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1.
J Photochem Photobiol B ; 203: 111777, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31931387

RESUMEN

Despite the high in vitro efficacy of photodynamic therapeutics, lack of tumor targeting significantly reduces their in vivo efficacy and thus limits their clinical use. Photoimmunotherapy (PIT) is a new synthetic strategy to target and treat cancer by photodynamic therapy (PDT). In this study, we describe design and synthesis of a third-generation photosensitizer comprising a PEGylated-phthalocyanine star-polymer photosensitizer that covalently bound to a myeloma tumor-selective antibody (MAb) via the carbodiimide chemistry. The free photosensitizer demonstrated a minimum dark toxicity when tested in mammalian myeloma cell line (SP2/OR); and a moderate phototoxicity after irradiation with non thermal laser red light as a result of light-induced production of cytotoxic singlet oxygen species. Covalent attachment of the photosensitizer (Pc) to the MAb resulted in a significantly enhanced phototoxicity. This is mainly ascribed to the fact that internalization enhances phototoxicity of Pc-MAb bioconjugates. The radioactivated photoimmuno-conjugates 131I(PcMAb) demonstrated the highest phototoxicity to myeloma cells. The suggested bioconjugates are promising candidates as multiple therapeutic models for in vivo treatment of myeloma.


Asunto(s)
Anticuerpos Monoclonales/química , Indoles/química , Fármacos Fotosensibilizantes/química , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/efectos de la radiación , Inmunoterapia , Indoles/farmacología , Radioisótopos de Yodo/química , Marcaje Isotópico , Luz , Ratones , Mieloma Múltiple/patología , Mieloma Múltiple/terapia , Fármacos Fotosensibilizantes/farmacología , Polietilenglicoles/química , Oxígeno Singlete/metabolismo
2.
Ann Hematol ; 99(1): 113-119, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31768678

RESUMEN

Novel anti-myeloma drugs have significantly improved the overall survival (OS) of patients with multiple myeloma (MM). However, not all MM patients treated with these drugs show survival benefits, and biologic and genetic prognostic factors are insufficient to predict the response to treatment. Decreasing treatment-related complications is important to improve the efficacy of treatment in patients with MM. The Controlling Nutritional Status (CONUT) score is a screening method for poor nutritional status, which is associated with poor prognosis in several cancers because it increases the rate of treatment-related complications. We retrospectively analyzed the OS of 64 patients with symptomatic MM and evaluated the correlation between the CONUT score and patient prognosis in MM. The median age at diagnosis was 66 years, and multivariate analysis showed that a high CONUT score (≥ 5; hazard ratio, 3.937; 95% confidence interval, 1.214-12.658; P = 0.022) was an independent prognostic risk factor. Subgroup analysis was performed according to patient age because the choice of treatment strategy, particularly autologous peripheral blood stem cell transplantation (auto-PBSCT), can vary depending on age in MM patients. Younger patients (< 65 years old) who received auto-PBSCT and had a lower CONUT score (0-3) showed a significantly better survival outcome than those with a higher CONUT score (≥ 4) (median OS, not reached vs. 64.1 months; P = 0.011). The CONUT score is simple to calculate and provides a useful prognostic indicator in patients with MM, especially transplant-eligible patients.


Asunto(s)
Mieloma Múltiple , Estado Nutricional , Trasplante de Células Madre de Sangre Periférica , Adulto , Anciano , Anciano de 80 o más Años , Autoinjertos , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/mortalidad , Mieloma Múltiple/patología , Mieloma Múltiple/fisiopatología , Mieloma Múltiple/terapia , Estudios Retrospectivos , Factores de Riesgo , Tasa de Supervivencia
3.
Expert Opin Investig Drugs ; 29(1): 5-14, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31815551

RESUMEN

Introduction: Kinesin spindle protein (KSP) is indispensable for the proper separation of spindle poles during mitosis. Importantly, this protein is expressed only in cells undergoing cell division and hence represents an appealing target for the treatment of cancer. Many KSP inhibitors have demonstrated a strong antitumoral effect in vitro, however, they have exhibited only limited activity in clinical trials. By contrast, the KSP inhibitor filanesib has demonstrated clinical efficacy in patients with multiple myeloma (MM).Areas covered: This article provides a comprehensive overview about the progress to date in the preclinical and clinical development of filanesib for the treatment of cancer, and particularly, MM.Expert opinion: Responses observed with filanesib alone or in combination with dexamethasone were encouraging in MM. However, the subsequent appearance of highly effective novel agents such as monoclonal antibodies, has hindered the development of agents such as filanesib that exhibit a more limited activity. Nevertheless, filanesib has shown interesting results for some patients when combined with carfilzomib and pomalidomide. Most importantly, the availability of a biomarker of response such as alpha 1-acid glycoprotein (AAG), could be key to the identification of patients that could benefit most from these combinations.


Asunto(s)
Antimitóticos/administración & dosificación , Mieloma Múltiple/tratamiento farmacológico , Tiadiazoles/administración & dosificación , Animales , Antimitóticos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica , Biomarcadores de Tumor/metabolismo , Desarrollo de Medicamentos , Humanos , Cinesina/antagonistas & inhibidores , Mieloma Múltiple/patología , Tiadiazoles/farmacología
6.
Ann Hematol ; 98(12): 2769-2780, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31748925

RESUMEN

Difficulty in regularly analyzing marrow myeloma cells (MMCs) and low frequency of circulating myeloma cells (CMCs) in blood presents challenges for monitoring minimal residual disease (MRD) in multiple myeloma (MM). We have developed a set of method for enrichment of CMCs by immunomagetic beads (IMB) combined with flow cytometry (IMB-FCM) based on CD38-APC/CD138-APC antibodies in U266-spiked samples and in 122 patient samples. U266 cell capture efficiency of CD38/CD138-IMB-FCM (6.960, 2.574) was 6- and 2-fold higher than that of FCM (1.032), and the sensitivity of FCM and IMB-FCM was 0.01% and 0.001%, respectively. In MM cohort, the positive rate of CMCs by IMB-FCM increased from 60.5~70.0 to 85~87.2% in newly diagnosed/relapsed and partial remission (PR) patients compared with by FCM (P < 0.05). Two complete remission (CR) patients contain certain amounts of CMCs by IMB-FCM while no CMCs and MMCs were detectable by FCM. Patients exhibiting PR and CR upon therapy had much lower CMC and MMC counts than newly diagnosed/relapsed patients (P < 0.005). Based on MRD measurement in BM and PB samples, all FCM-negative BM samples were also paired with FCM/IMB-FCM-negative PB samples among newly diagnosed, relapsed, and PR patients, and FCM-positive BM samples were accompanied by IMB-FCM-positive results in 88% of corresponding PB samples. CMCs strongly associated with other clinical biomarkers of disease burden, including elevated MMCs, ß2-MG, sCrea, and DS and ISS stages, and more serious anemia, bone destruction, and renal impairment (P < 0.05). Logistic regression analysis revealed that elevated ß2-MG and moderate-to-more anemia were significant risk factors for the presence of CMCs (P < 0.05). As a noninvasive "liquid biopsy" of monitoring MRD, the potential of IMB-FCM for CMC detection may complement or minimize bone marrow aspiration in future treatment of MM patients.


Asunto(s)
Citometría de Flujo , Separación Inmunomagnética , Mieloma Múltiple/sangre , Células Neoplásicas Circulantes/metabolismo , Adulto , Línea Celular Tumoral , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/patología , Mieloma Múltiple/terapia , Neoplasia Residual , Células Neoplásicas Circulantes/patología
7.
BMC Infect Dis ; 19(1): 957, 2019 Nov 10.
Artículo en Inglés | MEDLINE | ID: mdl-31707976

RESUMEN

BACKGROUND: Patients with multiple myeloma (MM) are known to be immune incompetent and experience higher incidences of infectious diseases. However, infective endocarditis (IE) is rarely observed in patients with MM and Morganella morganii (M. morganii) has rarely been associated with IE. CASE PRESENTATION: A 72-year-old female receiving 4th line treatment for MM presented with fever and concomitant confusion. Urinary culture revealed growth of Escherichia coli, wherefore broadspectrum penicillin and high-dose corticosteroids were initiated. However, blood cultures showed growth of M. morganii. Fluoroquinolone was added due to penicillin-resistance of the Morganella species. Two days after admission, the patient acutely deteriorated with hemodynamic instability. Gentamicin and high dose corticosteroids were added. Echocardiography showed marked aortic valve vegetation with severe aortic valve regurgitation, leading to the diagnosis of bacterial endocarditis of the native aortic valve. Shortly after diagnosis, the patient died. At autopsy, vegetation with gram-negative rods in the native aortic valve was observed, confirming the diagnosis of M. morganii-endocarditis. Additional staining for amyloid confirmed advanced light-chain (AL) amyloidosis with extensive amyloid depositions of the aortic valve and valvular damage as complications of her MM. CONCLUSIONS: Our case suggests that IE with M. morganii was facilitated by the combination of the cardiac amyloidosis with valvular impairment and the profound immune deficiency caused by the several chemo-immunomodulatory treatment lines and the MM itself. This case further illustrates that awareness for rare opportunistic infections in an era with growing potential of combined chemoimmunotherapy is warranted.


Asunto(s)
Endocarditis Bacteriana/diagnóstico , Morganella morganii/aislamiento & purificación , Mieloma Múltiple/patología , Anciano , Válvula Aórtica/diagnóstico por imagen , Válvula Aórtica/patología , Ecocardiografía , Endocarditis Bacteriana/complicaciones , Endocarditis Bacteriana/microbiología , Femenino , Humanos , Mieloma Múltiple/complicaciones
8.
Enzymes ; 46: 23-35, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31727275

RESUMEN

The chick embryo chorioallantoic membrane (CAM) has long been used as an in vivo assay for the study of tumor angiogenesis because when tumor grafts are placed at day 6-10 days of incubation the chick's immunocompetent system is not fully developed and the conditions for rejection have not been yet established. All studies for mammalian neoplasms, including multiple myeloma, have utilized tumor cell lines, tumor bioptic specimens, cell suspensions derived from tumors, mouse tumor xenografts bioptic specimens. CAM can also be used to study the effects of anti-angiogenic molecules on tumor cell suspensions of tumor bioptic specimens. This review article summarizes and discussed our experience concerning the use of the CAM to study multiple myeloma.


Asunto(s)
Membrana Corioalantoides/patología , Mieloma Múltiple/patología , Animales , Embrión de Pollo , Modelos Animales de Enfermedad , Ratones , Neovascularización Patológica
9.
Lancet Haematol ; 6(12): e616-e629, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31624047

RESUMEN

BACKGROUND: Multiple myeloma has been shown to have substantial clonal heterogeneity, suggesting that agents with different mechanisms of action might be required to induce deep responses and improve outcomes. Such agents could be given in combination or in sequence on the basis of previous response. We aimed to assess the clinical value of maximising responses by using therapeutic agents with different modes of action, the use of which is directed by the response to the initial combination therapy. We aimed to assess response-adapted intensification treatment with cyclophosphamide, bortezomib, and dexamethasone (CVD) versus no intensification treatment in patients with newly diagnosed multiple myeloma who had a suboptimal response to initial immunomodulatory triplet treatment which was standard of care in the UK at the time of trial design. METHODS: The Myeloma XI trial was an open-label, randomised, phase 3, adaptive design trial done at 110 National Health Service hospitals in the UK. There were three potential randomisations in the study: induction treatment, intensification treatment, and maintenance treatment. Here, we report the results of the randomisation to intensification treatment. Eligible patients were aged 18 years or older and had symptomatic or non-secretory, newly diagnosed multiple myeloma, had completed their assigned induction therapy as per protocol (cyclophosphamide, thalidomide, and dexamethasone or cyclophosphamide, lenalidomide, and dexamethasone) and achieved a partial or minimal response. For the intensification treatment, patients were randomly assigned (1:1) to cyclophosphamide (500 mg daily orally on days 1, 8, and 15), bortezomib (1·3 mg/m2 subcutaneously or intravenously on days 1, 4, 8, and 11), and dexamethasone (20 mg daily orally on days 1, 2, 4, 5, 8, 9, 11, and 12) up to a maximum of eight cycles of 21 days or no treatment. Patients were stratified by allocated induction treatment, response to induction treatment, and centre. The co-primary endpoints were progression-free survival and overall survival, assessed from intensification randomisation to data cutoff, analysed by intention to treat. Safety analysis was per protocol. This study is registered with the ISRCTN registry, number ISRCTN49407852, and clinicaltrialsregister.eu, number 2009-010956-93, and has completed recruitment. FINDINGS: Between Nov 15, 2010, and July 28, 2016, 583 patients were enrolled to the intensification randomisation, representing 48% of the 1217 patients who achieved partial or minimal response after initial induction therapy. 289 patients were assigned to CVD treatment and 294 patients to no treatment. After a median follow-up of 29·7 months (IQR 17·0-43·5), median progression-free survival was 30 months (95% CI 25-36) with CVD and 20 months (15-28) with no CVD (hazard ratio [HR] 0·60, 95% CI 0·48-0·75, p<0·0001), and 3-year overall survival was 77·3% (95% Cl 71·0-83·5) in the CVD group and 78·5% (72·3-84·6) in the no CVD group (HR 0·98, 95% CI 0·67-1·43, p=0·93). The most common grade 3 or 4 adverse events for patients taking CVD were haematological, including neutropenia (18 [7%] patients), thrombocytopenia (19 [7%] patients), and anaemia (8 [3%] patients). No deaths in the CVD group were deemed treatment related. INTERPRETATION: Intensification treatment with CVD significantly improved progression-free survival in patients with newly diagnosed multiple myeloma and a suboptimal response to immunomodulatory induction therapy compared with no intensification treatment, but did not improve overall survival. The manageable safety profile of this combination and the encouraging results support further investigation of response-adapted approaches in this setting. The substantial number of patients not entering this trial randomisation following induction therapy, however, might support the use of combination therapies upfront to maximise response and improve outcomes as is now the standard of care in the UK. FUNDING: Cancer Research UK, Celgene, Amgen, Merck, Myeloma UK.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bortezomib/administración & dosificación , Ciclofosfamida/administración & dosificación , Dexametasona/administración & dosificación , Mieloma Múltiple/tratamiento farmacológico , Anciano , Bortezomib/efectos adversos , Ciclofosfamida/efectos adversos , Dexametasona/efectos adversos , Relación Dosis-Respuesta a Droga , Monitoreo de Drogas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/mortalidad , Mieloma Múltiple/patología , Terapia Neoadyuvante , Análisis de Supervivencia , Resultado del Tratamiento , Reino Unido/epidemiología
10.
Cancer Sci ; 110(12): 3802-3810, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31583781

RESUMEN

The ubiquitin proteasome pathway is essential for the proliferation and survival of multiple myeloma (MM) cells. TAS4464, a novel highly potent inhibitor of NEDD8 activating enzyme, selectively inactivates cullin-RING ubiquitin E3 ligases, resulting in accumulation of their substrates. Here, we examined 14 MM cell lines treated with TAS4464. TAS4464 induced growth arrest and cell death in the MM cell lines even in the presence of bone marrow stromal cells. It also induced the accumulation of phospho-inhibitor of κBα and phospho-p100, impaired the activities of nuclear factor κB (NF-κB) transcription factors p65 and RelB, and decreased the expression of NF-κB target genes, suggesting that TAS4464 inhibits both the canonical and non-canonical NF-κB pathways. TAS4464 had similar effects in an in vivo human-MM xenograft mouse model in which it was also observed to have strong antitumor effects. TAS4464 synergistically enhanced the antitumor activities of the standard MM chemotherapies bortezomib, lenalidomide/dexamethasone, daratumumab and elotuzumab. Together, these results suggest that the anti-MM activity of TAS4464 occurs via inhibition of the NF-κB pathways, and that treatment with TAS4464 is a potential approach for treating MM by single and combination therapies.


Asunto(s)
Mieloma Múltiple/tratamiento farmacológico , Proteína NEDD8/antagonistas & inhibidores , FN-kappa B/antagonistas & inhibidores , Pirimidinas/farmacología , Pirroles/farmacología , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Humanos , Masculino , Ratones , Mieloma Múltiple/patología , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
11.
Cancer Sci ; 110(12): 3695-3707, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31571328

RESUMEN

Polycomb repressive complex 2 (PRC2) components, EZH2 and its homolog EZH1, and PI3K/Akt signaling pathway are focal points as therapeutic targets for multiple myeloma. However, the exact crosstalk between their downstream targets remains unclear. We herein elucidated some epigenetic interactions following Akt inhibition and demonstrated the efficacy of the combined inhibition of Akt and PRC2. We found that TAS-117, a potent and selective Akt inhibitor, downregulated EZH2 expression at the mRNA and protein levels via interference with the Rb-E2F pathway, while EZH1 was compensatively upregulated to maintain H3K27me3 modifications. Consistent with these results, the dual EZH2/EZH1 inhibitor, UNC1999, but not the selective EZH2 inhibitor, GSK126, synergistically enhanced TAS-117-induced cytotoxicity and provoked myeloma cell apoptosis. RNA-seq analysis revealed the activation of the FOXO signaling pathway after TAS-117 treatment. FOXO3/4 mRNA and their downstream targets were upregulated with the enhanced nuclear localization of FOXO3 protein after TAS-117 treatment. ChIP assays confirmed the direct binding of FOXO3 to EZH1 promoter, which was enhanced by TAS-117 treatment. Moreover, FOXO3 knockdown repressed EZH1 expression. Collectively, the present results reveal some molecular interactions between Akt signaling and epigenetic modulators, which emphasize the benefits of targeting PRC2 full activity and the Akt pathway as a therapeutic option for multiple myeloma.


Asunto(s)
Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Complejo Represivo Polycomb 2/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Sinergismo Farmacológico , Proteína Potenciadora del Homólogo Zeste 2/antagonistas & inhibidores , Proteína Potenciadora del Homólogo Zeste 2/fisiología , Proteína Forkhead Box O3/fisiología , Humanos , Mieloma Múltiple/patología , Complejo Represivo Polycomb 2/genética , Complejo Represivo Polycomb 2/fisiología , Regiones Promotoras Genéticas , Proteínas Proto-Oncogénicas c-akt/fisiología , Piridonas/uso terapéutico
13.
J Biol Regul Homeost Agents ; 33(5): 1387-1394, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31507136

RESUMEN

In this study, we investigated the expression of RhoC in the multiple myeloma (MM) cell line RPMI- 8226, as well as the effects of silencing RhoC on the growth of tumor xenografts and tumor-induced angiogenesis in nude mice with MM. For this purpose, we transduced RPMI-8226 cells with lentiviral particles overexpressing short hairpin RNAs (shRNA) targeting RhoC. Tumor xenografts were generated by subcutaneously injecting nude mice with RPMI-8226 cells overexpressing control shRNA [negative control (NC) group] or the RhoC shRNA [the experimental (S) group], respectively. RhoC protein and mRNA levels in the tumor xenografts were measured. Nude mice were also subcutaneously inoculated with Matrigel mixed with vascular endothelial growth factor, and CD31 and KI67 levels in the tumor xenografts were measured by immunohistochemistry. Similarly, we assessed tumor xenograft growth and angiogenesis in Matrigel implants in the mice of both groups. We found that RhoC levels, microvessel density, and CD31 labeling index were more reduced in the S group than in the NC group. However, there was no significant difference in the size of tumor xenografts between the 2 groups. The number of new vessels and the neovascular length in the Matrigel implants were significantly lower in the S group than in the NC group. Therefore, we concluded that RhoC expression in myeloma xenografts has important effects on the induction of angiogenesis.


Asunto(s)
Mieloma Múltiple/metabolismo , Neovascularización Patológica/genética , Proteína rhoC de Unión a GTP/genética , Animales , Línea Celular Tumoral , Silenciador del Gen , Antígeno Ki-67 , Ratones , Ratones Desnudos , Mieloma Múltiple/patología , Trasplante de Neoplasias , Molécula-1 de Adhesión Celular Endotelial de Plaqueta , Factor A de Crecimiento Endotelial Vascular
16.
Blood ; 134(14): 1176-1189, 2019 10 03.
Artículo en Inglés | MEDLINE | ID: mdl-31383640

RESUMEN

Dysregulation of polycomb repressive complex 2 (PRC2) promotes oncogenesis partly through its enzymatic function for inducing trimethylation of histone H3 lysine 27 (H3K27me3). However, it remains to be determined how PRC2 activity is regulated in normal and diseased settings. We here report a PRC2-associated cofactor, PHD finger protein 19 (PHF19; also known as polycomb-like 3), as a crucial mediator of tumorigenicity in multiple myeloma (MM). Overexpression and/or genomic amplification of PHF19 is found associated with malignant progression of MM and plasma cell leukemia, correlating to worse treatment outcomes. Using various MM models, we demonstrated a critical requirement of PHF19 for tumor growth in vitro and in vivo. Mechanistically, PHF19-mediated oncogenic effect relies on its PRC2-interacting and chromatin-binding functions. Chromatin immunoprecipitation followed by sequencing profiling showed a critical role for PHF19 in maintaining the H3K27me3 landscape. PHF19 depletion led to loss of broad H3K27me3 domains, possibly due to impaired H3K27me3 spreading from cytosine guanine dinucleotide islands, which is reminiscent to the reported effect of an "onco"-histone mutation, H3K27 to methionine (H3K27M). RNA-sequencing-based transcriptome profiling in MM lines also demonstrated a requirement of PHF19 for optimal silencing of PRC2 targets, which include cell cycle inhibitors and interferon-JAK-STAT signaling genes critically involved in tumor suppression. Correlation studies using patient sample data sets further support a clinical relevance of the PHF19-regulated pathways. Lastly, we show that MM cells are generally sensitive to PRC2 inhibitors. Collectively, this study demonstrates that PHF19 promotes MM tumorigenesis through enhancing H3K27me3 deposition and PRC2's gene-regulatory functions, lending support for PRC2 blockade as a means for MM therapeutics.


Asunto(s)
Carcinogénesis/metabolismo , Proteínas de Unión al ADN/metabolismo , Histonas/metabolismo , Mieloma Múltiple/metabolismo , Complejo Represivo Polycomb 2/metabolismo , Factores de Transcripción/metabolismo , Animales , Carcinogénesis/patología , Línea Celular Tumoral , Humanos , Metilación , Ratones , Mieloma Múltiple/patología
17.
Presse Med ; 48(7-8 Pt 1): 825-831, 2019.
Artículo en Francés | MEDLINE | ID: mdl-31447337

RESUMEN

Diagnosis criteria have been revised in 2014 and allow the treatment of some asymptomatic patients. Since 2015, a new prognostic score includes tumor plasma cells chromosomal abnormalities. It helps in the distinction between "standard risk" and "high risk" myelomas. Scanner, MRI and Pet Scan are the radiological reference exams to evaluate bone involvement. Alkylating agents, immunomodulators, proteasome inhibitors, and monoclonal antibodies became the most important antitumoral treatments. Risk notion will become more and more important for therapeutic choices. These choices will depend on residual disease evaluation. The next decade will be the immunotherapies development decade.


Asunto(s)
Detección Precóz del Cáncer/tendencias , Oncología Médica/tendencias , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/terapia , Terapias en Investigación/tendencias , Anticuerpos Monoclonales/uso terapéutico , Terapia Combinada/tendencias , Detección Precóz del Cáncer/métodos , Detección Precóz del Cáncer/normas , Humanos , Factores Inmunológicos/uso terapéutico , Inmunoterapia/métodos , Inmunoterapia/tendencias , Oncología Médica/métodos , Oncología Médica/normas , Mieloma Múltiple/patología , Guías de Práctica Clínica como Asunto , Pronóstico , Terapias en Investigación/métodos
19.
Orv Hetil ; 160(24): 944-951, 2019 Jun.
Artículo en Húngaro | MEDLINE | ID: mdl-31433233

RESUMEN

Introduction: Plasma cell myeloma is a hematological malignancy with heterogeneous genomic landscape and diverse clinical course. Recurrent chromosomal and subchromosomal aberrations commonly occur in this entity and are associated with the pathogenesis and progression of the disease. The identification of these alterations aids genetic characterization, classification and prognostication of patients. Aim: Molecular cytogenetic investigations of plasma cell myeloma patients treated at the University of Pécs Clinical Center and János Balassa County Hospital of Tolna County, Szekszárd, between 2005 and 2018 were evaluated in our study. Method: 231 patients were screened for genetic aberrations using fluorescence in situ hybridization. Translocations involving the immunoglobulin heavy chain gene, losses of 1p and 17p chromosome arms, gains of 1q chromosome arm and unbalanced aberrations of chromosome 13 were investigated. Losses and gains of 1p, 1q, 5q, 12p, 13q, 16q and 17p chromosome arms were analyzed using multiplex ligation-dependent probe amplification in 42 patients. During the investigated period, 116 bone marrow karyotyping was also performed. Results: In total, 233 genetic aberrations were identified using our targeted approaches; the frequency of specific aberrations correlated with data of the recent literature. Concordance of results gained by fluorescence in situ hybridization and multiplex ligation-dependent probe amplification was 96.2% by analyzing the same chromosome arms. The latter technique revealed 21 additional genetic aberrations in 16/42 patient samples (38%) as compared to fluorescence in situ hybridization. Conclusions: Our results suggest that the combined application of the two molecular cytogenetic methods may facilitate a more detailed characterization of genetic aberrations of plasma cell myeloma patients in Hungary. Orv Hetil. 2019; 160(24): 944-951.


Asunto(s)
Aberraciones Cromosómicas , Análisis Citogenético/métodos , Mieloma Múltiple/genética , Humanos , Hungría/epidemiología , Hibridación Fluorescente in Situ , Mieloma Múltiple/epidemiología , Mieloma Múltiple/patología
20.
Recenti Prog Med ; 110(7): 364-367, 2019.
Artículo en Italiano | MEDLINE | ID: mdl-31379372

RESUMEN

We report the case of a young man and good PS, diagnosed with a stage II A Durie-Salmon, II ISS and II Revised-ISS IgM kappa Multiple Myeloma. After refractoriety to the I and II-line induction therapies, including novel and novel novel agents, we decided to treat the patient with conventional high dose chemotherapy, with dexamethasone, cyclophosphamide, etoposide and cisplatin (DCEP), achieving a very good partial response (VGPR). Furthermore, we discuss histopathologic patterns, to make a correct differential diagnosis with others IgM-correlated disorders. Analyzing the literature, we demonstrated that more intensive therapy correlates with better therapeutic goals, therefore, empathizing that today IgM Multiple Myeloma is still a difficult pathological subtype to treat.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Inmunoglobulina M/metabolismo , Mieloma Múltiple/tratamiento farmacológico , Cisplatino/administración & dosificación , Ciclofosfamida/administración & dosificación , Dexametasona/administración & dosificación , Etopósido/administración & dosificación , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/patología , Resultado del Tratamiento
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