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1.
Int J Mol Sci ; 22(17)2021 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-34502317

RESUMO

Chronic lymphocytic leukemia (CLL) is considered a clonal B cell malignancy. Sporadically, CLL cases with multiple productive heavy and light-chain rearrangements were detected, thus leading to a bi- or oligoclonal CLL disease with leukemic cells originating either from different B cells or otherwise descending from secondary immunoglobulin rearrangement events. This suggests a potential role of clonal hematopoiesis or germline predisposition in these cases. During the screening of 75 CLL cases for kappa and lambda light-chain rearrangements, we could detect a single case with CLL cells expressing two distinct kappa and lambda light chains paired with two separate immunoglobulin heavy-chain variable regions. Furthermore, this patient also developed a prostate carcinoma. Targeted genome sequencing of highly purified light-chain specific CLL clones from this patient and from the prostate carcinoma revealed the presence of a rare germline polymorphism in the POLE gene. Hence, our data suggest that the detected SNP may predispose for cancer, particularly for CLL.


Assuntos
Processamento Alternativo , DNA Polimerase II/genética , Leucemia Linfocítica Crônica de Células B/patologia , Proteínas de Ligação a Poli-ADP-Ribose/genética , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/patologia , Humanos , Leucemia Linfocítica Crônica de Células B/complicações , Leucemia Linfocítica Crônica de Células B/genética , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias da Próstata/complicações , Neoplasias da Próstata/genética
2.
Int J Mol Sci ; 22(17)2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34502471

RESUMO

Philadelphia chromosome negative myeloproliferative neoplasms (MPN) are composed of polycythemia vera (PV), essential thrombocytosis (ET), and primary myelofibrosis (PMF). The clinical picture is determined by constitutional symptoms and complications, including arterial and venous thromboembolic or hemorrhagic events. MPNs are characterized by mutations in JAK2, MPL, or CALR, with additional mutations leading to an expansion of myeloid cell lineages and, in PMF, to marrow fibrosis and cytopenias. Chronic inflammation impacting the initiation and expansion of disease in a major way has been described. Neutrophilic granulocytes play a major role in the pathogenesis of thromboembolic events via the secretion of inflammatory markers, as well as via interaction with thrombocytes and the endothelium. In this review, we discuss the molecular biology underlying myeloproliferative neoplasms and point out the central role of leukocytosis and, specifically, neutrophilic granulocytes in this group of disorders.


Assuntos
Neoplasias Hematológicas/imunologia , Transtornos Mieloproliferativos/imunologia , Proteínas de Neoplasias/imunologia , Neutrófilos/imunologia , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patologia , Humanos , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/patologia , Proteínas de Neoplasias/genética , Neutrófilos/patologia , Cromossomo Filadélfia
3.
Pancreatology ; 21(8): 1466-1471, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34511398

RESUMO

BACKGROUND: Pancreatic carcinoma carries a devastating prognosis and is the 4th leading cause for cancer related death in the US and most European countries. Apart from imaging and CA 19-9, pancreatic carcinoma is still lacking reliable markers to assess tumor dynamics and to monitor treatment response over time. The aim of this study was to evaluate the feasibility of cell free tumor-DNA (cft-DNA), respectively KRAS mutation in peripheral blood, detection as a prognostic and predictive value for chemotherapy monitoring. METHODS: Serial plasma samples from 42 patients with KRAS mutated pancreatic cancer were prospectively collected and the ctKRAS Mutation Assay (Idylla™, Biocartis, Mechelen, Belgium) of cft-DNA was performed on 29 patients that did not receive curative surgery and went on to palliative chemotherapy. To monitor cft-DNA KRAS mutation levels during treatment quantitative assessment of cft-DNA was performed at baseline and during follow up at predetermined times. RESULTS: All 29 patients included in our analyses had a detected KRAS mutation in the tumor biopsy. In almost half (48.2%) of patients a KRAS mutation could also be detected in peripheral plasma. Patients with detectable KRAS mutations before treatment start in plasma had a significantly worse survival (16.8 months vs not reached, p < 0.031 and HR 3.303). Looking for a dynamic assessment of tumor response, we found a statistically significant association between the KRAS mutant ratio from first staging CT scan to basal levels with tumor response or progress (p = 0.014). CONCLUSION: Performing KRAS testing from peripheral blood for patients, who have no elevated tumor markers, might be a novel option for treatment monitoring complementing routine imaging techniques.

4.
Wien Klin Wochenschr ; 133(21-22): 1131-1136, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34528125

RESUMO

BACKGROUND: The addition of cisplatin or cetuximab to radiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) has significantly improved the outcome. While the superiority of cisplatin over cetuximab in combination with radiotherapy has been shown in a definitive setting, we set out to compare postoperative chemoradiotherapy with cisplatin to radioimmunotherapy with cetuximab and radiotherapy alone within the Austrian head and neck cancer registry of the Working Group on Pharmaceutical Tumor Treatment (AGMT) study group. MATERIAL AND METHODS: In the AGMT head and neck cancer registry, data of 557 patients with SCCHN from five Austrian cancer centers were prospectively collected between 2012 and 2017. Of these patients 120 received postoperative chemoradiotherapy with cisplatin, 26 patients received postoperative radioimmunotherapy with cetuximab and 56 patients were treated with adjuvant radiotherapy only. Patient characteristics, stage of disease, details on treatment as well as survival were analyzed by a chart-based review. RESULTS: In patients treated with postoperative radiotherapy the addition of cisplatin significantly improved progression-free survival (PFS) and overall survival (OS) compared to cetuximab (PFS 84.2 months vs. 17.0 months, p = 0.04, OS not reached vs. 46.0 months, p = 0.02) and PFS compared to radiotherapy alone (PFS 84.2 months vs. 28.5 months, p < 0.01). Patients treated with cetuximab were significantly older and had a worse performance score than patients receiving cisplatin or radiotherapy alone. CONCLUSION: This study confirmed the importance of multimodal treatment concepts in patients with locally advanced SCCHN. Postoperative cetuximab might be an option in patients not eligible for high-dose cisplatin but cisplatin should remain the standard of care.


Assuntos
Cisplatino , Neoplasias de Cabeça e Pescoço , Áustria , Cetuximab , Quimiorradioterapia , Humanos , Radioimunoterapia , Sistema de Registros
5.
Int J Mol Sci ; 22(11)2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34064196

RESUMO

BACKGROUND: Chimeric antigen receptor (CAR) T-cells are changing the therapeutic landscape of hematologic malignancies. Severe side effects include cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), but prolonged cytopenia has also been reported. The underlying mechanism for prolonged cytopenia is poorly understood so far. CASES: Severe pancytopenia with grade 2-3 anemia was marked 2-3 months after treatment. Laboratory evaluation revealed undetectable levels of haptoglobin with increased reticulocyte counts. Coomb's tests were negative, no schistocytes were detected on blood smear, and infectious causes were ruled out. Increased erythropoiesis without lymphoma infiltration was noted on bone marrow biopsy. A spontaneous increase in haptoglobin and hemoglobin levels was observed after several weeks. For one patient, peripheral CAR-T levels were monitored over time. We observed a decline at the same time as hemoglobin levels began to rise, implying a potential causality. CONCLUSION: To our knowledge, we describe the first two cases of Coombs-negative hemolytic anemia after CAR-T treatment for B-cell lymphoma. We encourage routine monitoring for hemolytic anemia after CAR-T treatment and also encourage further investigations on the underlying mechanism.


Assuntos
Anemia Hemolítica/etiologia , Terapia Baseada em Transplante de Células e Tecidos/efeitos adversos , Pancitopenia/etiologia , Receptores de Antígenos Quiméricos/imunologia , Feminino , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/terapia , Humanos , Linfoma/genética , Masculino , Pessoa de Meia-Idade
6.
Cancers (Basel) ; 13(11)2021 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-34073525

RESUMO

Adaptive somatic mutations conferring treatment resistance and accelerated disease progression is still a major problem in cancer therapy. Additionally in CLL, patients receiving novel, efficient drugs frequently become treatment refractory and eventually relapse. Activation-induced deaminase (AID) is a cytosine deaminase that catalyzes somatic hypermutation of genomic DNA at the immunoglobulin locus in activated B cells. As considerable off-target mutations by AID have been discerned in chronic lymphocytic leukemia, it is essential to investigate to which extent these mutations contribute to disease progression to estimate whether AID inhibition could counteract drug resistance mechanisms. In this study, we examined the TCL1 mouse model for CLL on an AID pro- and deficient background by comparing disease development and mutational landscapes. We provide evidence that AID contributes to the acquisition of somatic cancer-specific mutations also in the TCL1 model and accelerates CLL development particularly in the transplant setting. We conclude that AID is directly determining the fitness of the CLL clone, which prompts further studies to assess the effect of AID inhibition on the occurrence of drug resistance.

7.
Leukemia ; 35(11): 3059-3072, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34168283

RESUMO

Assessment of measurable residual disease (often referred to as "minimal residual disease") has emerged as a highly sensitive indicator of disease burden during and at the end of treatment and has been correlated with time-to-event outcomes in chronic lymphocytic leukemia. Undetectable-measurable residual disease status at the end of treatment demonstrated independent prognostic significance in chronic lymphocytic leukemia, correlating with favorable progression-free and overall survival with chemoimmunotherapy. Given its utility in evaluating depth of response, determining measurable residual disease status is now a focus of outcomes in chronic lymphocytic leukemia clinical trials. Increased adoption of measurable residual disease assessment calls for standards for nomenclature and outcomes data reporting. In addition, many basic questions have not been systematically addressed. Here, we present the work of an international, multidisciplinary, 174-member panel convened to identify critical questions on key issues pertaining to measurable residual disease in chronic lymphocytic leukemia, review evaluable data, develop unified answers in conjunction with local expert input, and provide recommendations for future studies. Recommendations are presented regarding methodology for measurable residual disease determination, assay requirements and in which tissue to assess measurable residual disease, timing and frequency of assessment, use of measurable residual disease in clinical practice versus clinical trials, and the future usefulness of measurable residual disease assessment. Nomenclature is also proposed. Adoption of these recommendations will work toward standardizing data acquisition and interpretation in future studies with new treatments with the ultimate objective of improving outcomes and curing chronic lymphocytic leukemia.

8.
Geroscience ; 43(4): 1877-1897, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33837912

RESUMO

COVID-19-associated case fatality rates up to 48% were reported among nursing facility residents. During the first wave of the COVID-19 pandemic, routine SARS-CoV-2 testing in long-term care facilities in the Province of Salzburg and centralized hospitalization in the COVID-19 unit of the Paracelsus Medical University Salzburg (Austria) irrespective of symptoms was implemented. Baseline characteristics and the course of COVID-19 disease were assessed among hospitalized long-term care facility residents within the COVID-19 Registry of the Austrian Group Medical Tumor Therapy (AGMT; NCT04351529). Between the 24th of March and the 20th of April 2020, 50 COVID-19-positive residents were hospitalized. The median age was 84.5 years (range: 79-88) and the median number of comorbidities and baseline medication classes was 6 (IQR: 4-7) and 5 (IQR: 3-6), respectively. At admission, 31 residents (62%) were symptomatic, nine residents (18%) pre-symptomatic whereas ten residents (20%) remained asymptomatic. The 30-day mortality rate from hospitalization was 32% and significantly higher in symptomatic residents at admission when compared to asymptomatic residents including pre-symptomatic residents (48% [95% CI: 27-63%] versus 5% [95% CI: 0-15%], p=0.006). The Early Warning Score (EWS) at admission was associated with 30-day mortality: high risk: 100%, intermediate risk: 50% (95% CI: 0-78%), and low risk: 21% (95% CI: 7-32%) (p<0.001). In light of comparably low mortality rates between asymptomatic and pre-symptomatic hospitalized COVID-19-positive residents, we suggest the supply of comparable intensity and quality of monitoring and care in long-term care facilities as an alternative to immediate hospitalization upon a positive COVID-19 test in asymptomatic residents.


Assuntos
COVID-19 , Idoso de 80 Anos ou mais , Teste para COVID-19 , Hospitalização , Humanos , Assistência de Longa Duração , Pandemias , Políticas , Sistema de Registros , SARS-CoV-2
9.
Stem Cells ; 39(6): 819-830, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33539629

RESUMO

Survival of chronic lymphocytic leukemia (CLL) cells critically depends on the support of an adapted and therefore appropriate tumor microenvironment. Increasing evidence suggests that B-cell receptor-associated kinases such as protein kinase C-ß (PKCß) or Lyn kinase are essential for the formation of a microenvironment supporting leukemic growth. Here, we describe the impact of PKCß on the glucose metabolism in bone marrow stromal cells (BMSC) upon CLL contact. BMSC get activated by CLL contact expressing stromal PKCß that diminishes mitochondrial stress and apoptosis in CLL cells by stimulating glucose uptake. In BMSC, the upregulation of PKCß results in increased mitochondrial depolarization and leads to a metabolic switch toward oxidative phosphorylation. In addition, PKCß-deficient BMSC regulates the expression of Hnf1 promoting stromal insulin signaling after CLL contact. Our data suggest that targeting PKCß and the glucose metabolism of the leukemic niche could be a potential therapeutic strategy to overcome stroma-mediated drug resistance.

10.
Cancers (Basel) ; 13(4)2021 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-33561953

RESUMO

Diffuse large B-cell lymphoma (DLBCL) usually needs to be treated immediately after diagnosis from a single lymph node biopsy. However, several reports in other malignancies have shown substantial spatial heterogeneity within large tumours. Therefore, we collected multiple synchronous biopsies of twelve patients that had diagnostic or therapeutic resections of large lymphoma masses and performed next-generation sequencing of 213 genes known to be important for lymphoma biology. Due to the high tumour cell content in the biopsies, we were able to detect several mutations which were present with a stable allelic frequency across all the biopsies of each patient. However, ten out of twelve patients had spatially discordant mutations and similar results were found by the analysis of copy number variants. The median Jaccard similarity coefficient, a measure of the similarity of a sample set was 0.77 (range 0.47-1), and some of the involved genes such as CARD11, CD79B, TP53, and PTEN have a known prognostic or therapeutic relevance in DLBCL. This shows that single biopsies underestimate the complexity of the disease and might overlook possible mechanisms of resistance and therapeutic targets. In the future, the broader application of liquid biopsies will have to overcome these obstacles.

11.
Support Care Cancer ; 29(9): 5197-5207, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33625586

RESUMO

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 , Vinorelbina
12.
Lancet Haematol ; 8(2): e135-e148, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33513373

RESUMO

BACKGROUND: Approval of hypomethylating agents in patients with chronic myelomonocytic leukaemia is based on trials done in patients with myelodysplastic syndromes. We aimed to investigate whether hypomethylating agents provide a benefit in subgroups of patients with chronic myelomonocytic leukaemia compared with other treatments. METHODS: For this retrospective cohort study, data were retrieved between Nov 30, 2017, and Jan 5, 2019, from 38 centres in the USA and Europe. We included non-selected, consecutive patients diagnosed with chronic myelomonocytic leukaemia, who received chronic myelomonocytic leukaemia-directed therapy. Patients with acute myeloid leukaemia according to 2016 WHO criteria at initial diagnosis (ie, ≥20% blasts in the bone marrow or peripheral blood) or with unavailability of treatment data were excluded. Outcomes assessed included overall survival, time to next treatment, and time to transformation to acute myeloid leukaemia. Analyses were adjusted by age, sex, platelet count, and Chronic myelomonocytic leukaemia-Specific Prognostic Scoring System (CPSS). Patients were grouped by first received treatment with either hydroxyurea, hypomethylating agents, or intensive chemotherapy, and stratified by risk according to blast count, French-American-British subtype, CPSS, WHO 2016 subtype, and the eligibility criteria of the DACOTA trial (NCT02214407). FINDINGS: 949 patients diagnosed with chronic myelomonocytic leukaemia between April 13, 1981, and Oct 26, 2018, were included. Median follow-up was 23·4 months (IQR 11·5-42·3) from diagnosis and 16·2 months (6·6-31·6) from start of first-line treatment. 412 (43%) of 949 patients received hypomethylating agents as first treatment, 391 (41%) hydroxyurea, and 83 (9%) intensive chemotherapy. Adjusted median overall survival for patients treated with hydroxyurea versus hypomethylating agents was 15·6 months (95% CI 13·1-17·3) versus 20·7 months (17·9-23·4); hazard ratio (HR) 1·39 (1·17-1·65; p=0·0002) and 14·0 months (9·8-17·2) versus 20·7 months (17·9-23·4; HR 1·55 [1·16-2·05]; p=0·0027) for those treated with intensive chemotherapy versus hypomethylating agents. In patients with myeloproliferative chronic myelomonocytic leukaemia (myeloproliferative CMML), median overall survival was 12·6 months (10·7-15·0) versus 17·6 months (14·8-21·5; HR 1·38 [1·12-1·70]; p=0·0027) for patients treated with hydroxyurea versus hypomethylating agents, and 12·3 months (8·4-16·6) versus 17·6 months (14·8-21·5; HR 1·44 [1·02-2·03]; p=0·040) for intensive chemotherapy versus hypomethylating agents. Hypomethylating agents did not confer an overall survival advantage for patients classified as having lower-risk disease (ie, myelodysplastic chronic myelomonocytic leukaemia with <10% blasts, CMML-0, or lower-risk CPSS). INTERPRETATION: These data suggest hypomethylating agents as the preferred therapy for patients with higher-risk chronic myelomonocytic leukaemia and those with myeloproliferative CMML. Our findings also suggest that CPSS is a valuable tool to identify patients who are most likely to benefit from hypomethylating agents. Further evidence from prospective cohorts would be desirable. FUNDING: The Austrian Group for Medical Tumor Therapy.


Assuntos
Antineoplásicos/uso terapêutico , Leucemia Mielomonocítica Crônica/tratamento farmacológico , Idoso , Azacitidina/uso terapêutico , Feminino , Humanos , Hidroxiureia/uso terapêutico , Estimativa de Kaplan-Meier , Leucemia Mielomonocítica Crônica/diagnóstico , Leucemia Mielomonocítica Crônica/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Resultado do Tratamento
13.
J Thromb Thrombolysis ; 51(1): 226-231, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32632558

RESUMO

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection has been linked to a higher risk of mortality compared to influenza, which is mainly due to severe secondary diseases, such as acute respiratory distress syndrome (ARDS). In turn, ARDS is characterized by an acute inflammation and an excessive activity of the coagulation cascade, rising the vulnerability for venous thromboembolic events. In order to investigate the relation of inflammation and the influence of coagulation factors on their release, human peripheral mononuclear blood cells (PBMCs) were treated with autologous serum, heparinized plasma and different doses of fibrin. Thereafter, the concentration of pro-inflammatory cytokines and chemokines in the secretome of PBMCs was measured by enzyme-linked immunosorbent assay. Our analyses revealed autologous serum to significantly increase the secretion of cytokines and chemokines after 24 h of incubation time. Furthermore, the addition of fibrin markedly increased the secretion of cytokines and chemokines by PBMCs in a dose-dependent manner. Consequently, in accordance with previous studies, our study outlines that anti-coagulation may constitute a promising tool for the treatment of SARS-CoV-2, reducing both, the cytokine storm, as well as the risk for thrombotic complications.


Assuntos
Coagulação Sanguínea , COVID-19/terapia , Síndrome da Liberação de Citocina , Fibrina , Inflamação , Coagulação Sanguínea/efeitos dos fármacos , Coagulação Sanguínea/imunologia , COVID-19/sangue , COVID-19/tratamento farmacológico , COVID-19/imunologia , Células Cultivadas , Quimiocinas/imunologia , Síndrome da Liberação de Citocina/sangue , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/etiologia , Relação Dose-Resposta a Droga , Fibrina/imunologia , Fibrina/farmacologia , Fibrinolíticos/farmacologia , Heparina/farmacologia , Humanos , Imunização Passiva , Inflamação/sangue , Inflamação/terapia , Leucócitos Mononucleares/efeitos dos fármacos , SARS-CoV-2
14.
Leukemia ; 35(4): 1053-1063, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-32728184

RESUMO

RNA editing-primarily conversion of adenosine to inosine (A > I)-is a widespread posttranscriptional mechanism, mediated by Adenosine Deaminases acting on RNA (ADAR) enzymes to alter the RNA sequence of primary transcripts. Hence, in addition to somatic mutations and alternative RNA splicing, RNA editing can be a further source for recoding events. Although RNA editing has been detected in many solid cancers and normal tissue, RNA editing in chronic lymphocytic leukemia (CLL) has not been addressed so far. We determined global RNA editing and recurrent, recoding RNA editing events from matched RNA-sequencing and whole exome sequencing data in CLL samples from 45 untreated patients. RNA editing was verified in a validation cohort of 98 CLL patients and revealed substantially altered RNA editing profiles in CLL compared with normal B cells. We further found that RNA editing patterns were prognostically relevant. Finally, we showed that ADAR knockout decreased steady state viability of MEC1 cells and made them more susceptible to treatment with fludarabine and ibrutinib in vitro. We propose that RNA editing contributes to the pathophysiology of CLL and targeting the RNA editing machinery could be a future strategy to maximize treatment efficacy.


Assuntos
Epigênese Genética , Perfilação da Expressão Gênica , Regulação Leucêmica da Expressão Gênica , Leucemia Linfocítica Crônica de Células B/genética , Edição de RNA , Transcriptoma , Adenosina Desaminase/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Elementos Alu , Linhagem Celular Tumoral , Aberrações Cromossômicas , Feminino , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Hibridização in Situ Fluorescente , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/terapia , Masculino , Pessoa de Meia-Idade , Mutação , Estadiamento de Neoplasias , Fases de Leitura Aberta , Proteínas de Ligação a RNA/genética
15.
ESC Heart Fail ; 8(1): 37-46, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33350605

RESUMO

AIMS: COVID-19, a respiratory viral disease causing severe pneumonia, also affects the heart and other organs. Whether its cardiac involvement is a specific feature consisting of myocarditis, or simply due to microvascular injury and systemic inflammation, is yet unclear and presently debated. Because myocardial injury is also common in other kinds of pneumonias, we investigated and compared such occurrence in severe pneumonias due to COVID-19 and other causes. METHODS AND RESULTS: We analysed data from 156 critically ill patients requiring mechanical ventilation in four European tertiary hospitals, including all n = 76 COVID-19 patients with severe disease course requiring at least ventilatory support, matched to n = 76 from a retrospective consecutive patient cohort of severe pneumonias of other origin (matched for age, gender, and type of ventilator therapy). When compared to the non-COVID-19, mortality (COVID-19 = 38.2% vs. non-COVID-19 = 51.3%, P = 0.142) and impairment of systolic function were not significantly different. Surprisingly, myocardial injury was even more frequent in non-COVID-19 (96.4% vs. 78.1% P = 0.004). Although inflammatory activity [C-reactive protein (CRP) and interleukin-6] was indifferent, d-dimer and thromboembolic incidence (COVID-19 = 23.7% vs. non-COVID-19 = 5.3%, P = 0.002) driven by pulmonary embolism rates (COVID-19 = 17.1% vs. non-COVID-19 = 2.6%, P = 0.005) were higher. CONCLUSIONS: Myocardial injury was frequent in severe COVID-19 requiring mechanical ventilation, but still less frequent than in similarly severe pneumonias of other origin, indicating that cardiac involvement may not be a specific feature of COVID-19. While mortality was also similar, COVID-19 is characterized with increased thrombogenicity and high pulmonary embolism rates.


Assuntos
COVID-19/complicações , Cardiomiopatias/etiologia , Doença Aguda , Idoso , COVID-19/mortalidade , COVID-19/terapia , Cardiomiopatias/mortalidade , Estudos de Casos e Controles , Feminino , Humanos , Unidades de Terapia Intensiva/estatística & dados numéricos , Tempo de Internação/estatística & dados numéricos , Masculino , Miocardite/etiologia , Miocardite/mortalidade , Pneumonia/complicações , Respiração Artificial , Estudos Retrospectivos , Centros de Atenção Terciária
17.
J Clin Med ; 9(6)2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32492882

RESUMO

BACKGROUND: In metastatic breast cancer (MBC) patients, no biomarker predicting benefit to a bevacizumab-containing therapy has been established yet. MicroRNAs (miRNAs) are involved in angiogenesis and treatment resistance and therefore could be of predictive value. METHODS: Profiling of 754 miRNAs was performed in tumor samples of 58 MBC patients treated with a bevacizumab-containing first-line regimen (learning set). Based on progression-free survival (PFS), patients were divided into responders (R) and non-responders (NR). Differentially expressed miRNAs between R and NR were analyzed in a cohort of 57 patients treated with first-line chemotherapy without bevacizumab (control set), to exclude miRNAs providing prognostic information. MiRNA candidates significantly associated with PFS in multivariate analysis were further validated in tumor samples of 203 patients treated within the phase III trial TANIA randomizing between chemotherapy either alone or with bevacizumab after progression on first-line bevacizumab. RESULTS: Low expression of miR-20a-5p (multivariate p = 0.035) and miR-21-5p (multivariate p = 0.004) were significantly associated with longer PFS in the learning set, but not in the control set. In samples from the TANIA trial, low expression of miR-20a-5p was also significantly associated with longer PFS (hazard ration (HR) 0.60; 95%-CI 0.37-0.89; p = 0.012) and longer overall survival (OS; HR 0.54; 95%-CI 0.32-0.83; p = 0.007) in the bevacizumab arm but not in the chemotherapy-only arm (PFS: HR 0.73, p = 0.119; OS: HR 1.01; p = 0.964). For miR-21-5p no significant association with PFS or OS in both treatment arms was observed. CONCLUSION: MiR-20a-5p expression in breast cancer tissue was predictive for a greater benefit from bevacizumab-containing therapy in two independent cohorts.

19.
Oncol Lett ; 19(2): 1551-1558, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31966080

RESUMO

The clinical decisions made when treating patients with metastatic cancer require knowledge of the current tumor extent and response to therapy. For the majority of solid tumors, a response assessment, which is based on imaging, is used to guide these decisions. However, measuring serum protein biomarkers (i.e. tumor markers) may be of additional use. Furthermore, tumor markers exhibit variable specificity and sensitivity and cannot therefore be solely relied upon when making decisions regarding cancer treatment. Therefore, there is a clinical requirement for the identification of specific, sensitive and quantitative biomarkers. In recent years, circulating cell-free DNA (cfDNA) and mutation-specific circulating cell-free tumor DNA (cftDNA) have been identified as novel potential biomarkers. In the current study, cfDNA and cftDNA were compared using imaging-based staging and current tumor markers in 15 patients with metastatic colorectal, pancreatic or breast cancer. These patients were treated at the Third Medical Department of Paracelsus Medical University Salzburg (Austria). The results of the current study demonstrated a statistically significant correlation between the concentration changes of cfDNA and cftDNA and response to treatment, which was assessed by imaging. A correlation was not indicated with current clinically used tumor markers, including carcinoembryonic antigen, carcinoma antigen 15-3 and carcinoma antigen 19-9. The present study also indicated a correlation between cfDNA and cftDNA and the tumor volume of metastatic lesions, which was not observed with the current clinically used tumor markers. In conclusion, cfDNA and cftDNA exhibit the potential to become novel biomarkers for the response assessment following cancer treatment, and may serve as a tool for the estimation of tumor volume. The current study further supports the increasingly important role of cfDNA and cftDNA as new monitoring tools for use during cancer therapy.

20.
Sci Transl Med ; 12(526)2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31941829

RESUMO

Overcoming drug resistance remains a key challenge to cure patients with acute and chronic B cell malignancies. Here, we describe a stromal cell-autonomous signaling pathway, which contributes to drug resistance of malignant B cells. We show that protein kinase C (PKC)-ß-dependent signals from bone marrow-derived stromal cells markedly decrease the efficacy of cytotoxic therapies. Conversely, small-molecule PKC-ß inhibitors antagonize prosurvival signals from stromal cells and sensitize tumor cells to targeted and nontargeted chemotherapy, resulting in enhanced cytotoxicity and prolonged survival in vivo. Mechanistically, stromal PKC-ß controls the expression of adhesion and matrix proteins, required for activation of phosphoinositide 3-kinases (PI3Ks) and the extracellular signal-regulated kinase (ERK)-mediated stabilization of B cell lymphoma-extra large (BCL-XL) in tumor cells. Central to the stroma-mediated drug resistance is the PKC-ß-dependent activation of transcription factor EB, regulating lysosome biogenesis and plasma membrane integrity. Stroma-directed therapies, enabled by direct inhibition of PKC-ß, enhance the effectiveness of many antileukemic therapies.


Assuntos
Proteína Quinase C beta/metabolismo , Apoptose/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Fosforilação/efeitos dos fármacos , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismo , Células Tumorais Cultivadas
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