Co-mutations of KRAS/BRAF and TP53 or the high tumor mutation burden to predict survival in patients with biliary tract carcinoma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16650-e16650
Author(s):  
Lingling Guo ◽  
Xiaoxia Kou ◽  
Panpan Song ◽  
Xiaoyu Zhang ◽  
Hongjuan Zhang ◽  
...  
Keyword(s):  
Biliary Tract ◽  
Poor Prognosis ◽  
Clinical Decision Making ◽  
Clinical Decision ◽  
Biliary Tract Carcinoma ◽  
Rank Test ◽  
Braf Mutations ◽  
Tumor Mutation Burden ◽  
Synonymous Mutations ◽  
Mutation Burden

e16650 Background: Biliary tract carcinoma (BTC), including cholangiocarcinoma and gallbladder carcinoma, is the second most common type of hepatobiliary cancer. Patients with BTC always show poor prognosis, here we revealed the molecular landscape of BTC in the Chinese population and evaluated the role of different mutations in informing prognosis. Methods: Formalin-Fixed Paraffin-Embedded (FFPE) or freshly-sampled tumor tissues from 59 BTC patients were conducted next-generation sequencing of 620 genes related to oncogenesis. Tumor mutation burden (TMB) value represents the number of non-synonymous mutations per mega base pairs in each sample. Kaplan-Meier survival curves were generated and compared using the log-rank test. Results: Altogether, 59 patients have mutations mainly in TP53, Ras/Raf, PI3K, CDK signaling pathways and SWI/SNF complex. The most frequently mutated gene was TP53(53%), followed by KRAS(23%), ARID1A(17%), ATM(12%), CDKN2A(10%), SMAD4(8%), BRCA2(8%), STK11(7%), BRAF(5%), IDH1(5%) and FGFR3 (3%). Noticeably, only one patient with FGFR2 fusion was detected. The Median TMB of these patients is 2.80 Muts/Mbp (0-36.52 Muts/Mbp). Existing data showed that KRAS/BRAF alterations were associated with a worse overall survival (OS) (median OS 166d vs. 294d, p= 0.063). Further analysis indicated that RAS/BRAF mutations were often co-current with TP53 alternations. And patients with coaltered RAS/BRAF and TP53 demonstrated the worst prognosis (media OS 123d vs. 294d, p= 0.087). In addition, a higher TMB ( > 2.80 Muts/Mb) was also associated with a worse survival (median OS 174d vs. 355d, p= 0.085). Conclusions: We identified KRAS/BRAF, or co-mutations with TP53 and high TMB could predict poor prognosis in BTC patients. These findings will be useful for clinical decision making in patients with refractory biliary tract cancer and for risk stratification of patients in future clinical studies.

scholarly journals Tumor Mutation Burden: A Predictive Biomarker for Gastric Cancer Immunotherapy

2020 ◽  
Author(s):  
Renshen Xiang ◽  
Tao Fu
Keyword(s):  
Gastric Cancer ◽  
T Cells ◽  
Clinical Decision Making ◽  
Immune Cell ◽  
Predictive Biomarker ◽  
Clinical Decision ◽  
Tumor Mutation Burden ◽  
Follicular Helper ◽  
Tumor Purity ◽  
Mutation Burden

Abstract Background: Few studies have focused on the underlying relationship between the prognosis of tumor mutation burden (TMB) and immune cell infiltration in gastric cancer (GC). This study aims to explore the relationship among TMB and various components in tumor microenvironment (TME). Methods: The transcription profiles and somatic mutation data of 375 tumor and 32 normal samples were obtained from TCGA. The specific mutation information was summarized and visualized with waterfall chart, then number of TMB per million bases of each GC sample was calculated. Immune/stromal scores and tumor purity were calculated by the ‘ESTIMATE’ package, and the fractions of 22 immune cells in each sample were evaluated by CIBERSORT algorithm. Finally, Lass regression analysis was utilized to generate a prognostic scoring signature with TCGA cohort as the training set, while GES84437 cohort as the validation set. Results: Higher TMB indicated favorable overall survival (OS, P = 0.043)，better disease specific survival (P = 0.029), and longer progression free interval (P = 0.004). TMB was positively correlated with MSI and tumor purity, while negatively associated with immune/stromal scores. Moreover, TMBhigh group has lower T cells CD4 memory resting (P < 0.001) and T cells regulatory (P < 0.001), and more T cells CD4 memory activated (P < 0.001) and T cells follicular helper (P = 0.009). More importanly, the infiltration of dendritic cells activated predicted a worse OS, while T cells CD4 memory activated and T cells follicular helper meant a better OS. Finally, a nomogram combined TMB-related signature with clinicopathologic variables can successfully predict the OS with high accuracy and efficiency.Conclusion: TMB can effectively reveal the immune infiltration status in TME of GC, and might serve as a prognostic classifier for individualized treatment of clinical decision-making.

scholarly journals Implementing Clinical Pharmacogenomics in the Classroom: Student Pharmacist Impressions of an Educational Intervention Including Personal Genotyping

Pharmacy ◽  
2018 ◽  
Vol 6 (4) ◽  
pp. 115 ◽  
Author(s):  
Amber Frick ◽  
Cristina Benton ◽  
Oscar Suzuki ◽  
Olivia Dong ◽  
Rachel Howard ◽  
...  
Keyword(s):  
Educational Intervention ◽  
Clinical Decision Making ◽  
Clinical Decision ◽  
Educational Interventions ◽  
Rank Test ◽  
Drug Dosing ◽  
Signed Rank ◽  
Signed Rank Test ◽  
Students Attitudes ◽  
Personalized Approach

Pharmacogenomics provides a personalized approach to pharmacotherapy by using genetic information to guide drug dosing and selection. However, partly due to lack of education, pharmacogenomic testing has not been fully implemented in clinical practice. With pharmacotherapy training and patient accessibility, pharmacists are ideally suited to apply pharmacogenomics to patient care. Student pharmacists (n = 222) participated in an educational intervention that included voluntary personal genotyping using 23andMe. Of these, 31% of students completed both pre- and post-educational interventions to evaluate their attitudes and confidence towards the use of pharmacogenomics data in clinical decision making, and 55% of this paired subset obtained personal genotyping. McNemar’s test and the Wilcoxon signed-rank test were used to analyze responses. Following the educational intervention, students regardless of genotyping were more likely to recommend personal genotyping (36% post-educational intervention versus 19% pre-educational intervention, p = 0.0032), more confident in using pharmacogenomics in the management of drug therapy (51% post-educational intervention versus 29% pre-educational intervention, p = 0.0045), and more likely to believe that personalized genomics would have an important role in their future pharmacy career (90% post-educational intervention versus 51% pre-educational intervention, p = 0.0072) compared to before receiving the educational intervention. This educational intervention positively influenced students’ attitudes and confidence regarding pharmacogenomics in the clinical setting. Future studies will examine the use of next-generation sequencing assays that selectively examine pharmacogenes in the education of student pharmacists.

scholarly journals Decoding Clinical Biomarker Space of COVID-19: Exploring Matrix Factorization-based Feature Selection Methods

2021 ◽  
Author(s):  
Farshad Saberi-Movahed ◽  
Mahyar Mohammadifard ◽  
Adel Mehrpooya ◽  
Mohammad Rezaei-Ravari ◽  
Kamal Berahmand ◽  
...  
Keyword(s):  
Feature Selection ◽  
Poor Prognosis ◽  
Clinical Decision Making ◽  
Unmet Need ◽  
Clinical Decision ◽  
Clinical Indicators ◽  
Arterial Blood Gas ◽  
Clinical Biomarkers ◽  
Arterial Blood ◽  
Global Pandemic

One of the most critical challenges in managing complex diseases like COVID-19 is to establish an intelligent triage system that can optimize the clinical decision-making at the time of a global pandemic. The clinical presentation and patients' characteristics are usually utilized to identify those patients who need more critical care. However, the clinical evidence shows an unmet need to determine more accurate and optimal clinical biomarkers to triage patients under a condition like the COVID-19 crisis. Here we have presented a machine learning approach to find a group of clinical indicators from the blood tests of a set of COVID-19 patients that are predictive of poor prognosis and morbidity. Our approach consists of two interconnected schemes: Feature Selection and Prognosis Classification. The former is based on different Ma- trix Factorization (MF)-based methods, and the latter is performed using Random Forest algorithm. Our model reveals that Arterial Blood Gas (ABG) O2 Saturation and C-Reactive Protein (CRP) are the most important clinical biomarkers determining the poor prognosis in these patients. Our approach paves the path of building quantitative and optimized clinical management systems for COVID-19 and similar diseases.

Mutation landscape of Chinese melanoma patients.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9563-9563
Author(s):  
Fuxue Huang ◽  
Dandan Li ◽  
Xizhi Wen ◽  
Fang Wang ◽  
Xiaoshi Zhang ◽  
...  
Keyword(s):  
Cutaneous Melanoma ◽  
Clinical Decision Making ◽  
Treatment Options ◽  
Clinical Decision ◽  
Genomic Profiling ◽  
Primary Tumors ◽  
Positive Correlation ◽  
Mutation Burden ◽  
Frequent Mutations ◽  
Melanoma Patients

9563 Background: Treatment options for melanoma, which has the highest mutation burden among common cancers, has proliferated in the past decade. Genomic profiling has becoming essential to clinical decision making. However, limited studies have interrogated the genomic landscape of Chinese melanoma patients. We also investigated the correlation between tumor mutation burden (TMB) and clinical outcomes of immunotherapy (IO). Methods: In this study, we retrospectively surveyed the genomic profiling of primary tumors of 81 (40 males, 41 females) metastatic Chinese melanoma patients with a median age of 52, using a panel consisting of 295 cancer-related genes, spanning 2.02MB of human genome. Patients used IO as first line treatment (n = 25) were enrolled for survival analyses. Results: In this cohort, 15, 24 and 42 were acral, mucosal and cutaneous melanoma, respectively. Collectively, we identified 1,114 mutations, spanning 248 genes, with BRAF, MYC and NBN being the most frequently mutated genes, occurring in 40%, 27% and 21% of patients, respectively. Mutation spectrum varied significantly by subtypes. BRAF (57%) and LRP1B (26%) were the most frequently mutated genes in cutaneous melanoma (CM). KIT and NRAS, reported to be frequently mutated in CM, each occurred in only 12% patients in this cohort. MYC amplification was the most commonly seen mutation in acral and mucosal melanoma (MM). Other frequent mutations in MM included: NBN (38%) RUNX1T1(29%) and TP53 (29%). In acral melanoma (AM), CCND1, FGF3/19, NF1and NBN were frequently mutated. It is interesting to note that no TP53 mutation was observed in AM. AM and MM had significantly more CNVs than CM. Of the 25 patients underwent IO, our data revealed a positive correlation between TMB and PFS (p = 0.007). Such correlation also exited in each subtype. Furthermore, we derived a cutoff of 15, which can effectively distinguish clinical response. Patients with TMB > 15 mut/Mb had a significantly longer PFS than patients harboring TMB < 15 mut/Mb (P = 0.02). Patients with CM had a longer PFS than patients with AM or MM (p = 0.018). No correlation between PDL1 expression and PFS was observed. Conclusions: Our study revealed a distinctive mutation landscape for each subtype. Furthermore, we also revealed a positive correlation between TMB and PFS as well as a lack of correlation between PDL1 expression and PFS.

Metastatic Colorectal Cancer: Current State and Future Directions

2015 ◽  
Vol 33 (16) ◽  
pp. 1809-1824 ◽  
Author(s):  
Marwan G. Fakih
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Targeted Therapies ◽  
Clinical Decision Making ◽  
Clinical Decision ◽  
Cytotoxic Agents ◽  
Braf Mutations ◽  
Curative Intent ◽  
Future Directions ◽  
Unresectable Metastatic Colorectal Cancer

Substantial improvements have been made in the management of metastatic colorectal cancer over the last two decades. The overall survival of patients diagnosed with unresectable metastatic colorectal cancer has increased from approximately 1 year during the era of fluoropyrimidine monotherapy to more than 30 months with the integration of multiple cytotoxic agents and targeted therapies. More effective therapeutic combinations have increased the rate of curative-intent surgical resections, resulting in median survival in this subgroup that exceed 5 years. Here we review the landscape of systemic therapies for unresectable metastatic colorectal cancer during the current era of targeted therapies, review the effects of RAS and BRAF mutations on clinical decision making, and reflect on future directions for the treatment of metastatic colorectal cancer.

Tumor mutation burden and immune microenvironment analysis of urothelial carcinoma.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 494-494
Author(s):  
Yuanyuan Jia ◽  
Ning He ◽  
Yadong Yang ◽  
Yuliang Huang ◽  
Xiaoyu Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
Urothelial Carcinoma ◽  
Cd8 T Cells ◽  
Immune Cell ◽  
Immune Therapy ◽  
Genetic Alterations ◽  
Rank Test ◽  
Immune Microenvironment ◽  
Tumor Mutation Burden ◽  
Mutation Burden

494 Background: Tumor mutation burden (TMB) has been established as a biomarker for response to immune therapy and prognosis in various cancers. However, the correlation between TMB and immune microenvironment remains unwell studied, especially in urothelial carcinoma. This study was aimed to investigate the relationship between TMB and other immunotherapy related biomarkers, including genetic alterations, APOBEC signature, microsatellite instability (MSI), PD-L1 expression and immune cell infiltration in urothelial carcinoma. Methods: 131 patients with urothelial carcinoma admitted from October 2018 to May 2020 were included. Total DNA was isolated from FFPE or fresh tissues. Mutation profiles, APOBEC signature and MSI scores were obtained by next-generation sequencing based a 642 cancer genes panel assay. PD-L1 expression, CD8+ T-cells and tumor-infiltrating lymphocytes density were evaluated by immunohistochemistry. The correlation was analyzed by Wilcoxon signed-rank test. Results: The mutation landscape showed that TP53 mutation is the most common alterations (n = 64/131, 48.9%), followed by KMT2D alterations (n = 49/131, 37.4%), KDM6A mutations (n = 42/131, 32.1%), MUC17 mutations (n = 42/131, 32.1%). The median TMB was 5.06 Muts/Mb (0-118 Muts/Mb). 2 of 131 patients showed MSI-H, who exhibited a much higher TMB (41, 118 Muts/Mb). Further analysis showed that TMB in the patients with certain gene mutations (such as TP53, KMT2D, KDM6A and MUC17) was significantly higher than those wild type ones (p < 0.05). Meanwhile, the high APOBEC-enrichment group has a higher TMB than the low APOBEC-enrichment group (p = 0.045). Furthermore,we observed that the patients with a higher PD-L1 expression (n = 28/131, 21.4%, at a combined positive score cut-off value of 10) also showed a significantly higher TMB (p = 0.016), and TMB in the patients with higher density of CD8+ T-cells (n = 42/131, 32.1%, at a cut-off value of 5%) was also significantly higher than that of the group with lower density of CD8+ T-cells (p = 0.039). Conclusions: This study provides new insights into the correlation between the TMB and the immune microenvironment in urothelial carcinoma. The result may be a reference to immunotherapy.

scholarly journals Genetics of Biliary Tract Cancers and Emerging Targeted Therapies

2010 ◽  
Vol 28 (21) ◽  
pp. 3531-3540 ◽  
Author(s):  
Aram F. Hezel ◽  
Vikram Deshpande ◽  
Andrew X. Zhu
Keyword(s):  
Clinical Trials ◽  
Biliary Tract ◽  
Targeted Therapies ◽  
Clinical Decision Making ◽  
Clinical Decision ◽  
Individual Treatment ◽  
Biliary Tract Cancers ◽  
Animal Modeling ◽  
Treatment Regimens ◽  
Tumor Genetics

Biliary tract cancers (BTC), which encompass intra- and extrahepatic cholangiocarcinomas and gallbladder carcinomas, are a genetically diverse collection of cancers. Evidence suggests distinct models of molecular and pathologic progression, and a growing body of genetics data points to a heterogeneous collection of underlying mutations in key oncogenes and tumor suppressor genes. Although tumor genetics have been used to tailor individual treatment regimens and guide clinical decision making in other cancers, these principles have not been applied in BTC. Recent clinical trials with targeted therapies seem promising, although the relationships between subsets of patients with positive responses to therapy and tumor genetics remain unexplored. Here, we summarize the molecular pathogenesis and genetics of BTCs and animal modeling and relate these to recent and ongoing clinical trials with targeted agents.

scholarly journals The natural history of intracranial carotid artery atherosclerosis

2005 ◽  
Vol 18 (1) ◽  
pp. 1-3
Author(s):  
Ricardo J. Komotar ◽  
J Mocco ◽  
David A. Wilson ◽  
E. Sander Connolly ◽  
Sean D. Lavine ◽  
...  
Keyword(s):  
Carotid Artery ◽  
Natural History ◽  
Medical Therapy ◽  
Poor Prognosis ◽  
Clinical Decision Making ◽  
Clinical Decision ◽  
Intracranial Atherosclerosis ◽  
Carotid Artery Atherosclerosis ◽  
History Of ◽  
Maximal Medical Therapy

Intracranial atherosclerosis is the cause of a significant number of strokes. Despite maximal medical therapy, this disease continues to carry a poor prognosis. The authors reviewed studies in which the outcomes after conservative management in patients with intracranial carotid artery atherosclerosis were reported. Analysis of the literature demonstrates that maximal medical therapy frequently fails with this disease, leaving patients at high risk for cerebral infarction and death. A better understanding of the pathophysiological aspects and natural history of this condition may serve to guide clinical decision making and the choice of therapeutic options in this patient population.

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