Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 28
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Front Immunol ; 10: 1943, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31475004

RESUMO

Follicular lymphoma (FL) is the second most frequent subtype of B non-Hodgkin's lymphomas (NHL) for which the treatment is based on the use of anti-CD20 mAbs. NK cells play a crucial role in their mechanism of action and the number of these cells mediating antibody-dependent cell cycotoxicity (ADCC) in the peripheral blood of FL patients predict the outcome. However, their presence in FL biopsies, their activation and their role have been poorly investigated. Moreover, in vitro studies have not deciphered the exact signaling cascades triggered by NK cells in presence of anti-CD20 mAbs on both effector and target cells in a relevant FL model. We performed in silico analyses and ex vivo functional assays to determine the presence and the activation status of NK cells in FL biopsies. We modelized ADCC phenomenon by developing a co-culture model composed by 3D-cultured FL cells and NK cells. Thus, we investigated the biological effect of anti-CD20 mAbs by fluorescent microscopy and the phosphorylation status of survival pathways by cell bar coding phosphoflow in target cells. In parallel, we measured the status of activation of downstream FcγRIIIa signaling pathways in effector cells and their activation (CD69, perforin, granzyme B, IFNγ) by flow cytometry. We determined by in vivo experiments the effects of anti-CD20 mAbs in presence of NK cells in SCID-Beige engrafted FL mice. Here, we show that functional NK cells infiltrate FL biopsies, and that their presence tends to correlate with the survival of FL patients. Using our 3D co-culture model, we show that rituximab and GA101 are able to promote degranulation, CD69 expression, IFNγ production and activate FcγRIIIa signaling cascade in NK cells, and inhibit survival pathways and induce apoptosis in FL cells. The effect of GA101 seems to be more pronounced as observed in vivo in a xenograft FL model. This study strongly supports the role of NK cells in FL and highlights the application of the 3D co-culture model for in vitro validation.

2.
Haematologica ; 2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31296574

RESUMO

CD38 is expressed in several types of non-Hodgkin lymphoma and constitutes a promising target for antibody-based therapy. Daratumumab (Darzalex) is a first-in-class anti-CD38 antibody approved for the treatment of relapsed/refractory multiple myeloma. It has also demonstrated clinical activity in Waldenstrom macroglobulinaemia and amyloidosis. Here, we have evaluated the activity and mechanism of action of daratumumab in preclinical in vitro and in vivo models of mantle cell lymphoma, follicular lymphoma and diffuse large B cell lymphoma, as monotherapy or in combination with standard chemo-immunotherapy. In vitro, daratumumab engages Fc-mediated cytotoxicity by antibody-dependent cell cytotoxicity and antibody-dependent cell phagocytosis in all lymphoma subtypes. In the presence of human serum, complement-dependent cell cytotoxicity was marginally engaged. We demonstrated by Selective Plane Illumination Microscopy that daratumumab fully penetrated a 3D lymphoma organoid and decreased organoid volume. In vivo, daratumumab completely prevents tumor outgrowth in models of mantle cell and follicular lymphoma, and shows comparable activity to rituximab in a disseminated in vivo model of blastic mantle cell lymphoma. Moreover, daratumumab improves overall survival in a mouse model of transformed CD20dim follicular lymphoma, where rituximab showed limited activity. Daratumumab potentiates the antitumor activity of CHOP and R-CHOP in mantle cell and follicular lymphoma xenografts. Furthermore, in a patient-derived diffuse large B cell lymphoma xenograft model, daratumumab anti-tumor activity was comparable to R-CHOP and the addition of daratumumab to either CHOP or R-CHOP led to full tumor regression. In summary, daratumumab constitutes a novel therapeutic opportunity in certain scenarios and these results warrant further clinical development.

3.
Oncotarget ; 10(43): 4354-4355, 2019 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-31320989
4.
Oncoimmunology ; 8(3): 1554175, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30723586

RESUMO

Follicular lymphoma (FL) is a common non Hodgkin's lymphoma subtype in which immune escape mechanisms are implicated in resistance to chemo-immunotherapy. Although molecular studies point to qualitative and quantitative deregulation of immune checkpoints, in depth cellular analysis of FL immune escape is lacking. Here, by functional assays and in silico analyses we show that a subset of FL patients displays a 'high' immune escape phenotype. These FL cases are characterized by abundant infiltration of PD1+ CD16+ TCRVγ9Vδ2 γδ T lymphocytes. In a 3D co-culture assay (MALC), γδ T cells mediate both direct and indirect (ADCC in the presence of anti-CD20 mAbs) cytolytic activity against FL cell aggregates. Importantly, PD-1, which is expressed by most FL-infiltrating γδ T lymphocytes with ADCC capacity, impairs these functions. In conclusion, we identify a PD1-regulated γδ T cell cytolytic immune component in FL. Our data provide a treatment rational by PD-1 blockade aimed at boosting γδ T cell anti-tumor functions in FL.

5.
Cell Rep ; 26(1): 94-107.e7, 2019 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-30605689

RESUMO

Despite the clinical success of blocking inhibitory immune checkpoint receptors such as programmed cell death-1 (PD-1) in cancer, the mechanisms controlling the expression of these receptors have not been fully elucidated. Here, we identify a post-transcriptional mechanism regulating PD-1 expression in T cells. Upon activation, the PDCD1 mRNA and ribonucleoprotein complexes coalesce into stress granules that require microtubules and the kinesin 1 molecular motor to proceed to translation. Hence, PD-1 expression is highly sensitive to microtubule or stress granule inhibitors targeting this pathway. Evidence from healthy donors and cancer patients reveals a common regulation for the translation of CTLA4, LAG3, TIM3, TIGIT, and BTLA but not of the stimulatory co-receptors OX40, GITR, and 4-1BB mRNAs. In patients, disproportionality analysis of immune-related adverse events for currently used microtubule drugs unveils a significantly higher risk of autoimmunity. Our findings reveal a fundamental mechanism of immunoregulation with great importance in cancer immunotherapy.

6.
Cancers (Basel) ; 10(11)2018 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-30384489

RESUMO

Therapeutic blockade of PD-1/PD-L1 shows promising results in Hodgkin's lymphoma (HL) and in some diffuse large B-cell lymphoma (DLBCL) patients, but biomarkers predicting such responses are still lacking. To this end, we recently developed a transcriptional scoring of immune escape (IE) in cancer biopsies. Using this method in DLBCL, we identified four stages of IE correlated with overall survival, but whether Hodgkin's lymphomas (HL) also display this partition was unknown. Thus, we explored the transcriptomic profiles of ~1000 HL and DLBCL using a comparative meta-analysis of their bulk microarrays. Relative to DLBCL, the HL co-clustered at the advanced stage of immune escape, displaying significant enrichment of both IE and T-cell activation genes. Analyses via transcriptome deconvolution and immunohistochemistry showed more CD3⁺ and CD4⁺ tumor-infiltrating lymphocytes (TILs) in HL than DLBCL. Both HL and non-GCB DLBCL shared a high abundance of infiltrating CD8⁺ T-cells, but HL had less CD68⁺CD163⁺ macrophages. The same cellular distribution of PD-1 and TIM-3 was observed in HL and DLBCL, though HL had more PD-L1 tumor cells and LAG-3 ME cells. This study illuminates the advanced stage of immune activation and escape in HL, consistent with the response to checkpoint blockade therapies for this type of lymphoma.

7.
Am J Hematol ; 2018 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-29884994

RESUMO

Anti-PD-1 therapy provides high response rates in Hodgkin lymphoma (HL) patients who have relapsed or are refractory (R/R) to autologous stem cell transplantation (ASCT) and brentuximab vedotin (BV), but median progression free survival (PFS) is only one year. The efficacy of treatment following anti-PD-1 is not well known. We retrospectively investigated the efficacy of salvage therapies for unsatisfactory response to anti-PD-1 therapy, assessed by PET-CT according to the Lugano criteria, in 30 R/R HL patients. Patients were highly pre-treated before anti-PD-1 (70% received ASCT and 93% BV). Unsatisfactory responses to anti-PD1 therapy were progressive disease (PD) (n=24) and partial response (PR) (n=6). For the 24 PD patients, median anti-PD-1 related PFS was 7.5 months (95%CI, 5.7-11.6); 17 received subsequent CT alone (Group 1) and 7 received CT in addition to anti-PD-1 (Group 2). 16/24 patients (67%) obtained an objective response. In the 15 patients treated with the same CT, twelve obtained PR or complete response (CR). In Group 1, there were 7 CR (41%), 3 PR (18%), and 7 PD (41%). In Group 2, there were 4 CR (57%), 2 PR (29%), and 1 SD (14%). No unexpected toxicity was observed. Six patients who achieved response proceeded to allogeneic SCT. With a median follow-up of 12.1 months (7-14.7), the median PFS following the initiation of CT was 11 months (95%CI, 6.3; not reached) and the median of overall survival was not reached. These observations in highly pre-treated HL patients suggest that anti-PD-1 therapy might re-sensitize tumor cells to CT. This article is protected by copyright. All rights reserved.

8.
Cancers (Basel) ; 10(5)2018 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-29783621

RESUMO

Functional imaging using 18-fluorodeoxyglycose ([18F]FDG) positron emission tomography combined with computed tomography (PET/CT) has become a major imaging modality in Hodgkin lymphoma. This imaging modality allows for a significant improvement in staging, increased sensitivity, which involves differentiating residual tumors from fibrosis during assessment, and highly impacts treatment decisions into new PET-driven strategies. This review presents the main scientific data concerning the current applications of [18F]FDG-PET/CT in Hodgkin lymphoma at baseline, interim, and the end of treatment evaluation along with the main PET-driven trials for therapeutic decisions. The emergence of total metabolic tumor volume as a new functional prognostic factor will also be discussed.

9.
Target Oncol ; 13(3): 287-308, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29556925

RESUMO

Antibody-drug conjugates (ADCs) are an emerging class of therapeutic agents that bring new opportunities for the treatment of hematological malignancies by meeting unmet medical needs. These drugs consist of a cytotoxic agent connected by a linker to a human, humanized, or chimeric antibody targeting a surface antigen specifically expressed by tumor cells. These ADCs are being developed to specifically deliver the cytotoxic agent into tumor cells. The cytotoxic payload is released from the ADC after internalization and cleavage of the linker, ultimately triggering the death of the cancer cell. Second- and even third-generation ADCs are currently being developed and have more stable linkers and more potent payloads, which should improve ADC efficacy even further. In this review, we analyze the results for the main ADCs currently developed and discuss the advantages and drawbacks of this therapeutic option.


Assuntos
Neoplasias Hematológicas/tratamento farmacológico , Imunoconjugados/uso terapêutico , Neoplasias Hematológicas/patologia , Humanos , Imunoconjugados/farmacologia
10.
Oncotarget ; 8(49): 85110-85119, 2017 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-29156707

RESUMO

Introduction: Infradiaphragmatic Hodgkin Lymphoma (IDHL) accounts for 3-11% of adult cases of stage I-II Hodgkin Lymphoma and the treatment strategy in IDHL is still heterogeneous. All previous published studies were conducted before the PET-CT era. PET may provide a more accurate evaluation of IDHL stage. The aim of this study was to analyze the clinical and biological characteristics of IDHL patients staged by CT scan or PET-CT in eight French hematology departments and their impact on outcomes in these patients. Methods: Baseline clinical and biological data and outcomes in patients with a first diagnosis of stage I-II IDHL treated with ABVD +/- radiotherapy were retrospectively collected. Results: Among the 99 patients included, 65 (66%) were staged with PET-CT. These patients were older (53 years vs 46 years, p=0.043), had lower ESR (27 vs 58mm, p=0.022), higher hemoglobin level (13.6 vs 12.8g/dL, p=0.015), less frequent Ann Arbor stage II (74% vs 91%) and less central adenopathy involvement (60% vs 82%, p=0.024). Treatment was chemotherapy alone in 55% of patients and the remaining patients received chemo-radiotherapy (CRT). Five-year PFS and OS rates in PET-CT-staged patients were 78% (95% CI 64-87) and 88% (95% CI 73-95), respectively, compared with 65% (p=0.225) and 82% (p=0.352) in CT-staged patients. The CRT strategy was associated with fewer relapses (p=0.027). Conclusion: This study showed that the characteristics of CT-staged IDHL patients were less favorable than those of PET-CT-staged patients and indicated that CRT provided better PFS than did chemotherapy alone.

11.
Front Immunol ; 8: 1347, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29098000

RESUMO

Multiple myeloma (MM) and its pre-cancerous stage monoclonal gammopathy of undetermined significance (MGUS) allow to study immune responses and the chronology of inflammation in the context of blood malignancies. Both diseases are characterized by the production of a monoclonal immunoglobulin (mc Ig) which for subsets of MGUS and MM patients targets pathogens known to cause latent infection, a major cause of inflammation. Inflammation may influence the structure of both polyclonal (pc) Ig and mc Ig produced by malignant plasma cells via the sialylation of Ig Fc fragment. Here, we characterized the sialylation of purified mc and pc IgGs from 148 MGUS and MM patients, in comparison to pc IgGs from 46 healthy volunteers. The inflammatory state of patients was assessed by the quantification in serum of 40 inflammation-linked cytokines, using Luminex technology. While pc IgGs from MGUS and MM patients showed heterogeneity in sialylation level, mc IgGs from both MGUS and MM patients exhibited a very low level of sialylation. Furthermore, mc IgGs from MM patients were less sialylated than mc IgGs from MGUS patients (p < 0.01), and mc IgGs found to target an infectious pathogen showed a lower level of sialylation than mc IgGs of undetermined specificity (p = 0.048). Regarding inflammation, 14 cytokines were similarly elevated with a p value < 0.0001 in MGUS and in MM compared to healthy controls. MM differed from MGUS by higher levels of HGF, IL-11, RANTES and SDF-1-α (p < 0.05). MGUS and MM patients presenting with hyposialylated pc IgGs had significantly higher levels of HGF, IL-6, tumor necrosis factor-α, TGF-ß1, IL-17, and IL-33 compared to patients with hyper-sialylated pc IgGs (p < 0.05). In MGUS and in MM, the degree of sialylation of mc and pc IgGs and the levels of four cytokines important for the anti-microbial response were correlated, either positively (IFN-α2, IL-13) or negatively (IL-17, IL-33). Thus in MGUS as in MM, hyposialylation of mc IgGs is concomitant with increased levels of cytokines that play a major role in inflammation and anti-microbial response, which implies that infection, inflammation, and abnormal immune response contribute to the pathogenesis of MGUS and MM.

12.
JCI Insight ; 2(19)2017 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-28978808

RESUMO

Subsets of mature B cell neoplasms are linked to infection with intracellular pathogens such as Epstein-Barr virus (EBV), hepatitis C virus (HCV), or Helicobacter pylori. However, the association between infection and the immunoglobulin-secreting (Ig-secreting) B proliferative disorders remains largely unresolved. We investigated whether the monoclonal IgG (mc IgG) produced by patients diagnosed with monoclonal gammopathy of undetermined significance (MGUS) or multiple myeloma (MM) targets infectious pathogens. Antigen specificity of purified mc IgG from a large patient cohort (n = 244) was determined using a multiplex infectious-antigen array (MIAA), which screens for reactivity to purified antigens or lysates from 9 pathogens. Purified mc IgG from 23.4% of patients (57 of 244) specifically recognized 1 pathogen in the MIAA. EBV was the most frequent target (15.6%), with 36 of 38 mc IgGs recognizing EBV nuclear antigen-1 (EBNA-1). MM patients with EBNA-1-specific mc IgG (14.0%) showed substantially greater bone marrow plasma cell infiltration and higher ß2-microglobulin and inflammation/infection-linked cytokine levels compared with other smoldering myeloma/MM patients. Five other pathogens were the targets of mc IgG: herpes virus simplex-1 (2.9%), varicella zoster virus (1.6%), cytomegalovirus (0.8%), hepatitis C virus (1.2%), and H. pylori (1.2%). We conclude that a dysregulated immune response to infection may underlie disease onset and/or progression of MGUS and MM for subsets of patients.


Assuntos
Anticorpos Antivirais/sangue , Imunoglobulina G/sangue , Gamopatia Monoclonal de Significância Indeterminada/imunologia , Mieloma Múltiplo/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Epitopos/imunologia , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/imunologia , Antígenos Nucleares do Vírus Epstein-Barr/imunologia , Feminino , Infecções por Helicobacter/complicações , Infecções por Helicobacter/imunologia , Helicobacter pylori/imunologia , Herpes Simples/complicações , Herpes Simples/imunologia , Herpesvirus Humano 1/imunologia , Herpesvirus Humano 4/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Gamopatia Monoclonal de Significância Indeterminada/microbiologia , Mieloma Múltiplo/microbiologia , Viroses/complicações , Viroses/imunologia , Adulto Jovem
13.
Oncotarget ; 8(27): 44960-44975, 2017 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-28402953

RESUMO

Immune checkpoint blockade therapeutics, notably antibodies targeting the programmed death 1 (PD-1) receptor and its PD-L1 and PD-L2 ligands, are currently revolutionizing the treatment of cancer. For a sizeable fraction of patients with melanoma, lung, kidney and several other solid cancers, monoclonal antibodies that neutralize the interactions of the PD-1/PD-L1 complex allow the reconstitution of long-lasting antitumor immunity. In hematological malignancies this novel therapeutic strategy is far less documented, although promising clinical responses have been seen in refractory and relapsed Hodgkin lymphoma patients. This review describes our current knowledge of PD-1 and PD-L1 expression, as reported by immunohistochemical staining in both non-Hodgkin lymphoma cells and their surrounding immune cells. Here, we discuss the multiple intrinsic and extrinsic mechanisms by which both T and B cell lymphomas up-regulate the PD-1/PD-L1 axis, and review current knowledge about the prognostic significance of its immunohistochemical detection. This body of literature establishes the cell surface expression of PD-1/PD-L1 as a critical determinant for the identification of non-Hodgkin lymphoma patients eligible for immune checkpoint blockade therapies.


Assuntos
Antígeno B7-H1/metabolismo , Biomarcadores Tumorais , Linfoma não Hodgkin/metabolismo , Linfoma não Hodgkin/mortalidade , Receptor de Morte Celular Programada 1/metabolismo , Animais , Antígeno B7-H1/genética , Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Linfoma não Hodgkin/diagnóstico , Linfoma não Hodgkin/terapia , Terapia de Alvo Molecular , Prognóstico , Receptor de Morte Celular Programada 1/genética , Transdução de Sinais
14.
Bull Cancer ; 104(2): 182-194, 2017 Feb.
Artigo em Francês | MEDLINE | ID: mdl-28088309

RESUMO

Classical Hodgkin lymphoma (HL) is a curable disease in 80% of advanced and 90% of localized stages. An improvement of the HL curability is still possible with the emergence of first-line therapy with a better balance between efficacy and toxicity and early identification patients with high risk of failure requiring specific treatment. 18FDG PET-CT gained a major role in the baseline staging and response assessment to HL treatment. The prognostic value of early PET-CT allowed to develop PET-CT guided therapies able to optimize the balance between efficacy and toxicity including the modulation of the chemotherapy intensity or the omission of radiotherapy for some localized diseases. New drugs emerged in the treatment of relapse or refractory HL (brentuximab vedotine [BV], immunological checkpoint inhibitor anti-PD1). Although their place in the strategies of salvage therapy is still debated several trials have reported relevant efficacy in some unmet medical need: refractory patients or relapses after auto/allograft. This review addresses the questions of PET-CT-based therapeutic strategies in first-line and the impact of new drugs targeting the micro-environment (anti-PD1) or the Hodgkin Reed Sternberg cells (BV).


Assuntos
Antineoplásicos/uso terapêutico , Doença de Hodgkin/tratamento farmacológico , Anticorpos Monoclonais/uso terapêutico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Fluordesoxiglucose F18 , Doença de Hodgkin/diagnóstico por imagem , Doença de Hodgkin/patologia , Doença de Hodgkin/radioterapia , Humanos , Imunoconjugados/uso terapêutico , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Prognóstico , Inibidores de Proteínas Quinases/uso terapêutico , Compostos Radiofarmacêuticos , Recidiva , Células de Reed-Sternberg , Terapia de Salvação , Microambiente Tumoral
15.
Oncotarget ; 7(51): 85573-85583, 2016 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-27458168

RESUMO

Peripheral T-cell lymphoma (PTCL) is a group of diseases with poor outcome and few therapeutic options. We aimed to assess the efficacy of bendamustine in real life cohort of patients.Between November 2009 and March 2015, 138 PTCL patients were treated with bendamustine in 27 centers. Population median age was 64 (28-89) years with male/female ratio of 1.4. There were mainly angio-immunoblastic (AITL = 71), PTCL-not otherwise specified (PTCL-NOS = 40) and anaplastic large cell lymphoma (ALCL = 8). The majority of patients (96%) had disseminated disease and extranodal localizations (77%). Median number of chemotherapy lines prior to bendamustine was 2 (1-8). Median duration of response (DoR) after the last chemotherapy prior to bendamustine was 4.3 months (1-70) and 50% of patients had refractory disease.Median number of administered bendamustine cycles was 2 (1-8) and 72 patients (52%) received less than 3 mostly because of disease progression. Median dose was 90 (50-150) mg/m². Overall response rate (ORR) was 32.6% with complete response (CR) rate of 24.6% and median DoR was 3.3 months (1-39). AITL patients were more sensitive than PTCL-NOS patients (ORR: 45.1 versus 20%, p = 0.01). Median PFS and OS were 3.1 (0.2-46.3) and 4.4 (0.2-55.4) months. On multivariate analysis, refractory disease (p = 0.001) and extranodal localization (p = 0.028) adversely influenced ORR. Grade 3-4 thrombocytopenia, neutropenia and infections were reported in 22, 17 and 23% of cases respectively.Bendamustine as single agent could be considered as a therapeutic option for relapsed or refractory PTCL, particularly in chemosensitive or AITL patients. Combinations of bendamustine with other drugs warrant further evaluation.


Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Cloridrato de Bendamustina/administração & dosagem , Linfoma de Células T Periférico/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Alquilantes/efeitos adversos , Cloridrato de Bendamustina/efeitos adversos , Progressão da Doença , Intervalo Livre de Doença , Esquema de Medicação , Resistencia a Medicamentos Antineoplásicos , Feminino , França , Humanos , Estimativa de Kaplan-Meier , Modelos Logísticos , Metástase Linfática , Linfoma de Células T Periférico/mortalidade , Linfoma de Células T Periférico/patologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Modelos de Riscos Proporcionais , Recidiva , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento
16.
Biochem Med (Zagreb) ; 26(2): 255-9, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27346972

RESUMO

INTRODUCTION: Major hyperferritinemia is a rare feature in clinical laboratories associated with a wide variety of disorders, including hemophagocytic lymphohistiocytosis (HLH). The diagnosis of HLH is based on clinical and biological criteria, such as those proposed by the Histiocyte Society. However, several of these criteria are not relevant in the specific setting of hematologic malignancies. MATERIALS AND METHODS: A 69-year-old male was treated for an acute myeloid leukaemia. On day 15 after the start of chemotherapy, he developed severe sepsis with high fever, low blood pressure and hepatosplenomegaly. RESULTS: Blood tests were marked by extreme hyperferritinemia (191,000 µg/L, reference range: 26-388 µg/L) with increased C-reactive protein (87.0 mg/L) and procalcitonin (1.94 µg/L) and aspartate aminotransferase (499 U/L 37 °C) in the setting of chemotherapy-induced aplasia. This unusual extreme ferritinemia led to suspect HLH triggered by an invasive infection. Under intensive treatment, the clinical status improved and ferritin levels significantly decreased. CONCLUSIONS: The diagnosis of HLH is usually based on clinical and biological criteria, mainly fever, splenomegaly, cytopenias, hypertriglyceridemia, hypofibrinogenemia, hemophagocytosis and hyperferritinemia. In this patient, the diagnosis of HLH was challenging because several criteria, such as hypertriglyceridemia, hemophagocytosis and hypofibrinogenemia, were absent. In addition, some criteria of HLH are not relevant in the setting of hematologic malignancy, in which fever, splenomegaly, cytopenias and elevated lactate dehydrogenase are commonly observed independently of HLH. This unusual case of extremely high ferritinemia emphasizes the important weight of the ferritin level for the diagnosis of HLH in adult patients in the setting of hematologic malignancies.


Assuntos
Ferritinas/sangue , Leucemia Mieloide Aguda/sangue , Linfo-Histiocitose Hemofagocítica/sangue , Sepse/fisiopatologia , Idoso , Humanos , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/fisiopatologia , Linfo-Histiocitose Hemofagocítica/etiologia , Linfo-Histiocitose Hemofagocítica/patologia , Masculino , Sepse/sangue , Sepse/induzido quimicamente
17.
PLoS One ; 10(10): e0140830, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26473950

RESUMO

AIM: To investigate the respective influence of software tool and total metabolic tumor volume (TMTV0) calculation method on prognostic stratification of baseline 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography ([18F]FDG-PET) in newly diagnosed Hodgkin lymphoma (HL). METHODS: 59 patients with newly diagnosed HL were retrospectively included. [18F]FDG-PET was performed before any treatment. Four sets of TMTV0 were calculated with Beth Israel (BI) software: based on an absolute threshold selecting voxel with standardized uptake value (SUV) >2.5 (TMTV02.5), applying a per-lesion threshold of 41% of the SUV max (TMTV041) and using a per-patient adapted threshold based on SUV max of the liver (>125% and >140% of SUV max of the liver background; TMTV0125 and TMTV0140). TMTV041 was also determined with commercial software for comparison of software tools. ROC curves were used to determine the optimal threshold for each TMTV0 to predict treatment failure. RESULTS: Median follow-up was 39 months. There was an excellent correlation between TMTV041 determined with BI and with the commercial software (r = 0.96, p<0.0001). The median TMTV0 value for TMTV041, TMTV02.5, TMTV0125 and TMTV0140 were respectively 160 (used as reference), 210 ([28;154] p = 0.005), 183 ([-4;114] p = 0.06) and 143 ml ([-58;64] p = 0.9). The respective optimal TMTV0 threshold and area under curve (AUC) for prediction of progression free survival (PFS) were respectively: 313 ml and 0.70, 432 ml and 0.68, 450 ml and 0.68, 330 ml and 0.68. There was no significant difference between ROC curves. High TMTV0 value was predictive of poor PFS in all methodologies: 4-years PFS was 83% vs 42% (p = 0.006) for TMTV02.5, 83% vs 41% (p = 0.003) for TMTV041, 85% vs 40% (p<0.001) for TMTV0125 and 83% vs 42% (p = 0.004) for TMTV0140. CONCLUSION: In newly diagnosed HL, baseline metabolic tumor volume values were significantly influenced by the choice of the method used for determination of volume. However, no significant differences were found in term of prognosis.


Assuntos
Glucose-6-Fosfato/análogos & derivados , Doença de Hodgkin , Processamento de Imagem Assistida por Computador/métodos , Tomografia por Emissão de Pósitrons , Software , Adolescente , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Seguimentos , Glucose-6-Fosfato/administração & dosagem , Doença de Hodgkin/diagnóstico por imagem , Doença de Hodgkin/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Radiografia , Taxa de Sobrevida
19.
Haematologica ; 100(4): 472-8, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25637056

RESUMO

Although numerous recent publications have demonstrated interest in multiparameter flow cytometry in the investigation of myelodysplastic disorders, it is perceived by many laboratory hematologists as difficult and expensive, requiring a high level of expertise. We report a multicentric open real-life study aimed at evaluating the added value of the technically simple flow cytometry score described by the Ogata group for the diagnosis of myelodysplastic syndromes. A total of 652 patients were recruited prospectively in four different centers: 346 myelodysplastic syndromes, 53 myelodysplastic/myeloproliferative neoplasms, and 253 controls. The Ogata score was assessed using CD45 and CD34 staining, with the addition of CD10 and CD19. Moreover, labeling of CD5, CD7 and CD56 for the evaluation of myeloid progenitors and monocytes was tested on a subset of 294 patients. On the whole series, the specificity of Ogata score reached 89%. Respective sensitivities were 54% for low-risk myelodysplastic syndromes, 68% and 84% for type 1 and type 2 refractory anemia with excess of blasts, and 72% for myelodysplastic/myeloproliferative neoplasms. CD5 expression was poorly informative. When adding CD56 or CD7 labeling to the Ogata score, sensitivity rose to 66% for low-risk myelodysplastic syndromes, to 89% for myelodysplastic/myeloproliferative neoplasms and to 97% for refractory anemia with excess of blasts. This large multicenter study confirms the feasibility of Ogata scoring in routine flow cytometry diagnosis but highlights its poor sensitivity in low-risk myelodysplastic syndromes. The addition of CD7 and CD56 in flow cytometry panels improves the sensitivity but more sophisticated panels would be more informative.


Assuntos
Antígenos CD7/metabolismo , Antígenos CD5/metabolismo , Antígeno CD56/metabolismo , Imunofenotipagem , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/metabolismo , Doenças Mieloproliferativas-Mielodisplásicas/diagnóstico , Doenças Mieloproliferativas-Mielodisplásicas/metabolismo , Idoso , Idoso de 80 Anos ou mais , Antígenos CD7/genética , Antígenos CD5/genética , Antígeno CD56/genética , Diagnóstico Diferencial , Citometria de Fluxo , Expressão Gênica , Humanos , Imunofenotipagem/métodos , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/genética , Doenças Mieloproliferativas-Mielodisplásicas/genética , Sensibilidade e Especificidade
20.
Leuk Lymphoma ; 56(10): 2876-82, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25641432

RESUMO

Non-Hodgkin lymphoma (NHL) represents a heterogeneous group of diseases that are known to carry a considerable risk of second primary cancer (SPC). However, little attention has been paid to SPC risk assessment according to NHL subtypes. Data from 10 French population-based cancer registries were used to establish a cohort of 7546 patients with a first diagnosis of NHL (eight subtypes) between 1989 and 2004. Standardized incidence ratios (SIRs) of metachronous SPC were estimated. Among the 7546 patients diagnosed with a NHL, the overall SPC risk was 25% higher than that in the reference population (SIR = 1.25, 95% confidence interval 1.15-1.36). In univariate analysis, the SPC risk differed by lymphoma subtype. Interestingly, multivariate analysis showed that SPC risk did not differ significantly across NHL subtypes after adjustment for the other covariates (p = 0.786). Patients with NHL have an increased risk of SPC that is not influenced by the histological NHL subtype.


Assuntos
Linfoma não Hodgkin/epidemiologia , Linfoma não Hodgkin/patologia , Segunda Neoplasia Primária/epidemiologia , Segunda Neoplasia Primária/etiologia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Seguimentos , França/epidemiologia , Humanos , Incidência , Lactente , Recém-Nascido , Linfoma não Hodgkin/diagnóstico , Masculino , Pessoa de Meia-Idade , Segunda Neoplasia Primária/diagnóstico , Vigilância da População , Sistema de Registros , Medição de Risco , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA