Analysis of MicroRNA Expression Changes During the Course of Therapy In Rectal Cancer Patients.
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ABSTRACT:
SUBMITTER: Cervena K
PROVIDER: S-EPMC8444897 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Since the response to chemoradiotherapy in patients with locally advanced rectal cancer is heterogeneous, valid biomarkers are needed to monitor tumor response. Circulating microRNAs are promising candidates, however analyses of circulating microRNAs in rectal cancer are still rare. 111 patients with rectal cancer and 46 age-matched normal controls were enrolled. The expression levels of 30 microRNAs were analyzed in 17 pre-treatment patients' plasma samples. Differentially regulated microRNAs were validated in 94 independent patients. For 52 of the 94 patients a paired comparison between pre-treatment and post-treatment samples was performed. miR-17, miR-18b, miR-20a, miR-31, and miR-193a_3p, were significantly downregulated in pre-treatment plasma samples of patients with rectal cancer (p < 0.05). miR-29c, miR-30c, and miR-195 showed a trend of differential regulation. After validation, miR-31 and miR-30c were significantly deregulated by a decrease of expression. In 52 patients expression analyses of the 8 microRNAs in matched pre-treatment and post-treatment samples showed a significant decrease for all microRNAs (p < 0.05) after treatment. Expression levels of miR-31 and miR-30c could serve as valid biomarkers if validated in a prospective study. Plasma microRNA expression levels do not necessarily represent miRNA expression levels in tumor tissue. Also, expression levels of microRNAs change during multimodal therapy.
| S-EPMC5485964 | biostudies-literature
Project description:PURPOSE:miRNAs play a prominent role in a variety of physiologic and pathologic biologic processes, including cancer. For rectal cancers, only limited data are available on miRNA expression profiles, whereas the underlying genomic and transcriptomic aberrations have been firmly established. We therefore, aimed to comprehensively map the miRNA expression patterns of this disease. EXPERIMENTAL DESIGN:Tumor biopsies and corresponding matched mucosa samples were prospectively collected from 57 patients with locally advanced rectal cancers. Total RNA was extracted, and tumor and mucosa miRNA expression profiles were subsequently established for all patients. The expression of selected miRNAs was validated using semi-quantitative real-time PCR. RESULTS:Forty-nine miRNAs were significantly differentially expressed (log(2)-fold difference >0.5 and P < 0.001) between rectal cancer and normal rectal mucosa. The predicted targets for these miRNAs were enriched for the following pathways: Wnt, TGF-beta, mTOR, insulin, mitogen-activated protein kinase, and ErbB signaling. Thirteen of these 49 miRNAs seem to be rectal cancer-specific, and have not been previously reported for colon cancers: miR-492, miR-542-5p, miR-584, miR-483-5p, miR-144, miR-2110, miR-652, miR-375, miR-147b, miR-148a, miR-190, miR-26a/b, and miR-338-3p. Of clinical impact, miR-135b expression correlated significantly with disease-free and cancer-specific survival in an independent multicenter cohort of 116 patients. CONCLUSION:This comprehensive analysis of the rectal cancer miRNAome uncovered novel miRNAs and pathways associated with rectal cancer. This information contributes to a detailed view of this disease. Moreover, the identification and validation of miR-135b may help to identify novel molecular targets and pathways for therapeutic exploitation.
| S-EPMC6298229 | biostudies-literature
Project description:IntroductionAn increasing number of studies have investigated microRNAs (miRNAs) as potential markers of diagnosis, treatment and prognosis. So far, agreement between studies has been minimal, which may in part be explained by intratumoral heterogeneity of miRNA expression. The aim of the present study was to assess the heterogeneity of a panel of selected miRNAs in rectal cancer, using two different technical approaches.Materials and methodsThe expression of the investigated miRNAs was analysed by real-time quantitative polymerase chain reaction (RT-qPCR) and in situ hybridization (ISH) in tumour specimens from 27 patients with T3-4 rectal cancer. From each tumour, tissue from three different luminal localisations was examined. Inter- and intra-patient variability was assessed by calculating intraclass correlation coefficients (ICCs). Correlations between RT-qPCR and ISH were evaluated using Spearman's correlation.ResultsICCsingle (one sample from each patient) was higher than 50% for miRNA-21 and miRNA-31. For miRNA-125b, miRNA-145, and miRNA-630, ICCsingle was lower than 50%. The ICCmean (mean of three samples from each patient) was higher than 50% for miRNA-21(RT-qPCR and ISH), miRNA-125b (RT-qPCR and ISH), miRNA-145 (ISH), miRNA-630 (RT-qPCR), and miRNA-31 (RT-qPCR). For miRNA-145 (RT-qPCR) and miRNA-630 (ISH), ICCmean was lower than 50%. Spearman correlation coefficients, comparing results obtained by RT-qPCR and ISH, respectively, ranged from 0.084 to 0.325 for the mean value from each patient, and from -0.085 to 0.515 in the section including the deepest part of the tumour.ConclusionIntratumoral heterogeneity may influence the measurement of miRNA expression and consequently the number of samples needed for representative estimates. Our findings with two different methods suggest that one sample is sufficient for adequate assessment of miRNA-21 and miRNA-31, whereas more samples would improve the assessment of miRNA-125b, miRNA-145, and miRNA-630. Interestingly, we found a poor correlation between the expression estimates obtained by RT-qPCR and ISH, respectively.
| S-EPMC4892647 | biostudies-literature
Project description:ImportanceAlthough both short-course radiotherapy and long-course chemoradiotherapy have been practiced in parallel for more than 15 years, no cost-effectiveness analysis comparing these 2 approaches in patients with locally advanced rectal cancer has been published.ObjectiveTo analyze the cost-effectiveness of short-course radiotherapy vs long-course chemoradiotherapy for the treatment of patients with locally advanced rectal cancer.Design, setting, and participantsThis economic evaluation used a cost-effectiveness model simulating 10-year outcomes for 1 million hypothetical patients aged 65 years with locally advanced rectal cancer treated with either short-course radiotherapy or long-course chemoradiotherapy, followed by surgery and chemotherapy. Utilities and probabilities from the literature and costs from the Healthcare Bluebook and Medicare fee schedules were used to determine incremental cost-effectiveness ratios. It was assumed that long-course chemoradiotherapy would result in higher rates of low anterior resection (LAR). To model preference-sensitive care, a 2-way sensitivity analysis was conducted in which the utilities of the no-evidence-of-disease (NED) states with LAR and abdominoperineal resection (APR) were simultaneously varied. The analysis was repeated for patients with distal rectal tumors. Analysis was conducted from January to October 2018.ExposuresShort-course radiotherapy and long-course chemoradiotherapy.Main outcomes and measuresIncremental cost-effectiveness ratios.ResultsShort-course radiotherapy was the cost-effective strategy compared with long-course chemoradiotherapy (incremental cost-effectiveness ratio, $133 495 per quality-adjusted life-year). Two-way sensitivity analysis revealed that the cost-effective approach for a given patient depended on the utilities for the NED-LAR and NED-APR states. Assuming that a greater proportion of patients with locally advanced distal tumors undergoing long-course chemoradiotherapy (39%) would proceed to LAR compared with those treated with short-course radiotherapy (19%), long-course chemoradiotherapy was the cost-effective approach (incremental cost-effectiveness ratio, $61 123 per quality-adjusted life-year).Conclusions and relevanceShort-course radiotherapy was the cost-effective strategy compared with long-course chemoradiotherapy for patients with locally advanced rectal cancer. The cost-effectiveness of short-course radiotherapy vs long-course chemoradiotherapy was sensitive to the utilities of the NED-LAR and NED-APR health states, highlighting the importance of care that is sensitive to patient preference. Long-course chemoradiotherapy was the cost-effective approach for patients with distal tumors.
| S-EPMC6481445 | biostudies-literature
Project description:BackgroundSeizure duration has long been measured as a potential marker of ECT treatment efficacy, with concern that short seizures may be clinically ineffective. Relatively small studies have documented a trend towards shorter seizures during acute course ECT, but data from large cohorts would help provide normative data on seizure duration changes during treatment.ObjectiveThis study analyzes the effects of age, sex, ECT dose, and treatment number on the duration of electrographic seizures during acute course ECT in a large single-center cohort.MethodsA single-center retrospective chart review was conducted of adult patients receiving a first course of ECT from 2000 to 2017 at a large freestanding psychiatric hospital.Results3648 patients met inclusion criteria, receiving 32,879 acute course ECT treatments. There was a shortening of mean ECT seizure duration over the acute course, with the greatest decrease in duration over the first 3 treatments but continuing decreases over the entire acute course. Older age, higher ECT dose, and increasing treatment number were all associated with shorter seizures, while sex was not significantly associated. Increasing treatment dose was associated with shorter seizures relative to no dose increase, with those patients receiving the highest cumulative doses also having the shortest cumulative seizure time.ConclusionsAmong patients undergoing acute-course ECT treatment, seizure duration decreased over the treatment course, and increases in applied electrical charge were associated with shorter seizures.
| S-EPMC8316429 | biostudies-literature
Project description:In rectal cancer, one of the most common cancers worldwide, the proper staging of the disease determines the subsequent therapy. For those with locally advanced rectal cancer, a neoadjuvant chemoradiotherapy (CRT) is recommended before any surgery. However, response to CRT ranges from complete response (responders) to complete resistance (non-responders). To date we are not able to separate in advance the first group from the second, due to the absence of a valid biomarker. Therefore all patients receive the same therapy regardless of whether they reap benefits. On the other hand almost all patients receive a surgical resection after the CRT, although a watch-and-wait procedure or an endoscopic resection might be sufficient for those who responded well to the CRT. Being highly conserved regulators of gene expression, microRNAs (miRNAs) seem to be promising candidates for biomarkers. Many studies have been analyzing the miRNAs expressed in rectal cancer tissue to determine a specific miRNA profile for the ailment. Unfortunately, there is only a small overlap of identified miRNAs between different studies, posing the question as to whether different methods or differences in tissue storage may contribute to that fact or if the results simply are not reproducible, due to unknown factors with undetected influences on miRNA expression. Other studies sought to find miRNAs which correlate to clinical parameters (tumor grade, nodal stage, metastasis, survival) and therapy response. Although several miRNAs seem to have an impact on the response to CRT or might predict nodal stage, there is still only little overlap between different studies. We here aimed to summarize the current literature on rectal cancer and miRNA expression with respect to the different relevant clinical parameters.
| S-EPMC4865709 | biostudies-literature
Project description:To develop novel biomarkers of rectal radiotherapy, we measured gene expression profiles on biopsies taken before and during preoperative radiotherapy.Six patients presenting with a locally advanced rectal cancer (T>T2, N0/Nx, M0) eligible for preoperative radiotherapy (45 Gy in 25 fractions) were selected in a pilot study. Six tumor and 3 normal tissues biopsies were taken before and during radiotherapy, after a dose of 7.2 Gy at a median time of 1 h following irradiation (0:27-2:12). Tumor or normal tissue purity was assessed by a pathologist prior to RNA extraction. Mean RNA content was 23 ?g/biopsy (14-37) before radiotherapy and 22.7 ?g/biopsy (12-35) during radiotherapy. After RNA amplification, biopsies were analysed with 54K HG-U133A Plus 2.0 Affymetrix expression micro-arrays. Data were normalized according to MAS5 algorithm. A gene expression ratio was calculated as: (gene expression during radiotherapy - gene expression before radiotherapy)/gene expression before radiotherapy. Were selected genes that showed a ratio higher than ± 0.5 in all 6 patients.Microarray analysis showed that preoperative radiotherapy significantly up-regulated 31 genes and down-regulated 6 genes. According to the Gene Ontology project classification, these genes are involved in protein metabolism (ADAMDEC1; AKAP7; CAPN5; CLIC5; CPE; CREB3L1; NEDD4L; RAB27A), ion transport (AKAP7; ATP2A3; CCL28; CLIC5; F2RL2; NEDD4L; SLC6A8), transcription (AKAP7; CREB3L1; ISX; PABPC1L; TXNIP), signal transduction (CAPN5; F2RL2; RAB27A; TNFRSF11A), cell adhesion (ADAMDEC1; PXDN; SPON1; S100A2), immune response (CCL28; PXDN; TNFRSF11A) and apoptosis (ITM2C; PDCD4; PVT1). Up-regulation of 3 genes (CCL28; CLIC5; PDCD4) was detected by 2 different probes and up-regulation of 2 genes (RAB27A; TXNIP) by 3 probes.Micro-arrays can efficiently assess early transcriptomic changes during preoperative radiotherapy for rectal cancer, and may help better understand tumor radioresistance.
| S-EPMC3671076 | biostudies-literature
Project description:One of the hallmarks of cancer is sustained angiogenesis. Favorable results have been reported in some breast cancer (BC) patients receiving antiangiogenic therapy with bevacizumab (Bev) in combination with chemotherapy, and further knowledge on how Bev can be optimally combined with conventional treatment to increase efficacy is strongly needed. In this randomized, neoadjuvant phase II clinical trial, 132 patients with HER2-negative, nonmetastatic BC were treated with Bev in combination with sequential chemotherapy. Biopsies were sampled before treatment, after 12 weeks with anthracycline and after taxane therapy at week 25. MicroRNA (miRNA) expression profiling was performed on biopsies from each time point. Altogether, 241 biopsies were analyzed with the aim of identifying miRNA-based biomarkers of response to therapy. Results from the miRNA analyses were reported for the ER-positive cohort, which were previously demonstrated to benefit from antiangiogenic therapy in this study. For both treatment arms of this cohort, significantly different expression was observed for 217 miRNAs between objective responding and nonresponding patients before treatment initiation. These miRNAs have been linked to regulation of epithelial-mesenchymal transition, metastasis, and tumor growth, among other processes. Bev in combination with chemotherapy resulted in similar miRNA changes to chemotherapy alone. However, the deregulation of miRNA expression occurred earlier in the Bev arm. In both arms, tumor suppressor miRNAs were found upregulated after treatment, while oncogenic miRNAs were downregulated in the Bev arm. Patients responding to Bev showed a strong correlation between deregulated miRNAs and decreased proliferation score during the course of treatment, with downregulation of miR-4465 as the strongest indicator of reduced proliferation. Integrative analyses at miRNA-, gene-, and protein expression further indicated a longitudinal decrease in proliferation. Altogether, the results indicate that proliferation might represent a predictive factor for increased Bev sensitivity, which may aid in the identification of patients who could potentially benefit from Bev.
| S-EPMC6763780 | biostudies-literature
Project description:PurposeAlcohol consumption has been purported to influence many diseases. MicroRNAs (miRNAs) may be influenced by compounds found in alcohol. In this investigation, we test the hypothesis that total alcohol, beer, wine, and hard liquor influence miRNA expression.MethodsWe studied 1447 colorectal (CR) cancer cases with normal CR mucosa and carcinoma miRNA expression data along with alcohol consumption data. We analyzed long-term and long-term and current (LTC) alcohol use for beer, liquor, and wine with miRNA expression between paired carcinoma and normal colon and rectal tissues, adjusting for multiple comparisons using the positive false discovery rate q-value. MiRNAs associated significantly with alcohol were examined with all-cause mortality (ACM). MiRNAs associated significantly with ACM were examined with RNA-Seq data.ResultsExpression of 84 miRNAs was associated significantly with LTC wine use in normal rectal mucosa. Higher expression of two of these miRNAs significantly worsened ACM: hsa-miR-210 (Hazard Ratio [HR] 1.12, 95% CI (1.03, 1.21), p-value = 0.004), and hsa-miR-92a-1-5p (HR 1.20, 95% CI (1.04, 1.38), p-value = 0.013). These miRNAs were downregulated across levels of LTC wine consumption.ConclusionsOur results suggest that wine influences miRNA expression in rectal cancer, supporting the hypothesis that components in alcohol influence miRNA expression.
| S-EPMC5400787 | biostudies-literature
Project description:PurposePrevious studies have reported data on the internal rectal motion of patients with rectal cancer treated in the prone position. With the introduction of intensity modulated techniques, more patients are treated in the more reproducible supine position. Data informing specific margins for this treatment position are sparse, as are data comparing rectal motion characteristics and factors in male and female patients. The purpose of this retrospective study was to quantify and compare the interfractional rectal movement characteristics of male and female patients with rectal cancer treated with long-course chemoradiation therapy in the supine position. The data will aid the generation of internal target volume margins accounting for this organ's internal physiological movements.Methods and materialsCone beam computed tomography (CBCT) images were acquired from 19 male and 16 female patients with rectal cancer on the first 3 days of treatment and weekly thereafter. The rectum, bladder, and femoral heads were delineated on the planning CT (PCT) and 6 CBCT for each patient. Overall, 245 images were analyzed. All patients were treated with a full bladder. The rectum was divided into three 5-cm segments (upper, mid, and lower). The motion of the rectum was quantified by documenting the anteroposterior and lateral distances as measured using fixed anatomic landmarks, namely from the anterior aspect of the sacrum and mid-left femoral head, respectively. These measurements were taken at 1-cm intervals from the inferior border of L5 vertebrae. The sigmoid was excluded from these measurements. Estimations of systematic and random physiological movement error were determined and margins were calculated.ResultsTwo hundred forty-five image sets (19 PCT + 114 CBCT for male, 16 PCT + 96 CBCT for female) on patients who had undergone long-course radiation therapy were analyzed. Rectal tumor location was 31% in the inferior rectum, 46% in the mid rectum, and 23% in the superior rectum. Random rectal motion (mean of the per-patient standard deviation [σ]) was largest for the upper and mid rectum in the anterior direction. There were statistically significant differences in σ between male and female patients in the left lateral motion of the mid and inferior rectum as well as the anterior, posterior, and right motion of the inferior rectum (mid left: P < .0005; lower left: P < .0005; lower posterior: P = .001; lower anterior: P = .032; lower right: P = .001). Suggested internal target volume margin guidelines are therefore nonisotropic and vary per segment of rectum and sex.ConclusionsIn our present study, interfractional rectal motion is shown to be significantly different between male and female patients. Our data suggest that the use of asymmetrical sex-specific margins in patients with rectal cancer treated in the supine position should be considered.
| S-EPMC9723314 | biostudies-literature