Double Drug Delivery Using Capped Mesoporous Silica Microparticles for the Effective Treatment of Inflammatory Bowel Disease

[EN] Silica mesoporous microparticles loaded with both rhodamine B fluorophore (S1) or hydrocortisone (S2), and capped with an olsalazine derivative, are prepared and fully characterized. Suspensions of Si and S2 in water at an acidic and a neutral pH show negligible dye/drug release, yet a notable delivery took place when the reducing agent sodium dithionite is added because of hydrolysis of an azo bond in the capping ensemble. Additionally, olsalazine fragmentation induced 5-aminosalicylic acid (5-ASA) release. In vitro digestion models show that S1 and S2 solids are suitable systems to specifically release a pharmaceutical agent in the colon. In vivo pharmacokinetic studies in rats show a preferential rhodamine B release from Si in the colon. Moreover, a model of ulcerative colitis is induced in rats by oral administration of 2,4,6-trinitrobenzenesulfonic acid (TNBS) solutions, which was also used to prove the efficacy of S2 for colitis treatment. The specific delivery of hydrocortisone and 5-ASA from S2 material to the colon tissue in injured rats markedly lowers the colon/body weight ratio and the clinical activity score. Histological studies showed a remarkable reduction in inflammation, as well as an intensive regeneration of the affected tissues.We thank the Generalitat Valenciana (Project PROMETE02018/024) and the Spanish Government (Projects AGL2015-70235-C2-2-R and MAT2015-64139-C4-1-R (MINECO/FEDER)) for support. A.H.T. thanks the Spanish MEC for his FPU fellowship. The authors also thank the support of the Electron Microscopy Service at the UPV. The SCSIE (of the Universitat de Valencia) is also gratefully acknowledged for all the equipment used. NMR spectra were measured at the U26 facility of ICTS "NANBIOSIS" at the Universitat de Valencia.Hernández Teruel, A.; Pérez-Esteve, É.; González-Álvarez, I.; González-Álvarez, M.; Costero Nieto, AM.; Ferri, D.; Gaviña, P.... (2019). Double Drug Delivery Using Capped Mesoporous Silica Microparticles for the Effective Treatment of Inflammatory Bowel Disease. Molecular Pharmaceutics. 16(6):2418-2429. https://doi.org/10.1021/acs.molpharmaceut.9b00041S24182429166Baumgart, D. C., & Sandborn, W. J. (2012). Crohn’s disease. The Lancet, 380(9853), 1590-1605. doi:10.1016/s0140-6736(12)60026-9Pierik, M., Yang, H., Barmada, M. M., Cavanaugh, J. A., Annese, V., Brant, S. R., … Vlietinck, R. (2005). The IBD International Genetics Consortium Provides Further Evidence for Linkage to IBD4 and Shows Gene-Environment Interaction. Inflammatory Bowel Diseases, 11(1), 1-7. doi:10.1097/00054725-200501000-00001Loftus, E. V. (2004). Clinical epidemiology of inflammatory bowel disease: incidence, prevalence, and environmental influences. Gastroenterology, 126(6), 1504-1517. doi:10.1053/j.gastro.2004.01.063Lupp, C., Robertson, M. L., Wickham, M. E., Sekirov, I., Champion, O. L., Gaynor, E. C., & Finlay, B. B. (2007). Host-Mediated Inflammation Disrupts the Intestinal Microbiota and Promotes the Overgrowth of Enterobacteriaceae. Cell Host & Microbe, 2(2), 119-129. doi:10.1016/j.chom.2007.06.010Takaishi, H., Matsuki, T., Nakazawa, A., Takada, T., Kado, S., Asahara, T., … Hibi, T. (2008). Imbalance in intestinal microflora constitution could be involved in the pathogenesis of inflammatory bowel disease. International Journal of Medical Microbiology, 298(5-6), 463-472. doi:10.1016/j.ijmm.2007.07.016Sokol, H., Seksik, P., Furet, J. P., Firmesse, O., Nion-Larmurier, I., Beaugerie, L., … Doré, J. (2009). Low counts of Faecalibacterium prausnitzii in colitis microbiota. Inflammatory Bowel Diseases, 15(8), 1183-1189. doi:10.1002/ibd.20903Friswell, M., Campbell, B., & Rhodes, J. (2010). The Role of Bacteria in the Pathogenesis of Inflammatory Bowel Disease. Gut and Liver, 4(3), 295-306. doi:10.5009/gnl.2010.4.3.295Qiu, X., Zhang, M., Yang, X., Hong, N., & Yu, C. (2013). Faecalibacterium prausnitzii upregulates regulatory T cells and anti-inflammatory cytokines in treating TNBS-induced colitis. Journal of Crohn’s and Colitis, 7(11), e558-e568. doi:10.1016/j.crohns.2013.04.002Yu, C. G., & Huang, Q. (2013). Recent progress on the role of gut microbiota in the pathogenesis of inflammatory bowel disease. Journal of Digestive Diseases, 14(10), 513-517. doi:10.1111/1751-2980.12087Kappelman, M. D., Rifas–Shiman, S. L., Porter, C. Q., Ollendorf, D. A., Sandler, R. S., Galanko, J. A., & Finkelstein, J. A. (2008). Direct Health Care Costs of Crohn’s Disease and Ulcerative Colitis in US Children and Adults. Gastroenterology, 135(6), 1907-1913. doi:10.1053/j.gastro.2008.09.012Kappelman, M. D., Rifas–Shiman, S. L., Porter, C. Q., Ollendorf, D. A., Sandler, R. S., Galanko, J. A., & Finkelstein, J. A. (2008). Direct Health Care Costs of Crohn’s Disease and Ulcerative Colitis in US Children and Adults. Gastroenterology, 135(6), 1907-1913. doi:10.1053/j.gastro.2008.09.012Rocchi, A., Benchimol, E. I., Bernstein, C. N., Bitton, A., Feagan, B., Panaccione, R., … Ghosh, S. (2012). Inflammatory Bowel Disease: A Canadian Burden of Illness Review. Canadian Journal of Gastroenterology, 26(11), 811-817. doi:10.1155/2012/984575Burisch, J., Jess, T., Martinato, M., & Lakatos, P. L. (2013). The burden of inflammatory bowel disease in Europe. Journal of Crohn’s and Colitis, 7(4), 322-337. doi:10.1016/j.crohns.2013.01.010Marchetti, M., & Liberato, N. L. (2014). Biological therapies in Crohn’s disease: are they cost-effective? A critical appraisal of model-based analyses. Expert Review of Pharmacoeconomics & Outcomes Research, 14(6), 815-824. doi:10.1586/14737167.2014.957682Park, S. J. (2014). Clinical characteristics and treatment of inflammatory bowel disease: A comparison of Eastern and Western perspectives. World Journal of Gastroenterology, 20(33), 11525. doi:10.3748/wjg.v20.i33.11525Ng, S. C., Tang, W., Ching, J. Y., Wong, M., Chow, C. M., Hui, A. J., … Chan, F. K. L. (2013). Incidence and Phenotype of Inflammatory Bowel Disease Based on Results From the Asia-Pacific Crohn’s and Colitis Epidemiology Study. Gastroenterology, 145(1), 158-165.e2. doi:10.1053/j.gastro.2013.04.007Sood, A. (2003). Incidence and prevalence of ulcerative colitis in Punjab, North India. Gut, 52(11), 1587-1590. doi:10.1136/gut.52.11.1587Tozun, N., Atug, O., Imeryuz, N., Hamzaoglu, H. O., Tiftikci, A., Parlak, E., … Yurdaydin, C. (2009). Clinical Characteristics of Inflammatory Bowel Disease in Turkey. Journal of Clinical Gastroenterology, 43(1), 51-57. doi:10.1097/mcg.0b013e3181574636Victoria, C. R., Sassak, L. Y., & Nunes, H. R. de C. (2009). Incidence and prevalence rates of inflammatory bowel diseases, in midwestern of São Paulo State, Brazil. Arquivos de Gastroenterologia, 46(1), 20-25. doi:10.1590/s0004-28032009000100009Fakhoury, M., Al-Salami, H., Negrulj, R., & Mooranian, A. (2014). Inflammatory bowel disease: clinical aspects and treatments. Journal of Inflammation Research, 113. doi:10.2147/jir.s65979Mowat, C., Cole, A., Windsor, A., Ahmad, T., Arnott, I., … Driscoll, R. (2011). Guidelines for the management of inflammatory bowel disease in adults. Gut, 60(5), 571-607. doi:10.1136/gut.2010.224154Di Sario, A., Bendia, E., Schiadà, L., Sassaroli, P., & Benedetti, A. (2016). Biologic Drugs in Crohn’;s Disease and Ulcerative Colitis: Safety Profile. Current Drug Safety, 11(1), 55-61. doi:10.2174/157488631101160212171757Collnot, E.-M., Ali, H., & Lehr, C.-M. (2012). Nano- and microparticulate drug carriers for targeting of the inflamed intestinal mucosa. Journal of Controlled Release, 161(2), 235-246. doi:10.1016/j.jconrel.2012.01.028Lamprecht, A., Rodero Torres, H., Schäfer, U., & Lehr, C.-M. (2000). Biodegradable microparticles as a two-drug controlled release formulation: a potential treatment of inflammatory bowel disease. Journal of Controlled Release, 69(3), 445-454. doi:10.1016/s0168-3659(00)00331-xTeruel, A., Coll, C., Costero, A., Ferri, D., Parra, M., Gaviña, P., … Sancenón, F. (2018). Functional Magnetic Mesoporous Silica Microparticles Capped with an Azo-Derivative: A Promising Colon Drug Delivery Device. Molecules, 23(2), 375. doi:10.3390/molecules23020375Teruel, A. H., Pérez-Esteve, É., González-Álvarez, I., González-Álvarez, M., Costero, A. M., Ferri, D., … Sancenón, F. (2018). Smart gated magnetic silica mesoporous particles for targeted colon drug delivery: New approaches for inflammatory bowel diseases treatment. Journal of Controlled Release, 281, 58-69. doi:10.1016/j.jconrel.2018.05.007Sancenón, F., Pascual, L., Oroval, M., Aznar, E., & Martínez-Máñez, R. (2015). Gated Silica Mesoporous Materials in Sensing Applications. ChemistryOpen, 4(4), 418-437. doi:10.1002/open.201500053Aznar, E., Oroval, M., Pascual, L., Murguía, J. R., Martínez-Máñez, R., & Sancenón, F. (2016). Gated Materials for On-Command Release of Guest Molecules. Chemical Reviews, 116(2), 561-718. doi:10.1021/acs.chemrev.5b00456Llopis-Lorente, A., Díez, P., Sánchez, A., Marcos, M. D., Sancenón, F., Martínez-Ruiz, P., … Martínez-Máñez, R. (2017). Interactive models of communication at the nanoscale using nanoparticles that talk to one another. Nature Communications, 8(1). doi:10.1038/ncomms15511De la Torre, C., Domínguez-Berrocal, L., Murguía, J. R., Marcos, M. D., Martínez-Máñez, R., Bravo, J., & Sancenón, F. (2018). ϵ -Polylysine-Capped Mesoporous Silica Nanoparticles as Carrier of the C 9h Peptide to Induce Apoptosis in Cancer Cells. Chemistry - A European Journal, 24(8), 1890-1897. doi:10.1002/chem.201704161Oroval, M., Díez, P., Aznar, E., Coll, C., Marcos, M. D., Sancenón, F., … Martínez-Máñez, R. (2016). Self-Regulated Glucose-Sensitive Neoglycoenzyme-Capped Mesoporous Silica Nanoparticles for Insulin Delivery. Chemistry - A European Journal, 23(6), 1353-1360. doi:10.1002/chem.201604104De la Torre, C., Casanova, I., Acosta, G., Coll, C., Moreno, M. J., Albericio, F., … Martínez-Máñez, R. (2014). Gated Mesoporous Silica Nanoparticles Using a Double-Role Circular Peptide for the Controlled and Target-Preferential Release of Doxorubicin in CXCR4-Expresing Lymphoma Cells. Advanced Functional Materials, 25(5), 687-695. doi:10.1002/adfm.201403822Giménez, C., Climent, E., Aznar, E., Martínez-Máñez, R., Sancenón, F., Marcos, M. D., … Rurack, K. (2014). Towards Chemical Communication between Gated Nanoparticles. Angewandte Chemie International Edition, n/a-n/a. doi:10.1002/anie.201405580García-Fernández, A., García-Laínez, G., Ferrándiz, M. L., Aznar, E., Sancenón, F., Alcaraz, M. J., … Orzáez, M. (2017). Targeting inflammasome by the inhibition of caspase-1 activity using capped mesoporous silica nanoparticles. Journal of Controlled Release, 248, 60-70. doi:10.1016/j.jconrel.2017.01.002Llopis-Lorente, A., Lozano-Torres, B., Bernardos, A., Martínez-Máñez, R., & Sancenón, F. (2017). Mesoporous silica materials for controlled delivery based on enzymes. Journal of Materials Chemistry B, 5(17), 3069-3083. doi:10.1039/c7tb00348jCabrera, S., El Haskouri, J., Guillem, C., Latorre, J., Beltrán-Porter, A., Beltrán-Porter, D., … Amorós *, P. (2000). Generalised syntheses of ordered mesoporous oxides: the atrane route. Solid State Sciences, 2(4), 405-420. doi:10.1016/s1293-2558(00)00152-7Lunn, G. (2005). HPLC Methods for Recently Approved Pharmaceuticals. doi:10.1002/0471711683Navarro, C., González-Álvarez, I., González-Álvarez, M., Manku, M., Merino, V., Casabó, V. G., & Bermejo, M. (2011). Influence of polyunsaturated fatty acids on Cortisol transport through MDCK and MDCK-MDR1 cells as blood–brain barrier in vitro model. European Journal of Pharmaceutical Sciences, 42(3), 290-299. doi:10.1016/j.ejps.2010.12.005Mura, C., Nácher, A., Merino, V., Merino-Sanjuan, M., Carda, C., Ruiz, A., … Diez-Sales, O. (2011). N-Succinyl-chitosan systems for 5-aminosalicylic acid colon delivery: In vivo study with TNBS-induced colitis model in rats. International Journal of Pharmaceutics. doi:10.1016/j.ijpharm.2011.06.025Sandborn, W. J., & Hanauer, S. B. (2002). The pharmacokinetic profiles of oral mesalazine formulations and mesalazine pro-drugs used in the management of ulcerative colitis. Alimentary Pharmacology & Therapeutics, 17(1), 29-42. doi:10.1046/j.1365-2036.2003.01408.xMladenovska, K., Raicki, R. S., Janevik, E. I., Ristoski, T., Pavlova, M. J., Kavrakovski, Z., … Goracinova, K. (2007). Colon-specific delivery of 5-aminosalicylic acid from chitosan-Ca-alginate microparticles. International Journal of Pharmaceutics, 342(1-2), 124-136. doi:10.1016/j.ijpharm.2007.05.028Oomen, A. G., Rompelberg, C. J. M., Bruil, M. A., Dobbe, C. J. G., Pereboom, D. P. K. H., & Sips, A. J. A. M. (2003). Development of an In Vitro Digestion Model for Estimating the Bioaccessibility of Soil Contaminants. Archives of Environmental Contamination and Toxicology, 44(3), 281-287. doi:10.1007/s00244-002-1278-0Versantvoort, C. H. M., Oomen, A. G., Van de Kamp, E., Rompelberg, C. J. M., & Sips, A. J. A. M. (2005). Applicability of an in vitro digestion model in assessing the bioaccessibility of mycotoxins from food. Food and Chemical Toxicology, 43(1), 31-40. doi:10.1016/j.fct.2004.08.007Tozaki, H., Fujita, T., Komoike, J., Kim, S.-I., Terashima, H., Muranishi, S., … Yamamoto, A. (1999). Colon-specific Delivery of Budesonide with Azopolymer-coated Pellets: Therapeutic Effects of Budesonide with a Novel Dosage Form against 2,4,6-Trinitrobenzenesulphonic Acid-induced Colitis in Rats. Journal of Pharmacy and Pharmacology, 51(3), 257-261. doi:10.1211/0022357991772420Tozaki, H., Odoriba, T., Okada, N., Fujita, T., Terabe, A., Suzuki, T., … Yamamoto, A. (2002). Chitosan capsules for colon-specific drug delivery: enhanced localization of 5-aminosalicylic acid in the large intestine accelerates healing of TNBS-induced colitis in rats. Journal of Controlled Release, 82(1), 51-61. doi:10.1016/s0168-3659(02)00084-6Yoo, J.-W., Naeem, M., Cao, J., Choi, M., Kim, W., Moon, H. R., … Jung, Y. (2015). Enhanced therapeutic efficacy of budesonide in experimental colitis with enzyme/pH dual-sensitive polymeric nanoparticles. International Journal of Nanomedicine, 4565. doi:10.2147/ijn.s8781

Prognostic utility of serum free light chain ratios and heavy-light chain ratios in multiple myeloma in three PETHEMA/GEM phase III clinical trials

© 2018 Lopez-Anglada et al.We investigated the prognostic impact and clinical utility of serum free light chains (sFLC) and serum heavy-light chains (sHLC) in patients with multiple myeloma treated according to the GEM2005MENOS65, GEM2005MAS65, and GEM2010MAS65 PETHEMA/GEM phase III clinical trials. Serum samples collected at diagnosis were retrospectively analyzed for sFLC (n = 623) and sHLC (n = 183). After induction or autologous transplantation, 309 and 89 samples respectively were available for sFLC and sHLC assays. At diagnosis, a highly abnormal (HA) sFLC ratio (sFLCr) (32) was not associated with higher risk of progression. After therapy, persistence of involved-sFLC levels >100 mg/L implied worse survival (overall survival [OS], P = 0.03; progression-free survival [PFS], P = 0.007). Among patients that achieved a complete response, sFLCr normalization did not necessarily indicate a higher quality response. We conducted sHLC investigations for IgG and IgA MM. Absolute sHLC values were correlated with monoclonal protein levels measured with serum protein electrophoresis. At diagnosis, HA-sHLCrs (73) showed a higher risk of progression (P = 0.006). Additionally, involved-sHLC levels >5 g/L after treatment were associated with shorter survival (OS, P = 0.001; PFS, P = 0.018). The HA-sHLCr could have prognostic value at diagnosis; absolute values of involved-sFLC >100 mg/L and involved-sHLC >5 g/L could have prognostic value after treatment.This research project was supported by grants PI06339, PS09/01370, and PI12/01761 awarded to Sara Borrell (CD13/00340) and Juan Rodes (JR14/00016) from the Fondo de Investigación Sanitaria (FIS), the Red Temática de Investigación Cooperativa en Cáncer (RTICC) of the Instituto de Salud Carlos III (Ministry of Economy, Industry, and Competitiveness, Madrid, Spain), FEDER (RD12/0036/0061, RD12/0036/0048m and RD12/0036/0058) from FIS, the Asociación Española Contra el Cáncer (AECC; GCB120981SAN), and the CRIS Foundation

Single versus tandem autologous stem-cell transplantation in patients with newly diagnosed multiple myeloma and high-risk cytogenetics. A retrospective, open-label study of the PETHEMA/Spanish Myeloma Group (GEM)

Tandem ASCT has been suggested as a valid approach to improve the prognosis of patients with MM and HR cytogenetic. In this observational, retrospective study, 213 patients with newly diagnosed MM and HR cytogenetic in 35 hospitals from the Spanish Myeloma Group underwent single or tandem ASCT between January 2015 and December 2019 after induction with VTD/VRD. HR cytogenetic was defined as having ≥1 of the following: del17p, t(4;14), t(14;16) or gain 1q21. More patients in the tandem group had R-ISS 3 and >1 cytogenetic abnormality at diagnosis. With a median follow-up of 31 months (range, 10–82), PFS after single ASCT was 41 months versus 48 months with tandem ASCT (p = 0.33). PFS in patients with del17p undergoing single ASCT was 41 months, while 52% of patients undergoing tandem ASCT were alive and disease free at 48 months. In conclusion, tandem ASCT partly overcomes the bad prognosis of HR cytogenetic

Maintenance therapy with bortezomib plus thalidomide or bortezomib plus prednisone in elderly multiple myeloma patients included in the GEM2005MAS65 trial

[EN]Maintenance therapy has become a hot field in myeloma, and it may be particularly relevant in elderly patients because the major benefit results from the initial therapy. We report the results of a randomized comparison of maintenance with bortezomib plus thalidomide (VT) or prednisone (VP) in 178 elderly untreated myeloma patients who had received 6 induction cycles with bortezomib plus either melphalan and prednisone or thalidomide and prednisone. The complete response (CR) rate increased from 24% after induction up to 42%, higher for VT versus VP (46% vs 39%). Median progression-free survival (PFS) was superior for VT (39 months) compared with VP (32 months) and overall survival (OS) was also longer in VT patients compared with VP (5-year OS of 69% and 50%, respectively) but the differences did not reach statistical significance. CR achievement was associated with a significantly longer PFS (P < .001) and 5-year OS (P < .001). The incidence of G3-4 peripheral neuropathy was 9% for VT and 3% for VP. Unfortunately, this approach was not able to overcome the adverse prognosis of cytogenetic abnormalities. In summary, these maintenance regimens result in a significant increase in CR rate, remarkably long PFS, and acceptable toxicity profile. The trial is registered at www.clinicaltrials.gov as NCT00443235

Depth of response in multiple myeloma: A pooled analysis of three PETHEMA/GEM clinical trials

On behalf of the GEM (Grupo Español de Mieloma)/PETHEMA (Programa para el Estudio de la Terapéutica en Hemopatías Malignas) Cooperative Study Group.[Purpose]: To perform a critical analysis on the impact of depth of response in newly diagnosed multiple myeloma (MM). [Patients and Methods]: Data were analyzed from 609 patients who were enrolled in the GEM (Grupo Español de Mieloma) 2000 and GEM2005MENOS65 studies for transplant-eligible MM and the GEM2010MAS65 clinical trial for elderly patients with MM who had minimal residual disease (MRD) assessments 9 months after study enrollment. Median follow-up of the series was 71 months. [Results]: Achievement of complete remission (CR) in the absence of MRD negativity was not associated with prolonged progression-free survival (PFS) and overall survival (OS) compared with near-CR or partial response (median PFS, 27, 27, and 29 months, respectively; median OS, 59, 64, and 65 months, respectively). MRD-negative status was strongly associated with prolonged PFS (median, 63 months; P operational cure> was high; median PFS was 12 years, and the 10-year OS rate was 94%. [Conclusion]: Our results demonstrate that MRD-negative status surpasses the prognostic value of CR achievement for PFS and OS across the disease spectrum, regardless of the type of treatment or patient risk group. MRD negativity should be considered as one of the most relevant end points for transplant-eligible and elderly fit patients with MM.Supported by the Centro de Investigación Biomédica en Red – Area de Oncologia - del Instituto de Salud Carlos III (CIBERONC; CB16/12/00369; CB16/12/00400; CB16/12/00233; CB16/12/00284), formerly named as Cooperative Research Thematic Network (Grants No. RD12/0036/0058, RD12/0036/0048, RD12/0036/0046, and RD12/0036/0061) of the Red de Cancer (Cancer Network of Excellence); Instituto de Salud Carlos III/Subdirección General de Investigación Sanitaria; funded in part by the European Regional Development Fund (FIS No. 98/1239, 00/10160, 01/0089, 02/0089, 02/0905, G03/136, PI051284, PI06033906/1354, PS09/01897/01370, PI12/01761, PI12/02311, PI13/01469, PI14/01867, G03/136); Sara Borrell (No. CD13/00340); Asociación Española Contra el Cáncer (No. GCB120981SAN); and Federación Española de Enfermedades Raras. Also supported internationally by the Black Swan Research Initiative of the International Myeloma Foundation and the European Research Council 2015 Starting Grant (MYELOMANEXT).Peer Reviewe

Diseño e implementación de estrategias de avance para la salud bucal en la comuna de La Serranita

Fil: Boltovskoy Exposito, Ana. Universidad Nacional de Córdoba. Facultad de Odontología; Argentina.Fil: Lopez Rotondo, Susana Elizabeth. Universidad Nacional de Córdoba. Facultad de Odontología; Argentina.Fil: Teruel Baez, Estefanía. Universidad Nacional de Córdoba. Facultad de Odontología; Argentina.Fil: Lozada Moreno, Lourdes. Universidad Nacional de Córdoba. Facultad de Odontología; Argentina.Fil: Solera, Daiana. Universidad Nacional de Córdoba. Facultad de Odontología; Argentina.Fil: Cano, Verónica Isabel. Universidad Nacional de Córdoba. Facultad de Odontología. Cátedra de Operatoria II A; Argentina.Fil: Marengo, Alejando Mario. Universidad Nacional de Córdoba. Facultad de Odontología. Cátedra de Odontología Preventiva y Comunitaria II; Argentina.Fil: Camusso, Vanesa del Valle. Universidad Nacional de Córdoba. Facultad de Odontología. Cátedra de Operatoria II A; Argentina.Fil: Cisneros Casanovas, Nora Alicia. Universidad Nacional de Córdoba. Facultad de Odontología. Cátedra de Operatoria II A; Argentina.Fil: Acevedo de Pauw, Paula Inés. Universidad Nacional de Córdoba. Facultad de Odontología; Argentina.Fil: Verducci, Patricia. Universidad Nacional de Córdoba. Facultad de Odontología. Cátedra Operatoria II A; Argentina.Se busca conocer el estado de salud bucal de niños, niñas y adolescentes residentes en La Serranita y contribuir a mejorarlo. Las acciones se iniciaron con diagnóstico del estado de salud bucal y de los factores de riesgo, mediante la ficha médica escolar realizada por el equipo de salud del CAPS. Se realizaron encuentros virtuales entre docentes de la escuela, equipo de salud y los integrantes universitarios. Estas reuniones se llevaron a cabo en época de aislamiento social y nos permitieron generar vínculos interpersonales e interinstitucionales y conocer la situación del contexto para diseñar estrategias acordes al mismo. Cuando fue posible asistir al contexto se realizó el reconocimiento del establecimiento escolar y la observación de los estudiantes en la atención odontológica en el CAPS. Se diseñaron estrategias de promoción y prevención de salud bucal que fueron implementadas en diferentes salidas a terreno: jornada de juegos con material de ludoteca, jornada de acciones de promoción con proyecciones, cuentos y elaboración de afiches, jornada de articulación con práctica docente de la Facultad de Artes. Queda pendiente el cierre del proyecto con salida a territorio donde se realizará enseñanzas de técnicas de higiene bucal individual a niñas y niños de nivel inicial y primario de la escuela.http://hdl.handle.net/11086/29594Fil: Boltovskoy Exposito, Ana. Universidad Nacional de Córdoba. Facultad de Odontología; Argentina.Fil: Lopez Rotondo, Susana Elizabeth. Universidad Nacional de Córdoba. Facultad de Odontología; Argentina.Fil: Teruel Baez, Estefanía. Universidad Nacional de Córdoba. Facultad de Odontología; Argentina.Fil: Lozada Moreno, Lourdes. Universidad Nacional de Córdoba. Facultad de Odontología; Argentina.Fil: Solera, Daiana. Universidad Nacional de Córdoba. Facultad de Odontología; Argentina.Fil: Cano, Verónica Isabel. Universidad Nacional de Córdoba. Facultad de Odontología. Cátedra de Operatoria II A; Argentina.Fil: Marengo, Alejando Mario. Universidad Nacional de Córdoba. Facultad de Odontología. Cátedra de Odontología Preventiva y Comunitaria II; Argentina.Fil: Camusso, Vanesa del Valle. Universidad Nacional de Córdoba. Facultad de Odontología. Cátedra de Operatoria II A; Argentina.Fil: Cisneros Casanovas, Nora Alicia. Universidad Nacional de Córdoba. Facultad de Odontología. Cátedra de Operatoria II A; Argentina.Fil: Acevedo de Pauw, Paula Inés. Universidad Nacional de Córdoba. Facultad de Odontología; Argentina.Fil: Verducci, Patricia. Universidad Nacional de Córdoba. Facultad de Odontología. Cátedra Operatoria II A; Argentina.Otras Ciencias de la Salu

Early myeloma-related death in elderly patients: development of a clinical prognostic score and evaluation of response sustainability role

Although survival of elderly myeloma patients has significantly improved there is still a subset of patients who, despite being fit and achieving optimal responses, will die within 2 years of diagnosis due to myeloma progression. The objective of this study was to define a scoring prognostic index to identify this group of patients. We have evaluated the outcome of 490 newly diagnosed elderly myeloma patients included in two Spanish trials (GEM2005-GEM2010). Sixty-eight patients (13.8%) died within 2 years of diagnosis (early deaths) due to myeloma progression. Our study shows that the use of simple scoring model based on 4 widely available markers (elevated LDH, ISS 3, high risk CA or >75 years) can contribute to identify up-front these patients. Moreover, unsustained response (<6 months duration) emerged as one important predictor of early myeloma-related mortality associated with a significant increase in the risk of death related to myeloma progression. The identification of these patients at high risk of early death is relevant for innovative trials aiming to maintain the depth of first response, since many of them will not receive subsequent lines of therapy.This study was supported by the Cooperative Research Thematic Networkgrants RD12/0036/0058 and RD12/0036/0046 of the Redde Cancer (Cancer Network of Excellence); Instituto deSalud Carlos III, Spain, Instituto de Salud Carlos III/SubdirecciónGeneral de Investigación Sanitaria part-financedby the European Regional Development Fund (FIS: PI12/01761; PI12/02311; PI13/01469; PI14/01867, G03/136;Sara Borrell: CD13/00340); Asociación Española Contra el Cáncer (GCB120981SAN) and FEDER

Depth of Response in Multiple Myeloma: A Pooled Analysis of Three PETHEMA/GEM Clinical Trials

[EN] Purpose—To perform a critical analysis on the impact of depth of response in newly diagnosed multiple myeloma (MM). Patients and Methods—Data were analyzed from 609 patients who were enrolled in the GEM (Grupo Español de Mieloma) 2000 and GEM2005MENOS65 studies for transplant-eligible MM and the GEM2010MAS65 clinical trial for elderly patients with MM who had minimal residual disease (MRD) assessments 9 months after study enrollment. Median follow-up of the series was 71 months. Results—Achievement of complete remission (CR) in the absence of MRD negativity was not associated with prolonged progression-free survival (PFS) and overall survival (OS) compared with near-CR or partial response (median PFS, 27, 27, and 29 months, respectively; median OS, 59, 64, and 65 months, respectively). MRD-negative status was strongly associated with prolonged PFS (median, 63 months; P < .001) and OS (median not reached; P < .001) overall and in subgroups defined by prior transplantation, disease stage, and cytogenetics, with prognostic superiority of MRD negativity versus CR particularly evident in patients with high-risk cytogenetics. Accordingly, Harrell C statistics showed higher discrimination for both PFS and OS in Cox models that included MRD (as opposed to CR) for response assessment. Superior MRD-negative rates after different induction regimens anticipated prolonged PFS. Among 34 MRD-negative patients with MM and a phenotypic pattern of bone marrow involvement similar to monoclonal gammopathy of undetermined significance at diagnosis, the probability of “operational cure” was high; median PFS was 12 years, and the 10-year OS rate was 94%. Conclusion—Our results demonstrate that MRD-negative status surpasses the prognostic value of CR achievement for PFS and OS across the disease spectrum, regardless of the type of treatment or patient risk group. MRD negativity should be considered as one of the most relevant end points for transplant-eligible and elderly fit patients with MM

Lenalidomide and dexamethasone with or without clarithromycin in patients with multiple myeloma ineligible for autologous transplant: a randomized trial

Although case-control analyses have suggested an additive value with the association of clarithromycin to continuous lenalidomide and dexamethasone (Rd), there are not phase III trials confirming these results. In this phase III trial, 286 patients with MM ineligible for ASCT received Rd with or without clarithromycin until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). With a median follow-up of 19 months (range, 0-54), no significant differences in the median PFS were observed between the two arms (C-Rd 23 months, Rd 29 months; HR 0.783, p = 0.14), despite a higher rate of complete response (CR) or better in the C-Rd group (22.6% vs 14.4%, p = 0.048). The most common G3-4 adverse events were neutropenia [12% vs 19%] and infections [30% vs 25%], similar between the two arms; however, the percentage of toxic deaths was higher in the C-Rd group (36/50 [72%] vs 22/40 [55%], p = 0.09). The addition of clarithromycin to Rd in untreated transplant ineligible MM patients does not improve PFS despite increasing the ?CR rate due to the higher number of toxic deaths in the C-Rd arm. Side effects related to overexposure to steroids due to its delayed clearance induced by clarithromycin in this elderly population could explain these results. The trial was registered in clinicaltrials.gov with the name GEM-CLARIDEX: Ld vs BiRd and with the following identifier NCT02575144. The full trial protocol can be accessed from ClinicalTrials.gov. This study received financial support from BMS/Celgene