Wilm’s Tumour 1 (WT1) Mutations Are Associated with FLT3-ITD Mutation and Poor Prognosis in Normal Karyotype AML.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2302-2302
Author(s):  
Jude Fitzgibbon ◽  
Karin Summers ◽  
Ioannis Kakkas ◽  
Jane Stevens ◽  
Matthew Smith ◽  
...  
Keyword(s):  
Overall Survival ◽  
Direct Sequencing ◽  
Mutation Screening ◽  
Uniparental Disomy ◽  
Normal Karyotype ◽  
Positive Association ◽  
Poor Overall Survival ◽  
Significant Positive Association ◽  
Mutation Profile ◽  
Wt1 Mutation

Abstract Our group has previously shown an association between acquired uniparental disomy 11p and homozygous gene mutation of Wilm’s tumour 1 (WT1) in a patient with normal karyotype acute myeloid leukemia (AML). Based on this observation the incidence of WT1 mutation was investigated in a cohort of normal karyotype AMLs. Mutation screening was performed on 70 patients (median age 55 years, range 19–78 years) by a PCR-direct sequencing approach using intronic primers flanking exons 2–10 of WT1. Mutation status was inferred from the resultant traces and confirmed by use of TOPO TA cloning and sequence analysis of the corresponding mutated clones. Mutations were detected in 7/70 (10%) patients; these typically resulted in insertion of 1–16 bp that led to the disruption of the DNA binding domain of the protein. The mutation profile of FLT3-ITD, NPM and CEBPA was also examined in this cohort of patients to compare the additional mutational events present in WT1 mutated and non-mutated cases. A significant positive association was observed between WT1 and FLT3-ITD mutation with 6/7 WT1 mutated cases having a FLT3-ITD compared to 20/63 non mutated cases (p=0.01). There was no association between mutations in WT1 and either of the good prognostic mutational markers, CEBPA and NPM. All 6 patients with both WT1 and FLT3 mutations were refractory to intensive induction chemotherapy with WT1 mutation showing a trend towards a worse overall survival when compared with the non-mutated group (p=0.07). We can conclude therefore that WT1 is mutated in 10% of normal karyotype AML, is positively associated with FLT3-ITD status and identifies a putative subgroup of normal karyotype AML who fail to achieve remission with conventional cytotoxic therapy and have a poor overall survival. Validation of this data in larger series would support the inclusion of WT1 in the current molecular risk stratification of normal karyotype AML based on CEBPA, NPM and FLT3-ITD status.

Prevalence and Prognostic Implications of WT1 Mutations in Pediatric AML Â: Report from Children’s Oncology Group

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 143-143 ◽  
Author(s):  
Jessica A Pollard ◽  
Rong Zeng ◽  
Phoenix Ho ◽  
Todd Alonzo ◽  
Robert Gerbing ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Direct Sequencing ◽  
Prognostic Significance ◽  
Normal Karyotype ◽  
Wt1 Gene ◽  
Molecular Alterations ◽  
Microcapillary Electrophoresis ◽  
Pediatric Aml ◽  
Wbc Count ◽  
Wt1 Mutation

Abstract Molecular alterations of the WT1 gene have been associated with clinical outcome in adult AML. We evaluated the prevalence and prognostic significance of WT1 mutations in a cohort of 842 pediatric patients treated on pediatric AML trials CCG-2941, CCG-2961, or COG-AAML03P1. Exons 6–10 of the WT1 gene were evaluated by microcapillary electrophoresis and direct sequencing. Of the 842 samples diagnostic specimens analyzed, 68 (8%) contained mutations in exon 7 (n=62), exon 8 (n= 5), or exon 9 (n=1). Correlation analyses were done to determine whether the presence of WT1 mutations is associated with laboratory and disease characteristics and clinical outcome. There were no differences in sex, race, median diagnostic blast %, or median diagnostic WBC count between samples from patients carrying WT1 mutations and those from patients who did not; however, such mutations were less common in the younger patients (age, 0–2 years; p<0.001) and in those with FAB M5 AML (p=0.009). Our evaluation of clinical outcome showed that the rate of complete remission after the first round of induction chemotherapy for those with and without WT1 mutations 74% and 80%, respectively (P=0.3) Actuarial overall survival (OS) from the time of study entry for patients with WT1 mutations was 35% vs. 52% for those without WT1 mutations; p=0.014. Corresponding event-free survival (EFS) was also significantly worse for those with WT1 mutations (27% vs. 41%; p=0.013). We also evaluated associations between WT1 mutations and cytogenetic and molecular alterations. In the patients with WT1 mutations, 31% had inv(16) or t(8;21). There was also substantial overlap between WT1 mutation and FLT3/ITD, i.e., 29% of those carrying a WT1 mutation were FLT3/ITD- positive, whereas only 7% of patients without WT1 were FLT3/ITD-positive (p<0.001). In addition, 11q23 alterations were rare in patients with WT1 mutations (4% vs. 24%; p=0.002). Prognostic significance of WT1 mutations in FLT3/ITD-negative patients was determined. In a comparison of samples from FLT3/ITD-negative patients with WT1 mutations and those from patients who did not carry the 2 mutations, the OS (51% vs. 54%, respectively; p=0.5) and the corresponding EFS (34% and 43%, respectively; p=0.22) were not significantly different. The prognostic significance of the WT1 mutation was also determined in patients with a normal karyotype who were FLT3/ITD-negative. No significant differences were found in the OS (40% and 55%, respectively; p=0.23) or in the corresponding EFS values (31% and 45%, respectively; p=0.335). We conclude that about 8% of children with AML carry WT1 mutations, including novel mutations identified in exon 8. These mutations are associated with other cytogenetic and molecular alterations, and despite their overall association with poor outcome, the prognostic significance of WT1 mutations is less pronounced once the data are corrected for FLT3/ITD and cytogenetic abnormalities.

Mutations of the TP53 Gene Occur in 13.4% of Acute Myeloid Leukemia and Are Strongly Associated with a Complex Aberrant Karyotype.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1913-1913
Author(s):  
Claudia Schoch ◽  
Frank Dicker ◽  
Hannes Herholz ◽  
Susanne Schnittger ◽  
Wolfgang Kern ◽  
...  
Keyword(s):  
Tp53 Mutation ◽  
Fusion Gene ◽  
Direct Sequencing ◽  
Mutation Screening ◽  
Molecular Genetic ◽  
Treatment Strategies ◽  
Normal Karyotype ◽  
Tp53 Gene ◽  
Trisomy 8 ◽  
Tp53 Mutations

Abstract The TP53 gene is the most frequently mutated gene in human tumors identified so far. In a prior study we demonstrated that 78% of AML with complex aberrant karyotype show a mutation of the TP53 gene. The aim of this study was to determine the frequency of TP53 mutations in an unselected cohort of AML and to analyze the relation to cytogenetic and molecular genetic aberrations. In total 149 AML cases were examined by chromosome banding analysis and screened for FLT3-length mutations (FLT3-LM), MLL partial tandem duplication (MLL-PTD), NPM1 mutations, and TP53 mutations. The cohort included cases with t(8;21) (n=10), t(15;17) (n=6), inv(16) (n=4), 11q23/MLL-rearrangement (n=6), trisomy 8 sole (n=13), AML with normal karyotype (n=46), AML with complex aberrant karyotype defined as showing 3 and more clonal abnormalities but no balanced rearrangement leading to a leukemia specific fusion gene (n=26), and AML with other abnormalities (n=38). FLT3-LM were observed in 21, MLL-PTD in 4, and NPM1-Mutations in 26 cases. TP53 mutation screening of exons 3–9 was performed by denaturing high performance liquid chromatography (DHPLC). All mutations detected were verified by direct sequencing. Overall, TP53 mutations were detected in 20 of the 149 cases (13.4%). Within this cohort of TP53 mutated cases, coincidences of FLT3-LM and MLL-PTD, respectively, with TP53 mutation were detected in one case each. A complex aberrant karyotype was present in 17 of 20 cases (85%) with TP53 mutation. The remaining 3 cases with TP53 mutation showed a normal karyotype, a trisomy 8, and t(8;21) as the sole abnormality, respectively. Therefore, we confirmed a high incidence of TP53 mutations in AML with complex aberrant karyotype (17/26, 65.4%). On the other hand TP53 mutations are very rare in AML without a complex aberrant karyotype (3/123, 2.4%). Furthermore, we divided AML with complex aberrant karyotype into two subgroups:AML with “typical” complex aberrant karyotype showing a deletion of at least one of the following regions: 5q31, 7q31, 17p13 (definition according to Schoch et al. GCC, 2005) andAML with “untypical” complex aberrant karyotype comprizing all others. Interestingly, the frequency of TP53 mutations within the “typical” complex aberrant karyotype group was 75% (15/20) while in the “untypical” group it was 33% (2/6) (p=0.138). In conclusion, the overall incidence of TP53 mutations is low in AML. TP53 mutations are highly associated with AML and complex aberrant karyotype and occur very infrequently in all other cytogenetic subgroups (p<0.001). They occur frequently in particular in the subgroup showing a typical pattern of chromosomal deletions (5q, 7q, 17p). TP53 mutations might explain in part the chemoresistance of AML with complex aberrant karyotype. In addition to cytogenetics a rapid diagnostic screening for TP53 mutations could be a valuable tool to identify a subgroup of AML with poor prognosis. This would allow the early assignment of patients to alternative treatment strategies using also options targeting the TP53 pathway.

Perceived Overprotection and Its Association With Quality of Life in Dementia

GeroPsych ◽  
2019 ◽  
Vol 32 (3) ◽  
pp. 125-134
Author(s):  
Mechthild Niemann-Mirmehdi ◽  
Andreas Häusler ◽  
Paul Gellert ◽  
Johanna Nordheim
Keyword(s):  
Quality Of Life ◽  
Patient Autonomy ◽  
Positive Association ◽  
Well Being ◽  
Negative Association ◽  
Significant Positive Association ◽  
Cross Sectional ◽  
People With Dementia ◽  
Mental Well Being

Abstract. To date, few studies have focused on perceived overprotection from the perspective of people with dementia (PwD). In the present examination, the association of perceived overprotection in PwD is examined as an autonomy-restricting factor and thus negative for their mental well-being. Cross-sectional data from the prospective DYADEM study of 82 patient/partner dyads (mean age = 74.26) were used to investigate the association between overprotection, perceived stress, depression, and quality of life (QoL). The analyses show that an overprotective contact style with PwD has a significant positive association with stress and depression, and has a negative association with QoL. The results emphasize the importance of avoiding an overprotective care style and supporting patient autonomy.

The Nexus Between Urbanisation and Human Empowerment: Income Group Based Findings of Bidirectional Causality

2019 ◽  
Vol 64 (1) ◽  
pp. 5-15
Author(s):  
Christos Kollias ◽  
Panayiotis Tzeremes
Keyword(s):  
Human Rights ◽  
Positive Association ◽  
Income Group ◽  
Academic Discourse ◽  
Access To Education ◽  
Democratic Institutions ◽  
Significant Positive Association ◽  
Public Action ◽  
Income Groups ◽  
Democratic Rule

Abstract The economic and social drivers of democratisation and the emergence and establishment of democratic institutions are longstanding themes of academic discourse. Within this broad body of literature, it has been argued that the process of urbanisation is also conducive to the emergence and consolidation of democracy through a number of different channels. Cities offer better access to education and facilitate organised public action and the demand for more democratic rule and respect of human rights. The nexus between urbanisation and human rights is the theme that is taken up in the present paper. Using a sample of 123 countries for the period 1981–2011, the paper examines empirically the association between urbanisation and human empowerment using the Cingranelli-Richards Index. In broad terms, the findings reported herein do not point to a strong nexus across all income groups. Nevertheless, there is evidence suggesting the presence of such a statistically significant positive association in specific cases.

Empirical analysis on corporate environmental performance and environmental disclosure in an emerging market context

2020 ◽  
Vol 15 (6) ◽  
pp. 1061-1082 ◽  
Author(s):  
Merve Acar ◽  
Hüseyin Temiz
Keyword(s):  
Environmental Performance ◽  
Emerging Market ◽  
Positive Association ◽  
Corporate Environmental Performance ◽  
Tobit Regression ◽  
Environmental Reporting ◽  
Environmental Disclosure ◽  
Significant Positive Association ◽  
Content Type ◽  
Environmental Disclosures

PurposeThe purpose of this study is to investigate the association between environmental performance of firms and the level of voluntary environmental disclosure in emerging markets.Design/methodology/approachWe used tobit regression OLS and t-test methods to reveal the association between environmental performance and the level of voluntary environmental disclosure.FindingsWe find a significant positive association between the level of discretionary environmental disclosures and corporate environmental performance. The result is in line with the arguments of economics disclosure theory that argues environmentally good performers disclose more.Practical implicationsMany of the environmentally good firms in Turkey are also listed in the “BIST Sustainability Index,” and this situation can be the result of the relative power of external regulations. Accordingly, it can be suggested to increase the community and governmental pressures for environmental reporting but also gives importance to increase intrinsic motivations for companies to engage in disclosure practices.Originality/valueThis study shed light on relation between environmental performance and environmental disclosure in an emerging market context. Also, it is revisited that the relation between environmental performance and the level of environmental disclosure by testing two different predictions on the level of environmental disclosures.

scholarly journals Can Anhedonia Be Considered a Suicide Risk Factor? A Review of the Literature

Medicina ◽  
2019 ◽  
Vol 55 (8) ◽  
pp. 458 ◽  
Author(s):  
Bonanni ◽  
Gualtieri ◽  
Lester ◽  
Falcone ◽  
Nardella ◽  
...  
Keyword(s):  
Suicidal Behavior ◽  
Affective Disorders ◽  
Suicide Attempts ◽  
Positive Association ◽  
Negative Association ◽  
Schizophrenia Spectrum Disorders ◽  
Post Traumatic Stress ◽  
Significant Positive Association ◽  
Search Terms ◽  
Schizophrenia Spectrum

Background and Objectives: At present, data collected from the literature about suicide and anhedonia are controversial. Some studies have shown that low levels of anhedonia are associated with serious suicide attempts and death by suicide, while other studies have shown that high levels of anhedonia are associated with suicide. Materials and Methods: For this review, we searched PubMed, Medline, and ScienceDirect for clinical studies published from 1 January 1990 to 31 December 2018 with the following search terms used in the title or in the abstract: “anhedonia AND suicid*.” We obtained a total of 155 articles; 133 items were excluded using specific exclusion criteria, the remaining 22 articles included were divided into six groups based on the psychiatric diagnosis: mood disorders, schizophrenia spectrum disorders, post-traumatic stress disorder (PTSD), other diagnoses, attempted suicides, and others (healthy subjects). Results: The results of this review reveal inconsistencies. Some studies reported that high anhedonia scores were associated with suicidal behavior (regardless of the diagnosis), while other studies found that low anhedonia scores were associated with suicidal behavior, and a few studies reported no association. The most consistent association between anhedonia and suicidal behavior was found for affective disorders (7 of 7 studies reported a significant positive association) and for PTSD (3 of 3 studies reported a positive association). In the two studies of patients with schizophrenia, one found no association, and one found a negative association. For patients who attempted suicide (undiagnosed), one study found a positive association, one a positive association only for depressed attempters, and one a negative association. Conclusions: We found the most consistent positive association for patients with affective disorders and PTSD, indicating that the assessment of anhedonia may be useful in the evaluation of suicidal risk.

scholarly journals Autophagic Markers in Chordomas: Immunohistochemical Analysis and Comparison with the Immune Microenvironment of Chordoma Tissues

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2169
Author(s):  
Georgia Karpathiou ◽  
Maroa Dridi ◽  
Lila Krebs-Drouot ◽  
François Vassal ◽  
Emmanuel Jouanneau ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Immune Cells ◽  
Immune Cell ◽  
Positive Association ◽  
Immunohistochemical Analysis ◽  
Vascular Density ◽  
Immune Microenvironment ◽  
Significant Positive Association ◽  
Sequestosome 1 ◽  
Cell Expression

Chordomas are notably resistant to chemotherapy. One of the cytoprotective mechanisms implicated in chemoresistance is autophagy. There are indirect data that autophagy could be implicated in chordomas, but its presence has not been studied in chordoma tissues. Sixty-one (61) chordomas were immunohistochemically studied for autophagic markers and their expression was compared with the expression in notochords, clinicopathological data, as well as the tumor immune microenvironment. All chordomas strongly and diffusely expressed cytoplasmic p62 (sequestosome 1, SQSTM1/p62), whereas 16 (26.2%) tumors also showed nuclear p62 expression. LC3B (Microtubule-associated protein 1A/1B-light chain 3B) tumor cell expression was found in 44 (72.1%) tumors. Autophagy-related 16‑like 1 (ATG16L1) was also expressed by most tumors. All tumors expressed mannose-6-phosphate/insulin-like growth factor 2 receptor (M6PR/IGF2R). LC3B tumor cell expression was negatively associated with tumor size, while no other parameters, such as age, sex, localization, or survival, were associated with the immunohistochemical factors studied. LC3B immune cell expression showed a significant positive association with programmed death-ligand 1 (PD-L1)+ immune cells and with a higher vascular density. ATG16L1 expression was also positively associated with higher vascular density. Notochords (n = 5) showed different immunostaining with a very weak LC3B and M6PR expression, and no p62 expression. In contrast to normal notochords, autophagic factors such as LC3B and ATG16L1 are often present in chordomas, associated with a strong and diffuse expression of p62, suggesting a blocked autophagic flow. Furthermore, PD-L1+ immune cells also express LC3B, suggesting the need for further investigations between autophagy and the immune microenvironment.

scholarly journals Melanoma Brain Metastases in the Era of Targeted Therapy and Checkpoint Inhibitor Therapy

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1489
Author(s):  
John M. Rieth ◽  
Umang Swami ◽  
Sarah L. Mott ◽  
Mario Zanaty ◽  
Michael D. Henry ◽  
...  
Keyword(s):  
Overall Survival ◽  
Brain Metastases ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Performance Status ◽  
Multivariable Analysis ◽  
Treatment Strategies ◽  
Poor Performance Status ◽  
Poor Overall Survival ◽  
Melanoma Brain Metastases

Brain metastases commonly develop in melanoma and are associated with poor overall survival of about five to nine months. Fortunately, new therapies, including immune checkpoint inhibitors and BRAF/MEK inhibitors, have been developed. The aim of this study was to identify outcomes of different treatment strategies in patients with melanoma brain metastases in the era of checkpoint inhibitors. Patients with brain metastases secondary to melanoma were identified at a single institution. Univariate and multivariable analyses were performed to identify baseline and treatment factors, which correlated with progression-free and overall survival. A total of 209 patients with melanoma brain metastases were identified. The median overall survival of the cohort was 5.3 months. On multivariable analysis, the presence of non-cranial metastatic disease, poor performance status (ECOG 2–4), whole-brain radiation therapy, and older age at diagnosis of brain metastasis were associated with poorer overall survival. Craniotomy (HR 0.66, 95% CI 0.45–0.97) and treatment with a CTLA-4 checkpoint inhibitor (HR 0.55, 95% CI 0.32–0.94) were the only interventions associated with improved overall survival. Further studies with novel agents are needed to extend lifespan in patients with brain metastases in melanoma.

scholarly journals PIM2 and NF-κβ gene expression in a sample of AML and ALL Egyptian patients and its relevance to response to treatment

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Shymaa Kamal El Din Abed El Rahman ◽  
Sanaa Sayed Abd Elshafy ◽  
Mohamed Samra ◽  
Hala Mohammed Ali ◽  
Rabab Afifi Mohamed
Keyword(s):  
Overall Survival ◽  
Acute Leukemia ◽  
De Novo ◽  
Lymphoblastic Leukemia ◽  
Expression Level ◽  
Response To Treatment ◽  
Control Group ◽  
Poor Overall Survival ◽  
Healthy Control ◽  
Complete Blood Counts

Abstract Background The relation between PIM2 and the transcriptional factor NF κβ have been controversial in literature. The significance of PIM2 and NF-κβ genes expression on the incidence of acute leukemia (AML and ALL) and its relevance to the response rate was evaluated. Sixty de novo acute leukemia patients were stratified in 2 groups: 30 acute myeloid leukemia (AML) and 30 acute lymphoblastic leukemia (ALL) patients and compared to 30 sex- and age-matched controls. The expression level of PIM2 and NF κβ genes was measured using quantitative real-time polymerase chain reaction (QRT-PCR). The patients were followed with clinical examination and complete blood counts. Results The expression level of PIM2 gene was significantly higher in AML patients (P<0.001) compared to the control group. The mean expression level of NF κβ gene was significantly high in AML and ALL patients compared to the healthy control group (P=0.037 and P<0.001; respectively). The overall survival in AML patients was higher in NF κβ gene low expressers compared to high expressers (P=0.047). The number of AML patients who achieved complete remission was significantly higher in PIM2 gene low expressers in comparison to PIM2 gene high expressers (P=0.042). Conclusion PIM2 and NF κβ genes might have a role in the pathogenesis of acute leukemia, poor overall survival, and failure of response to induction therapy.

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