scholarly journals MicroRNA-199b Downregulation Confers Resistance to 5-Fluorouracil Treatment and Predicts Poor Outcome and Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer Patients

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1655 ◽  
Author(s):  
Ion Cristóbal ◽  
Jaime Rubio ◽  
Andrea Santos ◽  
Blanca Torrejón ◽  
Cristina Caramés ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Rectal Cancer ◽  
Locally Advanced ◽  
Neoadjuvant Chemoradiotherapy ◽  
Advanced Rectal Cancer ◽  
Locally Advanced Rectal Cancer ◽  
Preoperative Treatment ◽  
Dependent Manner ◽  
Current Standard ◽  
Poor Outcome

Neoadjuvant 5-fluorouracil (5-FU)-based chemoradiotherapy followed by mesorectal excision is the current standard treatment in locally advanced rectal cancer (LARC) and the lack of complete response represents a major problem that compromises long-term patient survival. However, there is a lack of robust established markers predictive of response to this preoperative treatment available in the clinical routine. The tumor suppressor microRNA (miR)-199b directly targets the PP2A inhibitor SET, which has been involved in 5-FU resistance, and its downregulation has been found to correlate with poor outcome in metastatic colorectal cancer. Here, we studied the functional effects of miR-199b on 5-FU sensitivity after its ectopic modulation, and its expression was quantified by real-time-PCR in a cohort of 110 LARC patients to evaluate its potential clinical significance. Interestingly, our findings demonstrate that miR-199b enhances the sensitivity of colorectal cancer cells to 5-FU in a SET-dependent manner, and that both miR-199b overexpression and SET inhibition are able to overcome resistance to this drug using an acquired 5-FU-resistant model. MiR-199b was found downregulated in 26.4% of cases and was associated with positive lymph node levels after chemoradiotherapy (CRT, p = 0.007) and high pathological stage (p = 0.029). Moreover, miR-199b downregulation determined shorter overall (p = 0.003) and event-free survival (p = 0.005), and was an independent predictor of poor response to preoperative CRT (p = 0.004). In conclusion, our findings highlight the clinical impact of miR-199b downregulation predicting poor outcome and pathological response in LARC, and suggest the miR-199b/SET signaling axis as a novel molecular target to prevent the development of resistance to 5-FU treatment.

scholarly journals Fibrinogen and Albumin Score Changes during Preoperative Treatment Can Predict Prognosis in Patients with Locally Advanced Rectal Cancer

2019 ◽  
Vol 2019 ◽  
pp. 1-8
Author(s):  
Meng-Jun Tang ◽  
Shu-Bo Ding ◽  
Wang-Yuan Hu
Keyword(s):  
Rectal Cancer ◽  
Locally Advanced ◽  
Neoadjuvant Chemoradiotherapy ◽  
Disease Free Survival ◽  
Advanced Rectal Cancer ◽  
Locally Advanced Rectal Cancer ◽  
Preoperative Treatment ◽  
Prognostic Parameters ◽  
Group A ◽  
Group B

Background. Fibrinogen (Fib) and albumin (Alb) levels are indicators of systemic inflammatory responses. Elevated Fib and decreased Alb levels are considered negative prognostic factors in different types of cancer. Here, we explored the prognostic value of changes in pre- and post- neoadjuvant chemoradiotherapy (NCRT) plasma fibrinogen and serum albumin (FA) scores in patients with locally advanced rectal cancer (LARC). Methods. A total of 106 patients with LARC who underwent NCRT followed by surgical resection at Jinhua Municipal Central Hospital between 2011 and 2015 were analyzed. In addition, plasma Fib and serum Alb levels before and after NCRT were collected. FA scores were calculated based on the Fib and Alb levels dichotomized by clinical reference values. Patients were classified into two groups based on the changes in FA scores during NCRT: in group A, FA scores decreased or remained unchanged (n=84), and in group B, FA scores increased (n=22). Changes in FA scores were compared with patient outcomes. Results. Increased FA scores were associated with worse disease-free survival (DFS) and overall survival (OS) in patients with LARC. The occurrence of systemic failure was higher in group B than in group A (40.9% vs. 19%, P=0.032). In multivariate analysis, changes in FA scores, pretreatment carcinoembryonic antigen (CEA) levels, and pathologic differentiation were independent prognostic parameters for DFS and changes in FA scores and pretreatment CEA levels were independent prognostic parameters for OS. Conclusions. Increased FA score after NCRT was an independent negative prognostic factor for DFS and OS in patients with NCRT-treated LARC.

scholarly journals Neoadjuvant Сhemoradiotherapy of Locally Advanced Rectal Cancer with Local 5-Fluoracil Radiomodification

2021 ◽  
pp. 41-50
Author(s):  
A. R. Akhtemzyanov ◽  
O. V. Korytov ◽  
L. I. Korytova ◽  
A. V. Meshechkin ◽  
N. D. Oltarzhevskaya ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Locally Advanced ◽  
Neoadjuvant Chemoradiotherapy ◽  
Advanced Rectal Cancer ◽  
Locally Advanced Rectal Cancer ◽  
Modern Medicine ◽  
Chemotherapeutic Agents ◽  
Current Standard ◽  
Chemotherapy Agent ◽  
Derivatives Of

Chemoradiotherapy, along with following surgical treatment, including total mesorectal excision, is a current standard for treatment of locally advanced rectal cancer. Neoadjuvant chemoradiotherapy allows to downsize the tumor, up to complete clinical response in one third of all cases, which, in turn, allows increase in sphincter preserving operations, disease-free period and overall survivability. Derivatives of 5-fluoracil are used as basic chemotherapeutic agents. These drugs have a substantial amount of side effects, which lead to either plan corrections, or may even prevent its completion. Thus, search for new ways to increase chemotherapy agent in the tumor cells with reduction of systemic toxicity to improve neoadjuvant chemoradiotherapy results is an acute task for modern medicine. In this article authors suggest intrarectal application of sterile hydrogel material based on sodium alginate with incorporated 5-fluoracil as a method of neoadjuvant chemoradiotherapy.

Watch and wait approach following neoadjuvant chemoradiotherapy for rectal cancer patients: A single-centre experience.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 681-681
Author(s):  
Ji Zhu ◽  
Jingwen Wang
Keyword(s):  
Rectal Cancer ◽  
Cancer Patients ◽  
Locally Advanced ◽  
Neoadjuvant Chemoradiotherapy ◽  
Disease Free Survival ◽  
Complete Response ◽  
Advanced Rectal Cancer ◽  
Locally Advanced Rectal Cancer ◽  
Preoperative Treatment ◽  
Watch And Wait

681 Background: A watch-and-wait approach for patients with clinical complete response to neoadjuvant chemoradiation could avoid the morbidity of conventional surgery for rectal cancer. Here, we report the survival outcome of patients with this strategy in our center. Methods: We retrospectively analyzed the rectal cancer patients who received neoadjuvant chemoradiotherapy since 2015 in our center. Preoperative regimen included long-course radiotherapy (50 Gy / 25 Fx) combined fluoropyrimidin–based chemotherapy concurrently. MRI and endoscopic evaluation were performed after preoperative treatment. Patients with complete tumor response were referred to the “watch-and-wait” approach and omitted the surgery. Four to six cycles of consolidation chemotherapy were performed. Patients were followed up clinically, endoscopically, and radiologically to assess for local recurrence or disease progression. Results: From January 2015 to March 2018, a total of 47 patients with rectal cancer in our center received conservative treatment following neoadjuvant therapy. The median age of the patients is 58 (53-66). The proportions of stages I to IV are 4.3%, 12.8%, 70.2%, 8.5%, respectively. After a median follow-up of 20 month, tumor regrowth occurred in five out of 47 (10.6%) patients. All local regrowth was diagnosed in the first two years, and four out of five (80%) of local regrowth was located in the bowel wall. All patients underwent salvage surgery. Distant metastasis was diagnosed in four of 47 patients (8.5%). two-year overall survival was 89.9%, and two-year disease-free survival was 76.5%. Conclusions: Organ preservation for locally advanced rectal cancer is feasible for selected patients who achieve a complete response to individualized neoadjuvant CRT. The survival of patients is not impaired with “watch-and-wait” strategy.

scholarly journals Computertomography-Based Prediction of Complete Response Following Neoadjuvant Chemoradiotherapy of Locally Advanced Rectal Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Marina Maslova ◽  
Heinz Herden ◽  
Karin Schork ◽  
Michael Turewicz ◽  
Martin Eisenacher ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Locally Advanced ◽  
Neoadjuvant Chemoradiotherapy ◽  
Treatment Strategies ◽  
Complete Response ◽  
Advanced Rectal Cancer ◽  
Locally Advanced Rectal Cancer ◽  
Individual Treatment ◽  
Watch And Wait ◽  
Current Standard

Therapeutic strategies for patients with locally advanced rectal cancer (LARC) who are achieving a pathological complete response (pCR) after neoadjuvant radio-chemotherapy (neoCRT) are being increasingly investigated. Recent trials challenge the current standard therapy of total mesorectal excision (TME). For some patients, the treatment strategy of “watch-and-wait” seems a preferable procedure. The key factor in determining individual treatment strategies following neoCRT is the precise evaluation of the tumor response. Contrast-enhanced computer tomography (ceCT) has proven its ability to discriminate benign and malign lesions in multiple cancers. In this study, we retrospectively analyzed the ceCT based density of LARC in 30 patients, undergoing neoCRT followed by TME. We compared the tumors´ pre- and post-neoCRT density and correlated the results to the amount of residual vital tumor cells in the resected tissue. Overall, the density decreased after neoCRT, with the highest decrease in patients achieving pCR. Densitometry demonstrated a specificity of 88% and sensitivity of 68% in predicting pCR. Thus, we claim that ceCT based densitometry is a useful tool in identifying patients with LARC who may benefit from a “watch-and-wait” strategy and suggest further prospective studies.

scholarly journals O11: MYOFERLIN: A NOVEL BIOMARKER OF RADIOSENSITIVITY IN LOCALLY ADVANCED RECTAL CANCER

2021 ◽  
Vol 108 (Supplement_1) ◽  
Author(s):  
H Fowler ◽  
P Sutton ◽  
D Bowden ◽  
J Parsons ◽  
D Vimalachandran
Keyword(s):  
Colorectal Cancer ◽  
Rectal Cancer ◽  
Cancer Cells ◽  
Locally Advanced ◽  
Neoadjuvant Chemoradiotherapy ◽  
Advanced Rectal Cancer ◽  
Locally Advanced Rectal Cancer ◽  
Radiation Doses ◽  
Clonogenic Assays ◽  
Colorectal Cancer Cells

Abstract Introduction Our proteomic data has validated that high levels of the protein myoferlin confers poorer response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer. Myoferlin plays a role in membrane repair and VEGF signal transduction, and is associated with worse prognosis in numerous other epithelial cancers. We aim to assess the impact of myoferlin on the radiosensitivity of rectal cancer. Method Clonogenic assays were performed using immortalised colorectal cancer cells (HCT116,HT29,LIM,MDST8) to assess survival at escalating radiation doses following knockdown with myoferlin siRNA or a small molecular inhibitor(WJ460). 3D models (spheroids) were used to examine the effect of WJ460 on tumour growth. Result Quantification of myoferlin using immunoblotting demonstrated that MDST8 and LIM were higher expressors than HCT116 and HT29. Higher levels correlated with increasing radio-resistance as calculated by colony formation efficiency (CFE). Using clonogenic assays, cells treated with myoferlin siRNA or WJ460 demonstrated increased radiosensitivity compared to controls across all radiation doses, most significantly at 4Gy. Treatment of spheroids with WJ460 significantly reduced growth compared to controls at all radiation doses (p<0.05), with WJ460 limiting growth considerably more than treatment with the current gold standard 5-FU. HCT116 spheroid volume day 15; WJ460 4.96um3,5-FU 6.74um3,DMSO 24.9um3. Conclusion Inhibition of myoferlin is associated with increased radiosensitivity of colorectal cancer cells, and treatment with a small molecular inhibitor significantly reduces growth in spheroid models. Further work is required further validate its potential use as a biomarker in locally advanced rectal cancer. Take-home message We have found that myoferlin is a protein associated with poor response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer. Manipulation of this protein sensitises the cancer cells to radiotherapy.

Preoperative Treatment of Locally Advanced Rectal Cancer

2012 ◽  
Vol 08 (04) ◽  
pp. 224
Author(s):  
Davendra P S Sohal ◽  
Weijing Sun ◽  
◽  
Keyword(s):  
Colorectal Cancer ◽  
Rectal Cancer ◽  
Locally Advanced ◽  
Standard Of Care ◽  
Advanced Rectal Cancer ◽  
Locally Advanced Rectal Cancer ◽  
Preoperative Treatment ◽  
Preoperative Management

The preoperative management of locally advanced rectal cancer has evolved over the years to establish fluoropyrimidine-based chemoradiation as the usual standard of care. With the advent of newer agents – chemotherapeutic and biologic – for treatment of colorectal cancer, their role in this setting is being evaluated as well. This review is focusing on up-to-date data and studies regarding preoperative treatment of locally advanced rectal cancer.

Use of MRI-defined tumor distance from the anal verge to predict tumor response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 573-573
Author(s):  
Stanley Ka Tung Yu ◽  
Gina Brown ◽  
Diana M. Tait
Keyword(s):  
Rectal Cancer ◽  
Surgical Resection ◽  
Anal Verge ◽  
Locally Advanced ◽  
Neoadjuvant Chemoradiotherapy ◽  
Advanced Rectal Cancer ◽  
Locally Advanced Rectal Cancer ◽  
Low Rectal Cancer ◽  
Resected Specimen ◽  
Current Standard

573 Background: Neoadjuvant Chemoradiotherapy (CRT) and surgical resection is the current standard management for patients with locally advanced rectal cancer (i.e. T3 or 4 N0/1 M0) (LARC). Tumour predictive factors for response to CRT in rectal cancer remain controversial. Staging investigations are not standardised and MRI has not been used consistently to approach this. The aim of this study is to investigate whether tumour distance from anal verge, as measured on MRI, is a predictive factor for response to CRT in LARC. Methods: This is a retrospective study. Patients with LARC or low T2 N0/1 M0 rectal cancer (i.e. ≤ 5cm from anal verge measured by MRI) treated with preoperative CRT in 2003- 2009 were included. Pelvic MRIs acquired before CRT and no less than 4 weeks post CRT were reviewed. Patients with ypT0-2 in the resected specimen were classified as responders because ypT0-2 has been shown with significant OS and DFS benefit (Valentini V et al. Int J Radiat Oncol Biol Phys. 2002; 53(3): 664-74). Downstage of mrT2 low rectal cancer was defined as ypT0-1 post CRT. Univariate binary logistic regression (UBLR) was used to analyse the predictor associated between responders and non-responders to CRT treated in the same period of time. Results: 281 patients with LARC who underwent CRT were included in the study. 96% patients in this study had T3/T4 LARC and 4% had T2 low rectal cancer. 114 (41%) were responders as defined above, 167 (59%) were non-responders to CRT. The mean MRI defined tumour distance from anal verge was significantly less in responders (6.4cm [Confidence Intervals (CI) = 5.7 -7.1]) when compared with non-responders (7.9cm [CI =7.3 – 8.6]) (P<0.05). Conclusions: The UBLR analysis from our study indicated that an MRI measured tumour distance of ≤ 5cm from the anal verge independently predicted higher tumour downstaging rate (p < 0.001) to CRT in LARC. Further investigation is recommended regarding tumour downstaging and sphincter preserving surgical resection rate in low rectal cancer post neoadjuvant CRT. [Table: see text]

scholarly journals Neoadjuvant chemoradiation alters biomarkers of anticancer immunotherapy responses in locally advanced rectal cancer

2021 ◽  
Vol 9 (3) ◽  
pp. e001610
Author(s):  
Incheol Seo ◽  
Hye Won Lee ◽  
Sang Jun Byun ◽  
Jee Young Park ◽  
Hyeonji Min ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Locally Advanced ◽  
Enrichment Analysis ◽  
Advanced Rectal Cancer ◽  
Locally Advanced Rectal Cancer ◽  
Neoadjuvant Chemoradiation ◽  
Cytolytic Activity ◽  
Gene Set Enrichment Analysis ◽  
Preoperative Treatment ◽  
Rna Seq

BackgroundNeoadjuvant chemoradiation therapy (CRT) is a widely used preoperative treatment strategy for locally advanced rectal cancer (LARC). However, a few studies have evaluated the molecular changes caused by neoadjuvant CRT in these cancer tissues. Here, we aimed to investigate changes in immunotherapy-related immunogenic effects in response to preoperative CRT in LARC.MethodsWe analyzed 60 pairs of human LARC tissues before and after irradiation from three independent LARC cohorts, including a LARC patient RNA sequencing (RNA-seq) dataset from our cohort and GSE15781 and GSE94104 datasets.ResultsGene ontology analysis showed that preoperative CRT significantly enriched the immune response in LARC tissues. Moreover, gene set enrichment analysis revealed six significantly enriched Kyoto Encyclopedia of Genes and Genomes pathways associated with downregulated genes, including mismatch repair (MMR) genes, in LARC tissues after CRT in all three cohorts. Radiation also induced apoptosis and downregulated various MMR system-related genes in three colorectal cancer cells. One patient with LARC showed a change in microsatellite instability (MSI) status after CRT, as demonstrated by the loss of MMR protein and PCR for MSI. Moreover, CRT significantly increased tumor mutational burden in LARC tissues. CIBERSORT analysis revealed that the proportions of M2 macrophages and CD8 T cells were significantly increased after CRT in both the RNA-seq dataset and GSE94104. Notably, preoperative CRT increased various immune biomarker scores, such as the interferon-γ signature, the cytolytic activity and the immune signature.ConclusionsTaken together, our findings demonstrated that neoadjuvant CRT modulated the immune-related characteristics of LARC, suggesting that neoadjuvant CRT may enhance the responsiveness of LARC to immunotherapy.

scholarly journals Molecular and Dynamic Evaluation of Proteins Related to Resistance to Neoadjuvant Treatment with Chemoradiotherapy in Circulating Tumor Cells of Patients with Locally Advanced Rectal Cancer

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1539
Author(s):  
Virgílio Souza e Silva ◽  
Emne Ali Abdallah ◽  
Bianca de Cássia Troncarelli Flores ◽  
Alexcia Camila Braun ◽  
Daniela de Jesus Ferreira Costa ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Transforming Growth Factor ◽  
Locally Advanced ◽  
Neoadjuvant Treatment ◽  
Neoadjuvant Chemoradiotherapy ◽  
Disease Free Survival ◽  
Advanced Rectal Cancer ◽  
Locally Advanced Rectal Cancer

The heterogeneity of response to neoadjuvant chemoradiotherapy (NCRT) is still a challenge in locally advanced rectal cancer (LARC). The evaluation of thymidylate synthase (TYMS) and RAD23 homolog B (RAD23B) expression in circulating tumor cells (CTCs) provides complementary clinical information. CTCs were prospectively evaluated in 166 blood samples (63 patients) with LARC undergoing NCRT. The primary objective was to verify if the absence of RAD23B/TYMS in CTCs would correlate with pathological complete response (pCR). Secondary objectives were to correlate CTC kinetics before (C1)/after NCRT (C2), in addition to the expression of transforming growth factor-β receptor I (TGF-βRI) with survival rates. CTCs were isolated by ISET and evaluated by immunocytochemistry (protein expression). At C1, RAD23B was detected in 54.1% of patients with no pCR and its absence in 91.7% of patients with pCR (p = 0.014); TYMS− was observed in 90% of patients with pCR and TYMS+ in 51.7% without pCR (p = 0.057). Patients with CTC2 > CTC1 had worse disease-free survival (DFS) (p = 0.00025) and overall survival (OS) (p = 0.0036) compared with those with CTC2 ≤ CTC1. TGF-βRI expression in any time correlated with worse DFS (p = 0.059). To conclude, RAD23B/TYMS and CTC kinetics may facilitate the personalized treatment of LARC.

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