scholarly journals Prognostic Roles of BRAF, KIT, NRAS, IGF2R and SF3B1 Mutations in Mucosal Melanomas

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2216
Author(s):  
Joanna P. Wróblewska ◽  
Dora Dias-Santagata ◽  
Adam Ustaszewski ◽  
Cheng-Lin Wu ◽  
Masakazu Fujimoto ◽  
...  
Keyword(s):  
Prognostic Value ◽  
Sanger Sequencing ◽  
Multivariate Analyses ◽  
Independent Predictor ◽  
Advanced Stage ◽  
Nras Mutation ◽  
Recurrent Mutations ◽  
Clinicopathologic Parameters ◽  
Univariate Analyses ◽  
Generation Sequencing

Background: The prognostic value of commonly recurrent mutations remains unclear in mucosal melanomas. Methods: Clinicopathologic parameters of 214 cases of mucosal melanomas diagnosed in 1989–2020 in several clinical institutions were analyzed. NRAS, KIT, BRAF, IGF2R and SF3B1 mutational analyses by Sanger sequencing and next generation sequencing-based assay were performed in a subset of cases. Results: Of the triple (BRAF, NRAS, NF1)-negative cases, APC, KIT and KRAS are detected mainly in sinonasal, vulvovaginal and anorectal melanomas, respectively. NRAS, KIT, BRAF, IGF2R and SF3B1 mutations are detected in 19% (37/198), 22% (44/197), 12% (25/201), 16% (22/138) and 15% (20/133) of cases, respectively. In univariate analyses, advanced stage (p = 0.016), 65 years or older (p = 0.048) and presence of ulceration (p = 0.027) are significantly correlated with worse overall survival (OS), respectively. NRAS mutation significantly correlates with worse OS (p = 0.028) and worse melanoma-specific survival (MSS) (p = 0.03) for all cases of mucosal melanomas. In multivariate analyses, NRAS mutation remains as an independent predictor of worse OS (p = 0.036) and worse MSS (p = 0.024). Conclusion: NRAS mutation is a predictor of worse survival, independent of stage in mucosal melanomas. The significance of frequently mutated IGF2R in mucosal melanomas remains unclear.

scholarly journals Relevance of comorbidities and antithrombotic medication as risk factors for reoperation in patients with chronic subdural hematoma

2021 ◽  
Author(s):  
Alexander Younsi ◽  
Lennart Riemann ◽  
Cleo Habel ◽  
Jessica Fischer ◽  
Christopher Beynon ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Multivariate Analyses ◽  
Independent Predictor ◽  
Perioperative Complications ◽  
Chronic Subdural Hematoma ◽  
Western Society ◽  
Increased Risk ◽  
Surgical Evacuation ◽  
Antithrombotic Medication ◽  
Univariate Analyses

AbstractIn an aging Western society, the incidence of chronic subdural hematomas (cSDH) is continuously increasing. In this study, we reviewed our clinical management of cSDH patients and identified predictive factors for the need of reoperation due to residual or recurrent hematomas with a focus on the use of antithrombotic drugs. In total, 623 patients who were treated for cSDH with surgical evacuation between 2006 and 2016 at our department were retrospectively analyzed. Clinical and radiological characteristics and laboratory parameters were investigated as possible predictors of reoperation with univariate and multivariate analyses. Additionally, clinical outcome measures were compared between patients on anticoagulants, on antiplatelets, and without antithrombotic medication. In univariate analyses, patients on anticoagulants and antiplatelets presented significantly more often with comorbidities, were significantly older, and their risk for perioperative complications was significantly increased. Nevertheless, their clinical outcome was comparable to that of patients without antithrombotics. In multivariate analysis, only the presence of comorbidities, but not antithrombotics, was an independent predictor for the need for reoperations. Patients on antithrombotics do not seem to necessarily have a significantly increased risk for residual hematomas or rebleeding requiring reoperation after cSDH evacuation. More precisely, the presence of predisposing comorbidities might be a key independent risk factor for reoperation. Importantly, the clinical outcomes after surgical evacuation of cSDH are comparable between patients on anticoagulants, antiplatelets, and without antithrombotics.

scholarly journals Indeterminate and oncogenic potential: CHIP vs CHOP mutations in AML with NPM1 alteration

Leukemia ◽  
2021 ◽  
Author(s):  
Luca Vincenzo Cappelli ◽  
Manja Meggendorfer ◽  
Constance Baer ◽  
Niroshan Nadarajah ◽  
Stephan Hutter ◽  
...  
Keyword(s):  
Prognostic Value ◽  
Clonal Evolution ◽  
Molecular Remission ◽  
Oncogenic Potential ◽  
Clonal Hematopoiesis ◽  
Paired Samples ◽  
Evolution Analysis ◽  
Recurrent Mutations ◽  
Generation Sequencing ◽  
Worse Prognosis

AbstractIn AML patients, recurrent mutations were shown to persist in remission, however, only some have a prognostic value and persistent mutations might therefore reflect a re-established premalignant state or truly active disease causing relapse. We aimed to dissect the nature of co-mutations in NPM1 mutated AML where the detection of NPM1 transcripts allows highly specific and sensitive detection of complete molecular remission (CMR). We analysed 150 consecutive patients who achieved CMR following intensive treatment by next generation sequencing on paired samples at diagnosis, CMR and relapse (38/150 patients). Patients with persistence or the acquisition of non-DTA (DNMT3A, TET2, ASXL1) mutations at CMR (23/150 patients, 15%) have a significantly worse prognosis (EFS HR = 2.7, p = 0.003; OS HR = 3.6, p = 0.012). Based on clonal evolution analysis of diagnostic, CMR and relapse samples, we redefine pre-malignant mutations and include IDH1, IDH2 and SRSF2 with the DTA genes in this newly defined group. Only the persistence or acquisition of CHOP-like (clonal hematopoiesis of oncogenic potential) mutations was significantly associated with an inferior outcome (EFS HR = 4.5, p = 0.0002; OS HR = 5.5, p = 0.002). Moreover, the detection of CHOP-like mutations at relapse was detrimental (HR = 4.5, p = 0.01). We confirmed these findings in a second independent whole genome sequencing cohort.

scholarly journals Cardiac magnetic resonance derived global longitudinal strain outperfoms established functional parameters in prognostication after ST-elevation myocardial infarction

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
M Holzknecht ◽  
M Reindl ◽  
C Tiller ◽  
I Lechner ◽  
T Hornung ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Magnetic Resonance ◽  
Magnetic Resonance ◽  
Prognostic Value ◽  
Longitudinal Strain ◽  
Independent Predictor ◽  
Global Longitudinal Strain ◽  
Left Ventricular ◽  
Lv Function ◽  
St Elevation

Abstract Background Left ventricular ejection fraction (LVEF) is the parameter of choice for left ventricular (LV) function assessment and risk stratification of patients with ST-elevation myocardial infarction (STEMI); however, its prognostic value is limited. Other measures of LV function such as global longitudinal strain (GLS) and mitral annular plane systolic excursion (MAPSE) might provide additional prognostic information post-STEMI. However, comprehensive investigations comparing these parameters in terms of prediction of hard clinical events following STEMI are lacking so far. Purpose We aimed to investigate the comparative prognostic value of LVEF, MAPSE and GLS by cardiac magnetic resonance (CMR) imaging in the acute stage post-STEMI for the occurrence of major adverse cardiac events (MACE). Methods This observational study included 407 consecutive acute STEMI patients treated with primary percutaneous coronary intervention (PCI). Comprehensive CMR investigations were performed 3 [interquartile range (IQR): 2–4] days after PCI to determine LVEF, GLS and MAPSE as well as myocardial infarct characteristics. Primary endpoint was the occurrence of MACE defined as composite of death, re-infarction and congestive heart failure. Results During a follow-up of 21 [IQR: 12–50] months, 40 (10%) patients experienced MACE. LVEF (p=0.005), MAPSE (p=0.001) and GLS (p<0.001) were significantly related to MACE. GLS showed the highest prognostic value with an area under the curve (AUC) of 0.71 (95% CI 0.63–0.79; p<0.001) compared to MAPSE (AUC: 0.67, 95% CI 0.58–0.75; p=0.001) and LVEF (AUC: 0.64, 95% CI 0.54–0.73; p=0.005). After multivariable analysis, GLS emerged as sole independent predictor of MACE (HR: 1.22, 95% CI 1.11–1.35; p<0.001). Of note, GLS remained associated with MACE (p<0.001) even after adjustment for infarct size and microvascular obstruction. Conclusion CMR-derived GLS emerged as strong and independent predictor of MACE after acute STEMI with additive prognostic validity to LVEF and parameters of myocardial damage. Funding Acknowledgement Type of funding source: None

scholarly journals Prevalence of Epiretinal Membrane among Subjects in a Health Examination Program in Japan

Life ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 93
Author(s):  
Hiroshi Shimizu ◽  
Ryo Asaoka ◽  
Takashi Omoto ◽  
Yuri Fujino ◽  
Shingo Mitaki ◽  
...  
Keyword(s):  
Epiretinal Membrane ◽  
Multivariate Analyses ◽  
Multiple Logistic Regression Analysis ◽  
Body Height ◽  
Older Age ◽  
Health Examination ◽  
Multiple Logistic Regression ◽  
Older Subjects ◽  
Fundus Photographs ◽  
Univariate Analyses

The prevalence of an epiretinal membrane (ERM) was elucidated using a dataset from a health examination program database in Japan. From the cohort database, 5042 eyes of 2552 subjects were included. The presence of an ERM, cellophane macular reflex (CMR), or preretinal macular fibrosis (PMF) was detected using color fundus photographs, and crude and age-standardized prevalence were obtained. To further assess the possible risk factors of ERM, background parameters were compared between ERM+ and − groups, and multiple logistic regression analysis was performed. ERM was detected in fundus photographs of 275 eyes (eye-based prevalence of 5.5%) from 217 subjects (subject-based prevalence of 8.5%). CMR was detected in 169 eyes (3.4%) of 138 subjects (5.4%), and PMF was detected in 106 eyes (2.1%) of 97 subjects (3.8%). By univariate analyses, compared with ERM− eyes or subjects, higher Scheie’s H grade (p < 0.0001), S grade (p < 0.0001), and glaucoma prevalence (p = 0.0440) were found in ERM+ eyes, and older age (p < 0.0001), more frequent histories of hypertension (p = 0.0033) and hyperlipidemia (p = 0.0441), and more frequent uses of medication for hypertension (p = 0.0034) and hyperlipidemia (p = 0.0074), shorter body height (p = 0.0122), and higher systolic blood pressure (p = 0.0078), and thicker intimal medial thickness (p = 0.0318) were found in ERM+ subjects. By multivariate analyses, older age (p < 0.0001, estimate = 0.05/year) was the only significant factor of ERM prevalence. Age-standardized prevalence of ERM was calculated to be 2.4%, 6.7%, and 13.3% for all ages, subjects older than 40 years, and subjects older than 65 years, respectively. We reported the prevalence of ERM and its subclasses in Japanese subjects. Since its prevalence is remarkably high in older subjects, an ERM can be seen as an important cause of visual impairment in Japan and in areas of the world where individuals live to an advanced age.

Patient human leukocyte antigen (HLA) genotype may predict response to anti-programmed death receptor 1 (anti-PD1) in advanced melanoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21512-e21512
Author(s):  
Oliver Oey ◽  
Muhammad Adnan Khattak ◽  
Afaf Abed ◽  
Tarek Meniawy ◽  
Anna Reid ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Prognostic Value ◽  
Cox Regression ◽  
Multivariate Analyses ◽  
Locally Advanced ◽  
White Blood Cells ◽  
Advanced Melanoma ◽  
Hla B27 ◽  
Melanoma Patients ◽  
Hla Genotype

e21512 Background: Anti-PD-1 therapy has improved the outcome of advanced melanoma patients with a 5-year survival rate of about 40-45%. However, biomarkers predictive of response to immune checkpoint blockade therapy are lacking. There is limited data on the utility of host germline human leucocyte antigen (HLA) genotype as a predictor of response to anti-PD-1 therapy in advanced melanoma. Here, we investigate the prognostic value of HLA in predicting survival outcomes of patients with unresectable locally advanced, metastatic melanoma on anti-PD-1 therapy. Methods: Blood was collected from 113 metastatic melanoma patients who were treated with anti-PD-1 therapy at two major oncology centres in Western Australia. High quality DNA was extracted from white blood cells and subsequently HLA-I and HLA-II typed using clinically validated assay. Univariate analyses were conducted using Cox regression model correlating homozygosity at HLA-I and HLA-II loci with overall survival (OS). HLA-A and HLA-B were classified into 12 supertypes and correlated with OS. Multivariate analyses were performed while controlling for age, gender, prior therapy, BRAF mutation status, ECOG performance status and presence of liver and brain metastases. Results: Homozygosity at HLA-I or HLA-II loci was not associated with OS. However, the absence of HLA-B62 supertype was associated with a trend towards improved OS (HR: 0.53 [95% CI:0.25-1.10]; P = 0.09) as reported previously. Notably, the absence of HLA-B27 supertype was associated with improved OS which was statistically significant (HR: 0.45 [95% CI:0.24-0.85]; P = 0.01). In multivariate analyses, the prognostic value of HLA-B27 supertype (HR: 0.38 [95% CI:0.19-0.76]; P = 0.006) was maintained, whereas the prognostic value of HLA-B62 supertype significantly improved (HR: 0.42 [95% CI:0.19-0.94]; P = 0.03). Conclusions: Our results suggest a limited role of HLA homozygosity in predicting survival of melanoma patients treated with anti-PD-1 therapy. However, we identified that the absence of HLA-B62 and HLA-B27 supertype is associated with improved survival benefit. Therefore, HLA-B27 and HLA-B62 supertype may be used as adjunct biomarkers of response to anti-PD-1 therapy in patients with melanoma in addition to PD-L1 status, pending validation in prospective randomised clinical trials.

scholarly journals Prognostic value of CLIC3 mRNA overexpression in bladder cancer

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e8348
Author(s):  
Mei Chen ◽  
Shufang Zhang ◽  
Xiaohong Wen ◽  
Hui Cao ◽  
Yuanhui Gao
Keyword(s):  
Gene Expression ◽  
Bladder Cancer ◽  
Mrna Expression ◽  
Prognostic Value ◽  
Multivariate Analyses ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Functional Enrichment ◽  
Receptor Interaction ◽  
Normal Tissues

Background Human intracellular chloride channel 3 (CLIC3) is involved in the development of various cancers, but the expression and prognostic value of CLIC3 mRNA in bladder cancer (BC) remain unclear. Methods The gene expression data and clinical information of CLIC3 were obtained from the Gene Expression Omnibus (GEO) database and verified in the Oncomine and The Cancer Genome Atlas (TCGA) database. The expression of CLIC3 mRNA in BC tissues and adjacent normal tissues was detected by quantitative real-time polymerase chain reaction (qRT-PCR). The Kaplan-Meier method was used to analyze the relationship between the expression of CLIC3 mRNA and the prognosis of BC. Cox univariate and multivariate analyses were performed on the overall survival and tumor-specific survival of BC patients. The genes coexpressed with CLIC3 were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). CLIC3-related signal transduction pathways in BC were explored with gene set enrichment analysis (GSEA). Results The expression of CLIC3 mRNA in BC tissues was higher than that in normal tissues (P < 0.01). High CLIC3 mRNA expression was associated with age (P = 0.021) and grade (P = 0.045) in BC patients. High CLIC3 mRNA expression predicted a poor prognosis in BC patients (P < 0.05). Cox univariate and multivariate analyses showed that high CLIC3 mRNA expression was associated with tumor-specific survival in BC patients (P < 0.05). Functional enrichment analyses indicated that CLIC3 may be significantly associated with the cell cycle, focal adhesion, the extracellular matrix (ECM) receptor interaction and the P53 signaling pathway. Conclusions CLIC3 mRNA is highly expressed in BC, and its high expression is related to the adverse clinicopathological factors and prognosis of BC patients. CLIC3 can be used as a biomarker for the prognosis of BC patients.

scholarly journals Identification of Genetic Hereditary Predisposition to Hematologic Malignancies By Clinical Next-Generation Sequencing

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3854-3854 ◽  
Author(s):  
Amy E Knight Johnson ◽  
Lucia Guidugli ◽  
Kelly Arndt ◽  
Gorka Alkorta-Aranburu ◽  
Viswateja Nelakuditi ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Sanger Sequencing ◽  
Family Members ◽  
Hematologic Malignancies ◽  
Dyskeratosis Congenita ◽  
Molecular Diagnostic ◽  
Next Generation ◽  
Hereditary Predisposition ◽  
Ngs Data ◽  
Generation Sequencing

Abstract Introduction: Myelodysplastic syndrome (MDS) and acute leukemia (AL) are a clinically diverse and genetically heterogeneous group of hematologic malignancies. Familial forms of MDS/AL have been increasingly recognized in recent years, and can occur as a primary event or secondary to genetic syndromes, such as inherited bone marrow failure syndromes (IBMFS). It is critical to confirm a genetic diagnosis in patients with hereditary predisposition to hematologic malignancies in order to provide prognostic information and cancer risk assessment, and to aid in identification of at-risk or affected family members. In addition, a molecular diagnosis can help tailor medical management including informing the selection of family members for allogeneic stem cell transplantation donors. Until recently, clinical testing options for this diverse group of hematologic malignancy predisposition genes were limited to the evaluation of single genes by Sanger sequencing, which is a time consuming and expensive process. To improve the diagnosis of hereditary predisposition to hematologic malignancies, our CLIA-licensed laboratory has recently developed Next-Generation Sequencing (NGS) panel-based testing for these genes. Methods: Thirty six patients with personal and/or family history of aplastic anemia, MDS or AL were referred for clinical diagnostic testing. DNA from the referred patients was obtained from cultured skin fibroblasts or peripheral blood and was utilized for preparing libraries with the SureSelectXT Enrichment System. Libraries were sequenced on an Illumina MiSeq instrument and the NGS data was analyzed with a custom bioinformatic pipeline, targeting a panel of 76 genes associated with IBMFS and/or familial MDS/AL. Results: Pathogenic and highly likely pathogenic variants were identified in 7 out of 36 patients analyzed, providing a positive molecular diagnostic rate of 20%. Overall, 6 out of the 7 pathogenic changes identified were novel. In 2 unrelated patients with MDS, heterozygous pathogenic sequence changes were identified in the GATA2 gene. Heterozygous pathogenic changes in the following autosomal dominant genes were each identified in a single patient: RPS26 (Diamond-Blackfan anemia 10), RUNX1 (familial platelet disorder with propensity to myeloid malignancy), TERT (dyskeratosis congenita 4) and TINF2 (dyskeratosis congenita 3). In addition, one novel heterozygous sequence change (c.826+5_826+9del, p.?) in the Fanconi anemia associated gene FANCA was identified. . The RNA analysis demonstrated this variant causes skipping of exon 9 and results in a premature stop codon in exon 10. Further review of the NGS data provided evidence of an additional large heterozygous multi-exon deletion in FANCA in the same patient. This large deletion was confirmed using array-CGH (comparative genomic hybridization). Conclusions: This study demonstrates the effectiveness of using NGS technology to identify patients with a hereditary predisposition to hematologic malignancies. As many of the genes associated with hereditary predisposition to hematologic malignancies have similar or overlapping clinical presentations, analysis of a diverse panel of genes is an efficient and cost-effective approach to molecular diagnostics for these disorders. Unlike Sanger sequencing, NGS technology also has the potential to identify large exonic deletions and duplications. In addition, RNA splicing assay has proven to be helpful in clarifying the pathogenicity of variants suspected to affect splicing. This approach will also allow for identification of a molecular defect in patients who may have atypical presentation of disease. Disclosures No relevant conflicts of interest to declare.

scholarly journals Assay of frequency and spectrum of genetic variants in TTN in healthy russian population

2021 ◽  
Vol 8 (5) ◽  
pp. 29-37
Author(s):  
Yu. A. Vakhrushev ◽  
A. A. Kozyreva ◽  
S. V. Zhuk ◽  
O. P. Rotar ◽  
A. A. Kostareva
Keyword(s):  
Next Generation Sequencing ◽  
Genetic Variants ◽  
Sanger Sequencing ◽  
Heart Diseases ◽  
Genetic Research ◽  
Russian Population ◽  
Next Generation ◽  
Data Bases ◽  
International Data ◽  
Generation Sequencing

Background. Gene TTN associated with all types of cardiomyopathy, however its large size (294 b.p.) warrants a lot of individual unique genetic variants or variants with low frequency, that aggravates their interpretation. Besides that nowadays there is no data about spectrum of variants in this gene in healthy Russian population. Recognition frequency and spectrum of variants in gene TTN in healthy Russian population will allow us to use it for interpretation results of molecular genetic research for patients with different heart pathology, and define prognosis for different heart diseases.Objective. Recognize frequency and spectrum of single nucleotide and truncating variants in gene TTN in healthy Russian population and compare it with international data bases, and evaluate level of pathogenicity these variants and their distributing across titin structure.Design and methods. 192 men in age 55,8±6,6 years were tested with next-generation sequencing. Identified genetic variants were confirmed by Sanger sequencing. Results. Allele missense variant frequency (with frequency less than 0.1%) in TTN in healthy Russian population amount to 15.1 %, and truncating variants — 0.52 %. 37,9 % of them were variants of unknown significance, 62 % — likely-benign and 0.1 % — benign. There was no pathological and likely-pathological variants. Identified genetic variants distributed throughout the titin structure.Conclusion. Received result is congruent с international data bases and researches. Expended laboratory method (Next generation sequencing and confirmation with Sanger sequencing) can be used both in clinical practice, and in creating data bases of genetic variants in healthy Russian population.

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