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Hu H, Xu J, Xie X, Xie C, Wang K, Guo Y, Yi L, Chen X. MRI Morphological Features for Assessing Lymph Node Restaging in Rectal Cancer After Neoadjuvant Chemoradiotherapy. Acad Radiol 2025:S1076-6332(25)00434-9. [PMID: 40425434 DOI: 10.1016/j.acra.2025.05.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2025] [Revised: 05/01/2025] [Accepted: 05/04/2025] [Indexed: 05/29/2025]
Abstract
RATIONALE AND OBJECTIVES Accurate lymph node (LN) restaging after neoadjuvant chemoradiotherapy (nCRT) is critical for guiding subsequent treatment decisions in patients with rectal cancer. The currently recommended European Society of Gastrointestinal and Abdominal Radiology (ESGAR) method has shown limited accuracy. This study aimed to evaluate the diagnostic performance of specific MRI morphological features for LN restaging post-nCRT and to develop a reliable, clinically applicable imaging-based assessment method. MATERIALS AND METHODS In this retrospective multi-center study, one training cohort and two external validation cohorts were included. MRI morphological features were assessed for their association with pathological LN status using χ² tests and multivariable logistic regression. Diagnostic performance was evaluated using the area under the receiver operating characteristic curve (AUC). Interobserver agreement was evaluated using Cohen κ coefficient and the intraclass correlation coefficient (ICC [1,1]). RESULTS Among 238 patients in the training cohort, 64 (26%) had pathologically confirmed positive LNs. Multivariate analysis revealed that signal homogeneity (odds ratio [OR], 3.23; P=.02), interruption of vessels (OR, 6.97; P=.001), and tail sign (OR, 4.02; P=.002) were independent predictors of positive LN status. The developed "Three-features method" (positive if any two features were present) achieved an AUC of 0.83, with 69% sensitivity, 86% specificity, and 82% overall accuracy-significantly outperforming the ESGAR method (AUC=0.68). External validation showed consistent diagnostic performance (AUC=0.74 and 0.77). CONCLUSION The integration of signal homogeneity, interruption of vessels, and tail sign into a combined MRI-based "Three-features method" significantly improves the accuracy of LN restaging after nCRT compared to ESGAR method.
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Affiliation(s)
- Hengxiao Hu
- Department of Radiology, the Second Affiliated Hospital, School of Medicine, South China University of Technology, No. 1 Panfu Road, Yuexiu District, Guangzhou 510180, China (H.H., X.X., K.W., Y.G., L.Y., X.C.)
| | - Jing Xu
- Department of Radiation Oncology, The Second Affiliated Hospital and Cancer Institute, Zhejiang University School of Medicine, No. 88 Jiefang Road, Hangzhou 310009, China (J.X.)
| | - Xiaowen Xie
- Department of Radiology, the Second Affiliated Hospital, School of Medicine, South China University of Technology, No. 1 Panfu Road, Yuexiu District, Guangzhou 510180, China (H.H., X.X., K.W., Y.G., L.Y., X.C.)
| | - Chenyi Xie
- Guangdong Provincial Key Laboratory of Artificial Intelligence in Medical Image Analysis and Application, No. 98 Donghua South Road, Yuexiu District, Guangzhou 510199, China (C.X.); Department of Radiology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, No. 106 Zhongshan 2nd Road, Yuexiu District, Guangzhou 510080, China (C.X.)
| | - Kuanhong Wang
- Department of Radiology, the Second Affiliated Hospital, School of Medicine, South China University of Technology, No. 1 Panfu Road, Yuexiu District, Guangzhou 510180, China (H.H., X.X., K.W., Y.G., L.Y., X.C.)
| | - Yingying Guo
- Department of Radiology, the Second Affiliated Hospital, School of Medicine, South China University of Technology, No. 1 Panfu Road, Yuexiu District, Guangzhou 510180, China (H.H., X.X., K.W., Y.G., L.Y., X.C.)
| | - Liujun Yi
- Department of Radiology, the Second Affiliated Hospital, School of Medicine, South China University of Technology, No. 1 Panfu Road, Yuexiu District, Guangzhou 510180, China (H.H., X.X., K.W., Y.G., L.Y., X.C.)
| | - Xin Chen
- Department of Radiology, the Second Affiliated Hospital, School of Medicine, South China University of Technology, No. 1 Panfu Road, Yuexiu District, Guangzhou 510180, China (H.H., X.X., K.W., Y.G., L.Y., X.C.).
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Li QY, Yang D, Guan Z, Yan XY, Li XT, Sun RJ, Lu QY, Zhang XY, Sun YS. Extranodal Extension at Pretreatment MRI and the Prognostic Value for Patients with Rectal Cancer. Radiology 2024; 310:e232605. [PMID: 38530176 DOI: 10.1148/radiol.232605] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/27/2024]
Abstract
Background Detection of extranodal extension (ENE) at pathology is a poor prognostic indicator for rectal cancer, but whether ENE can be identified at pretreatment MRI is, to the knowledge of the authors, unknown. Purpose To evaluate the performance of pretreatment MRI in detecting ENE using a matched pathologic reference standard and to assess its prognostic value in patients with rectal cancer. Materials and Methods This single-center study included a prospective development data set consisting of participants with rectal adenocarcinoma who underwent pretreatment MRI and radical surgery (December 2021 to January 2023). MRI characteristics were identified by their association with ENE-positive nodes (χ2 test and multivariable logistic regression) and the performance of these MRI features was assessed (area under the receiver operating characteristic curve [AUC]). Interobserver agreement was assessed by Cohen κ coefficient. The prognostic value of ENE detected with MRI for predicting 3-year disease-free survival was assessed by Cox regression analysis in a retrospective independent validation cohort of patients with locally advanced rectal cancer (December 2019 to July 2020). Results The development data set included 147 participants (mean age, 62 years ± 11 [SD]; 87 male participants). The retrospective cohort included 110 patients (mean age, 60 years ± 9; 79 male participants). Presence of vessel interruption and fusion (both P < .001), heterogeneous internal structure, and the broken-ring and tail signs (odds ratio range, 4.10-23.20; P value range, <.001 to .002) were predictors of ENE at MRI, and together achieved an AUC of 0.91 (95% CI: 0.88, 0.93) in detecting ENE. Interobserver agreement was moderate for the presence of vessel interruption and fusion (κ = 0.46 for both) and substantial for others (κ = 0.61-0.67). The presence of ENE at pretreatment MRI was independently associated with worse 3-year disease-free survival (hazard ratio, 3.00; P = .02). Conclusion ENE can be detected at pretreatment MRI, and its presence was associated with worse prognosis for patients with rectal cancer. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Eberhardt in this issue.
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Affiliation(s)
- Qing-Yang Li
- From the Department of Radiology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, No. 52 Fu Cheng Rd, Hai Dian District, Beijing 100142, China
| | - Ding Yang
- From the Department of Radiology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, No. 52 Fu Cheng Rd, Hai Dian District, Beijing 100142, China
| | - Zhen Guan
- From the Department of Radiology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, No. 52 Fu Cheng Rd, Hai Dian District, Beijing 100142, China
| | - Xin-Yue Yan
- From the Department of Radiology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, No. 52 Fu Cheng Rd, Hai Dian District, Beijing 100142, China
| | - Xiao-Ting Li
- From the Department of Radiology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, No. 52 Fu Cheng Rd, Hai Dian District, Beijing 100142, China
| | - Rui-Jia Sun
- From the Department of Radiology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, No. 52 Fu Cheng Rd, Hai Dian District, Beijing 100142, China
| | - Qiao-Yuan Lu
- From the Department of Radiology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, No. 52 Fu Cheng Rd, Hai Dian District, Beijing 100142, China
| | - Xiao-Yan Zhang
- From the Department of Radiology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, No. 52 Fu Cheng Rd, Hai Dian District, Beijing 100142, China
| | - Ying-Shi Sun
- From the Department of Radiology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, No. 52 Fu Cheng Rd, Hai Dian District, Beijing 100142, China
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Shi C, Chen W, Davis R, Morse MA. Venous Invasion in Pancreatic Neuroendocrine Tumors Is Independently Associated With Disease-free Survival and Overall Survival. Am J Surg Pathol 2023; 47:678-685. [PMID: 37017316 DOI: 10.1097/pas.0000000000002038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/06/2023]
Abstract
In this study, we evaluated venous invasion and its association with survival in patients with resected pancreatic neuroendocrine tumor (PanNET). Surgical Pathology Archives were searched for pancreatectomies performed for PanNET between October 1, 2005, and December 31, 2019. Hematoxylin and eosin (H&E)-stained slides were evaluated for venous invasion, and Movat's stain was performed in all cases with no venous invasion detected on H&E stains. Pathology reports and electronic medical records were also reviewed. Venous invasion was identified in 23 of 145 (15.9%) cases on H&E stains, and Movat's stain identified additional 34 cases with venous invasion (39.3% overall). Orphan arteries with adjacent well-defined tumor nodules or subtle hyalinizing nodules in hyalinizing tumors are highly specific for venous invasion. In stage I-III cases (n=122), venous invasion was associated with larger tumor size, higher World Health Organization (WHO) tumor grade, perineural invasion, extrapancreatic extension, lymph node metastasis, and liver metastasis ( P <0.05). In univariate analyses, tumor size, WHO grade, venous invasion, perineural invasion, T stage, and lymph node metastasis all correlated with disease-free survival; however, only venous invasion was associated with worse disease-free survival in multivariate analyses ( P <0.01). In all-stage cases, venous invasion was the only attributor associated with worse overall survival in multivariate analyses ( P =0.03). In summary, venous invasion in PanNET can be histologically subtle, and Movat's stain can greatly increase the detection rate. More importantly, enhanced venous invasion by Movat's stain correlates independently with disease-free survival in patients with stage I-III tumors and overall survival in all-stage patients.
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Affiliation(s)
| | | | | | - Michael A Morse
- Medicine, Medical Oncology, Duke University Medical Center, Durham, NC
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Abdel-Rahman O. A real-world, population-based study for the outcomes of patients with metastatic colorectal cancer to the liver with distant lymph node metastases treated with metastasectomy. J Comp Eff Res 2022; 11:243-250. [PMID: 35075916 DOI: 10.2217/cer-2021-0133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Aim: To assess the impact of metastasectomy on survival outcomes of patients with concurrent liver and distant nodal metastases. Materials & methods: Surveillance, Epidemiology, and End Results (SEER) database was accessed and patients with colorectal liver metastases (with or without distant lymph node involvement) were reviewed. Kaplan-Meier survival estimates were then used to assess the impact of the presence of distant lymph node metastases as well as the impact of metastasectomy on overall and cancer-specific survival. A propensity score matching was then conducted between patients with distant lymph node metastases who had surgery versus those who did not have surgery. Results: A total of 15,325 patients were included in the current analysis including 1603 patients who have liver and distant nodal metastases (10.5%) and 13,722 patients who have liver metastases only (89.5%). The following factors were associated with better overall survival (OS): younger age (hazard ratio [HR] with increasing age: 1.024; 95% CI: 1.022-1.025), white race (HR for African-American race vs white race: 1.233; 95% CI: 1.175-1.295), distal site of the primary (HR: 0.808; 95% CI: 0.778-0.840), absence of distant lymph nodes (HR: 0.697; 95% CI: 0.659-0.737), metastasectomy (HR for no metastasectomy vs metastasectomy: 1.954; 95% CI: 1.858-2.056). Within the postpropensity cohort, metastasectomy was associated with improved OS among patients with concurrent distant lymph node and liver metastases (median OS of 20 vs 11 months; p < 0.001). Conclusion: Metastasectomy seems to be associated with improved survival among patients with concurrent lymph node and liver metastases. It is unclear if improved survival is related to the surgical intervention or to the fact that surgically treated patients have a better baseline general condition and hence improved outcomes.
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Affiliation(s)
- Omar Abdel-Rahman
- Department of Oncology, University of Alberta, Cross Cancer Institute, Edmonton, AB T6G 1Z2, Canada
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Lino-Silva L, Sánchez-Acosta C, Salcedo-Hernández R, Zepeda-Najar C. Extracapsular Extension Does Not Decrease Overall Survival in Rectal Cancer Patients with Lymph Node Metastasis Following Neoadjuvant Chemoradiotherapy. GASTROENTEROLOGY INSIGHTS 2020; 11:11-19. [DOI: 10.3390/gastroent11020004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Background. The Tumor-Node-Metastasis system does not include additional prognostic factors present in the Lymph Node Metastasis (LNM) such as extra-capsular extension (ECE), which is associated with decreased survival. There are not studies addressing this topic in rectal cancer patients with preoperative chemoradiotherapy (nCRT) and total mesorectal excision (TME). Aim. We aimed to examine the survival influence of ECE in patients with stage III rectal cancer who received nCRT followed by surgery. Methods. A retrospective study of 126 patients prospectively collected with rectal cancer in clinical stage III rated with nCRT and TME from 2010 to 2015 was performed. Results. In total, 71.6% of cases had 1 to 3 lymph node metastases, most tumors were grade 2 (52.4%), 25.4% had good pathologic response, 77.8% had a good quality TME, and the median tumor budding count was 4/0.785 mm2. Forty-four (34.9%) patients had ECE+, which was associated with a higher nodal stage (pN2), perineural invasion and a higher lymph node retrieval. The factors associated with the survival were a higher pathologic T stage, higher pathological N stage, high-grade tumors, and perineural invasion. The ECE did not decrease the 5–year survival with a similar median survival (86.5 months for the ECE+ group vs. 84.1 for the ECE–). Conclusion. Our results demonstrate that ECE has no impact on overall survival in rectal cancer patients who received nCRT and this was independent of nodal stage or number of lymph nodes examined.
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Affiliation(s)
- Leonardo Lino-Silva
- Surgical Pathology, Instituto Nacional de Cancerología, Tlalpan, 14080 Mexico City, Mexico
| | - Carmen Sánchez-Acosta
- Surgical Pathology, Instituto Nacional de Cancerología, Tlalpan, 14080 Mexico City, Mexico
| | - Rosa Salcedo-Hernández
- Surgical Oncology, Instituto Nacional de Cancerología, Tlalpan, 14080 Mexico City, Mexico
| | - César Zepeda-Najar
- Surgical Oncology, Hospital Ángeles Tijuana, 22010 Tijuana, Baja California Norte, Mexico
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Zaręba KP, Zińczuk J, Dawidziuk T, Rosołowski M, Pryczynicz A, Guzińska-Ustymowicz K, Kędra B. Can factors that influence nodal dissemination in patients with colorectal cancer be identified? Own experience. PRZEGLAD GASTROENTEROLOGICZNY 2020; 15:247-252. [PMID: 33005271 PMCID: PMC7509900 DOI: 10.5114/pg.2020.98542] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/10/2019] [Accepted: 10/01/2019] [Indexed: 12/01/2022]
Abstract
INTRODUCTION As one of the most common causes of cancer deaths in Poland, colorectal cancer, remains a mystery when factors affecting local and distant lymph node metastasis are concerned. AIM In this study the authors have analysed possible correlations between the number of regional (and distant) lymph nodes affected by cancer, location and stage of the primary tumour, levels of oncological markers CA19-9 and CEA, and the patients age, sex, body mass index (BMI), and other clinical symptoms. MATERIAL AND METHODS A special questionnaire was created for this study, and a group of 100 men and women was selected. All patients in the study group had undergone surgery due to colorectal cancer. RESULTS There were no statistically significant relationships between age, and number and location of metastases (p > 0.05). Primary tumour assessment did not show a statistically significant relationship with the presence of metastases to regional lymph nodes (p > 0.05). There was also no statistically significant correlation between tumour localisation and lymph node metastases (p > 0.05) or between tumour size, BMI, occurrence of physical symptoms, and involvement of distant lymph nodes (p > 0.05). The highest CEA was observed in a patient with nine regional lymph node metastases (612.46 ng/ml) and the lowest in one with metastases to two regional nodes (0.2 U/ml). CEA value above 5 ng/ml was found in 35.74% of patients with regional lymph node metastases. A statistically significant relationship was reported (p < 0.05). CONCLUSIONS The location of the primary tumour, and its pathological stage and size does not seem to have a direct correlation with the occurrence of regional lymph node metastases. Metastasis to distant lymph nodes seems to be a consequence of metastases in regional nodes. Elevated CEA tumour marker values are significantly related to metastases in regional lymph nodes. The elevation of CA 19-9 and CEA tumour markers significantly correlates with the presence of metastasis to distant lymph nodes. The location of the primary tumour determines the formation of metastases in distant lymph nodes.
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Affiliation(s)
- Konrad P Zaręba
- 2nd Department of General and Gastroenterological Surgery, Medical University of Bialystok, Bialystok, Poland
| | - Justyna Zińczuk
- Department of Clinical Laboratory Diagnostic, Medical University of Bialystok, Bialystok, Poland
| | - Tomasz Dawidziuk
- Department of Thoracic Surgery, Medical University of Bialystok, Bialystok, Poland
| | - Mariusz Rosołowski
- Department of Gastroenterology and Internal Medicine, Medical University of Bialystok, Bialystok, Poland
| | - Anna Pryczynicz
- Department of Pathomorphology, Medical University of Bialystok, Bialystok, Poland
| | | | - Bogusław Kędra
- 2nd Department of General and Gastroenterological Surgery, Medical University of Bialystok, Bialystok, Poland
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Tumour-infiltrating neutrophils counteract anti-VEGF therapy in metastatic colorectal cancer. Br J Cancer 2018; 120:69-78. [PMID: 30377339 PMCID: PMC6325148 DOI: 10.1038/s41416-018-0198-3] [Citation(s) in RCA: 61] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 06/25/2018] [Accepted: 07/04/2018] [Indexed: 12/30/2022] Open
Abstract
Background Immune infiltration is implicated in the development of acquired resistance to anti-angiogenic cancer therapy. We therefore investigated the correlation between neutrophil infiltration in metastasis of colorectal cancer (CRC) patients and survival after treatment with bevacizumab. Our study identifies CD177+ tumour neutrophil infiltration as an adverse prognostic factor for bevacizumab treatment. We further demonstrate that a novel anti-VEGF/anti-Ang2 compound (BI-880) can overcome resistance to VEGF inhibition in experimental tumour models. Methods A total of 85 metastatic CRC patients were stratified into cohorts that had either received chemotherapy alone (n = 39) or combined with bevacizumab (n = 46). Tumour CD177+ neutrophil infiltration was correlated to clinical outcome. The impact of neutrophil infiltration on anti-VEGF or anti-VEGF/anti-Ang2 therapy was studied in both xenograft and syngeneic tumour models by immunohistochemistry. Results The survival of bevacizumab-treated CRC patients in the presence of CD177+ infiltrates was significantly reduced compared to patients harbouring CD177− metastases. BI-880 treatment reduced the development of hypoxia associated with bevacizumab treatment and improved vascular normalisation in xenografts. Furthermore, neutrophil depletion or BI-880 treatment restored treatment sensitivity in a syngeneic tumour model of anti-VEGF resistance. Conclusions Our findings implicate CD177 as a biomarker for bevacizumab and suggest VEGF/Ang2 inhibition as a strategy to overcome neutrophil associated resistance to anti-angiogenic treatment.
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Nandi P, Girish GV, Majumder M, Xin X, Tutunea-Fatan E, Lala PK. PGE2 promotes breast cancer-associated lymphangiogenesis by activation of EP4 receptor on lymphatic endothelial cells. BMC Cancer 2017; 17:11. [PMID: 28056899 PMCID: PMC5217626 DOI: 10.1186/s12885-016-3018-2] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2016] [Accepted: 12/16/2016] [Indexed: 12/20/2022] Open
Abstract
Background Lymphatic metastasis, facilitated by lymphangiogenesis is a common occurrence in breast cancer, the molecular mechanisms remaining incompletely understood. We had earlier shown that cyclooxygenase (COX)-2 expression by human or murine breast cancer cells promoted lymphangiogenesis and lymphatic metastasis by upregulating VEGF-C/D production by tumor cells or tumor-associated macrophages primarily due to activation of the prostaglandin receptor EP4 by endogenous PGE2. It is not clear whether tumor or host-derived PGE2 has any direct effect on lymphangiogenesis, and if so, whether EP4 receptors on lymphatic endothelial cells (LEC) play any role. Methods Here, we address these questions employing in vitro studies with a COX-2-expressing and VEGF-C/D-producing murine breast cancer cell line C3L5 and a rat mesenteric (RM) LEC line and in vivo studies in nude mice. Results RMLEC responded to PGE2, an EP4 agonist PGE1OH, or C3L5 cell-conditioned media (C3L5-CM) by increased proliferation, migration and accelerated tube formation on growth factor reduced Matrigel. Native tube formation by RMLEC on Matrigel was abrogated in the presence of a selective COX-2 inhibitor or an EP4 antagonist. Addition of PGE2 or EP4 agonist, or C3L5-CM individually in the presence of COX-2 inhibitor, or EP4 antagonist, restored tube formation, reinforcing the role of EP4 on RMLEC in tubulogenesis. These results were partially duplicated with a human dermal LEC (HMVEC-dLyAd) and a COX-2 expressing human breast cancer cell line MDA-MB-231. Knocking down EP4 with shRNA in RMLEC abrogated their tube forming capacity on Matrigel in the absence or presence of PGE2, EP4 agonist, or C3L5-CM. RMLEC tubulogenesis following EP4 activation by agonist treatment was dependent on PI3K/Akt and Erk signaling pathways and VEGFR-3 stimulation. Finally in a directed in vivo lymphangiogenesis assay (DIVLA) we demonstrated the lymphangiogenic as well as angiogenic capacity of PGE2 and EP4 agonist in vivo. Discussion/conclusions These results demonstrate the roles of tumor as well as host-derived PGE2 in inducing lymphangiogenesis, at least in part, by activating EP4 and VEGFR-3 on LEC. EP4 being a common target on both tumor and host cells contributing to tumor-associated lymphangiogenesis reaffirms the therapeutic value of EP4 antagonists in the intervention of lymphatic metastasis in breast cancer.
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Affiliation(s)
- Pinki Nandi
- Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario, N6A5C1, Canada
| | - Gannareddy V Girish
- Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario, N6A5C1, Canada
| | - Mousumi Majumder
- Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario, N6A5C1, Canada.,Department of Biology, Brandon University, Brandon, Manitoba, R7A 6A9, Canada
| | - Xiping Xin
- Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario, N6A5C1, Canada
| | - Elena Tutunea-Fatan
- Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario, N6A5C1, Canada
| | - Peeyush K Lala
- Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario, N6A5C1, Canada. .,Department of Oncology, University of Western Ontario, London, Ontario, N6A5C1, Canada. .,Children's Health Research Institute, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, N6A5C1, Canada.
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Tanriverdi O, Yilmaz EM, Menekse S, Cokmert S, Oktay E, Pilanci KN, Kocar M, Avci N, Akman T, Goksel G, Meydan N, Barutca S. The recurrence with isolated intra-abdominal lymph node in patients with colorectal cancer: A study of the Turkish Descriptive Oncological Researches Group (intra-abdominal lymph node and colon cancer). JOURNAL OF ONCOLOGICAL SCIENCES 2016. [DOI: 10.1016/j.jons.2016.07.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
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Zhang J, Xu J, Zhang RX, Zhang Y, Ou QJ, Li JQ, Jiang ZZ, Wu XJ, Fang YJ, Zheng L. CD169 identifies an activated CD8(+) T cell subset in regional lymph nodes that predicts favorable prognosis in colorectal cancer patients. Oncoimmunology 2016; 5:e1177690. [PMID: 27622027 DOI: 10.1080/2162402x.2016.1177690] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2016] [Revised: 04/05/2016] [Accepted: 04/06/2016] [Indexed: 12/28/2022] Open
Abstract
PURPOSE CD169 was first identified on macrophages (Mϕ) and linked to antigen presentation. Here, we showed CD169 expression on some CD8(+) T lymphocytes in regional lymph nodes (LNs) and investigated the function and clinical relevance of CD169(+)CD8(+) T cells in tumor-draining LNs of colorectal cancer (CRC) patients. EXPERIMENTAL DESIGN Fresh tumor-draining LN tissues from 39 randomly enrolled patients were assessed by flow cytometry for activation and differentiation of CD169(+)CD8(+) T cells and T cell-mediated killing of tumor cells. In total, 114 tumor-draining LN paraffin sections from CRC patients were analyzed by multiple-color immunofluorescence for CD169(+)CD8(+) T cell distribution and clinical values. The prognostic significance of CD169(+)CD8(+) T cells was evaluated by Kaplan-Meier analysis. RESULTS A fraction of CD8(+) T cells in regional LNs, but not peripheral blood, tonsils, or tumors, expressed surface CD169. In situ detection of draining LNs revealed preferential localization of CD169(+)CD8(+) T cells to subcapsular sinus and interfollicular regions, closely associated with CD169(+) Mϕ. CD169(+)CD8(+) T cell ratios were significantly lower in peri-tumor LNs than distant-tumor LNs. CD169(+)CD8(+) T cells predominantly expressed activation markers (CD69, HLA-DR, PD-1) with slightly lower CD45RA and CD62L levels. They produced high granzyme B, perforin, TNF-α, and IFNγ levels, and promoted tumor-killing efficiency ex vitro. Moreover, CD169(+)CD8(+) T cells infiltrating tumor-draining LNs decreased with disease progression and were strongly associated with CRC patient survival. CONCLUSIONS We identified novel activated/cytolytic CD169(+)CD8(+) T cells selectively present in regional LNs, potentially serving as a powerful prognostic factor and indicator for selecting patients for immunotherapy.
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Affiliation(s)
- Jiali Zhang
- Key Laboratory of Gene Engineering of the Ministry of Education, School of Life Sciences, Sun Yat-sen University, Guangzhou, PR China; Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, PR China
| | - Jing Xu
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center , Guangzhou, PR China
| | - Rong-Xin Zhang
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center , Guangzhou, PR China
| | - Yi Zhang
- Key Laboratory of Gene Engineering of the Ministry of Education, School of Life Sciences, Sun Yat-sen University , Guangzhou, PR China
| | - Qing-Jian Ou
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center , Guangzhou, PR China
| | - Jin-Qing Li
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center , Guangzhou, PR China
| | - Ze-Zhou Jiang
- Key Laboratory of Gene Engineering of the Ministry of Education, School of Life Sciences, Sun Yat-sen University , Guangzhou, PR China
| | - Xiao-Jun Wu
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center , Guangzhou, PR China
| | - Yu-Jing Fang
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center , Guangzhou, PR China
| | - Limin Zheng
- Key Laboratory of Gene Engineering of the Ministry of Education, School of Life Sciences, Sun Yat-sen University, Guangzhou, PR China; Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, PR China
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Krbal L, Hanušová V, Soukup J, John S, Matoušková P, Ryška A. Contribution of in vitro comparison of colorectal carcinoma cells from primary and metastatic lesions to elucidation of mechanisms of tumor progression and response to anticancer therapy. Tumour Biol 2016; 37:9565-78. [PMID: 26790446 DOI: 10.1007/s13277-016-4839-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2015] [Accepted: 01/11/2016] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer has been a leading cause of cancer-related morbidity and mortality. For the research and individualization of therapy, primary cell lines of the colorectal cancer appear to be still an invaluable tool. We evaluated the differences in metastatic potential between four isolated primary colon cancer cells and cells derived from their lymph node metastasis. These results were compared with correspond immortalized cells-SW480 and SW620, respectively. The ability to migrate was tested using real-time measurement in xCELLigence system. Expressions of molecules involved in adhesion and invasion processes were examined using RT-PCR and western blot analysis. Furthermore, impact of cytotoxic effect of selected chemotherapeutics (irinotecan, oxaliplatin) and biological therapy (bevacizumab, cetuximab, panitumumab) was assessed by the WST assay. As expected, cell lines derived from lymph node migrated more aggressively and higher expression of adhesion molecules ICAM-1, EpCAM, and N-cadherin was detected. The expression of MMP-2 and -9 was elevated, on the other hand, in cell lines derived from primary tumor cancer cells as well as the expression of miR-21, miR-29a, and miR-200a. The most pronounced cytotoxic effect has been recorded with oxaliplatin and irinotecan (IC50 = 48.23 resp. 0.11 μg/ml), especially in cells originating from lymph node metastases. In total, comparison of isolated cell lines and immortalized cell lines has shown many similarities, as well as several differences. Adhesion/invasion molecules and several miRNAs, which play an important role in tumor development and the invasive and migratory behavior, could be a useful therapeutic target in malignant colorectal cancer.
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Affiliation(s)
- Lukáš Krbal
- The Fingerland Department of Pathology, Faculty of Medicine and Faculty Hospital in Hradec Králové, Charles University in Prague, Sokolská 581, Hradec Kralove, CZ-500 05, Czech Republic
| | - Veronika Hanušová
- Department of Medical Biology and Genetics, Faculty of Medicine in Hradec Králové, Charles University in Prague, Šimkova 870, Hradec Králové, CZ-500 38, Czech Republic.
| | - Jiří Soukup
- The Fingerland Department of Pathology, Faculty of Medicine and Faculty Hospital in Hradec Králové, Charles University in Prague, Sokolská 581, Hradec Kralove, CZ-500 05, Czech Republic
| | - Stanislav John
- Department of Medical Biology and Genetics, Faculty of Medicine in Hradec Králové, Charles University in Prague, Šimkova 870, Hradec Králové, CZ-500 38, Czech Republic.,Department of Oncology and Radiotherapy, Faculty of Medicine and Faculty Hospital in Hradec Králové, Charles University in Prague, Sokolská 581, Hradec Kralove, CZ-500 05, Czech Republic
| | - Petra Matoušková
- Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Heyrovského 1203, Hradec Králové, CZ-500 05, Czech Republic
| | - Aleš Ryška
- The Fingerland Department of Pathology, Faculty of Medicine and Faculty Hospital in Hradec Králové, Charles University in Prague, Sokolská 581, Hradec Kralove, CZ-500 05, Czech Republic
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12
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Kinoshita O, Kishimoto M, Murayama Y, Kuriu Y, Nakanishi M, Sakakura C, Otsuji E, Yanagisawa A. The number of metastatic lymph nodes exhibiting poorly differentiated clusters predicts survival in patients with pStage III colorectal cancer. Int J Colorectal Dis 2016; 31:283-90. [PMID: 26412250 PMCID: PMC4744259 DOI: 10.1007/s00384-015-2393-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/17/2015] [Indexed: 02/04/2023]
Abstract
PURPOSE Many studies have proposed alternative designations for lymph node (LN) status in colorectal cancer (CRC); however, knowledge of histopathological features in metastatic lymph nodes (MLNs) is limited. This study investigated the clinicopathological significance of poorly differentiated clusters (PDCs) in MLNs. METHODS Slides from 159 patients with pathological Stage III CRC were reviewed. Those with <12 dissected LNs (DLNs) were ineligible. PDCs composed of ≥5 cancer cells lacking full glandular formation and ≥10 PDCs under ×20 objective lens were defined as positive, and the number of MLNs with positive PDCs (MLNs-PDCs) was counted. Results were correlated with patient survival and comparisons made with other indications of LN status. RESULTS The mean numbers of MLNs and MLNs-PDCs were 2.8 and 1.0, respectively, and were moderately and positively correlated with each other. Univariate analysis identified cutoffs of ≥5 MLNs (86 vs. 55%, p = 0.024), ≥2 MLNs-PDCs (85 vs. 63%, p = 0.008), and ≥30% LN ratio (85 vs. 44%, p = 0.036) to indicate a positive LN status. However, no cutoff for DLNs was obtained. MLNs-PDCs (≥2) were associated with pT4 tumor (p = 0.0035), open surgery (p = 0.016), greater number of MLNs (p < 0.0001), and positive-PDC primary tumor (p < 0.0001). In multivariate analysis, a prognostic model incorporating ≥2 MLNs-PDCs provided the lowest Akaike information criterion value; consequently, both pT4 tumors (p < 0.001) and ≥2 MLNs-PDCs (p = 0.038) were revealed to be significant prognosticators. CONCLUSION Results showed that applying the number of MLNs-PDCs could improve stratification in pStage III CRC and may be a valuable candidate for LN status.
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Affiliation(s)
- Osamu Kinoshita
- Department of Surgical Pathology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan
- Department of Surgery, Division of Digestive Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Mitsuo Kishimoto
- Department of Surgical Pathology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan.
| | - Yasutoshi Murayama
- Department of Surgery, Division of Digestive Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Yoshiaki Kuriu
- Department of Surgery, Division of Digestive Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Masayoshi Nakanishi
- Department of Surgery, Division of Digestive Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Chohei Sakakura
- Department of Surgery, Division of Digestive Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Eigo Otsuji
- Department of Surgery, Division of Digestive Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Akio Yanagisawa
- Department of Surgical Pathology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan
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Abstract
The purpose of this study was to evaluate the presence of extracapsular invasion (ECI) in positive sentinel lymph nodes (SLNs) as a predictor of disease recurrence in breast cancer. SLN biopsy was performed on 318 breasts of 316 breast cancer patients, of which 50 (15.7%) had positive SLNs. Six (12.0%) of these 50 cases had disease recurrence. The clinicopathologic features of these cases were reviewed. The ECI at SLNs was not significantly associated with disease recurrence. The recurrence-free interval by Kaplan-Meier curves did not differ significantly among patients with and without ECI at SLNs. On the other hand, metastasis at non-SLNs was observed in 12 cases (24.0%) among the 50 cases with positive SLNs, and in the non-SLN metastasis group there were 7 patients with ECI at non-SLNs. Three of 7 cases with ECI at non-SLNs had disease recurrence and none of those 5 without ECI at non-SLNs had disease recurrence. Our current study suggests that the presence of ECI at metastatic SLNs is not associated with recurrent disease in breast cancer. Our results also imply that patients with ECI at positive non-SLNs have a high risk of disease recurrence.
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14
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Fujii T, Yajima R, Morita H, Hirakata T, Miyamoto T, Fujisawa T, Tsutsumi S, Ynagita Y, Iijima M, Kuwano H. Impact of Vascular Invasion of a Primary Tumor as a Strong Risk Factor for Disease Recurrence in Patients with Node-Positive Breast Cancer. Am Surg 2015. [DOI: 10.1177/000313481508100537] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
The presence of lymph node metastasis is considered to be the most significant indicator of prognosis. However, in some cases with node-positive breast cancer, cancer cell dissemination is localized to the lymphatic systems. It is, therefore, important to develop selection criteria for strong adjuvant therapy in patients with node-positive breast cancer. This study was undertaken to evaluate the presence of vascular invasion that may reflect systemic disease as a predictor of disease recurrence in node-positive breast cancer. We retrospectively evaluated the cases of 134 consecutive female patients with breast cancer with lymph node metastasis who underwent radical breast operations. We examined the relationship between recurrence and clinicopathological factors, particularly vascular invasion. The presence of vascular invasion was found to be significant in a univariate analysis. The presence of vascular invasion was the independent risk factor in a multivariate analysis. Among the 66 patients without vascular invasion, four (6.1%) had disease recurrence. On the other hand, among the 68 patients with vascular invasion, 15 (22.1%) had a recurrence. It is interesting to note that despite the presence of lymph node metastasis, the group without vascular invasion had few patients with distant metastases. Our results suggest that the presence of vascular invasion could be an indicator of high biological aggressiveness and may be a strong prognostic factor for node-positive breast cancer.
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Affiliation(s)
- Takaaki Fujii
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan and the Departments of
| | - Reina Yajima
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan and the Departments of
| | - Hiroki Morita
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan and the Departments of
| | | | | | | | - Soichi Tsutsumi
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan and the Departments of
| | - Yasuhiro Ynagita
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan and the Departments of
| | - Misa Iijima
- Pathology, Gunma Prefectural Cancer Center, Ota, Gunma, Japan
| | - Hiroyuki Kuwano
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan and the Departments of
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Yajima R, Fujii T, Yanagita Y, Fujisawa T, Miyamoto T, Hirakata T, Tsutsumi S, Iijima M, Kuwano H. Prognostic Value of Extracapsular Invasion of Axillary Lymph Nodes Combined with Peritumoral Vascular Invasion in Patients with Breast Cancer. Ann Surg Oncol 2014; 22:52-8. [DOI: 10.1245/s10434-014-3941-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2014] [Indexed: 12/30/2022]
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16
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Suzuki H, Fujii T, Asao T, Tsutsumi S, Wada S, Araki K, Kubo N, Watanabe A, Tsukagoshi M, Kuwano H. Extracapsular Lymph Node Involvement is Associated With Colorectal Liver Metastases and Impact Outcome After Hepatectomy for Colorectal Metastases. World J Surg 2014; 38:2079-88. [DOI: 10.1007/s00268-014-2488-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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17
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Devesa H, Pereira L, Gonçalves Á, Brito T, Almeida T, Torres R, Midões A. Axillary Lymph Node Metastasis of Colon Cancer—Case Report and Literature Review. ACTA ACUST UNITED AC 2014. [DOI: 10.4236/crcm.2014.312141] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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18
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Resch A, Langner C. Lymph node staging in colorectal cancer: Old controversies and recent advances. World J Gastroenterol 2013; 19:8515-8526. [PMID: 24379568 PMCID: PMC3870496 DOI: 10.3748/wjg.v19.i46.8515] [Citation(s) in RCA: 80] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2013] [Revised: 10/21/2013] [Accepted: 11/05/2013] [Indexed: 02/06/2023] Open
Abstract
Outcome prediction based on tumor stage reflected by the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) tumor node metastasis (TNM) system is currently regarded as the strongest prognostic parameter for patients with colorectal cancer. For affected patients, the indication for adjuvant therapy is mainly guided by the presence of regional lymph node metastasis. In addition to the extent of surgical lymph node removal and the thoroughness of the pathologist in dissecting the resection specimen, several parameters that are related to the pathological work-up of the dissected nodes may affect the clinical significance of lymph node staging. These include changing definitions of lymph nodes, involved lymph nodes, and tumor deposits in different editions of the AJCC/UICC TNM system as well as the minimum number of nodes to be dissected. Methods to increase the lymph node yield in the fatty tissue include methylene blue injection and acetone compression. Outcome prediction based on the lymph node ratio, defined as the number of positive lymph nodes divided by the total number of retrieved nodes, may be superior to the absolute numbers of involved nodes. Extracapsular invasion has been identified as additional prognostic factor. Adding step sectioning and immunohistochemistry to the pathological work-up may result in higher accuracy of histological diagnosis. The clinical value of more recent technical advances, such as sentinel lymph node biopsy and molecular analysis of lymph nodes tissue still remains to be defined.
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19
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Detailed stratification of TNM stage III rectal cancer based on the presence/absence of extracapsular invasion of the metastatic lymph nodes. Dis Colon Rectum 2013; 56:726-32. [PMID: 23652746 DOI: 10.1097/dcr.0b013e318286c518] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND The presence/absence of extracapsular invasion in metastatic lymph nodes has been reported as being significantly correlated with the prognosis in a wide variety of cancers. However, the influence of extracapsular invasion in the metastatic lymph nodes on the prognosis in patients with stage III rectal cancer has not yet been investigated. OBJECTIVE We investigated the presence/absence of extracapsular invasion in the metastatic nodes of the relevant main/lateral lymph node group in patients with rectal cancer to determine the usefulness of this parameter for stratifying the prognosis of patients with stage III rectal cancer. DESIGN This was a single-institution study. SETTINGS This study was conducted at a single institution. PATIENTS We enrolled 101 consecutive patients with stage III rectal cancer who had undergone curative surgery with extended lymph node dissection and investigated the presence/absence of extracapsular invasion in the regional metastatic lymph nodes to determine the usefulness of such stratification for a more precise prediction of the patient prognosis. MAIN OUTCOME MEASURES The main outcomes measured were the disease-free and overall survival rates. RESULTS Univariate analysis revealed a significantly poorer prognosis, in terms of both the disease-free survival rate (p = 0.003) and overall survival rate (p = 0.008), of the pN3-extracapsular invasion-positive cases in comparison with the pN3-extracapsular invasion-negative cases. Multivariate analysis revealed the presence/absence of extracapsular invasion in the metastatic lymph nodes as the only variable that was statistically significantly associated with the disease-free survival rate (p = 0.011). LIMITATIONS This was a retrospective study in a small number of patients from a single institution. There were no comparator groups. CONCLUSIONS Detailed stratification of pN3 cases based on the presence/absence of extracapsular invasion in metastatic lymph nodes has the potential to contribute significantly to more available prediction of the prognosis of patients with stage III colorectal cancer.
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