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Leucemia Neutrofílica Crónica , Reacción Leucemoide , Neutrófilos , Humanos , Leucemia Neutrofílica Crónica/genética , Leucemia Neutrofílica Crónica/complicaciones , Reacción Leucemoide/diagnóstico , Reacción Leucemoide/patología , Reacción Leucemoide/etiología , Neutrófilos/patología , Masculino , Diagnóstico Diferencial , Femenino , Anciano , Persona de Mediana EdadRESUMEN
An unresolved issue in chronic lymphocytic leukemia (CLL) is whether IGHV3-21 gene usage, in general, or the expression of stereotyped B-cell receptor immunoglobulin defining subset #2 (IGHV3-21/IGLV3-21), in particular, determines outcome for IGHV3-21-utilizing cases. We reappraised this issue in 8593 CLL patients of whom 437 (5%) used the IGHV3-21 gene with 254/437 (58%) classified as subset #2. Within subset #2, immunoglobulin heavy variable (IGHV)-mutated cases predominated, whereas non-subset #2/IGHV3-21 was enriched for IGHV-unmutated cases (P = .002). Subset #2 exhibited significantly shorter time-to-first-treatment (TTFT) compared with non-subset #2/IGHV3-21 (22 vs 60 months, P = .001). No such difference was observed between non-subset #2/IGHV3-21 vs the remaining CLL with similar IGHV mutational status. In conclusion, IGHV3-21 CLL should not be axiomatically considered a homogeneous entity with adverse prognosis, given that only subset #2 emerges as uniformly aggressive, contrasting non-subset #2/IGVH3-21 patients whose prognosis depends on IGHV mutational status as the remaining CLL.
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Regulación Leucémica de la Expresión Génica , Reordenamiento Génico de Cadena Pesada de Linfocito B/inmunología , Cadenas Pesadas de Inmunoglobulina/genética , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/genética , Anciano , Antineoplásicos/uso terapéutico , Linfocitos B/efectos de los fármacos , Linfocitos B/inmunología , Linfocitos B/patología , Femenino , Heterogeneidad Genética , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/mortalidad , Masculino , Persona de Mediana Edad , Pronóstico , Hipermutación Somática de Inmunoglobulina , Análisis de Supervivencia , Tiempo de Tratamiento , Resultado del TratamientoAsunto(s)
Ascitis/patología , Leucemia Prolinfocítica de Células T/diagnóstico , Anciano , Biomarcadores , Biopsia , Análisis Citogenético , Femenino , Humanos , Inmunofenotipificación , Leucemia Prolinfocítica de Células T/genética , Leucemia Prolinfocítica de Células T/metabolismo , Leucemia Prolinfocítica de Células T/terapiaAsunto(s)
Leucemia de Células Plasmáticas , Imagen por Resonancia Magnética , Síndrome de Pancoast , Tomografía Computarizada por Rayos X , Diagnóstico Diferencial , Humanos , Leucemia de Células Plasmáticas/diagnóstico por imagen , Leucemia de Células Plasmáticas/metabolismo , Leucemia de Células Plasmáticas/patología , Masculino , Persona de Mediana Edad , Síndrome de Pancoast/diagnóstico por imagen , Síndrome de Pancoast/metabolismo , Síndrome de Pancoast/patologíaRESUMEN
BACKGROUND AND OBJECTIVES: Trifluridine/tipiracil, registered for the treatment of patients with metastatic gastric and colorectal cancer, is a substrate and inhibitor for the organic cation transporter 2 (OCT2) and the multidrug and toxin extrusion protein 1 (MATE1), which raises the potential for drug-drug interactions with other OCT2/MATE1 modulators. Therefore, we prospectively examined the effect of an OCT2/MATE1 inhibitor (cimetidine) and substrate (metformin) on the pharmacokinetics of trifluridine. METHODS: In this three-phase crossover study, patients with metastatic colorectal or gastric cancer were sequentially treated with trifluridine/tipiracil alone (phase A), trifluridine/tipiracil concomitant with metformin (phase B) and trifluridine/tipiracil concomitant with cimetidine (phase C). The primary endpoint was the relative difference in exposure of trifluridine assessed by the area under the curve from timepoint zero to infinity. A > 30% change in exposure was considered clinically relevant. A p-value of < 0.025 was considered significant because of a Bonferroni correction. RESULTS: Eighteen patients were included in the analysis. Metformin did not significantly alter the exposure to trifluridine (- 12.6%; 97.5% confidence interval - 25.0, 1.8; p = 0.045). Cimetidine did alter the exposure to trifluridine significantly (+ 18.0%; 97.5% confidence interval 4.5, 33.3; p = 0.004), but this increase did not meet our threshold for clinical relevance. Metformin trough concentrations were not influenced by trifluridine/tipiracil. CONCLUSIONS: Our result suggests that the OCT2/MATE1 modulators cimetidine and metformin can be co-administered with trifluridine/tipiracil without clinically relevant effects on drug exposure. CLINICAL TRIAL REGISTRATION: NL8067 (registered 04-10-2019).
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Cimetidina , Estudios Cruzados , Interacciones Farmacológicas , Metformina , Proteínas de Transporte de Catión Orgánico , Trifluridina , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Cimetidina/farmacocinética , Cimetidina/farmacología , Cimetidina/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Combinación de Medicamentos , Metformina/farmacocinética , Metformina/administración & dosificación , Metformina/farmacología , Proteínas de Transporte de Catión Orgánico/metabolismo , Proteínas de Transporte de Catión Orgánico/antagonistas & inhibidores , Transportador 2 de Cátion Orgánico/metabolismo , Estudios Prospectivos , Pirrolidinas/farmacocinética , Pirrolidinas/administración & dosificación , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/metabolismo , Timina , Trifluridina/farmacocinética , Trifluridina/administración & dosificaciónAsunto(s)
Quimioterapia/mortalidad , Inmunoterapia/mortalidad , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/mortalidad , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Tasa de Supervivencia , Adulto JovenRESUMEN
This case concerns a 56-year-old female without medical history, who presents with a purple-red discoloration of the nose without clinical signs of sepsis. The patient rapidly deteriorates into multi-organ failure based on a pneumococcal sepsis with purpura fulminans.
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Infecciones Neumocócicas , Sepsis , Femenino , Humanos , Persona de Mediana Edad , Eritema , Insuficiencia Multiorgánica , NarizRESUMEN
Patients with MYC rearranged (MYC-R) diffuse large B-cell lymphoma (DLBCL) have a poor prognosis. Previously, we demonstrated in a single-arm phase II trial (HOVON-130) that addition of lenalidomide to R-CHOP (R2CHOP) is well-tolerated and yields similar complete metabolic remission rates as more intensive chemotherapy regimens in literature. In parallel with this single-arm interventional trial, a prospective observational screening cohort (HOVON-900) was open in which we identified all newly diagnosed MYC-R DLBCL patients in the Netherlands. Eligible patients from the observational cohort that were not included in the interventional trial served as control group in the present risk-adjusted comparison. R2CHOP treated patients from the interventional trial (n = 77) were younger than patients in the R-CHOP control cohort (n = 56) (median age 63 versus 70 years, p = 0.018) and they were more likely to have a lower WHO performance score (p = 0.013). We adjusted for differences at baseline using 1:1 matching, multivariable analysis, and weighting using the propensity score to reduce treatment-selection bias. These analyses consistently showed improved outcome after R2CHOP with HRs of 0.53, 0.51, and 0.59, respectively, for OS, and 0.53, 0.59, and 0.60 for PFS. Thus, this non-randomized risk-adjusted comparison supports R2CHOP as an additional treatment option for MYC-R DLBCL patients.
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Protocolos de Quimioterapia Combinada Antineoplásica , Linfoma de Células B Grandes Difuso , Humanos , Persona de Mediana Edad , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ciclofosfamida/uso terapéutico , Doxorrubicina/efectos adversos , Lenalidomida/uso terapéutico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/genética , Prednisona/uso terapéutico , Rituximab/uso terapéutico , Resultado del Tratamiento , Vincristina/efectos adversos , AncianoRESUMEN
BACKGROUND: Erythroderma could be the first sign of a cutaneous T-cell lymphoma (CTCL), such as Sézary syndrome. Causes of erythroderma include inflammatory dermatosis, toxicoderma, paraneoplastic erytroderma, and CTCL. Hence, diagnosing Sézary syndrome can be difficult. Sézary syndrome is a rare, aggressive disease characterized by erythroderma, generalized lymphadenopathy and the presence of clonally related neoplastic T-cells in skin, peripheral blood, and lymph nodes. Treatment consists of photochemotherapy (PUVA), radiotherapy, immunomodulatory agents, low dose cytotoxic agents, and intensive chemotherapy. Immunotherapy directed against CCR4 and PD1 are new, promising developments. CASE DESCRIPTION: A 51-year-old man presented with a 1-year history of progressive, itchy erythroderma and lymphocytosis. After extensive cytomorphological, histopathological and molecular examination the diagnosis of Sézary syndrome could be established. Combination treatment of interferon and photochemotherapy (PUVA) was started. CONCLUSION: Diagnostic delay in Sézary syndrome is common. Integrated cytomorphological, immunological, and molecular evaluation of peripheral blood in patients with unexplained erythroderma non-responsive to (topical) treatment is warranted.
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Dermatitis Exfoliativa , Síndrome de Sézary , Neoplasias Cutáneas , Diagnóstico Tardío , Dermatitis Exfoliativa/diagnóstico , Dermatitis Exfoliativa/etiología , Humanos , Masculino , Persona de Mediana Edad , Prurito/etiología , Síndrome de Sézary/complicaciones , Síndrome de Sézary/diagnóstico , Neoplasias Cutáneas/complicaciones , Neoplasias Cutáneas/diagnósticoRESUMEN
T-LGL cells arise as a consequence of chronic antigenic stimulation and inflammation and thrive because of constitutive activation of the STAT3 and ERK pathway. Notably, in 40% of patients, constitutive STAT3 activation is due to STAT3 activating mutations, whereas in 60% this is unknown. As miRNAs are amongst the most potent regulators in health and disease, we hypothesized that aberrant miRNA expression could contribute to dysregulation of these pathways. miRNA sequencing in T-LGL leukemia cases and aged-matched healthy control TEMRA cells revealed overexpression of miR-181a. Furthermore, geneset enrichment analysis (GSEA) of downregulated targets of miR-181a implicated involvement in regulating STAT3 and ERK1/2 pathways. Flow cytometric analyses showed increased SOCS3+ and DUSP6+ T-LGL cells upon miR-181a inhibition. In addition, miR-181a-transfected human CD8+ T cells showed increased basal STAT3 and ERK1/2 phosphorylation. By using TL1, a human T-LGL cell line, we could show that miR-181a is an actor in T-LGL leukemia, driving STAT3 activation by SOCS3 inhibition and ERK1/2 phosphorylation by DUSP6 inhibition and verified this mechanism in an independent cell line. In addition, miR-181a inhibition resulted in a higher sensitivity to FAS-mediated apoptosis. Collectively, our data show that miR-181a could be the missing link to explain why STAT3-unmutated patients show hyperactive STAT3.
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Leucemia Linfocítica Granular Grande , MicroARNs , Factor de Transcripción STAT3 , Linfocitos T CD8-positivos , Humanos , Leucemia Linfocítica Granular Grande/genética , MicroARNs/genética , Receptores de Antígenos de Linfocitos T alfa-beta , Factor de Transcripción STAT3/genéticaRESUMEN
Preclinical data suggests that protein and calorie restriction (PCR) might improve treatment tolerability without impairing antitumor efficacy. Therefore, we have studied the influence of PCR on irinotecan pharmacokinetics and toxicity. In this crossover trial, patients with liver metastases of solid tumors were included and randomized to treatment with irinotecan preceded by 5 days of PCR (~ 30% caloric and ~ 70% protein restriction) during the first cycle and a second cycle preceded by a normal diet or vice versa. Pharmacokinetic blood sampling and biopsies of both healthy liver and liver metastases were performed. The primary end point was the relative difference in geometric means for the active metabolite SN-38 concentration in healthy liver analyzed by a linear mixed model. No significant differences were seen in irinotecan (+ 16.8%, P = 0.22) and SN-38 (+ 9.8%, P = 0.48) concentrations between PCR and normal diet in healthy liver, as well as in liver metastases (irinotecan: -38.8%, P = 0.05 and SN-38: -13.8%, P = 0.50). PCR increased irinotecan plasma area under the curve from zero to 24 hours (AUC0-24h ) with 7.1% (P = 0.04) compared with normal diet, whereas the SN-38 plasma AUC0-24h increased with 50.3% (P < 0.001). Grade ≥ 3 toxicity was not increased during PCR vs. normal diet (P = 0.69). No difference was seen in neutropenia grade ≥ 3 (47% vs. 32% P = 0.38), diarrhea grade ≥ 3 (5% vs. 21% P = 0.25), and febrile neutropenia (5% vs. 16% P = 0.50) during PCR vs. normal diet. In conclusion, plasma SN-38 exposure increased dramatically after PCR, whereas toxicity did not change. PCR did not alter the irinotecan and SN-38 exposure in healthy liver and liver metastases. PCR might therefore potentially improve the therapeutic window in patients treated with irinotecan.
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Restricción Calórica , Dieta con Restricción de Proteínas , Irinotecán/efectos adversos , Irinotecán/farmacocinética , Neoplasias Hepáticas/tratamiento farmacológico , Anciano , Diarrea/inducido químicamente , Femenino , Humanos , Neoplasias Hepáticas/dietoterapia , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/secundario , Masculino , Persona de Mediana Edad , Neutropenia/inducido químicamenteRESUMEN
BACKGROUND: Circulating tumour cell (CTC)-derived organoids have the potential to provide a powerful tool for personalised cancer therapy but are restrained by low CTC numbers provided by blood samples. Here, we used diagnostic leukapheresis (DLA) to enrich CTCs from patients with metastatic prostate cancer (mPCa) and explored whether organoids provide a platform for ex vivo treatment modelling. METHODS: We prospectively screened 102 patients with mPCa and performed DLA in 40 patients with ≥5 CTCs/7.5 mL blood. We enriched CTCs from DLA using white blood cell (WBC) depletion alone or combined with EpCAM selection. The enriched CTC samples were cultured in 3D to obtain organoids and used for downstream analyses. RESULTS: The DLA procedure resulted in a median yield of 5312 CTCs as compared with 22 CTCs in 7.5 mL of blood. Using WBC depletion, we recovered 46% of the CTCs, which reduced to 12% with subsequent EpCAM selection. From the isolated and enriched CTC samples, organoid expansion succeeded in 35%. Successful organoid cultures contained significantly higher CTC numbers at initiation. Moreover, we performed treatment modelling in one organoid cell line and identified substantial tumour heterogeneity in CTCs using single cell DNA sequencing. CONCLUSIONS: DLA is an efficient method to enrich CTCs, although the modest success rate of culturing CTCs precludes large scale clinical application. Our data do suggest that DLA and subsequent processing provides a rich source of viable tumour cells. Therefore, DLA offers a promising alternative to biopsy procedures to obtain sufficient number of tumour cells to study sequential samples in patients with mPCa. TRIAL REGISTRATION NUMBER: NL6019.
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Separación Celular , Leucaféresis , Células Neoplásicas Circulantes/patología , Neoplasias de la Próstata/patología , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , ADN de Neoplasias/genética , Heterogeneidad Genética , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Células Neoplásicas Circulantes/efectos de los fármacos , Células Neoplásicas Circulantes/metabolismo , Organoides , Estudios Prospectivos , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/terapia , Resultado del Tratamiento , Células Tumorales CultivadasRESUMEN
Recent studies suggest the potential involvement of common antigenic stimuli on the ontogeny of monoclonal T-cell receptor (TCR)-alphabeta(+)/CD4(+)/NKa(+)/CD8(-/+dim) T-large granular lymphocyte (LGL) lymphocytosis. Because healthy persons show (oligo)clonal expansions of human cytomegalovirus (hCMV)-specific TCRVbeta(+)/CD4(+)/cytotoxic/memory T cells, we investigate the potential involvement of hCMV in the origin and/or expansion of monoclonal CD4(+) T-LGL. Peripheral blood samples from patients with monoclonal TCR-alphabeta(+)/CD4(+) T-LGL lymphocytosis and other T-chronic lymphoproliferative disorders were evaluated for the specific functional response against hCMV and hEBV whole lysates as well as the "MQLIPDDYSNTHSTRYVTVK" hCMV peptide, which is specifically loaded in HLA-DRB1*0701 molecules. A detailed characterization of those genes that underwent changes in T-LGL cells responding to hCMV was performed by microarray gene expression profile analysis. Patients with TCR-alphabeta(+)/CD4(+) T-LGL displayed a strong and characteristic hCMV-specific functional response, reproduced by the hCMV peptide in a subset of HLA-DRB1*0701(+) patients bearing TCRVbeta13.1(+) clonal T cells. Gene expression profile showed that the hCMV-induced response affects genes involved in inflammatory and immune responses, cell cycle progression, resistance to apoptosis, and genetic instability. This is the first study providing evidence for the involvement of hCMV in the ontogeny of CD4(+) T-LGL, emerging as a model disorder to determine the potential implications of quite a focused CD4(+)/cytotoxic immune response.
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Antígenos Virales/análisis , Proliferación Celular , Citomegalovirus/inmunología , Leucemia Linfocítica Granular Grande/patología , Linfocitosis/virología , Células T Asesinas Naturales/inmunología , Adulto , Formación de Anticuerpos/fisiología , Antígenos Virales/química , Antígenos CD4/metabolismo , Antígenos CD8/metabolismo , Análisis por Conglomerados , Perfilación de la Expresión Génica , Humanos , Inmunidad Celular/fisiología , Leucemia Linfocítica Granular Grande/genética , Leucemia Linfocítica Granular Grande/inmunología , Leucemia Linfocítica Granular Grande/metabolismo , Células T Asesinas Naturales/metabolismo , Células T Asesinas Naturales/patología , Análisis de Secuencia por Matrices de Oligonucleótidos , Fragmentos de Péptidos/inmunología , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismoRESUMEN
A 62-year-old woman who was treated with daratumumab, bortezomib and dexamethasone for multiple myeloma, developed a skin tumor on her back. Histologic examination of a biopsy from the nodule revealed cutaneous plasmacytoma. Secondary plasmacytoma is an indicator of poor prognosis.