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2.
J Cancer Res Clin Oncol ; 149(11): 8225-8234, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37062035

RESUMO

PURPOSE: For patients with cancer of unknown primary (CUP), treatment options are limited. Precision oncology, the interplay of comprehensive genomic profiling (CGP) and targeted therapies, aims to offer additional treatment options to patients with advanced and hard-to-treat cancers. We aimed to highlight the use of a molecular tumor board (MTB) in the therapeutic management of CUP patients. METHODS: In this single-center observational study, CUP patients, presented to the MTB of the Comprehensive Cancer Center Munich LMU, a tertiary care center, were analyzed retrospectively. Descriptive statistics were applied to describe relevant findings. RESULTS: Between June 2016 and February 2022, 61 patients with unfavorable CUP were presented to the MTB, detected clinically relevant variants in 74% (45/61) of patients, of which 64% (29/45) led to therapeutic recommendation. In four out of 29 patients (14%), the treatment recommendations were implemented, unfortunately without resulting in clinical benefit. Reasons for not following the therapeutic recommendation were mainly caused by the physicians' choice of another therapy (9/25, 36%), especially in the context of worsening of general condition, lost to follow-up (7/25, 28%) and death (6/25, 24%). CONCLUSION: CGP and subsequent presentation to a molecular tumor board led to a high rate of therapeutic recommendations in patients with CUP. Recommendations were only implemented at a low rate; however, late GCP diagnostic and, respectively, MTB referral were found more frequent for the patients with implemented treatment. This contrast underscores the need for early implementation of CGP into the management of CUP patients.


Assuntos
Neoplasias Primárias Desconhecidas , Humanos , Neoplasias Primárias Desconhecidas/diagnóstico , Neoplasias Primárias Desconhecidas/genética , Neoplasias Primárias Desconhecidas/terapia , Estudos Retrospectivos , Medicina de Precisão/métodos , Oncologia
3.
Ann Hematol ; 102(1): 99-106, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36409328

RESUMO

The prognostic impact of monocytosis has not yet been determined in patients with myelodysplastic syndromes (MDS). We examined absolute monocyte counts in the peripheral blood at the time of diagnosis in 1949 patients with a bone marrow blast count < 5%, a condition we call MDS < EB1 (MDS with a blast percentage lower than that of MDS with excess blasts 1, according to the WHO classification). Monocytosis (> 600/µl) was associated with higher median hemoglobin, WBC, and ANC, and more favorable karyotype (p = .001). Nevertheless, monocytosis was associated with shorter overall survival (OS) (108 vs. 126 months, p = .002) and earlier transformation into AML (p < .001). In patients with sideroblastic phenotype, the percentage of ring sideroblasts significantly correlated with the monocyte count (p = .005), and OS was significantly shorter when monocytosis was documented (88 vs. 132 months, p = .004). The survival disadvantage of patients with MDS < EB1 and peripheral blood monocytosis suggests that these patients suffer from a CMML-like disease. Even though they are generally classified as MDS with persistent monocytosis, such patients should be considered candidates for therapeutic options employed in CMML.


Assuntos
Medula Óssea , Síndromes Mielodisplásicas , Humanos , Prognóstico , Síndromes Mielodisplásicas/terapia , Síndromes Mielodisplásicas/tratamento farmacológico , Leucocitose , Contagem de Leucócitos
4.
Leuk Res ; 65: 1-4, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29216536

RESUMO

MDS patients may present with monocytic marrow proliferation not fulfilling criteria for CMML. We analyzed MDS patients with or without a marrow monocytic proliferation by following up the amount of monocytic proliferation and characterizing their molecular profile. 315 MDS patients of Duesseldorf MDS registry were divided into two groups: A) 183 patients with monocytic esterase positive cells in marrow and monocytes between 101 and 900/µl in blood and B) 132 patients without monocytic esterase positive cells in marrow and monocytes in blood ≤100/µl. Twenty patients of each group were screened with regard to ASXL1, TET2, RUNX1, SETBP1, NRAS, and SRSF2 using Illumina myeloid panel. Group A patients were older, had significantly higher WBC, hemoglobin levels, neutrophils and platelets. CMML evolution rates were 4.9% and 1.5%, respectively (p=n.s.). TET2, NRAS and SRFS2 mutation frequencies were higher in group A and four patients had coexisting TET2 and SRFS2 mutation, which was shown to be characteristic but not specific for CMML. MDS patients with marrow monocytic proliferation have a more CMML-like pheno- and genotype and develop CMML more often. Those patients could potentially be very early stages of CMML or represent a CMML-like myeloid neoplasma with marrow adherence of the monocytic cell population.


Assuntos
Medula Óssea/patologia , Leucemia Mielomonocítica Crônica/genética , Leucemia Mielomonocítica Crônica/patologia , Monócitos/patologia , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Medula Óssea/enzimologia , Proteínas de Transporte/genética , Proliferação de Células , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Proteínas de Ligação a DNA/genética , Dioxigenases , Esterases/metabolismo , Feminino , Genes ras , Testes Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Monócitos/enzimologia , Mutação , Taxa de Mutação , Proteínas Nucleares/genética , Prognóstico , Proteínas Proto-Oncogênicas/genética , Proteínas Repressoras/genética , Fatores de Processamento de Serina-Arginina/genética
5.
Leukemia ; 32(3): 736-743, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29064484

RESUMO

Cell adhesion in the multiple myeloma (MM) microenvironment has been recognized as a major mechanism of MM cell survival and the development of drug resistance. Here we addressed the hypothesis that the protein junctional adhesion molecule-A (JAM-A) may represent a novel target and a clinical biomarker in MM. We evaluated JAM-A expression in MM cell lines and in 147 MM patient bone marrow aspirates and biopsies at different disease stages. Elevated JAM-A levels in patient-derived plasma cells were correlated with poor prognosis. Moreover, circulating soluble JAM-A (sJAM-A) levels were significantly increased in MM patients as compared with controls. Notably, in vitro JAM-A inhibition impaired MM migration, colony formation, chemotaxis, proliferation and viability. In vivo treatment with an anti-JAM-A monoclonal antibody (αJAM-A moAb) impaired tumor progression in a murine xenograft MM model. These results demonstrate that therapeutic targeting of JAM-A has the potential to prevent MM progression, and lead us to propose JAM-A as a biomarker in MM, and sJAM-A as a serum-based marker for clinical stratification.


Assuntos
Biomarcadores Tumorais , Molécula A de Adesão Juncional/sangue , Mieloma Múltiplo/sangue , Mieloma Múltiplo/mortalidade , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Medula Óssea/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Expressão Gênica , Humanos , Molécula A de Adesão Juncional/genética , Masculino , Camundongos , Terapia de Alvo Molecular , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/patologia , Prognóstico
7.
Leukemia ; 30(8): 1725-33, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27046463

RESUMO

Mutations that activate FMS-like tyrosine kinase 3 (FLT3) are frequent occurrences in acute myeloid leukemia. Two distinct types of mutations have been described: internal duplication of the juxtamembranous domain (ITD) and point mutations of the tyrosine kinase domain (TKD). Although both mutations lead to constitutive FLT3 signaling, only FLT3-ITD strongly activates signal transducer and activator of transcription 5 (STAT5). In a murine transplantation model, FLT3-ITD induces a myeloproliferative neoplasm, whereas FLT3-TKD leads to a lymphoid malignancy with significantly longer latency. Here we report that the presence of STAT5 is critical for the development of a myeloproliferative disease by FLT3-ITD in mice. Deletion of Stat5 in FLT3-ITD-induced leukemogenesis leads not only to a significantly longer survival (82 vs 27 days) of the diseased mice, but also to an immunophenotype switch with expansion of the lymphoid cell compartment. Interestingly, we were able to show differential STAT5 activation in FLT3-ITD(+) myeloid and lymphoid murine progenitors. STAT5 target genes such as Oncostatin M were highly expressed in FLT3-ITD(+) myeloid but not in FLT3-ITD(+) lymphoid progenitor cells. Strikingly, FLT3-TKD expression in combination with Oncostatin M is sufficient to reverse the phenotype to a myeloproliferative disease in FLT3-TKD mice. Thus, lineage-specific STAT5 activation in hematopoietic progenitor cells predicts the FLT3(+)-mediated leukemic phenotype in mice.


Assuntos
Linhagem da Célula/genética , Células-Tronco Hematopoéticas/metabolismo , Leucemia Mieloide Aguda/patologia , Fator de Transcrição STAT5/genética , Ativação Transcricional/genética , Tirosina Quinase 3 Semelhante a fms/genética , Animais , Carcinogênese/genética , Leucemia Mieloide Aguda/genética , Células Progenitoras Linfoides/metabolismo , Camundongos , Mutação , Células Mieloides/metabolismo , Oncostatina M , Fator de Transcrição STAT5/metabolismo
9.
Oncogene ; 34(5): 578-88, 2015 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-24509876

RESUMO

Lung cancer is the leading cause of cancer-related deaths worldwide. Recently, we have shown that Notch1 inhibition resulted in substantial cell death of non-small cell lung cancer (NSCLC) cells in vitro. New compounds targeting Notch signal transduction have been developed and are now being tested in clinical trials. However, the tumorigenic role of individual Notch receptors in vivo remains largely unclear. Using a Kras(G12D)-driven endogenous NSCLC mouse model, we analyzed the effect of conditional Notch1 and Notch2 receptor deletion on NSCLC tumorigenesis. Notch1 deficiency led to a reduced early tumor formation and lower activity of MAPK compared with the controls. Unexpectedly, Notch2 deletion resulted in a dramatically increased carcinogenesis and increased MAPK activity. These mice died significantly earlier due to rapidly growing tumor burden. We found that Notch1 regulates Ras/MAPK pathway via HES1-induced repression of the DUSP1 promoter encoding a phosphatase specifically suppressing pERK1/2. Interestingly, Notch1 but not Notch2 ablation leads to decreased HES1 and DUSP1 expression. However, Notch2-depleted tumors showed an appreciable increase in ß-catenin expression, a known activator of HES1 and important lung cancer oncogene. Characteristically for ß-catenin upregulation, we found that the majority of Notch2-deficient tumors revealed an undifferentiated phenotype as determined by their morphology, E-Cadherin and TTF1 expression levels. In addition, these carcinomas showed aggressive growth patterns with bronchus invasion and obstruction. Together, we show that Notch2 mediates differentiation and has tumor suppressor functions during lung carcinogenesis, whereas Notch1 promotes tumor initiation and progression. These data are further supported by immunohistochemical analysis of human NSCLC samples showing loss or downregulation of Notch2 compared with normal lung tissue. In conclusion, this is the first study characterizing the in vivo functions of Notch1 and Notch2 in Kras(G12D)-driven NSCLC tumorigenesis. These data highlight the clinical importance of a thorough understanding of Notch signaling especially with regard to Notch-targeted therapies.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Transformação Celular Neoplásica/genética , Receptor Notch1/biossíntese , Receptor Notch2/biossíntese , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/biossíntese , Carcinoma Pulmonar de Células não Pequenas/patologia , Proliferação de Células/genética , Modelos Animais de Doenças , Fosfatase 1 de Especificidade Dupla/biossíntese , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/biossíntese , Humanos , Camundongos , Proteínas Proto-Oncogênicas p21(ras)/genética , Receptor Notch1/genética , Receptor Notch2/genética , Transdução de Sinais/genética , Fatores de Transcrição HES-1 , beta Catenina/biossíntese
11.
Eur J Vasc Endovasc Surg ; 39(6): 668-75, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20399126

RESUMO

OBJECTIVES: The search for markers predicting risk of plaque rupture in carotid atherosclerosis is still ongoing. Previous findings showed that pregnancy-associated plasma protein-A (PAPP-A) levels correlate with an adverse plaque morphology. However, the role of PAPP-A in plaque destabilisation is still uncertain. MATERIAL AND METHODS: Patients with carotid artery stenosis involved in the study were asymptomatic (n=29) and symptomatic (n=37). Carotid plaques were characterised by histology (n=33). Immunohistochemistry (n=17) was used to determine expression of PAPP-A and CD68 within the plaques. Serum levels of PAPP-A were measured by the enzyme-linked immunosorbent assay (ELISA). RESULTS: Circulating PAPP-A levels were significantly higher in patients with unstable versus stable plaques (0.10+/-0.06 vs. 0.07+/-0.04 microg ml(-1), p=0.047) and interestingly, in asymptomatic versus symptomatic patients (0.11+/-0.05 vs. 0.069+/-0.09 microg ml(-1), p=0.025). These differences remained statistically significant after adjustment for age, gender and degree of stenosis (p=0.050). PAPP-A expression in plaques correlated significantly with CD68 positive macrophages, cap-thickness and its serological values (r=+0.291, p<0.001, r=-0.639, p<0.001 and r=0.618, p<0.008, respectively). Furthermore, PAPP-A serum values demonstrated a significant positive predictive value of 68.8% for unstable plaques. CONCLUSION: Our present data confirmed the close relationship between expression of PAPP-A and plaque instability and furthermore correlated significantly with cap thickness. However, the question whether PAPP-A is a useful predictive marker of plaque instability remains unresolved.


Assuntos
Aterosclerose/sangue , Biomarcadores/sangue , Estenose das Carótidas/sangue , Proteína Plasmática A Associada à Gravidez/biossíntese , Idoso , Aterosclerose/complicações , Aterosclerose/patologia , Estenose das Carótidas/etiologia , Estenose das Carótidas/patologia , Ensaio de Imunoadsorção Enzimática , Feminino , Seguimentos , Humanos , Imuno-Histoquímica , Masculino , Prognóstico , Estudos Prospectivos , Índice de Gravidade de Doença
12.
Ultrasound Obstet Gynecol ; 23(4): 402-6, 2004 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15065194

RESUMO

Cytomegalovirus (CMV) is the most common cause of congenital infection worldwide. We report on a fatal fetal manifestation of primary maternal CMV infection including cerebellar hemorrhage and hydrops. The diagnosis was established by maternal serological tests, culture and polymerase chain reaction testing of amniotic fluid and fetal blood. The pregnancy was terminated. Postmortem examination confirmed the diagnosis.


Assuntos
Doenças Cerebelares/virologia , Hemorragia Cerebral/virologia , Infecções por Citomegalovirus/diagnóstico , Doenças Fetais/virologia , Complicações Infecciosas na Gravidez , Aborto Incompleto , Adulto , Doenças Cerebelares/diagnóstico , Doenças Cerebelares/diagnóstico por imagem , Hemorragia Cerebral/diagnóstico , Hemorragia Cerebral/diagnóstico por imagem , Infecções por Citomegalovirus/diagnóstico por imagem , Evolução Fatal , Feminino , Doenças Fetais/diagnóstico por imagem , Humanos , Gravidez , Complicações Infecciosas na Gravidez/diagnóstico , Ultrassonografia Pré-Natal/métodos
13.
Am J Pathol ; 152(5): 1281-9, 1998 May.
Artigo em Inglês | MEDLINE | ID: mdl-9588896

RESUMO

We compared 29 gastric carcinomas from patients with a variably strong family history for gastric cancer (group 1) with 36 gastric carcinomas from patients without a family history of this disease (group 2) for microsatellite instability (MSI) and loss of heterozygosity (LOH) with 12 microsatellite markers. Both study groups had similar proportions of histological types and tumor locations. Widespread MSI (alterations at > or = 6 loci) was seen in 5 of 29 (17%) of the tumors belonging to group 1 and in 4 of 36 (11%) group 2 tumors. MSI at a low level (alterations at 1 to 3 loci) was observed in 12 of 29 (41%) of tumors in group 1 and in 10 of 36 (28%) of tumors in group 2, differences that were not statistically significant. A significant difference with respect to low level MSI was observed between the two groups when considering the overall mutation rate of microsatellites. Seventeen of 281 (6%) analyzed microsatellite loci showed alterations in group 1 and 11 of 381 (2.9%) in group 2 (P = 0.046). Comparison of both types of MSI to the clinicopathological parameters in both groups revealed a significant association of low level MSI with advanced tumor stages (P = 0.046) in the group 2, whereas no such association was observed in group 1. In respect to LOH, a significant difference between the two groups was observed at chromosome 17p12, as 13 of 22 (59%) informative cases of group 1 showed LOH in comparison with 7 of 26 (27%) (P = 0.024) in group 2. No correlation of LOH at chromosome 17p12 to the pathological or clinical data was observed either in the two groups or in the study as a whole. Our data show that gastric carcinomas of patients with a positive family history of gastric cancer in group 1 are characterized by a higher mutation rate in respect to low level MSI, particularly at dinucleotide repeats, and by a higher frequency of LOH at chromosome 17p12, indicating that different genetic pathways are involved in the pathogenesis of gastric carcinomas arising in patients with and without a familial background of this disease.


Assuntos
Perda de Heterozigosidade/genética , Repetições de Microssatélites/genética , Neoplasias Gástricas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise Mutacional de DNA , DNA de Neoplasias/análise , Saúde da Família , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Proteína Supressora de Tumor p53/metabolismo
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