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By the 1940s, there was a widespread consensus that the major anatomical attributes of a tumor that determine its behavior are: size of the primary tumor (T), presence and extent of regional lymph node involvement (N), and presence of distant metastases (M). Starting in 1942, Pierre Denoix began the development of a cancer-staging system based on these attributes (1). Clinical stage classifications for cancers of the breast and larynx were first presented in 1958 (2). Recommendations for 23 other body sites were published in brochures by the International Union against Cancer (UICC), and consolidated into the ‘‘TNM Classification of Malignant Tumors’’ published by 11 12 Singletary evidence that is gathered before initial treatment of the primary tumor, and is used to make treatment recommendations.

39. Veenendall LM, Jin H, Ran S, Cheung L, Navone N, Marks JW, Waltenberger J, Thorpe P, Rosenblum MG. In vitro and in vivo studies of a VEGF121=r Gelonin chimeric fusion toxin targeting the neovasculature of solid tumors. Proc Natl Acad Sci USA 2002; 99: 7866–7871. 40. Suhardja A, Hoffman H. Role of growth factors and their receptors in proliferation of microvascular endothelial cells. Microsc Res Tech 2003; 60:70–75. 41. Wang JH, Wu QD, Bouchier-Hayes D, Redmond HP. Hypoxia upregulates Bcl-2 expression and suppresses interferon-gamma induced antiangiogenic activity in human tumor derived endothelial cells.

Cell 1991; 64:327–336. 21. Auerbach W, Auerbach R. Angiogenesis inhibition: a review. Pharmacol Ther 1994; 63:265–311. 22. Folkman J, Klagsbrun M. Angiogenic factors. Science 1987; 235:444–447. 23. Bouck N, Stellmach V, Hsu SC. How tumors become angiogenic. Adv Cancer Res 1996; 69:135–174. 24. Folkman J. Seminars in medicine of the Beth Israel Hospital, Boston, MA. Clinical applications of research on angiogenesis. N Engl J Med 1995; 333:1757–1763. 25. Cockerill GW, Gamble JR, Vadas MA. Angiogenesis: models and modulators.

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