimized liposomal formulation co-encapsulates both drugs with high encapsulation efficiency (> 95%), shows enhanced drug retention under tested conditions and delivers a drug:drug ratio capable of improving tumor cell growth inhibition with a mitoxantrone dose reduction of 2.6-fold as compared to single liposomal formulation. Therefore, our nanotechnology-based drug combined platform may constitute a promising strategy in prostate cancer therapy.

Tools for characterizing the whole-cell bio-oxidation of alkanes at microscale.

This article describes the first reported microwell whole-cell bioconversion using a water immiscible substrate that matches the specific activity and yield achieved in a 1.2 L stirred tank bioreactor. Maximum yields of 0.6 g/L(total) 1-dodecanol achieved in 24 h compare favorably to 0.28 g/L(total) 1-dodecanol after 48 h obtained in a stirred tank reactor. Using the microwell platform we present a rapid and systematic approach to identify the key bottlenecks in the bio-oxidation of long-chain alkanes using Escherichia coli expressing the alkane hydroxylase (alkB) complex. The results indicate that mass transfer rates limit productivity in the n-dodecane bio-oxidation system, rather than inherent enzyme activity. Furthermore, substrate solubility, oxygen availability and glucose concentration act cooperatively to affect the amount of by-product, dodecanoic acid. Optimizing these factors using response surface methodology enabled specific yields of 1-dodecanol to increase eightfold and overoxidation to dodecanoic acid to be reduced from 95% to 55%. This resulted in specific activities of 10.4 µmol/min/g(dcw) on n-dodecane; approximately 50% of the 21 µmol/min/g(dcw) obtained with n-octane. For the first time, this in vivo rate difference is within the range reported for the purified enzyme. Finally, the results obtained also provide strong evidence that the mechanism of E. coli interaction with alkanes is mainly via uptake of alkanes dissolved in the aqueous phase rather than by direct cell-droplet contact.

Improving quality of life after breast cancer: dealing with symptoms.

BACKGROUND: Advances in breast cancer therapies have given rise to a growing number of patient survivors. Nevertheless, these women deal with long-term sequelae that impair their quality of life and that are lacking satisfactory assessment and expeditious management. Importantly, a new era is raising in the oncology field, namely, survivorship. METHODS: A search for English-language articles on Medline was undertaken covering the last 15 years, using the terms "cancer survivorship", "quality of life", "fatigue", "insomnia", "sleep disturbances", "depression", "cognitive dysfunction", "chemofog", "peripheral neuropathy", "fertility", "sexual behaviour", "menopause", "lymphedema", "physical activity" and "breast neoplasms". Selection was limited to systematic reviews and meta-analysis, but their reference list was examined to include papers of potential interest. RESULTS: We found the most common symptoms affecting breast cancer survivors were fatigue, insomnia, depression, cognitive dysfunction, reproductive and menopausal symptoms and lymphoedema. CONCLUSION: Some of these symptoms have even been the objective of randomised controlled trials, but consistent data are missing. The available interventions include pharmacological, behavioural therapies and complementary and alternative medicine approaches and will mostly depend on the type of symptom.

Schedule treatment design and quantitative in vitro evaluation of chemotherapeutic combinations for metastatic prostate cancer therapy.

PURPOSE: Preclinical evaluation is essential for a rational design of combination chemotherapy as some agents, with known mechanisms of action and non-overlapping toxicities may increase the therapeutic index of anticancer drugs, whose clinical success is hindered by side effects and drug resistance. The present study investigated new drug combinations with potential outcome for the treatment of metastatic prostate cancer. This final clinical stage exhibits predominantly hormone-refractory prostate cancer (HRPC) cells but also a minority of hormone responsive cells. METHODS: Growth inhibition activity of simultaneous and sequential combinations was evaluated by resazurin assay. In vitro evaluation of synergism, additivity, or antagonism, against prostate cancer cell lines, was performed by the median effect analysis. The importance of dosage, exposure time, drug ratio, and type of treatment were investigated and compared. RESULTS: Most simultaneous combinations of two drugs with different mechanisms of action or of two topoisomerase II inhibitors resulted in mild antagonism of antiproliferative effects, particularly notorious at high cell death. Imatinib-mitoxantrone and ciprofloxacin-etoposide combinations were exceptions, as they yielded additivity and dose reduction index (DRI) values of 2.6 and 3.5-fold for mitoxantrone and etoposide, respectively. Sequential combinations (ciprofloxacin or imatinib pre-treatment) revealed additive growth inhibition effects, translated in much higher DRI values (from 7.0 to 15.3-fold). Moderate synergism was restricted to sequential ciprofloxacin combinations at high cell death. CONCLUSIONS: Ciprofloxacin and imatinib significantly improve growth inhibition activity of standard antineoplastic drugs in a schedule-dependent manner and, therefore, may have an important role as adjuvant therapeutic agents in a clinical setting.