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Blood ◽  
2021 ◽  
Vol 138 (Supplement 2) ◽  
pp. LBA-4-LBA-4
Author(s):  
Masayuki Umeda ◽  
Jing Ma ◽  
Benjamin J. Huang ◽  
Kohei Hagiwara ◽  
Tamara Westover ◽  
...  

Abstract Children with acute myeloid leukemia (AML) have a dismal prognosis due to a high relapse rate; however, the molecular basis leading to relapsed pediatric AML has not yet been fully characterized. To define the spectrum of alterations common at relapse, we performed integrated profiling of 136 relapsed pediatric AML cases with RNA sequencing (RNA-seq), whole-genome sequencing, and target-capture sequencing. In addition to well-characterized fusion oncoproteins, such as those involving KMT2A (n=36, 26.5%) or NUP98 (n=18, 13.2%), we also identified somatic mutations in UBTF (upstream binding transcription factor) in 12 of 136 cases (8.8%) of this relapsed cohort. Somatic alterations of the UBTF gene, which encodes a nucleolar protein that is a component of the RNA Pol I pre-initiation complex to ribosomal DNA promoters, have rarely been observed in AML. In our cohort, all alterations can be described as heterozygous in-frame exon 13 tandem duplications (UBTF-TD), either at the 3' end of exon 13 of UBTF or of the entire exon 13 (Fig. A). As we noticed limited detection in our pipeline as a result of complex secondary indels alongside the duplications, we established a soft-clipped read-based screening method to detect UBTF-TD more efficiently. Applying the screening to RNA-seq data of 417 additional pediatric AMLs from previous studies and our clinical service, we identified 15 additional UBTF-TDs, many of which have not been previously reported. At the amino acid level, UBTF-TDs caused amino acid insertions of variable sizes (15-181 amino acids), duplicating a portion of high mobility group domain 4 (HMG4), which includes short leucine-rich sequences. UBTF-TD AMLs commonly occurred in early adolescence (median age: 12.6, range: 2.4-19.6), and 19 of the total 27 cases had either normal karyotype (n=12) or trisomy 8 (n=7). UBTF-TD is mutually exclusive from other recurrent fusion oncoproteins, such as NUP98 and KMT2A rearrangements (Fig. B), but frequently occurred with FLT3-ITD (44.4%) or WT1 mutations (40.7%). The median variant allele fraction (VAF) of the UBTF-TD was 48.0% (range: 9.7-66.7%). In four cases with data at multiple disease time points, the identical UBTF-TDs were present at high allele fractions at all time points, suggesting that UBTF-TD is a clonal alteration. tSNE analysis of the transcriptome dataset showed that UBTF-TD AMLs share a similar expression pattern with NPM1 mutant and NUP98-NSD1 AML subtypes, including NKX2-3 and HOXB cluster genes (Fig. C) . Altogether, these findings suggest that UBTF-TD is a unique subtype of pediatric AML. To address the impact of UBTF-TD expression in primary hematopoietic cells, we introduced UBTF-TD and UBTF wildtype expression vectors into cord blood CD34+ cells via lentiviral transduction. UBTF-TD expression promotes colony-forming activity and cell growth, yielding cells with a persistent blast-like morphology (Fig. D). Further, transcriptional profiling of these cells demonstrated expression of HOXB genes and NKX2-3, similar to UBTF-TD AMLs in patients, indicating that UBTF-TD is sufficient to induce the leukemic phenotype. To investigate the prevalence of UBTF-TDs in larger de novo AML cohorts, we applied the above UBTF-TD screening method to the available de novo AML cohorts of TCGA (n=151, adult), BeatAML (n=220, pediatric and adult), and AAML1031 (n=1035, pediatric). We identified UBTF-TDs in 4.3% (45/1035) of the pediatric AAML1031 cohort, while the alteration is less common (0.9%: 3/329, p=0.002) in the adult AML cohorts (Fig. E). In the AAML1031 cohort, UBTF-TDs remain mutually exclusive with known molecular subtypes of AML and commonly occur with FLT3-ITD (66.7%) and WT1 (40.0%) mutations and either normal karyotype or trisomy 8. The presence of UBTF-TDs in the AAML1031 cohort is associated with a poor outcome (Fig. F, median overall survival, 2.3 years) and MRD positivity; multivariate analysis revealed that UBTF-TD and WT1 are independent risk factors for overall survival within FLT3-ITD+ AMLs. In conclusion, we demonstrate UBTF-TD defines a unique subtype of AMLs that previously lacked a clear oncogenic driver. While independent of subtype-defining oncogenic fusions, UBTF-TD AMLs are associated with FLT3-ITD and WT1 mutations, adolescent age, and poor outcomes. These alterations have been under-recognized by standard bioinformatic approaches yet will be critical for future risk-stratification of pediatric AML. Figure 1 Figure 1. Disclosures Iacobucci: Amgen: Honoraria; Mission Bio: Honoraria. Miller: Johnson & Johnson's Janssen: Current Employment. Mullighan: Pfizer: Research Funding; Illumina: Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; Amgen: Current equity holder in publicly-traded company.


2021 ◽  
Vol 2021 ◽  
pp. 1-7
Author(s):  
Pan Wang ◽  
Wei-sheng Xiao ◽  
Yue-hua Li ◽  
Xiao-ping Wu ◽  
Hong-bo Zhu ◽  
...  

Gastric cancer (GC) is still a vital malignant cancer across the world with unsatisfactory prognostic results. Matrilin-3 (MATN3) is a member of the extracellular matrix (ECM) protein family. The present research intends to explore the expression level of MATN3 in patients with GC and to explore the prognosis significance of MATN3. In this study, we observed that the MATN3 expression was remarkably upregulated in GC samples in contrast to noncancer samples. Clinical analyses unveiled that high MATN3 expression was related to age, tumor status, and clinical stages. Survival analyses unveiled that patients with high MATN3 expression displayed a poorer overall survival and progression-free survival than those with low MATN3 expression. The AUC of the relevant ROC curve for 1 year, 3 years, and 5 years of survival is 0.571, 0.596, and 0.720, separately. Multivariate assays revealed that MATN3 expression and stage were independent predictors of poor prognosis of GC patients. A meta-analysis unveiled that high MATN3 expression was tightly associated with better overall survival. Overall, our data indicated that MATN3 may have a diagnostic and prognostic value for patients with advanced gastric cancer and assist to improve clinical outcomes for GC patients.


2021 ◽  
Vol 11 ◽  
Author(s):  
Zhiyang Zhang ◽  
Penglian Gao ◽  
Zhengqi Bao ◽  
Linggong Zeng ◽  
Junyi Yao ◽  
...  

ObjectiveClear cell carcinoma (CCC) of the endometrium is an uncommon yet aggressive tumor. Few cohort studies are reporting the overall survival time of CCC patients. This study aimed to retrospectively analyze the clinicopathologic features, molecular characteristics and survival data of 27 endometrial CCC patients to improve the understanding of CCC.MethodsThe clinicopathologic features, molecular characteristics and survival data total of 27 CCC patients admitted to the BBMU affiliated hospital (Anhui, China) between January 2005 and December 2018 were retrospectively analyzed. Kaplan-Meier method was used to analyze the prognosis-related factors.ResultsThe median age of the patients was 60 years (range; 39 to 81 years). The average tumor size was 3.8 cm (range; 0.8 to 13.0cm). Myometrial infiltration greater than 50% was reported in 55.6% of the patients, while the Ki-67 index greater than 50% was reported in 70.4% of the patients. The patients’ FIGO (2009) surgical stages were as follows: 18 I, 3 II, 4 III, and 2 IV. Besides, 7 (25.6%) patients had lymphovascular invasion, 3 (11.1%) patients with distant metastasis, including 1 patient with bone metastasis, and 2 with liver metastasis. Adjuvant treatment included 7 with chemotherapy alone, 9 with radiotherapy alone, and 9 with both radiotherapy and chemotherapy. The median overall survival time from the time of CCC diagnosis was 56 months. ER and PR showed negative expression and P16 showed patchy immunostaining. 18 (63%) cases showed Napsin A positive expression. Loss of MSH2, MSH6 and PTEN were seen in 5, 4 and 7 cases respectively. All cases showed HER-2/nue negative expression.ConclusionCCC is a rare and invasive tumor. Age of diagnosis, FIGO stage, tumor size, myometrial infiltration, lymphovascular invasion, distant metastasis, Ki-67 index and P53 expression are important indicators to evaluate patient’s prognosis (P = 0.048, P < 0.001, P = 0.016, P = 0.043, P = 0.001, P < 0.001, P = 0.026, and P = 0.007, respectively). CCC has a worse prognosis than endometrioid carcinoma (P = 0.002), and there is no significant difference when compared with uterine papillary serous carcinoma (P = 0.155).


Author(s):  
Lingling Wu ◽  
Bharat Narasimhan ◽  
Kirtipal Bhatia ◽  
Kam S. Ho ◽  
Chayakrit Krittanawong ◽  
...  

Background Despite advances in resuscitation medicine, the burden of in‐hospital cardiac arrest (IHCA) remains substantial. The impact of these advances and changes in resuscitation guidelines on IHCA survival remains poorly defined. To better characterize evolving patient characteristics and temporal trends in the nature and outcomes of IHCA, we undertook a 20‐year analysis of a national database. Methods and Results We analyzed the National Inpatient Sample (1999–2018) using International Classification of Diseases , Ninth Revision and Tenth Revision, Clinical Modification ( ICD‐9‐CM and ICD‐10‐CM ) codes to identify all adult patients suffering IHCA. Subgroup analysis was performed based on the type of cardiac arrest (ie, ventricular tachycardia/ventricular fibrillation or pulseless electrical activity‐asystole). An age‐ and sex‐adjusted model and a multivariable risk‐adjusted model were used to adjust for potential confounders. Over the 20‐year study period, a steady increase in rates of IHCA was observed, predominantly driven by pulseless electrical activity‐asystole arrest. Overall, survival rates increased by over 10% after adjusting for risk factors. In recent years (2014–2018), a similar trend toward improved survival is noted, though this only achieved statistical significance in the pulseless electrical activity‐asystole cohort. Conclusions Though the ideal quality metric in IHCA is meaningful neurological recovery, survival is the first step toward this. As overall IHCA rates rise, overall survival rates are improving in tandem. However, in more recent years, these improvements have plateaued, especially in the realm of ventricular tachycardia/ventricular fibrillation‐related survival. Future work is needed to better identify characteristics of IHCA nonsurvivors to improve resource allocation and health care policy in this area.


2021 ◽  
Vol 8 ◽  
Author(s):  
Wei Yang ◽  
Fusheng Ge ◽  
Shuaibing Lu ◽  
Zhiming Shan ◽  
Liangqun Peng ◽  
...  

Numerous studies have shown that long uncoded RNA (lncRNA) MSC-AS1 may play an important role in the occurrence and development of some types of cancer. However, its role in gastric cancer has rarely been discussed. This study aimed to clarify the association between lncRNA MSC-AS1 and gastric cancer using The Cancer Genome Atlas (TCGA) database. We determined the expression of MSC-AS1 using the Wilcoxon rank sum test; in addition, logistic regression was applied to evaluate the association between MSC-AS1 and clinicopathological characteristics. Also, Kaplan-Meier and Cox regression were used to evaluate the relationship between MSC-AS1 and survival. A nomogram was conducted to predict the impact of MSC-AS1 on prognosis. Moreover, Gene Set enrichment analysis (GSEA) was performed to annotate the biological function of MSC-AS1. Quantitative analysis of immune infiltration was carried out by single-set GSEA (ssGSEA). The MSC-AS1 level was elevated in gastric cancer tissues. An increased MSC-AS1 level was significantly correlated with T stage (odds ratio [OR] = 2.55 for T3 and T4 vs. T1 and T2), histological type (OR = 5.28 for diffuse type vs. tubular type), histological grade (OR = 3.09 for grade 3 vs. grades 1 and 2), TP53 status (OR = 0.55 for mutated vs. wild type), and PIK3CA status (OR = 0.55 for mutated vs. wild type) (all p < 0.05) by univariate logistic regression. Kaplan-Meier survival analysis showed high MSC-AS1 expression had a poor overall survival [hazard ratio (HR) = 1.75; 95% confidence interval (CI): 1.25–2.45; p = 0.001] and progression-free interval (HR = 1.47; 95% CI: 1.03–2.10; p = 0.034). Multivariate survival analysis revealed that MSC-AS1 expression (HR = 1.681; 95% CI: 1.057–2.673; p = 0.028) was independently correlated with overall survival. GSEA demonstrated that the P38/MAPK pathway, the VEGF pathway, the cell adhesion molecules cams, the NOD-like receptor signaling pathway were differentially enriched in the high MSC-AS1 expression phenotype. SsGSEA and Spearman correlation revealed the relationships between MSC-AS1 and macrophages, NK cells, and Tems were the strongest. Coregulatory proteins were included in the PPI network. Upregulated lncRNA MSC-AS1 might be a potential biomarker for the diagnosis and prognosis of gastric cancer.


2021 ◽  
Vol 11 ◽  
Author(s):  
Ziwen Tao ◽  
Yuying Ruan ◽  
Zhi Peng ◽  
Kai Zhang ◽  
Yanjing Gao

BackgroundThe efficacy of transarterial chemoembolization (TACE) combined with endoscopic therapy for unresectable hepatocellular carcinoma with esophagogastric varices remains unclear.MethodsThe study has been registered on ClinicalTrials.gov with the number NCT05017922 (https://register.clinicaltrials.gov). Eligible patients were divided into combined group (received TACE plus endoscopic therapy) and control group (only received TACE). The occurrence of death and bleeding episodes during the follow-up was recorded. Kaplan–Meier analysis was used to compare outcomes between the two groups. Cox proportional hazard model was used to determine independent predictors for the survival.ResultsEighty-nine patients were included, 42 in the combined group, others in the control group. During the follow-up, 51 patients died, the 1-year, 2-year, and 3-year survival rates were 64.9%, 45.5%, and 34.5%. The cumulative survival was significantly higher in the combined group than in the control group (p = 0.027); the 1-year, 2-year, and 3-year survival rates were 75.5%, 55.9%, 43.8% and 55.0%, 35.9%, 26.6%, respectively. Forty-four patients experienced bleeding, the bleeding rate was significantly higher in the control group than in the combined group (77.4% vs. 56.8%, p = 0.016). Multivariate analysis showed that treatment, hemoglobin, portal vein tumor thrombosis, and aspartate aminotransferase were independent predictors for overall survival; the first three factors were also independent predictors for bleeding-free survival. Patients who received primary prophylaxis had longer overall survival (p = 0.042) and bleeding-free survival (p = 0.029) than those who received secondary prophylaxis.ConclusionsTACE combined with endoscopic therapy significantly improved survival and reduced bleeding rates in unresectable hepatocellular carcinoma with esophagogastric varices patients. Portal vein tumor thrombosis was a strong negative prognostic factor for both overall survival and bleeding-free survival. Primary prophylaxis improved survival benefits compared with secondary prophylaxis.


Author(s):  
Adam J. Lamble ◽  
Lisa Eidenschink Brodersen ◽  
Todd A. Alonzo ◽  
Jim Wang ◽  
Laura Pardo ◽  
...  

PURPOSE Increased CD123 surface expression has been associated with high-risk disease characteristics in adult acute myeloid leukemia (AML), but has not been well-characterized in childhood AML. In this study, we defined CD123 expression and associated clinical characteristics in a uniformly treated cohort of pediatric patients with newly diagnosed AML enrolled on the Children's Oncology Group AAML1031 phase III trial ( NCT01371981 ). MATERIALS AND METHODS AML blasts within diagnostic bone marrow specimens (n = 1,040) were prospectively analyzed for CD123 protein expression by multidimensional flow cytometry immunophenotyping at a central clinical laboratory. Patients were stratified as low-risk or high-risk on the basis of (1) leukemia-associated cytogenetic and molecular alterations and (2) end-of-induction measurable residual disease levels. RESULTS The study population was divided into CD123 expression–based quartiles (n = 260 each) for analysis. Those with highest CD123 expression (quartile 4 [Q4]) had higher prevalence of high-risk KMT2A rearrangements and FLT3-ITD mutations ( P < .001 for both) and lower prevalence of low-risk t(8;21), inv(16), and CEBPA mutations ( P < .001 for all). Patients in lower CD123 expression quartiles (Q1-3) had similar relapse risk, event-free survival, and overall survival. Conversely, Q4 patients had a significantly higher relapse risk (53% v 39%, P < .001), lower event-free survival (49% v 69%, P < .001), and lower overall survival (32% v 50%, P < .001) in comparison with Q1-3 patients. CD123 maintained independent significance for outcomes when all known contemporary high-risk cytogenetic and molecular markers were incorporated into multivariable Cox regression analysis. CONCLUSION CD123 is strongly associated with disease-relevant cytogenetic and molecular alterations in childhood AML. CD123 is a critical biomarker and promising immunotherapeutic target for children with relapsed or refractory AML, given its prevalent expression and enrichment in patients with high-risk genetic alterations and inferior clinical outcomes with conventional therapy.


2021 ◽  
Author(s):  
Jing Xue ◽  
Xianzhao Yang ◽  
Feng Jiang

Abstract Background: Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death worldwide. Steroid 5 alpha-reductase 3 (SRD5A3) was reported to be up-regulated in many types of cancer. However, its expression and role in HCC remains to be elucidated. We aim to evaluate the significance of SRD5A3 expression in HCC by using analysis of a public dataset from The Cancer Genome Atlas (TCGA).Methods: The relationship between clinical pathologic features and SRD5A3 were analyzed with the Kolmogorov‐Smirnov test and the logistic regression. Cox regression and the Kaplan-Meier method were used to assess the clinicopathologic characteristics associated with overall survival (OS) in TCGA patients. In addition, GSEA was used to predict potential hallmarks associated with different expression of SRD5A3 on transcriptional sequences from TCGA database.Results: SRD5A3 was highly expressed in HCC tumor tissue compared to normal tissue. A total of 184 upregulated DEGs (differentially expressed genes) and 58 downregulated DEGs were identified between high expression and low expression of SRD5A3. Among them, 22 hub genes mainly belonging to the keratin and MUC family demonstrated by connectivity degree in the PPI network were screened out. Kaplan-Meier method showed that HCC patients in the high SRD5A3 expression group had poorer overall survival (OS, HR=2.26(1.58-3.24), p<0.001). In addition, cell cycle mitotic, cell cycle checkpoints, mitotic nuclear division, Q-glycan processing, protein O-linked glycosylation were differentially enriched in the high SRD5A3 expression phenotype pathway. In addition, SRD5A3 expression level has significant correlations with infiltrating levels of Th17 (R = -0.238, p < 0.001), Cytotoxic cells (R = -0.234, p < 0.001) and Th2 cells (R = 0.258, p < 0.001) in HCC.Conclusions: High expression of SRD5A3 was significantly correlated with poor prognosis in HCC patients. It may be a potential biomarker in HCC.


Author(s):  
Melika Kooshki Forooshani ◽  
Rosa Scarpitta ◽  
Giuseppe Nicolò Fanelli ◽  
Mario Miccoli ◽  
Antonio Giuseppe Naccarato ◽  
...  

: Breast cancer (BC) is a heterogeneous disease and the most prevalent malignant tumor in women worldwide. The majority of BC cases are positive for estrogen receptor (ER) and progesterone receptor (PgR), both known to be involved in cancer pathogenesis, progression, and invasion. In line with this, hormonal deprivation therapy appears to be a useful tool and an effective treatment for these BC subtypes. Unfortunately, prognosis among patients with hormone-negative tumors or therapy-refractory and metastatic patients remains poor. Novel biomarkers are urgently needed in order to predict the course of the disease, make better therapy decisions and improve the overall survival of patients. In this respect, the androgen receptor (AR), a member of the hormonal nuclear receptor superfamily and ER and PgR, emerges as an interesting feature widely expressed in human BCs. Despite the advances, the precise tumorigenic mechanism of AR and the role of its endogenous ligands are yet not well-understood. In this review, we aim to elaborate on the prognostic impact of AR expression and current AR-targeting approaches based on previous studies investigating AR's role in different BC subtypes.


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