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Correlation and Heterogeneity of the Immune Microenvironment and Histopathological Growth Patterns in Resectable Colorectal Cancer Liver Metastases
This study aims to retrospectively analyze the status and spatial heterogeneity of the tumor microenvironment (TME) in liver metastases from patients with CRLM, as well as the association between HGPs at the tumor-liver interface and postoperative recurrence following resection of liver metastases. Furthermore, this study seeks to explore the underlying mechanisms through which HGPs influence patient prognosis.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| patients with CRLM who underwent R0 resection | According to the 2017 guidelines on histopathological growth patterns of liver metastases, HGPs are primarily classified into three types: the desmoplastic histopathological growth pattern (dHGP), the replacement histopathological growth pattern (rHGP), and the pushing histopathological growth pattern (pHGP). The tumor-liver interface was independently delineated by two pathologists using QuPath software, and distinct HGPs at the tumor-liver interface were identified. Formalin-fixed, paraffin-embedded (FFPE) sections of colorectal cancer liver metastases were stained with hematoxylin and eosin (H&E).Multiplex immunohistochemistry (mIHC) staining was performed on FFPE sections of liver metastases using two panels (Panel 1: CD4, CD8A, Foxp3, PD-L1, Panck; Panel 2: CD68, CD163, FAP-α, α-SMA, Panck), encompassing a total of nine immune cell markers. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Formalin-fixed, paraffin-embedded (FFPE) sections of colorectal cancer liver metastases were stained with hematoxylin and eosin (H&E) and Multiplex immunohistochemistry (mIHC) staining. | Other | Formalin-fixed, paraffin-embedded (FFPE) sections of colorectal cancer liver metastases were stained with hematoxylin and eosin (H&E) and Multiplex immunohistochemistry (mIHC) staining. |
| Measure | Description | Time Frame |
|---|---|---|
| OS(Overall survival) | OS was defined as the time from the date of the first liver metastasis resection to death due to any cause or loss to follow-up. | OS is defined as the time from the date of the first liver metastasis resection to death due to any cause or loss to follow-up, assessed up to 100 months. |
| RFS (Recurrence-free Survival) | The definition of recurrence-free survival is the time from the liver surgery to the first imaging evidence showing disease recurrence or death due to any cause, whichever occurs first. | From the date of liver resection until the first occurrence of a measurable recurrence of the disease, or until death due to any cause (whichever occurs first), the assessment period can be up to 100 months. |
| HGPs (Histopathological Growth Patterns) | The histopathological growth pattern of the tumor-liver interface. | From the completion of HE staining to the failure of staining or the damage and loss of the slides, the assessment period can be up to 100 months. |
| TME (Tumor Microenvironment) | Multiplex immunohistochemistry (mIHC) staining was performed on FFPE sections of liver metastases using two panels (Panel 1: CD4, CD8A, Foxp3, PD-L1, Panck; Panel 2: CD68, CD163, FAP-α, α-SMA, Panck), encompassing a total of nine immune cell markers. Using QuPath pathology imaging software, tissue sections were divided into the tumor center (defined as regions >500 μm from the liver-tumor interface) and the invasive tumor front (defined as a 1 mm region extending 500 μm on either side of the liver-tumor interface). Quantitative analysis of immune cell populations was performed in the tumor center, the invasive tumor front, and regions corresponding to different histopathological growth patterns. | From the completion of mIHC staining to the failure of staining or the damage and loss of the slides, the assessment period can be up to 100 months. |
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Inclusion Criteria:
Exclusion Criteria:
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This study enrolled patients with CRLM who underwent R0 resection.
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| West China Hospital of Sichuan University | Chengdu | Sichuan | 610041 | China |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 40946880 | Background | Zhang A, Zhang Y, Xu J, Zhu R, Liang T, Guo L. Molecular landscape of colorectal cancer liver metastasis: Tumor microenvironment heterogeneity and driver inference. Crit Rev Oncol Hematol. 2025 Dec;216:104946. doi: 10.1016/j.critrevonc.2025.104946. Epub 2025 Sep 12. | |
| 32601799 | Background | Liang JY, Xi SY, Shao Q, Yuan YF, Li BK, Zheng Y, Wang DS, Wu XJ, Ding PR, Chen G, Li LR, Wang FH, Wang ZQ, Pan ZZ, Xu RH, Li YH. Histopathological growth patterns correlate with the immunoscore in colorectal cancer liver metastasis patients after hepatectomy. Cancer Immunol Immunother. 2020 Dec;69(12):2623-2634. doi: 10.1007/s00262-020-02632-6. Epub 2020 Jun 29. |
| Label | URL |
|---|---|
| Pubmed Official website | View source |
| ID | Type | URL | Comment |
|---|---|---|---|
| qiumeng@wchscu.cn | Statistical Analysis Plan | View IPD |
First of all, there is a lack of sufficient funds or personnel to anonymize and maintain the data for a long time, such as the original imaging documents, which are difficult to organize compliance. Second, this study was an early exploratory study with small data size and high risk of identification. Finally, summary results are available after publication, and the data will be reassessed 5 years after the end of the study.
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jul 1, 2024 |
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Surgical resection samples of liver metastases from patients with colorectal cancer liver metastasis
|
| 36195882 | Background | He Y, Han Y, Fan AH, Li D, Wang B, Ji K, Wang X, Zhao X, Lu Y. Multi-perspective comparison of the immune microenvironment of primary colorectal cancer and liver metastases. J Transl Med. 2022 Oct 4;20(1):454. doi: 10.1186/s12967-022-03667-2. |
| 32418992 | Background | Hoppener DJ, Nierop PMH, Hof J, Sideras K, Zhou G, Visser L, Gouw ASH, de Jong KP, Sprengers D, Kwekkeboom J, Vermeulen PB, Grunhagen DJ, Verhoef C. Enrichment of the tumour immune microenvironment in patients with desmoplastic colorectal liver metastasis. Br J Cancer. 2020 Jul;123(2):196-206. doi: 10.1038/s41416-020-0881-z. Epub 2020 May 18. |
| 32205863 | Background | Stremitzer S, Vermeulen P, Graver S, Kockx M, Dirix L, Yang D, Zhang W, Stift J, Wrba F, Gruenberger T, Lenz HJ, Scherer SJ. Immune phenotype and histopathological growth pattern in patients with colorectal liver metastases. Br J Cancer. 2020 May;122(10):1518-1524. doi: 10.1038/s41416-020-0812-z. Epub 2020 Mar 24. |
| 28982110 | Background | van Dam PJ, van der Stok EP, Teuwen LA, Van den Eynden GG, Illemann M, Frentzas S, Majeed AW, Eefsen RL, Coebergh van den Braak RRJ, Lazaris A, Fernandez MC, Galjart B, Laerum OD, Rayes R, Grunhagen DJ, Van de Paer M, Sucaet Y, Mudhar HS, Schvimer M, Nystrom H, Kockx M, Bird NC, Vidal-Vanaclocha F, Metrakos P, Simoneau E, Verhoef C, Dirix LY, Van Laere S, Gao ZH, Brodt P, Reynolds AR, Vermeulen PB. International consensus guidelines for scoring the histopathological growth patterns of liver metastasis. Br J Cancer. 2017 Nov 7;117(10):1427-1441. doi: 10.1038/bjc.2017.334. Epub 2017 Oct 5. |
| 35650276 | Background | Latacz E, Hoppener D, Bohlok A, Leduc S, Tabaries S, Fernandez Moro C, Lugassy C, Nystrom H, Bozoky B, Floris G, Geyer N, Brodt P, Llado L, Van Mileghem L, De Schepper M, Majeed AW, Lazaris A, Dirix P, Zhang Q, Petrillo SK, Vankerckhove S, Joye I, Meyer Y, Gregorieff A, Roig NR, Vidal-Vanaclocha F, Denis L, Oliveira RC, Metrakos P, Grunhagen DJ, Nagtegaal ID, Mollevi DG, Jarnagin WR, D'Angelica MI, Reynolds AR, Doukas M, Desmedt C, Dirix L, Donckier V, Siegel PM, Barnhill R, Gerling M, Verhoef C, Vermeulen PB. Histopathological growth patterns of liver metastasis: updated consensus guidelines for pattern scoring, perspectives and recent mechanistic insights. Br J Cancer. 2022 Oct;127(6):988-1013. doi: 10.1038/s41416-022-01859-7. Epub 2022 Jun 1. |
Survival analysis was estimated using the Kaplan-Meier method and compared using the log-rank test. Quantitative data regarding the immune microenvironment were compared using the t-test or the Mann-Whitney U test, as appropriate. Changes between initial resection and secondary resection were analyzed using the nonparametric test for two paired samples. The endpoints of this study included patient clinical outcomes (OS and PFS), spatial distribution differences of immune cells within TME of liver metastases, distribution patterns of HGPs and their correlation with survival, and analysis of the immune microenvironment in relation to HGPs. |
| Apr 27, 2026 |
| Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | Jul 1, 2024 | Apr 27, 2026 | ICF_001.pdf |
| ID | Term |
|---|---|
| D015179 | Colorectal Neoplasms |
| ID | Term |
|---|---|
| D007414 | Intestinal Neoplasms |
| D005770 | Gastrointestinal Neoplasms |
| D004067 | Digestive System Neoplasms |
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D004066 | Digestive System Diseases |
| D005767 | Gastrointestinal Diseases |
| D003108 | Colonic Diseases |
| D007410 | Intestinal Diseases |
| D012002 | Rectal Diseases |
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| ID | Term |
|---|---|
| D006416 | Hematoxylin |
| D004801 | Eosine Yellowish-(YS) |
| D013194 | Staining and Labeling |
| ID | Term |
|---|---|
| D001578 | Benzopyrans |
| D011714 | Pyrans |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D005452 | Fluoresceins |
| D013141 | Spiro Compounds |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| D014966 | Xanthenes |
| D006575 | Heterocyclic Compounds, 3-Ring |
| D011083 | Polycyclic Compounds |
| D016591 | Histocytological Preparation Techniques |
| D003584 | Cytological Techniques |
| D019411 | Clinical Laboratory Techniques |
| D019937 | Diagnostic Techniques and Procedures |
| D003933 | Diagnosis |
| D006652 | Histological Techniques |
| D008919 | Investigative Techniques |
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