520 research outputs found

    Phase I/II study of oxaliplatin with oral S-1 as first-line therapy for patients with metastatic colorectal cancer

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    Two phase II studies of S-1 monotherapy have shown promising response rates (RR) of 35–40% with good tolerability in patients with untreated metastatic colorectal cancer. To investigate the usefulness of S-1 plus oxaliplatin (SOX) as an alternative to infusional 5-fluorouracil/leucovorin plus oxaliplatin, the recommended dose (RD) of SOX was determined, and its safety and preliminary efficacy were evaluated in a phase I/II study. Oxaliplatin was administered at a dose of 100 mg m−2 (level 1) or 130 mg m−2 (level 2) on day 1, and S-1 (80–120) was given twice daily for 2 weeks followed by a 1-week rest. This schedule was repeated every 3 weeks. Level 2 was determined to be the RD. For the 28 patients who received the RD, the median treatment course was 6.5 cycles (2–14), RR of 50% (1 CR and 13 PR: 95% CI 31–69%), with a median progression-free survival of 196 days. Survival rate (1 year) was 79%. Peripheral neuropathy was observed in all patients but with no functional disorders. Major grade 3 or 4 adverse reactions at the RD were neutropaenia (14%), thrombocytopaenia (28%), and diarrhoea (3%). SOX regimen is effective and easily manageable without central vein access

    Working towards a consensus on the oncological approach of breakthrough pain: A Delphi survey of Spanish experts

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    Purpose: There is a lack of standards for the diagnosis, assessment and management of breakthrough cancer pain (BTcP). La Fundación ECO (the Foundation for Excellence and Quality in Oncology) commissioned a study to establish a consensus and lay the foundations for the appropriate management of BTcP in oncology patients. Patients and methods: A modified Delphi survey comprising two rounds was used to gather and analyze data, which was conducted over the Internet. Each statement that reached a consensus with the respondents was defined as a median consensus score (MED) of =7, and agreement among panelists as an interquartile range (IQR) of =3. Results: In total, 69 medical oncologists responded, with a broad consensus that BTcP implied exacerbations of high-intensity pain, as opposed to moderate pain. Furthermore, they concurred that appropriate diagnostic equipment is needed, and that rapid-onset fentanyl formulations should be the preferred treatment for BTcP management. The panelists agreed that a lack of appropriate information and training to attend to patients, as well as limited patient visitation rights, were barriers to effective BTcP management. Regarding gaps in detected knowledge, the panelists were unsure of the measures necessary to assess the burden of the disease on the patient’s quality of life and associated medication costs. Alongside this, there was a lack of awareness of the technical specifics of the different formulations of rapid-onset fentanyl. Conclusion: These results represent the current status of BTcP management. They may inform recommendations and provide a framework for future research

    XELOX vs FOLFOX-4 as first-line therapy for metastatic colorectal cancer: NO16966 updated results

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    BACKGROUND: We report updated overall survival (OS) data from study NO16966, which compared capecitabine plus oxaliplatin (XELOX) vs 5-fluorouracil/folinic acid plus oxaliplatin (FOLFOX4) as first-line therapy in metastatic colorectal cancer. METHODS: NO16966 was a randomised, two-arm, non-inferiority, phase III comparison of XELOX vs FOLFOX4, which was subsequently amended to a 2 x 2 factorial design with further randomisation to bevacizumab or placebo. A planned follow-up exploratory analysis of OS was performed. RESULTS: The intent-to-treat (ITT) population comprised 2034 patients (two-arm portion, n = 634; 2 x 2 factorial portion, n 1400). For the whole NO16966 study population, median OS was 19.8 months in the pooled XELOX/XELOX-placebo/XELOX-bevacizumab arms vs 19.5 months in the pooled FOLFOX4/FOLFOX4-placebo/FOLFOX4-bevacizumab arms (hazard ratio 0.95 (97.5% CI 0.85-1.06)). In the pooled XELOX/XELOX-placebo arms, median OS was 19.0 vs 18.9 months in the pooled FOLFOX4/FOLFOX4-placebo arms (hazard ratio 0.95 (97.5% CI 0.83-1.09)). FOLFOX4 was associated with more grade 3/4 neutropenia/granulocytopenia and febrile neutropenia than XELOX, and XELOX with more grade 3 diarrhoea and grade 3 hand-foot syndrome than FOLFOX4. CONCLUSION: Updated survival data from study NO16966 show that XELOX is similar to FOLFOX4, confirming the primary analysis of progression-free survival. XELOX can be considered as a routine first-line treatment option for patients with metastatic colorectal cancer

    Transcriptomic Analysis of Trichoderma atroviride Overgrowing Plant-Wilting Verticillium dahliae Reveals the Role of a New M14 Metallocarboxypeptidase CPA1 in Biocontrol

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    Verticillium dahliae, a vascular-colonizing fungus, causes economically important wilt diseases in many crops, including olive trees. Trichoderma spp. have demonstrated an effective contribution as biocontrol agents against this pathogen through a variety of mechanisms that may involve direct mycoparasitism and antibiosis. However, molecular aspects underlaying Trichoderma–V. dahliae interactions are not well known yet due to the few studies in which this pathogen has been used as a target for Trichoderma. In the present study, Trichoderma atroviride T11 overgrew colonies of V. dahliae on agar plates and inhibited growth of highly virulent defoliating (D) V. dahliae V-138I through diffusible molecules and volatile organic compounds produced before contact. A Trichoderma microarray approach of T11 growing alone (CON), and before contact (NV) or overgrowing (OV) colonies of V-138I, helped to identify 143 genes that differed significantly in their expression level by more than twofold between OV and CON or NV. Functional annotation of these genes indicated a marked up-regulation of hydrolytic, catalytic and transporter activities, and secondary metabolic processes when T11 overgrew V-138I. This transcriptomic analysis identified peptidases as enzymatic activity overrepresented in the OV condition, and the cpa1 gene encoding a putative carboxypeptidase (ID number 301733) was selected to validate this study. The role of cpa1 in strain T11 on antagonism of V-138I was analyzed by a cpa1-overexpression approach. The increased levels of cpa1 expression and protease activity in the cpa1-overexpressed transformants compared to those in wild-type or transformation control strains were followed by significantly higher antifungal activity against V-138I in in vitro assays. The use of Trichoderma spp. for the integrated management of plant diseases caused by V. dahliae requires a better understanding of the molecular mechanisms underlying this interaction that might provide an increase on its efficiency

    Oncological translational research in the Spanish national health system: the INTRO study

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    Under the auspices of the Foundation for Excellence and Quality in Oncology (ECO), the Translational Research in Oncology Medical Services Study (INTRO) was conducted with the aim of describing the current state of, and future expectations for translational cancer research in Spanish medical centres. The first step in the investigation was intended to analyse the current condition of the national Medical Oncology Services network by examining different aspects of the oncology research field. A descriptive and observational multicentre study was performed at a statewide level; information was collected by surveying a cross-section of all those responsible for Medical Oncology Services in Spain. The survey was completed by key informants, who were selected independently by each service, between September 2010 and April 2011. We were able to gather comprehensive data from a total of 27 Spanish hospitals. These data enabled us to describe the allocation of human and material resources devoted to clinical and translational research across the Medical Oncology Services and to describe the organisational and functional components of these services and units. These data included information pertaining to the activities developed, their funding sources, and their functional dependence on other internal or external bodies. Finally, we explored the degree of dissemination and use of some specific techniques used for the genetic diagnosis of cancer, which have recently been introduced in Medical Oncology within the Spanish healthcare system. A wide range of variability exists between different oncology services in Spanish hospitals. Time should be spent reflecting on the need and opportunities for improvement in the development of translational research within the field of oncology.Caballero, C.; Jantus-Lewintre, E.; Carrato, A.; GarcĂ­a Foncillas, J.; Gascon, P.; Blasco, A.; Moreno Nogueira, JA.... (2014). Oncological translational research in the Spanish national health system: the INTRO study. Clinical and Translational Oncology. 16(8):686-695. doi:10.1007/s12094-013-1138-6S686695168DĂ­az-Rubio E. Translational research in clinical oncology: challenges and opportunities. Farm Hosp. 2010;34(Supl.1):1–7.Marincola FM. Translational medicine: a two-way road. J Transl Med. 2003;1(1):1.Ablin RJ, Marincola FM, Natali PG. The “excellence in translational medicine” and “bedside-to-bench” awards 2008–09. J Transl Med. 2010;13(8):95.GarcĂ­a-SĂĄenz JA, Bueno C, SanPedro T, DĂ­az-Rubio E. La nueva oncologĂ­a mĂ©dica: aportaciĂłn de la biologĂ­a molecular al diagnĂłstico y tratamiento del cĂĄncer. In: DĂ­az-Rubio E, editor. Tomo IV. Madrid: You and Us; 2006. p. 1–24.ORDEN SCO/709/2002, BoletĂ­n Oficial del Estado, 3 de abril de 2003, nĂșm. 80, pp. 12742–12746. http://www.boe.es/boe/dias/2002/04/03/pdfs/A12742-12746.pdf . Accessed 30 sept 2013.Soto-MartĂ­nez JL, Baselga-Torres J, Carrato-Mena A. La investigaciĂłn Translacional en OncologĂ­a MĂ©dica. En Primer Libro blanco de la OncologĂ­a MĂ©dica en España. Dosier 2006. Madrid: Editorial Dispublic SL; 2007. p. 177–99.Ministerio de Sanidad y Consumo. Agencia de Calidad del Sistema Nacional de Salud. Estrategia en CĂĄncer del Sistema Nacional de Salud. 2006. http://www.msc.es/organizacion/ sns/planCalidadSNS/docs/estratCancerSNS.pdf. Accessed 30 sept 2013.Lenfant C. Shattuck lecture–clinical research to clinical practice-lost in translation? N Engl J Med. 2003;349(9):868–74.Laurence J. Translating translational research. Transl Res. 2006;148(1):1–3.Lemieux-Charles L, McGuire WL. What do we know about health care team effectiveness? A review of the literature. Med Care Res Rev. 2006;63(3):263–300.Oandasan I, Baker RG, Barker K, Bosco C, D’Amour D, Jones L, et al. Teamwork in health care: promoting effective teamwork in healthcare in Canada; policy synthesis and recommendations. June 2006. http://www.chsrf.ca/Migrated/PDF/teamwork-synthesis-report_e.pdf . Accessed 30 Sep 2013.Mankoff SP, Brander C, Ferrone S, Marincola FM. Lost in Translation: obstacles to translational medicine. J Transl Med. 2004;2(1):14.Curran T. Lost in translation: the future of cancer research? Clin Cancer Res. 2005;11(13):4644.Valladares Y. Memoria y actas del primer congreso de investigaciĂłn sobre el cĂĄncer en España. Madrid; 1983.Vicente J. Apuntes para una historia de la OncologĂ­a en España. Los orĂ­genes. OncologĂ­a. 2000;23(7):310–7.Legido-Quigley H, Otero L, la Parra D, Alvarez-Dardet C, Martin-Moreno JM, McKee M. Will austerity cuts dismantle the Spanish healthcare system? BMJ. 2013;13(346):f2363

    Structural Determinants of the Dictyostatin Chemotype for Tubulin Binding Affinity and Antitumor Activity Against Taxane- and Epothilone-Resistant Cancer Cells

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    A combined biochemical, structural, and cell biology characterization of dictyostatin is described, which enables an improved understanding of the structural determinants responsible for the high-affinity binding of this anticancer agent to the taxane site in microtubules (MTs). The study reveals that this macrolide is highly optimized for MT binding and that only a few of the structural modifications featured in a library of synthetic analogues resulted in small gains in binding affinity. The high efficiency of the dictyostatin chemotype in overcoming various kinds of clinically relevant resistance mechanisms highlights its potential for therapeutic development for the treatment of drug-resistant tumors. A structural explanation is advanced to account for the synergy observed between dictyostatin and taxanes on the basis of their differential effects on the MT lattice. The X-ray crystal structure of a tubulin−dictyostatin complex and additional molecular modeling have allowed the rationalization of the structure−activity relationships for a set of synthetic dictyostatin analogues, including the highly active hybrid 12 with discodermolide. Altogether, the work reported here is anticipated to facilitate the improved design and synthesis of more efficacious dictyostatin analogues and hybrids with other MT-stabilizing agents.We thank Peter T. Northcote for peloruside A, W.-S. Fang for Flutax-2, K. H. Altmann for epothilone D, Dr. Paraskevi Giannakakou (Weill Cornell Medical Center, New York) for the 1A9, PTX10, PTX22, and A8 cell lines, and Prof. Richard Ludueñ a (University of Texas) for the HeLa ÎČIII-transfected cells. We thank Matadero INCOVA (Segovia) for the calf brains for tubulin purification. This work was supported in part by grants BIO2013-42984-R (J.F.D.) and SAF2012-39760-C02-02 (F.G.) from Ministerio de Economia y Competitividad, grant S2010/ ́ BMD-2457 BIPEDD2 from Comunidad Autonoma de Madrid ́ (F.G. and J.F.D.), and the Swiss National Science Foundation grants 310030B_138659 and 31003A_166608 (M.O.S.). The authors acknowledge networking contribution by the COST Action CM1407 “Challenging organic syntheses inspired by naturefrom natural products chemistry to drug discovery” and the COST action CM1470. I.P. thanks the EPSRC and AstraZeneca for funding, Dr. John Leonard (AstraZeneca) for useful discussions, Dr. Stuart Mickel (Novartis) for the provision of chemicals, and the EPSRC UK National Mass Spectrometry Facility at Swansea University for mass spectra

    Structural Determinants of the Dictyostatin Chemotype for Tubulin Binding Affinity and Antitumor Activity Against Taxane- and Epothilone-Resistant Cancer Cells

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    A combined biochemical, structural, and cell biology characterization of dictyostatin is described, which enables an improved understanding of the structural determinants responsible for the high-affinity binding of this anticancer agent to the taxane site in microtubules (MTs). The study reveals that this macrolide is highly optimized for MT binding and that only a few of the structural modifications featured in a library of synthetic analogues resulted in small gains in binding affinity. The high efficiency of the dictyostatin chemotype in overcoming various kinds of clinically relevant resistance mechanisms highlights its potential for therapeutic development for the treatment of drug-resistant tumors. A structural explanation is advanced to account for the synergy observed between dictyostatin and taxanes on the basis of their differential effects on the MT lattice. The X-ray crystal structure of a tubulin−dictyostatin complex and additional molecular modeling have allowed the rationalization of the structure−activity relationships for a set of synthetic dictyostatin analogues, including the highly active hybrid 12 with discodermolide. Altogether, the work reported here is anticipated to facilitate the improved design and synthesis of more efficacious dictyostatin analogues and hybrids with other MT-stabilizing agents.We thank Peter T. Northcote for peloruside A, W.-S. Fang for Flutax-2, K. H. Altmann for epothilone D, Dr. Paraskevi Giannakakou (Weill Cornell Medical Center, New York) for the 1A9, PTX10, PTX22, and A8 cell lines, and Prof. Richard Ludueñ a (University of Texas) for the HeLa ÎČIII-transfected cells. We thank Matadero INCOVA (Segovia) for the calf brains for tubulin purification. This work was supported in part by grants BIO2013-42984-R (J.F.D.) and SAF2012-39760-C02-02 (F.G.) from Ministerio de Economia y Competitividad, grant S2010/ ́ BMD-2457 BIPEDD2 from Comunidad Autonoma de Madrid ́ (F.G. and J.F.D.), and the Swiss National Science Foundation grants 310030B_138659 and 31003A_166608 (M.O.S.). The authors acknowledge networking contribution by the COST Action CM1407 “Challenging organic syntheses inspired by naturefrom natural products chemistry to drug discovery” and the COST action CM1470. I.P. thanks the EPSRC and AstraZeneca for funding, Dr. John Leonard (AstraZeneca) for useful discussions, Dr. Stuart Mickel (Novartis) for the provision of chemicals, and the EPSRC UK National Mass Spectrometry Facility at Swansea University for mass spectra

    Pharmacoeconomic analysis of adjuvant oral capecitabine vs intravenous 5-FU/LV in Dukes' C colon cancer: the X-ACT trial

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    Oral capecitabine (Xeloda<sup>®</sup>) is an effective drug with favourable safety in adjuvant and metastatic colorectal cancer. Oxaliplatin-based therapy is becoming standard for Dukes' C colon cancer in patients suitable for combination therapy, but is not yet approved by the UK National Institute for Health and Clinical Excellence (NICE) in the adjuvant setting. Adjuvant capecitabine is at least as effective as 5-fluorouracil/leucovorin (5-FU/LV), with significant superiority in relapse-free survival and a trend towards improved disease-free and overall survival. We assessed the cost-effectiveness of adjuvant capecitabine from payer (UK National Health Service (NHS)) and societal perspectives. We used clinical trial data and published sources to estimate incremental direct and societal costs and gains in quality-adjusted life months (QALMs). Acquisition costs were higher for capecitabine than 5-FU/LV, but higher 5-FU/LV administration costs resulted in 57% lower chemotherapy costs for capecitabine. Capecitabine vs 5-FU/LV-associated adverse events required fewer medications and hospitalisations (cost savings ÂŁ3653). Societal costs, including patient travel/time costs, were reduced by >75% with capecitabine vs 5-FU/LV (cost savings ÂŁ1318), with lifetime gain in QALMs of 9 months. Medical resource utilisation is significantly decreased with capecitabine vs 5-FU/LV, with cost savings to the NHS and society. Capecitabine is also projected to increase life expectancy vs 5-FU/LV. Cost savings and better outcomes make capecitabine a preferred adjuvant therapy for Dukes' C colon cancer. This pharmacoeconomic analysis strongly supports replacing 5-FU/LV with capecitabine in the adjuvant treatment of colon cancer in the UK

    Structural Determinants of the Dictyostatin Chemotype for Tubulin Binding Affinity and Antitumor Activity Against Taxane- and Epothilone-Resistant Cancer Cells

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    13 p.-5 fig.-2 tab.-1 graph.abst.A combined biochemical, structural, and cell biology characterization of dictyostatin is described, which enables an improved understanding of the structural determinants responsible for the high-affinity binding of this anticancer agent to the taxane site in microtubules (MTs). The study reveals that this macrolide is highly optimized for MT binding and that only a few of the structural modifications featured in a library of synthetic analogues resulted in small gains in binding affinity. The high efficiency of the dictyostatin chemotype in overcoming various kinds of clinically relevant resistance mechanisms highlights its potential for therapeutic development for the treatment of drug-resistant tumors. A structural explanation is advanced to account for the synergy observed between dictyostatin and taxanes on the basis of their differential effects on the MT lattice. The X-ray crystal structure of a tubulin–dictyostatin complex and additional molecular modeling have allowed the rationalization of the structure–activity relationships for a set of synthetic dictyostatin analogues, including the highly active hybrid 12 with discodermolide. Altogether, the work reported here is anticipated to facilitate the improved design and synthesis of more efficacious dictyostatin analogues and hybrids with other MT-stabilizing agents.This work was supported in part by grants BIO2013-42984-R (J.F.D.) and SAF2012-39760-C02-02 (F.G.) from Ministerio de Economía y Competitividad, grant S2010/BMD-2457 BIPEDD2 from Comunidad Autónoma de Madrid (F.G. and J.F.D.), and the Swiss National Science Foundation grants 310030B_138659 and 31003A_166608 (M.O.S.). The authors acknowledge networking contribution by the COST Action CM1407 “Challenging organic syntheses inspired by nature—from natural products chemistry to drug discovery” and the COST action CM1470. I.P. thanks the EPSRC and AstraZeneca for funding, Dr. John Leonard (AstraZeneca) for useful discussions, Dr. Stuart Mickel (Novartis) for the provision of chemicals, and the EPSRC UK National Mass Spectrometry Facility at Swansea University for mass spectra

    Design and baseline characteristics of SALT‐HF trial: hypertonic saline therapy in ambulatory heart failure

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    Aims Hypertonic saline solution (HSS) plus intravenous (IV) loop diuretic appears to enhance the diuretic response in patients hospitalized for heart failure (HF). The efficacy and safety of this therapy in the ambulatory setting have not been evaluated. We aimed to describe the design and baseline characteristics of the SALT-HF trial participants. Methods and results 'Efficacy of Saline Hypertonic Therapy in Ambulatory Patients with HF' (SALT-HF) trial was a multicenter, double-blinded, and randomized study involving ambulatory patients who experienced worsening heart failure (WHF) without criteria for hospitalization. Enrolled patients had to present at least two signs of volume overload, use >= 80 mg of oral furosemide daily, and have elevated natriuretic peptides. Patients were randomized 1:1 to treatment with a 1-h infusion of IV furosemide plus HSS (2.6-3.4% NaCl depending on plasmatic sodium levels) versus a 1-h infusion of IV furosemide at the same dose (125-250 mg, depending on basal loop diuretic dose). Clinical, laboratory, and imaging parameters were collected at baseline and after 7 days, and a telephone visit was planned after 30 days. The primary endpoint was 3-h diuresis after treatment started. Secondary endpoints included (a) 7-day changes in congestion data, (b) 7-day changes in kidney function and electrolytes, (c) 30-day clinical events (need of IV diuretic, HF hospitalization, cardiovascular mortality, all-cause mortality or HF-hospitalization). Results A total of 167 participants [median age, 81 years; interquartile range (IQR), 73-87, 30.5% females] were randomized across 13 sites between December 2020 and March 2023. Half of the participants (n = 82) had an ejection fraction >50%. Most patients showed a high burden of comorbidities, with a median Charlson index of 3 (IQR: 2-4). Common co-morbidities included diabetes mellitus (41%, n = 69), atrial fibrillation (80%, n = 134), and chronic kidney disease (64%, n = 107). Patients exhibited a poor functional NYHA class (69% presenting NYHA III) and several signs of congestion. The mean composite congestion score was 4.3 (standard deviation: 1.7). Ninety per cent of the patients (n = 151) presented oedema and jugular engorgement, and 71% (n = 118) showed lung B lines assessed by ultrasound. Median inferior vena cava diameter was 23 mm, (IQR: 21-25), and plasmatic levels of N-terminal-pro-B-type natriuretic peptide (NTproBNP) and antigen carbohydrate 125 (CA125) were increased (median NT-proBNP 4969 pg/mL, IQR: 2508-9328; median CA125 46 U/L, IQR: 20-114). Conclusions SALT-HF trial randomized 167 ambulatory patients with WHF and will determine whether an infusion of hypertonic saline therapy plus furosemide increases diuresis and improves decongestion compared to equivalent furosemide administration alone
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