scholarly journals The Prognostic Significance of Global Histones Deacetylation in Colorectal Cancer Patients Treated with Fluoropyrimdine Therapy

2020 ◽  
Vol 11 (4) ◽  
pp. 5708-5722
Author(s):  
Mariam A. Fouad ◽  
Salem S E ◽  
Hussein M M ◽  
Zekri AR N ◽  
Hafez H F ◽  
...  

To study the impact of fluoropyrimidine (FP)- therapy on the acetylation level of histones (H3 and H4), and its correlation to treatment outcome in colorectal cancer (CRC) patients. Total histone protein was extracted, and the level of global histones (H3 and H4) acetylation was determined in the peripheral blood of 66 CRC patients before treatment with FP therapy, and also in 48 and 32 of those patients after 3 and 6 months of treatment, respectively. Clinicopathological stratification of patients was conducted for subgroup analysis. After three years of follow up, event-free survival (EFS) and the hazard of recurrence and progression were determined by Kaplan –Meier and COX regression analyses, respectively. Baseline CRC patients showed global H3 hyperacetylation by 160%, but H4 hypoacetylation by 87% relative to healthy control. FP therapy significantly reduced global H3 and H4 acetylation levels especially in subgroups of CRC patients > 45 years, females, with right colon tumours, with normal baseline levels of CEA and CA19.9, with negative lymph nodes and negative metastasis, and also in the patients who showed no signs of recurrence or progression after three years of follow up. Survival analyses showed decreased median EFS time and increased the hazard of recurrence and progression in patients with high CEA (HR= 3.38, P= 0.023), positive metastasis (HR= 1.16, P<0.001), and H4 hypoacetylation <87% (HR= 1.55, P=0.014). FP therapy-induced reduction in the global level of histones acetylation declared in subgroups of CRC patients with excellent prognostic features.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 11548-11548
Author(s):  
Olga Vornicova ◽  
Jay Wunder ◽  
Peter W. M. Chung ◽  
Abha A. Gupta ◽  
Rebecca Anne Gladdy ◽  
...  

11548 Background: The mainstay therapy of operable STS remains surgery, which may include (neo)adjuvant therapies. Within the TSP, marginally inoperable STS are often treated with sequential chemo (CTX) and radiation (RT) therapy, followed by surgery (SX). Herein we present our experience of multi-modality therapies for marginally inoperable STS patients (pts). Methods: This was a dual-center, single program, retrospective review. Pts were included if deemed to have marginally inoperable primary or recurrent STS, as determined at the TSP tumor board. Pts included must have had CTX with the intent of having RT and SX after. Pts demographics, treatment details and clinical outcomes data were collected. Relapse free survival (RFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Multivariate analysis of the influence of disease characteristics and treatment on outcomes was assessed using Cox regression. Results: From June 2005 to May 2019, 75 pts were identified. Median age was 52 years (range 16-72). Pts were predominantly male (55%). Histological subtypes included dedifferentiated liposarcoma (29%), leiomyosarcoma (27%), synovial sarcoma (19%) and others (25%). Primary tumor was located in the retroperitoneum (48%), extremity (23%), pelvis (12%), thorax (9%), and other sites (8%). All pts had doxorubicin and ifosfamide CTX (median 4 cycles; range 1-6), while RT dose delivered was 50.4Gy/28 fractions in 58 (77%) of cases. Twenty three pts (31%) achieved partial response, 40 pts (53%) had stable disease and 12 pts (16%) had progression of disease (PD) on CTX, of which half (8%) did not undergo further treatment. Nine pts (12%) underwent CTX followed by SX due to significant response, 9 pts (12%) underwent CTX and RT without SX due to persistent tumor unresectability or PD. The final 50 pts (67%) completed multi-modality treatment (CTX, RT & SX). Overall, 59 pts (79%) had SX; negative margins were achieved in 53 (71%). 19 pts (25%) had postoperative complications, causing death in 2 pts (2.7%). With a median follow-up of 72 months, median RFS and OS were 26.9 months (95% CI: 0-86.0), and 65 months (95% CI: 13.5-116.4). Extremity location was associated with superior RFS (median not reached [NR], HR 0.28 95% CI 0.09-0.83, p = 0.022), and OS (median NR, HR 0.29 95% CI 0.09-0.90, p = 0.032). Receipt of RT was associated with superior RFS (median NR, HR 0.23 95% CI 0.10-0.52, p < 0.001); and OS (median NR, HR 0.21 95% CI 0.09-0.50, p < 0.001). Pts who had PD after CTX were associated with poor outcomes - RFS (median 4.7 months, HR 2.03 95% CI 0.61-6.76, p = 0.24); and OS (median 21.9 months, HR 2.48 95% CI 0.73-8.47, P = 0.144). Conclusions: Multi-modality approach resulted in successful resection for most pts with marginally inoperable STS. Extremity location and RT administration were associated with better RFS and OS, while progression on CTX confers worse survival outcomes.


2020 ◽  
Author(s):  
Keqian Zhang ◽  
Tianqi Mao ◽  
Zhicheng He ◽  
Xiaojiao Wu ◽  
Yu Peng ◽  
...  

Abstract Background: This study was conducted to detect the expression of Cdc42 interacting protein 4 (CIP4) in patients with colorectal cancer (CRC), and explore the role of CIP4 in prognosis of CRC patients.Methods: The expression of CIP4 mRNA was determined by quantitative real-time PCR (qRT-CPR) and compared by student’s t-test between groups. Relationships of clinical characteristics and CIP4 expression were analyzed by Chi-square test. Kaplan-Meier curves were used to estimate the overall survival of CRC patients. And Cox regression analysis was conducted to identify the prognostic biomarkers for CRC patients.Results: The qRT-PCR results showed that CRC tissues were detected with significantly high CIP4 mRNA expression compared with adjacent normal controls (P<0.0001). The overexpression of CIP4 in CRC tissues was influenced by distant metastasis (P=0.021), lymphatic invasion (P=0.012) and TNM stage (P=0.006). But, other clinical factors including age, gender, differentiation and tumor site were proved to have no obvious effects on CIP4 expression (all, P>0.05). The survival curves showed that patients with high CIP4 expression generally lived shorter than those with low CIP4 expression (P<0.001). In addition, the multivariate analysis revealed that differentiation (P=0.044, HR=1.631, 95%CI=1.013-2.626) and CIP4 expression (P=0.000, HR=5.283, 95%CI=3.138-8.893) were of great prognostic significance for CRC patients.Conclusion: Taken together, up-regulation of CIP4 in CRC tissues represented poor prognosis for patients.


2020 ◽  
Vol 27 (1) ◽  
pp. 107327482090338
Author(s):  
Fabian Haak ◽  
Isabelle Obrecht ◽  
Nadia Tosti ◽  
Benjamin Weixler ◽  
Robert Mechera ◽  
...  

Objectives: Analysis of tumor immune infiltration has been suggested to outperform tumor, node, metastasis staging in predicting clinical course of colorectal cancer (CRC). Infiltration by cells expressing OX40, a member of the tumor necrosis factor receptor family, or CD16, expressed by natural killer cells, monocytes, and dendritic cells, has been associated with favorable prognosis in patients with CRC. We hypothesized that assessment of CRC infiltration by both OX40+ and CD16+ cells might result in enhanced prognostic significance. Methods: Colorectal cancer infiltration by OX40 and CD16 expressing cells was investigated in 441 primary CRCs using tissue microarrays and specific antibodies, by immunohistochemistry. Patients’ survival was evaluated by Kaplan-Meier and log-rank tests. Multivariate Cox regression analysis, hazard ratios, and 95% confidence intervals were also used to evaluate prognostic significance of OX40+ and CD16+ cell infiltration. Results: Colorectal cancer infiltration by OX40+ and CD16+ cells was subclassified into 4 groups with high or low infiltration levels in all possible combinations. High levels of infiltration by both OX40+ and CD16+ cells were associated with lower pT stage, absence of peritumoral lymphocytic (PTL) inflammation, and a positive prognostic impact. Patients bearing tumors with high infiltration by CD16+ and OX40+ cells were also characterized by significantly longer overall survival, as compared with the other groups. These results were confirmed by analyzing an independent validation cohort. Conclusions: Combined infiltration by OX40+ and CD16+ immune cells is an independent favorable prognostic marker in CRC. The prognostic value of CD16+ immune cell infiltration is significantly improved by the combined analysis with OX40+ cell infiltration.


2006 ◽  
Vol 24 (28) ◽  
pp. 4565-4569 ◽  
Author(s):  
Javier Rangel ◽  
Sima Torabian ◽  
Ladan Shaikh ◽  
Mehdi Nosrati ◽  
Frederick L. Baehner ◽  
...  

Purpose To assess the prognostic significance of nuclear receptor coactivator-3 (NCOA3) overexpression in primary cutaneous melanoma. Patients and Methods NCOA3 expression was assessed using immunohistochemical analysis of a melanoma tissue microarray (TMA) containing primary melanomas from 343 patients with defined histology and follow-up. The impact of the presence or absence of various prognostic factors on relapse-free survival (RFS) and disease-specific survival (DSS) of melanoma patients was assessed using Cox regression and Kaplan-Meier analysis. The impact of presence or absence of various factors on sentinel lymph node (SLN) metastasis was assessed using logistic regression analysis. Results Increasing degree of NCOA3 expression was significantly predictive of SLN metastasis (P = .013) and the mean number of SLN metastases (P = .031). Kaplan-Meier analysis demonstrated a significant association between NCOA3 overexpression and reduced RFS (P = .021) and DSS (P = .030). Logistic regression analysis revealed increasing degree of NCOA3 expression to be an independent predictor of SLN status (P = .017). Multivariate Cox regression analysis showed the independent impact of NCOA3 expression on RFS (P = .0095) and DSS (P = .021). NCOA3 was the most powerful factor predicting DSS, outperforming tumor thickness and ulceration. Conclusion These results identify NCOA3 as a novel, independent marker of melanoma outcome, with a significant impact on SLN metastasis, RFS, and DSS.


2007 ◽  
Vol 25 (33) ◽  
pp. 5267-5274 ◽  
Author(s):  
Sung-Gyeong Kim ◽  
Eun-Cheol Park ◽  
Jae-Hyun Park ◽  
Myung-Il Hahm ◽  
Jin-Hwa Lim ◽  
...  

PurposeTo identify the initiation or discontinuation of complementary therapy (CT) and determine the impact of sociodemographic and clinical factors on CT use among cancer patients.Patients and MethodsEligible patients were age 20 or older; newly diagnosed with stomach, liver, or colorectal cancer; and started their initial treatment at the National Cancer Center, Korea, between April 1, 2001, and April 30, 2003. In total, 541 cancer patients were surveyed in face-to-face interviews at baseline, and telephone follow-up interviews were performed every 3 months for 3 years.ResultsA total of 281 patients commenced CT after diagnosis; 164 patients stopped using CT during the follow-up period. The overall cumulative probability of starting CT at 1, 2, and 3 years was 50%, 54%, and 55%, respectively. In a Cox multivariate analysis, stomach and liver cancer were associated with an increased probability of initiating CT compared with colorectal cancer. Patients who were classified as stage I, II, or III at diagnosis were associated with a decreased probability of discontinuing CT compared with stage IV.ConclusionMost cancer patients started to use CT during the initial treatment period. Thus, physicians should communicate with cancer patients about CT at this phase. In particular, more attention should be paid to women and individuals with higher household incomes because these groups are more likely to start CT.


Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2343-2343
Author(s):  
Jingmei Hsu ◽  
Anita J. Kumar ◽  
Martin P. Carroll ◽  
Noelle V. Frey ◽  
Nirav N. Shah ◽  
...  

Abstract Background: Additional sex combs like transcription factor 1 (ASXL1) is a member of the polycomb group protein. ASXL1 mutation has been implicated in myeloid malignancy transformation. It is hypothesized that mutated ASXL1 leads to the loss of polycomb repressive complex 2 (PRC2) mediated gene repression and subsequent transforming events. Recent studies identify ASXL1 mutation as a poor prognostic marker in patients (pts) with de novo acute myeloid leukemia (AML) who present with intermediate–risk cytogenetic lesions (Patel, NEJM 2012; Schnittger, Leukemia2013). To study the impact of ASXL1 mutations in an unselected AML population, we analyzed clinical and molecular characteristics of patients with untreated AML who express ASXL1 mutation at presentation. Methods: Using next generation sequencing, 254 adult patients with AML seen at the Hospital of the University of Pennsylvania were analyzed for mutations, including ASXL1, using a 33-gene hematologic malignancy panel. Clinical characteristics were obtained from retrospective chart review. Kaplan-Meier estimates were used to calculate overall survival (OS) from time of diagnosis. Living patients were censored at date last seen. Results: ASXL1 mutations were detected in 36/254 (14%) AML pts. There were 29 known pathologic mutations, 1 benign, 1 probable pathologic, and 9 variants of unknown clinical significance (VUS). In 6/36 (16.7%) pts, ASXL1 was the sole mutation identified. Of the 30 pts with additional mutations (Figure 1), 6/30 (20%) pts harbored 2 independent ASXL1 mutations. When the 27 patients with pathologic ASCL mutations were analyzed for co-mutations, TET2 (13/27, 48%) was the most frequent ASXL1 co-mutation. FLT3 (0/27, 0%) and NPM1 (1/27, 3.7%) were notable for their absence. Median age of pts at diagnosis was 69 years (range 23-80). Prior myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN) was noted in 9/36 (25%) and 11/36 (30.6%) pts, respectively. Four pts (11.1%) had received chemotherapy and/or radiation therapy for a prior non-myeloid neoplasm. Karyotype was normal in 18/36 (50%) pts, and 7 additional pts had intermediate cytogenetic lesions. There were 7 pts (19.4%) with unfavorable cytogenetics (complex karyotype (3 pts), 7q- (3 pts), and 5q- (1 pt)). Four pts (11.1%) had a favorable karyotype, with t(8;21) in 3 pts and t(15;17) in 1 pt. At presentation, median white blood cell count (WBC) was 6.4x103/uL (1.0 x -103). In pts whose AML transformed from prior MPN, median WBC was 50 X103/uL (3.3-140). Standard induction chemotherapy with an anthracycline and cytarabine was given to 17/36 (47%) pts. An additional 3/36 (8.3%) pts underwent induction therapy with clofarabine. Complete remission (CR) was documented in 14/20 (70%) evaluable pts. Of the remaining pts, 11 received a hypomethylating agent, and 5 received other therapies. Thirty-day treatment mortality for all 36 pts and for 27 pts with known ASXL1 pathologic mutation was 13.4% and 18.5% respectively. Kaplan-Meier estimate showed a median overall survival of 349 days (median follow up of 107 days (range 15-1570)). For the 27 pts with a pathologic ASXL1 mutation, the OS was 276 days (Figure 2, median follow up of 145 days (range 18-1570)). Conclusion: ASXL1 mutations in de novo AML with intermediate-risk cytogenetics is associated with poor clinical outcome in cooperative group trials. Strikingly we demonstrate in a single institution, retrospective analysis that 66.7% of pts who present with ASXL1 mutations in the setting of previously untreated AML had documented MDS, MPN and/or prior chemotherapy/radiation. Further studies are necessary to evaluate if ASXL1 mutation has independent prognostic significance in AML or if it is primarily a marker for secondary leukemia. Figure 1: ASXL1 and co-mutations Figure 1:. ASXL1 and co-mutations Figure 2: Overall survival for AML patients with ASXL1 pathologic mutation Figure 2:. Overall survival for AML patients with ASXL1 pathologic mutation Disclosures No relevant conflicts of interest to declare.


2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 613-613
Author(s):  
M. S. Pugliese ◽  
M. M. Stempel ◽  
S. M. Patil ◽  
M. Hsu ◽  
H. S. Cody ◽  
...  

613 Background: Modern surgical and pathologic techniques can detect small volume axillary metastases in breast cancer. The clinical significance of these metastases was evaluated in comparison to patients with negative sentinel lymph nodes (Neg-SN). Methods: Retrospective database review from 1997 through 2003 for eligible patients with unilateral breast cancer and no history of significant non-breast malignancy identified 232 patients with sentinel lymph node (SLN) metastases identified only by immunohistochemical stains (IHC-SN). They were compared to 252 Neg-SN controls selected at random from the same database population. Statistical analysis was performed with 2-sample tests, Kaplan-Meier, and Cox regression methods. Results: IHC-SN patients had worse prognostic features and received more systemic therapy than controls (Table). Age and ER status were similar. In 123 IHC-SN patients treated with axillary dissection (ALND), 16% had macrometastases in the non-SLNs. Only one axillary recurrence occurred in the group of IHC-SN patients without ANLD (n=109). With median follow up of 5 years (range 0.01–12.0), 28 recurrences and 25 deaths occurred. There were no differences between cases and controls for recurrence-free survival (RFS) or overall survival (OS) both by univariate and multivariate models that included variables such as age, tumor size, chemotherapy and hormone therapy [HR 0.99 (95%CI 0.43–2.28, p=0.99) for RFS, HR 2.06 (95%CI 0.79–5.35) p=0.14 for OS]. In IHC-SN patients treated with ALND, patients with positive non-SLNs (n=20) tended to have worse RFS than those with negative non-SLNs (n=103) [RFS 89% vs. 97% at 5 yrs (p=0.06)]. Conclusions: A significant number of IHC-SN patients had a macrometastasis identified at ALND. In patients not undergoing dissection, axillary recurrence was a rare event. However, failure to identify additional metastases by omitting ALND may result in understaging and inadequate systemic treatment in some patients. [Table: see text] No significant financial relationships to disclose.


2021 ◽  
Vol 15 (Supplement_1) ◽  
pp. S201-S202
Author(s):  
M Kabir ◽  
K Curtius ◽  
P Kalia ◽  
I Al Bakir ◽  
C H R Choi ◽  
...  

Abstract Background Racial disparities in inflammatory bowel disease (IBD) phenotypic presentations and outcomes are recognised. However, there are conflicting data from Western population-based cohort studies as to whether racial differences in colitis-associated colorectal cancer (CRC) incidence exists. To our knowledge this is the first study to investigate the impact of ethnicity on the natural history of dysplasia in ulcerative colitis (UC). Methods We performed a retrospective multi-centre cohort study of adult patients with UC whose first low-grade dysplasia (LGD) diagnosis within the extent of colitis was made between 1 January 2001 and 30 December 2018. Only patients with at least one follow-up colonoscopy or colectomy by 30 August 2019 were included. The study end point was time to CRC or end of follow-up. Statistical differences between groups were evaluated using Mann-Whitney U tests and Chi-squared tests. Survival analyses were performed using Kaplan-Meier estimation and multivariate Cox proportional hazards models. Results 408 patients met the inclusion criteria (see Figure 1 for patient and clinical demographics). More patients from a Black or Asian (BAME) background progressed to CRC [13.4% vs. 6.4%; p=0.036] compared to their White Caucasian counterparts, despite having surveillance follow-up. Figure 2 displays Kaplan-Meier curves demonstrating the probability of remaining CRC-free after LGD diagnosis and categorised by ethnicity. BAME patients were more likely to have moderate-severe inflammatory activity on colonic biopsy within the 5 preceding years [42.0% vs. 28.9%; p=0.023], but no significant differences in medication use and a longer median time interval from LGD diagnosis to colectomy date [32 months vs. 11 months; p=0.021]. After adjusting for sex, age and UC duration at time of LGD diagnosis and presence of moderate-severe histological inflammation, being Black or Asian was a predictive factor for CRC progression on multivariate Cox proportional hazard analysis [HR 2.97 (95% CI 1.22 – 7.20); p = 0.016]. However, ethnicity was no longer predictive of CRC progression on sub-analysis of the 317 patients who did not have a colectomy during the follow-up period. Conclusion In this UK multi-centre cohort of UC surveillance patients diagnosed with LGD, delays in receiving cancer preventative colectomy may contribute to an increased CRC incidence in certain ethnic groups. Further work is required to elucidate whether these delays are related to institutional factors (e.g. inequity in the content of decision-making support given or access to healthcare) or cultural factors.


1996 ◽  
Vol 14 (4) ◽  
pp. 1122-1127 ◽  
Author(s):  
A Yamaguchi ◽  
T Urano ◽  
T Goi ◽  
M Saito ◽  
K Takeuchi ◽  
...  

PURPOSE To determine the expression of the CD44 variant containing a variant exon 8 to 10 product (CD44v8-10) in colorectal cancer and to evaluate its prognostic value. MATERIALS AND METHODS CD44v8-10 was studied in resected tumors and normal mucosae obtained from 215 colorectal cancer patients (118 colon cancer and 97 rectal cancer). The expression of CD44v8-10 was analyzed immunohistochemically using the anti-CD44v8-10 monoclonal antibody (mAb) 44-1V. RESULTS One hundred of 215 cancer tissues expressed CD44v8-10. Positive staining was intense mainly on the cell membranes. There was no significant correlation between expression of CD44v8-10 and histologic type, primary tumor, lymphatic invasion, venous invasion, or peritoneal invasion. There were significant correlations between CD44v8-10 immunoreactivity and both lymph node and hematogenous metastasis. Patients with CD44v8-10-positive tumors had a greater relative risk of death compared with those whose tumors were CD44v8-10-negative. Among 169 patients who underwent curative resection, CD44v8-10 expression correlated with a high recurrence rate. The 5- and 10-year survival rates were 90.3% of patients with CD44v8-10-negative tumors, and 72.1% and 58.0% of those with CD44v8-10-positive tumors, respectively; these differences between the two groups of patients were significant (P < .01). In multivariate analysis using the Cox regression model, CD44v8-10 expression emerged as an independent prognostic indicator. CONCLUSION The results suggest that CD44v8-10 plays a role in metastasis of colorectal cancer, and tha CD44v8-10 expression may be a biologic marker of prognostic significance.


2017 ◽  
Vol 32 (2) ◽  
pp. 218-223 ◽  
Author(s):  
Xiangke Li ◽  
Feng Wang ◽  
Yan Sun ◽  
Qingxia Fan ◽  
Guangfei Cui

Background Long noncoding RNAs (lncRNAs) are emerging as key molecules in human cancer. In the present study, we explored the role of the lncRNA PANDAR in colorectal cancer (CRC). Methods The relative expression level of lncRNA PANDAR in CRC tissues and cell lines was determined by quantitative real-time polymerase chain reaction (qRT-PCR). The associations between PANDAR expression and clinicopathological features of CRC patients were further analyzed. Kaplan-Meier survival analysis was performed to evaluate the value of PANDAR in the prognosis of CRC patients. Furthermore, the biological function of PANDAR on CRC cell growth, apoptosis and mobility was investigated through MTT, flow cytometry, transwell migration and invasion assays in vitro. Results The expression level of PANDAR was higher in CRC tissues and cells compared with adjacent nontumor tissues and normal colonic cell line NCM460. PANDAR expression was significantly correlated with local invasion, lymph node metastasis and TNM stage. Kaplan-Meier analysis showed that patients with high PANDAR expression had poorer overall survival than patients with low PANDAR expression. Multivariate Cox regression analysis indicated that PANDAR might be an independent prognostic factor for CRC patients. Furthermore, PANDAR knockdown significantly inhibited cell proliferation, cycle progression, migration and invasion of CRC in vitro. Conclusions Our results suggest that high expression of PANDAR was involved in CRC progression and could act as an independent biomarker for prognosis of CRC patients.


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