Prognostic Significance of Bcl-2, Tumor-Associated Macrophages, and Total Neoplastic and Inflammatory Lymph Node Involvement in Advanced Stage Classical Hodgkin’s Lymphoma

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Abstract

Background: Although Hodgkin’s lymphoma (HL) is a curable cancer, current treatment strategies based on risk stratification and response modulation are not precise enough. The predictive power of biological and morphological parameters is controversial, with prognostic models not reaching wide acceptance. Patients and Methods: We analyzed the prognostic relevance of 8 parameters in 85 advancedstage classical HL patients, in order to determine whether tissue-based variables could add prognostic value to standard clinical parameters, thus contributing to better risk stratification at presentation. Results: Univariate analysis confirmed 5 indicators of shorter overall survival (OS): Bcl-2 overexpression; increased CD68+ tumor-associated macrophages (TAM); international prognostic score (IPS) > 2; bulky disease; and total lymph node involvement (TLNI) with regard to neoplastic and inflammatory cells. Apart from TLNI, these parameters influenced lower event-free survival (EFS). Multivariate analysis identified 5 independent factors for OS: Bcl-2 overexpression; increased CD68+ TAM; TLNI; IPS > 2; and bulky disease. Increased CD68+ TAM, IPS > 2, and bulky disease affected the EFS. Utilizing the cumulative score of unfavorable prognostic factors for OS, we designed a prognostic model stratifying patients into 4 risk groups (with 0–1, 2, 3, or 4–5 factors), each with progressively reduced OS (p < 0.001). Conclusion: Our findings support the combination of tissue-based variables with clinical parameters at diagnosis, identifying patients who are at higher risk of poor outcome.

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A prognostic score for advanced Hodgkin's disease. International Prognostic Factors Project on Advanced Hodgkin's Disease.

D Hasenclever, V Diehl (1998)

Two thirds of patients with advanced Hodgkin's disease are cured with current approaches to treatment. Prediction of the outcome is important to avoid overtreating some patients and to identify others in whom standard treatment is likely to fail. Data were collected from 25 centers and study groups on a total of 5141 patients treated with combination chemotherapy for advanced Hodgkin's disease, with or without radiotherapy. The data included the outcome and 19 demographic and clinical characteristics at diagnosis. The end point was freedom from progression of disease. Complete data were available for 1618 patients; the final Cox model was fitted to these data. Data from an additional 2643 patients were used for partial validation. The prognostic score was defined as the number of adverse prognostic factors present at diagnosis. Seven factors had similar independent prognostic effects: a serum albumin level of less than 4 g per deciliter, a hemoglobin level of less than 10.5 g per deciliter, male sex, an age of 45 years or older, stage IV disease (according to the Ann Arbor classification), leukocytosis (a white-cell count of at least 15,000 per cubic millimeter), and lymphocytopenia (a lymphocyte count of less than 600 per cubic millimeter, a count that was less than 8 percent of the white-cell count, or both). The score predicted the rate of freedom from progression of disease as follows: 0, or no factors (7 percent of the patients), 84 percent; 1 (22 percent of the patients), 77 percent; 2 (29 percent of the patients), 67 percent; 3 (23 percent of the patients), 60 percent; 4 (12 percent of the patients), 51 percent; and 5 or higher (7 percent of the patients), 42 percent. The prognostic score we developed may be useful in designing clinical trials for the treatment of advanced Hodgkin's disease and in making individual therapeutic decisions, but a distinct group of patients at very high risk could not be identified on the basis of routinely documented demographic and clinical characteristics.

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Preparing the "soil": the premetastatic niche.

Rosandra Kaplan, Shahin Rafii, David Lyden (2006)

Current focus on cancer metastasis has centered on the intrinsic factors regulating the cell autonomous homing of the tumor cells to the metastatic site. Specific up-regulation of fibronectin and clustering of bone marrow-derived cellular infiltrates coexpressing matrix metalloproteinases in distant tissue sites before tumor cell arrival are proving to be indispensable for the initial stages of metastasis. These bone marrow-derived hematopoietic progenitors that express vascular endothelial growth factor receptor 1 mobilize in response to the unique array of growth factors produced by the primary tumor. Their arrival in distant sites represents early changes in the local microenvironment, termed the "premetastatic niche," which dictate the pattern of metastatic spread. Focus on the early cellular and molecular events in cancer dissemination and selectivity will likely lead to new approaches to detect and prevent metastasis at its earliest inception.

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The tumor microenvironment and its contribution to tumor evolution toward metastasis.

Girieca Lorusso, Curzio Ruegg (2008)

Cancer cells acquire cell-autonomous capacities to undergo limitless proliferation and survival through the activation of oncogenes and inactivation of tumor suppressor genes. Nevertheless, the formation of a clinically relevant tumor requires support from the surrounding normal stroma, also referred to as the tumor microenvironment. Carcinoma-associated fibroblasts, leukocytes, bone marrow-derived cells, blood and lymphatic vascular endothelial cells present within the tumor microenvironment contribute to tumor progression. Recent evidence indicates that the microenvironment provides essential cues to the maintenance of cancer stem cells/cancer initiating cells and to promote the seeding of cancer cells at metastatic sites. Furthermore, inflammatory cells and immunomodulatory mediators present in the tumor microenvironment polarize host immune response toward specific phenotypes impacting tumor progression. A growing number of studies demonstrate a positive correlation between angiogenesis, carcinoma-associated fibroblasts, and inflammatory infiltrating cells and poor outcome, thereby emphasizing the clinical relevance of the tumor microenvironment to aggressive tumor progression. Thus, the dynamic and reciprocal interactions between tumor cells and cells of the tumor microenvironment orchestrate events critical to tumor evolution toward metastasis, and many cellular and molecular elements of the microenvironment are emerging as attractive targets for therapeutic strategies.

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Author and article information

Journal

Journal ID (publisher-id): ONK

Journal ID (nlm-ta): Oncol Res Treat

Journal ID (doi): 10.1159/issn.2296-5270

Title: Oncology Research and Treatment

Publisher: S. Karger AG

ISSN (Print): 2296-5270

ISSN (Electronic): 2296-5262

Publication date Subscription-year: 2012

Publication date (Print): December 2012

Publication date (Electronic): 20 November 2012

Volume: 35

Issue: 12

Pages: 733-739

Affiliations

^aClinic for Hematology, Clinical Center of Serbia, ^bFaculty of Medicine, University of Belgrade, ^cDepartment for Histopathology, Clinical Center of Serbia, ^dInstitute of Histology and Embryology, Faculty of Medicine University of Belgrade, Belgrade, Serbia

Article

Publisher ID: 343664 Other ID: Onkologie 2012;35:733–739

DOI: 10.1159/000343664

PubMed ID: 23207618

SO-VID: a840e4e2-b9e4-4365-824d-fb460bfb20d8

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Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

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Prognostic Significance of Bcl-2, Tumor-Associated Macrophages, and Total Neoplastic and Inflammatory Lymph Node Involvement in Advanced Stage Classical Hodgkin’s Lymphoma

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Karger: Oncology

Most cited references 33

A prognostic score for advanced Hodgkin's disease. International Prognostic Factors Project on Advanced Hodgkin's Disease.

Preparing the "soil": the premetastatic niche.

The tumor microenvironment and its contribution to tumor evolution toward metastasis.

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