94 results on '"Hernandez MT"'
Search Results
2. Original Research Lenalidomide-dexamethasone versus observation in high-risk smoldering myeloma after 12 years of median follow-up time: A randomized, open-label study*
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Mateos, MV, Hernandez, MT, Salvador, C, de la Rubia, J, de Arriba, F, Lopez-Corral, L, Rosinol, L, Paiva, B, Palomera, L, Bargay, J, Oriol, A, Prosper, F, Lopez, J, Arguinano, JM, Blade, J, Lahuerta, JJ, and San-Miguel, J
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Smoldering multiple ,myeloma ,Drug therapy ,Followup study ,Lenalidomide ,Dexamethasone - Abstract
SMM randomized to treatment or observation. Treatment consisted of nine 4-week induction cycles (lenalidomide [Rd], 25 mg on days 1-21 plus dexamethasone, 20 mg on days 1-4 and 12-15), followed by maintenance (R, 10 mg on days 1-21) for up to 2 years. The primary endpoint was time to progression (TTP) to myeloma based on per protocol population. Secondary end-points were overall survival (OS), response rate, and safety. An update of the trial after a long-term follow-up is presented here. This trial was registered with ClinicalTrials.gov (NCT00480363). Findings: After a median follow-up time of 12.5 years (range: 10.4-13.6), the median TTP to MM was 2.1 years in the observation arm and 9.5 years in the Rd arm (HR: 0.28, 95% CI: 0.18 -0.44, p < 0.0001). The median OS was 8.5 years in the abstention arm and not reached in the Rd group (HR: 0.57, 95% CI: 0.34-0.95, p = 0.032). Patients who progressed received optimized treatments according to the standards of care, and the OS from progression was comparable in both arms (p = 0.96). Interpretation: This analysis confirms that early treatment with Rd for high-risk SMM translates into a sustained benefit in both TTP and OS. Funding: Pethema (Spanish Program for the Treatment of Hematologic Diseases), Spain. 2022 Elsevier Ltd. All rights reserved.
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- 2022
3. Deep MRD profiling defines outcome and unveils different modes of treatment resistance in standard and high risk myeloma
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Goicoechea I, Puig N, Cedena MT, Burgos L, Cordón L, Vidriales MB, Flores-Montero J, Gutierrez NC, Calasanz MJ, Martin Ramos ML, Lara-Astiaso D, Vilas-Zornoza A, Alignani D, Rodriguez I, Sarvide S, Alameda D, Garcés JJG, Rodriguez S, Fresquet V, Celay J, Garcia-Sanz R, Martinez-Lopez J, Oriol A, Rios R, Martin-Sanchez J, Martinez-Martinez R, Sarra J, Hernandez MT, de la Rubia J, Krsnik I, Moraleda JM, Palomera L, Bargay J, Martinez-Climent JA, Orfao A, Rosiñol L, Mateos MV, Lahuerta JJ, Blade J, San Miguel J, and Paiva B
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body regions ,hemic and lymphatic diseases - Abstract
Patients with multiple myeloma (MM) carrying high-risk cytogenetic abnormalities (CA) have inferior outcome despite achieving similar complete response (CR) rates when compared to cases with standard-risk CA. This questions the legitimacy of CR as treatment endpoint for high-risk MM, and represents a biological conundrum regarding the nature of tumor reservoirs persisting after therapy in patients with standard- and high-risk CA. Here, we used next-generation flow (NGF) to evaluate measurable residual disease (MRD) in MM patients with standard- (N=300) vs high-risk CA (N=90) enrolled in the PETHEMA/GEM2012MENOS65 trial (NCT01916252), and to identify mechanisms determining MRD resistance in both patient subgroups (N=40). The 36-month progression-free and overall survival rates were higher than 90% in patients with undetectable MRD, with no significant differences (P=0.202) between cases having standard- vs high-risk CA. Persistent MRD resulted in median progression-free survival of approximately three and two years in patients with standard- and high-risk CA, respectively (P
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- 2020
4. Immunogenomic identification and characterization of granulocytic myeloid-derived suppressor cells in multiple myeloma
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Perez, C, Botta, C, Zabaleta, A, Puig, N, Cedena, MT, Goicoechea, I, Alameda, D, San Jose-Eneriz, E, Merino, J, Rodriguez-Otero, P, Maia, C, Alignani, D, Maiso, P, Manrique, I, Lara-Astiaso, D, Vilas-Zornoza, A, Sarvide, S, Riillo, C, Rossi, M, Rosinol, L, Oriol, A, Blanchard, MJ, Rios, R, Sureda, A, Martin, J, Martinez, R, Bargay, J, De la Rubia, J, Hernandez, MT, Martinez-Lopez, J, Orfao, A, Agirre, X, Prosper, F, Mateos, MV, Lahuerta, JJ, Blade, J, San-Miguel, JF, Paiva, B, Grp Espanol Mieloma, and Programa Estudio Terapeutica Hemop
- Abstract
Granulocytic myeloid-derived suppressor cells (G-MDSCs) promote tumor growth and immunosuppression in multiple myeloma (MM). However, their phenotype is not well established for accurate monitoring or clinical translation. We aimed to provide the phenotypic profile of G-MDSCs based on their prognostic significance in MM, immunosuppressive potential, and molecular program. The preestablished phenotype of G-MDSCs was evaluated in bone marrow samples from controls and MM patients using multidimensional flow cytometry; surprisingly, we found that CD11b(+)CD14(-)CD15(+)CD33(+) HLADR(+) cells over-lapped with common eosinophils and neutrophils, which were not expanded in MM patients. Therefore, we relied on automated clustering to unbiasedly identify all granulocytic subsets in the tumor microenvironment: basophils, eosinophils, and immature, intermediate, and mature neutrophils. In a series of 267 newly diagnosed MM patients (GEM2012MENOS65 trial), only the frequency of mature neutrophils at diagnosis was significantly associated with patient outcome, and a high mature neutrophil/T-cell ratio resulted in inferior progression-free survival (P < .001). Upon fluorescence-activated cell sorting of each neutrophil subset, T-cell proliferation decreased in the presence of mature neutrophils (0.5-fold; P = .016), and the cytotoxic potential of T cells engaged by a BCMAxCD3-bispecific antibody increasednotably with the depletion of mature neutrophils (fourfold; P = .0007). Most interestingly, RNA sequencing of the 3 subsets revealed that G-MDSC-related genes were specifically upregulated in mature neutrophils from MM patients vs controls because of differential chromatin accessibility. Taken together, our results establish a correlation between the clinical significance, immunosuppressive potential, and transcriptional network of well-defined neutrophil subsets, providing for the first time a set of optimal markers (CD11b/CD13/CD16) for accurate monitoring of G-MDSCs in MM.
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- 2020
5. Biological and clinical signi fi cance of dysplastic hematopoiesis in patients with newly diagnosed multiple myeloma
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Maia, C, Puig, N, Cedena, MT, Goicoechea, I, Valdes-Mas, R, Vazquez, I, Chillon, MC, Aguirre, P, Sarvide, S, Gracia-Aznarez, FJ, Alkorta, G, Calasanz, MJ, Garcia-Sanz, R, Gonzalez, M, Gutierrez, NC, Martinez-Lopez, J, Perez, JJ, Merino, J, Moreno, C, Burgos, L, Alignani, D, Botta, C, Prosper, F, Matarraz, S, Orfao, A, Oriol, A, Teruel, AI, de Paz, RD, de Arriba, F, Hernandez, MT, Palomera, L, Martinez, R, Rosinol, L, Mateos, MV, Lahuerta, JJ, Blade, J, San Miguel, JF, and Paiva, B
- Abstract
Risk of developing myelodysplastic syndrome (MDS) is significantly increased in both multiple myeloma (MM) and monoclonal gammopathy of undetermined significance, suggesting that it is therapy independent. However, the incidence and sequelae of dys- plastic hematopoiesis at diagnosis are unknown. Here, we used multidimensional flow cytometry (MFC) to prospectively screen for the presence of MDS-associated phenotypic alterations (MDS-PA) in the bone marrow of 285 patients with MM enrolled in the PETHEMA/GEM2012MENOS65 trial (#NCT01916252). We investigated the clinical significance of monocytic MDS-PA in a larger series of 1252 patients enrolled in 4 PETHEMA/GEM protocols. At diagnosis, 33 (11.6%) of 285 cases displayed MDS-PA. Bulk and single-cell-targeted sequencing of MDS recurrently mutated genes in CD34(+) progenitors (and dysplastic lineages) from 67 patients revealed clonal hematopoiesis in 13 (50%) of 26 cases with MDS-PA vs 9 (22%) of 41 without MDS-PA; TET2 and NRAS were the most frequently mutated genes. Dynamics of MDS-PA at diagnosis and after autologous transplant were evaluated in 86 of 285 patients and showed that in most cases (69 of 86 [80%]), MDS-PA either persisted or remained absent in patients with or without MDS-PA at diagnosis, respectively. Noteworthy, MDS-associated mutations infrequently emerged after high-dose therapy. Based on MFC profiling, patients with MDS-PA have altered hematopoiesis and T regulatory cell distribution in the tumor microenvironment. Importantly, the presence of monocytic MDS-PA at diagnosis anticipated greater risk of hematologic toxicity and was independently associated with inferior progression-free survival (hazard ratio, 1.5; P = .02) and overall survival (hazard ratio, 1.7; P = .01). This study reveals the biological and clinical significance of dysplastic hematopoiesis in newly diagnosed MM, which can be screened with moderate sensitivity using cost-effective MFC. (Blood. 2020;135(26):2375-2387)
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- 2020
6. Depth of Response in Multiple Myeloma: A Pooled Analysis of Three PETHEMA/GEM Clinical Trials
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Lahuerta, JJ, Paiva, B, Vidriales, MB, Cordon, L, Cedena, MT, Puig, N, Martinez-Lopez, J, Rosiñol L, Gutierrez, NC, Martin-Ramos, ML, Oriol, A, Teruel, AI, Echeveste, MA, de Paz, R, de Arriba, F, Hernandez, MT, Palomera, L, Martinez, R, Martin, A, Alegre, A, De la Rubia, J, Orfao, A, Mateos, MV, Blade, J, San-Miguel, JF, and GEM (Grupo Español de Mieloma)/PETHEMA (Programa para el Estudio de la Terapéuti
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hemic and lymphatic diseases - Abstract
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 Espanol 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. (C) 2017 by American Society of Clinical Oncology
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- 2017
7. The National Institutes of Health Fogarty International Center Global Health Scholars and Fellows Program: Collaborating Across Five Consortia to Strengthen Research Training
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Zunt, JR, Chi, BH, Heimburger, DC, Cohen, CR, Strathdee, S, Hobbs, N, Thomas, Y, Bale, K, Salisbury, K, Hernandez, MT, Riley, LW, Vermund, SH, and Van Der Horst, C
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Good Health and Well Being ,Biomedical Research ,Internationality ,National Institutes of Health (U.S.) ,Tropical Medicine ,Mentors ,Humans ,HIV/AIDS ,Fellowships and Scholarships ,Global Health ,Medical and Health Sciences ,United States - Abstract
© Copyright 2016 by The American Society of Tropical Medicine and Hygiene. As demand for global health research training continues to grow, many universities are striving to meet the needs of trainees in a manner complementary to research priorities of the institutions hosting trainees, while also increasing capacity for conducting research. We provide an overview of the first 4 years of the Global Health Program for Fellows and Scholars, a collaboration of 20 U.S. universities and institutions spread across 36 low- and middleincome countries funded through the National Institutes of Health Fogarty International Center. We highlight many aspects of our program development that may be of interest to other multinational consortia developing global health research training programs.
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- 2016
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8. Airborne observations of regional variation in fluorescent aerosol across the United States
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Perring, AE, Schwarz, JP, Baumgardner, D, Hernandez, MT, Spracklen, DV, Heald, CL, Gao, RS, Kok, G, McMeeking, GR, McQuaid, JB, and Fahey, DW
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Airborne observations of fluorescent aerosol were made aboard an airship during CloudLab, a series of flights that took place in September and October of 2013 and covered a wideband of longitude across the continental U.S. between Florida and California and between 28 and 37-N latitudes. Sampling occurred from near the surface to 1000-m above the ground. A Wideband Integrated Bioaerosol Sensor (WIBS-4) measured average concentrations of supermicron fluorescent particles aloft (1-μm to 10-μm), revealing number concentrations ranging from 2.1-±-0.8 to 8.7-±-2.2-×-104 particles m-3 and representing up to 24% of total supermicron particle number. We observed distinct variations in size distributions and fluorescent characteristics in different regions, and attribute these to geographically diverse bioaerosol. Fluorescent aerosol detected in the east is largely consistent with mold spores observed in a laboratory setting, while a shift to larger sizes associated with different fluorescent patterns is observed in the west. Fluorescent bioaerosol loadings in the desert west were as high as those near the Gulf of Mexico, suggesting that bioaerosol is a substantial component of supermicron aerosol both in humid and arid environments. The observations are compared to model fungal and bacterial loading predictions, and good agreement in both particle size and concentrations is observed in the east. In the west, the model underestimated observed concentrations by a factor between 2 and 4 and the prescribed particle sizes are smaller than the observed fluorescent aerosol. A classification scheme for use with WIBS data is also presented. Key Points Fluorescent supermicron aerosol loads are reported across the southern U.S. Regional variations in fluorescent behavior and particle size are observed Comparison to modeled emissions shows an underestimate in the west
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- 2015
9. Superiority of bortezomib, thalidomide, and dexamethasone (VTD) as induction pretransplantation therapy in multiple myeloma: a randomized phase 3 PETHEMA/GEM study
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Rosinol, L, Oriol, A, Teruel, AI, Hernandez, D, Lopez-Jimenez, J, de la Rubia, J, Granell, M, Besalduch, J, Palomera, L, Gonzalez, Y, Etxebeste, MA, Diaz-Mediavilla, J, Hernandez, MT, de Arriba, F, Gutierrez, NC, Martin-Ramos, ML, Cibeira, MT, Mateos, MV, Martinez, J, Alegre, A, Lahuerta, JJ, San Miguel, J, and Blade, J
- Abstract
The Spanish Myeloma Group conducted a trial to compare bortezomib/thalidomide/dexamethasone (VTD) versus thalidomide/dexamethasone (TD) versus vincristine, BCNU, melphalan, cyclophosphamide, prednisone/vincristine, BCNU, doxorubicin, dexamethasone/bortezomib (VBMCP/VBAD/B) in patients aged 65 years or younger with multiple myeloma. The primary endpoint was complete response (CR) rate postinduction and post-autologous stem cell transplantation (ASCT). Three hundred eighty-six patients were allocated to VTD (130), TD (127), or VBMCP/VBAD/B (129). The CR rate was significantly higher with VTD than with TD (35% vs 14%, P = .001) or with VBMCP/VBAD/B (35% vs 21%, P = .01). The median progression-free survival (PFS) was significantly longer with VTD (56.2 vs 28.2 vs 35.5 months, P = .01). In an intention-to-treat analysis, the post-ASCT CR rate was higher with VTD than with TD (46% vs 24%, P = .004) or with VBMCP/VBAD/B (46% vs 38%, P = .1). Patients with high-risk cytogenetics had a shorter PFS and overall survival in the overall series and in all treatment groups. In conclusion, VTD resulted in a higher pre- and posttransplantation CR rate and in a significantly longer PFS although it was not able to overcome the poor prognosis of high-risk cytogenetics. Our results support the use of VTD as a highly effective induction regimen prior to ASCT. The study was registered with http://www.clinicaltrials.gov (NCT00461747) and Eudra CT (no. 2005-001110-41). (Blood. 2012;120(8):1589-1596)
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- 2012
10. Under Scope of the Current Redefinition Process of Optimal Response in Multiple Myeloma: Assesment of Molecular Response by Fluorescent PCR of Ig Genes Has Similar Applicability and Prognosis Impact to Immunophenotypic Response. (A GEM/PETHEMA study),
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Fernandez Redondo, Elena, primary, Martinez-Lopez, Joaquin, additional, García-Sanz, Ramón, additional, Montalbán, María-Angeles, additional, Martinez-Sanchez, Pilar, additional, Paiva, Bruno, additional, Mateos, Maria-Victoria, additional, Rosiñol, Laura, additional, Martin, Maria Luisa, additional, Ayala, Rosa M., additional, Martinez, Rafael, additional, Lopez, Javier, additional, Alegre, Adrian, additional, Besalduch, Joan, additional, Bargay, Joan, additional, Hernandez, MT, additional, Sarasquete, Maria Eugenia, additional, sanchez-Godoy, P., additional, Callis, Manuel, additional, Fernandez, Manuela, additional, Blade, Joan, additional, San Miguel, Jesus F., additional, and Lahuerta, Juan José, additional
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- 2011
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11. Patient dose reference levels for interventional radiology: a national approach.
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Vano E, Sanchez R, Fernandez JM, Gallego JJ, Verdu JF, de Garay MG, Azpiazu A, Segarra A, Hernandez MT, Canis M, Diaz F, Moreno F, and Palmero J
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- 2009
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12. Knock-knock: a population-based survey of risk behavior, health care access, and Chlamydia trachomatis infection among low-income women in the San Francisco Bay area.
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Klausner JD, McFarland W, Bolan G, Hernandez MT, Molitor F, Lemp GF, Cahoon-Young B, Morrow S, and Ruiz J
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To estimate the prevalence of urogenital chlamydial infection among young, low-income women in northern California and to describe correlates of infection, a population-based door-to-door household cluster survey was conducted from 1996 through 1998. The participants included 1439 women 18-29 years of age, with a mean age of 24 years, most of whom were African American (43%) or Latina (23%) and had a median income of $500-$999 per month. Most (94%) had received health care in the past year, and approximately 50% was covered by state insurance programs. Although more than half (62%) had had a recent pelvic examination, only 42% had recently used a condom with a new partner. The prevalence of urogenital chlamydial infection was 3.2% (95% confidence interval, 2.2%-4.2%). Women with chlamydia were more likely to be younger (18-21 years of age) and nonwhite and to have lower socioeconomic status. These data demonstrated an approximately 2-3-fold greater burden of infection than routine surveillance data have suggested. © 2001 Infectious Diseases Society of America [ABSTRACT FROM AUTHOR]
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- 2001
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13. Hepatitis B prevalence in young women living in low-income areas: the population-based San Francisco Bay area's Young Women's Survey.
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Hernandez MT, Klausner JD, McFarland W, Wong E, Bolan G, Molitor F, Ruiz JD, Young Women's Survey Team, Hernandez, M T, Klausner, J D, McFarland, W, Wong, E, Bolan, G, Molitor, F, and Ruiz, J D
- Abstract
Background: The risk of sexually transmitted hepatitis B virus infection is proportionally higher for young adults and women. Low socioeconomic groups have high rates of hepatitis B infection with no identified source of transmission. The prevalence and correlates of transmission of hepatitis B virus among young women of low socioeconomic status have not been well documented.Goal: To determine the population-based prevalence and correlates of sexually acquired hepatitis B virus infection in young low-income women in the San Francisco Bay Area.Study Design: A three-county, door-to-door serosurvey of hepatitis B virus core antibody among young women living in low-income areas was conducted from April 1996 to January 1998. Multivariate analysis of sexually acquired hepatitis B virus infection excluded participants of Asian or Pacific Islander ethnicity or with a history of intravenous drug use or transfusion.Results: The prevalence of sexually acquired hepatitis B virus infection was 6.4% (95% CI, 4.7%-8.1%). Correlates of infection were black race (odds ratio, 3.9; 95% CI, 1.2-11.9 compared with white race) and herpes simplex virus type 2 infection (odds ratio, 2.0; 95% CI, 1.0-3.9).Conclusions: Young black women have a higher risk of sexually acquired hepatitis B virus infection. Herpes simplex virus type 2 infection may predispose to hepatitis B virus infection and/or be a marker for lifetime sexual risk behavior. [ABSTRACT FROM AUTHOR]- Published
- 2000
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14. Efficacy of Lenalidomide in Different Clinical Settings in Patients with Relapsed or Progressive Multiple Myeloma: Updated Analysis of 111 Cases of the Spanish Compassionate Use Program
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Alegre, A., Aguado, B., Giraldo, P., Cánovas, P., Ibáñez, A., Castillo, I., Blanes, M., Ríos, E., Rodríguez, J.N., Palomera, L., Hernández, MT, Oriol, A., Sancho, E., Menchaca, C., Vercher, J., González, AP, Arilla, M.J., Ramírez, G., Pérez, R., Asensio, A., De la Serna, Javier, Osorio, S., Aguilar, C., Ansó, V., Calvo, J.M., Casanova, M., Fuertes, M., Guzmán, J.L., López, L., López, A., Olalla, J.L., Hernández, J.M, Ríos, P., Villalon, L., García, I., García, A., Larregla, S., Lara, F., and Lahuerta, J.L.
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- 2008
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15. Autologous Peripheral Blood Stem Cell (APBSCT) in Multiple Myeloma (MM): the Spanish multicentre experience
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Amor, Aa, Juan José Lahuerta, Sanz-Rodriguez, C., Diaz-Mediavilla, J., Martinez, R., Garcia-Larana, J., Caballero, D., La Rubia, J., Sureda, A., Blade, J., Vidal, Mj, Escudero, A., Gastearena, J., Conde, E., Ruiz, Jcg, Cabrera, R., Moraleda, Jm, Leon, A., Besalduch, J., Hernandez, Mt, Rifon, J., Canales, M., Solano, C., Palomera, L., Parody, R., Gonzalez-San Miguel, Jd, Mataix, R., Maldonado, J., Constela, J., Carrera, D., Bello, Jl, Pablos, Jm, Morales, A., Ojanguren, J., Prieto, E., Acebedo, G., Penarrubia, Mj, Torres, P., Diez-Martin, Jl, Rivas, A., Sanchez, Jm, Granda, A., Martinez-Chamorro, C., Gonzalez, Ma, and San Miguel, J.
16. Dielectric data of Zn-doped alumina materials obtained from different precursor powders
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MARIA GONZALEZ, Hernandez, Mt, Vila, R., Molla, J., and TTP
17. Minimally Invasive Assessment of Peripheral Residual Disease During Maintenance or Observation in Transplant-Eligible Patients With Multiple Myeloma.
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Lasa M, Notarfranchi L, Agullo C, Gonzalez C, Castro S, Perez JJ, Burgos L, Guerrero C, Calasanz MJ, Flores-Montero J, Oriol A, Bargay J, Rios R, Cabañas V, Cabrera C, Martinez-Martinez R, Encinas C, De Arriba F, Hernandez MT, Palomera L, Orfao A, Martinez-Lopez J, Mateos MV, San-Miguel J, Lahuerta JJ, Rosiñol L, Blade J, Cedena MT, Puig N, and Paiva B
- Abstract
Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. In multiple myeloma (MM), measurable residual disease (MRD) is assessed in bone marrow (BM). However, less invasive evaluation of peripheral residual disease (PRD) in blood could be advantageous and less cumbersome. We investigated the prognostic value of PRD monitoring after 24 cycles of maintenance in 138 transplant-eligible patients with MM enrolled in the GEM2012MENOS65/GEM2014MAIN clinical trials. PRD was assessed using next-generation flow (NGF) and mass spectrometry (MS). Positive PRD by NGF in 16/138 (11.5%) patients was associated with a 13-fold increased risk of progression and/or death; median progression-free survival (PFS) and overall survival (OS) were 2.5 and 47 months, respectively. Considering patients' MRD status in BM as the reference, PRD detection using NGF showed positive and negative predictive values of 100% and 73%, respectively. Presence of PRD helped identifying patients at risk of imminent progression among those with positive MRD in BM. Patients with undetectable PRD according to both NGF and MS showed 2-year PFS and OS rates of 97% and 100%, respectively. In multivariate analyses including the Revised International Staging System and the complete remission status, only MRD in BM and PRD by NGF showed independent prognostic value for PFS. This study supports the use of less invasive PRD monitoring during maintenance or observation in transplant-eligible patients with MM.
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- 2024
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18. The genomic profiling of high-risk smoldering myeloma patients treated with an intensive strategy unveils potential markers of resistance and progression.
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Medina-Herrera A, Vazquez I, Cuenca I, Rosa-Rosa JM, Ariceta B, Jimenez C, Fernandez-Mercado M, Larrayoz MJ, Gutierrez NC, Fernandez-Guijarro M, Gonzalez-Calle V, Rodriguez-Otero P, Oriol A, Rosiñol L, Alegre A, Escalante F, De La Rubia J, Teruel AI, De Arriba F, Hernandez MT, Lopez-Jimenez J, Ocio EM, Puig N, Paiva B, Lahuerta JJ, Bladé J, San Miguel JF, Mateos MV, Martinez-Lopez J, Calasanz MJ, and Garcia-Sanz R
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- Humans, Male, Female, Middle Aged, Aged, High-Throughput Nucleotide Sequencing, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Drug Resistance, Neoplasm genetics, Disease Progression, Smoldering Multiple Myeloma genetics, Mutation, Biomarkers, Tumor genetics
- Abstract
Smoldering multiple myeloma (SMM) precedes multiple myeloma (MM). The risk of progression of SMM patients is not uniform, thus different progression-risk models have been developed, although they are mainly based on clinical parameters. Recently, genomic predictors of progression have been defined for untreated SMM. However, the usefulness of such markers in the context of clinical trials evaluating upfront treatment in high-risk SMM (HR SMM) has not been explored yet, precluding the identification of baseline genomic alterations leading to drug resistance. For this reason, we carried out next-generation sequencing and fluorescent in-situ hybridization studies on 57 HR and ultra-high risk (UHR) SMM patients treated in the phase II GEM-CESAR clinical trial (NCT02415413). DIS3, FAM46C, and FGFR3 mutations, as well as t(4;14) and 1q alterations, were enriched in HR SMM. TRAF3 mutations were specifically associated with UHR SMM but identified cases with improved outcomes. Importantly, novel potential predictors of treatment resistance were identified: NRAS mutations and the co-occurrence of t(4;14) plus FGFR3 mutations were associated with an increased risk of biological progression. In conclusion, we have carried out for the first time a molecular characterization of HR SMM patients treated with an intensive regimen, identifying genomic predictors of poor outcomes in this setting., (© 2024. The Author(s).)
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- 2024
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19. Predictors of unsustained measurable residual disease negativity in transplant-eligible patients with multiple myeloma.
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Guerrero C, Puig N, Cedena MT, Calasanz MJ, Gutierrez NC, Fernandez M, Oriol A, Ríos-Tamayo R, Hernandez MT, Martínez-Martínez R, Bargay J, de Arriba F, Palomera L, Gonzalez-Rodriguez AP, Gonzalez Perez MS, Orfao A, Mateos MV, Martinez-Lopez J, Rosiñol L, Bladé J, Lahuerta JJ, San-Miguel JF, and Paiva B
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- Humans, Treatment Outcome, Risk Factors, Neoplasm, Residual diagnosis, Multiple Myeloma therapy, Multiple Myeloma drug therapy
- Abstract
Abstract: The role of measurable residual disease (MRD) negativity as a biomarker to stop treatment is being investigated in transplant-eligible patients with multiple myeloma (MM). Thus, it is important to identify risk factors of MRD resurgence and/or progressive disease (PD) among patients achieving undetectable MRD to avoid undertreating them. Here, we studied 267 newly diagnosed transplant-eligible patients with MM enrolled in the GEM2012MENOS65 and GEM2014MAIN clinical trials who achieved MRD negativity by next-generation flow cytometry. After a median follow-up of 73 months since the first MRD negative assessment, 111 of the 267 (42%) patients showed MRD resurgence and/or PD. The only prognostic factors at diagnosis that predicted MRD resurgence and/or PD were an International Staging System (ISS) 3 and the presence of ≥0.01% circulating tumor cells (CTCs). Failure to achieve MRD negativity after induction also predicted higher risk of MRD resurgence and/or PD. Patients having 0 vs 1 vs ≥2 risk factors (ISS 3, ≥0.01% CTCs, and late MRD negativity) showed 5-year rates of MRD resurgence and/or PD of 16%, 33%, and 57%, respectively (P < .001). Thus, these easily measurable risk factors could help refine the selection of patients for whom treatment cessation after MRD negativity is being investigated in clinical trials. This trial was registered at www.clinicaltrials.gov as NCT01916252 and NCT02406144., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)
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- 2024
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20. STK4 deficiency and epidermodysplasia verruciformis-like lesions: A case report.
- Author
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Gutierrez-Marin PA, Castano-Jaramillo LM, Velez-Tirado N, Villamil-Osorio M, Patiño E, Reina MF, and Hernandez MT
- Subjects
- Male, Humans, Adolescent, Papillomaviridae, Protein Serine-Threonine Kinases, Intracellular Signaling Peptides and Proteins, Epidermodysplasia Verruciformis diagnosis, Epidermodysplasia Verruciformis genetics, Epidermodysplasia Verruciformis pathology, Skin Diseases, Primary Immunodeficiency Diseases diagnosis
- Abstract
Serine/threonine kinase 4 deficiency (STK4 or MST1, OMIM:614868) is an autosomal recessive (AR) combined immunodeficiency that can present with skin lesions such as epidermodysplasia verruciformis-like lesions (EVLL). Herein, we describe a 17-year-old male patient born from consanguineous parents presenting with recurrent respiratory infections, verruciform plaques, poikiloderma, chronic benign lymphoproliferation, and Sjögren syndrome with suspected interstitial lymphocytic pneumonia., (© 2023 Wiley Periodicals LLC.)
- Published
- 2024
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21. Large T cell clones expressing immune checkpoints increase during multiple myeloma evolution and predict treatment resistance.
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Botta C, Perez C, Larrayoz M, Puig N, Cedena MT, Termini R, Goicoechea I, Rodriguez S, Zabaleta A, Lopez A, Sarvide S, Blanco L, Papetti DM, Nobile MS, Besozzi D, Gentile M, Correale P, Siragusa S, Oriol A, González-Garcia ME, Sureda A, de Arriba F, Rios Tamayo R, Moraleda JM, Gironella M, Hernandez MT, Bargay J, Palomera L, Pérez-Montaña A, Goldschmidt H, Avet-Loiseau H, Roccaro A, Orfao A, Martinez-Lopez J, Rosiñol L, Lahuerta JJ, Blade J, Mateos MV, San-Miguel JF, Martinez Climent JA, and Paiva B
- Subjects
- Adult, Humans, Animals, Mice, T-Lymphocytes, Programmed Cell Death 1 Receptor genetics, Lenalidomide, Clone Cells, Multiple Myeloma drug therapy, Multiple Myeloma genetics
- Abstract
Tumor recognition by T cells is essential for antitumor immunity. A comprehensive characterization of T cell diversity may be key to understanding the success of immunomodulatory drugs and failure of PD-1 blockade in tumors such as multiple myeloma (MM). Here, we use single-cell RNA and T cell receptor sequencing to characterize bone marrow T cells from healthy adults (n = 4) and patients with precursor (n = 8) and full-blown MM (n = 10). Large T cell clones from patients with MM expressed multiple immune checkpoints, suggesting a potentially dysfunctional phenotype. Dual targeting of PD-1 + LAG3 or PD-1 + TIGIT partially restored their function in mice with MM. We identify phenotypic hallmarks of large intratumoral T cell clones, and demonstrate that the CD27
- and CD27+ T cell ratio, measured by flow cytometry, may serve as a surrogate of clonal T cell expansions and an independent prognostic factor in 543 patients with MM treated with lenalidomide-based treatment combinations., (© 2023. Springer Nature Limited.)- Published
- 2023
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22. Definition and Clinical Significance of the Monoclonal Gammopathy of Undetermined Significance-Like Phenotype in Patients With Monoclonal Gammopathies.
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Burgos L, Tamariz-Amador LE, Puig N, Cedena MT, Guerrero C, Jelínek T, Johnson S, Milani P, Cordon L, Perez JJ, Lasa M, Termini R, Oriol A, Hernandez MT, Palomera L, Martinez-Martinez R, de la Rubia J, de Arriba F, Rios R, Gonzalez ME, Gironella M, Cabañas V, Casanova M, Krsnik I, Perez-Montaña A, González-Calle V, Rodriguez-Otero P, Maisnar V, Hajek R, Van Rhee F, Jimenez-Zepeda V, Palladini G, Merlini G, Orfao A, de la Cruz J, Martinez-Lopez J, Lahuerta JJ, Rosiñol L, Blade J, Mateos MV, San-Miguel JF, and Paiva B
- Subjects
- Humans, Clinical Relevance, Disease Progression, Phenotype, Monoclonal Gammopathy of Undetermined Significance diagnosis, Monoclonal Gammopathy of Undetermined Significance therapy, Immunoglobulin Light-chain Amyloidosis, Paraproteinemias diagnosis, Paraproteinemias therapy, Multiple Myeloma diagnosis
- Abstract
Purpose: The existence of patients with multiple myeloma (MM) and light-chain (AL) amyloidosis who present with a monoclonal gammopathy of undetermined significance (MGUS)-like phenotype has been hypothesized, but methods to identify this subgroup are not standardized and its clinical significance is not properly validated., Patients and Methods: An algorithm to identify patients having MGUS-like phenotype was developed on the basis of the percentages of total bone marrow (BM) plasma cells (PC) and of clonal PC within the BM PC compartment, determined at diagnosis using flow cytometry in 548 patients with MGUS and 2,011 patients with active MM. The clinical significance of the algorithm was tested and validated in 488 patients with smoldering MM, 3,870 patients with active MM and 211 patients with AL amyloidosis., Results: Patients with smoldering MM with MGUS-like phenotype showed significantly lower rates of disease progression (4.5% and 0% at 2 years in two independent series). There were no statistically significant differences in time to progression between treatment versus observation in these patients. In active newly diagnosed MM, MGUS-like phenotype retained independent prognostic value in multivariate analyses of progression-free survival (PFS; hazard ratio [HR], 0.49; P = .001) and overall survival (OS; HR, 0.56; P = .039), together with International Staging System, lactate dehydrogenase, cytogenetic risk, transplant eligibility, and complete remission status. Transplant-eligible patients with active MM with MGUS-like phenotype showed PFS and OS rates at 5 years of 79% and 96%, respectively. In this subgroup, there were no differences in PFS and OS according to complete remission and measurable residual disease status. Application of the algorithm in two independent series of patients with AL predicted for different survival., Conclusion: We developed an open-access algorithm for the identification of MGUS-like patients with distinct clinical outcomes. This phenotypic classification could become part of the diagnostic workup of MM and AL amyloidosis.
- Published
- 2023
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23. European Society of Thoracic Surgeons expert consensus recommendations on technical standards of segmentectomy for primary lung cancer.
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Brunelli A, Decaluwe H, Gonzalez M, Gossot D, Petersen RH, Augustin F, Assouad J, Baste JM, Batirel H, Falcoz PE, Almanzar SF, Furak J, Gomez-Hernandez MT, de Antonio DG, Hansen H, Jimenez M, Koryllos A, Meacci E, Opitz I, Pages PB, Piwkowski C, Ruffini E, Schneiter D, Stupnik T, Szanto Z, Thomas P, Toker A, Tosi D, and Veronesi G
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- Humans, Pneumonectomy, Consensus, Neoplasm Staging, Retrospective Studies, Carcinoma, Non-Small-Cell Lung surgery, Lung Neoplasms surgery, Lung Neoplasms pathology
- Published
- 2023
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24. Commercial toilets emit energetic and rapidly spreading aerosol plumes.
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Crimaldi JP, True AC, Linden KG, Hernandez MT, Larson LT, and Pauls AK
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- Humans, SARS-CoV-2, COVID-19
- Abstract
Aerosols can transmit infectious diseases including SARS-CoV-2, influenza and norovirus. Flushed toilets emit aerosols that spread pathogens contained in feces, but little is known about the spatiotemporal evolution of these plumes or the velocity fields that transport them. Using laser light to illuminate ejected aerosols we quantify the kinematics of plumes emanating from a commercial flushometer-type toilet, and use the motion of aerosol particles to compute velocity fields of the associated flow. The toilet flush produces a strong chaotic jet with velocities exceeding 2 m/s; this jet transports aerosols to heights reaching 1.5 m within 8 seconds of initiating a flush. Quantifying toilet plumes and associated flow velocities provides a foundation for future design strategies to mitigate plume formation or to disinfect pathogens within it., (© 2022. The Author(s).)
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- 2022
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25. Investigating transmission of SARS-CoV-2 using novel face mask sampling: a protocol for an observational prospective study of index cases and their contacts in a congregate setting.
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Jaenisch T, Lamb MM, Gallichotte EN, Adams B, Henry C, Riess J, van Sickle JT, Hawkins KL, Montague BT, Coburn C, Conners Bauer L, Kovarik J, Hernandez MT, Bronson A, Graham L, James S, Hanenberg S, Kovacs J, Spencer JS, Zabel M, Fox PD, Pluss O, Windsor W, Winstanley G, Olson D, Barer M, Berman S, Ebel G, and Chu M
- Subjects
- Humans, Observational Studies as Topic, Personal Protective Equipment, Prospective Studies, SARS-CoV-2, COVID-19 diagnosis, COVID-19 epidemiology, COVID-19 prevention & control, Masks
- Abstract
Introduction: This study aims to measure how transmission of SARS-CoV-2 occurs in communities and to identify conditions that lend to increased transmission focusing on congregate situations. We will measure SARS-CoV-2 in exhaled breath of asymptomatic and symptomatic persons using face mask sampling-a non-invasive method for SARS-CoV-2 detection in exhaled air. We aim to detect transmission clusters and identify risk factors for SARS-CoV-2 transmission in presymptomatic, asymptomatic and symptomatic individuals., Methods and Analysis: In this observational prospective study with daily follow-up, index cases and their respective contacts are identified at each participating institution. Contact definitions are based on Centers for Disease Control and Prevention and local health department guidelines. Participants will wear masks with polyvinyl alcohol test strips adhered to the inside for 2 hours daily. The strips are applied to all masks used over at least 7 days. In addition, self-administered nasal swabs and (optional) finger prick blood samples are performed by participants. Samples are tested by standard PCR protocols and by novel antigen tests., Ethics and Dissemination: This study was approved by the Colorado Multiple Institutional Review Board and the WHO Ethics Review Committee. From the data generated, we will analyse transmission clusters and risk factors for transmission of SARS-CoV-2 in congregate settings. The kinetics of asymptomatic transmission and the evaluation of non-invasive tools for detection of transmissibility are of crucial importance for the development of more targeted control interventions-and ultimately to assist with keeping congregate settings open that are essential for our social fabric., Trial Registration Number: ClinicalTrials.gov (#NCT05145803)., Competing Interests: Competing interests: TJ, MML, WW, BA, GE and MC report grant support from WHO for this study for salaries or equipment/reagents. SB, OP, AB, CH, JR, JKovacs and MZ report grant/salary support for unrelated research without conflict of interest. EG, MH, CC, DO, SH, JKovarik, LCB, JTvS, SJ, JSS and LG report no conflict of interest. MZ reports speaker honoraria at academic institutions. BM reports industry support from Regeneron and Eli Lilly Foundation (as investigator, to the institution), MB reports support from the UK National Core Study on Transmission, and PF reports stock in Darwin Biosciences and support (equipment and reagents) from Ceres Nanosciences., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)
- Published
- 2022
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26. Circulating Tumor Cells for the Staging of Patients With Newly Diagnosed Transplant-Eligible Multiple Myeloma.
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Garcés JJ, Cedena MT, Puig N, Burgos L, Perez JJ, Cordon L, Flores-Montero J, Sanoja-Flores L, Calasanz MJ, Ortiol A, Blanchard MJ, Rios R, Martin J, Martínez-Martinez R, Bargay J, Sureda A, de la Rubia J, Hernandez MT, Rodriguez-Otero P, de la Cruz J, Orfao A, Mateos MV, Martinez-Lopez J, Lahuerta JJ, Rosiñol L, Blade J, San-Miguel JF, and Paiva B
- Subjects
- Antineoplastic Combined Chemotherapy Protocols therapeutic use, Bortezomib therapeutic use, Dexamethasone therapeutic use, Humans, Lactate Dehydrogenases, Lenalidomide therapeutic use, Neoplasm, Residual drug therapy, Multiple Myeloma drug therapy, Neoplastic Cells, Circulating pathology
- Abstract
Purpose: Patients with multiple myeloma (MM) may show patchy bone marrow (BM) infiltration and extramedullary disease. Notwithstanding, quantification of plasma cells (PCs) continues to be performed in BM since the clinical translation of circulating tumor cells (CTCs) remains undefined., Patients and Methods: CTCs were measured in peripheral blood (PB) of 374 patients with newly diagnosed MM enrolled in the GEM2012MENOS65 and GEM2014MAIN trials. Treatment included bortezomib, lenalidomide, and dexamethasone induction followed by autologous transplant, consolidation, and maintenance. Next-generation flow cytometry was used to evaluate CTCs in PB at diagnosis and measurable residual disease (MRD) in BM throughout treatment., Results: CTCs were detected in 92% (344 of 374) of patients with newly diagnosed MM. The correlation between the percentages of CTCs and BM PCs was modest. Increasing logarithmic percentages of CTCs were associated with inferior progression-free survival (PFS). A cutoff of 0.01% CTCs showed an independent prognostic value (hazard ratio: 2.02; 95% CI, 1.3 to 3.1; P = .001) in multivariable PFS analysis including the International Staging System, lactate dehydrogenase levels, and cytogenetics. The combination of the four prognostic factors significantly improved risk stratification. Outcomes according to the percentage of CTCs and depth of response to treatment showed that patients with undetectable CTCs had exceptional PFS regardless of complete remission and MRD status. In all other cases with detectable CTCs, only achieving MRD negativity (and not complete remission) demonstrated a statistically significant increase in PFS., Conclusion: Evaluation of CTCs in PB outperformed quantification of BM PCs. The detection of ≥ 0.01% CTCs could be a new risk factor in novel staging systems for patients with transplant-eligible MM.
- Published
- 2022
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27. A Machine Learning Model Based on Tumor and Immune Biomarkers to Predict Undetectable MRD and Survival Outcomes in Multiple Myeloma.
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Guerrero C, Puig N, Cedena MT, Goicoechea I, Perez C, Garcés JJ, Botta C, Calasanz MJ, Gutierrez NC, Martin-Ramos ML, Oriol A, Rios R, Hernandez MT, Martinez-Martinez R, Bargay J, de Arriba F, Palomera L, Gonzalez-Rodriguez AP, Mosquera-Orgueira A, Gonzalez-Perez MS, Martinez-Lopez J, Lahuerta JJ, Rosiñol L, Blade J, Mateos MV, San-Miguel JF, and Paiva B
- Subjects
- Aged, Biomarkers, Humans, Machine Learning, Neoplasm, Residual diagnosis, Survival Rate, Multiple Myeloma diagnosis, Multiple Myeloma pathology, Multiple Myeloma therapy
- Abstract
Purpose: Undetectable measurable residual disease (MRD) is a surrogate of prolonged survival in multiple myeloma. Thus, treatment individualization based on the probability of a patient achieving undetectable MRD with a singular regimen could represent a new concept toward personalized treatment, with fast assessment of its success. This has never been investigated; therefore, we sought to define a machine learning model to predict undetectable MRD at the onset of multiple myeloma., Experimental Design: This study included 487 newly diagnosed patients with multiple myeloma. The training (n = 152) and internal validation cohorts (n = 149) consisted of 301 transplant-eligible patients with active multiple myeloma enrolled in the GEM2012MENOS65 trial. Two external validation cohorts were defined by 76 high-risk transplant-eligible patients with smoldering multiple myeloma enrolled in the Grupo Español de Mieloma(GEM)-CESAR trial, and 110 transplant-ineligible elderly patients enrolled in the GEM-CLARIDEX trial., Results: The most effective model to predict MRD status resulted from integrating cytogenetic [t(4;14) and/or del(17p13)], tumor burden (bone marrow plasma cell clonality and circulating tumor cells), and immune-related biomarkers. Accurate predictions of MRD outcomes were achieved in 71% of cases in the GEM2012MENOS65 trial (n = 214/301) and 72% in the external validation cohorts (n = 134/186). The model also predicted sustained MRD negativity from consolidation onto 2 years maintenance (GEM2014MAIN). High-confidence prediction of undetectable MRD at diagnosis identified a subgroup of patients with active multiple myeloma with 80% and 93% progression-free and overall survival rates at 5 years., Conclusions: It is possible to accurately predict MRD outcomes using an integrative, weighted model defined by machine learning algorithms. This is a new concept toward individualized treatment in multiple myeloma. See related commentary by Pawlyn and Davies, p. 2482., (©2022 American Association for Cancer Research.)
- Published
- 2022
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28. Unsupervised machine learning improves risk stratification in newly diagnosed multiple myeloma: an analysis of the Spanish Myeloma Group.
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Mosquera Orgueira A, González Pérez MS, Diaz Arias J, Rosiñol L, Oriol A, Teruel AI, Martinez Lopez J, Palomera L, Granell M, Blanchard MJ, de la Rubia J, López de la Guia A, Rios R, Sureda A, Hernandez MT, Bengoechea E, Calasanz MJ, Gutierrez N, Martin ML, Blade J, Lahuerta JJ, San Miguel J, and Mateos MV
- Subjects
- Humans, Neoplasm Staging, Prognosis, Risk Assessment, Unsupervised Machine Learning, Multiple Myeloma diagnosis, Multiple Myeloma drug therapy, Multiple Myeloma epidemiology
- Abstract
The International Staging System (ISS) and the Revised International Staging System (R-ISS) are commonly used prognostic scores in multiple myeloma (MM). These methods have significant gaps, particularly among intermediate-risk groups. The aim of this study was to improve risk stratification in newly diagnosed MM patients using data from three different trials developed by the Spanish Myeloma Group. For this, we applied an unsupervised machine learning clusterization technique on a set of clinical, biochemical and cytogenetic variables, and we identified two novel clusters of patients with significantly different survival. The prognostic precision of this clusterization was superior to those of ISS and R-ISS scores, and appeared to be particularly useful to improve risk stratification among R-ISS 2 patients. Additionally, patients assigned to the low-risk cluster in the GEM05 over 65 years trial had a significant survival benefit when treated with VMP as compared with VTD. In conclusion, we describe a simple prognostic model for newly diagnosed MM whose predictions are independent of the ISS and R-ISS scores. Notably, the model is particularly useful in order to re-classify R-ISS score 2 patients in 2 different prognostic subgroups. The combination of ISS, R-ISS and unsupervised machine learning clusterization brings a promising approximation to improve MM risk stratification., (© 2022. The Author(s).)
- Published
- 2022
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29. Characterization of the public transit air microbiome and resistome reveals geographical specificity.
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Leung MHY, Tong X, Bøifot KO, Bezdan D, Butler DJ, Danko DC, Gohli J, Green DC, Hernandez MT, Kelly FJ, Levy S, Mason-Buck G, Nieto-Caballero M, Syndercombe-Court D, Udekwu K, Young BG, Mason CE, Dybwad M, and Lee PKH
- Subjects
- Bacteria genetics, Geography, Hong Kong, Humans, Metagenome genetics, Microbiota genetics
- Abstract
Background: The public transit is a built environment with high occupant density across the globe, and identifying factors shaping public transit air microbiomes will help design strategies to minimize the transmission of pathogens. However, the majority of microbiome works dedicated to the public transit air are limited to amplicon sequencing, and our knowledge regarding the functional potentials and the repertoire of resistance genes (i.e. resistome) is limited. Furthermore, current air microbiome investigations on public transit systems are focused on single cities, and a multi-city assessment of the public transit air microbiome will allow a greater understanding of whether and how broad environmental, building, and anthropogenic factors shape the public transit air microbiome in an international scale. Therefore, in this study, the public transit air microbiomes and resistomes of six cities across three continents (Denver, Hong Kong, London, New York City, Oslo, Stockholm) were characterized., Results: City was the sole factor associated with public transit air microbiome differences, with diverse taxa identified as drivers for geography-associated functional potentials, concomitant with geographical differences in species- and strain-level inferred growth profiles. Related bacterial strains differed among cities in genes encoding resistance, transposase, and other functions. Sourcetracking estimated that human skin, soil, and wastewater were major presumptive resistome sources of public transit air, and adjacent public transit surfaces may also be considered presumptive sources. Large proportions of detected resistance genes were co-located with mobile genetic elements including plasmids. Biosynthetic gene clusters and city-unique coding sequences were found in the metagenome-assembled genomes., Conclusions: Overall, geographical specificity transcends multiple aspects of the public transit air microbiome, and future efforts on a global scale are warranted to increase our understanding of factors shaping the microbiome of this unique built environment.
- Published
- 2021
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30. Deep MRD profiling defines outcome and unveils different modes of treatment resistance in standard- and high-risk myeloma.
- Author
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Goicoechea I, Puig N, Cedena MT, Burgos L, Cordón L, Vidriales MB, Flores-Montero J, Gutierrez NC, Calasanz MJ, Ramos MM, Lara-Astiaso D, Vilas-Zornoza A, Alignani D, Rodriguez I, Sarvide S, Alameda D, Garcés JJ, Rodriguez S, Fresquet V, Celay J, Garcia-Sanz R, Martinez-Lopez J, Oriol A, Rios R, Martin-Sanchez J, Martinez-Martinez R, Sarra J, Hernandez MT, de la Rubia J, Krsnik I, Moraleda JM, Palomera L, Bargay J, Martinez-Climent JA, Orfao A, Rosiñol L, Mateos MV, Lahuerta JJ, Blade J, San Miguel J, and Paiva B
- Subjects
- Adult, Aged, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Boron Compounds therapeutic use, Bortezomib therapeutic use, Chromosome Aberrations, Dexamethasone therapeutic use, Female, Flow Cytometry, Glycine analogs & derivatives, Glycine therapeutic use, Humans, Lenalidomide therapeutic use, Male, Middle Aged, Progression-Free Survival, Treatment Outcome, Drug Resistance, Neoplasm genetics, Multiple Myeloma drug therapy, Multiple Myeloma genetics, Multiple Myeloma pathology, Neoplasm, Residual pathology
- Abstract
Patients with multiple myeloma (MM) carrying standard- or high-risk cytogenetic abnormalities (CAs) achieve similar complete response (CR) rates, but the later have inferior progression-free survival (PFS). This questions the legitimacy of CR as a treatment endpoint and represents a biological conundrum regarding the nature of tumor reservoirs that persist after therapy in high-risk MM. We used next-generation flow (NGF) cytometry to evaluate measurable residual disease (MRD) in MM patients with standard- vs high-risk CAs (n = 300 and 90, respectively) enrolled in the PETHEMA/GEM2012MENOS65 trial, and to identify mechanisms that determine MRD resistance in both patient subgroups (n = 40). The 36-month PFS rates were higher than 90% in patients with standard- or high-risk CAs achieving undetectable MRD. Persistent MRD resulted in a median PFS of ∼3 and 2 years in patients with standard- and high-risk CAs, respectively. Further use of NGF to isolate MRD, followed by whole-exome sequencing of paired diagnostic and MRD tumor cells, revealed greater clonal selection in patients with standard-risk CAs, higher genomic instability with acquisition of new mutations in high-risk MM, and no unifying genetic event driving MRD resistance. Conversely, RNA sequencing of diagnostic and MRD tumor cells uncovered the selection of MRD clones with singular transcriptional programs and reactive oxygen species-mediated MRD resistance in high-risk MM. Our study supports undetectable MRD as a treatment endpoint for patients with MM who have high-risk CAs and proposes characterizing MRD clones to understand and overcome MRD resistance. This trial is registered at www.clinicaltrials.gov as #NCT01916252., (© 2021 by The American Society of Hematology.)
- Published
- 2021
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31. Women in thoracic surgery: European perspectives.
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Pompili C, Veronesi G, Novoa NM, Gomez-Hernandez MT, Sharkey AJ, Bhatti F, and Opitz I
- Abstract
During the last decades, women have been discouraged from entering the medical career and in particular in the surgical specialties. This situation is changing across continents and national and international initiatives are supporting aspiring female surgeons in pursuing the surgical career through mentorship and fellowship programmes. Due to the differences in training programmes, Health Care systems and cultural backgrounds, it's not easy to describe unanimously the pathways and obstacles that junior female thoracic surgeons are experiencing in Europe. The development of female surgical associations, mentorship programmes and national initiatives will further champion the gender equality in this specialty across Europe. During the recent years, the European Society of Thoracic Surgeons (ESTS) has established initiatives like the first ESTS Women in Thoracic Surgery Scientific Session or the annual Women in Thoracic ESTS Reception during the Annual Conference, which are done in an effort to encourage all female colleagues to join this specialty and increase the opportunity to share their experience and meet potential mentors. In this article we will depict the situation in some of the European countries whose female thoracic surgeons have led their way. We aim to give the next generation the examples that can influence women's choice of surgical career, and the possible strategies and initiatives to reduce the gender discrimination within healthcare., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/jtd-2020-wts-09). The series “Women in Thoracic Surgery” was commissioned by the editorial office without any funding or sponsorship. CP served as an unpaid Guest Editor of the series and serves as an unpaid editorial board member of Journal of Thoracic Disease from Sept 2018 to Aug 2020. Dr. GV reports grants from Associazione Italiana per la Ricerca sul Cancro (AIRC), Ministry of Health, Istituto nazionale Assicurazione Infortuni sul Lavoro (INAIL), personal fees from Medtronic, personal fees from Ab Medica, personal fees from Johnson & Johnson, outside the submitted work. The other authors have no other conflicts of interest to declare., (2021 Journal of Thoracic Disease. All rights reserved.)
- Published
- 2021
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32. Comparison of next-generation sequencing (NGS) and next-generation flow (NGF) for minimal residual disease (MRD) assessment in multiple myeloma.
- Author
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Medina A, Puig N, Flores-Montero J, Jimenez C, Sarasquete ME, Garcia-Alvarez M, Prieto-Conde I, Chillon C, Alcoceba M, Gutierrez NC, Oriol A, Rosinol L, Bladè J, Gironella M, Hernandez MT, Gonzalez-Calle V, Cedena MT, Paiva B, San-Miguel JF, Lahuerta JJ, Mateos MV, Martinez-Lopez J, Orfao A, Gonzalez M, and Garcia-Sanz R
- Subjects
- Adult, Disease-Free Survival, Female, Follow-Up Studies, Humans, Male, Middle Aged, Neoplasm, Residual, Survival Rate, Flow Cytometry, High-Throughput Nucleotide Sequencing, Multiple Myeloma blood, Multiple Myeloma genetics, Multiple Myeloma mortality, Multiple Myeloma therapy
- Abstract
Detecting persistent minimal residual disease (MRD) allows the identification of patients with an increased risk of relapse and death. In this study, we have evaluated MRD 3 months after transplantation in 106 myeloma patients using a commercial next-generation sequencing (NGS) strategy (LymphoTrack®), and compared the results with next-generation flow (NGF, EuroFlow). The use of different marrow pulls and the need of concentrating samples for NGS biased the applicability for MRD evaluation and favored NGF. Despite that, correlation between NGS and NGF was high (R
2 = 0.905). The 3-year progression-free survival (PFS) rates by NGS and NGF were longer for undetectable vs. positive patients (NGS: 88.7% vs. 56.6%; NGF: 91.4% vs. 50%; p < 0.001 for both comparisons), which resulted in a 3-year overall survival (OS) advantage (NGS: 96.2% vs. 77.3%; NGF: 96.6% vs. 74.9%, p < 0.01 for both comparisons). In the Cox regression model, NGS and NGF negativity had similar results but favoring the latter in PFS (HR: 0.20, 95% CI: 0.09-0.45, p < 0.001) and OS (HR: 0.21, 95% CI: 0.06-0.75, p = 0.02). All these results reinforce the role of MRD detection by different strategies in patient prognosis and highlight the use of MRD as an endpoint for multiple myeloma treatment.- Published
- 2020
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33. Immunogenomic identification and characterization of granulocytic myeloid-derived suppressor cells in multiple myeloma.
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Perez C, Botta C, Zabaleta A, Puig N, Cedena MT, Goicoechea I, Alameda D, San José-Eneriz E, Merino J, Rodríguez-Otero P, Maia C, Alignani D, Maiso P, Manrique I, Lara-Astiaso D, Vilas-Zornoza A, Sarvide S, Riillo C, Rossi M, Rosiñol L, Oriol A, Blanchard MJ, Rios R, Sureda A, Martin J, Martinez R, Bargay J, de la Rubia J, Hernandez MT, Martinez-Lopez J, Orfao A, Agirre X, Prosper F, Mateos MV, Lahuerta JJ, Blade J, San-Miguel JF, and Paiva B
- Subjects
- Female, Follow-Up Studies, Humans, Lymphocyte Count, Male, Middle Aged, Neutrophils immunology, Neutrophils metabolism, Neutrophils pathology, T-Lymphocytes immunology, T-Lymphocytes metabolism, T-Lymphocytes pathology, Transcription, Genetic immunology, Antigens, CD blood, Antigens, CD genetics, Antigens, CD immunology, Multiple Myeloma blood, Multiple Myeloma genetics, Multiple Myeloma immunology, Multiple Myeloma pathology, Myeloid-Derived Suppressor Cells immunology, Myeloid-Derived Suppressor Cells metabolism, Myeloid-Derived Suppressor Cells pathology, Neoplasm Proteins blood, Neoplasm Proteins genetics, Neoplasm Proteins immunology
- Abstract
Granulocytic myeloid-derived suppressor cells (G-MDSCs) promote tumor growth and immunosuppression in multiple myeloma (MM). However, their phenotype is not well established for accurate monitoring or clinical translation. We aimed to provide the phenotypic profile of G-MDSCs based on their prognostic significance in MM, immunosuppressive potential, and molecular program. The preestablished phenotype of G-MDSCs was evaluated in bone marrow samples from controls and MM patients using multidimensional flow cytometry; surprisingly, we found that CD11b+CD14-CD15+CD33+HLADR- cells overlapped with common eosinophils and neutrophils, which were not expanded in MM patients. Therefore, we relied on automated clustering to unbiasedly identify all granulocytic subsets in the tumor microenvironment: basophils, eosinophils, and immature, intermediate, and mature neutrophils. In a series of 267 newly diagnosed MM patients (GEM2012MENOS65 trial), only the frequency of mature neutrophils at diagnosis was significantly associated with patient outcome, and a high mature neutrophil/T-cell ratio resulted in inferior progression-free survival (P < .001). Upon fluorescence-activated cell sorting of each neutrophil subset, T-cell proliferation decreased in the presence of mature neutrophils (0.5-fold; P = .016), and the cytotoxic potential of T cells engaged by a BCMA×CD3-bispecific antibody increased notably with the depletion of mature neutrophils (fourfold; P = .0007). Most interestingly, RNA sequencing of the 3 subsets revealed that G-MDSC-related genes were specifically upregulated in mature neutrophils from MM patients vs controls because of differential chromatin accessibility. Taken together, our results establish a correlation between the clinical significance, immunosuppressive potential, and transcriptional network of well-defined neutrophil subsets, providing for the first time a set of optimal markers (CD11b/CD13/CD16) for accurate monitoring of G-MDSCs in MM., (© 2020 by The American Society of Hematology.)
- Published
- 2020
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34. Biological and clinical significance of dysplastic hematopoiesis in patients with newly diagnosed multiple myeloma.
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Maia C, Puig N, Cedena MT, Goicoechea I, Valdes-Mas R, Vazquez I, Chillon MC, Aguirre P, Sarvide S, Gracia-Aznárez FJ, Alkorta G, Calasanz MJ, Garcia-Sanz R, Gonzalez M, Gutierrez NC, Martinez-Lopez J, Perez JJ, Merino J, Moreno C, Burgos L, Alignani D, Botta C, Prosper F, Matarraz S, Orfao A, Oriol A, Teruel AI, de Paz R, de Arriba F, Hernandez MT, Palomera L, Martinez R, Rosiñol L, Mateos MV, Lahuerta JJ, Blade J, San Miguel JF, and Paiva B
- Subjects
- Aged, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Clinical Trials, Phase III as Topic, Combined Modality Therapy, Female, Flow Cytometry methods, Hematopoietic Stem Cell Transplantation, High-Throughput Nucleotide Sequencing, Humans, In Situ Hybridization, Fluorescence, Kaplan-Meier Estimate, Male, Middle Aged, Multiple Myeloma drug therapy, Multiple Myeloma mortality, Multiple Myeloma therapy, Mutation, Prognosis, Progression-Free Survival, Prospective Studies, Randomized Controlled Trials as Topic, Transplantation, Autologous, Tumor Microenvironment, Clonal Hematopoiesis, Multiple Myeloma pathology, Myelodysplastic Syndromes etiology
- Abstract
Risk of developing myelodysplastic syndrome (MDS) is significantly increased in both multiple myeloma (MM) and monoclonal gammopathy of undetermined significance, suggesting that it is therapy independent. However, the incidence and sequelae of dysplastic hematopoiesis at diagnosis are unknown. Here, we used multidimensional flow cytometry (MFC) to prospectively screen for the presence of MDS-associated phenotypic alterations (MDS-PA) in the bone marrow of 285 patients with MM enrolled in the PETHEMA/GEM2012MENOS65 trial (#NCT01916252). We investigated the clinical significance of monocytic MDS-PA in a larger series of 1252 patients enrolled in 4 PETHEMA/GEM protocols. At diagnosis, 33 (11.6%) of 285 cases displayed MDS-PA. Bulk and single-cell-targeted sequencing of MDS recurrently mutated genes in CD34+ progenitors (and dysplastic lineages) from 67 patients revealed clonal hematopoiesis in 13 (50%) of 26 cases with MDS-PA vs 9 (22%) of 41 without MDS-PA; TET2 and NRAS were the most frequently mutated genes. Dynamics of MDS-PA at diagnosis and after autologous transplant were evaluated in 86 of 285 patients and showed that in most cases (69 of 86 [80%]), MDS-PA either persisted or remained absent in patients with or without MDS-PA at diagnosis, respectively. Noteworthy, MDS-associated mutations infrequently emerged after high-dose therapy. Based on MFC profiling, patients with MDS-PA have altered hematopoiesis and T regulatory cell distribution in the tumor microenvironment. Importantly, the presence of monocytic MDS-PA at diagnosis anticipated greater risk of hematologic toxicity and was independently associated with inferior progression-free survival (hazard ratio, 1.5; P = .02) and overall survival (hazard ratio, 1.7; P = .01). This study reveals the biological and clinical significance of dysplastic hematopoiesis in newly diagnosed MM, which can be screened with moderate sensitivity using cost-effective MFC., (© 2020 by The American Society of Hematology.)
- Published
- 2020
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35. Measurable Residual Disease by Next-Generation Flow Cytometry in Multiple Myeloma.
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Paiva B, Puig N, Cedena MT, Rosiñol L, Cordón L, Vidriales MB, Burgos L, Flores-Montero J, Sanoja-Flores L, Lopez-Anglada L, Maldonado R, de la Cruz J, Gutierrez NC, Calasanz MJ, Martin-Ramos ML, Garcia-Sanz R, Martinez-Lopez J, Oriol A, Blanchard MJ, Rios R, Martin J, Martinez-Martinez R, Sureda A, Hernandez MT, de la Rubia J, Krsnik I, Moraleda JM, Palomera L, Bargay J, Van Dongen JJM, Orfao A, Mateos MV, Blade J, San-Miguel JF, and Lahuerta JJ
- Subjects
- Antineoplastic Combined Chemotherapy Protocols therapeutic use, Bortezomib administration & dosage, Clinical Trials, Phase III as Topic, Dexamethasone administration & dosage, Female, Humans, Lenalidomide administration & dosage, Longitudinal Studies, Male, Middle Aged, Multiple Myeloma drug therapy, Neoplasm, Residual pathology, Randomized Controlled Trials as Topic, Flow Cytometry methods, Multiple Myeloma pathology
- Abstract
Purpose: Assessing measurable residual disease (MRD) has become standard with many tumors, but the clinical meaning of MRD in multiple myeloma (MM) remains uncertain, particularly when assessed by next-generation flow (NGF) cytometry. Thus, we aimed to determine the applicability and sensitivity of the flow MRD-negative criterion defined by the International Myeloma Working Group (IMWG)., Patients and Methods: In the PETHEMA/GEM2012MENOS65 trial, 458 patients with newly diagnosed MM had longitudinal assessment of MRD after six induction cycles with bortezomib, lenalidomide, and dexamethasone (VRD), autologous transplantation, and two consolidation courses with VRD. MRD was assessed in 1,100 bone marrow samples from 397 patients; the 61 patients without MRD data discontinued treatment during induction and were considered MRD positive for intent-to-treat analysis. The median limit of detection achieved by NGF was 2.9 × 10
-6 . Patients received maintenance (lenalidomide ± ixazomib) according to the companion PETHEMA/GEM2014MAIN trial., Results: Overall, 205 (45%) of 458 patients had undetectable MRD after consolidation, and only 14 of them (7%) have experienced progression thus far; seven of these 14 displayed extraosseous plasmacytomas at diagnosis and/or relapse. Using time-dependent analysis, patients with undetectable MRD had an 82% reduction in the risk of progression or death (hazard ratio, 0.18; 95% CI, 0.11 to 0.30; P < .001) and an 88% reduction in the risk of death (hazard ratio, 0.12; 95% CI, 0.05 to 0.29; P < .001). Timing of undetectable MRD (after induction v intensification) had no impact on patient survival. Attaining undetectable MRD overcame poor prognostic features at diagnosis, including high-risk cytogenetics. By contrast, patients with Revised International Staging System III status and positive MRD had dismal progression-free and overall survivals (median, 14 and 17 months, respectively). Maintenance increased the rate of undetectable MRD by 17%., Conclusion: The IMWG flow MRD-negative response criterion is highly applicable and sensitive to evaluate treatment efficacy in MM.- Published
- 2020
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36. Radical consolidative treatments a hope for patients with oligometastatic non-small cell lung cancer.
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Jimenez MF and Gomez-Hernandez MT
- Abstract
Competing Interests: Conflicts of Interest: MF Jimenez: Medtronic, Baxter and BD -Honoraria, Advisor. Another author has no conflicts of interest to declare.
- Published
- 2019
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37. An aggregate score to stratify the technical complexity of video-assisted thoracoscopic lobectomy.
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Miyazaki T, Imperatori A, Jimenez M, Drosos P, Gomez-Hernandez MT, Varela G, Novoa N, Nagayasu T, and Brunelli A
- Subjects
- Aged, Female, Humans, Male, Operative Time, Lung Neoplasms surgery, Pneumonectomy methods, Thoracic Surgery, Video-Assisted methods
- Abstract
Objectives: The purpose of this study was to develop a score to predict the complexity of video-assisted thoracoscopic surgery (VATS) lobectomies preoperatively., Methods: One hundred and thirty-nine consecutive patients undergoing VATS lobectomy operated on by a single surgeon as the first operator were included. Complex operations were defined as: operation time >180 min (corresponding to the 75th percentile) or a conversion to thoracotomy. Several patient-related baseline and radiological variables were tested for a possible association with surgical complexity by logistic regression analysis. An aggregate score was created by weighing the regression estimates of the significant predictors. Patients were then grouped in classes of risk according to their scores. Finally, the score was validated in an external population of 154 VATS lobectomy patients., Results: Twenty-nine VATS lobectomies (21%) were classified as complex. The following variables were found to be significantly associated with a complex operation and were used to calculate the risk score in each patient (1 point each): male (P = 0.006), presence of thick pleura (P = 0.003), presence of emphysema (P = 0.001), enlarged hilar nodes (P = 0.003). Patients were grouped in 4 classes showing an incremental incidence of complex operations (P < 0.0001): score 0, 7.4%; score 1, 18%; score 2, 27%; score >2, 67%. In the external validation set, the score confirmed its association with the incidence of complex operations (P < 0.001): score 0, 7.3%; score 1, 10%; score 2, 16%; score >2 50%., Conclusions: The complexity score appeared to be reproducible in an external setting and can be used to preoperatively identify appropriate candidates for VATS lobectomies to improve the efficiency and safety of the training phase., (© The Author(s) 2018. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)
- Published
- 2019
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38. Fostering Global Health Practice: An Undergraduate Nursing Student Exchange and International Service-Learning Program.
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Noone J, Kohan T, Hernandez MT, Tibbetts D, and Richmond R
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- Humans, Learning, Mexico, Nursing Education Research, Nursing Evaluation Research, Oregon, Students, Nursing psychology, Education, Nursing, Baccalaureate organization & administration, Global Health education, International Educational Exchange, Schools, Nursing organization & administration
- Abstract
Background: Nurses increasingly are identified as key health care members on global health initiatives, and nursing curricula should address this competency to prepare students to work in a global environment. This article will share how processes and structures were established for an international undergraduate nursing student exchange and service-learning experience between two schools of nursing., Method: The goals of the project were to (a) implement an annual nursing student exchange of approximately 3 weeks in length; (b) select eight students from each school, accompanied by a faculty member, to participate; and (c) provide opportunities for students to participate in service-learning assessments in identified communities., Results: To date, an annual exchange is in its fourth year of existence., Conclusion: An international service-learning opportunity is one way to improve nursing students' ability to provide culturally competent health care. [J Nurs Educ. 2019;58(4):235-239.]., (Copyright 2019, SLACK Incorporated.)
- Published
- 2019
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39. Monitoring and modeling of household air quality related to use of different Cookfuels in Paraguay.
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Tagle M, Pillarisetti A, Hernandez MT, Troncoso K, Soares A, Torres R, Galeano A, Oyola P, Balmes J, and Smith KR
- Subjects
- Biomass, Cross-Sectional Studies, Electricity, Environmental Monitoring, Housing, Humans, Linear Models, Paraguay, Particle Size, Rural Population, Surveys and Questionnaires, Wood, Air Pollution, Indoor analysis, Carbon Monoxide analysis, Cooking methods, Particulate Matter analysis
- Abstract
In Paraguay, 49% of the population depends on biomass (wood and charcoal) for cooking. Residential biomass burning is a major source of fine particulate matter (PM
2.5 ) and carbon monoxide (CO) in and around the household environment. In July 2016, cross-sectional household air pollution sampling was conducted in 80 households in rural Paraguay. Time-integrated samples (24 hours) of PM2.5 and continuous CO concentrations were measured in kitchens that used wood, charcoal, liquefied petroleum gas (LPG), or electricity to cook. Qualitative and quantitative household-level variables were captured using questionnaires. The average PM2.5 concentration (μg/m3 ) was higher in kitchens that burned wood (741.7 ± 546.4) and charcoal (107.0 ± 68.6) than in kitchens where LPG (52.3 ± 18.9) or electricity (52.0 ± 14.8) was used. Likewise, the average CO concentration (ppm) was higher in kitchens that used wood (19.4 ± 12.6) and charcoal (7.6 ± 6.5) than in those that used LPG (0.5 ± 0.6) or electricity (0.4 ± 0.6). Multivariable linear regression was conducted to generate predictive models for indoor PM2.5 and CO concentrations (predicted R2 = 0.837 and 0.822, respectively). This study provides baseline indoor air quality data for Paraguay and presents a multivariate statistical approach that could be used in future research and intervention programs., (© 2018 The Pan-American Health Organization. Indoor Air published by John Wiley & Sons Ltd.)- Published
- 2019
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40. Prognostic utility of serum free light chain ratios and heavy-light chain ratios in multiple myeloma in three PETHEMA/GEM phase III clinical trials.
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Lopez-Anglada L, Cueto-Felgueroso C, Rosiñol L, Oriol A, Teruel AI, Lopez de la Guia A, Bengoechea E, Palomera L, de Arriba F, Hernandez JM, Granell M, Peñalver FJ, Garcia-Sanz R, Besalduch J, Gonzalez Y, Martinez RB, Hernandez MT, Gutierrez NC, Puerta P, Valeri A, Paiva B, Blade J, Mateos MV, San Miguel J, Lahuerta JJ, and Martinez-Lopez J
- Subjects
- Antineoplastic Combined Chemotherapy Protocols therapeutic use, Clinical Trials, Phase III as Topic, Humans, Induction Chemotherapy, Kaplan-Meier Estimate, Prognosis, Retrospective Studies, Stem Cell Transplantation methods, Transplantation, Autologous, Immunoglobulin Heavy Chains blood, Immunoglobulin Light Chains blood, Multiple Myeloma blood, Multiple Myeloma therapy
- Abstract
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) (<0.03 or >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 (<0.29 or >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., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2018
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41. Prognostic value of antigen expression in multiple myeloma: a PETHEMA/GEM study on 1265 patients enrolled in four consecutive clinical trials.
- Author
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Arana P, Paiva B, Cedena MT, Puig N, Cordon L, Vidriales MB, Gutierrez NC, Chiodi F, Burgos L, Anglada LL, Martinez-Lopez J, Hernandez MT, Teruel AI, Gironella M, Echeveste MA, Rosiñol L, Martinez R, Oriol A, De la Rubia J, Orfao A, Blade J, Lahuerta JJ, Mateos MV, and San Miguel JF
- Subjects
- Adult, Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Neoplasm Recurrence, Local metabolism, Neoplasm Recurrence, Local pathology, Neoplasm, Residual metabolism, Neoplasm, Residual pathology, Prognosis, Antigens, CD metabolism, Multiple Myeloma metabolism, Multiple Myeloma pathology
- Abstract
Persistence of minimal residual disease (MRD) after treatment for myeloma predicts inferior outcomes, but within MRD-positive patients there is great heterogeneity with both early and very late relapses. Among different MRD techniques, flow cytometry provides additional information about antigen expression on tumor cells, which could potentially contribute to stratify MRD-positive patients. We investigated the prognostic value of those antigens required to monitor MRD in 1265 newly diagnosed patients enrolled in the GEM2000, GEM2005MENOS65, GEM2005MAS65 and GEM2010MAS65 protocols. Overall, CD19
pos , CD27neg , CD38lo , CD45pos , CD81pos , CD117neg and CD138lo expression predicted inferior outcomes. Through principal component analysis, we found that simultaneous CD38low CD81pos CD117neg expression emerged as the most powerful combination with independent prognostic value for progression-free survival (HR:1.69; P=0.002). This unique phenotypic profile retained prognostic value among MRD-positive patients. We then used next-generation flow to determine antigen stability throughout the course of the disease, and found that the expression of antigens required to monitor MRD is mostly stable from diagnosis to MRD stages, except for CD81 whose expression progressively increased from baseline to chemoresistant tumor cells (14 vs 28%). Altogether, we showed that the phenotypic profile of tumor cells provides additional prognostic information, and could be used to further predict risk of relapse among MRD-positive patients.- Published
- 2018
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42. Depth of Response in Multiple Myeloma: A Pooled Analysis of Three PETHEMA/GEM Clinical Trials.
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Lahuerta JJ, Paiva B, Vidriales MB, Cordón L, Cedena MT, Puig N, Martinez-Lopez J, Rosiñol L, Gutierrez NC, Martín-Ramos ML, Oriol A, Teruel AI, Echeveste MA, de Paz R, de Arriba F, Hernandez MT, Palomera L, Martinez R, Martin A, Alegre A, De la Rubia J, Orfao A, Mateos MV, Blade J, and San-Miguel JF
- Subjects
- Age Factors, Aged, Clinical Trials as Topic methods, Clinical Trials as Topic statistics & numerical data, Disease-Free Survival, Humans, Multiple Myeloma pathology, Neoplasm, Residual, Proportional Hazards Models, Stem Cell Transplantation statistics & numerical data, Survival Rate, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Multiple Myeloma therapy, Stem Cell Transplantation methods
- Abstract
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.
- Published
- 2017
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43. Teaching video-assisted thoracic surgery lobectomy-using an ex vivo simulation model.
- Author
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Jimenez M and Gomez-Hernandez MT
- Abstract
Video-assisted thoracic surgery (VATS) is gradually replacing conventional open thoracotomy as the standard approach of many lung resections and thoracic surgical trainees and experienced surgeons must learn and master this technique. Simulation based training may be a good option to acquire or improve these advanced skills, however realistic and inexpensive simulators are not accessible or commercially available. We developed a low cost and hi fidelity simulation model using porcine heart-lung blocks., Competing Interests: Conflict of Interest: The authors have no conflicts of interest to declare.
- Published
- 2017
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44. Refraining from smoking shortly before lobectomy has no influence on the risk of pulmonary complications: a case-control study on a matched population.
- Author
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Rodriguez M, Gómez-Hernandez MT, Novoa N, Jiménez MF, Aranda JL, and Varela G
- Subjects
- Case-Control Studies, Databases, Factual, Female, Forced Expiratory Volume physiology, Humans, Male, Middle Aged, Pneumonectomy methods, Pneumonia etiology, Postoperative Complications, Preoperative Care methods, Pulmonary Atelectasis etiology, Risk Factors, Smoking adverse effects, Vital Capacity physiology, Carcinoma, Non-Small-Cell Lung surgery, Lung Neoplasms surgery, Pneumonectomy adverse effects, Smoking Cessation
- Abstract
Objectives: Whether or not smoking increases the risk of postoperative pulmonary complications (PPCs) in lung resection patients remains controversial. The objective of this study was to evaluate whether active smoking at the time of surgery increases the risk of PPCs compared to abstention shortly before the procedure., Methods: We conducted a case-control study on 378 patients who underwent non-extended lobectomy in our institution. Cases were active smokers at the time of surgery, and controls were patients who quit smoking at any time up to 16 weeks before surgery. All patients received the same perioperative care, including chest physiotherapy. The occurrence of PPCs was the considered outcome. PPCs were defined as pneumonia (American Thoracic Society criteria, 2004) or atelectasis requiring bronchoscopy. Cases and controls were matched according to age, body mass index, forced expiratory volume in the first second of expiration (FEV1%), FEV1/forced vital capacity, type of approach and diagnosis of non-small-cell lung cancer. We calculated the odds ratio (OR) with 95% confidence interval (CI) for PPCs., Results: The overall prevalence of PPCs was 4.7% (18/378); 5.3% (13 out of 244) in the active smokers group and 3.7% (5 out of 134) in the ex-smokers group. After matching, two sets of 134 patients each were compared. The prevalence was 4.5% (6/134) in active and 3.7% (5/134) in ex-smokers (OR 1.21 95% CI: 0.29-5.13, P = 0.76)., Conclusions: In this population of patients strictly matched according to risk criteria for PPCs, smoking at the time of surgery was not identified as a risk variable. Therefore, the practice of postponing surgery until tobacco abstention has been achieved does not seem to be justified., (© The Author 2016. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)
- Published
- 2017
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45. Differentiation stage of myeloma plasma cells: biological and clinical significance.
- Author
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Paiva B, Puig N, Cedena MT, de Jong BG, Ruiz Y, Rapado I, Martinez-Lopez J, Cordon L, Alignani D, Delgado JA, van Zelm MC, Van Dongen JJ, Pascual M, Agirre X, Prosper F, Martín-Subero JI, Vidriales MB, Gutierrez NC, Hernandez MT, Oriol A, Echeveste MA, Gonzalez Y, Johnson SK, Epstein J, Barlogie B, Morgan GJ, Orfao A, Blade J, Mateos MV, Lahuerta JJ, and San-Miguel JF
- Subjects
- Adult, Antigens, CD metabolism, Biomarkers, Bone Marrow metabolism, Bone Marrow pathology, Bone Marrow Cells metabolism, Bone Marrow Cells pathology, Case-Control Studies, Cell Cycle, DNA Methylation, Female, Gene Expression Profiling, Genetic Heterogeneity, High-Throughput Nucleotide Sequencing, Humans, Immunophenotyping, In Situ Hybridization, Fluorescence, Male, Middle Aged, Multiple Myeloma genetics, Multiple Myeloma mortality, Mutation, Neoplasm Grading, Phenotype, Prognosis, Single-Cell Analysis, Young Adult, Multiple Myeloma diagnosis, Multiple Myeloma metabolism, Plasma Cells metabolism, Plasma Cells pathology
- Abstract
The notion that plasma cells (PCs) are terminally differentiated has prevented intensive research in multiple myeloma (MM) about their phenotypic plasticity and differentiation. Here, we demonstrated in healthy individuals (n=20) that the CD19-CD81 expression axis identifies three bone marrow (BM)PC subsets with distinct age-prevalence, proliferation, replication-history, immunoglobulin-production, and phenotype, consistent with progressively increased differentiation from CD19+CD81+ into CD19-CD81+ and CD19-CD81- BMPCs. Afterwards, we demonstrated in 225 newly diagnosed MM patients that, comparing to normal BMPC counterparts, 59% had fully differentiated (CD19-CD81-) clones, 38% intermediate-differentiated (CD19-CD81+) and 3% less-differentiated (CD19+CD81+) clones. The latter patients had dismal outcome, and PC differentiation emerged as an independent prognostic marker for progression-free (HR: 1.7; P=0.005) and overall survival (HR: 2.1; P=0.006). Longitudinal comparison of diagnostic vs minimal-residual-disease samples (n=40) unraveled that in 20% of patients, less-differentiated PCs subclones become enriched after therapy-induced pressure. We also revealed that CD81 expression is epigenetically regulated, that less-differentiated clonal PCs retain high expression of genes related to preceding B-cell stages (for example: PAX5), and show distinct mutation profile vs fully differentiated PC clones within individual patients. Together, we shed new light into PC plasticity and demonstrated that MM patients harbouring less-differentiated PCs have dismal survival, which might be related to higher chemoresistant potential plus different molecular and genomic profiles.
- Published
- 2017
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46. Elotuzumab in combination with thalidomide and low-dose dexamethasone: a phase 2 single-arm safety study in patients with relapsed/refractory multiple myeloma.
- Author
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Mateos MV, Granell M, Oriol A, Martinez-Lopez J, Blade J, Hernandez MT, Martín J, Gironella M, Lynch M, Bleickardt E, Paliwal P, Singhal A, and San-Miguel J
- Subjects
- Aged, Aged, 80 and over, Antibodies, Monoclonal, Humanized administration & dosage, Antineoplastic Combined Chemotherapy Protocols adverse effects, Dexamethasone administration & dosage, Drug Resistance, Neoplasm, Female, Humans, Male, Middle Aged, Multiple Myeloma mortality, Neoplasm Staging, Recurrence, Retreatment, Survival Analysis, Thalidomide administration & dosage, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Multiple Myeloma drug therapy, Multiple Myeloma pathology
- Abstract
Elotuzumab is an immunostimulatory, humanized immunoglobulin G1 monoclonal antibody that selectively targets and kills signalling lymphocytic activation molecule family member 7-expressing myeloma cells. We evaluated the safety and tolerability of elotuzumab 10 mg/kg combined with thalidomide 50-200 mg and dexamethasone 40 mg (with/without cyclophosphamide 50 mg) in patients with relapsed/refractory multiple myeloma (RRMM). The primary endpoint was the proportion of grade ≥3 non-haematological adverse events (AEs); other endpoints included the number of dose reductions/discontinuations and efficacy. Forty patients were treated, who had a median of three previous therapies, including bortezomib (98%) and lenalidomide (73%). Grade ≥3 non-haematological AEs were reported in 63% of patients, most commonly asthenia (35%) and peripheral oedema (25%). Six (15%) patients had an infusion reaction. Twenty-six (65%) patients had ≥1 dose reduction/discontinuation due to an AE, none related to elotuzumab. Overall response rate was 38%; median progression-free survival was 3·9 months. Median overall survival was 16·3 months and the 1-year survival rate was 63%. Minimal incremental toxicity was observed with addition of elotuzumab to thalidomide/dexamethasone with or without cyclophosphamide, and efficacy data suggest clinical benefit in a highly pre-treated population. Elotuzumab combined with thalidomide may provide an additional treatment option for patients with RRMM., (© 2016 John Wiley & Sons Ltd.)
- Published
- 2016
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47. A qualitative exploration of perceived gender differences in methamphetamine use among women who use methamphetamine on the Mexico-U.S. border.
- Author
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Loza O, Ramos R, Ferreira-Pinto J, Hernandez MT, and Villalobos SA
- Subjects
- Adult, Female, Humans, Mexico ethnology, Qualitative Research, Amphetamine-Related Disorders ethnology, Central Nervous System Stimulants, Methamphetamine, Women
- Abstract
The purpose of this study is to extend the research on contextual factors that influence the initiation and continued use of methamphetamine (meth) by women on the U.S.-Mexico border. At present, a minimal body of literature exists that explores meth use on the Mexico-U.S. border. A purposeful sample of 20 women who were active meth users aged ≥18 years was recruited by trained outreach workers from a variety of meth-user networks in Ciudad Juárez, Mexico, the city bordering El Paso, Texas. Respondents participated in in-depth, semi-structured interviews including questions on users' perceived familial, social, and environmental influences of meth use. Gender-based themes emerged from the analysis: (1) patterns of meth use; (2) places where drugs were used; (3) effects of relationship networks on meth use; (4) differential access to drugs; (5) trading sex for drugs; (6) perceived class differences; and (7) long-term drug use and its consequences. Respondents reported a preference for using meth as powder or pills as opposed to smoking or injecting the drug. They reported being introduced to meth by men they trust and relying on men for drug acquisition in spaces less accessible and more dangerous to women. They described how the drug changed their lifestyle and their behavior towards family members and friends, including instances of physical and psychological violence. Interventions for women on the Mexico-U.S. border should be developed based on users' social networks to target social processes to prevent initiation and to bring active meth users into treatment.
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- 2016
- Full Text
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48. The National Institutes of Health Fogarty International Center Global Health Scholars and Fellows Program: Collaborating Across Five Consortia to Strengthen Research Training.
- Author
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Zunt JR, Chi BH, Heimburger DC, Cohen CR, Strathdee S, Hobbs N, Thomas Y, Bale K, Salisbury K, Hernandez MT, Riley LW, Vermund SH, and van der Horst C
- Subjects
- Humans, Internationality, Mentors, United States, Biomedical Research education, Fellowships and Scholarships organization & administration, Global Health education, National Institutes of Health (U.S.) organization & administration
- Abstract
As demand for global health research training continues to grow, many universities are striving to meet the needs of trainees in a manner complementary to research priorities of the institutions hosting trainees, while also increasing capacity for conducting research. We provide an overview of the first 4 years of the Global Health Program for Fellows and Scholars, a collaboration of 20 U.S. universities and institutions spread across 36 low- and middle-income countries funded through the National Institutes of Health Fogarty International Center. We highlight many aspects of our program development that may be of interest to other multinational consortia developing global health research training programs., (© The American Society of Tropical Medicine and Hygiene.)
- Published
- 2016
- Full Text
- View/download PDF
49. Minimal residual disease monitoring and immune profiling in multiple myeloma in elderly patients.
- Author
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Paiva B, Cedena MT, Puig N, Arana P, Vidriales MB, Cordon L, Flores-Montero J, Gutierrez NC, Martín-Ramos ML, Martinez-Lopez J, Ocio EM, Hernandez MT, Teruel AI, Rosiñol L, Echeveste MA, Martinez R, Gironella M, Oriol A, Cabrera C, Martin J, Bargay J, Encinas C, Gonzalez Y, Van Dongen JJ, Orfao A, Bladé J, Mateos MV, Lahuerta JJ, and San Miguel JF
- Subjects
- Aged, Aged, 80 and over, Biomarkers, Pharmacological blood, Biomarkers, Tumor blood, Dexamethasone administration & dosage, Drug Monitoring methods, Female, Humans, Immunity physiology, Lenalidomide, Male, Melphalan therapeutic use, Multiple Myeloma blood, Multiple Myeloma mortality, Neoplasm, Residual, Prednisone therapeutic use, Prognosis, Survival Analysis, Thalidomide administration & dosage, Thalidomide analogs & derivatives, Vincristine therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Immunity drug effects, Monitoring, Physiologic methods, Multiple Myeloma diagnosis, Multiple Myeloma drug therapy
- Abstract
The value of minimal residual disease (MRD) in multiple myeloma (MM) has been more frequently investigated in transplant-eligible patients than in elderly patients. Because an optimal balance between treatment efficacy and toxicity is of utmost importance in patients with elderly MM, sensitive MRD monitoring might be particularly valuable in this patient population. Here, we used second-generation 8-color multiparameter-flow cytometry (MFC) to monitor MRD in 162 transplant-ineligible MM patients enrolled in the PETHEMA/GEM2010MAS65 study. The transition from first- to second-generation MFC resulted in increased sensitivity and allowed us to identify 3 patient groups according to MRD levels: MRD negative (<10(-5); n = 54, 34%), MRD positive (between <10(-4) and ≥10(-5); n = 20, 12%), and MRD positive (≥10(-4); n = 88, 54%). MRD status was an independent prognostic factor for time to progression (TTP) (hazard ratio [HR], 2.7; P = .007) and overall survival (OS) (HR, 3.1; P = .04), with significant benefit for MRD-negative patients (median TTP not reached, 70% OS at 3 years), and similar poorer outcomes for cases with MRD levels between <10(-4) and ≥10(-5) vs ≥10(-4) (both with a median TTP of 15 months; 63% and 55% OS at 3 years, respectively). Furthermore, MRD negativity significantly improved TTP of patients >75 years (HR, 4.8; P < .001), as well as those with high-risk cytogenetics (HR, 12.6; P = .01). Using second-generation MFC, immune profiling concomitant to MRD monitoring also contributed to identify patients with poor, intermediate, and favorable outcomes (25%, 61%, and 100% OS at 3 years, respectively; P = .01), the later patients being characterized by an increased compartment of mature B cells. Our results show that similarly to transplant candidates, MRD monitoring is one of the most relevant prognostic factors in elderly MM patients, irrespectively of age or cytogenetic risk. This trial was registered at www.clinicaltrials.gov as #NCT01237249., (© 2016 by The American Society of Hematology.)
- Published
- 2016
- Full Text
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50. Phenotypic and genomic analysis of multiple myeloma minimal residual disease tumor cells: a new model to understand chemoresistance.
- Author
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Paiva B, Corchete LA, Vidriales MB, Puig N, Maiso P, Rodriguez I, Alignani D, Burgos L, Sanchez ML, Barcena P, Echeveste MA, Hernandez MT, García-Sanz R, Ocio EM, Oriol A, Gironella M, Palomera L, De Arriba F, Gonzalez Y, Johnson SK, Epstein J, Barlogie B, Lahuerta JJ, Blade J, Orfao A, Mateos MV, and San Miguel JF
- Subjects
- Aged, Bortezomib administration & dosage, Cell Adhesion Molecules metabolism, Dexamethasone administration & dosage, Disease Progression, Down-Regulation, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Genomics, Humans, Immunophenotyping, Integrins metabolism, Lenalidomide, Male, Melphalan administration & dosage, Models, Genetic, Multiple Myeloma pathology, Neoplasm, Residual pathology, Phenotype, Plasma Cells pathology, Prednisone administration & dosage, Prognosis, Thalidomide administration & dosage, Thalidomide analogs & derivatives, Drug Resistance, Neoplasm, Multiple Myeloma drug therapy, Multiple Myeloma genetics, Neoplasm, Residual drug therapy, Neoplasm, Residual genetics
- Abstract
Persistence of chemoresistant minimal residual disease (MRD) plasma cells (PCs) is associated with inferior survival in multiple myeloma (MM). Thus, characterization of the minor MRD subclone may represent a unique model to understand chemoresistance, but to our knowledge, the phenotypic and genetic features of the MRD subclone have never been investigated. Here, we compared the antigenic profile of MRD vs diagnostic clonal PCs in 40 elderly MM patients enrolled in the GEM2010MAS65 study and showed that the MRD subclone is enriched in cells overexpressing integrins (CD11a/CD11c/CD29/CD49d/CD49e), chemokine receptors (CXCR4), and adhesion molecules (CD44/CD54). Genetic profiling of MRD vs diagnostic PCs was performed in 12 patients; 3 of them showed identical copy number alterations (CNAs), in another 3 cases, MRD clonal PCs displayed all genetic alterations detected at diagnosis plus additional CNAs that emerged at the MRD stage, whereas in the remaining 6 patients, there were CNAs present at diagnosis that were undetectable in MRD clonal PCs, but also a selected number of genetic alterations that became apparent only at the MRD stage. The MRD subclone showed significant downregulation of genes related to protein processing in endoplasmic reticulum, as well as novel deregulated genes such as ALCAM that is prognostically relevant in MM and may identify chemoresistant PCs in vitro. Altogether, our results suggest that therapy-induced clonal selection could be already present at the MRD stage, where chemoresistant PCs show a singular phenotypic signature that may result from the persistence of clones with different genetic and gene expression profiles. This trial was registered atwww.clinicaltrials.gov as #NCT01237249., (© 2016 by The American Society of Hematology.)
- Published
- 2016
- Full Text
- View/download PDF
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