Mitochondrial Cumulative Damage Induced by Mitoxantrone: Late Onset Cardiac Energetic Impairment

Mitoxantrone (MTX) is a chemotherapeutic agent, which presents late irreversible cardiotoxicity. This work aims to highlight the mechanisms involved in the MTX-induced cardiotoxicity, namely the effects toward mitochondria using in vivo and in vitro studies. Male Wistar rats were treated with 3 cycles of 2.5 mg/kg MTX at day 0, 10, and 20. One treated group was euthanized on day 22 (MTX22) to evaluate the early MTX cardiac toxic effects, while the other was euthanized on day 48 (MTX48), to allow the evaluation of MTX late cardiac effects. Cardiac mitochondria isolated from 4 adult untreated rats were also used to evaluate in vitro the MTX (10 nM, 100 nM, and 1 lM) direct effects upon mitochondria functionality. Two rats of MTX48 died on day 35, and MTX treatment caused a reduction in relative body weight gain in both treated groups with no significant changes in water and food intake. Decreased levels of plasma total creatine kinase and CK-MB were detected in the MTX22 group, and increased plasma levels of lactate were seen in MTX48. Increased cardiac relative mass and microscopic changes were evident in both treated groups. Considering mitochondrial effects, for the first time, it was evidenced that MTX induced an increase in the complex IV and complex V activities in MTX22 group, while a decrease in the complex V activity was accompanied by the reduction in ATP content in the MTX48 rats. No alterations in mitochondria transmembrane potential were found in isolated mitochondria from MTX48 rats or in isolated mitochondria directly incubated with MTX. This study highlights the relevance of the cumulative MTX-induced in vivo mitochondriopathy to the MTX cardiotoxicity.This work was supported by the Fundação para a Ciência e Tecnologia (FCT)—project (EXPL/DTP-FTO/0290/ 2012)—QREN initiative with EU/FEDER financing through COMPETE— Operational Programme for Competitiveness Factors. LGR, VMC, and RJD-O thank FCT for their PhD Grant (SFRH/BD/63473/ 2009) and Post-doc Grants (SFRH/BPD/63746/2009) and (SFRH/ BPD/36865/2007), respectively. The authors are grateful to Fundação para a Ciência e Tecnologia for grant no. Pest C/EQB/LA0006/2011

Significado da recidiva local no tratamento conservador do câncer de mama

Conservative surgery associated with radiotherapy has shown overall survival rates similar to those of radical mastectomy, despite a great deal of variation in the rate of local recurrence according to different surgical approach. The free margins and absence of radiotherapy have a significant impact on local recurrence. In this review, factors associated with positive or negative outcomes are reviewed , as well diagnosis and treatment difficulties. At the moment, the best predictive factor for outcome of local recurrence is disease extension at initial diagnosis and treatment. Despite the fact that local recurrence after mastectomy is associated with systemic disease, patients with recurrence after BCT seem to have a more positive prognosis.A cirurgia conservadora associada à radioterapia tem demonstrado sobrevida semelhante à cirurgia radical, porém com grande variação nas taxas de recidiva local, conforme o tipo de cirurgia: a redução das margens cirúrgicas e a ausência de radioterapia apresentaram influência significativa na taxa de recidiva local. Nesta revisão, são estudados os fatores relacionados – de forma positiva ou negativa – na ocorrência da recidiva local, bem como as formas de diagnóstico, tratamento e seu significado em termos de prognóstico. Atualmente, o melhor fator preditivo do desfecho da paciente que apresenta recidiva local é a extensão da doença no momento do tratamento primário; e embora a recidiva local após a mastectomia seja habitualmente um prenúncio de doença sistêmica, a paciente com recorrência após TC aparentemente tem um melhor prognóstico

Câncer de mama: de 1993 a 2001

In a special article published in December 1993, entitled "Breast Cancer after 2001", the authors presented a forecast concerning epidemiology, diagnosis, and treatment of breast cancer for the new millenium. Eight years later it is our objective to review and compare the forecasts and present facts. Significant progress has happened, the cure rates are higher, mortality has been reduced, and treatment is more humane. The advancements of Medicine in chronic diseases like cancer, however, are observably slow and demand long periods of time to be better understood. Em um artigo especial publicado em dezembro de 1993, sob o o título de Câncer de mama: depois de 2001, os autores fizeram uma projeção sobre o que ocorreria com a epidemiologia, o diagnóstico e o tratamento do câncer de mama no início do novo milênio. Oito anos depois retomam o assunto e estabelecem uma comparação entre as previsões efetuadas e a realidade dos fatos. Significativos progressos aconteceram: as curas aumentaram, a mortalidade diminuiu e a terapêutica se tornou mais humana, porém os avanços da medicina em doenças crônicas como o câncer se fazem lentamente e exigem grandes períodos de tempo para se tornarem mais evidentes

Tratamento sistêmico adjuvante em câncer de mama

Since the 1970s, substantial progress has been made in the understanding of the biology of breast cancer, on diagnostic approaches, and in determination of risk factors. This progress has been associated with advancements in the efficacy of treatments. Currently, many patients are receiving treatments that used to be reserved for cases with metastases. Clinical, multi-centered trials carried out by different authors have allowed for a continuous reevaluation of the basis of knowledge and recommendations of adjuvant therapy. Breast cancer, in this sense, is now understood as a systemic disease, which corroborates the use of systemic therapy in early breast cancer.Um significativo progresso no conhecimento e compreensão da biologia do câncer de mama, dos métodos diagnósticos e da determinação dos fatores de risco ocorreu desde os anos 70, acompanhado de avanços na eficácia dos tratamentos. Hoje, muitas pacientes recebem tratamentos anteriormente reservados para casos metastáticos. Os ensaios clínicos multicêntricos desenvolvidos por diferentes grupos permitem uma contínua reavaliação das bases de conhecimento e indicações de tratamento adjuvante. O câncer de mama deixou de ser considerado loco-regional e é reconhecido como sistêmico desde o seu início, o que sustenta o uso de terapia sistêmica em casos iniciais

Mastectomia profilática: o sentimento e a razão

We carried out a review based on the study by Hartmann et al. (1), which showed new aspects on the controversial matter of Prophylactic Mastectomy for breast cancer prevention. The results of the study indicated a dramatic 90% reduction on the relative risk for developing breast cancer. We reviewed the subject observing the matters of exposure and risk for developing breast cancer. We also assessed the results published in the literature in order to understand the magnitude of the risk and the potential benefits related to the procedure.É realizada uma revisão, baseada no artigo pioneiro de Hartmann et al. (1), que lançou um novo enfoque sobre o controverso tema da mastectomia profilática na prevenção do câncer de mama, mostrando uma dramática redução de 90% no risco relativo de desenvolver a doença. 0 assunto é revisado, observando aspectos da exposição e determinação do risco de desenvolver câncer de mama, bem como a forma de interpretar os resultados publicados de modo a compreender a magnitude risco e o potencial de benefício associado à intervenção proposta para sua redução

Manejo das lesões mamárias impalpáveis

Impalpable breast lesions are subclinical findings discovered by mammography screening. These lesions are quite common, representing an important reason for appointments in mastology clinics. Nodules, microcalcifications, distortion of the mammary parenchymal architecture and asymmetrical densities are the main impalpable breast lesions. We describe their characteristics and relation with BIRADS classification as an alternative treatment. The treatment includes clinical follow up, cytological and histopathological evaluation (core biopsy) – both guided by ultrasonography or stereotaxy –, mammotomy, and wire-directed localization biopsyNeste artigo são abordadas as lesões mamárias impalpáveis, que correspondem aos achados mamográficos anormais, sem tradução ao exame clínico. Representam atualmente importante parcela das consultas às clínicas mastológicas. Podemos destacar os nódulos, microcalcificações, distorções arquiteturais do parênquima e as densidades assimétricas como as principais lesões mamárias impalpáveis. São descritas suas características e relação com as categorias da classificação de BIRADS, bem como as opções de manejo, que incluem o acompanhamento clínico, punções citológicas (PAAF) e punções biópsia (core biopsy) guiadas por ecografia ou estereotaxia, a mamotomia, e as biópsias cirúrgicas guiadas por fio-metálico (agulhamento)

Manejo da mastalgia

Breast pain is a common problem in the setting of both primary care and specialized breast treatment clinics. For the majority of women, breast pain is a self-limiting condition that requires no treatment other than reassurance. Nevertheless, in a few cases, severe, prolonged cyclical or noncyclical breast pain may affect social, sexual, and work aspects of the patient's life. Firstly, when confronted with patients complaining of breast pain, physicians must determine whether it is of mammary or extramammary source. If the problem originates from the breast itself, further management depends on its nature, severity, and duration. In average, only 3 per cent of patients complaining from breast pain require pharmacological treatment. In this study, we reviewed the main aspects of breast pain, its etiology, and its pharmacological treatment.Mastalgia ou dor mamária é um sintoma comum tanto em clínicas especializadas quanto na atenção primária. Na maioria dos casos é condição auto-limitada que não requer outro tratamento senão esclarecimento e tranqüilização. Em poucos casos, no entanto, mastalgia severa, prolongada, cíclica ou não, pode levar a distúrbios social, sexual e profissional sérios para a paciente. Primeiramente, o clínico deve estabelecer se a patologia é de fato de origem mamária, ou extramamária, para após quantificar tal queixa e estabelecer tratamento farmacológico, ou não. Em média, apenas 3% das pacientes com mastalgia requerem tratamento medicamentoso. Neste estudo, fez-se revisão das principais causas de dor mamária e dos tratamentos farmacológicos mais importantes disponíveis no momento

Doença de Mondor secundária a herpes zoster torácico

The Mondor's disease, or phlebitis of the thoracoepigastric vein, is self-restricted and clinically manifested by local pain associated with a tender, palpable, subcutaneous cord. It can be secondary to a local trauma, surgery, inflamatory processes or even to a breast cancer. Mammography and/or ultrasound should be carried out in women with this diagnosis who are age 35 or older to exclude the possibility of a nonpalpable breast cancer. Even though the disease not necessarily has to be associated to another event, twenty-five percent are associated with a subjacent neoplasia. We reported here a case of Mondor's disease secondary to an infra-mammary Herpes Zoster. The disease is rare on clinical practice and the physician must be aware of this rare diagnosis. In this case, the finding associated to herpetic lesions made it even more curious and special.A doença de Mondor, ou flebite da veia toracoepigástrica, é auto-limitada e manifestase clinicamente por dor local acompanhada por um cordão subcutâneo de temperatura elevada. Pode ser achado isolado ou estar associada a trauma local, intervenções cirúrgicas, processos inflamatórios ou mesmo a um carcinoma. Pacientes com esse diagnóstico e idade igual ou superior a 35 anos têm indicação de complementar sua avaliação radio e/ou ecograficamente para excluir carcinoma de mama impalpável, pois a doença de Mondor pode estar associada à neoplasia maligna subjacente em até 25% das vezes. Relatamos aqui um caso de doença de Mondor secundária a herpes Zoster em região infra-mamária. A doença de Mondor é entidade rara na prática médica e necessita de profissionais experientes para que se firme o diagnóstico, que é exclusivamente clínico. Vale salientar que, neste caso, o curioso e surpreendente é a doença estar associada a lesões herpéticas.&nbsp

Systematic survey of randomized trials evaluating the impact of alternative diagnostic strategies on patient-important outcomes

Objectives: To provide a perspective on the current practice of randomized clinical trials (RCTs) of diagnostic strategies focusing on patient-important outcomes. Study Design and Setting: We conducted a comprehensive search of MEDLINE and included RCTs published in full-text reports that evaluated alternative diagnostic strategies. Results: Of 56,912 unique citations, we sampled 7,500 and included 103 eligible RCTs, therefore suggesting that MEDLINE includes approximately 781 diagnostic RCTs. The 103 eligible trials reported on: mortality (n = 41; 39.8%); morbidities (n = 63; 61.2%); symptoms/quality of life/functional status (n = 14; 13.6%); and on composite end points (n = 10; 9.7%). Of the studies that reported statistically significant results (n = 12; 11.6%), we judged 7 (58.3%) as at low risk of bias with respect to missing outcome data and 4 (33.3%) as at low risk of bias regarding blinding. Of the 41 RCTs that reported on mortality, only one (2.4%) reported statistically significant results. Of 63 RCTs addressing morbidity outcomes, 11 (17.5%) reported statistically significant results, all of which reported relative effects of greater than 20%. Conclusion: RCTs of diagnostic tests are not uncommon, and sometimes suggest benefits on patient-important outcomes but often suffer from limitations in sample size and conduct. (C) 2017 Elsevier Inc. All rights reserved.Peer reviewe