TP53 status is an important prognostic marker for patients with hepatic metastases from colorectal carcinoma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10092-10092
Author(s):  
D. G. Mollevi ◽  
T. Serrano ◽  
M. M. Ginesta ◽  
J. Valls ◽  
J. Torras ◽  
...  
Keyword(s):  
Colorectal Carcinoma ◽  
Liver Metastases ◽  
Prognostic Marker ◽  
Hepatic Metastases ◽  
Tp53 Gene ◽  
Consecutive Series ◽  
Mobility Patterns ◽  
Primary Tumors ◽  
Tp53 Mutations ◽  
Mutational Status

10092 Background: The aim of this study was to analyze the value of TP53 gene mutations as a prognostic marker to improve the selection of patients candidates to surgery in a consecutive series of liver metastases from colorectal cancer patients. Methods: 91 patients with liver metastases from colorectal carcinoma (CRC) were included. Mutational study of TP53 gene, exons 4 to 10, was assessed both in paraffin-embedded hepatic metastasis and normal liver parenchyma by SSCP (Single Strand Chain Polymorphism) followed by sequencing of abnormal electrophoretic mobility patterns. Immunostaining of P53 and P21 proteins were assessed in the same group of patients. Results: Forty-eight out 91 (50.05%) metastases showed mutation in TP53. Higher incidence of mutations was detected in exons 5–8, although exons 9 and 10 were mutated in 28.26% of metastases. Protein-truncating mutations (nonsense and frameshift) occur in 47.8% of metastasis harboring TP53 mutations. TP53 mutation was associated with poor prognosis in univariate (P=0.0062) and multivariate Cox proportional hazard model (P=0.012) analysis. Prognosis association was maintained in the group of patients undergoing radical resection, named R0 series (n=79; P=0.008). High prevalence of TP53 mutations happen in patients with >3 metastases (65.6%; P=0.034), primary tumors Duke’s C-D stages (57.4%; 63.0%; respectively; p=0.026) and patients with age <57 years at resection. Interestingly, patients with TP53 mutations in their metastases relapsed earlier after the resection of the primary tumor (P=0.026). Postoperative 5-FU-based chemotherapy showed a better survival outcome in patients with wild-type TP53 hepatic metastases (HR: 2.92; 95% CI: 1.32–6.46; P=0.006). Conclusions: TP53 mutational status seems to be an important prognostic factor in patients with hepatic metastases from CRC. No significant financial relationships to disclose.

Mutational Status of the TP53 Gene As a Predictor of Response and Survival in Patients With Chronic Lymphocytic Leukemia: Results From the LRF CLL4 Trial

2011 ◽  
Vol 29 (16) ◽  
pp. 2223-2229 ◽  
Author(s):  
David Gonzalez ◽  
Pilar Martinez ◽  
Rachel Wade ◽  
Sarah Hockley ◽  
David Oscier ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Survival Data ◽  
Prognostic Value ◽  
Gene Mutations ◽  
Progression Free Survival ◽  
Tp53 Gene ◽  
Lymphocytic Leukemia ◽  
Tp53 Mutations ◽  
Mutational Status ◽  
Gene Tp53

Purpose TP53 mutations have been described in chronic lymphocytic leukemia (CLL) and have been associated with poor prognosis in retrospective studies. We aimed to address the frequency and prognostic value of TP53 abnormalities in patients with CLL in the context of a prospective randomized trial. Patients and Methods We analyzed 529 CLL samples from the LRF CLL4 (Leukaemia Research Foundation Chronic Lymphocytic Leukemia 4) trial (chlorambucil v fludarabine with or without cyclophosphamide) at the time of random assignment for mutations in the TP53 gene. TP53 mutation status was correlated with response and survival data. Results Mutations of TP53 were found in 40 patients (7.6%), including 25 (76%) of 33 with 17p deletion and 13 (3%) of 487 without that deletion. There was no significant correlation between TP53 mutations and age, stage, IGHV gene mutations, CD38 and ZAP-70 expression, or any other chromosomal abnormality other than 17p deletion, in which concordance was high (96%). TP53 mutations were significantly associated with poorer overall response rates (27% v 83%; P < .001) and shorter progression-free survival (PFS) and overall survival (OS; 5-year PFS: 5% v 17%; 5-year OS: 20% v 59%; P < .001 for both). Multivariate analysis that included baseline clinical variables, treatment, and known adverse genetic factors confirmed that TP53 mutations have added prognostic value. Conclusion TP53 mutations are associated with impaired response and shorter survival in patients with CLL. Analysis of TP53 mutations should be performed in patients with CLL who have progressive disease before starting first-line treatment, and those with mutations should be selected for novel experimental therapies.

The Clinical Relevance of Tumor Marker Cea, Ca 19-9 in Regional Chemotherapy of Hepatic Metastases of Colorectal Carcinoma

1988 ◽  
Vol 3 (2) ◽  
pp. 101-106 ◽  
Author(s):  
F. Safi ◽  
R. Roscher ◽  
R. Bittner ◽  
H.G. Beger
Keyword(s):  
Complete Remission ◽  
Colorectal Carcinoma ◽  
Liver Metastases ◽  
Clinical Relevance ◽  
Hepatic Metastases ◽  
Tumor Stage ◽  
Regional Chemotherapy ◽  
Danger Signal ◽  
Tumor Spread ◽  
Angio Ct

Up to December 1986, 50 patients with documented hepatic metastases from colorectal carcinoma were treated with 5-fluoro-2-deoxyuridine (FUDR) using Infusaid pumps. The response of liver metastases to regional chemotherapy was studied by computerized tomography (CT) and carcino-embryonal antigen (CEA), and/or CA 19-9 antigen serum assays. Preoperative CEA values were pathological in 94% of the patients but only 48% had a pathological concentration of the antigen CA 19-9 of over 37 U/ml. The course of CEA and CA 19-9 in combination with the arterial angio-CT reflected the response of liver metastases to regional chemotherapy. A decrease or normalisation of CEA and CA 19-9 after the beginning of therapy is an indication of partial or complete remission of metastases (68% of the patients showed lowered CEA serum values). If the marker continues to rise in serum this is a danger signal of progression of liver metastases or of extrahepatic tumor spread if the tumor stage in the liver remains unchanged.

Mutational Status of the TP53 Gene as a Predictor of Response and Survival in CLL Patients with and without 17p Deletion

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 784-784 ◽  
Author(s):  
David Gonzalez ◽  
Pilar Martinez ◽  
Rachel Wade ◽  
Sarah Lorna Hockley ◽  
Vasantha Brito-Babapulle ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Tp53 Gene ◽  
Response To Treatment ◽  
Prognostic Indicators ◽  
Free Survival ◽  
Tp53 Mutations ◽  
Cd38 Expression ◽  
Mutational Status ◽  
The Uk ◽  
Tp53 Mutational Status

Abstract Background: Deletion of 17p in chronic lymphocytic leukaemia (CLL) is associated with resistance to conventional therapy and a poor clinical outcome. Though TP53 mutations have been described in some of these cases, the extent to which they occur in CLL patients and their clinical implications remain unclear. We investigated the prognostic value of TP53 mutations in the clinical course of CLL patients. Methods: We analysed 529 CLL samples from the UK LRF CLL4 clinical trial (Chlorambucil vs Fludarabine±Cyclophosphamide) for the presence of TP53 mutations and their association with response to treatment, progression-free survival (PFS) and overall survival (OS). We also investigated the correlation between TP53 mutations and other well-known prognostic indicators in CLL including stage, chromosomal aberrations, VH mutational status and CD38 and ZAP-70 expression. Results: Mutations of TP53 were found in 44 of 529 patients overall (8.3%). TP53 mutations were present in 26 out of 32 (81%) patients with 17p deletion in >20% of cells (p<0.0001). TP53 mutations were also present at lower frequencies in samples with no 17p deletion (13/446; 2.9%) or with <20% of cells with 17p deletion (4/47; 8.5%). Overall response rates were significantly better in patients without TP53 mutations compared to those with mutations (82% vs 34%; p<0.0001), including complete or nodular partial responses in 42% of patients without TP53 patients compared to only 10% of patients with mutations (p<0.0001). TP53 mutations were associated with significantly poorer OS; 36% (95% CI 22–51) at 3 years versus 79% (95% CI 75–83) for patients without mutations, p<0.00001 (Figure 1a). Similarly, PFS was significantly shorter for patients with TP53 mutations (3 year PFS: 9% [95% CI: 1–18]) compared to those without (34% [95% CI 30–38], p<0.00001; Figure 1b). CLL patients with TP53 haploinsufficiency -either TP53 mutation or >20% of 17p deletion- define a subgroup with intermediate prognosis (3 year OS: 52% [95% CI 32–73]) compared to those with neither (80% [95% CI 76–83]) or both (23% [95% CI 7–39]) (p(trend)<0.00001, Figure 2). There was no significant association between TP53 mutations and age, stage, VH mutations, CD38 expression, ZAP-70 expression or any other chromosomal abnormality other than 17p deletion. Conclusions: Our data shows that TP53 mutations are associated with a poor outcome in CLL patients regardless of the deletion of 17p. Furthermore, the clinical significance of 17p deletion seems to be tightly linked to the presence of mutations in the remaining TP53 allele, and these patients with no wild-type TP53 genes have the lowest OS and PFS rates. Finally, the group of CLL patients with TP53 haploinsufficiency (either by mutation or deletion in >20% of the cells) presents an intermediate prognosis and will be further investigated. Fig 1a - OS by TP53 mutational status Fig 1a -. OS by TP53 mutational status Fig 1b - PFS by TP53 mutational status Fig 1b -. PFS by TP53 mutational status Fig 2 - OS by TP53 mutational status and/or 17p deletion Fig 2 -. OS by TP53 mutational status and/or 17p deletion

Long-term results of selective internal radioembolization (SIRT) to control progressive liver metastases of gastro-intestinal stromal tumors (GIST) beyond treatment with tyrosine kinase inhibitors (TKI).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 11538-11538
Author(s):  
Peter Hohenberger ◽  
Nils Rathmann ◽  
Karen Buesing ◽  
Franka Menge ◽  
Steffen Diehl
Keyword(s):  
Liver Metastases ◽  
Treatment Options ◽  
Hepatic Metastases ◽  
Progression Free Survival ◽  
Long Term Results ◽  
Mutational Status ◽  
Exon 9 ◽  
Exon 11

11538 Background: Liver and peritoneum are the main area of metastatic spread in GIST. Liver resection does not play a role for hepatic metastases in comparison to f.e. colorectal cancer. If hepatic metastases are the only or major area of tumor progression and are resistant to available TKIs due to a missing mutation in KIT/PDGFRA/SDH ( ‘wildtype’) or after treatment with 1st/2nd/3rd/4th line therapy, interventional radioembolization with yttrium-90 (90Y) microspheres are promising treatment options, as radiation doses as high as 200Gy can be applied locally. We analyzed the long-term results of SIRT with respect to hepatic-progression-free survival (HEP-PFS) in a consecutive cohort of patients.. Methods: From 1/2008 to 1/2018, 25 pts (12f, 13m) with biopsy proven liver metastases of GIST which were the only (n = 13) or the dominant site of progression (n = 12) were treated by SIRT. Median age at GIST diagnosis had been 51.8 yrs and when receiving SIRT was 57.6yrs (range, 18–75yrs). The mutational status was ‘wildtype’ (n = 7, 2 NF-1), exon 11 (n = 7), exon 11+2nd mutation (n = 6), exon 9 (n = 3), exon 9+2ndmut (n = 1), and, exon 13 (n = 1). All patients except of two had prior TKI therapy: 1 line n = 3, 2 lines n = 11, 3-4 lines n = 9. Follow-up after SIRT was done via dynamic MRI and contrast-enhanced (CE)-CT, the median follow-up is 30.6 mos (range, 12-100mos) and all patients were followed until death. Results: The median hepatic-progression free survival (HEP-PFS) after SIRT was 17 months (range, 5-53+, 95%CI 11.8-22.1 mos). Of the patients with concomitant extrahepatic disease, the extraHEP-PFS was median 10 months. Twelve patients received next-line TKI therapy for progressive extrahepatic disease, whereas six patients required this for progressive liver metastases. When comparing the results according to the mutational status, patients with a ‘wildtype’ tumor showed a better median HEP-PFS of 19 mos (range, 12-53+, 95%CI 16.7-21.2 mos.) in comparison to KIT exon 9/11/13 mutated patients with only 14 months (range, 4-34 mos., 95%CI 6.5-21.4 mos), p < 0.11 (Wilcoxon). Conclusions: 90Y radioembolization (SIRT) offers a safe and effective treatment for patients with liver metastases of GISTs being the dominant site of tumor progression and with no drug treatment options available. In patients known to have no mutation in KIT/PDGFRA (wt, also NF-1 associated) it looks whether the results might be even more promising and SIRT could be used in early treatment lines.

Hepatic arterial infusion of floxuridine in patients with liver metastases from colorectal carcinoma: long-term results of a prospective randomized trial.

1992 ◽  
Vol 10 (7) ◽  
pp. 1112-1118 ◽  
Author(s):  
P Rougier ◽  
A Laplanche ◽  
M Huguier ◽  
J M Hay ◽  
J M Ollivier ◽  
...  
Keyword(s):  
Survival Rate ◽  
Colorectal Carcinoma ◽  
Liver Metastases ◽  
Randomized Study ◽  
Hepatic Metastases ◽  
Hepatic Arterial Infusion ◽  
Long Term Results ◽  
Control Group ◽  
Arterial Infusion ◽  
Extrahepatic Metastases

PURPOSE A multicentric randomized study that compared patients who received intrahepatic arterial infusion (HAI) to a group of patients who did not receive HAI (control group) was performed for unresectable hepatic metastases from primary colorectal carcinoma. PATIENTS AND METHODS One hundred sixty-six patients were assigned randomly to HAI of floxuridine (5 fluoro-2'deoxyuridine [FUDR]) 0.3 mg/kg/d for 14 days every 4 weeks or to the control group; this latter group, depending on the investigator's choice, was either under observation or received systemic fluorouracil (5-FU). The same regimen of systemic 5-FU also was administered to the HAI group in the event of extrahepatic progression. No crossover from the control group to the HAI group was permitted. The mean duration of follow-up was 54 months (range, 31 to 72), and 163 patients were analyzed. RESULTS A significant improvement was observed in the survival rate for the 81 patients assigned to HAI group (P less than .02) with a 1-year survival rate of 64% versus 44% in the control group (82 patients). The 2-year survival rate was 23% versus 13%. The median survival was 15 months versus 11 months for the HAI group and the control group, respectively. Survival was better for patients with a less than 30% liver involvement, and for those treated in more specialized centers. The hepatotoxic effects of HAI were observed in 47 patients (chemical hepatitis [n = 28], and biliary sclerosis [n = 19]). The 1-year rate of sclerosing cholangitis was equal to 25%. Gastrointestinal toxicity was infrequent and consisted of gastritis or diarrhea. CONCLUSIONS Therapy with HAI of FUDR improves the survival of patients with liver metastases over colorectal carcinoma. However, the methods that are used to diminish the toxicity of HAI and efficient systemic chemotherapy, such as a combination of 5-FU and leucovorin, are required to prevent extrahepatic metastases.

Serial levels of CA 19-9 and CEA in colonic cancer.

1986 ◽  
Vol 4 (6) ◽  
pp. 987-993 ◽  
Author(s):  
B H Novis ◽  
E Gluck ◽  
P Thomas ◽  
G D Steele ◽  
V R Zurawski ◽  
...  
Keyword(s):  
Retrospective Study ◽  
Colorectal Carcinoma ◽  
Metastatic Disease ◽  
Tumor Recurrence ◽  
Colonic Cancer ◽  
Hepatic Metastases ◽  
Carbohydrate Antigen ◽  
Hepatic Lobectomy ◽  
Primary Tumors ◽  
Embryonic Antigen

The use of serial carbohydrate antigen (CA) 19-9 assays was assessed by comparison with serial carcino-embryonic antigen (CEA) levels on the plasmas of 53 patients with colorectal carcinoma. The patients had all undergone resection for their primary tumors and in six instances subsequent resections for hepatic metastases. Initial CA 19-9 levels were greater than or equal to 37 U/mL in 22 of the 53 patients (41%) and in 68% of the patients with metastatic disease. Similar trends of serial CA 19-9 and CEA levels were found in 79% of the 53 patients. One patient with initially normal CEA levels had elevated CA 19-9 levels from the start. In ten of the 53 patients (19%), serial CA 19-9 levels remained low despite tumor recurrence or progression, and despite increasing CEA levels above 5 ng/mL. The increasing serial CEA trends predicted recurrence in 88% and increasing CA 19-9 trends in 50% of cases, which was increased to 70% by including trends of CA 19-9 levels below 37 U/mL. Following hepatic lobectomy, both serial CEA and CA 19-9 levels decreased rapidly. Used alone, serial CA 19-9 levels did not appear to be as sensitive as standard CEA in this retrospective study of selected patients.

scholarly journals Proteomics analysis of the matrisome from MC38 experimental mouse liver metastases

2019 ◽  
Vol 317 (5) ◽  
pp. G625-G639
Author(s):  
Arseniy E. Yuzhalin ◽  
Su Yin Lim ◽  
Alex N. Gordon-Weeks ◽  
Roman Fischer ◽  
Benedikt M. Kessler ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Extracellular Matrix ◽  
Liver Metastases ◽  
Cancer Cell ◽  
Mouse Liver ◽  
Hepatic Metastases ◽  
Mass Spectrometry Analysis ◽  
Annexin A1 ◽  
Primary Tumors

Dissemination of primary tumors to distant anatomical sites has a substantial negative impact on patient prognosis. The liver is a common site for metastases from colorectal cancer, and patients with hepatic metastases have generally much shorter survival, raising a need to develop and implement novel strategies for targeting metastatic disease. The extracellular matrix (ECM) is a meshwork of highly crosslinked, insoluble high-molecular-mass proteins maintaining tissue integrity and establishing cell–cell interactions. Emerging evidence identifies the importance of the ECM in cancer cell migration, invasion, intravasation, and metastasis. Here, we isolated the ECM from MC38 mouse liver metastases using our optimized method of mild detergent solubilization followed by biochemical enrichment. The matrices were subjected to label-free quantitative mass spectrometry analysis, revealing proteins highly abundant in the metastatic matrisome. The resulting list of proteins upregulated in the ECM significantly predicted survival in patients with colorectal cancer but not other cancers with strong involvement of the ECM component. One of the proteins upregulated in liver metastatic ECM, annexin A1, was not previously studied in the context of cancer-associated matrisome. Here, we show that annexin A1 was markedly upregulated in colon cancer cell lines compared with cancer cells of other origin and also over-represented in human primary colorectal lesions, as well as hepatic metastases, compared with their adjacent healthy tissue counterparts. In conclusion, our study provides a comprehensive ECM characterization of MC38 experimental liver metastases and proposes annexin A1 as a putative target for this disease. NEW & NOTEWORTHY Here, the authors provide an extensive proteomics characterization of murine colorectal cancer liver metastasis matrisome (the ensemble of all extracellular matrix molecules). The findings presented in this study may enable identification of therapeutic targets or biomarkers of hepatic metastases.

Colorectal cancer patients before resection of hepatic metastases

2004 ◽  
Vol 43 (04) ◽  
pp. 135-140 ◽  
Author(s):  
G. Meimarakis ◽  
A. Stahl ◽  
R. Bumm ◽  
K. Hahn ◽  
K. Tatsch ◽  
...  
Keyword(s):  
Colorectal Carcinoma ◽  
Liver Metastases ◽  
Fdg Pet ◽  
Hepatic Metastases ◽  
Abdominal Ultrasound ◽  
Helical Computed Tomography ◽  
Additional Information ◽  
Extrahepatic Metastases ◽  
Colorectal Cancer Patients ◽  
Conventional Staging

Summary Aim: Evaluation of the role of FDG-PET in comparison to conventional staging methods for detecting extrahepatic tumour deposits prior to resection of liver metastases. Patients, Methods: In our prospective study, 58 patients (24 women, 34 men; age 33-81 years) with liver metastases of colorectal carcinoma underwent FDG-PET. Images were acquired in 3D-mode including transmission scans and reconstructed iteratively. For conventional staging all patients underwent abdominal ultrasound, helical computed tomography (CT) of the thorax and abdomen, and colonoscopy/rectoscopy. A preliminary therapeutic decision was established without knowledge of the FDG-PET findings. Thereafter, it was revised or confirmed according to the results of FDG-PET. Results: In 3/58 patients extrahepatic tumour deposits were concordantly identified with both conventional staging methods and FDG-PET. However, in one case, both conventional methods and FDG-PET were false positive regarding pulmonary metastases. In 12/58 patients, nothing but FDG-PET detected extrahepatic tumour masses, which were later confirmed either by histology or follow-up. Conclusion: Our study suggests that in 21% of patients exclusively FDG-PET is an appropriate diagnostic tool to reveal extrahepatic metastases or local recurrence of colorectal carcinoma. Our results demonstrate that FDG-PET provides relevant additional information for accurate therapeutic planning as compared to the conventional combination of staging methods. Therefore, FDG-PET has to exert a decisive influence on the decision for resection of hepatic metastases.

scholarly journals MiRNA-21 Expression Decreases from Primary Tumors to Liver Metastases in Colorectal Carcinoma

PLoS ONE ◽  
2016 ◽  
Vol 11 (2) ◽  
pp. e0148580 ◽  
Author(s):  
Fabian Feiersinger ◽  
Elke Nolte ◽  
Sven Wach ◽  
Tilman T. Rau ◽  
Nikolaos Vassos ◽  
...  
Keyword(s):  
Colorectal Carcinoma ◽  
Liver Metastases ◽  
Primary Tumors
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