Methylated DNA markers for monitoring palliative chemotherapy response in advanced colorectal cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15511-e15511
Author(s):  
Mojun Zhu ◽  
Douglas W. Mahoney ◽  
Kelli Burger ◽  
Patrick H. Foote ◽  
Karen A. Doering ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Treatment Response ◽  
Systemic Therapy ◽  
Small Sample Size ◽  
High Sensitivity ◽  
Response Assessment ◽  
Small Sample ◽  
Chemotherapy Response ◽  
Continuous Variables ◽  
Methylated Dna

e15511 Background: Aberrantly methylated DNA marker (MDM) candidates are strongly associated with primary colorectal cancer (CRC) before treatment and detect CRC recurrence with high sensitivity when assayed from plasma. The relationship of these MDMs in association to chemotherapy treatment response is unknown. Methods: In a prospective cohort of patients receiving systemic therapy for advanced CRC, peripheral blood was collected serially during restaging visits. 15 patients were retrospectively identified to have partial response (PR), stable disease (SD) and progressive disease (PD) to treatment (n=5 for each group) based on the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Using paired samples from each patient before and after response assessment, we analyzed 11 MDMs ( GRIN2D, ZNF671, ANKRD13B, QKI, VAV3, JAM3, SFMBT2, CHST2, ZNF568, FER1L4 and CNNM1) to assess correlation with treatment response. Cell-free DNA was extracted and bisulfite treated before MDMs were quantified by target enrichment long-probe quantitative-amplified signal assay and normalized to a methylated sequence of B3GALT6. Continuous variables are summarized as a median with corresponding interquartile ranges (IQR) and comparisons between subgroups were based on the Wilcox Rank Sums test. Results: The median interval between pre- and post-response assessment visits was 69 days (IQR: 63-83 days) and the level of tumor burden at pre-assessment was similar across all response types (Table 1). Patients with PD had higher levels of methylated GRIN2D, ZNF671 and ANKRD13B than those with PR or SD at baseline and may offer additional prognostic value over CEA which was similar in the PR and PD groups before treatment (Table 1). Elevation of pre-assessment MDMs preceded radiographic evidence of disease progression by 82 days (IQR 69-83 days). Conclusions: Three MDMs, GRIN2D, ZNF671 and ANKRD13B, were found to reflect treatment response (PD vs. PR + SD) as shown in the table. Although this pilot study was limited by a small sample size, it demonstrated the feasibility of using plasma-based MDMs in monitoring treatment response to systemic therapy for advanced CRC and should be compared to CEA in a larger study.[Table: see text]

Abstract W P224: Higher Pre-Hospital Blood Pressure Prolongs Door to Needle Thrombolysis Times

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Digvijaya Navalkele ◽  
Chunyan Cai ◽  
Mohammad Rahbar ◽  
Renganayaki Pandurengan ◽  
Tzu-Ching Wu ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Small Sample Size ◽  
Heart Association ◽  
Small Sample ◽  
Categorical Variables ◽  
Continuous Variables ◽  
Intravenous Tissue Plasminogen Activator ◽  
Number Of Patients

Background: Per American Heart Association guidelines, blood pressure (BP) should be < 185/110 to be eligible for intravenous tissue plasminogen activator (tPA). It is shown that door to needle (DTN) time is prolonged in patients who require anti-hypertensive medications prior to thrombolysis in the emergency department (ED). To our knowledge, no studies have focused on pre-hospital BP and its impact on DTN times. We hypothesize that DTN times are longer for patients with higher pre-hospital BP. Methods: We conducted a retrospective review of acute ischemic stroke patients who presented between 1/2010 and 12/2010 to our ED through Emergency Medical Services (EMS) within 3-hrs of symptom onset. Patients were identified from our registry and categorized into two groups: Pre-hospital BP ≥ 185/110 (Pre-hsp HBP) and < 185/110 (Pre-hsp LBP). BP records were abstracted from EMS sheets. Two groups were compared using two-sample t-test or Wilcoxon rank sum test for continuous variables and Chi-square test or Fisher’s exact test for categorical variables. Results: A total of 107 consecutive patients were identified. Out of these, 75 patients (70%) were treated with tPA. Among the patients who received thrombolysis, 35% had pre-hospital BP ≥ 185/110 (n= 26/75). Greater number of patients required anti-hypertensive medications in ED in high BP group compared to low BP group (Pre-hsp HBP n= 14/26, 54%; Pre-hsp LBP n= 13/49, 27%, p < 0.02). Mean door to needle times were significantly higher in Pre-hsp HBP group. (mean ± SD 87.5± 34.2 Vs. 59.7±18.3, p<0.0001). Analysis of patients only within the Pre-hsp HBP group (n= 26) revealed that DTN times were shorter if patients received pre-hsp BP medications compared to patients in the same group who did not receive pre-hsp BP medication (n= 10 vs 16; mean ± SD 76.5 ± 25.7 Vs. 94.3 ± 37.7, p = 0.20) Conclusion: Higher pre-hospital BP is associated with prolonged DTN times and it stays prolonged if pre-hospital high BP remains untreated. Although the later finding was not statistical significant due to small sample size, pre-hospital blood pressure control could be a potential area for improvement to reduce door to needle times in acute ischemic stroke.

scholarly journals Multiplex methylated DNA testing in plasma with high sensitivity and specificity for colorectal cancer screening

2019 ◽  
Vol 8 (12) ◽  
pp. 5619-5628 ◽  
Author(s):  
Guodong Zhao ◽  
Hui Li ◽  
Zixuan Yang ◽  
Zhenzhen Wang ◽  
Manqiu Xu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Screening ◽  
Colorectal Cancer Screening ◽  
Sensitivity And Specificity ◽  
High Sensitivity ◽  
Dna Testing ◽  
Methylated Dna

scholarly journals Roles of Methylated DNA Biomarkers in Patients with Colorectal Cancer

2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
Zhiyao Ma ◽  
Marissa Williams ◽  
Yuen Yee Cheng ◽  
Wai K. Leung
Keyword(s):  
Colorectal Cancer ◽  
Occult Blood ◽  
Chemotherapy Response ◽  
Methylated Dna ◽  
Septin 9 ◽  
Faecal Occult ◽  
Related Transcription Factor ◽  
Prediction Of Prognosis ◽  
Low Sensitivity ◽  
Serum Detection

Colorectal cancer (CRC) is a leading cancer globally; therefore, early diagnosis and surveillance of this cancer are of paramount importance. Current methods of CRC diagnosis rely heavily on endoscopy or radiological imaging. Noninvasive tests including serum detection of the carcinoembryonic antigen (CEA) and faecal occult blood testing (FOBT) are associated with low sensitivity and specificity, especially at early stages. DNA methylation biomarkers have recently been found to have higher accuracy in CRC detection and enhanced prediction of prognosis and chemotherapy response. The most widely studied biomarker in CRC is methylated septin 9 (SEPT9), which is the only FDA-approved methylation-based biomarker for CRC. Apart from SEPT9, other methylated biomarkers including tachykinin-1 (TAC1), somatostatin (SST), and runt-related transcription factor 3 (RUNX3) have been shown to effectively detect CRC in a multitude of sample types. This review will discuss the performances of various methylated biomarkers used for CRC diagnosis and monitoring, when used alone or in combination.

An observational study of a team management approach for first-line XELOX therapy in patients with advanced/recurrent colorectal cancer: The SMILE study (the study of metastatic colorectal cancer to investigate impact of learning effect).

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 554-554
Author(s):  
Michio Nakamura ◽  
HIroshi Matsuoka ◽  
Yoshihisa Shibata ◽  
Yoshinori Munemoto ◽  
Hiroyuki Okuda ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Observational Study ◽  
Small Sample Size ◽  
Depression Scale ◽  
Dose Intensity ◽  
Small Sample ◽  
Management Approach ◽  
First Line ◽  
Fighting Spirit ◽  
Supportive Interventions

554 Background: Although oral chemotherapies such as XELOX are widely favored for convenience and flexibility, these have several disadvantages such as drug non-compliance and delayed discovery of adverse events. So we designed a multicenter, prospective, observational study to evaluate the efficacy of supportive interventions in first-line XELOX for colorectal cancer (CRC) patients (pts). Methods: CRC pts undergoing first-line XELOX (+Bevacizumab) therapy practicing one or more of supportive interventions as follows: 1) a telephone follow-up (TF), 2) instruction on dosage and administration by a pharmacist, 3) skin care instruction by a nurse, and 4) pts education by a doctor were eligible. The objective was to evaluate the incident rate of grade 2 or worse hand-foot syndrome (HFS), QoL, safety, and efficacy. QoL was assessed at baseline, 2, 4, 5 and 8 cycles after the treatment started, using the Hospital Anxiety and Depression Scale (HADS) and the Mental adjustment to cancer scale (MAC). Results: From April 2011 to September 2012, 80 pts were enrolled from 14 institutes. The characteristics were as follows: male/female: 46/34, age median: 63 (36-75), and supportive intervention 1)/2)/3)/4): 36/68/73/78. The incidence of grade 2 or worse HFS during 6 months were 11.1% (n=4) for those received TF (n=36), and 20.5% (n=9) for those received other intervention except TF (n=44). Relative dose intensity (RDI) was 75.7% (TF+/-: 77.7/74.3%) in oxaliplatin and 77.5% (TF+/-: 80.2/75.3%) in capecitabine, respectively. Although a tendency of the QoL score improvement about anxiety, fighting spirit and helplessness in a TF group was observed during the periods from start of therapy to 4 courses, there were no significant differences compared to other interventions except TF. Conclusions: We confirmed that HFS incidence was mitigated in a TF group. In regard to QoL, although we could not show the statistical differences due to some limitations of this study such as small sample size and non-randomized, it was indicated that TS had the potential to improve several QoL about anxiety, fighting spirit, and helplessness. Clinical trial information: UMIN000007185.

Molecular profiling of TOPO1: A way to evaluate irinotecan treatment in colorectal cancer?

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 546-546
Author(s):  
Julia Marie Cunningham ◽  
Petra Prins ◽  
Brian Conkright ◽  
Simina Boca ◽  
Shruti Rao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Small Sample Size ◽  
Predictive Marker ◽  
Molecular Profiling ◽  
Small Sample ◽  
Comprehensive Cancer Center ◽  
Cancer Center ◽  
Control Group ◽  
Similar Response ◽  
Second Line

546 Background: Front-line chemotherapy for metastatic colorectal cancer (mCRC) consists of a fluoropyrimidine backbone plus either oxaliplatin (FOLFOX or XELOX) or irinotecan (FOLFIRI or XELIRI). Large, prospective trials enrolling chemotherapy-naïve patients (pts) show FOLFOX and FOLFIRI treatment to be equivalent with similar response rates. Methods: Irinotecan inhibits TOPO1, which is now a candidate marker for irinotecan treatment benefit. Thus, we retrospectively analyzed TOPO1 expression level in 49 pts with mCRC who were treated with irinotecan-containing regimens at the Lombardi Comprehensive Cancer Center between 2009 and 2014. Patient characteristics and outcomes were compiled through chart review and the effect of TOPO1 expression on clinical outcomes was assessed. TOPO1 expression in tumor tissue from each pt was analyzed using a commercially available molecular profiling (MP) service (Caris Life Sciences). Results: The median overall survival (OS) for all pts was 33.9 months (mo), defined as the time from metastasis to death or censorship. When grouped by “high” or “low” TOPO1 expression, as defined by Caris at the time of the testing, 29 pts were high-expressers and 20 were low-expressers. High TOPO1 expressers receiving irinotecan (n = 22) had a median OS of 27.2 mo, compared with median 41.5 mo for low-expressers (n = 14) (p = 0.27). Irinotecan is conventionally given as second-line therapy. The median OS of pts receiving second-line irinotecan was 38.2 mo for high-expressers [n = 11] vs. 68.5 mo for low-expressers [n = 5]) (p = 0.32). Conclusions: Our limited data do not support the use of TOPO1 expression levels as a predictive marker for irinotecan therapy in mCRC. However, our conclusions are limited by small sample size, lack of a control group to distinguish prognostic from predictive markers, and timing of TOPO1 measurement, which in many cases was after irinotecan therapy. Physicians currently lack an evidence-based way to choose between potentially efficacious regimens for mCRC. More rigorous studies are needed to assess the benefit of MP in mCRC care. We are currently planning a prospective study with the hope of validating the use of TOPO1 expression as a predictive marker for treatment of this disease.

Early progression (progr) in patients (pts) with metastatic pancreatic cancer (mPaC) and a germline BRCA mutation (gBRCAm): Phase III POLO trial of olaparib (O) versus placebo (P).

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 750-750
Author(s):  
Teresa Macarulla ◽  
Hedy L. Kindler ◽  
Pascal Hammel ◽  
Michele Reni ◽  
Eric Van Cutsem ◽  
...  
Keyword(s):  
Small Sample Size ◽  
Brca Mutation ◽  
Standard Of Care ◽  
Complete Response ◽  
Small Sample ◽  
Phase Iii ◽  
Stepwise Logistic Regression ◽  
Continuous Variables ◽  
Platinum Based Chemotherapy ◽  
Stepwise Logistic Regression Model

750 Background: In POLO (NCT02184195), maintenance O was associated with significant progr-free survival benefit vs P in pts with a gBRCAm and mPaC (Golan NEJM 2019). Early progr or death (within 4 months [m]) occurs in ~35−45% of pts on standard-of-care first-line (1L) chemotherapy for mPaC (Conroy NEJM 2011; von Hoff NEJM 2013); however, predictive factors are currently unknown and early progr has not been addressed in the maintenance setting. We examined factors potentially associated with early progr in POLO. Methods: Following ≥16 weeks of 1L platinum-based chemotherapy (PBC) without progr, pts were randomized to maintenance O (tablets; 300 mg bd) or P until progr or unacceptable toxicity. Early progr was defined as progr (by blinded independent central review) or death within 4 m of randomization. A stepwise logistic regression model included baseline (BL) factors age, albumin, lactate dehydrogenase (LDH), global health status (GHS) and physical functioning (PhysF) as continuous variables, and discrete variables listed in the Table. Results: 62/154 randomized pts (40%) were defined as early progressors (EP; Table). Due to missing BL data, the multivariate analysis included 127 pts (56 EPs [44%]). Lower BL PhysF score (continuous) was significantly associated with early progr ( P= 0.02); no difference for partial/complete response (PR/CR) vs stable disease (SD). Conclusions: While small sample size limited analysis power, PhysF score was the only BL factor significantly associated with early progr in pts with a gBRCAm and mPaC in the POLO trial of maintenance O vs P. Clinical trial information: NCT02184195 . [Table: see text]

Prognostic implications of tumor sidedness in colorectal cancer patients in South Dakota, 2006-2015.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 46-46
Author(s):  
Jonathan Scott Bleeker ◽  
Muslim Atiq ◽  
Morgan Nelson ◽  
Kay Dosch
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
South Dakota ◽  
Metastatic Disease ◽  
Small Sample Size ◽  
Hepatic Flexure ◽  
Small Sample ◽  
Colon And Rectum ◽  
Prognostic Implications ◽  
Colorectal Cancer Patients

46 Background: Tumor “sidedness” is emerging as an important prognostic and predictive factor in patients with metastatic colorectal cancer (CRC), with right sided colon cancer (RC) associated with poorer overall survival (OS) than left sided colon cancer (LC). This distinction has been noted in clinical trials and large databases, where American Indian (AI) populations are generally underrepresented. This project aims to investigate the prognostic implications of CRC sidedness in the state of South Dakota, focusing on the AI population. Methods: Data from patients diagnosed with CRC in the South Dakota cancer registry from January 1, 2006 to December 31, 2015 were analyzed for demographic and presenting features as well as survival outcomes. A total of 3,637 cases were included in the analysis, of which 191 (5%) were AI. Tumors arising from the cecum, ascending colon, hepatic flexure and transverse colon were considered RC while those arising from the splenic flexure, descending colon, sigmoid colon and rectum were considered LC. Results: In all patients, 47.1% of cases were RC; Caucasians (C) were significantly more likely to have RC, as 47.7% of cases in Caucasians were RC, whereas in the AI population, 35.6% cases were RC (p=0.005). Patients with RC were more likely to be female and older and less likely to present with metastatic disease than LC. Tumor sidedness was not associated with OS when analyzing all patients regardless of stage or in patients with non-metastatic disease. In patients with metastatic disease, RC was associated with inferior OS compared to LC [Median OS (mo): 9.9 v. 23.6, p<0.001]. When analyzed by race, RC was associated with inferior OS in C [Median OS (mo): 9.6 v. 23.6, p=0.002] but not in AI [Median OS (mo): 10.2 v. 10.4, p=0.082]. Conclusions: Although limited by small sample size, this analysis is hypothesis generating, as AI patients with CRC were more likely to have LC than Caucasians and the well described prognostic implications of RC were not noted in the AI population. Larger population studies and further investigation as to potential explanations for this finding are recommended.

scholarly journals Identification of Gene Signatures Used to Recognize Biological Characteristics of Gastric Cancer upon Gene Expression Data

2014 ◽  
Vol 9 ◽  
pp. BMI.S13059 ◽  
Author(s):  
Zhi Yan ◽  
Brian T. Luke ◽  
Shirley X. Tsang ◽  
Rui Xing ◽  
Yuanming Pan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gastric Cancer ◽  
Information Gain ◽  
Small Sample Size ◽  
High Sensitivity ◽  
Small Sample ◽  
Machine Learning Algorithms ◽  
Biological Characteristics ◽  
Gene Signatures ◽  
Mining Model

High-throughput gene expression microarrays can be examined by machine-learning algorithms to identify gene signatures that recognize the biological characteristics of specific human diseases, including cancer, with high sensitivity and specificity. A previous study compared 20 gastric cancer (GC) samples against 20 normal tissue (NT) samples and identified 1,519 differentially expressed genes (DEGs). In this study, Classification Information Index (CII), Information Gain Index (IGI), and RELIEF algorithms are used to mine the previously reported gene expression profiling data. In all, 29 of these genes are identified by all three algorithms and are treated as GC candidate biomarkers. Three biomarkers, COL1A2, ATP4B, and HADHSC, are selected and further examined using quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC) staining in two independent sets of GC and normal adjacent tissue (NAT) samples. Our study shows that COL1A2 and HADHSC are the two best biomarkers from the microarray data, distinguishing all GC from the NT, whereas ATP4B is diagnostically significant in lab tests because of its wider range of fold-changes in expression. Herein, a data-mining model applicable for small sample sizes is presented and discussed. Our result suggested that this mining model may be useful in small sample-size studies to identify putative biomarkers and potential biological features of GC.

scholarly journals Deep learning for the prediction of early on-treatment response in metastatic colorectal cancer from serial medical imaging

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Lin Lu ◽  
Laurent Dercle ◽  
Binsheng Zhao ◽  
Lawrence H. Schwartz
Keyword(s):  
Colorectal Cancer ◽  
Deep Learning ◽  
Metastatic Colorectal Cancer ◽  
Treatment Response ◽  
Morphological Change ◽  
Tumor Size ◽  
Tumor Response ◽  
Treatment Decision ◽  
Response Assessment ◽  
Size Change

AbstractIn current clinical practice, tumor response assessment is usually based on tumor size change on serial computerized tomography (CT) scan images. However, evaluation of tumor response to anti-vascular endothelial growth factor therapies in metastatic colorectal cancer (mCRC) is limited because morphological change in tumor may occur earlier than tumor size change. Here we present an analysis utilizing a deep learning (DL) network to characterize tumor morphological change for response assessment in mCRC patients. We retrospectively analyzed 1,028 mCRC patients who were prospectively included in the VELOUR trial (NCT00561470). We found that DL network was able to predict early on-treatment response in mCRC and showed better performance than its size-based counterpart with C-Index: 0.649 (95% CI: 0.619,0.679) vs. 0.627 (95% CI: 0.567,0.638), p = 0.009, z-test. The integration of DL network with size-based methodology could further improve the prediction performance to C-Index: 0.694 (95% CI: 0.661,0.720), which was superior to size/DL-based-only models (all p < 0.001, z-test). Our study suggests that DL network could provide a noninvasive mean for quantitative and comprehensive characterization of tumor morphological change, which may potentially benefit personalized early on-treatment decision making.

Species Distribution Modeling of American Beech (Fagus Grandifolia) Distribution in Southwest Ohio

2017 ◽  
Vol 8 (3) ◽  
pp. 16-36 ◽  
Author(s):  
Brandon Flessner ◽  
Mary C. Henry ◽  
Jerry Green
Keyword(s):  
Linear Model ◽  
Species Distribution ◽  
Small Sample Size ◽  
Basal Area ◽  
Fagus Grandifolia ◽  
Small Sample ◽  
Environmental Data ◽  
Continuous Variables ◽  
American Beech ◽  
Boosted Regression Tree

The ability to predict American beech distribution (Fagus grandifolia Ehrh.) from environmental data was tested by using a geographic information system (GIS) in tandem with species distribution models (SDMs). The study was conducted in Butler and Preble counties in Ohio, USA. Topography, soils, and disturbance were approximated through 15 predictor variables with presence/absence and basal area serving as the response variables. Using a generalized linear model (GLM) and a boosted regression tree (BRT) model, curvature, elevation, and tasseled cap greenness were shown to be significant predictors of beech presence. Each of these variables was positively related to beech presence. A linear model using presence only data was not effective in predicting basal area due to a small sample size. This study demonstrates that SDMs can be used successfully to advance one's understanding of the relationship between tree species presence and environmental factors. Large sample sizes are needed to successfully model continuous variables.

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