Factores pronósticos en el mieloma múltiple en fase asintomática y sintomática

Tesis por compendio de publicaciones[ES]Esta tesis es un compendio de tres trabajos sobre factores pronósticos en el mieloma múltiple en fase asintomática y sintomática. 1. En relación al valor de la proteinuria de Bence Jones en pacientes diagnosticados de mieloma asintomático (MMQ): - La proteinuria de Bence Jones fue un marcador independiente de progresión a mieloma múltiple (MM). La validación de este resultado justificaría un seguimiento más estrecho de los MMQ con proteinuria de Bence Jones. - El nivel de proteinuria de Bence Jones > 500 mg al día identificó a pacientes con un riesgo muy alto de progresión a MM. La confirmación de este resultado en otros estudios podría suponer la inclusión de estos pacientes en el grupo de mielomas candidatos a tratamiento. 2. En cuanto al modelo de riesgo R-ISS (Revised International Staging System) aplicado en pacientes con MM que recibieron trasplante autólogo en la Clínica Mayo y el Complejo Asistencial Universitario de Salamanca: - El R-ISS fue un factor pronóstico independiente para la supervivencia global. - Los pacientes del grupo R-ISS II pudieron reclasificarse en dos subgrupos, con diferente supervivencia global de acuerdo a la presencia o ausencia de alteraciones citogenéticas de alto riesgo. 3. En relación a la identificación de factores pronósticos en el MM tras el trasplante autólogo: - La recuperación de las inmunoglobulinas policlonales fue un proceso gradual que se asoció con la proporción de CP normales en la médula ósea detectadas por citometría en el día +100. - Esta recuperación un año después del trasplante autólogo fue un marcador independiente de progresión y supervivencia a largo plazo

Implementación de una metaheurística para la solución de la red de tránsito en el caso de transporte masivo de Bogotá

El presente trabajo abordó el problema indicado para una situación trabajada en la literatura anteriormente para el cual se implemento una heurística para la cual se diseñó un aplicativo en Python que busca un conjunto de rutas iniciales las cuales cumplían con satisfacer toda la demanda entre todos los pares de nodos posibles respetando las conexiones admitidas por el sistema. Además, se buscó que las demandas se lograran satisfacer con viajes directos o con máximo un transbordo, para esto, se necesitan como datos de entrada los tiempos y demandas entre nodos. Dicha heurística también calculó las respectivas frecuencias de cada una de las rutas que se dan en buses por minuto. Una vez se obtuvieron los resultados anteriores se pasó a calcular las funciones objetivo donde la primera calculaba el tiempo total de los usuarios en el sistema y la segunda, el número de buses necesarios para satisfacer la demanda. Con base a las rutas y frecuencias iniciales se procede a implementar la metaheurística LNS (Large Neighborhood Search, por sus siglas en inglés) para la cual se diseñó un aplicativo en VBA, que busca soluciones competitivas mediante el cambio de vecindario iterativamente, propuesta por Shaw (Pisinger, Ropke, 2010) que se define implícitamente por un método de destrucción y reparación, el método de destrucción destruye partes de la solución inicial y el método de reparación construye lo destruido.The current document focuses on a previous situation in which a heuristic standpoint was implemented. An application was designed in Python that looked for a set of initial routes which satisfied the demand between all the pairs of possible nodes and connections admitted by the system. In addition, the demands were met with direct trips or with a máximum transfer-for this, time and demands between nodes were needed as input data. This approach also calculated the respective frequencies of each of the routes that are given in buses per minute. Once the previous results were obtained, the objective functions were calculated. The first calculated the total time of the users in the system and the second the number of buses needed to satisfy the demand. Based on the routes and initial frequencies, the LNS (Large neighborhood Search) metaheuristic approach was implemented. An application was designed in VBA (Visual Basic for Applications), which aims for competitive Solutions through the change of neighborhood iteratively, something proposed by Shaw (Pisinger, Ropke, 2010) and is defined implicitly by a method of destruction and repair; the destruction method destroys parts of the initial solution and the method of repair constructs what is destroyed.Ingeniero (a) IndustrialPregrad

Disposable electrochemical immunoplatform to shed light on the role of the multifunctional glycoprotein TIM-1 in cancer cells invasion

Detecting overexpression of cancer biomarkers is an excellent tool for diagnostic/prognostic and follow-up of patients with cancer or their response to treatment. This work illustrates the relevance of interrogating the levels of T-cell immunoglobulin and mucin domain 1 (TIM-1) protein as a diagnostic/prognostic biomarker of high-prevalence breast and lung cancers by using an amperometric disposable magnetic microparticles-assisted immunoplatform. The developed method integrates the inherent advantages of carboxylic acid-functionalized magnetic beads (HOOC-MBs) as pre-concentrator support and the amperometric transduction at screen-printed carbon electrodes (SPCEs). The immunoplatform involves a sandwich-type immunoassay assembled on HOOC-MBs through the specific capture/labeling of TIM-1 using capture antibodies and horseradish peroxidase (HRP)-conjugated biotinylated detection antibodies as biorecognition elements. The magnetic immunoconjugates were confined onto the working electrode (WE) surface of the SPCEs for amperometric detection using the hydroquinone/hydrogen peroxide/HRP (HQ/H2O2/HRP) redox system. The method allows the selective detection of TIM-1 protein over the 87-7500 pg mL-1 concentration range in only 45 min, with a limit of detection of 26 pg mL-1. The developed bioplatform was successfully applied to the analysis of breast and lung cancer cell extracts, providing the first quantitative results of the target glycoprotein in these types of samples.The financial support of PID2019-103899RB-I00 (Spanish Ministerio de Ciencia e Innovación) Research Projects and PI20CIII/00019 Grant from the AES-ISCIII Program co-founded by FEDER funds and the TRANSNANOAVANSENS-CM Program from the Comunidad de Madrid (Grant S2018/NMT-4349) are gratefully acknowledged. A.M-C. was supported by a FPU predoctoral contract supported by the Spanish Ministerio de Educación, Cultura y Deporte. J.Q. was founded by Minciencias, Mineducacion, MINCIT, and ICETEX through the Program Ecosistema Cientifico Cod. FP44842-211–2018, project number 58536. J.O. thanks support from the University of Antioquia and the Max Planck Society through the cooperation agreement 566–1, 2014.S

Selinexor, daratumumab, bortezomib and dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma: results of the phase II, non-randomized, multicenter GEM-SELIBORDARA study

The treatment landscape for multiple myeloma has significantly evolved in the last decade. Notwithstanding, a large proportion of patients continue to relapse and novel combinations continue to be needed. In this phase II study, selinexor, a first -in -class inhibitor of exportin-1 was evaluated in combination with standard daratumumab-bortezomib-dexamethasone (DVd), for the treatment of relapsed and refractory multiple myeloma (RRMM). The aim of the trial was to assess the efficacy and safety of the combination of selinexor with DVd (S-DVd). A total of 57 patients were enrolled in the two parts of the study. Part 1 enrolled a heavily pretreated population with at least three prior lines (PL) of therapy and part 2 enrolled an early relapse population with at least one PL of therapy. The primary endpoint was complete response (CR) rate in part 2 and overall response rate (ORR) in part 1. In the latter, 24 patients were treated with a median of three PL. Overall response rate (ORR) was 50% with two CR. Median progression -free survival (PFS) was 7 months. In part 2, 33 patients were enrolled, with a median of one PL. ORR was 82% and CR or better was 33%. Median PFS was 24 months. In lenalidomide-refractory patients, a median PFS of 22.1 months was observed. Thrombocytopenia was the most common hematological adverse event (69%; grade 3-4: 34%) and nausea, the most frequent non -hematological adverse event (38%; grade 3-4: 6%). Sixty-two percent of the patients required dose modifications. In summary, although the primary endpoint of the study was not met, the combination of S-DVd showed encouraging clinical efficacy with a generally manageable safety profile representing a potential option for the treatment of RRMM patients

Assessment of the psychometric properties of the Spanish version of EORTC QLQ-MY20 and evaluation of health-related quality of Life outcomes in patients with relapsed and/or refractory multiple myeloma in the real-world setting in Spain: results from the CharisMMa study

We evaluated the psychometric properties of the Spanish version of the European Organization for Research and Treatment of Multiple Myeloma (MM) specific quality-of-life (QoL) questionnaire module (QLQ-MY20) in relapsed/refractory MM (RRMM) patients. This was an observational, cross-sectional, multicenter study using EORTC QLQ-C30 and QLQ-MY20 in RRMM patients (ClinicalTrials.gov ID NCT03188536). We assessed the non-response rate, ceiling/floor effects, internal consistency, test-retest reliability, and validity. The study included 276 patients (53.3% males, mean [SD] age of 67.4 [10.5] years). The EORTC QLQ-MY20 showed a low non-response rate, very low ceiling and floor effects, and good internal consistency. The test-retest reliability assessment revealed good temporary stability, the construct validity analysis stated four main factors similar to the ones of the original version, and the criterion validity assessment showed no differences between groups. In conclusion, the Spanish version of EORTC QLQ-MY20 is a reliable and valid tool for assessing QoL in RRMM patients.The study was sponsored and funded by Takeda Farmacéutica España.Peer reviewe

Interlaboratory analytical validation of a Next-generation sequencing strategy for clonotypic assessment and minimal residual disease monitoring in multiple myeloma

[Context]: Minimal residual disease (MRD) is a major prognostic factor in multiple myeloma, although validated technologies are limited. [Objective]: To standardize the performance of the LymphoTrack next-generation sequencing (NGS) assays (Invivoscribe), targeting clonal immunoglobulin rearrangements, in order to reproduce the detection of tumor clonotypes and MRD quantitation in myeloma. [Design]: The quantification ability of the assay was evaluated through serial dilution experiments. Paired samples from 101 patients were tested by LymphoTrack, using Sanger sequencing and EuroFlow's next-generation flow (NGF) assay as validated references for diagnostic and follow-up evaluation, respectively. MRD studies using LymphoTrack were performed in parallel at 2 laboratories to evaluate reproducibility. [Results]: Sensitivity was set as 1.3 tumor cells per total number of input cells. Clonality was confirmed in 99% and 100% of cases with Sanger and NGS, respectively, showing great concordance (97.9%), although several samples had minor discordances in the nucleotide sequence of rearrangements. Parallel NGS was performed in 82 follow-up cases, achieving a median sensitivity of 0.001%, while for NGF, median sensitivity was 0.0002%. Reproducibility of LymphoTrack-based MRD studies (85.4%) and correlation with NGF (R2 > 0.800) were high. Bland-Altman tests showed highly significant levels of agreement between flow and sequencing. [Conclusions]: Taken together, we have shown that LymphoTrack is a suitable strategy for clonality detection and MRD evaluation, with results comparable to gold standard procedures. Multiple myeloma (MM) is a plasma-cell dyscrasia characterized by the accumulation of plasma cells in the bone marrow that produces an excess of clonal immunoglobulins (M-protein or monoclonal component).1 New treatment approaches have increased the number of patients achieving complete response (CR),2–5 progressively improving progression-free and overall survival rates in the last 10 years.6–11 Nonetheless, the presence of low levels of drug-resistant cells (known as minimal residual disease, MRD)12–14 that remain undetected by conventional serologic and morphologic methods explains frequent relapses with this disease, which is still considered an incurable illness.Minimal residual disease is currently considered one of the most informative prognostic parameters, since those patients with undetectable disease have shown prolonged survival rates as compared with MRD-positive patients,15–17 and this difference is still significant even when patients achieving only stringent complete response (sCR) are taken into account.18 The International Myeloma Working Group (IMWG) defined MRD positivity as the persistence of clonal malignant plasma cells assessed with a sensitivity of at least 10−5 (1 malignant cell per hundred thousand normal cells)19 ; therefore, MRD should be monitored with only highly sensitive methods. To date, 3 different approaches have been tested for MRD monitoring in hematologic malignancies: immunophenotypic (multiparametric flow cytometry [MFC]),20 molecular (quantitative polymerase chain reaction [PCR], next-generation sequencing [NGS], digital PCR),21–23 and imaging tools (positron emission tomography–computed tomography; magnetic resonance imaging).24,25 However, in MM standardization has been achieved only for MFC26 and NGS.27,28 As a result, the IMWG recommended the use of highly sensitive, standardized flow and sequencing approaches,19 including EuroFlow's next-generation flow (NGF)29 and Adaptive Biotechnologies' ClonoSEQ solutions (Adaptive Biotechnologies, Seattle, Washington). NGF is a 2-tube, 8-color flow assay that allows the simultaneous analysis of 10 million cells, providing a sensitivity of around 2·10−6.This work was partially supported by the Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Economy and Competitiveness PI15/01956, CIBERONC-CB16/12/00233, and “Una manera de hacer Europa” (Innocampus; CEI-2010-1-0010). García-Álvarez, Prieto-Conde, and Jiménez were supported by the Fundación Española de Hematología y Hemoterapia (FEHH, cofunded by Fundación Cris in the latter case), Medina by the European Social Fund through the University of Salamanca and the ISCIII (FI19/00320), and Sarasquete by the ISCIII (CPII18/00028). All Spanish funding is cosponsored by the European Union FEDER program

Liquid biopsy: a non-invasive approach for Hodgkin lymphoma genotyping

The Hodgkin lymphoma (HL) genomic landscape is hardly known due to the scarcity of tumour cells in the tissue. Liquid biopsy employing circulating tumour DNA (ctDNA) can emerge as an alternative tool for non-invasive genotyping. By using a custom next generation sequencing (NGS) panel in combination with unique molecule identifiers, we aimed to identify somatic variants in the ctDNA of 60 HL at diagnosis. A total of 277 variants were detected in 36 of the 49 samples (73·5%) with a good quality ctDNA sample. The median number of variants detected per patient was five (range 1–23) with a median variant allele frequency of 4·2% (0·84–28%). Genotyping revealed somatic variants in the following genes: SOCS1 (28%), IGLL5 (26%), TNFAIP3 (23%), GNA13 (23%), STAT6 (21%) and B2M (19%). Moreover, several poor prognosis features (high LDH, low serum albumin, B-symptoms, IPI ≥ 3 or at an advanced stage) were related to significantly higher amounts of ctDNA. Variant detection in ctDNA by NGS is a feasible approach to depict the genetic features of HL patients at diagnosis. Our data favour the implementation of liquid biopsy genotyping for the routine evaluation of HL patients.This work was partially supported by the Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Economy and Competitiveness CIBERONC-CB16/12/00233, and “Una manera de hacer Europa” (Innocampus; CEI-2010-1-0010)”, the Health Council of the Junta de Castilla y León (GRS2037/A/19) (GRS1845/A/18) and private Gilead (GLD/18/00063). MGA is supported with a grant from the Accelerator consortia (Cancer Research UK; C355/A26819). CJ and AM are supported by the ISCII (CD19/00030 and FI19/00320). MES is supported by Contrato Miguel Servet tipo II (CPII18/00028). MA is financed by CIBER-CB16/12/00233. All Spanish funding is co-sponsored by the European Union FEDER program

Assessment of the psychometric properties of the Spanish version of EORTC QLQ-MY20 and evaluation of health-related quality of Life outcomes in patients with relapsed and/or refractory multiple myeloma in the real-world setting in Spain: results from the CharisMMa study

We evaluated the psychometric properties of the Spanish version of the European Organization for Research and Treatment of Multiple Myeloma (MM) specific quality-of-life (QoL) questionnaire module (QLQ-MY20) in relapsed/refractory MM (RRMM) patients. This was an observational, cross-sectional, multicenter study using EORTC QLQ-C30 and QLQ-MY20 in RRMM patients (ClinicalTrials.gov ID NCT03188536). We assessed the non-response rate, ceiling/floor effects, internal consistency, test-retest reliability, and validity. The study included 276 patients (53.3% males, mean [SD] age of 67.4 [10.5] years). The EORTC QLQ-MY20 showed a low non-response rate, very low ceiling and floor effects, and good internal consistency. The test-retest reliability assessment revealed good temporary stability, the construct validity analysis stated four main factors similar to the ones of the original version, and the criterion validity assessment showed no differences between groups. In conclusion, the Spanish version of EORTC QLQ-MY20 is a reliable and valid tool for assessing QoL in RRMM patientsEl estudio fue patrocinado y financiado por Takeda Farmacéutica Españ

Recovery of polyclonal immunoglobulins during treatment in patients ineligible for autologous stem-cell transplantation is a prognostic marker of longer progression-free survival and overall survival

Immunoparesis is the suppression of normal polyclonal immunoglobulins and is present in most patients with newly diagnosed multiple myeloma (MM). The association of immunoparesis at diagnosis, and particularly its recovery along with treatment, with survival in patients ineligible for autologous stem-cell transplantation (ASCT) has not been well established. This retrospective study evaluated the impact of immunoparesis in 431 patients diagnosed with MM, ineligible for ASCT, with a median overall survival of 36 months [95% confidence interval (CI): 31–40]. Immunoparesis was present in 81.2% of patients at diagnosis and was associated with a trend to a worse overall response rate (ORR: 84.8% vs. 74.9%; OR 1.88 (95% CI: 0.97–3.63), shorter progression-free survival (PFS) [22.0 vs. 18.2 months; hazard ratio (HR) 0.775; 95%CI: 0.590–1.018; p = 0.066], and overall survival (OS) (45.9 vs. 34.2 months; HR 0.746; 95% CI: 0.551–1.010; p = 0.057). Twenty-four per cent of patients who had immunoparesis at diagnosis recovered polyclonal immunoglobulins in the follow-up period. Interestingly, these patients had a better ORR (96.3% vs. 68.2%; OR 12.29 (95% CI: 3.77–40.06), PFS (HR 0.703; 95CI%: 0.526–0.941; p = 0.018) and OS (HR 0.678; 95 CI%: 0.503–0.913; p = 0.011) than patients who did not recover it. In summary, restoring a healthy immune system along with first-line treatment in patients with MM, not receiving ASCT, is associated with better outcomes

Real-World Health Care Services Utilization Associated With the Management of Patients With Relapsed and Refractory Multiple Myeloma in Spain: The CharisMMa Study

[Background]: Most patients with multiple myeloma (MM) relapse or become refractory, resulting in high health care costs. However, real-world data regarding the utilization of health care services among the relapsed/refractory MM (RRMM) population are scarce.[Methods]: Observational, cross-sectional, multicenter study of the utilization of health care services by RRMM patients who had relapsed within the previous 6 months in Spain in a real-world setting. Data were collected from the clinical records and during a single structured interview and included sociodemographic and clinical characteristics at last relapse, the treatment and health care services nature, and were presented using descriptive statistics.[Results]: The 276 patients enrolled (53.3% males), with a mean [SD] age of 67.4 [10.5] years, had experienced their most recent relapse a median (IQR) of 1.61 (0.74, 3.14) months before entering the study. Patients lived a median (IQR) of 9.0 (3.0, 30.0) km away from the hospital and visited the hospital a median (IQR) of 3.0 (2.0, 5.0) times/month to receive treatment for their most recent relapse. They spent a median (IQR) of 15.84 (5.0, 42.0) euros/month on transportation. Since their most recent relapse, most patients had been admitted to a hospital unit (n = 155, 56.2%), had required ≥1 diagnostic tests (n = 227, 82.2%), and had consulted the hematologist (n = 270, 97.8%) a mean (SD) of 5.5 (5.4) times. In half of the visits, patients were accompanied by an actively working caregiver (n = 112, 54.4%).[Conclusions]: RRMM treatments are associated with a high utilization of health care services and pose a significant burden for patients and caregivers.The study was sponsored and funded by Takeda Farmacéutica España.Peer reviewe