Cytotoxic drugs for patients with breast cancer in the era of targeted treatment: Back to the future?

Background: Despite current trend of targeted therapy development, cytotoxic agents are a mainstay of treatment of patients with breast cancer. We reviewed recent advances in cytotoxic therapy for patients with metastatic breast cancer (MBC). Materials and methods: Medline searches were conducted for English language studies using the term =MBC= and 'cytotoxic drugs'. The data search was restricted to the period 2000-2011. Results: Several novel cytotoxic compounds, all microtubule inhibitors, have been approved for clinical use in MBC: (i) nab-paclitaxel, reported to improve tumour response and decrease hypersensitivity reactions in comparison with other taxanes; (ii) ixabepilone, shown to have clinical benefit in taxane- and anthracycline-resistant disease and (iii) eribulin, shown to improve overall survival in heavily pre-treated patients, when compared with best available standard treatment. Agents, such as larotaxel, vinflunine, trabectidin and formulations, including cationic liposomal paclitaxel or paclitaxel poliglumex, are currently under evaluation in phase II/III trials. Conclusion: Toxicity and chemotherapy resistance are still major limitations in the treatment of patients with MBC. Further research into new cytotoxic compounds is needed in order to maximise benefit, whilst minimising toxicity

Electrochemical Determination Of Antioxidant Capacity For Physical Exercise Evaluation [determinação Eletroquímica Da Capacidade Antioxidante Para Avaliação Do Exercício Físico]

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Prevention Strategies For Chemotherapy-induced Hand-foot Syndrome: A Systematic Review And Meta-analysis Of Prospective Randomised Trials

Purpose: Hand-foot syndrome (HSF) is a distinctive adverse event relatively frequent to some chemotherapeutic agents as capecitabine, pegylated liposomal doxorubicin, sorafenib and other tyrosine-kinase inhibitors. Since the prevention of HFS would be crucial to avoid treatment interruptions and delays, many studies have been conducted with this purpose. Methods: The aim of this systematic review and meta-analysis was to analyze the clinical efficacy of prevention strategies for HFS, through a wide search of electronic databases as well as congress abstracts. The endpoints evaluated were the dichotomic data for mild (Grade 1), moderate to severe (Grades 2 to 3) and all-grade HFS. Meta-analysis was calculated through RevMan v5.1 software. Results: Amongst 295 studies identified, only ten met the inclusion criteria. Celecoxib prevented both moderate to severe (odds ratio [OR] 0.39, 95 % confidence interval [CI] 0.20-0.73, P=0.003) and all-grade HFS (OR 0.47, 95 % CI 0.29-0.78, P=0.003), whereas pyridoxine and topical urea/lactic acid formulations failed to prove efficacy. There were no proven benefits in mild HFS. The use of topical antiperspirant has not been shown to improve results, according to a single trial. Conclusions: From all available possibilities for the prevention of HFS, celecoxib appears to be the most promising, with statistically significant results. Larger, multicentric studies are required to reinforce this finding. © 2014 Springer-Verlag.22615851593Almeida Da Cruz, L., Hoff, P.M., Ferrari, C.L., Riechelmann, R.S., Unilateral hand-foot syndrome: Does it take sides? Case report and literature review (2012) Clin Colorectal Cancer, 11, pp. 82-84Hoesly, F.J., Baker, S.G., Gunawardane, N.D., Cotliar, J.A., Capecitabine-induced hand-foot syndrome complicated by pseudomonal superinfection resulting in bacterial sepsis and death: Case report and review of the literature (2011) Arch Dermatol, 147, pp. 1418-1423Belum, V.R., Wu, S., Lacouture, M.E., Risk of hand-foot skin reaction with the novel multikinase inhibitor regorafenib: A meta-analysis (2013) Invest New Drugs, 31, pp. 1078-1086Fischer, A., Wu, S., Ho, A.L., Lacouture, M.E., The risk of hand-foot skin reaction to axitinib, a novel VEGF inhibitor: A systematic review of literature and meta-analysis (2013) Invest New Drugs, 31, pp. 787-797Balagula, Y., Wu, S., Su, X., The risk of hand foot skin reaction to pazopanib, a novel multikinase inhibitor: A systematic review of literature and meta-analysis (2012) Invest New Drugs, 30, pp. 1773-1781Chu, D., Lacouture, M.E., Weiner, E., Wu, S., Risk of hand-foot skin reaction with the multitargeted kinase inhibitor sunitinib in patients with renal cell and non-renal cell carcinoma: A meta-analysis (2009) Clin Genitourin Cancer, 7, pp. 11-19Lin, E., Morris, J.S., Ayers, G.D., Effect of celecoxib on capecitabine-induced hand-foot syndrome and antitumor activity (2002) Oncology, 16, pp. 31-37. , Williston ParkFitzpatrick, J.E., The cutaneous histopathology of chemotherapeutic reactions (1993) J Cutan Pathol, 20, pp. 1-14Jacobi, U., Waibler, E., Schulze, P., Sehouli, J., Oskay-Ozcelik, G., Schmook, T., Sterry, W., Lademann, J., Release of doxorubicin in sweat: First step to induce the palmar-plantar erythrodysesthesia syndrome? 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In 5.1 Edition, , http://ims.cochrane.org/revmanLiberati, A., Altman, D.G., Tetzlaff, J., The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: Explanation and elaboration (2009) J Clin Epidemiol, 62, pp. e1-e34Braik, T., Yim, B., Evans, A.T., A randomized trial to determine if vitamin B6 can prevent hand and foot syndrome in cancer patients treated with capecitabine chemotherapy (2012) J Clin Oncol, 30 (SUPPL.). , abstr 9085Corrie, P.G., Bulusu, R., Wilson, C.B., A randomised study evaluating the use of pyridoxine to avoid capecitabine dose modifications (2012) Br J Cancer, 107, pp. 585-587Fabi, A., Metro, G., Papaldo, P., Impact of celecoxib on capecitabine tolerability and activity in pretreated metastatic breast cancer: Results of a phase II study with biomarker evaluation (2008) Cancer Chemother Pharmacol, 62, pp. 717-725Kang, Y.K., Lee, S.S., Yoon, D.H., Pyridoxine is not effective to prevent hand-foot syndrome associated with capecitabine therapy: Results of a randomized, double-blind, placebo-controlled study (2010) J Clin Oncol, 28, pp. 3824-3829Kanis, M., Kesterson, J.P., Lele, S., The use of cod liver oil by patients receiving pegylated liposomal doxorubicin is associated with a lack of severe palmar-plantar erythrodysesthesia (2009) Eur J Gynaecol Oncol, 30, pp. 387-388Kluschke, F., Martschick, A., Darvin, M.E., Application of an ointment with high radical protection factor as a prevention strategy against PPE (2012) J Clin Oncol, 30 (SUPPL.). , abstr 5064Kohne, C.-H., De Greve, J., Hartmann, J.T., Lang, I., Vergauwe, P., Becker, K., Braumann, D., Van Cutsem, E., Irinotecan combined with infusional 5-fluorouracil/folinic acid or capecitabine plus celecoxib or placebo in the first-line treatment of patients with metastatic colorectal cancer. EORTC study 40015 (2008) Annals of Oncology, 19 (5), pp. 920-926. , DOI 10.1093/annonc/mdm544Lyass, O., Lotem, M., Edelmann, D., Protective effect of amifostine (AMF) on doxil/caelyx-induced palmar-plantar erythrodysesthesia (PPE) in patients (pts) with advanced cancer (2001) Clin Oncol, 20. , Proc Am Soc, abstr 2148Mangili, G., Petrone, M., Gentile, C., Prevention strategies in palmar-plantar erythrodysesthesia onset: The role of regional cooling (2008) Gynecol Oncol, 108, pp. 332-335Ren, Z., Zhu, K., Kang, H., A randomized controlled phase II study of the prophylactic effect of urea-based creamon the hand-foot skin reaction associated with sorafenib in advanced hepatocellular carcinoma (2012) J Clin Oncol, 30 (SUPPL.). , abstr 4008Ruhstaller, T., Ribi, K., Sun, H., Prevention of palmoplantar erythrodysesthesia (PPE) with an antiperspirant in breast cancer patients treated with pegylated liposomal doxorubicin (PLD), a placebo-controlled, double blinded, phase lll trial (SAKK 92/08) (2012) J Clin Oncol, 30 (SUPPL.). , abstr 9059Von Gruenigen, V., Frasure, H., Fusco, N., A double-blind, randomized trial of pyridoxine versus placebo for the prevention of pegylated liposomal doxorubicin-related hand-foot syndrome in gynecologic oncology patients (2010) Cancer, 116, pp. 4735-4743Wolf, S.L., Qin, R., Menon, S.P., Placebo-controlled trial to determine the effectiveness of a urea/lactic acid-based topical keratolytic agent for prevention of capecitabine-induced hand-foot syndrome: North Central Cancer Treatment Group Study N05C5 (2010) J Clin Oncol, 28, pp. 5182-5187Yoshimoto, N., Yamashita, T., Fujita, T., Impact of prophylactic pyridoxine on occurrence of hand-foot syndrome in patients receiving capecitabine for advanced or metastatic breast cancer (2010) Breast Cancer, 17, pp. 298-302Zhang, R.X., Wu, X.J., Lu, S.X., The effect of COX-2 inhibitor on capecitabine-induced hand-foot syndrome in patients with stage II/III colorectal cancer: A phase II randomized prospective study (2011) J Cancer Res Clin Oncol, 137, pp. 953-957Zhang, R.X., Wu, X.J., Wan, D.S., Celecoxib can prevent capecitabine-related hand-foot syndrome in stage II and III colorectal cancer patients: Result of a single-center, prospective randomized phase III trial (2012) Ann Oncol, 23, pp. 1348-1353Kawaguchi, K., Ishiguro, H., Morita, S., Correlation between docetaxel-induced skin toxicity and the use of steroids and H(2) blockers: A multi-institution survey (2011) Breast Cancer Res Treat, 130, pp. 627-634Nardone, B., Hensley, J.R., Kulik, L., The effect of hand-foot skin reaction associated with the multikinase inhibitors sorafenib and sunitinib on health-related quality of life (2012) J Drugs Dermatol, 11, pp. e61-e65Gressett, S.M., Stanford, B.L., Hardwicke, F., Management of hand-foot syndrome induced by capecitabine (2006) Journal of Oncology Pharmacy Practice, 12 (3), pp. 131-141. , DOI 10.1177/1078155206069242Rose, P.G., Pegylated liposomal doxorubicin: Optimizing the dosing schedule in ovarian cancer (2005) Oncologist, 10, pp. 205-214Adams, R.A., Meade, A.M., Madi, A., Toxicity associated with combination oxaliplatin plus fluoropyrimidine with or without cetuximab in the MRC COIN trial experience (2009) Br J Cancer, 100, pp. 251-258Maughan, T.S., Adams, R.A., Smith, C.G., Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: Results of the randomised phase 3 MRC COIN trial (2011) Lancet, 377, pp. 2103-2114Johnsen, S.P., Larsson, H., Tarone, R.E., McLaughlin, J.K., Norgard, B., Friis, S., Sorensen, H.T., Risk of hospitalization for myocardial infarction among users of rofecoxib, celecoxib, and other NSAIDs: A population-based case-control study (2005) Archives of Internal Medicine, 165 (9), pp. 978-984. , DOI 10.1001/archinte.165.9.978Chen, Y.F., Jobanputra, P., Barton, P., Cyclooxygenase-2 selective non-steroidal anti-inflammatory drugs (etodolac, meloxicam, celecoxib, rofecoxib, etoricoxib, valdecoxib and lumiracoxib) for osteoarthritis and rheumatoid arthritis: A systematic review and economic evaluation (2008) Health Technol Assess, 12, pp. 1-278+iiiFuchs, C.S., Marshall, J., Mitchell, E., Wierzbicki, R., Ganju, V., Jeffery, M., Schulz, J., Barrueco, J., Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: Results from the BICC-C study (2007) Journal of Clinical Oncology, 25 (30), pp. 4779-4786. , http://jco.ascopubs.org/cgi/reprint/25/30/4779, DOI 10.1200/JCO.2007.11.3357Fabian, C.J., Molina, R., Slavik, M., Dahlberg, S., Giri, S., Stephens, R., Pyridoxine therapy for palmar-plantar erythrodysesthesia associated with continuous 5-fluorouracil infusion (1990) Investigational New Drugs, 8 (1), pp. 57-6

Electrocatalytic Determination Of Reduced Glutathione In Human Erythrocytes

The determination of reduced glutathione (GSH) in human erythrocytes using a simple, fast and sensitive method employing a glassy carbon electrode modified with cobalt tetrasulfonated phthalocyanine (CoTSPc) immobilized in poly(l-lysine) (PLL) film was investigated. This modified electrode showed very efficient electrocatalytic activity for anodic oxidation of GSH, decreasing substantially the anodic overpotentials for 0.2 V versus Ag/AgCl. The modified electrode presented better performance in 0.1 mol l-1 piperazine-N,N-bis(2-ethanesulfonic acid) buffer at pH 7.4. The other experimental parameters, such as the concentration of CoTSPc and PLL in the membrane preparation, pH, type of buffer solution and applied potential, were optimized. Under optimized operational conditions, a linear response from 50 to 2,160 nmol l-1 was obtained with a high sensitivity of 1.5 nA l nmol-1 cm-2. The detection limit for GSH determination was 15 nmol l-1. The proposed sensor presented good repeatability, evaluated in terms of the relative standard deviation (1.5%) for n∈=∈10. The modified electrode was applied for determination of GSH in erythrocyte samples and the results were in agreement with those obtained by a comparative method described in the literature The average recovery for these fortified samples was 100∈±∈1)%. 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Multidisciplinary approach in the treatment of patients with small cell bladder carcinoma

Small cell carcinoma of the urinary bladder (SCCUB) is considered to be a tumor with a neuroendocrine phenotype characterised by aggressive behaviour and poor prognosis. Small cell carcinoma of the urinary bladder comprises 0.35 to 1% of all bladder cancers and is frequently observed in combination with other histological subtypes of carcinoma. Clinical presentation is characterized by advanced stage at diagnosis and rapidly progressive disease. In daily clinical practice there is no gold standard for the management of patients affected by this disease. Treatment of patients with limited disease combines neoadjuvant platinum-based chemotherapy followed by specific local treatment of the primary tumour. Cystectomy or radiotherapy should be proposed on an individual basis. In the metastatic setting, prognosis remains poor with a potential benefit from chemotherapy containing platinum compounds. Treatment of small cell carcinoma of the urinary bladder is based on evidence obtained from case reports and retrospective analyses. Due to low disease frequency there is a lack of randomized trials to provide guidance as to optimal therapy. Thus, systemic and local approaches are extrapolated from the literature available for the treatment of small cell carcinomas at other (non-urological) sites. We provide an overview of the currently available literature with it's main focus on the treatment of either locally advanced or metastatic small cell carcinoma of the urinary bladder

Heterozigose individual e materna sobre o ganho de peso do nascimento ao desmame de terneiros Pampiano-Braford Individual and maternal heterozigosis on preweaning weight gain of Pampiano-Braford calves

Foram analisados dados de ganho de peso do nascimento ao desmame (GNDa) de animais Pampiano-Braford (cruzamento de Nelore X Hereford) criados no Rio Grande do Sul com a finalidade de verificar a influência da heterose individual (HI) e materna (HM) sobre o GNDa e quantificá-la. Os dados foram pré-ajustados para idade da vaca (IV), data juliana de nascimento (DJN) e idade do terneiro ao desmame (IT). Entretanto, análises exploratórias sugeriram que as pré-correções para IV, DJN e IT não estão ajustando corretamente os dados (P<0,01) no período pré-desmame. Em função da estrutura e conexidade do conjunto de dados, as análises foram realizadas de duas maneiras distintas. Em uma primeira etapa, estimou-se simultaneamente HI e HM a partir de um arquivo contendo 4186 animais (arquivo 2), obtendo-se valores de 31,91 e 33,53kg, respectivamente. Na segunda etapa, estimou-se HI a partir de um subconjunto do arquivo 2 (subconjunto 1) com 1507 registros com heterozigose materna 0,0000 e HM de outro subconjunto do arquivo 2 (subconjunto 2) com 2777 registros com heterozigose materna individual 0.5000; os valores estimados foram 13,79 e 34,08kg, respectivamente. Todos os valores de heterose sobre o GNDa encontrados foram significativos (P<0,01), e a relação entre heterose e heterozigose para esta característica apresentou um comportamento linear (P<0,01), considerando-se que o cruzamento estudado foi somente entre uma raça taurina e uma zebuína. Verificou-se que neste trabalho, os animais Hereford possuíam valor genético aditivo superior ao dos cruzados, todavia o mesmo não foi suficiente para contrabalançar os efeitos da heterose sobre o GNDa. Na comparação com os valores utilizados pelo Método GenSys, os valores de HI e HM, obtidos no presente trabalho, produziram diferenças na ordem de classificação de produtos ao desmame, mas o número de animais selecionados em comum pelos dois métodos não sofreu grandes mudanças. As vacas com composição racial 1/2 tiveram o melhor desempenho no GNDa, enquanto os terneiros com heterozigose individual máxima (composição racial 1/2) foram superados pelos 3/8 (filhos de vacas 1/2), quando se inclui a HM no desempenho dos mesmos, salientando a importância da HM sobre o GNDa.<br>Data on preweanning gain (GNDa) of Pampiano-Braford animals raised in Rio Grande do sul were analyzed to verify the influence of individual (HI) and maternal (HM) heterosis in GNDa, and to quantify it. Data were adjusted for dam age (IV), julian birth date (DJN)and calf age at weaning,(IT). However, exploratory analysis have suggested that the adjustment factors for IV, DJN, and IT are not doing this adjustment correctly (P<0.01). Because of the structure and connectedness of the major data set, the analysis was done in two different ways. In the first phase, HI and HM were estimated simultaneously, in file 2, compose of 4186 animals, and the values obtained were 31.91 and 33.53kg, respectively. In the second phase, HI was estimated in a subset of file 2 (subset 1) compose of 1507 animals with maternal heterozigosis 0.0000; HM was estimated in subset 2 of file 2 with 2777 animals with individual heterozigozis 0.5000. The values found were 13.79 and 34.08kg, respectively. All the values found for heterosis on GNDa were significant (P <0.01), and the relation between heterosis and heterozigosis for this characteristic was linear (P< 0.01). It was show that the Hereford animals, in this study, had greater genetic additive values than crossbreeds, but this difference was not sufficient to supress the effects of heterosis on GNDa. In comparison with the values used in GenSys Method, the HI and HM values, obtained in this study produced a change in the ranking of calves at preweaning, but the number of animals chosen in common by the two methods did not differ much. The cows with 1/2 breed composition had the best performance on GNDa, while the calves with maximum heterosis (breed composition 1/2) were excelled by those 3/8, when HM was included in the performance, emphasizing the importance of HM on GNDa