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OBJECTIVE: To compare structural findings between US, micro-CT (µCT) and histology in people with OA of the hands. METHODS: We analysed DIP and PIP joints of 31 fingers from 15 dissecting-room cadavers with OA of the hands. The occurrence of bone erosions and osteophytes were recorded by US, µCT and histology at 16 regions for each joint and compared for each method. RESULTS: In total, US (n = 558, 56.2% of 992 examined regions) and µCT (n = 493, 49.7%) detected a higher frequency of osteophytes at PIP and DIP joints than histology (n = 161, 23.4% of 689 histological examined regions; P = 0.01). We found a comparable number of erosions with each method [US, n = 52 (5.2%); µCT, n = 43 (4.3%); histology, n = 35 (5.2%)]. Both imaging techniques correlated moderately with each other regarding the detection of osteophytes (r = 0.54, P = 0.002) and erosions (r = 0.43, P = 0.017). Neither US nor µCT correlated with histology regarding erosions or osteophytes. With histology as the reference, US had a sensitivity of 80% and a specificity of 32% to detect osteophytes, whereas µCT had a sensitivity of 73% and a specificity of 27%. For erosions, sensitivities (US 10% and µCT 6%, respectively) were much lower. Microscopically, erosions contained fibrous myxoid tissue extending from subcortical cavities through the breach of cortical bone. CONCLUSIONS: The ability of US to identify osteophytes was comparable to that of µCT, yielding a good sensitivity when histology was used as the gold standard. The sensitivity of US and µCT to detecting erosions was low compared with histology.
Assuntos
Osteoartrite , Osteófito , Mãos/patologia , Humanos , Osteoartrite/diagnóstico por imagem , Osteoartrite/patologia , Osteófito/diagnóstico por imagem , Osteófito/patologia , Tomografia Computadorizada por Raios X , Ultrassonografia/métodosRESUMO
Chemokine receptors and their ligands have been identified as playing an important role in the development of diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, and Richter syndrome (RS). Our aim was to investigate the different expression profiles in de novo DLBCL, transformed follicular lymphoma (tFL), and RS. Here, we profiled the mRNA expression levels of 18 chemokine receptors (CCR1-CCR9, CXCR1-CXCR7, CX3CR1 and XCR1) using RQ-PCR, as well as immunohistochemistry of seven chemokine receptors (CCR1, CCR4-CCR8 and CXCR2) in RS, de novo DLBCL, and tFL biopsy-derived tissues. Tonsil-derived germinal center B-cells (GC-B) served as non-neoplastic controls. The chemokine receptor expression profiles of de novo DLBCL and tFL substantially differed from those of GC-B, with at least 5-fold higher expression of 15 out of the 18 investigated chemokine receptors (CCR1-CCR9, CXCR1, CXCR2, CXCR6, CXCR7, CX3CR1 and XCR1) in these lymphoma subtypes. Interestingly, the de novo DLBCL and tFL exhibited at least 22-fold higher expression of CCR1, CCR5, CCR8, and CXCR6 compared with RS, whereas no significant difference in chemokine receptor expression profile was detected when comparing de novo DLBCL with tFL. Furthermore, in de novo DLBCL and tFLs, a high expression of CCR7 was associated with a poor overall survival in our study cohort, as well as in an independent patient cohort. Our data indicate that the chemokine receptor expression profile of RS differs substantially from that of de novo DLBCL and tFL. Thus, these multiple dysregulated chemokine receptors could represent novel clinical markers as diagnostic and prognostic tools. Moreover, this study highlights the relevance of chemokine signaling crosstalk in the tumor microenvironment of aggressive lymphomas.
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Leucemia Linfocítica Crônica de Células B , Linfoma Folicular , Linfoma Difuso de Grandes Células B , Linfócitos B/metabolismo , Centro Germinativo/metabolismo , Humanos , Linfoma Folicular/genética , Linfoma Folicular/patologia , Linfoma Difuso de Grandes Células B/patologia , Recidiva Local de Neoplasia , Microambiente TumoralRESUMO
Disease progression in myelodysplastic syndromes (MDS) and myelodysplastic-myeloproliferative neoplasms (MDS/MPN) is a major source of mortality. The European Bone Marrow Working Group organized a dedicated workshop to address MDS and MDS/MPN progression, and myeloid neoplasms with histiocytic and lymphoblastic outgrowths in 2019 in Frankfurt, Germany. In this report, we summarize clinical, histopathological, and molecular features of 28 cases. Most cases illustrate that prognostic mutational profiles change during follow-up due to accumulation of high-risk mutations in the trunk clone, and that results from repeated molecular testing can often explain the clinical progression, suggesting that regular genetic testing may predict transformation by early detection of aggressive clones. Importantly, identical mutations can be linked to different clinical behaviors or risks of fibrotic progression and/or transformation in a context-dependent manner, i.e., MDS or MDS/MPN. Moreover, the order of mutational acquisition and the involved cell lineages matter. Several cases exemplify that histiocytic outgrowths in myeloid neoplasms are usually accompanied by a more aggressive clinical course and may be considered harbinger of disease progression. Exceptionally, lymphoblastic transformations can be seen. As best estimable, the histiocytic and lymphoblastic compounds in all occasions were clonally related to the myeloid compound and-where studied-displayed genomic alterations of, e.g., transcription factor genes or genes involved in MAPK signaling that might be mechanistically linked to the respective type of non-myeloid outgrowth.
Assuntos
Medula Óssea/patologia , Transformação Celular Neoplásica/patologia , Progressão da Doença , Educação/métodos , Síndromes Mielodisplásicas/patologia , Doenças Mieloproliferativas-Mielodisplásicas/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Transformação Celular Neoplásica/genética , Europa (Continente) , Feminino , Alemanha , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/genética , Doenças Mieloproliferativas-Mielodisplásicas/genéticaRESUMO
BACKGROUND: A combination of rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is the standard first-line therapy for diffuse large B cell lymphoma (DLBCL), the most common aggressive lymphoma in adults. One of the major adverse effects of this regimen is vincristine-induced polyneuropathy which leads to discontinuation of vincristine in up to 30% of DLBCL-patients. Dose reduction of vincristine might worsen treatment outcomes of DLBCL but identification of treatment alternatives for patients exhibiting peripheral neuropathy during R-CHOP is an unmet need in hematology. METHODS: In this retrospective cohort study, comprising 987 patients with de novo DLBCL, we delineated the role of vinorelbine as a substitute for vincristine in R-CHOP by measuring improvements in neuropathy and outcome variables. RESULTS: Five-year overall survival (OS) and progression-free survival (PFS) were 72.6% and 63.1% in patients who received regular doses of vincristine, as compared to 60.6% and 51.7% in patients who received reduced doses of vincristine (p = 0.022 and p = 0.003, respectively). Of 199 patients who switched to vinorelbine, the majority experienced an improvement of neuropathy Furthermore, vinorelbine-switched patients showed favorable oncologic outcomes. CONCLUSION: Replacement of vincristine by vinorelbine due to neuropathy is effective and safe, and results in a significant improvement in neuropathy as compared to treatment with R-CHOP.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Linfoma Difuso de Grandes Células B , Doenças do Sistema Nervoso Periférico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/efeitos adversos , Doxorrubicina/efeitos adversos , Feminino , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/epidemiologia , Prednisona/efeitos adversos , Estudos Retrospectivos , Rituximab/efeitos adversos , Transplante Autólogo , Vincristina/efeitos adversos , VinorelbinaRESUMO
The manuscript focuses on effects in nonrandomized studies with two outcome measurement occasions and one explanatory variable, and in which groups already differ at the pretest. Such study designs are often encountered in educational and instructional research. Two prominent approaches to estimate effects are (1) covariance analytical approaches and (2) latent change-score models. In current practice, both approaches are applied interchangeably, without a clear rationale for when to use which approach. The aim of this contribution is to outline under which conditions the approaches produce unbiased estimates of the instruction effect. We present a theoretical data generating model in which we decompose the variances of the relevant variables, and examine under which data generating conditions the estimated instruction effect is unbiased. We show that, under specific assumptions, both methods can be used to answer the general question of whether instruction has an effect. Another implication from the results is that practitioners need to consider which underlying data generating assumptions the approaches make, since a violation of those assumptions will lead to biased effects. Based on our results, we give recommendations for preferable research designs.
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The well-known divergence between what policy and protocol look like on paper, and what happens in the actual practice of daily life remains a central challenge in health services provision and research. This disparity is usually referred to as the theory-practice gap and contributes to concerns that scientific evidence fails to make substantial impacts on the processes of service delivery. In this article, we present an argument for the inclusion of ethnographic methods in health services research and show that this approach enables researchers to address this divergence by working within it. We trace how ethnography, through generative processes of oscillation, can take us beyond lamenting the gap and capture the relational dynamics of people working together in complex systemic arrangements. By moving from example to methodological reflection, to principle of research, we demonstrate how the oscillation of ethnographic research between theory and practice can productively contribute to the field of health service research.
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Antropologia Cultural , Projetos de Pesquisa , Pesquisa sobre Serviços de Saúde , Humanos , Modalidades de Fisioterapia , Pesquisa QualitativaRESUMO
RAS-signaling mutations induce the myelomonocytic differentiation and proliferation of hematopoietic stem and progenitor cells. Moreover, they are important players in the development of myeloid neoplasias. RAF kinase inhibitor protein (RKIP) is a negative regulator of RAS-signaling. As RKIP loss has recently been described in RAS-mutated myelomonocytic acute myeloid leukemia, we now aimed to analyze its role in myelomonocytic differentiation and RAS-driven leukemogenesis. Therefore, we initially analyzed RKIP expression during human and murine hematopoietic differentiation and observed that it is high in hematopoietic stem and progenitor cells and lymphoid cells but decreases in cells belonging to the myeloid lineage. By employing short hairpin RNA knockdown experiments in CD34+ umbilical cord blood cells and the undifferentiated acute myeloid leukemia cell line HL-60, we show that RKIP loss is indeed functionally involved in myelomonocytic lineage commitment and drives the myelomonocytic differentiation of hematopoietic stem and progenitor cells. These results could be confirmed in vivo, where Rkip deletion induced a myelomonocytic differentiation bias in mice by amplifying the effects of granulocyte macrophage-colony-stimulating factor. We further show that RKIP is of relevance for RAS-driven myelomonocytic leukemogenesis by demonstrating that Rkip deletion aggravates the development of a myeloproliferative disease in NrasG12D -mutated mice. Mechanistically, we demonstrate that RKIP loss increases the activity of the RAS-MAPK/ERK signaling module. Finally, we prove the clinical relevance of these findings by showing that RKIP loss is a frequent event in chronic myelomonocytic leukemia, and that it co-occurs with RAS-signaling mutations. Taken together, these data establish RKIP as novel player in RAS-driven myeloid leukemogenesis.
Assuntos
Leucemia Mieloide Aguda , Proteína de Ligação a Fosfatidiletanolamina , Animais , Diferenciação Celular , Leucemia Mieloide Aguda/genética , Camundongos , Monócitos/metabolismo , Proteína de Ligação a Fosfatidiletanolamina/genética , Proteína de Ligação a Fosfatidiletanolamina/metabolismo , Transdução de SinaisRESUMO
Overexpression of bcl-2 and c-myc are defining features of double-expressor-lymphoma (DEL) but may also occur separately in patients with primary central nervous system lymphoma (PCNSL). Despite all progress in optimizing treatment regimen, there is lack of sufficient risk stratification models. Here, we first describe the relationship between DEL biology, the National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI), treatment response, disease progression, and mortality in PCNSL. In this study, we determined c-myc and bcl-2 status immunohistochemically in samples of 48 patients with newly diagnosed PCNSL and followed these patients for a median interval of 6.2 years. Twelve, 18, and 17 patients harbored none, one, or both DEL features. Corresponding overall response rates after first-line therapy were strongly associated with DEL biology (100%, 42%, and 44% in patients with 0, 1, or 2 DEL features). Patients with one or both DEL features had a 5-fold and 13-fold higher 5-year risk of progression and/or death than patients without DEL features. These associations prevailed after adjusting for the NCCN-IPI. DEL improved the discriminatory capability of the NCCN-IPI (P = .0001). Furthermore, we could show that addition of DEL biology to the NCCN-IPI significantly improved the score's discriminatory potential both toward progression-free survival (increase in Harell's c = 0.15, P = .005) and overall survival (increase in Harell's c = 0.11, P = .029). In conclusion, DEL biology is a strong and simple-to-use predictor of adverse outcome in PCNSL. Addition of DEL to the NCCN-IPI improves its prognostic potential. Disease progression from PCNSL harboring both DEL features is invariably fatal. This defines a novel PCNSL patient subset with a great unmet need for improved therapy.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/metabolismo , Neoplasias do Sistema Nervoso Central/mortalidade , Imuno-Histoquímica/métodos , Recidiva Local de Neoplasia/mortalidade , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/metabolismo , Neoplasias do Sistema Nervoso Central/patologia , Citarabina/administração & dosagem , Progressão da Doença , Feminino , Seguimentos , Humanos , Masculino , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Prognóstico , Estudos Retrospectivos , Medição de Risco , Taxa de SobrevidaRESUMO
BACKGROUND: Data on management of gray zone lymphoma (GZL) in children and adolescents are scarce. PROCEDURE: This retrospective study assessed clinical characteristics and outcome in six Austrian patients with GZL less than 18 years of age (male-to-female ratio: 1:1; median age: 15.8 years). RESULTS: Two patients each had a classical Hodgkin lymphoma (cHL)-like and composite GZL subtype, and one patient each had a large B-cell non-Hodgkin lymphoma (LBCL)-like and sequential GZL subtype. All had advanced disease with mediastinal and extranodal involvement. Five patients received an LBCL- and one patient a cHL-directed polychemotherapy ± radiotherapy. Out of the former patients, three survived, including two who relapsed and underwent high-dose chemotherapy with autologous stem cell rescue. The latter patient survived. CONCLUSIONS: GZL remains a diagnostic and therapeutic challenge, necessitating the development of novel treatment concepts performed in a prospective setting.
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Quimiorradioterapia , Linfoma Difuso de Grandes Células B/terapia , Neoplasias do Mediastino/terapia , Transplante de Células-Tronco , Adolescente , Áustria , Autoenxertos , Feminino , Seguimentos , Humanos , Linfoma Difuso de Grandes Células B/diagnóstico , Masculino , Neoplasias do Mediastino/diagnóstico , Estudos RetrospectivosRESUMO
In tumor cells of more than 20 different cancer types, the CXCR4-CXCL12-axis is involved in multiple key processes including proliferation, survival, migration, invasion, and metastasis. Since data on this axis in diffuse large B cell lymphoma (DLBCL) are inconsistent and limited, we comprehensively studied the CXCR4-CXCL12-axis in our DLBCL cohort as well as the effects of CXCR4 antagonists on lymphoma cell lines in vitro. In DLBCL, we observed a 140-fold higher CXCR4 expression compared to non-neoplastic controls, which was associated with poor clinical outcome. In corresponding bone marrow biopsies, we observed a correlation of CXCL12 expression and lymphoma infiltration rate as well as a reduction of CXCR4 expression in remission of bone marrow involvement after treatment. Additionally, we investigated the effects of three CXCR4 antagonists in vitro. Therefore, we used AMD3100 (Plerixafor), AMD070 (Mavorixafor), and WKI, the niacin derivative of AMD070, which we synthesized. WK1 demonstrated stronger pro-apoptotic effects than AMD070 in vitro and induced expression of pro-apoptotic genes of the BCL2-family in CXCR4-positive lymphoma cell lines. Finally, WK1 treatment resulted in the reduced expression of JNK-, ERK1/2- and NF-κB/BCR-target genes. These data indicate that the CXCR4-CXCL12-axis impacts the pathogenesis of DLBCL and represents a potential therapeutic target in aggressive lymphomas.
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Apoptose/efeitos dos fármacos , Quimiocina CXCL12/metabolismo , Linfoma Difuso de Grandes Células B/metabolismo , Receptores CXCR4/metabolismo , Transdução de Sinais/efeitos dos fármacos , Aminoquinolinas , Antineoplásicos/farmacologia , Benzimidazóis , Biomarcadores , Butilaminas , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Quimiocina CXCL12/genética , Éxons , Feminino , Expressão Gênica , Compostos Heterocíclicos com 1 Anel/farmacologia , Humanos , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/patologia , Masculino , Mutação , Estadiamento de Neoplasias , Prognóstico , Receptores CXCR4/antagonistas & inibidores , Receptores CXCR4/genéticaRESUMO
Regarding diagnosis of polycythemia vera (PV), discussion persists about hemoglobin (Hb) and/or hematocrit (Hct) threshold values as surrogate markers for red cell mass (RCM) and the diagnostic impact of bone marrow (BM) morphology. We performed a retrospective study on 290 patients with PV (151 males, 139 females; median age 65 years) presenting with characteristic BM features (initial biopsies, centralized evaluation) and endogenous erythroid colony (EEC) formations. This cohort included (1) a group of 229 patients when following the 2008 versus 256 patients diagnosed according to the 2016 World Health Organization (WHO) guidelines, all presented with increased RCM; (2) masked PV patients with low Hb (n = 143)/Hct (n = 45) recruited from the 2008 WHO cohort; (3) a cohort of 17 PV patients with elevated diagnostic Hb/Hct levels but low RCM; and (4) nine PV patients with increased RCM, opposing low Hb/Hct values. All patients were treated according to current PV guidelines (phlebotomies 87%, hydroxyurea 79%, and acetylsalicylic acid 87%). Applying the 2016 WHO criteria significantly increased concordance between RCM and Hb values compared with the 2008 WHO criteria (90 vs. 43% in males and 83 vs. 64% in females). Further analysis of the WHO 2016 PV cohort revealed that increased RCM is associated with increased Hb/Hct (93.8/94.6%). Our study supports and extends the diagnostic impact of the 2016 revised WHO classification for PV by highlighting the importance of characteristic BM findings and implies that Hb/Hct threshold values may be used as surrogate markers for RCM measurements.
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Volume de Eritrócitos/fisiologia , Eritrócitos/patologia , Hematócrito , Hemoglobinas/análise , Policitemia Vera/diagnóstico , Idoso , Biomarcadores/análise , Forma Celular , Feminino , Hematócrito/normas , Testes Hematológicos/normas , Humanos , Masculino , Oncologia/normas , Pessoa de Meia-Idade , Policitemia Vera/sangue , Estudos Retrospectivos , Organização Mundial da SaúdeRESUMO
Calcitonin (CT), a tumor marker for medullary thyroid cancer (MTC), can be stimulated with pentagastrin or calcium. Because of the unavailability of pentagastrin, basal CT measurement is frequently used for the preoperative diagnosis of MTC. The aim of the study was to define basal serum calcitonin (bCT) cut-off thresholds for diagnosing MTC. Within a retrospective analysis, 114 patients (51 males) were included fulfilling the criteria of an increased preoperative bCT level (>10 pg/ml) and the criteria of an available postoperative histology analysis. Based on a ROC plot analysis, the cut-off values for the diagnosis of MTC vs. non-malignancy (C cell hyperplasia and goiter) were identified. The most precise bCT thresholds for the identification of MTC were ≥46 pg/ml for males (sensitivity: 93.6%, specificity: 95.0%, PPV: 97%, NPV: 90%) and ≥35 pg/ml for females (sensitivity: 87.3%, specificity: 87.5%, PPV: 98%, NPV: 50%). Using these cut-offs, only 6% of male patients were not identified of having MTC, whereas 5% were false positive (having instead C cell hyperplasia). In females, the discrepancy was higher since 13% of female MTC patients were false negative by using the cut-off of ≥35 pg/ml, and 13% had false positive results (suffering from C cell hyperplasia). Gender-specific bCT cut-offs for the identification of MTC vs. C cell hyperplasia and non-malignancy were defined, which can be used in clinical routine. In female patients, however, the accuracy is much lower compared to males.
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Calcitonina/sangue , Carcinoma Neuroendócrino/sangue , Carcinoma Neuroendócrino/diagnóstico , Neoplasias da Glândula Tireoide/sangue , Neoplasias da Glândula Tireoide/diagnóstico , Feminino , Humanos , Hiperplasia , Masculino , Pessoa de Meia-Idade , Curva ROC , Valores de Referência , Sensibilidade e EspecificidadeRESUMO
In the last decade there has been a rapid expansion in clinical trials using mesenchymal stromal cells (MSCs) from a variety of tissues. However, despite similarities in morphology, immunophenotype, and differentiation behavior in vitro, MSCs sourced from distinct tissues do not necessarily have equivalent biological properties. We performed a genome-wide methylation, transcription, and in vivo evaluation of MSCs from human bone marrow (BM), white adipose tissue, umbilical cord, and skin cultured in humanized media. Surprisingly, only BM-derived MSCs spontaneously formed a BM cavity through a vascularized cartilage intermediate in vivo that was progressively replaced by hematopoietic tissue and bone. Only BM-derived MSCs exhibited a chondrogenic transcriptional program with hypomethylation and increased expression of RUNX3, RUNX2, BGLAP, MMP13, and ITGA10 consistent with a latent and primed skeletal developmental potential. The humanized MSC-derived microenvironment permitted homing and maintenance of long-term murine SLAM(+) hematopoietic stem cells (HSCs), as well as human CD34(+)/CD38(-)/CD90(+)/CD45RA(+) HSCs after cord blood transplantation. These studies underscore the profound differences in developmental potential between MSC sources independent of donor age, with implications for their clinical use. We also demonstrate a tractable human niche model for studying homing and engraftment of human hematopoietic cells in normal and neoplastic states.
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Linhagem da Célula , Epigênese Genética , Células-Tronco Hematopoéticas/citologia , Células-Tronco Mesenquimais/citologia , Nicho de Células-Tronco , Western Blotting , Células da Medula Óssea/citologia , Diferenciação Celular/fisiologia , Condrogênese/fisiologia , Citometria de Fluxo , Humanos , Osteogênese/fisiologiaRESUMO
The 2016 revised WHO criteria for the diagnosis of pre-fibrotic/early primary myelofibrosis (pre-PMF) require at least one of the following four borderline expressed minor clinical criteria: anemia, leukocytosis, elevated lactate dehydrogenase and splenomegaly. In this study, we evaluated the relative frequency of these four criteria in a group of 170 pre-PMF patients and compared them to 225 ET cases. More than 91% of pre-PMF cases showed one or more of these features required for diagnosis, by contrast with only 48% of ET patients. According to clinical data the cumulative risk of progression to advanced/overt PMF in pre-PMF was 36.9% after 15 years. After fitting cox regression models to analyze the impact of the minor criteria on overall survival, only leukocytosis remained as a significant predictor of survival in both pre-PMF and ET. Molecular characterization showed differences in survival in pre-PMF but not ET, with CALR being a more favorable mutation than JAK2. The different outcome of pre-PMF versus ET and associated molecular genetic data supports the concept of two different entities, rather than a continuum of the same disease. Although slightly less than 50% of ET patients also show one or more minor clinical criteria, accurate distinction between ET and pre-PMF is possible by following an integrated approach including histomorphological diagnosis and presence of minor clinical criteria.
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Mielofibrose Primária/diagnóstico , Mielofibrose Primária/mortalidade , Trombocitemia Essencial/diagnóstico , Trombocitemia Essencial/mortalidade , Idoso , Calreticulina/genética , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Janus Quinase 2/genética , Masculino , Pessoa de Meia-Idade , Mutação , Mielofibrose Primária/genética , Mielofibrose Primária/terapia , Fatores de Risco , Taxa de Sobrevida , Trombocitemia Essencial/genética , Trombocitemia Essencial/terapia , Organização Mundial da SaúdeRESUMO
BACKGROUND: Blood-based parameters are gaining increasing interest as potential prognostic biomarkers in patients with diffuse large B-cell lymphoma (DLBCL). The aim of this study was to comprehensively evaluate the prognostic significance of pretreatment plasma uric acid levels in patients with newly diagnosed DLBCL. METHODS: The clinical course of 539 DLBCL patients, diagnosed and treated between 2004 and 2013 at two Austrian high-volume centres with rituximab-based immunochemotherapy was evaluated retrospectively. The prognostic influence of uric acid on overall survival (OS) and progression-free survival (PFS) were studied including multi-state modelling, and analysis of conditional survival. RESULTS: Five-year OS and PFS were 50.4% (95% CI: 39.2-60.6) and 44.0% (33.4-54.0) in patients with uric acid levels above the 75th percentile of the uric acid distribution (Q3, cut-off: 6.8 mg dl-1), and 66.2% (60.4-71.5) and 59.6% (53.7-65.0%) in patients with lower levels (log-rank P=0.002 and P=0.0045, respectively). In univariable time-to-event analysis, elevated uric acid levels were associated with a worse PFS (hazard ratio (HR) per 1 log increase in uric acid 1.47, 95% CI: 1.10-1.97, P=0.009) and a worse OS (HR=1.60, 95% CI: 1.16-2.19, P=0.004). These associations prevailed upon multivariable adjustment for the NCCN-IPI score. Uric acid levels significantly improved the predictive performance of the R-IPI and NCCN-IPI scores, and in multi-state analysis, it emerged as a highly significant predictor of an increased risk of death without developing recurrence (transition-HR=4.47, 95% CI: 2.17-9.23, P<0.0001). CONCLUSIONS: We demonstrate that elevated uric acid levels predict poor long-term outcomes in DLBCL patients beyond the NCCN-IPI risk index.
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Antineoplásicos/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/patologia , Rituximab/uso terapêutico , Ácido Úrico/sangue , Adulto , Idoso , Áustria , Biomarcadores Tumorais/sangue , Intervalo Livre de Doença , Feminino , Humanos , Imunoterapia/métodos , Estimativa de Kaplan-Meier , Linfoma Difuso de Grandes Células B/sangue , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Prognóstico , Modelos de Riscos Proporcionais , Estudos RetrospectivosRESUMO
NR4A1 (Nur77) and NR4A3 (Nor-1) function as tumor suppressor genes as demonstrated by the rapid development of acute myeloid leukemia in the NR4A1 and NR4A3 knockout mouse. The aim of our study was to investigate NR4A1 and NR4A3 expression and function in lymphoid malignancies. We found a vastly reduced expression of NR4A1 and NR4A3 in chronic lymphocytic B-cell leukemia (71%), in follicular lymphoma (FL, 70%), and in diffuse large B-cell lymphoma (DLBCL, 74%). In aggressive lymphomas (DLBCL and FL grade 3), low NR4A1 expression was significantly associated with a non-germinal center B-cell subtype and with poor overall survival. To investigate the function of NR4A1 in lymphomas, we overexpressed NR4A1 in several lymphoma cell lines. Overexpression of NR4A1 led to a higher proportion of lymphoma cells undergoing apoptosis. To test the tumor suppressor function of NR4A1 in vivo, the stable lentiviral-transduced SuDHL4 lymphoma cell line harboring an inducible NR4A1 construct was further investigated in xenografts. Induction of NR4A1 abrogated tumor growth in the NSG mice, in contrast to vector controls, which formed massive tumors. Our data suggest that NR4A1 has proapoptotic functions in aggressive lymphoma cells and define NR4A1 as a novel gene with tumor suppressor properties involved in lymphomagenesis.
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Apoptose/genética , Linfoma de Células B/genética , Linfoma de Células B/mortalidade , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Animais , Western Blotting , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/genética , Xenoenxertos , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Modelos de Riscos Proporcionais , Receptores de Esteroides/genética , Receptores dos Hormônios Tireóideos/genéticaRESUMO
AIMS: In the era of potentially disease-modifying agents such as Janus kinase inhibitors, accurate grading and differentiation of bone marrow (BM) fibrosis has become more relevant to assess staging of disease and therapeutic effects. However, different fibrosis grading models have been used in the past without uniformity, including the proposal by the World Health Organization. Current scoring systems are based only on reticulin fibrosis. Therefore, additional assessment of collagen and the grade of osteosclerosis appear to be essential to discriminate all components of the complex BM fibrous matrix. METHODS AND RESULTS: We evaluated problems and pitfalls regarding staining techniques and the interpretation of reticulin fibrosis on a total of 352 samples. Furthermore, we propose a minor modification of the current grading and separate scoring for collagen deposition and osteosclerosis. Reproducibility of gradings was tested among 11 haematopathologists in a blinded assessment. Overall, the inter-rater reliability of all three grading systems ranged between 0.898 and 0.926. CONCLUSIONS: A standardized assessment of BM fibrosis with differentiation between reticulin, collagen and osteosclerosis is recommended to evaluate the various components of the fibrous matrix which may be delinked after therapy. In this regard, quality of staining and application of laboratory standards enable a highly reproducible scoring.
Assuntos
Medula Óssea/patologia , Colágeno/análise , Transtornos Mieloproliferativos/patologia , Osteosclerose/patologia , Reticulina/análise , Fibrose/patologia , Histocitoquímica , Humanos , Reprodutibilidade dos TestesRESUMO
Genetic alterations causing constitutive activation of the nuclear factor kappa B (NF-κB) signaling pathway has been associated with the development of lymphomas. A20 (TNFAIP3) is a key regulator of NF-κB signaling. Its suppressor functions are often inactivated by deletions and/or mutations in various hematologic malignancies. Since we recently found the rs143002189 polymorphism in the A20 loci in our multiple myeloma samples, we further investigated this polymorphism in different lymphoid neoplasias. For this purpose, we tested 479 cases of the most common B cell malignancies for the presence of the rs143002189 polymorphism. We found a significant higher occurrence of the rs143002189 polymorphism in diffuse large B cell lymphoma (DLBCL) compared to non-neoplastic controls and other types of B cell malignancies. Furthermore, structure analyses of the mutated A20 protein led to the assumption that the new steric interaction within the protein is responsible for a reduced or inactivated A20 protein. Our data indicates that in a significant fraction of patients, rs143002189 might contribute to the development of DLBCL.
Assuntos
Linfoma Difuso de Grandes Células B/genética , Polimorfismo de Nucleotídeo Único , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética , Estudos de Casos e Controles , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Incidência , Linfoma Difuso de Grandes Células B/epidemiologia , Modelos Moleculares , Fases de Leitura AbertaRESUMO
US28, a constitutively active G-protein-coupled receptor encoded by the human cytomegalovirus, leads to mechanistically unknown programmed cell death. Here we show that expression of wild-type US28 in human melanoma cells leads to apoptotic cell death via caspase 3 activation along with reduced cell proliferation. Reduced tumor growth upon US28 expression was observed in a xenograft mouse model. The signaling mute US28R129A showed a reduced antiproliferative effect. On evaluating different G-proteins coupled to US28 for signal transduction, Gα13 was identified as the main G-protein executing the apoptotic effect. Silencing of Gα13 but not Gαq resulted in a substantial increase in cell survival. Overexpression of Gα13 but not Gαq and their GTPase deficient forms Gα13Q226L and GαqQ209L, respectively, confirmed the requirement of Gα13 for US28 mediated cell death. Increasing expression of Gα13 alone induced cell death underscoring its relay function for US28 mediated decreased cell viability. Further reduced expression of Gα13 in melanoma cell lines isolated from advanced lesions and melanoma tissue was observed. These findings identified Gα13 as crucial for US28-induced cell death, substantiating that the effect of US28 on cell fate depends on preferred G-protein binding.