RESUMEN
The prognostic value of radiomic quantitative features measured on pre-treatment 18F-FDG PET/CT was investigated in patients with follicular lymphoma (FL). We conducted a retrospective study of 126 FL patients (grade 1-3a) diagnosed between 2006 and 2020. A dozen of PET/CT-derived features were extracted via a software (Oncometer3D) from baseline 18F-FDG PET/CT images. The receiver operating characteristic (ROC) curve, Kaplan-Meier method and Cox analysis were used to assess the prognostic factors for progression of disease within 24 months (POD24) and progression-free survival at 24 months. Four different clusters were identified among the twelve PET parameters analyzed: activity, tumor burden, fragmentation-massiveness and dispersion. On ROC analyses, TMTV, the total metabolic tumor volume, had the highest AUC (0.734) followed by medPCD, the median distance between the centroid of the tumors and their periphery (AUC: 0.733). Patients with high TMTV (HR = 4.341; p < 0.001), high Tumor Volume Surface Ratio (TVSR) (HR = 3.204; p < 0.003) and high medPCD (HR = 4.507; p < 0.001) had significantly worse prognosis in both Kaplan-Meier and Cox univariate analyses. Furthermore, a synergistic effect was observed in Kaplan-Meier and Cox analyses combining these three PET/CT-derived parameters (HR = 12.562; p < 0.001). Having two or three high parameters among TMTV, TVSR and medPCD was able to predict POD24 status with a specificity of 68% and a sensitivity of 75%. TMTV, TVSR and baseline medPCD are strong prognostic factors in FL and their combination better predicts disease prognosis.
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Linfoma Folicular , Tomografía Computarizada por Tomografía de Emisión de Positrones , Humanos , Pronóstico , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Fluorodesoxiglucosa F18 , Linfoma Folicular/diagnóstico por imagen , Estudios Retrospectivos , Carga TumoralRESUMEN
BACKGROUND: Retrospective studies in hematological unit have suggested that single red blood cell (1-RBC) unit transfusion policy may reduce the number of RBC used without negative clinical impact. METHOD: Acute leukemia patients requiring intensive chemotherapy or patients receiving autologous or allogeneic transplantation were randomly assigned to receive either single RBC (1-RBC arm) or double RBC (2-RBC arm) per transfusion with a hemoglobin trigger of 8 g/dL. The primary composite endpoint was the percentage of patients experiencing serious complications, such as a non-hematological adverse event grade ≥ 3 or intensive care admission or death. FINDINGS: A total of 981 and 592 RBC transfusions were required in the 1-RBC arm (n = 125) and the 2-RBC arm (n = 120), respectively. The mean pre-transfusion hemoglobin levels were 7.49 ± 0.83 g/dL in the 1-RBC arm and 7.46 ± 0.67 g/dL in the 2-RBC arm (p = 0.275). The predefined non-inferiority criteria was achieved with 28/125 patients reaching the primary endpoint in the 1-RBC arm (22.4 %) and 28/120 patients in the 2-RBC arm (23.3 %) (Risk difference 0.009; 95 %, Confidence interval [-0.0791 to 0.0978], p = 0.021). The median (IQR) of RBC units transfused per patient was 7 (4-12) in the 1-RBC arm and 8 (4-12) in 2-RBC arm. Hemoglobin levels at discharge were also comparable in both arms. INTERPRETATION: The results of this trial indicate that a single RBC transfusion policy is not inferior to a double RBC transfusion policy for patients receiving a bone marrow transplant or intensive chemotherapy in a hematological intensive care unit. However, the single RBC transfusion policy did not reduce the number of RBC units transfused per stay. FUNDING: This trial was funded by a grant from the French Ministry of Health.
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Enfermedades Hematológicas , Leucemia Mieloide Aguda , Humanos , Estudios Retrospectivos , Transfusión de Eritrocitos/efectos adversos , Hemoglobinas , Leucemia Mieloide Aguda/etiología , Enfermedad AgudaRESUMEN
BACKGROUND: Anti-PD-1 and anti-CTLA-4 monoclonal antibodies are used in melanoma, while anti-PD-1 are also used in Hodgkin's lymphoma. Primary central nervous system lymphoma is a rare form of non-Hodgkin's lymphoma with few effective treatments. However, several recent studies have reported multiple cases of non-Hodgkin's lymphoma and primary central nervous system lymphoma treated by anti-PD-1 antibodies with favourable responses. PATIENTS AND METHODS: This study focuses on the case of a 59-year-old man with metastatic melanoma treated by immunotherapy (anti-CTLA-4 followed by anti-PD-1). He underwent 28 courses of therapy with pembrolizumab. Treatment was stopped after clinical and radiological remission. The patient presented left hemiparesis and a primary central nervous system lymphoma was diagnosed two months after discontinuation of immunotherapy. He started urgent high-dose methotrexate chemotherapy but without significant results. Despite second-line chemotherapy with R-ICE (rituximab-ifosfamide, carboplatin and etoposide), the patient died. DISCUSSION: Several hypotheses may be advanced regarding a possible relationship between immunotherapy and the occurrence of this primary central nervous system lymphoma. The lymphoma may have been pre-existing and controlled by immunotherapy, but progressing rapidly after treatment, or it may have been induced by the immunotherapy. However, immunotherapy may have played no role; the relationship between melanoma and lymphoma is well known. CONCLUSION: While immunotherapy cannot be unequivocally incriminated in primary central nervous system lymphoma, this case raises many questions about the imputability of immunotherapy in the occurrence of secondary cancers, including lymphomas.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Neoplasias Encefálicas/patología , Linfoma de Células B Grandes Difuso/patología , Melanoma/tratamiento farmacológico , Neoplasias Encefálicas/diagnóstico por imagen , Resultado Fatal , Humanos , Linfoma de Células B Grandes Difuso/diagnóstico por imagen , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Paresia/etiología , Neoplasias Cutáneas/tratamiento farmacológicoRESUMEN
PURPOSE: This study evaluated the predictive significance of total metabolic tumour volume (TMTV) measured on baseline FDG PET/CT and its value in addition to gene expression profiling using a new method of gene analysis (rapid reverse transcriptase multiplex ligation-dependent probe amplification assay, RT-MLPA) in patients with diffuse large B-cell lymphoma treated with R-CHOP or R-CHOP-like chemotherapies. METHODS: The analysis included 114 patients. TMTV was measured using a 41% SUVmax threshold and tumours were classified into GCB or ABC subtypes according to the RT-MLPA assay. RESULTS: The median follow-up was 40 months. the 5-year progression-free survival (PFS) was 54% and the 5-year overall survival (OS) was 62%. The optimal TMTV cut-off value was 261 cm3. In 59 patients with a high TMTV the 5-year PFS and OS were 37% and 39%, respectively, in comparison with 72% and 83%, respectively, in 55 patients with a low TMTV (p = 0.0002 for PFS, p < 0.0001 for OS). ABC status was significantly associated with a worse prognosis. TMTV combined with molecular data identified three groups with very different outcomes: (1) patients with a low TMTV whatever their phenotype (n = 55), (2) patients with a high TMTV and GCB phenotype (n = 33), and (3) patients with a high TMTV and ABC phenotype (n = 26). In the three groups, 5-year PFS rates were 72%, 51% and 17% (p < 0.0001), and 5-year OS rates were 83%, 55% and 17% (p < 0.0001), respectively. In multivariate analysis, TMTV, ABC/GCB phenotype and International Prognostic Index were independent predictive factors for both PFS and OS (p < 0.05 for both). CONCLUSIONS: This integrated risk model could lead to more accurate selection of patients that would allow better individualization of therapy.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Perfilación de la Expresión Génica , Linfoma de Células B Grandes Difuso/diagnóstico por imagen , Tomografía Computarizada por Tomografía de Emisión de Positrones , Supervivencia sin Enfermedad , Femenino , Fluorodesoxiglucosa F18 , Humanos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/genética , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Pronóstico , Estudios Retrospectivos , Transcriptoma , Carga TumoralRESUMEN
The histone methyltransferase EZH2 has an essential role in the development of follicular lymphoma (FL). Recurrent gain-of-function mutations in EZH2 have been described in 25% of FL patients and induce aberrant methylation of histone H3 lysine 27 (H3K27). We evaluated the role of EZH2 genomic gains in FL biology. Using RNA sequencing, Sanger sequencing and SNP-arrays, the mutation status, copy-number and gene-expression profiles of EZH2 were assessed in a cohort of 159 FL patients from the PRIMA trial. Immunohistochemical (IHC) EZH2 expression (n=55) and H3K27 methylation (n=63) profiles were also evaluated. In total, 37% of patients (59/159) harbored an alteration in the EZH2 gene (mutation n=46, gain n=23). Both types of alterations were associated with highly similar transcriptional changes, with increased proliferation programs. An H3K27me3/me2 IHC score fully distinguished mutated from wild-type samples, showing its applicability as surrogate for EZH2 mutation analysis. However, this score did not predict the presence of gains at the EZH2 locus. The presence of an EZH2 genetic alteration was an independent factor associated with a longer progression-free survival (hazard ratio 0.58, 95% confidence interval 0.36-0.93, P=0.025). We propose that the copy-number status of EZH2 should also be considered when evaluating patient stratification and selecting patients for EZH2 inhibitor-targeted therapies.
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Proteína Potenciadora del Homólogo Zeste 2/genética , N-Metiltransferasa de Histona-Lisina/genética , Linfoma Folicular/genética , Adulto , Anciano , Línea Celular Tumoral , Supervivencia sin Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Histona Metiltransferasas , Humanos , Linfoma Folicular/tratamiento farmacológico , Linfoma Folicular/patología , Masculino , Metilación/efectos de los fármacos , Persona de Mediana Edad , Mutación/genética , Polimorfismo de Nucleótido Simple/genética , Análisis de Secuencia de ARNRESUMEN
BACKGROUND: Our aim was to evaluate whether the cell of origin (COO) as defined by the Hans algorithm and MYC/BCL2 coexpression, which are the two main biological risk factors in elderly patients treated with rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisolone (R-CHOP), maintain their prognostic value in a large prospective clinical trial. PATIENTS AND METHODS: We evaluated 285 paraffin-embedded samples from patients (60-80 years of age) enrolled in the Lymphoma Study Association trial LNH03-6B who were treated with R-CHOP. We correlated the COO defined by the transcriptome according to the Wright algorithm with that defined by the Hans algorithm in a subset of 62 tumors with available frozen tissue samples. RESULTS: The non-germinal center B-cell-like phenotype according to the Hans algorithm and BCL2 expression (but not MYC and BCL2 coexpression) predicted worse progression-free survival [hazard ratio (HR)=1.78, P = 0.003 and HR = 1.79, P = 0.003, respectively] and overall survival (HR = 1.85, P = 0.005 and HR = 1.67, P = 0.02, respectively) independently of the International Prognostic Index. The correlation between the Hans algorithm and the Wright algorithm was 91%, with an almost perfect concordance according to a kappa test (0.81). CONCLUSIONS: Our results suggest that immunohistochemically defined COO remains a useful tool for predicting prognosis in diffuse large B-cell lymphoma when performed under optimized standardized conditions and that BCL2 expression may help to identify elderly patients at risk for relapse and who could potentially respond to anti-BCL2 targeted agents. In this prospective phase III trial, the coexpression of MYC and BCL2 does not appear to predict worse survival. CLINICAL TRIAL NUMBER: NCT00144755.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-myc/genética , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Anticuerpos Monoclonales de Origen Murino/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biomarcadores de Tumor/genética , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Supervivencia sin Enfermedad , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/patología , Masculino , Persona de Mediana Edad , Prednisona/administración & dosificación , Prednisona/efectos adversos , Pronóstico , Factores de Riesgo , Rituximab , Resultado del Tratamiento , Vincristina/administración & dosificación , Vincristina/efectos adversosAsunto(s)
Bioensayo , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Leucemia/diagnóstico , Leucemia/genética , Proteínas de Fusión Oncogénica/análisis , Enfermedad Aguda , Secuencia de Bases , Cromosomas Humanos Par 15 , Cromosomas Humanos Par 17 , Cromosomas Humanos Par 21 , Análisis Citogenético , Secuenciación de Nucleótidos de Alto Rendimiento/instrumentación , Humanos , Leucemia/patología , Datos de Secuencia Molecular , Sondas de Oligonucleótidos/síntesis química , Proteínas de Fusión Oncogénica/genética , Estudios Retrospectivos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Translocación GenéticaAsunto(s)
Antivirales/uso terapéutico , Trasplante de Células Madre de Sangre del Cordón Umbilical/efectos adversos , Ganciclovir/uso terapéutico , Herpesvirus Humano 6/patogenicidad , Encefalitis Límbica/etiología , Adulto , Antivirales/administración & dosificación , Trasplante de Células Madre de Sangre del Cordón Umbilical/métodos , Ganciclovir/administración & dosificación , Humanos , Masculino , Adulto JovenRESUMEN
BCR-ABL1 negative myeloproliferative neoplasms (MPNs) are known to contain alterations of the tyrosine kinase JAK2 (located on 9p24) that result in constitutive activation of the encoded protein. JAK2 fusions are reported in acute and chronic leukemias of myeloid and lymphoid phenotypes. Here, we report an unclassified case of MPN (MPN-U) showing a t(9;22)(p24;q11), which generates a BCR-JAK2 fusion gene by fusing the BCR at intron 13 to JAK2 at intron 17 on the derivative chromosome 22. Most reported JAK2 fusions cases reveal an aggressive clinical course and long-term remissions have only been achieved after allogeneic stem cell transplantation (ASCT). To the best of our knowledge, this is the thirteenth case reported worldwide to describe a BCR-JAK2 fusion transcript in MPN-U. The present report revealed a sustained complete clinical, hematologic, and cytogenetic remission 35 months after diagnosis and ~24 months after ASCT. Regarding BCR-ABL1 negative MPN patients this case report provides strong support for a role of JAK2 activation in the oncogenesis and suggests a possible diagnostic and therapeutic target that should be investigated.
RESUMEN
In diffuse large B-cell lymphomas (DLBCL), a recurrent deletion of the 19p13 region has recently been described. CD70 and TNFSF9 genes are suspected tumor suppressor genes, but previous studies suggest an oncogenic role for CD70. Therefore, we studied the consequences of variation in CD70 copy number and epigenetic modifications on CD70 expression. Copy-number variation was investigated in 144 de novo DLBCL tissues by comparative genomic hybridization array and quantitative multiplex PCR. Gene expression was assessed by quantitative RT-PCR, and CD70 promoter methylation was determined by pyrosequencing. The 19p13.3.2 region was deleted in 21 (14.6%) cases, which allowed the minimal commonly deleted region of 57 Kb that exclusively includes the CD70 gene to be defined. Homozygous deletions were observed in four (2.7%) cases, and acquired single-nucleotide variations of CD70 were detected in nine (6.3%) cases. CD70 was highly expressed in both germinal centre B-cell-like (GCB) and activated B-cell-like (ABC) DLBCL compared to normal tissue, with distinct molecular mechanisms of mRNA expression regulation. A gene dosage effect was observed in the GCB subtype, whereas promoter methylation was the predominant mechanism of down regulation in the ABC subtype. However, high CD70 expression levels correlated to shorter overall survival in both the GCB (P = 0.0021) and the ABC (P =0.0158) subtypes. In conclusion, CD70 is targeted by recurrent deletions, somatic mutations and promoter hypermethylation, but its high level of expression is related to an unfavorable outcome, indicating that this molecule may constitute a potential therapeutic target in selected DLBCL.
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Ligando CD27/genética , Variaciones en el Número de Copia de ADN/genética , Metilación de ADN/genética , Linfoma de Células B Grandes Difuso/genética , Ligando CD27/aislamiento & purificación , Puntos de Rotura del Cromosoma , Deleción Cromosómica , Regulación Neoplásica de la Expresión Génica , Humanos , Hibridación Fluorescente in Situ , Linfoma de Células B Grandes Difuso/patología , Regiones Promotoras Genéticas , Análisis de SupervivenciaRESUMEN
AIM: We assessed in this study the influence of contrast-enhanced CT (ceCT) on PET/CT interpretation and PET/CT on ceCT interpretation in patients with lymphoma, before and after chemotherapy. METHODS: Fifty patients with Hodgkin disease (N.=17) or non-Hodgkin lymphomas (N.=33) were assessed before and after chemotherapy. PET/CT were performed 60 minutes after injection of FDG. Iopamidol was then injected and followed, 50 seconds later, by another CT. PET images were successively reconstructed using non-enhanced CT (PET-) and ceCT (PET+). Four nuclear physicians rated PET- and PET+ in random order. Three radiologists initially rated ceCT alone and then ceCT along with PET+. RESULTS: Before chemotherapy, global agreement (GA) was 99% (k=0.96) when PET- was compared to PET+. Nine (5%) lesions were discordant, 5 according to PET- and 4 to PET+. After chemotherapy, GA was 99% (k=0.91). Eight (15%) lesions were discordant, 3 according to PET- and 5 to PET+. Before chemotherapy, GA was 97% (k=0.91) when ceCT was compared to ceCT with PET+. Twenty-one (12%) lesions were discordant, 16 when ceCT were analyzed alone and 5 when ceCT was analyzed with PET+. After chemotherapy, GA was 95% (k=0.76). All 30 (35%) discordant lesions were positive according to ceCT alone. A significant difference between the 2 procedures was found in the pelvis and in the groin (P<0.05). CONCLUSION: PET+ did not differ from PET-, before and after chemotherapy. Fewer abnormalities were observed, when ceCT was analyzed with PET+, particularly after chemotherapy, due to residual masses that are better analyzed with functional imaging.
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Linfoma/diagnóstico por imagen , Adulto , Anciano , Medios de Contraste , Femenino , Enfermedad de Hodgkin/diagnóstico por imagen , Enfermedad de Hodgkin/tratamiento farmacológico , Humanos , Linfoma/tratamiento farmacológico , Linfoma no Hodgkin/diagnóstico por imagen , Linfoma no Hodgkin/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Medicina Nuclear , Variaciones Dependientes del Observador , Tomografía de Emisión de Positrones , Interpretación de Imagen Radiográfica Asistida por Computador , Radiología , Tomografía Computarizada por Rayos XRESUMEN
Gene expression profiling has identified two major molecular subtypes of diffuse large B-cell lymphoma (DLBCL) that are histologically indistinguishable but differ in cure rates. Here, we investigated whether the isotype of the B-cell receptor (BCR) expressed by the tumoral cells correlated with the molecular subtype and survival. Gene expression analysis clustered the 53 patients included in this study into three subgroups, 17 germinal center B-cell-like (GCB) cases, 26 activated B-cell-like (ABC) cases and 10 intermediate cases. The molecular subtype was correlated with the isotype, as 15/17 GCB cases expressed a secondary isotype (immunoglobulin (Ig)G or IgA), whereas 24/26 ABC cases expressed a primary isotype (IgM or IgD) (P<0.0001). There was a trend toward a worse outcome for patients with an ABC DLBCL and a shorter overall survival for patients with IgM+ tumor (P=0.21 and 0.014, respectively). Finally, fluorescence in situ hybridization (FISH) analysis revealed a striking asymmetric pattern, as the IGHM gene is conserved only on the productive IGH allele in most IgM+ tumors. Taken together, these data indicate that the isotype of the BCR is a reliable indicator for the GCB and ABC subtypes in DLBCL, and suggest that the conservation of an IgM is required for ABC DLBCL lymphomagenesis to occur.
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Linfocitos B/patología , Centro Germinal/patología , Linfoma de Células B Grandes Difuso/clasificación , Linfoma de Células B Grandes Difuso/genética , Receptores de Antígenos de Linfocitos B/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Femenino , Perfilación de la Expresión Génica , Humanos , Técnicas para Inmunoenzimas , Cadenas Pesadas de Inmunoglobulina/genética , Inmunoglobulina M/genética , Hibridación Fluorescente in Situ , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tasa de SupervivenciaRESUMEN
Array-based comparative genomic hybridization (aCGH) is a powerful tool to detect genomic imbalances in the human genome. The analysis of aCGH data sets has revealed the existence of a widespread technical artifact termed as 'waves', characterized by an undulating data profile along the chromosome. Here, we describe the development of a novel noise-reduction algorithm, waves aCGH correction algorithm (WACA), based on GC content and fragment size correction. WACA efficiently removes the wave artifact, thereby greatly improving the accuracy of aCGH data analysis. We describe the application of WACA to both real and simulated aCGH data sets, and demonstrate that our algorithm, by systematically correcting for all known sources of bias, is a significant improvement on existing aCGH noise reduction algorithms. WACA and associated files are freely available as Supplementary Data.
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Algoritmos , Artefactos , Hibridación Genómica Comparativa/métodos , Composición de Base , Aberraciones Cromosómicas , Simulación por Computador , ADN/química , Humanos , Neoplasias/genética , Análisis de Secuencia por Matrices de Oligonucleótidos/métodosRESUMEN
OBJECTIVE: We previously reported that early continuous veno-venous hemodiafiltration (CVVHDF) enables rapid identification of a subgroup of patients with "refractory" septic shock and a 100% risk of death. The objective of this study was to investigate whether early administration of drotrecogin alpha (activated) (DrotAA) to this selected subgroup of septic patients at extremely high risk of death would significantly improve prognosis. METHOD: Prospective observational study in a medical intensive-care unit of a University Hospital. Twenty-three patients with refractory septic shock were included. "Refractory" shock was defined as persistent circulatory failure despite adequate circulatory support, associated with persisting lactic acidosis despite early CVVHDF. Response to CVVDHF was assessed after 6 h of this continuous procedure. Patients selected by this strategy received DrotAA infusion for four days. RESULTS: The 28-day mortality rate of the 23 patients was 39%. No difference was observed at inclusion between survivors and nonsurvivors. In patients who finally survived, 12 h of DrotAA infusion was associated with a significant decrease in lactic acidosis and in norepinephrine dose. CONCLUSION: DrotAA therapy was associated with unexpectedly high 28-day survival in patients with "refractory" septic shock.
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Antiinfecciosos/uso terapéutico , Proteína C/uso terapéutico , Choque Séptico/tratamiento farmacológico , Acidosis Láctica , Anciano , Antiinfecciosos/administración & dosificación , Antiinfecciosos/farmacología , Relación Dosis-Respuesta a Droga , Femenino , Francia/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Insuficiencia Multiorgánica , Estudios Prospectivos , Proteína C/administración & dosificación , Proteína C/farmacología , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/farmacología , Proteínas Recombinantes/uso terapéutico , Choque Séptico/mortalidad , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
CD4+CD56+ haematodermic neoplasms (HDN) constitute a rare disease characterized by aggressive clinical behaviour and a poor prognosis. Tumour cells from HDN are leukaemic counterparts of plasmacytoid dendritic cells (pDCs). Despite increased knowledge of the ontogenetic origin of these tumours, the genetic causes and oncogenic signalling events involved in malignant transformation are still unknown. To delineate novel candidate regions and disease-related genes, we studied nine typical CD4+CD56+ HDN cases using genome-wide high-resolution array comparative genomic hybridization (CGH). Genomic imbalances, which were predominantly losses, were frequently detected. Gross genomic losses or gains involving an entire chromosome were observed in eight cases. The most frequent imbalances were deletions of chromosome 9, chromosome 13 and partial losses affecting 17p or 12p. Combinations of deletions of tumour suppressor genes (TSG), namely RB1, CDKN1B (p27), CDKN2A, (p16(ink4a), p14(arf)) or TP53 (p53), were observed in all cases. These results indicate that deletion events altering G1/S regulation are crucial for HDN oncogenesis. Furthermore, in addition to frequent sporadic gene losses, in one case we observed a 8q24 interstitial deletion that brought MYC closer to miR-30b/miR-30d, which may be related to their deregulation. Taken together, these results indicate that in addition to frequent G1/S checkpoint alterations, various genetic events could contribute to the chemoresistance of the tumour.
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Antígenos CD4 , Antígeno CD56 , Aberraciones Cromosómicas , Fase G1/genética , Eliminación de Gen , Genes Supresores de Tumor , Neoplasias Hematológicas/genética , Adulto , Anciano , Cromosomas Humanos Par 12 , Cromosomas Humanos Par 13 , Cromosomas Humanos Par 17 , Cromosomas Humanos Par 9 , Hibridación Genómica Comparativa , Femenino , Neoplasias Hematológicas/patología , Humanos , Masculino , Persona de Mediana Edad , Fase S/genéticaRESUMEN
Alemtuzumab is a humanized monoclonal antibody directed against lymphocytes through the CD-52 receptor, an antigen being found on > 95% of peripheral blood lymphocytes and monocytes, and to a smaller extent on granulocytes. It is an effective immunotherapeutic agent in patients with malignancies such as non-Hodgkin lymphoma, B cell chronic lymphocytic leukemia and T cell pro- lymphocytic leukemia. Adverse side effects are increasingly recognized in patients receiving alemtuzumab, mainly including fever, rigors, nausea/vomiting, skin rash; other severe alemtuzumab-related reactions have also been described, such as lymphopenia and neutropenia leading to both opportunistic (e.g. cytomegalovirus) and non-opportunistic infections. Digestive complications have more rarely been described, i.e.: gastroenteritis and peritonitis. We recently observed a case of particular interest as the patient with T cell prolymphocytic leukaemia treated with alemtuzumab, exhibited symptomatic reactivation of CMV infection and developed subsequently typhlitis.
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Anticuerpos Monoclonales/efectos adversos , Anticuerpos Antineoplásicos/efectos adversos , Antineoplásicos/efectos adversos , Tiflitis/diagnóstico , Tiflitis/etiología , Alemtuzumab , Anticuerpos Monoclonales Humanizados , Femenino , Humanos , Leucemia Prolinfocítica/inmunología , Leucemia Prolinfocítica/terapia , Leucemia de Células T/inmunología , Leucemia de Células T/terapia , Persona de Mediana Edad , Tiflitis/inmunologíaRESUMEN
Chromosomal translocations joining the immunoglobulin (IG) and MYC genes have been extensively reported in Burkitt's and non-Burkitt's lymphomas but data concerning MYC rearrangements with non-IG partners are scarce. In this study, 8q24 breakpoints from 17 B-cell lymphomas involving non-IG loci were mapped by fluorescence in situ hybridization (FISH). In seven cases the breakpoint was inside a small region encompassing MYC: in one t(7;8)(p12;q24) and two t(3;8)(q27;q24), it was telomeric to MYC whereas in four cases, one t(2;8)(p15;q24) and three t(8;9)(q24;p13) it was located in a 85 kb region encompassing MYC. In these seven cases, partner regions identified by FISH contained genes known to be involved in lymphomagenesis, namely BCL6, BCL11A, PAX5 and IKAROS. Breakpoints were cloned in two t(8;9)(q24;p13), 2.5 and 7 kb downstream from MYC and several hundred kb 5' to PAX5 on chromosome 9, joining MYC to ZCCHC7 and to ZBTB5 exon 2, two genes encoding zinc-finger proteins. In these seven cases, MYC expression measured by quantitative reverse transcription-polymerase chain reaction (RT-PCR) was significantly higher when compared to that of patients without 8q24 rearrangement (P=0.006). These results suggest that these rearrangements are the consequence of a non-random process targeting MYC together with non-IG genes involved in lymphocyte differentiation and lymphoma progression.