678 prostate cancer patients with NRLN metastasis; however, the presence of bone metastasis could predict worse prognosis. They explained that metastases and primary tumors have different clonal compositions and that there is a preferential environment for the growth of prostate cancer cells, particularly in the bone rather than soft tissue. In our study, patients with regional lymph node meta- stases had a 2.574-fold higher HR relative to those without lymph node metastases, and patients with NRLN meta- stasis had 2.740-fold higher HR with regard to pro- gression-free time to CRPC. Additionally, patients with EOD 1 grade had a 4.263-fold higher HR relative to those without bone metastases, and patients with EOD grade 2 had a 7.668-fold increased HR. These results of our study were similar to the findings to a previous study [9], because NRLN metastasis decreased the progression-free time to CRPC, although EOD grade more strongly influenced the progression-free time to CRPC than did lymph node meta- stasis burden. The mechanisms by which prostate cancer metastasizes to bone tissues are not yet fully understood [16], although the “seed and soil” hypothesis and the “homing” mecha- nism provide some explanation [17,18]. The “seed and soil” hypothesis was the first proposed by Stephen Paget in 1889 and is based on the idea that primary tumors spread into distant metastatic sites as a plant disperses its seeds [19]. The seeds are carried in all directions, but they can only grow in the most suitable soil. However, this hypothesis was challenged by a recent gene expression study [20,21]. Cancer cells may hone in to specific metastatic sites in or- gans with specific metastatic gene expression signatures; these gene signatures might be superimposed on a poor-prognosis signature in the parent tumor, which might account for the various gene expression patterns observed in certain tumors [21]. Furuya et al. [9] explained their re- sults in terms of the seed and soil hypothesis; however, this homing mechanism could also explain our results in which the EOD grade more strongly influenced the pro- gression-free time to CRPC than did the lymph node meta- stasis burden. In the present study, we also evaluated the prognostic effect of NRLN metastasis in patients with CRPC receiving chemotherapy and evaluated other potential prognostic predictors. Berry et al. [22] identified factors that predicted decreased survival in an analysis of 85 patients with meta- static hormone-resistant prostate cancer. They reported that age (＞65 years), severe bone pain, poor performance status, the presence of soft tissue metastases, anemia, and elevated levels of LDH, acid phosphatase, ALP, and pro- lactin were poor prognostic factors. Emrich et al. [23] iden- tified in an analysis of 1,020 patients the following factors predictive of survival in order of importance: previous hor- mone response, anorexia, elevated acid phosphatase, pain, elevated ALP, obstructive symptoms, tumor grade, per- formance status, anemia, and age at diagnosis. Kantoff et al. [24] identified prognostic factors on the basis of 242 metastatic hormone-resistant prostate cancer patients; Korean J Urol 2012;53:673-679 Cho et al the factors they identified included ALP, LDH, baseline PSA, and hemoglobin. In our study, however, we could not identify independent prognostic factors among previously mentioned parameters such as performance status, base- line hemoglobin level, visceral involvement, baseline acid phosphatase, ALP and LDH levels, time from initiation of androgen deprivation to initiation of chemotherapy, re- sponse to therapy, decline in post-therapy serum PSA (≥4 weeks), baseline PSA, EOD on bone scan, and continuation of androgen deprivation. In addition, NRLN metastasis and EOD of bone metastasis were not significant in- dependent factors that were predictive of chemotherapy re- sponse, progression of disease, or overall survival by multi- variate analysis. As shown in our study, NRLN metastasis is an in- dependent prognostic factor for predicting reduced pro- gression time to CRPC, although the associated relative risk was lower than that of bone metastasis. However, NRLN was not an independent prognostic factor for pre- dicting the chemotherapeutic response or decreased can- cer-specific survival. Although the sample size was rela- tively small, this is the first study that investigated the prognostic significance of NRLN metastasis with regard to both hormonal therapy and chemotherapy response in metastatic prostate cancer. To select the proper treatment strategy in metastatic prostate cancer patients and to de- termine those with very low survival rates, additional stud- ies aimed at identifying factors to predict poor prognosis are needed. CONCLUSIONS Twelve (11.4%) of 105 patients with NRLN metastasis had only lymph node metastases without bone metastases. Therefore, we speculate that prostate cancer with NRLN metastases exhibits a unique tumor biology. In addition, NRLN metastasis was a significant prognostic factor for predicting decreased progression-free time to CRPC. We suggest that large-scale, multicenter studies including metastatic prostate cancer patients and those with lymph node metastasis are required, and studies aimed at delin- eating the mechanisms underlying the unique tumor biol- ogy associated with metastatic prostate cancer are also needed. CONFLICTS OF INTEREST The authors have nothing to disclose. REFERENCES 1. McCullough DL, Prout GR Jr, Daly JJ. Carcinoma of the prostate and lymphatic metastases. J Urol 1974;111:65-71. 2. Park SK, Sakoda LC, Kang D, Chokkalingam AP, Lee E, Shin HR, et al. Rising prostate cancer rates in South Korea. Prostate 2006;66:1285-91. 3. Galasko CS. Skeletal metastases. Clin Orthop Relat Res 1986; (210):18-30. 4. Logothetis CJ, Navone NM, Lin SH. Understanding the biology