Recent advances in the detection of bone marrow micrometastases: A promising area for research or just another false hope? A review of the literature

Chambers, A. F. (2004). Biology of the metastatic process. In American Society of Clinical Oncology (ASCO) (Ed.), ASCO 2004 educational book (pp. 696–700). USA: Lisa Graves Publisher. Pantel, K., & Woelfle, U. (2004). Cancer micrometastasis: Detection, clinical relevance, and molecular description. In American Society of Clinical Oncology (ASCO) (Ed.), ASCO 2004 educational book (pp. 701–708). USA: Lisa Graves Publisher. Pantel, K., Cote, R. J., & Fodstad, O. (1991). Detection and clinical importance of micrometastatic disease. Journal of the National Cancer Institute, 91, 1113–1124. Choesmel, V., Pierga, J.-Y., Nos, C., Vincent-Salomon, A., Sigal-Zafrani, B., Thiery, J.-P., et al. (2004). Enrichment methods to detect bone marrow micrometastases in breast carcinoma patients: Clinical relevance. Breast Cancer Research, 6, R556–R570. Carter, C. L., Allen, C., & Henson, D. E. (1989). Relation of tumor size, lymph node status, and survival in 24,740 breast cancer cases. Cancer, 63, 181–187. Rosner, D., & Lane, W. W. (1993). Predicting recurrence in axillary-node negative breast cancer patients. Breast Cancer Research and Treatment, 25, 127–139. Feezor, R. J., Copeland, E. M., 3rd, & Hochwald, S. N. (2002). Significance of micrometastases in colorectal cancer. Annals of Surgical Oncology, 9, 944–953. Pantel, K., & Braun, S. (2001). Molecular determinants of occult metastatic tumor cells in bone marrow. Clinical Breast Cancer, 2, 222–228. Seeliger, H., Spatz, H., & Jauch, K. W. (2003). Minimal residual disease in gastric cancer. Recent Results in Cancer Research, 162, 79–87. Zehentner, B. K. (2002). Detection of disseminated tumor cells: Strategies and diagnostic implications. Expert Review of Molecular Diagnostics, 2, 41–48. Zhu, L., Lam, C. K., & Chow, L. W. C. (2004). Sentinel lymph node biopsy or detection of micrometastasis in bone marrow: Which might be an alternative to axillary lymph node dissection in breast cancer patients? Asian Journal of Surgery, 27, 279–283. Dearnaley, D. P., Sloane, J. P., Ormerod, M. G., Steele, K., Coombes, R. C., Clink, H. M., et al. (1981). Increased detection of mammary carcinoma cells in marrow smears using antisera to epithelial membrane antigen. British Journal of Cancer, 44, 85–90. Timar, J., Csuka, O., Orosz, Z., Jeney, A., & Kopper, L. (2002). Molecular pathology of tumor metastasis: II. Molecular staging and differential diagnosis. Pathology Oncology Research, 8, 204–219. Guinebretiere, J. M., & Contesso, G. (2001). “Micrometastases”: The pathologist’s point of view. Bulletin du Cancer, 88, 549–550, 555–560. MacDonald, I. C., Groom, A. C., & Chambers, A. F. (2002). Cancer spread and micometastasis development: Quantitative approaches for in vivo models. Bioessays, 24, 885–893. Chambers, A. F., Naumov, G. N., Varghese, H. J., Nadkarni, K. V., MacDonald, I. C., & Groom, A. C. (2001). Critical steps in hematogenous metastasis: An overview. Surgical Oncology Clinics of North America, 10, 243–255. Chambers, A., F, MacDonald, I. C., Schmidt, E. E., Morris, V. L., & Groom, A. C. (1999). Pre-clinical assessment of anti-cancer therapeutic strategies using in vivo videomicroscopy. Cancer Metastasis Reviews, 17, 263–269. Fidler, I. J. (1975). Biological behavior of malignant melanoma cells correlated to their survival in vivo. Cancer Research, 35, 218–224. Cameron, M. D., Schmidt, E. E., Kerkvliet, N., Nadkarni, K. V., Morris, V. L., Groom, A. C., et al. (2000). Temporal progression of metastasis in lung: Cell survival, dormancy and location dependence of metastatic inefficiency. Cancer Research, 60, 2541–2546. Murphy, B. O., Joshi, S., Kessinger, A., Reed, E., & Sharp, J. G. (2002). A murine model of bone marrow micrometastasis in breast cancer. Clinical & Experimental Metastasis, 19, 561–569. Tarin, D., Price, J. E., Kettlewell, M. G., Souter, R. G., Vass, A. C., & Crossley, B. (1984). Mechanisms of human tumor metastasis studies in patients with peritoneovenous shunts. Cancer Research, 44, 3584–3592. Gangnus, R., Langer, S., Breit, E., Pantel, K., & Spercher, M. R. (2004). Genomic profiling of viable and proliferative micrometastatic cells from early-stage breast cancer patients. Clinical Cancer Research, 10, 3457–3464. Naumov, G. N., MacDonald, I. C., Weinmeister, P. M., Kerkvliet, N., Nadkarni, K. V., Wilson, S. M., et al. (2002). Persistence of solitary mammary carcinoma cells in a secondary site: A possible contributor to dormancy. Cancer Research, 62, 2162–2168. Demicheli, R., Abbattista, A., Miceli, R., Valagussa, P., & Bonnadonna, G. (1996). Time distribution of the recurrence risk for breast cancer patients undergoing mastectomy: Further support about the concept of tumor dormancy. Breast Cancer Research and Treatment, 41, 177–185. Gimbrone, M. A., Jr., Leapman, S. B., Cotran, R. S., & Folkman, J. (1972). Tumor dormancy in vivo by prevention of neovascularization. Journal of Experimental Medicine, 136, 261–276. Michelson, S., & Leith, J. T. (1994). Dormancy, regression and recurrence: Towards a unifying theory of growth control. Journal of Theoretical Biology, 169, 327–338. Stewart, T. H. (1996). Immune mechanisms and tumor dormancy. Medicina (Buenos Aires), 56, 74–82. Yu, W., Kim, J., & Ossowski, L. (1997). Reduction in surface urokinase receptor forces malignant cells in a protracted state of dormancy. Journal of Cell Biology, 137, 767–777. Solakoglu, O., Maierhofer, C., Lahr, G., Breit, E., Scheunemann, P., Heumos, I., et al. (2002). Heterogeneous proliferative potential of occult metastatic cells in bone marrow of patients with solid epithelial tumors. Proceedings of the National Academy of Sciences of the United States of America, 99, 2246–2251. Guba, M., Cernaianu, G., Koehl, G., Geissler, E. K., Jauch, K.-W., Anthuber, W. F., et al. (2001). A primary tumor promotes dormancy of solitary tumor cells before inhibiting angiogenesis. Cancer Research, 61, 5575–5579. Holmgren, L., O’Reilly, M. S., & Folkman, J. (1995). Dormancy of micrometastases: Balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nature Medicine, 1, 149–153. O’Reilly, M. S., Holmgren, L., Shing, Y., Chen, C., Rosenthal, R. A., Moses, M., et al. (1994). Angiostatin: A novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell, 79, 315–328. Luzzi, K. J., MacDonald, I. C., Schmidt, E. E., Kerkvliet, N., Morris, V. L., Chambers, A. F., et al. (1998). Multistep nature of metastatic inefficiency: Dormancy of solitary cells after successful extravasation and limited survival of early micrometastases. American Journal of Pathology, 153, 865–873. Murray, C. (1995). Tumor dormancy: Not so sleepy after all. Nature Medicine, 1, 117–118. O’Reilly, M. S., Boehm, T., Shing, Y., Fukai, N., Vasios, G., Lane, W. S., et al. (1997). Endostatin: An endogenous inhibitor of angiogenesis and tumor growth. Cell, 88, 277–285. O’Reilly, M. S., Pirie-Shepherd, S., Lane, W. S., & Folkman, J. (1999). Antiangiogenic activity of the cleaved conformation of the serpin antithrombin. Science, 285, 1926–1928. Farrar, J. D., Katz, K. H., Windsor, J., Thrush, G., Scheuermann, R. H., Uhr, J. W., et al. (1999). Cancer dormancy VII. A regulatory role for CD8+ T cells and IFN-γ in establishing and maintaining the tumor dormant state. Journal of Immunology, 162, 2842–2849. Stevenson, F. K., George, A. J., & Glennie, M. J. (1990). Anti-idiotypic therapy of leukemias and lymphomas. Chemical Immunology, 48, 126–166. Schirrmacher, V. (2001). T-cell immunity in the induction and maintenance of a tumor dormant state. Seminars in Cancer Biology, 11, 285–295. Dyke, R. J., McBride, H., George, A. J., Hamblin, T. J, & Stevenson, F. K. (1991). Idiotypic vaccination against B-cell lymphoma leads to dormant tumor. Cellular Immunology, 132, 70–83. Uhr, J. W., Tucker, T., May, R. D., Siu, H., & Vitetta, E. S. (1991). Cancer dormancy: Studies of the murine BCL1 lymphoma. Cancer Research, 51, 50455–50535. Meng, S., Tripathy, D., Frenkel, E. P., Shete, S., Naftalis, E. Z., Huth, J. F., et al. (2004). Circulating tumor cells in patients with breast cancer dormancy. Clinical Cancer Research, 10, 8152–8162. Andratschke, M., Pauli, C., Stein, M., Chaubal, S., & Wollenberg, B. (2003). MHC-class I antigen expression on micrometastases in bone marrow of patients with head and neck squamous cell cancer. Anticancer Research, 23, 1467–1471. Schlimok, G., Kutter, D., Schaller, G., Geuz, T., Wiebecke, B., Backmann, R., et al. (1991). Frequent down-regulation of major histocompatibility class I antigen expression on individual micrometastatic carcinoma cells. Cancer Research, 51, 4712–4715. Schlimok, G., Funke, I., Bock, B., Schweiberer, B., Witte, J., & Riethmuller, G. (1990). Epithelial tumor cells in bone marrow of patients with colorectal cancer: Immunocytochemical detection, phenotypic characterization and prognostic significance. Journal of Clinical Oncology, 8, 831–837. Reynolds, T. (1998). Researchers slowly unveil where cancer cells hide. Journal of the National Cancer Institute, 90, 1690–1691. Korah, R., Boots, M., & Wieder, R. (2004). Integrin α5β1 promotes survival of growth-arrested breast cancer cells: An in vivo paradigm for breast cancer dormancy in bone marrow. Cancer Research, 64, 4514–4522. Ree, A. H., Tvermyr, M., Engebraaten, O., Rooman, M., Rosok, O., Hovig, E., et al. (1999). Expression of a novel factor in human breast cancer cells with metastatic potential. Cancer Research, 59, 4675–4680. Mansi, J. L., Berger, U., McDonnell, T., Pople, A., Rayter, Z., Gazet, J. C., et al. (1989). The fate of bone marrow micrometastases in patients with primary breast cancer. Journal of Clinical Oncology, 7, 445–449. Pantel, K. (2005). Symposium 34-2. Bone marrow: Homing organ for dormant micrometastatic cancer cells. Proceedings of the American Association for Cancer Research, 46, 1477–1478. Putz, E., Witter, K., Offner, S., Stosiek, P., Zippelius, A., Johnson, J., et al. (1999). Phenotypic characteristics of cell lines derived from disseminated cancer cells in bone marrow of patients with solid epithelial tumors: Establishment of working models for human micrometastases. Cancer Research, 59, 241–248. Willipinski-Stapelfeldt, B., Riethdorf, S., Assmann, V., Woelfle, U., Rau, T., Sauter, G., et al. (2005). Changes in cytoskeletal proteins composition indicative of an epithelial–mesenchymal transition in human micrometastatic and primary breast carcinoma cells. Clinical Cancer Research, 11, 8006–8014. Fodstad, O., & Kjonniksen, I. (1994). Microenvironment revisited: Time for reappraisal of some prevailing concepts of cancer metastasis. Journal of Cellular Biochemistry, 56, 23–28. Fidler, I. J. (1995). Modulation of the organ microenvironment for treatment of cancer metastasis. Journal of the National Cancer Institute, 87, 1588–1592. Uhr, J. W., Scheuermann, R. H., Street, N. E., & Vitetta, E. S. (1997). Cancer dormancy: Opportunities for new therapeutic approaches. Nature Medicine, 3, 505–509. Folkman, J. (1995). Angiogenesis in cancer, vascular, rheumatoid and other diseases. Nature Medicine, 1, 27–31. Woelfle, U., Cloos, J., Sauter, G., Riethdorf, L., Janicke, F., van Diest, P., et al. (2003). Molecular signature associated with bone marrow micrometastasis in human breast cancer. Cancer Research, 63, 5679–5684. Varambally, S., Dhanasekaran, S. M., Zhou, M., Kumar-Sinha, C., Sanda, M. G., Ghosh, D., et al. (2002). The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature, 419, 624–629. Benoy, I. H., Salgado, R., Elst, H., Van Dam, P., Weyler, J., Van Marck, E., et al. (2005). Relative microvessel area of the primary tumor, and not lymph node status, predicts the presence of bone marrow micrometastases detected by reverse transcriptase polymerase chain reaction in patients with clinically non-metastatic breast cancer. Breast Cancer Research, 7, R210–R219. Z’graggen, K., Centeno, B. A., Fernandez-del Castillo, C., Jimenez, R. E., Werner, J., & Warshaw, A. L. (2001). Biological implications of tumor cells in blood and bone marrow of pancreatic cancer patients. Surgery, 129, 537–546. Zippelius, A., & Pantel, K. (2000). RT-PCR based detection of occult disseminated tumor cells in peripheral blood and bone marrow of patients with solid tumors. An overview. Annals of the New York Academy of Sciences, 906, 110–123. Vona, G., Sabile, A., Louha, M., Sitruk, V., Romana, S., Schutze, K., et al. (2000). Isolation by size of epithelial tumor cells: A new method for the immunomorphological and molecular characterization of circulating tumor cells. American Journal of Pathology, 156, 57–63. Mehes, G., Luegmayr, A., Amros, I. M., Ladenstein, R., & Ambros, P. F. (2001). Combined automatic immunological and molecular cytogenetic analysis allows exact identification and quantification of tumor cells in the bone marrow. Clinical Cancer Research, 7, 1969–1975. Schmidt-Kittler, O., Ragg, T., Daskalakis, A., Granzow, M., Ahr, A., Blankenstein, T. J., et al. (2003). From latent disseminated cells to overt metastasis: Genetic analysis of systemic breast cancer progression. Proceedings of the National Academy of Sciences of the United States of America, 100, 7737–7742. Klein, C. A., Blakenstein, T. J., Schmidt-Kittler, O., Petronio, M., Polzer, B., Stoecklein, N. H., et al. (2002). Genetic heterogeneity of single disseminated tumor cells in minimal residual disease. Lancet, 360, 683–689. Albertson, D. G., Collins, C., McCormick, F., & Gray, J. W. (2003). Chromosome aberrations in solid tumors. Nature Genetics, 34, 369–376. Diel, I. J., Kaufmann, M., Costa, S. D., Holle, R., von Minckwitz, G., Solomayer, E. F., et al. (1996). Micrometastatic breast cancer cells in bone marrow at primary surgery: Prognostic value in comparison with nodal status. Journal of the National Cancer Institute, 88, 1652–1658. Molino, A., Pelosi, G., Turazza, M., Sperotto, L., Bonetti, A., Nortilli, R., et al. (1997). Bone marrow micrometastases in 109 breast cancer patients: Correlations with clinical and pathological features and prognosis. Breast Cancer Research and Treatment, 42, 23–30. Landys, K., Persson, S., Kovarik, J., Hultborn, R., & Holmberg, E. (1998). Prognostic value of bone marrow biopsy in operable breast cancer patients at the time of initial diagnosis: Results of a 20-year median follow-up. Breast Cancer Research and Treatment, 49, 27–33. Mansi, J. L., Gogas, H., Bliss, J. M., Gazet, J. C., Berger, U., & Coombes, R. C. (1999). Outcome of primary-breast-cancer patients with micrometastases: A long-term follow-up. Lancet, 354, 197–202. Braun, S., Pantel, K., Muller, P., Janni, W., Hepp, F., Kentenich, C. R., et al. (2000). Cytokeratin-positive cells in the bone marrow and survival of patients with stage I, II or III breast cancer. New England Journal of Medicine, 342, 525–533. Janni, W., Gastroph, S., Hepp, F., Kentenich, C., Rjosk, D., Schindlbeck, C., et al. (2000). Prognostic significance of an increased number of micrometastatic tumor cells in the bone marrow of patients with first recurrence of breast carcinoma. Cancer, 88, 2252–2259. Gerber, B., Krause, A., Muller, H., Richter, D., Reimer, T., Makovitzky, J., et al. (2001). Simultaneous immunohistochemical detection of tumor cells in lymph nodes and bone marrow aspirates in breast cancer and its correlation with other prognostic factors. Journal of Clinical Oncology, 19, 960–971. Gebauer, G., Fehm, T., Merkle, E., Beck, E. P., Lang, N., & Jager, W. (2001). Epithelial cells in bone marrow of breast cancer patients at time of primary surgery: Clinical outcome during long-term follow-up. Journal of Clinical Oncology, 19, 3669–3674. Wiedswang, G., Borgen, E., Karesen, R., Kvalheim, G., Nesland, J. M., Qvist, H., et al. (2003). Detection of isolated tumor cells in bone marrow is an independent prognostic factor in breast cancer. Journal of Clinical Oncology, 21, 3469–3478. Braun, S., Vogl, F. D., Naume, B., Janni, W., Osborne, M. P., Coombes, R. C., et al. (2005). A pooled analysis of bone marrow micrometastasis in breast cancer. New England Journal of Medicine, 353, 793–802. Lindemann, F., Schlimok, K., Dirschedl, P., Witte, J., & Riethmuller, G. (1992). Prognostic significance of micrometastatic cells in bone marrow of colorectal cancer patients. Lancet, 340, 685–689. Leinung, S., Wurl, P., Schonfelder, A., Weiss, C. L., Roder, I., & Schonfelder, M. (2000). Detection of cytokeratin-positive cells in bone marrow in breast cancer and colorectal carcinoma in comparison with other factors of prognosis. Journal of Hematotherapy & Stem Cell Research, 9, 905–911. Werther, K., Normark, M., Brunner, N., & Nielsen, H. J. (2002). Cytokeratin-positive cells in preoperative blood and bone marrow aspirates of patients with colorectal cancer. Scandinavian Journal of Clinical & Laboratory Investigation, 62, 49–57. Jauch, K. W., Heiss, M. M., Gruetzner, U., Funke, I., Pantel, K., Babic, R., et al. (1996). Prognostic significance of bone marrow micrometastases in patients with gastric cancer. Journal of Clinical Oncology, 14, 1810–1817. Heiss, M. M., Simon, E. H., Beyer, B. C., Gruetzner, K. U., Tarabichi, A., Babic, R., et al. (2002). Minimal residual disease in gastric cancer: Evidence of an independent prognostic relevance of urokinase receptor expression by disseminated tumor cells in the bone marrow. Journal of Clinical Oncology, 20, 2005–2016. de Manzoni, G., Pelosi, G., Pavanel, F., Di Leo, A., Pedrazzani, C., Durante, E., et al. (2002). The presence of bone marrow cytokeratin-immunoreactive cells does not predict outcome in gastric cancer patients. British Journal of Cancer, 86, 1047–1051. Inoue, H., Kajiyama, Y., & Tsurumaru, M. (2004). Clinical significance of bone marrow micrometastases in esophageal cancer. Diseases of the Esophagus, 17, 328–332. O’Sullivan, G. C., Sheehan, D., Clarke, A., Stuart, R., Kelly, J., Kiely, M. D., et al. (1999). Micrometastases in esophagogastric cancer: High detection rate in resected rib segments. Gastroenterologist, 116, 543–548. Thorban, S., Rosenberg, R., Busch, R., & Roder, R. J. (2000). Epithelial cells in bone marrow of oesophageal cancer patients: A significant prognostic factor in multivariate analysis. British Journal of Cancer, 83, 35–39. Ryan, P., McCarthy, S., Kelly, J., Collins, J. K., Dunne, C., Grogan, L., et al. (2004). Prevalence of bone marrow micrometastases in esophagogastric cancer patients with and without neoadjuvant chemoradiotherapy. Journal of Surgical Research, 117, 121–126. Passlick, B. (2001). Micrometastases in non-small cell lung cancer (NSLC). Lung Cancer, 34(Suppl 3), S25–S29. Pantel, K., Izbicki, J., Passlick, B., Angstwurm, M., Haussinger, K., Thetter, O., et al. (1996). Frequency and prognostic significance of isolated tumor cells in bone marrow of patients with non-small-cell lung cancer without overt metastases. Lancet, 347, 649–653. Sugio, K., Kase, S., Sakada, T., Yamazaki, K., Yamaguchi, M., Ondo, K., et al. (2002). Micrometastasis in the bone marrow of patients with lung cancer associated with a reduced expression of E-cadherin and beta-catenin: Risk assessment by immunohistochemistry. Surgery, 131(Suppl), S226–S231. Braun, S., Schindlbeck, C., Hepp, F., Janni, W., Kentenich, C., Riethmuller, G., et al. (2001). Occult tumor cells in bone marrow of patients with locoregionally restricted ovarian cancer predicts early distant metastatic relapse. Journal of Clinical Oncology, 19, 368–375. Marth, C., Kisic, J., Kaern, J., Trope, C., & Fodstad, O. (2002). Circulating tumor cells in the peripheral blood and bone marrow of patients with ovarian carcinoma do not predict prognosis. Cancer, 94, 707–712. Janni, W., Hepp, F., Strobl, B., Rack, B., Rjosk, D., Kentenich, C., et al. (2003). Patterns of disease recurrence influenced by hematogenous tumor cell dissemination in patients with cervical carcinoma of the uterus. Cancer, 97, 405–411. Scheungraber, C., Muller, B., Kohler, C., Possover, M., Leistritz, S., Schneider, A., et al. (2002). Detection of disseminated tumor cells in patients with cervical cancer. Journal of Cancer Research and Clinical Oncology, 128, 329–335. Rack, B., Janni, W., Kentenich, C., Strobl, B., Klanner, E., Schindlbeck, C., et al. (2002). Incidence and prognostic significance of disseminated tumor cells in patients with cervical cancer. Acta Medica Austriaca. Supplement, 59, 36–41. Ellis, W. J., Pfitzenmaier, J., Colli, J., Arfman, E., Lange, P. H., & Vessella, R. L. (2003). Detection and isolation of prostate cancer cells from peripheral blood and bone marrow. Urology, 61, 277–281. van Heek, N. T., Tascilar, M., van Beekveld, J. L., Drillenburg, P., Offerhaus, G. J., & Gouma, D. J. (2001). Micrometastases in bone marrow of patients with suspected pancreatic and ampullary cancer. European Journal of Surgical Oncology, 27, 740–745. Z’graggen, K., Centeno, B. A., Fernandez-del Castillo, C., Jimenez, R. E., Werner, J., & Warshaw, A. L. (2001). Biological implications of tumor cells in blood and bone marrow of pancreatic cancer patients. Surgery, 129, 537–546. Trocciola, S. M., Hoda, S., Osborne, M. P., Christos, P. J., Levin, H., Martins, D., et al. (2005). Do bone marrow micrometastases correlate with sentinel lymph node metastases in breast cancer patients? Journal of the American College of Surgeons, 200, 720–725. Janni, W., Rack, B., Schindlbeck, C., Strobl, B., Rjosk, D., Braun, S., et al. (2005). The persistence of isolated tumor cells on bone marrow from patients with breast carcinoma predicts an increased risk for recurrence. Cancer, 103, 884–891. Naume, B., Wiedswang, G., Borgen, E., Kvalheim, G., Karesen, R., Qvist, H., et al. (2004). The prognostic value of isolated tumor cells in bone marrow in breast cancer patients: Evaluation of morphological categories and the number of clinically significant cells. Clinical Cancer Research, 10, 3091–3097. Janni, W., Rack, B., Lindemann, K., & Harbeck, N. (2005). Detection of micrometastatic disease in bone marrow. Is it ready for prime time? Oncologist, 10, 480–492. Borgen, E., Beiske, K., Trachsel, S., Nesland, J. M., Kvalheim, G., Herstad, T. K., et al. (1998). Immunocytochemical detection of isolated epithelial cells in bone marrow: Non-specific staining and contribution by cells directly reactive to alkaline phosphatase. Journal of Pathology, 185, 427–434. Braun, S., Muller, M., Hepp, F., Schlimok, G., Riethmuller, G., & Pantel, K. (1998). Re: Micrometastatic breast cancer cells in bone marrow at primary surgery: Prognostic value in comparison with nodal status. Journal of the National Cancer Institute, 90, 1099–1101. Pantel, K., Schlimok, G., Angstwurm, M., Wechermann, D., Schmaus, W., Gath, H., et al. (1994). Methodological analysis of immunocytochemical screening for disseminated epithelial tumor cells in bone marrow. Journal of Hematotherapy, 3, 165–173. Krag, D. N., Kusminsky, R., Manna, E., Ambaye, A., Weaver, D. L., Harlow, S. P., et al. (2005). The detection of isolated tumor cells in bone marrow comparing bright-field immunocytochemistry and multicolor immunofluorescence. Annals of Surgical Oncology, 12, 753–760. Skinner, L. J., Conlon, B. J., Russell, J. D., O’Sullivan, G. C., & O’Dwyer T. P. (2005). Detection of bone marrow micrometastases in the rib marrow of head and neck cancer patients: A prospective pilot study. European Archives of Oto-rhino-laryngology, 262, 103–106. Fetsch, P. A., Cowan, K. H., Weng, D. E., Freifield, A., Filie, A. C., & Abati, A. (2000). Detection of circulating tumor cells and micrometastases in stage II, III, and IV breast cancer patients utilizing cytology and immunocytochemistry. Diagnostic Cytopathology, 22, 323–328. Ooka, M., Tamaki, Y., Sakita, I., Fujiwara, Y., Yamamoto, H., Miyake, Y., et al. (2001). Bone marrow micrometastases detected by RT-PCR for mammaglobin can be an alternative prognostic factor of breast cancer. Breast Cancer Research and Treatment, 67, 169–175. Rouzier, R., Bourstyn, E., Grozier, F., Berger, A., Louvard, D., & Robins, S. (2001). Immunocytochemical detection of bone marrow micrometastases in colorectal carcinoma patients, using a monoclonal antibody to villin. Cytometry, 46, 281–289. Ciudad, J., San Miguel, J. F., Lopez-Berges, M. C., Vidriales, B., Valverde, B., Ocqueteau, M., et al. (1998). Prognostic value of immunophenotypic detection of minimal residual disease in acute lymphoblastic leukemia. Journal of Clinical Oncology, 16, 3774–3781. Jennings, C. D., & Foon, K. A. (1997). Recent advances in flow cytometry: Application to the diagnosis of hematologic malignancy. Blood, 90, 2863–2892. Wingren, S., Guerrieri, C., Franlund, B., & Stal, O. (1995). Loss of cytokeratins in breast cancer cells using multiparameter DNA flow cytometry is related to both cellular factors and preparation procedure. Analytical Cellular Pathology, 9, 229–233. Vredenburgh, J. J., Silva, O., Tyer, C., DeSombre, K., Abou-Ghalia, A., Cook, M., et al. (1996). A comparison of immunohistochemistry, two color immunofluorescence, and flow cytometry with cell sorting for the detection of micrometastatic breast cancer in the bone marrow. Journal of Hematotherapy, 5, 57–62. Sidransky, D. (1997). Nucleic acid-based methods for the detection of cancer. Science, 278, 1054–1059. Ghossein, R. A., Carusone, L., & Bhattacharya, S. (1999). Review: Polymerase chain reaction detection of micrometastases and circulating tumor cells: Application to melanoma, prostate and thyroid carcinomas. Diagnostic Molecular Pathology, 8, 165–175. Jung, R., Petersen, K., Kruger, W., Wolf, M., Wagener, C., Zander, A., et al. (1999). Detection of micrometastasis by cytokeratin 20 RT-PCR is limited due to stable background transcription in granulocytes. British Journal of Cancer, 81, 870–873. Bostick, P. J., Chatterjee, S., Chi, D. D., Huynh, K. T., Giuliano, A. E., Cote, R., et al. (1998). Limitations of specific reverse-transcriptase polymerase chain reaction markers in the detection of metastases in the lymph nodes and blood of breast cancer patients. Journal of Clinical Oncology, 2632–2640. Forus, A., Hoifodt, H. K., Overli, G. E., Myklebost, O., & Fodstad, O. (1999). Sensitive fluorescent in situ hybridization method for the characterisation of breast cancer cells in bone marrow aspirates. Molecular Pathology, 52, 68–74. Mueller, P., Carroll, P., Bowers, E., Moore, D., 2nd, Cher, M., Presti, J., et al. (1998). Low frequency epithelial cells in bone marrow aspirates from prostate carcinoma are cytogenetically aberrant. Cancer, 83, 538–546. Debernardi, S., Lillington, D., & Young, B. D. (2004). Understanding cancer at the chromosome level: 40 years of progress. European Journal of Cancer, 40, 1960–1967. Grimwade, D., Walker, H., Oliver, F., Wheatley, K., Harrison, C., Harrison, G., et al. (1998). The importance of diagnostic cytogenetics on outcome in AML: Analysis of 1612 patients entered into the MRC AML 10 trial. The medical research council adult and children’s leukemia working parties. Blood, 92, 2322–2333. Polyak, K., & Riggins, G. J. (2001). Gene discovery using the serial analysis of gene expression technique: Implications for cancer research. Journal of Clinical Oncology, 19, 2948–2958. Velculescu, V. E., Zhang, L., Vogelstein, B., & Kinzler, K. W. (1995). Serial analysis of gene expression. Science, 270, 484–487. Chee, M., Yang, R., Hubbell, E., Berno, A., Huang, X. C., Stern, D., et al. (1996). Accessing genetic information with high-density DNA arrays. Science, 274, 610–614. Woelfle, U., Cloos, J., Sauter, G., Riethdorf, L., Janicke, F., van Diest, P., et al. (2003). Molecular signature associated with bone marrow micrometastasis in human breast cancer. Cancer Research, 63, 5679–5684. Kraus, J., Pantel, K., Pinkel, D., Albertson, D. G., & Speicher, M. R. (2003). High-resolution genomic profiling of occult micrometastatic tumor cells. Genes, Chromosomes & Cancer, 36, 159–166. Weihrauch, M. R., Skibowski, E., Koslowsky, T. C., Voiss, W., Re, D., Kuhn-Regnier, F., et al. (2002). Immunomagnetic enrichment and detection of micrometastases in colorectal cancer: Correlation with established clinical parameters. Journal of Clinical Oncology, 20, 4338–4343. Faye, R. S., Aamdal, S., Hoifodt, H. K., Jacobsen, E., Holstad, L., Skovlund, E., et al. (2004). Immunomagnetic detection and clinical significance of micrometastatic tumor cells in malignant melanoma patients. Clinical Cancer Research, 10, 4134–4139. Naume, B., Borgen, E., Nesland, J. M., Beiske, K., Gilen, E., Renolen, A., et al. (1998). Increased sensitivity for detection of micrometastases in bone marrow/peripheral blood stem-cell products from breast-cancer patients by negative immunomagnetic separation. International Journal of Cancer, 78, 556–560. Loo, W. T. Y., Fong, J. H. M., Zhui, L., Cheung, M. N. B., & Chow, L. W. C. (2005). The value of bone marrow aspirates culture for the detection of bone marrow micrometastases in breast cancer. Biomedicine & Pharmacotherapy, 59, S384–S386. Braun, S., Kentenich, C., Janni, W., Hepp, F., de Waal, J., Willgeroth, F., et al. (2000). Lack of effect of adjuvant chemotherapy on the elimination of single dormant tumor cells in bone marrow of high-risk breast cancer patients. Journal of Clinical Oncology, 18, 80–86. Hohaus, S., Pforsich, M., Murea, S., Abdallah, A., Lin, Y. S., Funk, L., et al. (1997). Immunomagnetic selection of CD34+ peripheral blood stem cells for autografting in patients with breast cancer. British Journal of Haematology, 97, 881–888. Riethmuller, G., Holz, E., Schlimok, G., Schmiegel, W., Raab, R., Hoffken, K., et al. (1998). Monoclonal antibody therapy for resected Dukes’ C colorectal cancer: Seven-year outcome of a multicenter randomized trial. Journal of Clinical Oncology, 16, 1788–1794. Braun, S., Hepp, F., Kentenich, C. R., Janni, W., Pantel, K., Riethmuller, G., et al. (1999). Monoclonal antibody therapy with edrecolomab in breast cancer patients: Monitoring of elimination of disseminated cytokeratin-positive tumor cells in bone marrow. Clinical Cancer Research, 5, 3999–4004. Kirchner, E. M., Gerhards, R., & Voigtmann, R. (2002). Sequential immunochemotherapy and edrecolomab in the adjuvant therapy of breast cancer: Reduction of 17-1A-positive disseminated tumor cells. Annals of Oncology, 13, 1044–1048. Punt, C. J., Nagy, A., Douillard, J. Y., Figer, A., Skovsgaard, T., Monson, J., et al. (2002). Edrecolomab alone or in combination with fluorouracil and folinic acid in the adjuvant treatment of stage III colon cancer: A randomized study. Lancet, 360, 671–677. Najmi, S., Korah, R., Chandra, R., Abdellatif, M., & Wieder, R. (2005). Flavopiridol blocks integrin-mediated survival in dormant breast cancer cells. Clinical Cancer Research, 11, 2038–2046. Ross, J. S., Fletcher, J. A., Bloom, K. J., Linette, G. P., Stec, J., Symmans, W. F., et al. (2004). Targeted therapy in breast cancer: The HER-2/neu gene and protein. Molecular & Cellular Proteomics, 3, 379–398. Bloom, K. J., Govil, H., Gattuso, P., Reddy, V., & Francescatti, D. (2001). Status of HER-2 in male and female breast carcinoma. American Journal of Surgery, 182, 389–392. Stark, A., Hulka, B. S., Joens, S., Novotny, D., Thor, A. D., Wold, L. E., et al. (2000). HER-2/neu amplification in benign breast disease and the risk of subsequent breast cancer. Journal of Clinical Oncology, 18, 267–274. Huston, J. S., & George, A. J. (2001). Engineered antibodies take center stage. Human Antibodies, 10, 127–142. Slamon, D. J., Leyland-Jones, B., Shak, S., Fuchs, H., Paton, V., Bajamonde, A., et al. (2001). Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. New England Journal of Medicine, 344, 783–792. Hortobagyi, G. N. (2001). Overview of treatment results with trastuzumab (Herceptin) in metastatic breast cancer. Seminars in Oncology, 28, 43–47. McKeage, K., & Perry, C. M. (2002). Trastuzumab: A review of its use in the treatment of metastatic breast cancer overexpressing HER2. Drugs, 62, 209–243. Goss, P. E., Ingle, J. N., Martino, S., Robert, N. J., Muss, H. B., Piccart, M. J., et al. (2003). A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. New England Journal of Medicine, 349, 1793–1802. Sachelarie, I., Grossbard, M. L., Chadha, M., Feldman, S., Ghesani, M., & Blum, R. H. (2006). Primary systemic therapy of breast cancer. Oncologist, 11, 574–589. Diel, I. J., Solomayer, E. F., Costa, S. D., Gollan, C., Goerner, R., Wallwiener, D., et al. (1998). Reduction in new metastases in breast cancer with adjuvant clodronate treatment. New England Journal of Medicine, 339, 357–363. Demicheli, R., Retsky, M. W., Swartzendruber, D. E., & Bonadonna, G. (1997). Proposal for a new model of breast cancer metastatic development. Annals of Oncology, 8, 1075–1080.