Clinical value of extended biologic staging by bone marrow micrometastases and tumor-associated proteases in gastric cancer
To investigate whether extended staging, including biologic grading and aspects of an early systemic disease component, would give additional prognostic information on patients with curatively resected gastric cancer. Tumor-associated proteolytic mechanisms have been shown to be essential for invasi...
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Published in | Annals of surgery Vol. 226; no. 6; pp. 736 - 745 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
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United States
01.12.1997
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Abstract | To investigate whether extended staging, including biologic grading and aspects of an early systemic disease component, would give additional prognostic information on patients with curatively resected gastric cancer.
Tumor-associated proteolytic mechanisms have been shown to be essential for invasion and metastasis. The urokinase-type plasminogen activator (uPA) system is of major biologic impact, but different interactive proteases and inhibitors with modulating effects also must be considered. The detection of early tumor cell dissemination indicates the systemic character of a primarily local gastric cancer. The confrontation of the organism with these cells determines the often unpredictable course of an individual tumor after presumed curative primary treatment.
In a prospective study of 247 consecutive patients with gastric cancer, detection of disseminated tumor cells in bone marrow aspirates was immunocytochemically performed in 180 patients. The expression of uPA, activators of uPA (cathepsin D, antithrombin III), uPA substrates (plasminogen, matrix-metalloproteinase 2 [collagenase IV, 72 kD; MMP-2]), uPA/plasmin inhibitors (plasminogen activator inhibitor type 1 and 2 [PAI-1, PAI-2], alpha1-antitrypsin, alpha2-antiplasmin), uPA receptor (uPA-R), and parameters of the uPA-R cycle (alpha2-macroglobulin, alpha1-antichymotrypsin) could be determined immunohistochemically and were scored semiquantitatively in 203 patients. Kaplan-Meier statistical techniques and multivariate Cox regression models were used for prognostic analyses.
In multivariate analysis considering all the established risk factors, disease-free survival was independently predicted by PAI-1 (relative risk 2.21, 1.32-3.73) and cathepsin D (relative risk 2.98, 1.28-6.91) besides pT, pN, and extended resection. Tumor cell dissemination was found to be an additional prognostic factor in early tumor stages (pT1, T2) and lymphnode-negative patients. Stepwise regression analysis revealed an extended staging system with new risk groups. Node-positive, curatively resected pT1/2 patients with low expression of PAI-1 had a favorable prognosis (mean recurrence-free survival [MRT] 54.84 months), similar to that of node-negative patients (MRT 54.76 months). In node-negative, curatively resected pT1/2 patients, detection of bone marrow tumor cells and high expression of PAI-1 defined a subgroup with a steep decrease of prognosis (MRT 36.60 months), which was worse than that of node-positive patients (MRT 45.81).
This new staging model gives better prognostic differentiation of subgroups, which should be considered in future adjuvant therapy protocols. In addition, it indicates that the uPA system might be a future therapeutic target. |
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AbstractList | OBJECTIVETo investigate whether extended staging, including biologic grading and aspects of an early systemic disease component, would give additional prognostic information on patients with curatively resected gastric cancer.BACKGROUNDTumor-associated proteolytic mechanisms have been shown to be essential for invasion and metastasis. The urokinase-type plasminogen activator (uPA) system is of major biologic impact, but different interactive proteases and inhibitors with modulating effects also must be considered. The detection of early tumor cell dissemination indicates the systemic character of a primarily local gastric cancer. The confrontation of the organism with these cells determines the often unpredictable course of an individual tumor after presumed curative primary treatment.METHODSIn a prospective study of 247 consecutive patients with gastric cancer, detection of disseminated tumor cells in bone marrow aspirates was immunocytochemically performed in 180 patients. The expression of uPA, activators of uPA (cathepsin D, antithrombin III), uPA substrates (plasminogen, matrix-metalloproteinase 2 [collagenase IV, 72 kD; MMP-2]), uPA/plasmin inhibitors (plasminogen activator inhibitor type 1 and 2 [PAI-1, PAI-2], alpha1-antitrypsin, alpha2-antiplasmin), uPA receptor (uPA-R), and parameters of the uPA-R cycle (alpha2-macroglobulin, alpha1-antichymotrypsin) could be determined immunohistochemically and were scored semiquantitatively in 203 patients. Kaplan-Meier statistical techniques and multivariate Cox regression models were used for prognostic analyses.RESULTSIn multivariate analysis considering all the established risk factors, disease-free survival was independently predicted by PAI-1 (relative risk 2.21, 1.32-3.73) and cathepsin D (relative risk 2.98, 1.28-6.91) besides pT, pN, and extended resection. Tumor cell dissemination was found to be an additional prognostic factor in early tumor stages (pT1, T2) and lymphnode-negative patients. Stepwise regression analysis revealed an extended staging system with new risk groups. Node-positive, curatively resected pT1/2 patients with low expression of PAI-1 had a favorable prognosis (mean recurrence-free survival [MRT] 54.84 months), similar to that of node-negative patients (MRT 54.76 months). In node-negative, curatively resected pT1/2 patients, detection of bone marrow tumor cells and high expression of PAI-1 defined a subgroup with a steep decrease of prognosis (MRT 36.60 months), which was worse than that of node-positive patients (MRT 45.81).CONCLUSIONThis new staging model gives better prognostic differentiation of subgroups, which should be considered in future adjuvant therapy protocols. In addition, it indicates that the uPA system might be a future therapeutic target. OBJECTIVE: To investigate whether extended staging, including biologic grading and aspects of an early systemic disease component, would give additional prognostic information on patients with curatively resected gastric cancer. BACKGROUND: Tumor-associated proteolytic mechanisms have been shown to be essential for invasion and metastasis. The urokinase-type plasminogen activator (uPA) system is of major biologic impact, but different interactive proteases and inhibitors with modulating effects also must be considered. The detection of early tumor cell dissemination indicates the systemic character of a primarily local gastric cancer. The confrontation of the organism with these cells determines the often unpredictable course of an individual tumor after presumed curative primary treatment. METHODS: In a prospective study of 247 consecutive patients with gastric cancer, detection of disseminated tumor cells in bone marrow aspirates was immunocytochemically performed in 180 patients. The expression of uPA, activators of uPA (cathepsin D, antithrombin III), uPA substrates (plasminogen, matrix-metalloproteinase 2 [collagenase IV, 72 kD; MMP-2]), uPA/plasmin inhibitors (plasminogen activator inhibitor type 1 and 2 [PAI-1, PAI-2], alpha1-antitrypsin, alpha2-antiplasmin), uPA receptor (uPA-R), and parameters of the uPA-R cycle (alpha2-macroglobulin, alpha1-antichymotrypsin) could be determined immunohistochemically and were scored semiquantitatively in 203 patients. Kaplan-Meier statistical techniques and multivariate Cox regression models were used for prognostic analyses. RESULTS: In multivariate analysis considering all the established risk factors, disease-free survival was independently predicted by PAI-1 (relative risk 2.21, 1.32-3.73) and cathepsin D (relative risk 2.98, 1.28-6.91) besides pT, pN, and extended resection. Tumor cell dissemination was found to be an additional prognostic factor in early tumor stages (pT1, T2) and lymphnode-negative patients. Stepwise regression analysis revealed an extended staging system with new risk groups. Node-positive, curatively resected pT1/2 patients with low expression of PAI-1 had a favorable prognosis (mean recurrence-free survival [MRT] 54.84 months), similar to that of node-negative patients (MRT 54.76 months). In node-negative, curatively resected pT1/2 patients, detection of bone marrow tumor cells and high expression of PAI-1 defined a subgroup with a steep decrease of prognosis (MRT 36.60 months), which was worse than that of node-positive patients (MRT 45.81). CONCLUSION: This new staging model gives better prognostic differentiation of subgroups, which should be considered in future adjuvant therapy protocols. In addition, it indicates that the uPA system might be a future therapeutic target. To investigate whether extended staging, including biologic grading and aspects of an early systemic disease component, would give additional prognostic information on patients with curatively resected gastric cancer. Tumor-associated proteolytic mechanisms have been shown to be essential for invasion and metastasis. The urokinase-type plasminogen activator (uPA) system is of major biologic impact, but different interactive proteases and inhibitors with modulating effects also must be considered. The detection of early tumor cell dissemination indicates the systemic character of a primarily local gastric cancer. The confrontation of the organism with these cells determines the often unpredictable course of an individual tumor after presumed curative primary treatment. In a prospective study of 247 consecutive patients with gastric cancer, detection of disseminated tumor cells in bone marrow aspirates was immunocytochemically performed in 180 patients. The expression of uPA, activators of uPA (cathepsin D, antithrombin III), uPA substrates (plasminogen, matrix-metalloproteinase 2 [collagenase IV, 72 kD; MMP-2]), uPA/plasmin inhibitors (plasminogen activator inhibitor type 1 and 2 [PAI-1, PAI-2], alpha1-antitrypsin, alpha2-antiplasmin), uPA receptor (uPA-R), and parameters of the uPA-R cycle (alpha2-macroglobulin, alpha1-antichymotrypsin) could be determined immunohistochemically and were scored semiquantitatively in 203 patients. Kaplan-Meier statistical techniques and multivariate Cox regression models were used for prognostic analyses. In multivariate analysis considering all the established risk factors, disease-free survival was independently predicted by PAI-1 (relative risk 2.21, 1.32-3.73) and cathepsin D (relative risk 2.98, 1.28-6.91) besides pT, pN, and extended resection. Tumor cell dissemination was found to be an additional prognostic factor in early tumor stages (pT1, T2) and lymphnode-negative patients. Stepwise regression analysis revealed an extended staging system with new risk groups. Node-positive, curatively resected pT1/2 patients with low expression of PAI-1 had a favorable prognosis (mean recurrence-free survival [MRT] 54.84 months), similar to that of node-negative patients (MRT 54.76 months). In node-negative, curatively resected pT1/2 patients, detection of bone marrow tumor cells and high expression of PAI-1 defined a subgroup with a steep decrease of prognosis (MRT 36.60 months), which was worse than that of node-positive patients (MRT 45.81). This new staging model gives better prognostic differentiation of subgroups, which should be considered in future adjuvant therapy protocols. In addition, it indicates that the uPA system might be a future therapeutic target. |
Author | Schildberg, F W Heiss, M M Babic, R Jauch, K W Allgayer, H Gruetzner, K U |
AuthorAffiliation | Department of Surgery, Klinikum Grosshadern, Ludwig Maximillians University of Munich, Germany |
AuthorAffiliation_xml | – name: Department of Surgery, Klinikum Grosshadern, Ludwig Maximillians University of Munich, Germany |
Author_xml | – sequence: 1 givenname: M M surname: Heiss fullname: Heiss, M M organization: Department of Surgery, Klinikum Grosshadern, Ludwig Maximillians University of Munich, Germany – sequence: 2 givenname: H surname: Allgayer fullname: Allgayer, H – sequence: 3 givenname: K U surname: Gruetzner fullname: Gruetzner, K U – sequence: 4 givenname: R surname: Babic fullname: Babic, R – sequence: 5 givenname: K W surname: Jauch fullname: Jauch, K W – sequence: 6 givenname: F W surname: Schildberg fullname: Schildberg, F W |
BackLink | https://www.ncbi.nlm.nih.gov/pubmed/9409572$$D View this record in MEDLINE/PubMed |
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– volume: 39 start-page: 2475 year: 1977 ident: R30-10-20110409 publication-title: Cancer doi: 10.1002/1097-0142(197706)39:6<2475::AID-CNCR2820390626>3.0.CO;2-L contributor: fullname: Ming |
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Snippet | To investigate whether extended staging, including biologic grading and aspects of an early systemic disease component, would give additional prognostic... OBJECTIVETo investigate whether extended staging, including biologic grading and aspects of an early systemic disease component, would give additional... OBJECTIVE: To investigate whether extended staging, including biologic grading and aspects of an early systemic disease component, would give additional... |
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SubjectTerms | Aged Alkaline Phosphatase - metabolism Biomarkers, Tumor - metabolism Bone Marrow Examination Bone Marrow Neoplasms - metabolism Bone Marrow Neoplasms - secondary Female Gastrectomy Humans Immunohistochemistry Male Middle Aged Multivariate Analysis Neoplasm Proteins - metabolism Neoplasm Staging - methods Plasminogen Activator Inhibitor 1 - metabolism Prognosis Prospective Studies Regression Analysis Stomach Neoplasms - metabolism Stomach Neoplasms - mortality Stomach Neoplasms - pathology Stomach Neoplasms - surgery Survival Analysis Urokinase-Type Plasminogen Activator - metabolism |
Title | Clinical value of extended biologic staging by bone marrow micrometastases and tumor-associated proteases in gastric cancer |
URI | https://www.ncbi.nlm.nih.gov/pubmed/9409572 https://search.proquest.com/docview/79478702 https://pubmed.ncbi.nlm.nih.gov/PMC1191148 |
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