Differences in mutation rates between right- and left-sided colorectal adenocarcinoma.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 622-622 ◽  
Author(s):  
Christopher E. Jensen ◽  
Arturo Loaiza-Bonilla ◽  
Jonathan Yap Villanueva ◽  
Jennifer J. Morrissette
Keyword(s):  
Medical Center ◽  
Genetic Difference ◽  
Statistical Significance ◽  
Academic Medical Center ◽  
Mutation Rates ◽  
Next Generation Sequencing Data ◽  
Sequencing Data ◽  
Braf Mutations ◽  
Kras Mutations ◽  
Pik3ca Mutations

622 Background: Recent reports have demonstrated inferior outcomes for patients with right-sided colorectal cancer (CRC) compared to patients with left-sided disease (Schrag et al 2016, JCO 34 (suppl; abstr 3505)) as well as differences in treatment response based on disease sidedness (Venook et al 2016, JCO 34 (suppl; abstr 3504)). However, the biological and genetic underpinnings of these clinical differences are incompletely understood. Methods: We compared mutation rates among 38 genes in a retrospective review of next-generation sequencing data of CRC samples obtained in routine clinical practice at a single academic medical center. Primary location was identified via chart review. Right = cecum to transverse colon; Left = descending colon to rectum. Results: Among 293 samples (167 left-sided, 103 right, 23 synchronous or without clear primary), BRAF and CTNNB1 mutations were more prevalent in right-sided CRC. BRAF was mutated in 15.5% of right-sided CRC (95% CI: 8.5-22.5%) compared to 4.8% (CI: 1.6-8.0%) (p=0.003). CTNNB1 was mutated in 3.9% of right-sided CRC (CI: 0.2-7.6%) compared to no instances of CTNNB1 mutations in left-sided disease (p=0.01). Among right-sided CRC, there was a trend toward more KRAS mutations at 57.3% (CI: 47.7-66.8%) versus 44.9% (CI: 37.4-52.5%) and more PIK3CA mutations at 26.2% (CI:17.7-34.7%) versus 17.4% (CI: 11.6-23.1%), though these differences did not rise to the level of statistical significance. The overall rate of BRAF mutations in our sample (8.9%, CI: 5.5-12.3%) was consistent with the rate of BRAF mutations among large intestine adenocarcinomas in the COSMIC database (10.6%, CI: 10.4-10.8%), lending support to the external validity of these data. Conclusions: These differing mutation rates may implicate these genetic pathways in the mechanisms underlying the discrepant outcomes and treatment responses between right and left-sided disease described in prior studies. Further work is needed to more clearly elucidate genetic difference between right and left-sided CRC, as well as the mechanistic relationship between these mutations and prognosis.

Applying SLICC and ACR/EULAR systemic lupus erythematosus classification criteria in a cohort of patients with undifferentiated connective tissue disease

Lupus ◽  
2020 ◽  
pp. 096120332097693
Author(s):  
Kyle R Drehmel ◽  
Alan R Erickson ◽  
Bryant R England ◽  
Kaleb D Michaud ◽  
Harlan R Sayles ◽  
...  
Keyword(s):  
Lupus Erythematosus ◽  
Medical Center ◽  
Statistical Significance ◽  
Academic Medical Center ◽  
Renal Involvement ◽  
Classification Criteria ◽  
Academic Medical ◽  
Dsdna Antibody ◽  
Record Review

Background/objective New classification criteria for SLE have recently been developed. How these criteria affect the classification of patients with the SLE-mimicking condition UCTD is poorly understood. This study investigated the reclassification of UCTD patients using newly derived SLE criteria. Methods Patients with UCTD were identified within a single academic medical center using ICD9/10 codes. Medical record review was performed to confirm UCTD diagnosis and identify disease features present at diagnosis. The SLICC and ACR/EULAR criteria were applied, after which we compared the proportion of patients reclassified as SLE and determined which disease features were associated with reclassification. Results A total of 129 patients were included in the study. When applying the SLICC and ACR/EULAR criteria, 18 (14.0%) and 26 patients (20.2%) were reclassified as SLE. Comparison with McNemar’s test trended toward statistical significance (p = 0.057). Cohen’s kappa coefficient was 0.62 (p < 0.001), indicating substantial agreement between these criteria. Disease features associated with reclassification as SLE were renal involvement, leukopenia, thrombocytopenia, anti- dsDNA antibody, hypocomplementemia, non-scarring alopecia (SLICC), and arthritis (ACR/EULAR). Conclusions Both the SLICC and ACR/EULAR criteria exhibit increased SLE classification. These newer classification criteria could be used to increase the number of SLE patients in future clinical studies.

Does multiple mutational analysis of the EGFR pathway have a prognostic role in advanced colorectal cancer (CRC)?

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3612-3612
Author(s):  
Luisa Foltran ◽  
Giuseppe Aprile ◽  
Giovanna De Maglio ◽  
Federica Edith Pisa ◽  
Mariaelena Casagrande ◽  
...  
Keyword(s):  
Braf Mutation ◽  
Advanced Colorectal Cancer ◽  
Mutational Analysis ◽  
Wild Type ◽  
Prognostic Role ◽  
Braf Mutations ◽  
Kras Mutations ◽  
Pik3ca Mutations ◽  
Negative Prognostic Factor ◽  
Impact On Survival

3612 Background: BRAF mutation is widely recognised as a strong negative prognostic factor in advanced CRC, while the prognostic value of KRAS mutations in codons 12-13 remains controversial. Exploring mutations in other downstream components of the EGFR pathway may have an impact on survival. Methods: A consecutive cohort of 201 metastatic CRC patients treated with systemic chemotherapy were analysed for KRAS (12-13-61-146), BRAF, PIK3CA and NRAS genotypes by pyrosequencing on PyroMarkTMQ96 ID instrument (Qiagen, Germany) with commercially available kits Anti-EGFR MoAb response (Diatech Pharmacogenetics, Italy). Accurate microdissection guaranteed more than 70% of cancer cells for each sample. For the purpose of the survival analysis 4 categories were created: (1) KRAS mutated (codons 12-13 only); (2) BRAF mutated; (3) any of KRAS codons 61-146, PIK3CA or NRAS mutations; (4) all-wild type. Log-rank and Cox proportional tests were applied for statistical analysis. Results: KRAS mutations were present in 96 (47.8%) patients: 86 (42.8%) were in codons 12-13. BRAF mutations were found in 11 (5.5%) samples while PIK3CA and NRAS in 33 (16.4%) and 7 (3.5%), respectively. All mutations were mutually exclusive except for 24 (11.9%) patients with concomitant KRAS/PIK3CA mutations. Median survivals for different categories are shown. Patients harbouring BRAF mutation had the worst outcome (p=0.0006). Mutations of any codon of KRAS (12-13-61-146) also negatively impacted on survival (p=0.026), while the all wild-type (KRAS/BRAF/PIK3CA/NRAS) patients had the longest survival (p=0.002). Conclusions: This study suggests the usefulness for early molecular profiling for advanced CRC patients. Mutational analysis of all EGFR pathway components may identify different prognostic subgroups. This information may drive treatment selection in clinical practice and stratification in clinical trials. [Table: see text]

scholarly journals A Bayesian framework for inferring the influence of sequence context on single base modifications

2019 ◽  
Author(s):  
Guy Ling ◽  
Danielle Miller ◽  
Rasmus Nielsen ◽  
Adi Stern
Keyword(s):  
Context Effects ◽  
Genetic Material ◽  
Simulated Data ◽  
Mutation Rates ◽  
Next Generation Sequencing Data ◽  
Sequencing Data ◽  
Sequence Context ◽  
Specific Sequence ◽  
Single Base ◽  
Base Modifications

AbstractThe probability of single base modifications (mutations and DNA/RNA modifications) is expected to be highly influenced by the flanking nucleotides that surround them, known as the sequence context. This phenomenon may be mainly attributed to the enzyme that modifies or mutates the genetic material, since most enzymes tend to have specific sequence contexts that dictate their activity. Thus, identification of context effects may lead to the discovery of additional editing sites or unknown enzymatic factors. Here, we develop a statistical model that allows for the detection and evaluation of the effects of different sequence contexts on mutation rates from deep population sequencing data. This task is computationally challenging, as the complexity of the model increases exponentially as the context size increases. We established our novel Bayesian method based on sparse model selection methods, with the leading assumption that the number of actual sequence contexts that directly influence mutation rates is minuscule compared to the number of possible sequence contexts. We show that our method is highly accurate on simulated data using pentanucleotide contexts, even when accounting for noisy data. We next analyze empirical population sequencing data from polioviruses and detect a significant enrichment in sequence contexts associated with deamination by the cellular deaminases ADAR 1/2. In the current era, where next generation sequencing data is highly abundant, our approach can be used on any population sequencing data to reveal context-dependent base alterations, and may assist in the discovery of novel mutable sites or editing sites.

Analysis of KRAS and BRAF mutant colorectal cancers in a multiracial population.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 1599-1599
Author(s):  
Jared David Acoba ◽  
Christopher A. Lum ◽  
Lambert T Leong
Keyword(s):  
Braf Mutation ◽  
Proportional Hazards ◽  
Mutational Analysis ◽  
Comprehensive Evaluation ◽  
Statistical Significance ◽  
Cox Proportional Hazards ◽  
Racial Groups ◽  
Braf Mutations ◽  
Kras Mutations ◽  
Braf Mutant

1599 Background: We previously demonstrated racial disparities in colorectal cancer (CRC) survival despite adjustments for tumor and socioeconomic factors. Molecular differences in breast and lung tumors contribute to racial survival inequality, yet in CRC, molecular tumor characteristics have not been studied extensively in a racially diverse cohort. We performed a comprehensive evaluation of KRAS and BRAF mutations in a multiracial population to determine the prevalence in CRC and the degree to which these molecular traits impact survival. Methods: A retrospective cohort study of patients diagnosed with CRC between 2008 and 2011 from hospital tumor registries was performed. The prevalence of KRAS and BRAF mutations was determined for the study population and individual racial groups. Multivariable Cox proportional hazards regression models for survival were built for KRAS and BRAF mutation status while adjusting for age at diagnosis, race, and stage of disease. Results: Of 706 patients diagnosed with CRC, KRAS mutational analysis was performed on 148 subjects. 14% of subjects were white (W), 64% Asian (A), and 21% Native Hawaiian/Pacific Islander (NH). KRAS mutation was identified in 48 subjects (32%). The prevalence of mutant tumors among racial groups was W 33%, A 36%, and NH 30%. Analysis for KRAS G13D mutations revealed a prevalence of W 11%, A 9%, and NH 7%. When compared to published datasets of predominantly white patients, our multiracial cohort had a significantly higher rate of KRAS G13D mutant tumors, p=0.039. Of 74 subjects tested for the BRAF mutation, two mutant tumors were detected (3%). The prevalence of the BRAF mutation by race was 10% W, 3% A, and 0% NH (p=0.18). BRAF and KRAS G13D mutations were adverse prognostic factors in a multivariate analysis, although the odds ratios failed to meet statistical significance. Conclusions: The prevalence of BRAF and KRAS mutations in this multiracial cohort is similar to what has been previously reported. However the rates of KRAS G13D and BRAF mutant tumors in our cohort are higher than prior reports. Furthermore, KRAS G13D which has been postulated to be a favorable prognostic factor for CRC, may adversely impact survival of minority patients.

Relationship between tumor location and oncogenes mutations (RAS, BRAF, and PIK3CA) in colorectal cancer.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 580-580 ◽  
Author(s):  
Daisuke Inagaki ◽  
Manabu Shiozawa ◽  
Tetta Satoyoshi ◽  
Yousuke Atsumi ◽  
Masaaki Murakawa ◽  
...  
Keyword(s):  
Braf Mutation ◽  
Tumor Stage ◽  
Tumor Location ◽  
Clinicopathological Characteristics ◽  
Braf Mutations ◽  
Kras Mutations ◽  
Pik3ca Mutations ◽  
Oncogenic Mutation ◽  
Colon Cancers ◽  
The Difference

580 Background: Several studies have reported that right-sided colon cancers (RCC) and left-sided colon cancers (LCC) differ in several factors including genetic features. We investigated the difference in clinicopathological characteristics and oncogenic mutation status between patients with RCC and LCC in all stages. Methods: This study was a prospective, observational study. Patients were recruited from December 2014 to February 2016. Formalin-fixed paraffin-embedded tissue blocks were collected and DNA wes extracted from tissue sections from 158 cases. Mutations in KRAS, NRAS, HRAS, BRAF and PIK3CAwere detected by next-generation DNA sequencer. Tumors from cecum to transverse colon were defined as RCC, and tumors from descending colon to rectsigmoid were defined as LCC. Results: RCC was 66 patients and LCC was 92 patients. Poorly differentiated adenocarcinoma or mutinous adenocarcinoma were significantly more frequent in RCC compared to LCC (P = 0.047). KRAS mutations were detected in 35 patients with RCC (53.0%) and in 32 patients with LCC (34.8%). NRAS mutations were detected in 2 patients with RCC (3.0%) and in 3 patients with LCC (3.3%). There was no HRAS mutation in all patients. BRAF mutations were detected in 7 patient with RCC (10.6%) and in 2 patients with LCC (2.2%). PIK3CA mutations were detected in 8 patients with RCC (12.1%) and in 10 patients with LCC (10.9%). KRAS and BRAF mutation in RCC were significantly more frequent than in LCC (P = 0.022 and P = 0.024, respectively). These mutations were not significantly different according to tumor stage. In this study, both KRAS and BRAFmutations were exclusive. Conclusions: KRAS and BRAF mutation were more frequent in the patients with RCC compared to those with LCC in all stages. This study suggested that it was important to evaluate BRAF mutation in addition to KRAS in order to select more effective treatments, especially in RCC.

Acceptability of mobile health technology among cancer patients.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e18139-e18139
Author(s):  
Rashmika Potdar ◽  
Arun Thomas ◽  
Matthew DiMeglio ◽  
Kamran Mohiuddin ◽  
Djeneba Audrey Djibo ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Mobile Health ◽  
Patient Engagement ◽  
Mobile Application ◽  
Medical Center ◽  
Statistical Significance ◽  
Academic Medical Center ◽  
Categorical Variables ◽  
College Level ◽  
Cross Sectional Survey

e18139 Background: Advances in wireless technology have led to the increasing use of mobile health platforms. This approach, tele-medicine, enables healthcare providers to communicate remotely with patients, thereby enhancing timeliness and quality of care, and patient engagement. However, few studies address barriers to its implementation, especially in medically under served populations. Methods: A cross-sectional survey of 151 cancer patients was conducted at an academic medical center in North Philadelphia, PA. A trained interviewer performed structured interviews regarding the barriers and facilitators of patients’ current and desired utilization of technology for healthcare services. Statistical significance was defined as p < 0.05 on a two-tailed distribution. Chi-Square test was used for categorical variables. Odds ratios from logistic regression analysis were used to identify the relationship between demographic factors and willingness to utilize a mobile application for health surveillance. Results: Of the 151 patients who completed the survey, 35.8% were male; ages ranged from 21-104 years. Forty-two percent were married, 49.0% were single, and 9% were divorced at the time of the survey. No significant associations existed between the willingness to utilize a mobile health application and gender ( p = 0.73) or marital status ( p = 0.97). After controlling for other demographic variables, patients older than 70 were significantly less likely to utilize a mobile application. Conversely, patients with a college-level education or more were significantly more likely to utilize a mobile application [OR = 2.78, p = 0.01]. Conclusions: Age and education level represent potential barriers to mobile health applications for cancer patients in socioeconomically diverse community. Health networks should consider these factors when launching patient engagement platforms. [Table: see text]

Cirrhosis, Thrombosis, Finding FaXts about Doses: Dosing of Unfractionated Heparin for Venous Thromboembolism in Cirrhosis

2019 ◽  
Vol 54 (5) ◽  
pp. 450-456
Author(s):  
Nicholas D. Franz ◽  
Adamo Brancaccio ◽  
Adam C. Robinson ◽  
Randolph E. Regal
Keyword(s):  
Venous Thromboembolism ◽  
Unfractionated Heparin ◽  
Medical Center ◽  
Statistical Significance ◽  
Severe Disease ◽  
Academic Medical Center ◽  
The United States ◽  
Monitoring Methods ◽  
Heparin Infusion ◽  
Severe Cirrhosis

Background: Despite known disease-specific alterations to anti–factor Xa (AXA) levels, the physiological response of patients with cirrhosis to unfractionated heparin (UFH) infusions is not well established in clinical settings. Objective: The purpose of this study was to characterize the dosing and safety profile of UFH in patients with varying degrees of cirrhosis when treated for venous thromboembolism (VTE). Methods: This retrospective observational study was conducted at a single academic medical center in the United States. Patients with a diagnosis of cirrhosis who received UFH infusions for greater than 48 hours for treatment of VTE were included. Comparisons between heparin infusion rates, AXA levels, and safety outcomes based on severity of cirrhosis were made to define differences between those groups. Results: When compared by compensation status or by Child-Turcotte-Pugh (CTP) class, patients with more severe disease trended toward lower initial AXA levels on heparin initiation and higher heparin requirements to achieve therapeutic levels and were significantly less likely to achieve therapeutic levels than patients with less severe disease ( P = 0.001 for compensation, P = 0.017 for CTP). Additionally, bleeding rates were higher in patients with more severe disease, without reaching statistical significance. Conclusion and Relevance: Patients with severe cirrhosis required higher doses of heparin to achieve the same therapeutic AXA levels, but also tended to have higher rates of bleeding compared with less severe cirrhosis. These results represent further evidence of changes in heparin response as cirrhosis severity increases and may suggest that current monitoring methods are suboptimal in this patient population.

scholarly journals The impact of drug order complexity on prospective medication order review and verification time

2019 ◽  
Vol 27 (2) ◽  
pp. 284-293
Author(s):  
David S Dakwa ◽  
Vincent D Marshall ◽  
Bruce W Chaffee
Keyword(s):  
Medical Center ◽  
Statistical Significance ◽  
Academic Medical Center ◽  
Low Complexity ◽  
Primary Study ◽  
Medication Order ◽  
High Complexity ◽  
Verification Time ◽  
The Impact ◽  
Drug Order

Abstract Objective To assess if the amount of time a pharmacist spends verifying medication orders increases as medication orders become more complex. Materials and Methods The study was conducted by observing pharmacist verification of adult medication orders in an academic medical center. Drug order complexity was prospectively defined and validated using a classification system derived from 3 factors: the degree of order variability, ISMP high-alert classification, and a pharmacist perception survey. Screen capture software was used to measure pharmacist order review time for each classification. The annualized volume of low complexity drug orders was used to calculate the potential time savings if these were verified using an alternate system that did not require pharmacist review. Results The primary study hypothesis was not achieved. Regression results did not show statistical significance for moderate (n = 30, 23.7 seconds, sd = 23.3) or high complexity (n = 30, 18.6 seconds, sd = 23.1) drugs relative to the low complexity drugs (n = 30, 8.0 seconds, sd = 14.4) nor for moderate vs high complexity; (βmoderate vs low = 15.6, P = .113), (βhigh vs low = 10.3, P = .235), (βmoderate vs high = 5.3, P = .737). The sensitivity analysis showed statistical significance in the high vs low comparison (βhigh vs low = 13.8, P = .017). Discussion This study showed that verifying pharmacists spent less time than projected to verify medication orders of different complexities, but the time did not correlate with the classifications used in our complexity scale. Several mitigating factors, including operational aspects associated with timing antimicrobial orders, likely influenced order verification time. These factors should be evaluated in future studies which seek to define drug order complexity and optimize pharmacist time spent in medication order verification. Conclusion The findings suggest that there may be other factors involved in pharmacist decision-making that should be considered when categorizing drugs by perceived complexity.

scholarly journals A randomized controlled trial to improve engagement of hospitalized patients with their patient portals

2018 ◽  
Vol 25 (12) ◽  
pp. 1626-1633 ◽  
Author(s):  
S Ryan Greysen ◽  
James D Harrison ◽  
Charles Rareshide ◽  
Yimdriuska Magan ◽  
Neil Seghal ◽  
...  
Keyword(s):  
Randomized Controlled Trial ◽  
Medical Center ◽  
Controlled Trial ◽  
Statistical Significance ◽  
Academic Medical Center ◽  
Intervention Group ◽  
Patient Portals ◽  
Post Discharge ◽  
Patient Centered ◽  
Randomized Controlled

AbstractObjectivesTo test a patient-centered, tablet-based bedside educational intervention in the hospital and to evaluate the efficacy of this intervention to increase patient engagement with their patient portals during hospitalization and after discharge.Materials and MethodsWe conducted a randomized controlled trial of adult patients admitted to the hospitalist service in one large, academic medical center. All participants were supplied with a tablet computer for 1 day during their inpatient stay and assistance with portal registration and initial login as needed. Additionally, intervention group patients received a focused bedside education to demonstrate key functions of the portal and explain the importance of these functions to their upcoming transition to post-discharge care. Our primary outcomes were proportion of patients who logged into the portal and completed specific tasks after discharge. Secondary outcomes were observed ability to navigate the portal before discharge and self-reported patient satisfaction with bedside tablet use to access the portal.ResultsWe enrolled 97 participants (50 intervention; 47 control); overall 57% logged into their portals ≥1 time within 7 days of discharge (58% intervention vs. 55% control). Mean number of logins was higher for the intervention group (3.48 vs. 2.94 control), and mean number of specific portal tasks performed was higher in the intervention group; however, no individual comparison reached statistical significance. Observed ability to login and navigate the portal in the hospital was higher for the intervention group (64% vs. 60% control), but only 1 specific portal task was significant (view provider messaging tab: 92% vs. 77% control, P = .04). Time needed to deliver the intervention was brief (&lt;15 min for 80%), and satisfaction with the bedside tablet to access the portal was high in the intervention group (88% satisfied/very satisfied).ConclusionOur intervention was highly feasible and acceptable to patients, and we found a highly consistent, but statistically non-significant, trend towards higher inpatient engagement and post-discharge use of key portal functions among patients in the intervention group.

scholarly journals A Bayesian Framework for Inferring the Influence of Sequence Context on Point Mutations

2019 ◽  
Vol 37 (3) ◽  
pp. 893-903 ◽  
Author(s):  
Guy Ling ◽  
Danielle Miller ◽  
Rasmus Nielsen ◽  
Adi Stern
Keyword(s):  
Genetic Material ◽  
Point Mutations ◽  
Simulated Data ◽  
Mutation Rates ◽  
Next Generation Sequencing Data ◽  
Sequencing Data ◽  
Sequence Context ◽  
Specific Sequence ◽  
Significant Enrichment ◽  
Actual Sequence

Abstract The probability of point mutations is expected to be highly influenced by the flanking nucleotides that surround them, known as the sequence context. This phenomenon may be mainly attributed to the enzyme that modifies or mutates the genetic material, because most enzymes tend to have specific sequence contexts that dictate their activity. Here, we develop a statistical model that allows for the detection and evaluation of the effects of different sequence contexts on mutation rates from deep population sequencing data. This task is computationally challenging, as the complexity of the model increases exponentially as the context size increases. We established our novel Bayesian method based on sparse model selection methods, with the leading assumption that the number of actual sequence contexts that directly influence mutation rates is minuscule compared with the number of possible sequence contexts. We show that our method is highly accurate on simulated data using pentanucleotide contexts, even when accounting for noisy data. We next analyze empirical population sequencing data from polioviruses and HIV-1 and detect a significant enrichment in sequence contexts associated with deamination by the cellular deaminases ADAR 1/2 and APOBEC3G, respectively. In the current era, where next-generation sequencing data are highly abundant, our approach can be used on any population sequencing data to reveal context-dependent base alterations and may assist in the discovery of novel mutable sites or editing sites.

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