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1.
Ann Hematol ; 99(3): 477-486, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31965270

RESUMO

Genetic and morphological markers are well-established prognostic factors in acute myeloid leukemia (AML). However, further reliable markers are urgently needed to improve risk stratification in AML. CD318 (CDCP1) is a transmembrane protein which in solid tumors promotes formation of metastasis and correlates with poor survival. Despite its broad expression on hematological precursor cells, its prognostic significance in hematological malignancies so far remains unclear. Here, we evaluated the role of CD318 as novel prognostic marker in AML by immunophenotyping of leukemic blasts. Flow cytometric evaluation of CD318 on leukemic cells in 70 AML patients revealed a substantial expression in 40/70 (57%) of all cases. CD318 surface levels were significantly correlated with overall survival in patients receiving anthracycline-based induction therapy or best available alternative therapy. Using receiver-operating characteristics, we established a cut-off value to define CD318lo and CD318hi expression in both cohorts. Notably, high CD318 expression correlated inversely as prognostic marker in both treatment cohorts: as poor prognostic marker in patients receiving intense therapy, whereas upon palliative care it correlated with better outcome. In conclusion, FACS-based determination of CD318 expression may serve as novel prognostic factor depending on implemented therapy in AML patients.


Assuntos
Antígenos de Neoplasias/sangue , Biomarcadores Tumorais/sangue , Crise Blástica , Moléculas de Adesão Celular/sangue , Regulação Leucêmica da Expressão Gênica , Leucemia Mieloide Aguda , Adulto , Idoso , Idoso de 80 Anos ou mais , Crise Blástica/sangue , Crise Blástica/mortalidade , Crise Blástica/patologia , Intervalo Livre de Doença , Feminino , Humanos , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida
2.
Eur J Haematol ; 104(1): 26-35, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31541609

RESUMO

BACKGROUND AND OBJECTIVES: In patients with multiple myeloma (MM), unexpected bleeding complications remain a major issue. Since routine coagulation parameters are often inconspicuous, diagnosis and treatment of the underlying coagulation disorders are challenging. PATIENTS AND METHODS: In our single-center observational study, we analyzed 164 patients with MM for coagulation disorders and bleeding complications. RESULTS: Prolonged closure times (CTs), measured by PFA-100, were the most common, abnormal coagulation test, found in 66% of bleeding patients vs 5% in non-bleeding, followed by qualitative defects of von Willebrand factor (VWF:CB/VWF:Ag ratios), found in 34% vs 1% in the non-bleeding group. Increased serum free light chains (SFLC) and SFLC ratios were significantly associated with prolonged CTs and acquired von Willebrand syndrome (AVWS). Prolonged CTs and AVWS were associated with disease progression, determined by dynamics of SFLC ratios (P < .001), serum creatinine level (P = .013), Beta-2 microglobulin (P = .03), LDH (P = .016), and bone marrow infiltration (P < .001). Of note, response to myeloma therapy was frequently correlated with normalization of coagulation parameters. CONCLUSIONS: Bleeding complications in MM are predominantly caused by defects in primary hemostasis and associated with disease progression. In a peri-interventional workup, determination of CTs and VWF:CB/VWF:Ag ratios are of significant importance to assess bleeding risk.

3.
Sci Rep ; 9(1): 18337, 2019 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-31797971

RESUMO

While several genetic and morphological markers are established and serve to guide therapy of acute myeloid leukaemia (AML), there is still profound need to identify additional markers to better stratify patients. CD105 (Endoglin) is a type I transmembrane protein reported to induce activation and proliferation of endothelial cells. In addition, CD105 is expressed in haematological malignancies and the vessels of solid tumours. Here, CD105 associates with unfavourable disease course, but so far no data are available on the prognostic relevance of CD105 in haematological malignancies. We here generated a novel CD105 antibody for analysis of expression and prognostic relevance of CD105 in a cohort of 62 AML patients. Flow cytometric analysis revealed substantial expression in the various AML FAB types, with FAB M3 type displaying significantly lower surface levels. Next we established a cut-off specific fluorescence level of 5.22 using receiver-operating characteristics, which allowed to group patients in cases with CD105lo and CD105hi surface expression and revealed that high CD105 expression correlated significantly with poor overall and progression free survival. In conclusion, we here identify CD105 expression as a novel prognostic marker in AML, which may serve to optimize follow up and treatment decisions for AML patients.

4.
Arthritis Res Ther ; 21(1): 212, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31615552

RESUMO

BACKGROUND: Systemic sclerosis (SSc) is a potentially fatal autoimmune disease that leads to extensive fibrosis of the skin and internal organs. Invariant natural killer T (iNKT) cells are potent immunoregulatory T lymphocytes being able to orchestrate dysregulated immune responses. The purpose of this study was to evaluate numbers and function of iNKT cells in patients with SSc and to analyze their correlation with disease parameters. METHODS: Human iNKT cells from 88 patients with SSc and 33 healthy controls were analyzed by flow cytometry. Their proliferative capacity and cytokine production were investigated following activation with CD1d ligand α-galactosylceramide (α-GalCer). RESULTS: We observed an absolute and relative decrease of iNKT cells in patients with SSc compared with healthy controls. Interestingly, the subtype of SSc, disease severity, or treatment with immunosuppressive drugs did not affect iNKT cell numbers. However, T helper (Th) cell immune polarization was biased towards a Th17 immunophenotype in SSc patients. Moreover, iNKT cells from patients with SSc showed a significantly decreased expansion capacity upon stimulation with α-GalCer. CONCLUSION: iNKT cells are deficient and functionally impaired in patients with SSc. Therefore, adoptive transfer strategies using culture-expanded iNKT cells could be a novel approach to treat SSc patients.

5.
Eur J Radiol ; 116: 98-105, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31153581

RESUMO

PURPOSE: Identification of prognostic CT-textural features in patients with gastrointestinal stromal tumors undergoing tyrosine kinase inhibitor (TKI) therapy. METHODS AND MATERIALS: We identified 25 GIST patients (mean age, 70.58 ± 9.7 years; range, 41.25-84.08 years; 20 males, 5 females) with a total of 123 scans, each examined with a standardized CT protocol between 1/2014-7/2018. 92 texture features, based on pyradiomics library, were extracted and correlated to response categories; evaluated with help of modified Choi criteria. All patients underwent therapy with imatinib in the first line and different tyrosine kinase inhibitors after disease progression. KIT and PDGFR-mutations were registered in all patients as well as the number of previous treatment regimens, patient's age as well as gender and the presence of contrast enhancement (vitality) in tumor. The lesion with the largest diameter was chosen and contoured using the spherical VOI tool. Inter-rater testing was performed by a second experienced radiologist. Regression and AUC analysis was performed. RESULTS: Ten variables could be confirmed to be significantly associated with disease progression. Of them, four textural parameters were significantly positively associated with disease progression and negatively with progression free survival (Glcm Id [grey-level co-occurrence matrix inverse difference], p = 0.012, HR 3.83; 95% CI 1.697-8.611, Glcm Idn [grey-level co-occurrence matrix inverse difference normalized], p = 0.045, HR 2.06, 95% CI 1.015-4.185, Glrlm [grey-level run length matrix] normalized, p = 0.005, HR 3.181; 95% CI 1.418-7.138 and Ngtdm [neighboring grey-tone difference matrix] coarseness, p < 0.001, HR 3.156, 95% CI 1.554-6.411). Single variables were shown to be significantly inferior to the combination of all variables. After 6 months, 90% of patients with 0-1 risk factors (group 1), 64.4% with 2-3 risk variables and 38.1% of patients presenting > 3 structural risk variables showed stable disease. Gclm Id, Gclm Idn and Glrlm non-uniformity were associated with the number of previous treatments, Glrlm non-uniformity also with tumor vitality (enhancement), whereas Gclm Idn and Ngtdm coarseness were associated with the number of tumor mutations. CONCLUSION: Some of the CT-textural features correlate with disease progression and the progressive free survival as well as with the number of gene mutations and the number of treatment regimens the patients were exposed to as well as with the tumor enhancement. All these features reflect tumor homogeneity.


Assuntos
Neoplasias Gastrointestinais/diagnóstico por imagem , Neoplasias Gastrointestinais/tratamento farmacológico , Tumores do Estroma Gastrointestinal/diagnóstico por imagem , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Tomografia Computadorizada por Raios X/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/patologia , Trato Gastrointestinal/diagnóstico por imagem , Trato Gastrointestinal/patologia , Humanos , Mesilato de Imatinib/uso terapêutico , Masculino , Pessoa de Meia-Idade , Prognóstico , Resultado do Tratamento
6.
Cancers (Basel) ; 11(3)2019 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-30813611

RESUMO

NK cells play an important role in tumor immunosurveillance. Their reactivity is governed by various activating and inhibitory surface receptors, which include several members of the TNF/TNF receptor family. For more than 50 years, it has been recognized that tumor immunosurveillance and in particular NK cell antitumor reactivity is largely influenced by platelets, but the underlying mechanisms remain to be fully elucidated. Here we report that upon activation, which reportedly occurs following interaction with cancer cells, platelets upregulate the TNF family member RANKL. Comparative analysis of the expression of RANK among different NK cell subsets and RANKL on platelets in cancer patients and healthy volunteers revealed a distinct malignant phenotype, and platelet-derived RANKL was found to inhibit the activity of normal NK cells against cancer cells. Notably, NK cell antitumor reactivity could be partially restored by application of denosumab, a RANKL-neutralizing antibody approved for treatment of benign and malignant osteolysis. Together, our data not only unravel a novel mechanism of tumor immune evasion mediated by platelets, but they also provide a functional explanation for the clinical observation that denosumab, beyond protecting from bone loss, may prolong disease-free survival in patients with solid tumors.

7.
Eur Radiol ; 29(1): 450-457, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29915885

RESUMO

OBJECTIVES: We aimed to test the hypothesis that the spleen-to-liver-attenuation ratio on portal-venous enhancement phase CT images can identify diffuse splenic infiltration in subjects with lymphoma. METHODS: A database search yielded 70 subjects with malignant haematological diseases who underwent contrast-enhanced CT (CECT) between December 2010 and March 2018. Additionally, consecutive control subjects were evaluated. We compared the splenic volume, splenic attenuation, spleen-to-liver, spleen-to-aorta and spleen-to-musculature ratios on portal-venous phase CECT images, pre- to post-treatment and between the different lymphoma entities. The standard of reference for splenic involvement was normalisation of the spleen volume following chemotherapy or normalisation of FDG-uptake. RESULTS: In subjects with diffuse splenic involvement, the spleen attenuation was significantly lower before treatment (93.48 HU) compared to controls (112.39 HU; p < .01) and after successful treatment (113.39 HU; p < .01). The spleen-to-liver attenuation ratio significantly increased after treatment (p < .001) and proved significantly lower at baseline when compared to control subjects (p < .01). The spleen volume significantly decreased after successful treatment (from 586.14.87 cm3 to 284.90 cm3; p < .001). Spleen-to-liver ratio significantly increased in lymphoma patients after therapy, inversely correlating with the decline in FDG-uptake (n=10) even in patients with normal-sized spleens (2/10), staying unchanged at follow-up. The outcome variables were not significantly different between the lymphoma subtypes. CONCLUSIONS: We suggest the additional use of spleen-to-liver attenuation ratio to splenic volume alone for detection of diffuse splenic infiltration in subjects with lymphoma. The course of spleen-to-liver attenuation ratio inversely correlated with that of FDG-uptake in a subgroup of patients working accurately in normal-sized diffusely involved spleens. KEY POINTS: • Involvement of the spleen is frequent in haematological malignancies and is important for staging and appropriate treatment. • Diffuse splenic infiltration often results in only homogeneous splenomegaly without a focal lesion, but even no or only minimal increase in splenic volume is possible. In these cases diagnosis of spleen involvement is a challenge for the radiologist. • Our data support the use of the spleen-to-liver attenuation ratio in addition to size measurements for the detection of diffuse splenic infiltration in subjects with lymphoma.


Assuntos
Meios de Contraste/farmacologia , Neoplasias Hematológicas/diagnóstico , Baço/diagnóstico por imagem , Neoplasias Esplênicas/diagnóstico , Tomografia Computadorizada por Raios X/métodos , Adulto , Idoso , Feminino , Humanos , Fígado , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Reprodutibilidade dos Testes
9.
J Vis Exp ; (142)2018 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-30582586

RESUMO

Chronic lymphocytic leukemia (CLL) is characterized by the expansion of malignant B cell clones and represents the most common leukemia in western countries. The majority of CLL patients show an indolent course of the disease as well as an anergic phenotype of their leukemia cells, referring to a B cell receptor unresponsive to external stimulation. We have recently shown that the transcription factor NFAT2 is a crucial regulator of anergy in CLL. A major challenge in the analysis of the role of a transcription factor in different diseases is the identification of its specific target genes. This is of great significance for the elucidation of pathogenetic mechanisms and potential therapeutic interventions. Chromatin immunoprecipitation (ChIP) is a classic technique to demonstrate protein-DNA interactions and can, therefore, be used to identify direct target genes of transcription factors in mammalian cells. Here, ChIP was used to identify LCK as a direct target gene of NFAT2 in human CLL cells. DNA and associated proteins are crosslinked using formaldehyde and subsequently sheared by sonication into DNA fragments of approximately 200-500 base pairs (bp). Cross-linked DNA fragments associated with NFAT2 are then selectively immunoprecipitated from cell debris using an αNFAT2 antibody. After purification, associated DNA fragments are detected via quantitative real-time PCR (qRT-PCR). DNA sequences with evident enrichment represent regions of the genome which are targeted by NFAT2 in vivo. Appropriate shearing of the DNA and the selection of the required antibody are particularly crucial for the successful application of this method. This protocol is ideal for the demonstration of direct interactions of NFAT2 with target genes. Its major limitation is the difficulty to employ ChIP in large-scale assays analyzing the target genes of multiple transcription factors in intact organisms.


Assuntos
Imunoprecipitação da Cromatina/métodos , Leucemia Linfocítica Crônica de Células B/metabolismo , Fatores de Transcrição NFATC/genética , Fatores de Transcrição NFATC/metabolismo , Humanos , Leucemia Linfocítica Crônica de Células B/genética
10.
PLoS One ; 13(6): e0197544, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29874250

RESUMO

OBJECTIVES: The aim of this multicenter retrospective study was to investigate safety and efficacy of direct acting antiviral (DAA) treatment in the rare subgroup of patients with HCV/HIV-coinfection and advanced liver cirrhosis on the liver transplant waiting list or after liver transplantation, respectively. METHODS: When contacting 54 German liver centers (including all 23 German liver transplant centers), 12 HCV/HIV-coinfected patients on antiretroviral combination therapy were reported having received additional DAA therapy while being on the waiting list for liver transplantation (patient characteristics: Child-Pugh A (n = 6), B (n = 5), C (n = 1); MELD range 7-21; HCC (n = 2); HCV genotype 1a (n = 8), 1b (n = 2), 4 (n = 2)). Furthermore, 2 HCV/HIV-coinfected patients were denoted having received DAA therapy after liver transplantation (characteristics: HCV genotype 1a (n = 1), 4 (n = 1)). RESULTS: Applied DAA regimens were SOF/DAC (n = 7), SOF/LDV/RBV (n = 3), SOF/RBV (n = 3), PTV/r/OBV/DSV (n = 1), or PTV/r/OBV/DSV/RBV (n = 1), respectively. All patients achieved SVR 12, in the end. In one patient, HCV relapse occurred after 24 weeks of SOF/DAC therapy; subsequent treatment with 12 weeks PTV/r/OBV/DSV achieved SVR 12. One patient underwent liver transplantation while on DAA treatment. Analysis of liver function revealed either stable parameters or even significant improvement during DAA therapy and in follow-up. MELD scores were found to improve in 9/13 therapies in patients on the waiting list for liver transplantation; in only 2 patients a moderate increase of MELD scores persisted at the end of follow-up. CONCLUSION: DAA treatment was safe and highly effective in this nation-wide cohort of patients with HCV/HIV-coinfection awaiting liver transplantation or being transplanted.


Assuntos
Coinfecção/tratamento farmacológico , Infecções por HIV/tratamento farmacológico , Hepatite C/tratamento farmacológico , Transplante de Fígado , Adulto , Terapia Antirretroviral de Alta Atividade , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Coinfecção/patologia , Coinfecção/virologia , Quimioterapia Combinada , Feminino , Alemanha , Infecções por HIV/patologia , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/patogenicidade , Hepacivirus/efeitos dos fármacos , Hepacivirus/patogenicidade , Hepatite C/patologia , Hepatite C/virologia , Humanos , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/patologia , Cirrose Hepática/virologia , Masculino , Pessoa de Meia-Idade , Ribavirina/administração & dosagem , Ritonavir/administração & dosagem , Sofosbuvir/administração & dosagem , Resultado do Tratamento
11.
Dtsch Med Wochenschr ; 143(5): 334-342, 2018 Mar.
Artigo em Alemão | MEDLINE | ID: mdl-29506300

RESUMO

More and more follow-up care gets important in the treatment of oncological patients. In addition to detection of recurrent and secondary diseases, the focus should be put particularly on identifying and medicating sequelae associated with therapy. Anamnesis and clinical examination remain at the centre of follow-up treatment. Further contents of follow-up care are based on the disease situation, previous therapies and individual risk factors. For most entities there is no recommendation for routine radiological diagnosis in asymptomatic patients. However, imaging measures are indicated especially when symptoms require clarification. The increasing rate of oral long-term and permanent therapies implies new tasks in after-care. Here, potential side effects have to be registered specifically. Furthermore, treatment success should be monitored regularly.


Assuntos
Assistência ao Convalescente , Neoplasias/terapia , Neoplasias Hematológicas/terapia , Humanos , Guias de Prática Clínica como Assunto
12.
Oncoimmunology ; 7(2): e1364827, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29308299

RESUMO

Platelets promote metastasis, among others by coating cancer cells traveling through the blood, which results in protection from NK cell immune-surveillance. The underlying mechanisms, however, remain to be fully elucidated. Here we report that platelet-coating reduces surface expression of NKG2D ligands, in particular MICA and MICB, on tumor cells, which was mirrored by enhanced release of their soluble ectodomains. Similar results were obtained upon exposure of tumor cells to platelet-releasate and can be attributed to the sheddases ADAM10 and ADAM17 that are detectable on the platelet surface and in releasate following activation and at higher levels on platelets of patients with metastasized lung cancer compared with healthy controls. Platelet-mediated NKG2DL-shedding in turn resulted in impaired "induced self" recognition by NK cells as revealed by diminished NKG2D-dependent lysis of tumor cells. Our results indicate that platelet-mediated NKG2DL-shedding may be involved in immune-evasion of (metastasizing) tumor cells from NK cell reactivity.

13.
Eur J Haematol ; 100(5): 403-411, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29360177

RESUMO

BACKGROUND AND OBJECTIVES: Protein Z (PZ) deficiency has been implicated both in bleeding diatheses and in thrombophilia. Considering its ambiguous nature and the conflicting clinical data so far, we set out to evaluate the impact of low PZ on perioperative bleeding in patients who underwent surgical (ENT) interventions involving a high risk of bleeding. PATIENTS AND METHODS: After exclusion of other coagulation disorders, 154 Patients were stratified into quartiles according to PZ plasma concentrations to evaluate the relation between PZ and bleeding complications. RESULTS: Low PZ levels were associated with increased blood loss (P < .001), increased need for blood transfusions (P < .001), and a higher rate of surgical revisions (P = .009) in a concentration-dependent fashion. Low PZ caused earlier (within 24 hours) and repetitive bleedings (P = .005). The number of major bleeding episodes was significantly increased when low PZ was combined with bleeding history (P < .05). Finally, ROC analyses confirmed the predictive value of low PZ for bleeding complications and PZ-thresholds for clinical practice were determined. CONCLUSIONS: Low PZ appears to be an underestimated risk factor for perioperative bleeding. Determination of PZ plasma concentrations might be useful in the preoperative workup in patients with a bleeding history, when detailed clotting analyses remain inconclusive.


Assuntos
Proteínas Sanguíneas , Hemorragia/sangue , Hemorragia/etiologia , Período Perioperatório , Procedimentos Cirúrgicos Operatórios/efeitos adversos , Adolescente , Adulto , Variação Biológica da População , Biomarcadores , Coagulação Sanguínea , Perda Sanguínea Cirúrgica , Criança , Feminino , Hemorragia/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Curva ROC , Reprodutibilidade dos Testes , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Procedimentos Cirúrgicos Operatórios/métodos , Adulto Jovem
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