scholarly journals Abundant intratumoral fibrosis prevents lymphocyte infiltration into peritoneal metastases of colorectal cancer

PLoS ONE ◽  
2021 ◽  
Vol 16 (7) ◽  
pp. e0255049
Author(s):  
En Wang ◽  
Masatsune Shibutani ◽  
Hisashi Nagahara ◽  
Tatsunari Fukuoka ◽  
Yasuhito Iseki ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Immunohistochemical Staining ◽  
Lung Metastases ◽  
Treatment Resistance ◽  
Tumor Infiltrating Lymphocytes ◽  
Distant Metastases ◽  
Collagen Fibers ◽  
Peritoneal Metastases ◽  
Cancer Associated Fibroblasts ◽  
Primary Tumors

Background Tumor-infiltrating lymphocytes (TILs) have been reported to reflect the anti-tumor immune status. However, recent investigations have demonstrated that intratumoral fibrosis is important as a factor affecting the infiltration of TILs. This study investigated the organ specificities of TIL infiltration and intratumoral fibrosis in primary colorectal cancer and distant metastases, as well as the relationship between the distribution of TILs and intratumoral fibrosis. Methods Patients who underwent resection of primary tumors or distant metastases for colorectal cancer with distant metastases were enrolled. We evaluated the TIL infiltration by immunohistochemical staining with CD3&CD8 and intratumoral fibrosis by immunohistochemical staining with α-SMA positive cancer-associated fibroblasts and Masson’s trichrome staining against collagen fibers. The "ImageJ" was used to evaluate fibrosis, and the density of TILs in the dense and sparse areas of fibrosis was calculated. The Immunoscore (IS) was obtained based on the density of CD3+/CD8+TILs in the tumor center and invasive margin of the primary tumor. Results The degree of CD3+/CD8+TIL infiltration in peritoneal metastases was significantly lower than that in liver and lung metastases. The area ratio of α-SMA positive cancer-associated fibroblasts and collagen fibers in peritoneal metastases was significantly higher than that of liver and lung metastases. Furthermore, the density of TILs in the high-fibrosis area was significantly lower than that in the low-fibrosis area. In the high-IS group of primary tumors, the degree of TIL infiltration in distant metastases was significantly higher than that in the low-IS group. Conclusion The infiltration of T lymphocytes into tumors is prevented in peritoneal metastases of colorectal cancer due to the high intratumoral fibrosis, which may lead to treatment resistance and a poor prognosis.

scholarly journals Nomogram based on homogeneous and heterogeneous associated factors for predicting distant metastases in patients with colorectal cancer

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Tianwen Luo ◽  
Yutong Wang ◽  
Xuefeng Shan ◽  
Ye Bai ◽  
Chun Huang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Risk Factors ◽  
Lung Metastases ◽  
Roc Curves ◽  
Distant Metastases ◽  
Good Prediction ◽  
Operating Characteristics ◽  
Good Prediction Performance ◽  
Different Types ◽  
Associated Risk Factors

Abstract Background The identification of the homogeneous and heterogeneous risk factors for different types of metastases in colorectal cancer (CRC) may shed light on the aetiology and help individualize prophylactic treatment. The present study characterized the incidence differences and identified the homogeneous and heterogeneous risk factors associated with distant metastases in CRC. Methods CRC patients registered in the SEER database between 2010 and 2016 were included in this study. Logistic regression was used to analyse homogeneous and heterogeneous risk factors for the occurrence of different types of metastases. Nomograms were constructed to predict the risk for developing metastases, and the performance was quantitatively assessed using the receiver operating characteristics (ROC) curve and calibration curve. Results A total of 204,595 eligible CRC patients were included in our study, and 17.07% of them had distant metastases. The overall incidences of liver metastases, lung metastases, bone metastases, and brain metastases were 15.34%, 5.22%, 1.26%, and 0.29%, respectively. The incidence of distant metastases differed by age, gender, and the original CRC sites. Poorly differentiated grade, more lymphatic metastasis, higher carcinoembryonic antigen (CEA), and different metastatic organs were all positively associated with four patterns of metastases. In contrast, age, sex, race, insurance status, position, and T stage were heterogeneously associated with metastases. The calibration and ROC curves exhibited good performance for predicting distant metastases. Conclusions The incidence of distant metastases in CRC exhibited distinct differences, and the patients had homogeneous and heterogeneous associated risk factors. Although limited risk factors were included in the present study, the established nomogram showed good prediction performance.

Deleted in Colon Cancer Protein Expression in Colorectal Cancer Metastases: A Major Predictor of Survival in Patients With Unresectable Metastatic Disease Receiving Palliative Fluorouracil-Based Chemotherapy

2004 ◽  
Vol 22 (18) ◽  
pp. 3758-3765 ◽  
Author(s):  
Carlo Aschele ◽  
Domizia Debernardis ◽  
Sara Lonardi ◽  
Roberto Bandelloni ◽  
Stefania Casazza ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Protein Expression ◽  
Regional Lymph Node ◽  
Survival Rates ◽  
Distant Metastases ◽  
Patient Characteristics ◽  
Rank Test ◽  
Primary Tumors ◽  
Major Predictor

Purpose To determine whether deleted in colon cancer (DCC) protein expression in colorectal cancer (CRC) metastases could predict outcome to palliative fluorouracil (FU)-based chemotherapy and to assess whether it is similar to that observed in the corresponding primary tumors. Patients and Methods DCC protein expression was assessed immunohistochemically on archival specimens of CRC metastases from 42 patients homogeneously treated by methotrexate-modulated bolus FU alternated to 6-S-leucovorin–modulated infused FU and was retrospectively correlated with patient characteristics and clinical outcome. In a subset analysis, DCC immunoreactivity was compared between metastatic CRC and the corresponding primary tumors and regional lymph node metastases. Results Positive immunoreactivity for DCC was found in 45% of patients. Eighteen (78%) of 23 patients for whom multiple samples were available displayed a similar pattern of expression in distant metastases and primary tumors. The median survival time was 14.3 months in patients without DCC expression and 21.4 months in patients with DCC-positive tumors (log-rank test, P = .04); the 2-year survival rates were 8.5% and 42.5%, respectively. Response rates to chemotherapy were not significantly different between the two groups. By multivariate analysis, DCC protein expression maintained its prognostic value and showed to be the single best predictor of survival, with a relative risk of 2.16. Conclusion Our results indicate that expression of the DCC protein in CRC metastases is similar to that observed in the corresponding primary tumors and represents a dominant predictor of survival in patients with unresectable, advanced CRC who are undergoing palliative FU-based chemotherapy.

scholarly journals The clonal evolution of metastatic colorectal cancer

2020 ◽  
Vol 6 (24) ◽  
pp. eaay9691 ◽  
Author(s):  
Ha X. Dang ◽  
Bradley A. Krasnick ◽  
Brian S. White ◽  
Julie G. Grossman ◽  
Matthew S. Strand ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Tumor Heterogeneity ◽  
Clonal Selection ◽  
Clonal Evolution ◽  
Human Tumor ◽  
Treatment Resistance ◽  
Distant Metastases ◽  
Metastasis Model ◽  
Genomic Studies

Tumor heterogeneity and evolution drive treatment resistance in metastatic colorectal cancer (mCRC). Patient-derived xenografts (PDXs) can model mCRC biology; however, their ability to accurately mimic human tumor heterogeneity is unclear. Current genomic studies in mCRC have limited scope and lack matched PDXs. Therefore, the landscape of tumor heterogeneity and its impact on the evolution of metastasis and PDXs remain undefined. We performed whole-genome, deep exome, and targeted validation sequencing of multiple primary regions, matched distant metastases, and PDXs from 11 patients with mCRC. We observed intricate clonal heterogeneity and evolution affecting metastasis dissemination and PDX clonal selection. Metastasis formation followed both monoclonal and polyclonal seeding models. In four cases, metastasis-seeding clones were not identified in any primary region, consistent with a metastasis-seeding-metastasis model. PDXs underrepresented the subclonal heterogeneity of parental tumors. These suggest that single sample tumor sequencing and current PDX models may be insufficient to guide precision medicine.

HER2 and HER3 expression in hepatic metastases of colorectal cancer: New targets for specific treatment approaches?

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 567-567
Author(s):  
Lena-Christin Conradi ◽  
Hanna Styczen ◽  
Thilo Sprenger ◽  
Hendrik A. Wolff ◽  
Peter Middel ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Treatment Options ◽  
Significant Proportion ◽  
Specific Treatment ◽  
Hepatic Metastases ◽  
Distant Metastases ◽  
Her2 Status ◽  
Primary Tumors ◽  
Her3 Expression

567 Background: Even though treatment options for coloretal cancer liver metastases have improved with the implementation of multimodal strategies and new agents, progression of distant metastases is still limiting the prognosis of affected patients. In this context we investigated the expression of HER2 and HER3 in patients with metastatic colorectal cancer and primary tumors. Methods: In this study 226 consecutive patients with hepatic metastases of colorectal cancer were included. HER2 and HER3 expression were determined in the tissue from resected metastases and—if available—in primary tumors. Immunohistochemical scoring (IHC 0 to IHC 3) and S-ISH-amplification-detection (for HER2) were used to determine the HER2 and HER3 status. Results: A positive HER2 status was found in 8.4% of all hepatic metastases; an overexpression of HER-3 in 74,8% of all cases. There was a high congruence of the expression pattern of HER2 and HER3 between hepatic metastases and available primary tumors (>90%). Conclusions: HER2 amplification and HER3 overexpression is detectable in a significant proportion of hepatic metastases of colorectal cancer. These results suggest that innovative new targeted treatment agents might be possible opportunities for the specific therapy of patients with HER2/HER3 positive metastatic colorectal cancer and should be further assessed within prospective clinical trials.

Adjunctive local therapy in metastatic colorectal cancer in an unselected cohort: Improved patient-survival in comparison to systemic therapies.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 4096-4096
Author(s):  
Jan Schroeder ◽  
Evrim Tasci ◽  
Claus Nolte-Ernsting ◽  
Peter Michels ◽  
Natalie Wetzel ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Lung Metastases ◽  
Local Therapy ◽  
Distant Metastases ◽  
Reference Population ◽  
Systemic Treatments ◽  
Radiofrequency Therapy ◽  
Study Population ◽  
Prospective Longitudinal

4096 Background: Patients with distant metastases in colorectal cancer have a poor prognosis and a low overall survival (OS). In addition to systemic treatments and irradiation, the tumor burden can be reduced by loco-regional therapeutics, including microwave ablation (MWA), radiofrequency therapy (RFA) and trans-arterial chemoembolization (TACE) available. To evaluate the benefit of such local therapies, we compared OS of a single-centre study population to a reference population of patients who underwent no loco-regional treatment within the German Tumor Registry Colorectal Cancer (TKK). Methods: The study population consists of a cohort of 51 patients (n = 51) treated loco-regionally in addition to systemic therapy. The patients were recruited in a single cancer centre in Mülheim, Germany during the years 2006 to 2015. A reference population of 788 patients was chosen from a prospective, longitudinal registry of the TKK. Time to event data analysis included the estimation of Kaplan-Meier cumulative survival probabilities and hazard ratios (HR) with corresponding 95% confidence intervals (95% CI) from Cox proportional hazards regression. Results: The median OS was 31.3 months (95% CI 26.8 - 41.6) in the study population, as compared to the reference population, where it was 21.9 months (95% CI 20.1 – 24.6). Patients with liver and lung metastases in the study population had an OS of 41.6 months (95% CI 30.5 – 78.2), the corresponding patients from the reference population 21.7 months (95% CI 16.7 – 24.6). Furthermore, patients in the reference group had a 1.79-fold death-rate, as compared to patients treated with additional loco-regional therapy (HR = 2.02; 95% CI: 1.29-3.16). Conclusions: Additional treatment with loco-regional therapies of distant metastases in patients with metastatic colorectal cancer appears to be associated with improved OS by nearly 10 months compared to systemic treatments only. [Table: see text]

scholarly journals Mitochondrial DNA alteration in primary and metastatic colorectal cancer: Different frequency and association with selected clinicopathological and molecular markers

Tumor Biology ◽  
2017 ◽  
Vol 39 (3) ◽  
pp. 101042831769224 ◽  
Author(s):  
Britta Kleist ◽  
Thuja Meurer ◽  
Micaela Poetsch
Keyword(s):  
Colorectal Cancer ◽  
Lymph Node ◽  
Microsatellite Instability ◽  
Metastatic Colorectal Cancer ◽  
Lymph Node Metastases ◽  
Primary Tumor ◽  
Distant Metastases ◽  
Primary Tumors ◽  
Node Metastases ◽  
Mitochondrial Microsatellite Instability

This study attempts to determine whether primary tumor tissue could reliably represent metastatic colorectal cancer in therapy-guiding analysis of mitochondrial microsatellite instability. Therefore, we investigated the concordance of microsatellite instability in D310, D514, and D16184 (mitochondrial DNA displacement loop), and its association with selected clinical categories and KRAS/NRAS/BRAF/PIK3CA/TP53 mutation status between primary and metastatic colorectal cancer tissue from 119 patients. Displacement loop microsatellite instability was significantly more frequently seen in lymph node metastases (53.1%) compared to primary tumors (37.5%) and distant metastases (21.4%) ( p = 0.0183 and p = 0.0005). The discordant rate was significantly higher in lymph node metastases/primary tumor pairs (74.6%) than in distant metastases/primary tumor pairs (52.4%) or lymph node metastases/distant metastases pairs (51.6%) ( p = 0.0113 and p = 0.0261) with more gain (86.7%) than loss (61.1%) of microsatellite instability in the discordant lymph node metastases ( p = 0.0024). Displacement loop instability occurred significantly more frequently in lymph node metastases and distant metastases of patients with early colorectal cancer onset age <60 years ( p = 0.0122 and p = 0.0129), was found with a significant high rate in a small cohort of TP53-mutated distant metastases ( p = 0.0418), and was associated with TP53 wild-type status of primary tumors ( p = 0.0009), but did not correlate with KRAS, NRAS, BRAF, or PIK3CA mutations. In conclusion, mitochondrial microsatellite instability and its association with selected clinical and molecular markers are discordant in primary and metastatic colorectal cancer, which could have importance for surveillance and therapeutic strategies.

scholarly journals The tumor microenvironment of colorectal cancer metastases: opportunities in cancer immunotherapy

Immunotherapy ◽  
2020 ◽  
Vol 12 (14) ◽  
pp. 1083-1100
Author(s):  
Yasmin Kamal ◽  
Stephanie L Schmit ◽  
Hildreth Robert Frost ◽  
Christopher I Amos
Keyword(s):  
Colorectal Cancer ◽  
Tumor Microenvironment ◽  
Cancer Immunotherapy ◽  
Standard Of Care ◽  
Distant Metastases ◽  
Current Understanding ◽  
Primary Tumors ◽  
Cancer Metastases ◽  
Colorectal Cancer Metastases

About a fifth of individuals with colorectal cancer (CRC) present with disease metastasis at the time of diagnosis. While the role of the tumor microenvironment (TME) in governing CRC progression is undeniable, the role of the TME in either establishing or suppressing the formation of distant metastases of CRC is less well established. Despite advances in immunotherapy, many individuals with metastatic CRC do not respond to standard-of-care therapy. Therefore, understanding the role of the TME in establishing distant metastases is essential for developing new immunological agents. Here, we summarize our current understanding of the TME of CRC metastases, describe differences between the TME of primary tumors and their distant metastases, and discuss advances in the design and combinations of immunotherapeutic agents.

scholarly journals Clinicopathologic and Prognostic Association of GRP94 Expression in Colorectal Cancer with Synchronous and Metachronous Metastases

2021 ◽  
Vol 22 (13) ◽  
pp. 7042
Author(s):  
Sumi Yun ◽  
Sukmook Lee ◽  
Ho-Young Lee ◽  
Hyeon Jeong Oh ◽  
Yoonjin Kwak ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Infiltrating Lymphocytes ◽  
Distant Metastases ◽  
Significant Heterogeneity ◽  
Metastatic Lesions ◽  
Group Survival ◽  
Metastatic Sites ◽  
Infiltrating Lymphocytes ◽  
Prognostic Association ◽  
Metachronous Metastases

Patients with advanced colorectal cancer (CRC) with distant metastases have a poor prognosis. We evaluated the clinicopathological relevance of GRP94 expression in these cases. The immunohistochemical expression of GRP94 was studied in 189 CRC patients with synchronous (SM; n = 123) and metachronous metastases (MM; n = 66), using tissue microarray; the association between GRP94 expression, outcome, and tumor-infiltrating lymphocytes (TILs) was also evaluated. GRP94 was expressed in 64.6% (122/189) patients with CRC; GRP94 positivity was found in 67.5% and 59.1% patients with SM and MM, respectively. In the SM group, high GRP94 expression was more common in patients with a higher density of CD4+ TILs (p = 0.002), unlike in the MM group. Survival analysis showed that patients with GRP94 positivity had significantly favorable survival (p = 0.030); after multivariate analysis, GRP94 only served as an independent prognostic factor (p = 0.034; hazard ratio, 0.581; 95% confidence interval, 0.351–0.961) in the SM group. GRP94 expression was detected in 49.4% of metastatic sites and showed significant heterogeneity between primary and metastatic lesions (p = 0.012). GRP94 is widely expressed in CRC with distant metastases; its expression was associated with favorable prognosis in the SM group, unlike in the MM group.

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