Tissue-specific regulation of IRS-1 in unilaterally nephrectomized rats

FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCNPQ – CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOInsulin stimulates the tyrosine kinase activity of its receptor, resulting in the phosphorylation of its cytosolic substrate, insulin receptor substrate 1 (IRS-1). IRS-1 is also a substrate for different peptides and growth factors, and a transgenic mouse knockout for this protein does not have normal growth. However, the role of IRS-1 in kidney hypertrophy and/or hyperplasia was not investigated. In the present study we investigated IRS-1 protein and tyrosine phosphorylation levels in the remnant kidney after unilateral nephrectomy (UNX) in 6-week-old male Wistar rats. After insulin stimulation the levels of insulin receptor and IRS-1 tyrosine phosphorylation were reduced to 79 ± 5% (P<0.005) and 58 ± 6% (P<0.0001), respectively, of the control (C) levels, in the remnant kidney. It is possible that a circulating factor and/or a local (paracrine) factor playing a role in kidney growth can influence the early steps of insulin action in parallel. To investigate the hypothesis of a circulating factor, we studied the early steps of insulin action in liver and muscle of unilateral nephrectomized rats. There was no change in pp185 tyrosine phosphorylation levels in liver (C 100 ± 12% vs UNX 89 ± 9%, NS) and muscle (C 100 ± 22% vs UNX 91 ± 17%, NS), and also there was no change in IRS-1 phosphorylation levels in both tissues. These data demonstrate that after unilateral nephrectomy there is a decrease in insulin-induced insulin receptor and IRS-1 tyrosine phosphorylation levels in kidney but not in liver and muscle. It will be of interest to investigate which factors, probably paracrine ones, regulate these early steps of insulin action in the contralateral kidney of unilaterally nephrectomized rats.Insulin stimulates the tyrosine kinase activity of its receptor, resulting in the phosphorylation of its cytosolic substrate, insulin receptor substrate 1 (IRS-1). IRS-1 is also a substrate for different peptides and growth factors, and a transgenic mouse knockout for this protein does not have normal growth. However, the role of IRS-1 in kidney hypertrophy and/or hyperplasia was not investigated. In the present study we investigated IRS-1 protein and tyrosine phosphorylation levels in the remnant kidney after unilateral nephrectomy (UNX) in 6-week-old male Wistar rats. After insulin stimulation the levels of insulin receptor and IRS-1 tyrosine phosphorylation were reduced to 79 ± 5% (P<0.005) and 58 ± 6% (P<0.0001), respectively, of the control (C) levels, in the remnant kidney. It is possible that a circulating factor and/or a local (paracrine) factor playing a role in kidney growth can influence the early steps of insulin action in parallel. To investigate the hypothesis of a circulating factor, we studied the early steps of insulin action in liver and muscle of unilateral nephrectomized rats. There was no change in pp185 tyrosine phosphorylation levels in liver (C 100 ± 12% vs UNX 89 ± 9%, NS) and muscle (C 100 ± 22% vs UNX 91 ± 17%, NS), and also there was no change in IRS-1 phosphorylation levels in both tissues. These data demonstrate that after unilateral nephrectomy there is a decrease in insulin-induced insulin receptor and IRS-1 tyrosine phosphorylation levels in kidney but not in liver and muscle. It will be of interest to investigate which factors, probably paracrine ones, regulate these early steps of insulin action in the contralateral kidney of unilaterally nephrectomized rats301011631167FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCNPQ – CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCNPQ – CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOsem informaçãosem informaçã

Magnetic Resonance Image In The Diagnosis And Evaluation Of Extra-prostatic Extension And Involvement Of Seminal Vesicles Of Prostate Cancer: A Systematic Review Of Literature And Meta-analysis.

Systematic review of literature and meta-analysis to evaluate the results of magnetic resonance image 1.5T with endorectal coil in the diagnosis and evaluation of extra-prostatic extension and involvement of seminal vesicles of prostate cancer, compared to the histopathological results of the radical prostatectomy specimen. It was conducted a systematic review of literature and meta-analyses of all studies data published after 2008. In those studies, the patients with prostate cancer with indication to radical prostatectomy were submitted to magnetic resonance image (MRI) at pre-operatory period and the results were compared to those of histopathological studies after the surgery. The selected terms for research included prostate cancer, magnetic resonance, radical prostatectomy, and prostate cancer diagnosis, in the databases EMBASE, LILACS, PUBMED/MEDLINE and Cochrane Library. The data were collected using a specific qualitative instrument and the meta-analysis data were presented in the forest plot graphics, homogeneity test and sROC curves and funnel plot. A total of seven studies were included, with a total of 603 patients. Among these studies, six evaluated the value of MRI for the detection of prostate cancer, and the median sensitivity of meta-analysis was 0.6 and specificity 0.58, but with heterogeneity among the studies. Three studies evaluated extra-prostatic extension with a median sensitivity of 0.49, specificity 0.82 and heterogeneity only for sensitivity. Three studies evaluated invasion of seminal vesicles, with median sensitivity of 0.45 and specificity 0.96, with heterogeneity in both analysis. Magnetic resonance of 1.5T with endocoil showed low values of sensitivity and specificity for the diagnosis and staging of prostate cancer. The reviewed studies showed a significant heterogeneity among them. The best observed result was MRI specificity for invasion of seminal vesicles. More studies are necessary to evaluate new techniques and parameters before recommending the routine use of MRI in clinical practice.39215516

Cost-effectiveness Analysis Of Adjuvant Anastrozol In Postmenopausal Women With Breast Cancer [estudo De Custo-efetividade Do Anastrozol Adjuvante No Câncer De Mama Em Mulheres Pós-menopausa]

Objectives. Carry out an economic analysis of the incorporation of anastrozole as adjuvant hormone therapy in postmeno-pausal women with breast cancer in a Brazilian setting. Methods. The cost-effectiveness estimate comparing anastrozole to tamoxifen was made from the perspectives of the patient, private health insurance, and government. A Markov model was designed based on data from ATAC trial after 100 months follow-up in a hypothetical cohort of 1000 postmeno-pausal women in Brazil, using outcomes projections for a 25-year period. Resource utilization and associated costs were obtained from preselected sources and specialists' opinions. Treatment costs varied according to the perspective used. The incremental benefit was inserted in the model to obtain the cost of quality-adjusted life-year gained (QALY). Results. Benefit extrapolations for a 25-year time line showed an estimate of 0.29 QALY gained with anastrozole compared to tamoxifen. The cost-effectiveness ratio per QALY gained depended on which perspective was used. There was an increment of R$32.403,00/QALY in the public health system/ government, R$ 32.230,00/QALY for private health system, and R$ 55.270,00/QALY for patients. Conclusion. The benefit from adjuvant anastrozole in post-menopausal patients with breast cancer is associated to major differences in cost-effectiveness ratio and varies with the different perspectives. According to current WHO parameters, the increment is considered acceptable under public and private health system perspectives, but not from that of the patient.555535540(2006), http:www.inca.gov.br/estimativa, Instituto Nacional do Câncer - INCA, Estimativa 2008: incidência de cancer no Brasil. 2008 [citado 01 set 2008]. Disponível emBanco de dados do Registro Hospitalar de Câncer. 2008, , http://www.fosp.saude.sp.gov.br, Fundação Oncocentro do Estado de São Paulo - FOSP, [citado 15 ago 2008]. Disponível emKapoor, A., Vogel, V.G., Prognostic factors for breast cancer and their use in the clinical setting (2005) Expert Rev Anticancer Ther., 5 (2), pp. 269-81Hochster, H.S., Capecitabine plus oxaliplatin vs infusional 5-fluorouracil plus oxaliplatin in the treatment of colorectal cancer. Con: Pumpin FU (or, avoiding that oral fixation) (2005) Clin Adv Hematol Oncol., 3 (5), pp. 405-6Rochefort, H., Borgna, J.L., Differences between oestrogen receptor activation by oestrogen and antioestrogen (1981) Nature, 292 (5820), pp. 257-9Forbes, J.F., Cuzick, J., Buzdar, A., Howell, A., Tobias, J.S., Baum, M., Effect of anas-trozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial (2008) Lancet Oncol., 9 (1), pp. 45-53Howell, A., Cuzick, J., Baum, M., Buzdar, A., Dowsett, M., Forbes, J.F., Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years adjuvant treatment for breast cancer (2005) Lancet, 365 (9453), pp. 60-2Duffy, S.R., Distler, W., Howell, A., Cuzick, J., Baum, M., A lower incidence of gynecologic adverse events and interventions with anastrozole than with tamoxifen in the ATAC trial (2009) Am J Obstet Gynecol., 200 (1). , 80 e1-7Colozza, M., Califano, R., Minenza, E., Dinh, P., Azambuja, E., Aromatase inhibitors: A new reality for the adjuvant endocrine treatment of early-stage breast cancer in postmenopausal women (2008) Mini Rev Med Chem., 8 (6), pp. 564-74Balducci, L., Treating elderly patients with hormone sensitive breast cancer: What do the data show? (2009) Cancer Treat Rev., 35 (1), pp. 47-56Buzdar, A., Howell, A., Cuzick, J., Wale, C., Distler, W., Hoctin-Boes, G., Comprehensive side-effect profile of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: Long-term safety analysis of the ATAC trial (2006) Lancet Oncol., 7 (8), pp. 633-43Mano, M., The burden of scientific progress: Growing inequalities in the delivery of cancer care (2006) Acta Oncol., 45 (1), pp. 84-6Barros, A.J., Bertoldi, A.D., Out-of-pocket health expenditurein a population covered by the Family Health Program in Brazil (2008) Int J Epidemiol., 37 (4), pp. 758-65Mansel, R., Locker, G., Fallowfield, L., Benedict, A., Jones, D., Cost-effectiveness analysis of anastrozole vs tamoxifen in adjuvant therapy for early stage breast cancer in the United Kingdom: The 5-year completed treatment analysis of the ATAC (Arimidex, Tamoxifen alone or in combination) trial (2007) Br J Cancer, 97 (2), pp. 152-61Moeremans, K., Annemans, L., Cost-effectiveness of anastrozole compared to tamoxifen in hormone receptor-positive early breast cancer. Analysis based on the ATAC trial (2006) Int J Gynecol Cancer, 16 (SUPPL. 2), pp. 576-8Locker, G.Y., Mansel, R., Cella, D., Dobrez, D., Sorensen, S., Gandhi, S.K., Cost-effectiveness analysis of anastrozole versus tamoxifen as primary adjuvant therapy for postmenopausal women with early breast cancer: A US healthcare system perspective. The 5-year completed treatment analysis of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial (2007) Breast Cancer Res Treat, 106 (2), pp. 229-38Rocchi, A., Verma, S., Anastrozole is cost-effective vs tamoxifen as initial adjuvant therapy in early breast cancer: Canadian perspectives on the ATAC completed- treatment analysis (2006) Support Care Cancer, 14 (9), pp. 917-27Sonnenberg, F.A., Beck, J.R., Markov models in medical decision making: A practical guide (1993) Med Decis Making, 13 (4), pp. 322-38Kamby, C., Sengelov, L., Pattern of dissemination and survival following isolated locoregional recurrence of breast cancer. A prospective study with more than 10 years of follow up (1997) Breast Cancer Res Treat, 45 (2), pp. 181-92Anexo da Revista ABCFARMA - Lista de Preços. Fevereiro 2008. Ano 16, Edição 198Associação Médica Brasileira. Classificação Brasileira Hierarquizada de Procedimentos Médicos. Setembro 2008, 5a. edição. ISBN 85-89073-03-3Sorensen, S.V., Benedict, A., Flood, D., Revicki, D., Brown, R., Patient-rated utilities in postmenopausal early breast cancer (EBC): A cross-country comparison (2004) Value Health, 7 (6), pp. 641-2Muennig, P., (2002) Designing and conducting cost-effectiveness analyses in medicine and health careMeropol, N.J., Schulman, K.A., Cost of cancer care: Issues and implications (2007) J Clin Oncol., 25 (2), pp. 180-6Rawlins, M., Paying for modern cancer care--a global perspective (2007) Lancet Oncol., 8 (9), pp. 749-5

Duration Of Chemotherapy For Metastatic Non-small-cell Lung Cancer: More May Be Not Better

[No abstract available]2735Soon, Y.Y., Stockler, M.R., Askie, L.M., Duration of chemotherapy for advanced non-small-cell lung cancer: A systematic review and meta-analysis of randomized trials (2009) J Clin Oncol, 27, pp. 3277-3283Chemotherapy in non-small cell lung cancer: A meta-analysis using updated data on individual patients from 52 randomised clinical trials: Non-small Cell Lung Cancer Collaborative Group (1995) BMJ, 311, pp. 899-909Ciuleanu, T.E., Brodowicz, C., Belani, C.P., Maintenance pemetrexed plus best supportive care (BSC) versus placebo plus BSC: A phase III study (2008) J Clin Oncol, 26. , abstr 8011, 426sLima, J.P., dos Santos, L.V., Sasse, E.C., Optimal duration of first-line chemotherapy for advanced non-small cell lung cancer: A systematic review with meta-analysis (2009) Eur J Cancer, 45, pp. 601-60

Camptothecins Compared With Etoposide In Combination With Platinum Analog In Extensive Stage Small Cell Lung Cancer: Systematic Review With Meta-analysis

Superiority of camptothecin regimens over etoposide-both combined with platinum analogs-in extensive disease small cell lung cancer has been a matter of debate with contradictory findings in randomized trials. A systematic review was sought to elucidate this issue. Methods: Randomized controlled trials comparing first-line camptothecin-platinum doublets versus etoposide-platinum doublets in patients with extensive disease small cell lung cancer were searched in MEDLINE, EMBASE, LILACS, and CENTRAL databases, European Society of Medical Oncology, American Society of Clinical Oncology, and International Association for the Study of Lung Cancer meeting sites. Meta-analyses were performed using fixed-effects model. Subgroup analyses were undertaken comparing each type of camptothecin to etoposide-based regimens. The outcomes of interest were overall survival (OS), progression-free survival (PFS), response rate (RR), and toxicities. Results: Eight studies (3086 patients) were included. The meta-analysis of topotecan regimens (TP) was not reliable due to impending heterogeneity. Meta-analysis of trials testing irinotecan combinations (IP) versus etoposide regimens (EP; 1561 patients) stated an OS improvement in favor of IP arm, though with considerable heterogeneity, whose origin seemed to be a Japanese trial. In the analyses without that study (1407 patients left), IP brought a significant improvement in OS (hazard ratio = 0.87; 95% confidence interval 0.78-0.97; p = 0.02; I 2 = 0). IP also increased PFS (hazard ratio = 0.83; 95% confidence interval 0.73-0.95; p = 0.006; I 2 = 0%). There was no impact in RR (absolute RR 56% with IP; 53% with EP; p = 0.17). IP caused more diarrhea (p < 0.0001) but less hematological toxicities (p < 0.001) than EP. Conclusions: The present meta-analysis demonstrates statistically significant OS and PFS benefits of IP over EP regimens in western and eastern patients. Specific characteristics of safety profile should be taken into account when administrating IP chemotherapy. Copyright © 2010 by the International Association for the Study of Lung Cancer.51219861993Parkin, D.M., Bray, F., Ferlay, J., Global cancer statistics 2002 (2005) CA Cancer J. Clin., 55, pp. 74-108Lara Jr., P.N., Natale, R., Crowley, J., Phase III trial of irinotecan/ cisplatin compared with etoposide/cisplatin in extensive-stage small-cell lung cancer: Clinical and pharmacogenomic results from SWOG S0124 (2009) J. Clin. 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Eval. Clin. Pract., 14, pp. 951-957Hande, K., Messenger, M., Wagner, J., Krozely, M., Kaul, S., Inter- and intrapatient variability in etoposide kinetics with oral and intravenous drug administration (1999) Clinical Cancer Research, 5 (10), pp. 2742-2747Hande, K.R., Krozely, M.G., Greco, F.A., Bioavailability of low-dose oral etoposide (1993) J. Clin. Oncol., 11, pp. 374-377Hotta, K., Kiura, K., Fujiwara, Y., Association between incremental gains in the objective response rate and survival improvement in phase III trials of first-line chemotherapy for extensive disease small-cell lung cancer (2009) Ann. Oncol., 20, pp. 829-834Yao, N., Jiang, L., Yang, K., Irinotecan/cisplatin versus etoposide/cisplatin for patients with extensive stage small cell lung cancer: A systematic review (2009) Chin. J. Lung. Cancer, 12, pp. 884-88

Pharmacoeconomic Evaluation Of Eligard® And Other Lhrh Analogues As Androgen Deprivation Therapy For Advanced And Metastatic Prostate Cancer [avaliação Farmacoeconômica De Diferentes Apresentações De Eligard® E Outros Análogos Lhrh Para Supressão Androgênica Em Pacientes Com Câncer De Próstata Avançado Ou Metastático]

[No abstract available]715135141Siegel, R., Ma, J., Zou, Z., Jemal, A., Cancer statistics, 2014 (2014) CA: A Cancer Journal for Clinicians, 64, pp. 9-29Cooperberg, M.R., Lubeck, D.P., Meng, M.V., Mehta, S.S., Carroll, P.R., The changing face of low-risk prostate cancer: Trends in clinical presentation and primary management (2004) Journal of Clinical Oncology, 22 (11), pp. 2141-2149. , DOI 10.1200/JCO.2004.10.062Rodrigues, N.A., Chen, M.-H., Catalona, W.J., Roehl, K.A., Richie, J.P., D'Amico, A.V., Predictors of mortality after androgen-deprivation therapy in patients with rapidly rising prostate-specific antigen levels after local therapy for prostate cancer (2006) Cancer, 107 (3), pp. 514-520. , DOI 10.1002/cncr.22018White, J.W., I. The Results of Double Castration in Hypertrophy of the Prostate (1895) Annals of Surgery, 22, pp. 1-80Huggins, C., Hodges, C.V., Studies on prostatic cancer: I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. 1941 (2002) The Journal of Urology, 168, pp. 9-12Seidenfeld, J., Samson, D.J., Hasselblad, V., Aronson, N., Albertsen, P.C., Bennett, C.L., Wilt, T.J., Single-therapy androgen suppression in men with advanced prostate cancer: A systematic review and meta-analysis (2000) Annals of Internal Medicine, 132 (7), pp. 566-577Conn, P.M., Crowley Jr., W.F., Gonadotropin-releasing hormone and its analogues (1991) N Engl J Med, 324, pp. 93-103Lepor, H., Comparison of single-agent androgen suppression for advanced prostate cancer (2005) Reviews in Urology, 7 (SUPPL. 5), pp. S3-S12Fleming, M.T., Morris, M.J., Heller, G., Scher, H.I., Post-therapy changes in PSA as an outcome measure in prostate cancer clinical trials (2006) Nature Clinical Practice Oncology, 3 (12), pp. 658-667. , DOI 10.1038/ncponc0664, PII NCPONC0664Sartor, O., Eligard: Leuprolide acetate in a novel sustained-release delivery system (2003) Urology, 61 (2 SUPPL.), pp. 25-31. , DOI 10.1016/S0090-4295(02)02396-8, PII S0090429502023968Eisenberger, M.A., Blumenstein, B.A., Crawford, E.D., Miller, G., McLeod, D.G., Loehrer, P.J., Wilding, G., Lowe, B.A., Bilateral orchiectomy with or without flutamide for metastatic prostate cancer (1998) New England Journal of Medicine, 339 (15), pp. 1036-1042. , DOI 10.1056/NEJM199810083391504Berthold, D.R., Pond, G.R., Soban, F., De Wit, R., Eisenberger, M., Tannock, I.F., Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: Updated survival in the TAX 327 study (2008) J Clin Oncol, 26, pp. 242-245Tannock, I.F., De Wit, R., Berry, W.R., Horti, J., Pluzanska, A., Chi, K.N., Oudard, S., Eisenberger, M.A., Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer (2004) New England Journal of Medicine, 351 (15), pp. 1502-1512. , DOI 10.1056/NEJMoa040720De Bono, J.S., Logothetis, C.J., Molina, A., Abiraterone and increased survival in metastatic prostate cancer (2011) N Engl J Med, 364, pp. 1995-2005Ryan, C.J., Smith, M.R., De Bono, J.S., Abiraterone in metastatic prostate cancer without previous chemotherapy (2013) N Engl J Med, 368, pp. 138-148Kelly, W.K., Halabi, S., Carducci, M., Randomized, double-blind, placebo-controlled phase III trial comparing docetaxel and prednisone with or without bevacizumab in men with metastatic castrationresistant prostate cancer: CALGB 90401 (2012) J Clin Oncol, 30, pp. 1534-1540De Bono, J.S., Oudard, S., Ozguroglu, M., Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: A randomised open-label trial (2010) Lancet, 376, pp. 1147-1154Wex, J., Sidhu, M., Odeyemi, I., Abou-Setta, A.M., Retsa, P., Tombal, B., Leuprolide acetate 1-, 3- and 6-monthly depot formulations in androgen deprivation therapy for prostate cancer in nine European countries: Evidence review and economic evaluation (2013) Clinico-Economics and Outcomes Research: CEOR, 5, pp. 257-26

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? [4] (2005) Annals of Oncology, 16 (7), pp. 1210-1211. , DOI 10.1093/annonc/mdi204Sibaud, V., Dalenc, F., Chevreau, C., HFS-14, a specific quality of life scale developed for patients suffering from hand-foot syndrome (2011) Oncologist, 16, pp. 1469-1478Von Moos, R., Thuerlimann, B.J., Aapro, M., Pegylated liposomal doxorubicin-associated hand-foot syndrome: Recommendations of an international panel of experts (2008) Eur J Cancer, 44, pp. 781-790Trotti, A., Colevas, A.D., Setser, A., Rusch, V., Jaques, D., Budach, V., Langer, C., Rubin, P., CTCAE v3.0: Development of a comprehensive grading system for the adverse effects of cancer treatment (2003) Seminars in Radiation Oncology, 13 (3), pp. 176-181. , DOI 10.1016/S1053-4296(03)00031-6Egger, M., Smith, G.D., Schneider, M., Minder, C., Bias in meta-analysis detected by a simple, graphical test (1997) British Medical Journal, 315 (7109), pp. 629-634Sterne, J.A.C., Egger, M., Funnel plots for detecting bias in meta-analysis: Guidelines on choice of axis (2001) Journal of Clinical Epidemiology, 54 (10), pp. 1046-1055. , DOI 10.1016/S0895-4356(01)00377-8, PII S0895435601003778(2011) Review Manager V5.1. 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

HEALTH ECONOMIC EVALUATION OF BIOLOGIC AGENTS FOR METASTATIC COLORECTAL CANCER PATIENTS IN BRAZIL

Objectives: To evaluate the cost-effectiveness of different treatment strategies for metastatic colorectal cancer (mCRC) in the Brazilian public health system (SUS). Methods: We built a Markov model to analyze costs and impacts of the incorporation of cetuximab (CET) or bevacizumab (BEV) to standard therapy (FOLFOX and FOLFIRI), over a time horizon of 10 years. Depending on KRAS status, the patients were assumed to receive one of these sequential schedules: (1) FOLFOX ® FOLFIRI; (2) FOLFIRI± CET ® FOLFOX + BEV; (3) FOLFIRI + CET or BEV ® FOLFOX; and (4) FOLFIRI + BEV ® FOLFOX + BEV ® Irinotecan ± CET. Efficacy data were derived from randomized clinical trials and treatment costs from price tables issued by the Health Ministry. Sensitivity analyses were undertaken to explore uncertainty. Adoption of infusion pumps was investigated as an alternative strategy. Results: Compared to chemotherapy, the incorporation of the CET and BEV resulted in an incremental effectiveness ranging from 23 to 32 life years, and a considerable cost differences, as total costs ranged from US$30,053 to around US$96,020. Strategy 2 resulted in an incremental cost-effectiveness ratio of US$182,617 compared to standard therapy, which far exceeds the pre-specified threshold for cost-effectiveness (U$28,715) considered. Strategies 3 and 4 were dominated by strategy 2 Acquisition of biological agents was the principal driver of the cost difference. Adopting an infusion pump for use at home for 100% of patients could reduce around 45% of the total costs of chemotherapy. Conclusions: From the SUS perspective, and at current prices, biologic agents are not cost-effective for the treatment of mCRC. Chemotherapy continues to be the most cost-effective approach. Home infusion should be promoted to be the standard of care for Brazilian mCRC-patients

Tissue-specific regulation of IRS-1 in unilaterally nephrectomized rats

Insulin stimulates the tyrosine kinase activity of its receptor, resulting in the phosphorylation of its cytosolic substrate, insulin receptor substrate 1 (IRS-1). IRS-1 is also a substrate for different peptides and growth factors, and a transgenic mouse "knockout" for this protein does not have normal growth. However, the role of IRS-1 in kidney hypertrophy and/or hyperplasia was not investigated. In the present study we investigated IRS-1 protein and tyrosine phosphorylation levels in the remnant kidney after unilateral nephrectomy (UNX) in 6-week-old male Wistar rats. After insulin stimulation the levels of insulin receptor and IRS-1 tyrosine phosphorylation were reduced to 79 ± 5% (P<0.005) and 58 ± 6% (P<0.0001), respectively, of the control (C) levels, in the remnant kidney. It is possible that a circulating factor and/or a local (paracrine) factor playing a role in kidney growth can influence the early steps of insulin action in parallel. To investigate the hypothesis of a circulating factor, we studied the early steps of insulin action in liver and muscle of unilateral nephrectomized rats. There was no change in pp185 tyrosine phosphorylation levels in liver (C 100 ± 12% vs UNX 89 ± 9%, NS) and muscle (C 100 ± 22% vs UNX 91 ± 17%, NS), and also there was no change in IRS-1 phosphorylation levels in both tissues. These data demonstrate that after unilateral nephrectomy there is a decrease in insulin-induced insulin receptor and IRS-1 tyrosine phosphorylation levels in kidney but not in liver and muscle. It will be of interest to investigate which factors, probably paracrine ones, regulate these early steps of insulin action in the contralateral kidney of unilaterally nephrectomized rats