New domestic processing methods: effect on potato nutritional composition

Background and objectives: Potatoes nutritional and bioactive features are influenced by thermal processing conditions, defining its nutritional composition and health impact. Consumers seek increasingly for faster domestic cooking methods, such as microwave cooking in alternative to current frying or baking. Also, several devices are being commercialized for healthier frying simulation, without a documented characterization of the final processed food nutritional data. Thus, this study aimed to assess and compare the influence of these domestic processing methods on the quality of potatoes processed with olive oil. Methods: Potatoes were processed by frying, baking, microwave and a low-fat frying device, with equivalent shape and olive oil amounts, except frying. Samples were evaluated for crude fat, fatty acid composition, vitamin E, total carotenoids and total phenols. Results: Microwave cooked potatoes presented similar fat contents as standard frying, higher than those achieved by baking or with the low-fat frying device tested, but the fatty acid composition was similar. Vitamin E loss was comparatively higher after frying but no significant differences were found for total carotenoids. Potatoes phenolic compounds were partially loss during cooking, being apparently higher after baking. Conclusions: The distinct nutritional features obtained highlight for the importance of detailing the food compositional tables regarding each processing method, including the “new” domestic methodologies, increasingly used by consumers

The consumption of generic medicaments: perception and level of knowledge

Introduction: The generic medicine has the same qualitative and quantitative composition in active substances, pharmaceutical form and dosage, administered by the same way with the same therapeutic indication and security than the reference medicine (1). Objectives: To analyze the perception and level of knowledge about generic medicines and to study the correlation with socio-economic variables such as education level, monthly medicines expenses, employment, age and gender. Materials and Methods: It was developed a cross-sectional study. A non-probabilistic sample of 381 individuals was collected in northern Portuguese localities during January and February 2015. To collect the data was applied a questionnaire developed by Lopes, Silva, Pinto e Ribeiro (2). Most respondents were female (53.5%) with ages between 18 and 88 years. Results and Discussion: The level of knowledge about generic medicines was very poor (14.8%); poor (21.0%); fair (39.9%); good (23.1%) and very good (1.2%). Most respondents (91.4%) consumed generic medicines although they consider that reference medicines are more effective. The level of knowledge is positive correlated with the education level and negatively correlated with age and monthly medicines expenses. Gender was associated with the level of knowledge. Employment wasn’t associated with the level of knowledge. Conclusion: A significative proportion of respondents were misinformed about generic medicines, preferring to consume the reference medicines that they consider more effective. According to the literature, doctors are primarily responsible by the scarce information provided to the patient about generic medicines and by not prescribing these medicines. References: 1. Branco, M. & Nunes, B. (2009). Uma observação sobre o consumo de Genéricos. Departamento de Epidemiologia. Instituto Nacional de Saúde, Doutor Ricardo Jorge. Lisboa. 2. Lopes, C.; Silva, F.; Pinto, Isabel; Ribeiro, Maria (2011). A perspectiva dos consumidores portugueses sobre os medicamentos de marca vs medicamentos genéricos. In XXV Encontro Nacional APLF. Coimbra

Incorporation of natural colorants obtained from edible flowers in yogurts

The substitution of artificial dyes by natural colouring agents is among the top concerns of food industry to fulfil current consuming trends, justifying the prospection of novel natural sources of these compounds. Herein, the hydrophilic extracts from rose, cornflower and dahlia were tested as potential substitutes to E163 (anthocyanin extract). Besides comparing the colouring capacity, the potential occurrence of changes in the chemical composition of yogurts (nutritional parameters, free sugars and fatty acids) was also assessed throughout storage (up to 7 days) and compared with a “blank” (free of any additive) yogurt formulation. In general, yogurts prepared with flower extracts, presented similar nutritional value and free sugars profile to those prepared with E163 and to the “blank” yogurt. Nevertheless, rose extract turned out to be the most suitable alternative to E163 as these two groups of yogurts had similar nutritional composition, free sugars and fatty acids composition, besides presenting close scores in colour parameters.The authors are grateful to the Foundation for Science and Technology (FCT, Portugal) for financial support to CIMO (strategic project UID/AGR/00690/2013), to REQUIMTE (national funds and cofinanced by FEDER, under the Partnership Agreement PT2020), Tânia Pires (SFRH/BD/129551/2017) and João C.M. Barreira and L. Barros contracts. The GIP-USAL is financially supported by the Spanish Government through the project AGL2015-64522-C2-2-R. The authors are also grateful to FEDER-Interreg España-Portugal programme for financial support through the project 0377_Iberphenol_6_E; the European Structural and Investment Funds (FEEI) through the Regional Operational Program North 2020, within the scope of Project NORTE- 01-0145-FEDER-023289: DeCodE and Project Mobilizador Norte-01- 0247-FEDER-024479: ValorNatural®.info:eu-repo/semantics/publishedVersio

Rosa canina L. as new food ingredient an source of bioactive compounds

Sustainable food options are increasing among the most concerned consumers, in which they seek to combine new ingredients with potential health benefits [1]. Edible flowers provide new colors, textures and vibrancy to any dish, and apart from the "glam" factor, they can provide bioactive compounds [2]. In the presentwork, the edible petals of Rosa canina L, gently supplied by the RBR Foods Company (Portugal), were tested for their cytotoxic activity against tumor cell lines. The assays were conducted in the hydromethanolic extract and in the lyophilized infusion, being both of them re-dissolved in water in order to obtain stock solutions at 100 mg/mL for successive dilutions until determination of Glso values (concentration that inhibits 50% of the net cell growth). Four human tumor cell lines were tested: MCF-7 (breast adenocarcinoma), NCIH460 (non-small cell lung câncer), HeLa (cervical carcinoma) and HepG2 (hepatocellular carcinoma). A non-tumour primary cells' culture (assigned as PLP2) was also prepared from a freshly harvested porcine liver, and used in the bioassays. Ellipticine was used as the positive contrai. While the hydromethanolic extract inhibited the growth of HeLa (308 pg/mL), the lyophilized infusion inhibited MCF-7 (377 pg/mL), respectively. Both extracts presented cytotoxicity for HepG2 (297 |jg/mL and 315 pg/mL for hydromethanolic extract and infusion, respectively). Nane of the extracts showed toxicity towards PLP2. After chemical characterization of the extracts, flavonoids were the only phenolic compounds present, being quercetin-3-O-glucoside and kaempferol-3-O-glucoside the major compounds present in both extracts. These results showed that R. canina edible flowers are sources of bioactive compounds related with cytotoxic properties in human tumor cell lines, highlighting their applicability potential in nutraceutical and pharmaceutical fields.The authors are grateful to lhe Foundation for Science and Technology (FCT, Portugal) and FEDER under Pmgramme PT2020 for financial support to CIMO (UID/AGR/00690/2013). L. Barras (SFR/BPD/107855/2015) and M. l. Dias (SFRH/BD/84485/2012) grants.info:eu-repo/semantics/publishedVersio

Antioxidant and antimicrobial properties of dried Portuguese apple variety (Malus domestica Borkh. cv Bravo de Esmolfe)

Malus domestica Borkh apples are one of the most consumed fruits in the world, due to their sweetness and flavour. Herein, ‘Bravo de Esmolfe’ apple fruits were characterized regarding their nutritional value, chemical composition and bioactive properties. Besides nutrients, flavan-3-ols (i.e., epicatechin and B-type procyanidins) as also hydroxycinnamoyl-quinic acids and phloretin derivatives were identified in the samples. Extracts prepared from ‘Bravo de Esmolfe’ also proved to have antioxidant activity and antibacterial effects against Gram-positive bacteria, namely methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA), Listeria monocytogenes and Enterococcus faecalis, and against the Gram-negative bacteria Escherichia coli, Escherichia coli (ESBL) (producing extended spectrum ß-lactamases) and Morganella morganii. There is very little information about ‘Bravo de Esmolfe’ apple, so this study is important to inform consumers about an alternative source of nutritional and bioactive compounds.info:eu-repo/semantics/publishedVersio

Consumo de medicamentos não sujeitos a receita médica: fatores associados

Medicamentos não sujeitos a receita médica são aqueles que se destinam ao tratamento de patologias com grau de gravidade inferior e que podem ser adquiridos sem receita médica, devido à sua elevada segurança e eficácia. Contudo, o seu uso inadequado pode acarretar vários riscos, levando ao aumento da mortalidade, morbidade, reações adversas e interações medicamentosas. A grande disponibilidade destes medicamentos leva à automedicação, arriscando-se a retardar o tratamento de uma patologia de maior gravidade. O objetivo do presente trabalho foi caracterizar o perfil de consumo de Medicamentos não Sujeitos a Receita Médica (MNSRM) e os fatores associados. O estudo é do tipo transversal, observacional e descritivo-correlacional. A população alvo foram os residentes nos concelhos de Baião, Porto de Mós e Santa Maria da Feira. A amostra, constituída por 390 indivíduos, foi do tipo acidental pelo que se considera não probabilística. O instrumento de recolha de dados que se utilizou foi um questionário. Para a análise estatística usaram-se medidas de tendência central e dispersão e aplicou-se o teste do qui-quadrado através do programa informático SPSS 23. Verificou-se que o género feminino é o maior consumidor de MNSRM (82,6%) e com a idade este consumo vai diminuindo. A idade mostrou diferenças estatisticamente significativas e relação ao uso de MNSRM (p-value = 0.040). A maioria dos inquiridos pratica automedicação (88,2%), pelo menos 4x/ano, devido a “pouca gravidade da situação” (66,2%). A gripe, constipação e tosse foram as situações que mais justificaram o uso de MNSRM (85,4%) e foram os analgésicos e antipiréticos (92,8%) os medicamentos mais utilizados. Quanto ao papel do profissional de Farmácia no aconselhamento de MNSRM verificou-se que os indivíduos solicitam aconselhamento (96,2%), que este é maioritariamente realizado com uma postura e linguagem adequadas, recolhendo todas as informações sobre o problema e mostrando boa disponibilidade para responder às dúvidas do utente. Os utentes confiam e seguem as recomendações dos profissionais de Farmácia aquando do aconselhamento. O consumidor de MNSRM é do sexo feminino, com idade entre os 18-24 anos e com o ensino secundário. Apresenta um conhecimento suficiente em relação aos MNSRM adquirido maioritariamente através dos profissionais de Farmácia.info:eu-repo/semantics/publishedVersio

Phenolic profile and effects of acetone fractions obtained from the inflorescences of: Calluna vulgaris (L.) Hull on vaginal pathogenic and non-pathogenic bacteria

The phenolic profile and the antibacterial activity against pathogenic commensal vaginal bacteria exhibited by different fractions of the acetone extract of heather was assessed. The acetone extract of Calluna vulgaris (L.) Hull was fractionated by silica gel column chromatography through an eluent system of increasing polarity, obtaining 10 different fractions (Fr 1 to Fr 10). The phenolic profile was analyzed by HPLCDAD- ESI/MS. Type B (epi)catechin dimers, (-)-epicatechin and (+)-catechin were the main phenolic compounds present in the fractions. The antibacterial activity was also analyzed against pathogenic bacteria and the effect in the beneficial microflora was also accessed. Some of the obtained fractions revealed the capacity to inhibit pathogenic microorganisms without affecting the beneficial microflora, especially Fr 7 and Fr 8. For instance, Neisseria gonorrhoeae was inhibited by both of the fractions, while Fr 7 was more active against Klebsiella pneumoniae and Morganella morganii, and Fr 8 against methicillin resistance Staphylococcus aureus (MRSA) and methicillin susceptible Staphylococcus aureus (MSSA), without affecting Lactobacillus strains. This study corroborates the therapeutic use of this matrix in traditional medicine.The authors are grateful to the Foundation for Science and Technology (FCT, Portugal) and FEDER under Programmer PT2020 for financial support to CIMO (UID/AGR/00690/2019), CQ-VR (UID/QUI/00616/2013), and to FEDER-Interreg España-Portugal program for financial support through the project 0377_Iberphenol_6_E. The authors are also grateful to the Foundation for Science and Technology (FCT, Portugal) for Sandrina A. Heleno (SFRH/BPD/101413/2014) grant and L. Barros contract.info:eu-repo/semantics/publishedVersio

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. Oncol., 27, pp. 2530-2535Govindan, R., Page, N., Morgensztern, D., Read, W., Tierney, R., Vlahiotis, A., Spitznagel, E.L., Piccirillo, J., Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: Analysis of the surveillance, epidemiologic, and end results database (2006) Journal of Clinical Oncology, 24 (28), pp. 4539-4544. , DOI 10.1200/JCO.2005.04.4859Lorigan, P., Woll, P.J., O'Brien, M.E.R., Ashcroft, L.F., Sampson, M.R., Thatcher, N., Randomized phase III trial of dose-dense chemotherapy supported by whole-blood hematopoietic progenitors in better-prognosis small-cell lung cancer (2005) Journal of the National Cancer Institute, 97 (9), pp. 666-674. , DOI 10.1093/jnci/dji114Chute, J.P., Chen, T., Feigal, E., Simon, R., Johnson, B.E., Twenty years of phase III trials for patients with extensive-stage small-cell lung cancer: Perceptible progress (1999) Journal of Clinical Oncology, 17 (6), pp. 1794-1801Jones, D., Klementich, V.F.L.R., Phase II trial of Docetaxel and carboplatin in patients with newly diagnosed extensive-stage small cell carcinoma of the lung SCLC (2005) J. Clin. Oncol., 23. , Abstract 7346Gridelli, C., Perrone, F., Ianniello, G.P., Brancaccio, L., Iaffaioli, R.V., Curcio, C., D'Aprile, M., Bianco, A.R., Carboplatin plus vinorelbine, a new well-tolerated and active regimen for the treatment of extensive-stage small-cell lung cancer: A phase II study (1998) Journal of Clinical Oncology, 16 (4), pp. 1414-1419Dimitroulis, J., Rapti, A., Stathopoulos, G.P., Comparison of cisplatinpaclitaxel combination versus cisplatin-etoposide in patients with smallcell lung cancer: A phase III study (2008) Oncol. Rep., 20, pp. 879-884Mavroudis, D., Papadakis, E., Veslemes, M., Tsiafaki, X., Stavrakakis, J., Kouroussis, C., Kakolyris, S., Georgoulias, V., A multicenter randomized clinical trial comparing paclitaxel-cisplatin- etoposide versus cisplatin-etoposide as first-line treatment in patients with small-cell lung cancer (2001) Annals of Oncology, 12 (4), pp. 463-470. , DOI 10.1023/A:1011131303391Niell, H.B., Herndon II, J.E., Miller, A.A., Watson, D.M., Sandler, A.B., Kelly, K., Marks, R.S., Green, M.R., Randomized phase III intergroup trial of etoposide and cisplatin with or without paclitaxel and granulocyte colony-stimulating factor in patients with extensive-stage small-cell lung cancer: Cancer and Leukemia Group B trial 9732 (2005) Journal of Clinical Oncology, 23 (16), pp. 3752-3759. , DOI 10.1200/JCO.2005.09.071Socinski, M.A., Smit, E.F., Lorigan, P., Phase III study of pemetrexed plus carboplatin PC versus etoposide plus carboplatin EC in chemonaive patients pts with extensive-stage disease small cell lung cancer ED-SCLC: Interim results (2008) ASCO Meeting Category Lung Cancer Local-Regional and Adjuvant Therapy Abs NSANegoro, S., Fukuoka, M., Niitani, H., A phase II study of CPT-11 a camptothecin derivative in patients with primary lung cancer CPT-11 cooperative study group (1991) Gan. To Kagaku. Ryoho., 18, pp. 1013-1019Rocha-Lima, C.M., Herndon III, J.E., Lee, M.E., Phase II trial of irinotecan/gemcitabine as second-line therapy for relapsed and refractory small-cell lung cancer: Cancer and leukemia group B study 39902 (2007) Ann. Oncol., 18, pp. 331-337Masuda, N., Fukuoka, M., Kusunoki, Y., CPT-11: A new derivative of camptothecin for the treatment of refractory or relapsed small-cell lung cancer (1992) J. Clin. Oncol., 10, pp. 1225-1229Noda, K., Nishiwaki, Y., Kawahara, M., Negoro, S., Sugiura, T., Yokoyama, A., Fukuoka, M., Saijo, N., Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer (2002) New England Journal of Medicine, 346 (2), pp. 85-91. , DOI 10.1056/NEJMoa003034Hanna, N., Bunn Jr., P.A., Langer, C., Einhorn, L., Guthrie Jr., T., Beck, T., Ansari, R., Sandler, A., Randomized phase III trial comparing irinotecan/cisplatin with etoposide/cisplatin in patients with previously untreated extensive-stage disease small-cell lime cancer (2006) Journal of Clinical Oncology, 24 (13), pp. 2038-2043. , DOI 10.1200/JCO.2005.04.8595Hermes, A., Bergman, B., Bremnes, R., Irinotecan plus carboplatin versus oral etoposide plus carboplatin in extensive small-cell lung cancer: A randomized phase III trial (2008) J. Clin. Oncol., 26, pp. 4261-4267Sørensen, M., Felip, E., ESMO guidelines working group small-cell lung cancer: ESMO clinical recommendations for diagnosis treatment and follow-up (2008) Ann. Oncol., pp. ii41-ii42Kalemkerian, G.P., Akerley, W., Downey, R.J., Ettinger, D.S., Fossella, F., Grecula, J.C., Jahan, T., Williams Jr., C.C., Small cell lung cancer (2008) JNCCN Journal of the National Comprehensive Cancer Network, 6 (3), pp. 294-314Eckardt, J.R., Von Pawel, J., Papai, Z., Tomova, A., Tzekova, V., Crofts, T.E., Brannon, S., Ross, G., Open-label, multicenter, randomized, phase III study comparing oral topotecan/cisplatin versus etoposide/cisplatin as treatment for chemotherapy-naive patients with extensive-disease small-cell lung cancer (2006) Journal of Clinical Oncology, 24 (13), pp. 2044-2051. , DOI 10.1200/JCO.2005.03.3332Moher, D., Cook, D.J., Eastwood, S., Improving the quality of reports of meta-analyses of randomised controlled trials: The quorom statement quality of reporting of meta-analyses (1999) Lancet, 354, pp. 1896-1900Parmar, M.K.B., Torri, V., Stewart, L., Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints (1998) Statistics in Medicine, 17 (24), pp. 2815-2834. , DOI 10.1002/(SICI)1097-0258(19981230)17:243.0. CO;2-8Tierney, J.F., Stewart, L.A., Ghersi, D., Burdett, S., Sydes, M.R., Practical methods for incorporating summary time-to-event data into meta-analysis (2007) Trials, 8, p. 16. , DOI 10.1186/1745-6215-8-16Sterne, J.A.C., Egger, M., Smith, G.D., Investigating and dealing with publication and other biases (2001) Systematic Reviews in Health Care: Metaanalysis in Context, pp. 189-210. , In M Egger, GD Smith, DG Altman (Eds 2nd Ed. London: BMJ Publication GroupDerSimonian, R., Laird, N., Meta-analysis in clinical trials (1986) Controlled Clinical Trials, 7 (3), pp. 177-188. , DOI 10.1016/0197-2456(86)90046-2Higgins, J.P., Thompson, S.G., Deeks, J.J., Measuring inconsistency in meta-analyses (2003) BMJ, 327, pp. 557-560Seiter, K., Toxicity of the topoisomerase I inhibitors (2005) Expert Opin. Drug. Saf., 4, pp. 45-53Hartmann, J.T., Lipp, H.P., Camptothecin and podophyllotoxin derivatives: Inhibitors of topoisomerase I and II-mechanisms of action pharmacokinetics and toxicity profile (2006) Drug. Saf., 29, pp. 209-230Pan, D., Hou, M., Li, H., Yu, P., Liu, J., Irinotecan plus cisplatin compared with etoposide plus cisplatin for small cell lung cancer: A randomized clinical trial (2006) Chinese Journal of Lung Cancer, 9 (5), pp. 443-446Heigener, D.F., Freitag, L., Eschbach, C., Topotecan/cisplatin TP compared to cisplatin/etoposide PE for patients with extensive diseasesmall cell lung cancer ED-SCLC: Final results of a randomised phase III trial (2008) J. Clin. Oncol., 26. , bstract 7513Zhang, S., Wang, J., Wang, Q., Zhang, H., Hu, F., Yang, X., Fan, X., Li, Xi., A randomized study comparing topotecan plus cisplatin versus etoposide plus carboplatin for previously untreated small cell lung cancer (2007) Chinese Journal of Lung Cancer, 10 (2), pp. 144-147Schmittel, A.H., Sebastian, M., Fischer Von Weikersthal, L., Irinotecan plus carboplatin versus etoposide plus carboplatin in extensive disease small cell lung cancer: Results of the German randomized phase III trial (2009) J. Clin. Oncol., 27. , Abstract 8029Natale, R.B., Lara, P.N., Chansky, K., S0124: A randomized phase III trial comparing irinotecan/cisplatin IP with etoposide/cisplatin EP in patients pts with previously untreated extensive stage small cell lung cancer E-SCLC (2008) J. Clin. Oncol., 26. , Abstract 7512Eckardt, J.R., Von Pawel, J., Pujol, J.-L., Papai, Z., Quoix, E., Ardizzoni, A., Poulin, R., Ross, G., Phase III study of oral compared with intravenous topotecan as second-line therapy in small-cell lung cancer (2007) Journal of Clinical Oncology, 25 (15), pp. 2086-2092. , DOI 10.1200/JCO.2006.08.3998Ardizzoni, A., Manegold, C., Debruyne, C., Gaafar, R., Buchholz, E., Smit, E.F., Lianes, P., Giaccone, G., European Organization for Research and Treatment of Cancer (EORTC) 08957 phase II study of topotecan in combination with cisplatin as second-line treatment of refractory and sensitive small cell lung cancer (2003) Clinical Cancer Research, 9 (I1), pp. 143-150Naka, N., Kawahara, M., Okishio, K., Hosoe, S., Ogawara, M., Atagi, S., Takemoto, Y., Furuse, K., Phase II study of weekly irinotecan and carboplatin for refractory or relapsed small-cell lung cancer (2002) Lung Cancer, 37 (3), pp. 319-323. , DOI 10.1016/S0169-5002(02)00073-9, PII S0169500202000739Hirose, T., Horichi, N., Ohmori, T., Ogura, K., Hosaka, T., Ando, K., Ishida, H., Adachi, M., Phase II study of irinotecan and carboplatin in patients with the refractory or relapsed small cell lung cancer (2003) Lung Cancer, 40 (3), pp. 333-338. , DOI 10.1016/S0169-5002(03)00075-8Takigawa, N., Fujiwara, K., Ueoka, H., Kiura, K., Tabata, M., Hiraki, A., Shibayama, T., Harada, M., Fractionated administration of irinotecan and cisplatin for treatment of extensive-disease small-cell lung cancer: A phase II study (2003) Anticancer Research, 23 (B1), pp. 557-560Ioannidis, J.P., Interpretation of tests of heterogeneity and bias in metaanalysis (2008) J. 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