Elucidation and Regulation of Tyrosine Kinase Inhibitor Resistance in Renal Cell Carcinoma Cells from the Perspective of Glutamine Metabolism.

Tyrosine kinase inhibitors (TKIs) play a crucial role in the treatment of advanced renal cell carcinoma (RCC). However, there is a lack of useful biomarkers for assessing treatment efficacy. Through urinary metabolite analysis, we identified the metabolites and pathways involved in TKI resistance and elucidated the mechanism of TKI resistance. To verify the involvement of the identified metabolites obtained from urine metabolite analysis, we established sunitinib-resistant RCC cells and elucidated the antitumor effects of controlling the identified metabolic pathways in sunitinib-resistant RCC cells. Through the analysis of VEGFR signaling, we aimed to explore the mechanisms underlying the antitumor effects of metabolic control. Glutamine metabolism has emerged as a significant pathway in urinary metabolite analyses. In vitro and in vivo studies have revealed the antitumor effects of sunitinib-resistant RCC cells via knockdown of glutamine transporters. Furthermore, this antitumor effect is mediated by the control of VEGFR signaling via PTEN. Our findings highlight the involvement of glutamine metabolism in the prognosis and sunitinib resistance in patients with advanced RCC. Additionally, the regulating glutamine metabolism resulted in antitumor effects through sunitinib re-sensitivity in sunitinib-resistant RCC. Our results are expected to contribute to the more effective utilization of TKIs with further improvements in prognosis through current drug therapies.

The efficacy of molecular targeted therapy and nivolumab therapy for metastatic non-clear cell renal cell carcinoma: A retrospective analysis using the Michinoku Japan urological cancer study group database.

OBJECTIVES: To investigate the efficacy of pharmacotherapy for metastatic non-clear cell renal cell carcinoma (nccRCC) in Japanese population. METHODS: In this retrospective analysis, we compared the time to treatment failure (TTF) for molecular-targeted agents as first-line therapy, or nivolumab therapy as sequential therapy between ccRCC and nccRCC using the data of Japanese metastatic RCC patients registered in the Michinoku Japan Urological Cancer Study Group database. RESULTS: In total, 511 cases of ccRCC and 77 cases of nccRCC were treated with pharmacotherapy. After excluding the patients who received cytokine therapy, chemotherapy, or others, there were 391 ccRCC patients and 60 nccRCC patients who were treated with tyrosine kinase inhibitors (TKIs), and 7 ccRCC patients and 7 nccRCC patients who were treated with mammalian-target of rapamycin inhibitors (mTORIs). In addition, 132 ccRCC patients and 16 nccRCC patients received nivolumab. There was no significant difference in IMDC risk classification before first-line therapy between ccRCC and nccRCC groups, or in each subgroup within the nccRCC group. TTF for TKIs (161 days, 95% CI: 75-212 days) and mTORIs (21 days, 95% CI: 9-31 days) didn't differ significantly between nccRCC and ccRCC groups (205 days, 95% CI: 174-243 days and 33 days, 95% CI: 8-113 days, respectively). TTF for TKIs was significantly longer than that for mTORIs in nccRCC group (p<0.01). There was no significant difference in TTF between the different TKIs in nccRCC group. In addition, no significant difference in TTF for nivolumab was seen between ccRCC and nccRCC groups. CONCLUSIONS: The results showed that the efficacy of molecular-targeted agents as first-line therapy was similar oncological outcomes between metastatic nccRCC and ccRCC in Japanese patients. TKIs may be more effective than mTORIs in metastatic nccRCC patients. Nivolumab administration might also be as effective in nccRCC patients as in ccRCC patients in Japanese population.

Impact of Gleason pattern 5 on prognosis for newly diagnosed metastatic hormone-sensitive prostate cancer with Gleason score ≥8.

OBJECTIVE: We evaluated the impact of Gleason pattern 5 presence on prognosis among de novo metastatic hormone-sensitive prostate cancer patients with a Gleason score ≥8. METHODS: The data of 559 patients diagnosed as metastatic hormone-sensitive prostate cancer with a Gleason score ≥8, who were initially treated with androgen deprivation therapy from 2008 to 2016, were retrospectively collected. Patients were divided into two groups as high and low volume based on the CHAARTED trial criteria. RESULTS: The median overall survival of the 559 metastatic hormone-sensitive prostate cancer patients with Gleason score ≥8 was 70 months, with a median follow-up period of 36 months. Gleason pattern 5 was confirmed in 341 patients (61.0%), in which primary Gleason pattern 5 was confirmed in 164 patients (29.3%). The number of patients with high metastatic volume group was 363 (64.9%). In total and high metastatic volume groups, hemoglobin and lactate dehydrogenase were significant factors for predicting overall survival, but both Gleason pattern 5 and primary Gleason pattern 5 did not show a statistically significant difference. In the low-volume metastatic group, the median overall survival in patients with or without primary Gleason pattern 5 was 40 and 78 months, respectively. In multivariate analysis, only primary Gleason pattern 5 was an independent predictive factor for overall survival in the low-volume metastatic group (hazard ratio 2.76, 95% confidence interval 1.88-8.67; P = 0.0026). CONCLUSION: The presence of Gleason pattern 5 was not associated with overall survival in metastatic hormone-sensitive prostate cancer with a Gleason score ≥8. In low-metastatic volume metastatic hormone-sensitive prostate cancer, primary Gleason pattern 5 was a poor prognostic factor, which might show a separate treatment option for this group.

Surgery to Avoid Stoma Construction in Invasive Prostate Cancer Extensively Infiltrating the Rectum.

A 61-year-old man tested positive for occult urinary and fecal occult blood and was diagnosed with invasive prostate cancer extensively infiltrating the rectum. After scrutiny, he was diagnosed with cT4N1M0 prostate cancer, and androgen deprivation therapy (ADT) was initiated with a gonadotropin-releasing hormone antagonist. A prostatic rectal resection was performed 6 months after ADT began. The bladder and urethra were anastomosed, the anus was preserved intact, and the sigmoid colon was anastomosed to the anus. A temporary ileostomy was constructed to allow eating and to prevent fistula formation. The ileostomy was closed 5 months post-operation as the patient wanted to live without a stoma. Although the patient died of other disease factors, he remained untreated for 1 year and 7 months post-operation, and his symptoms and disease control were well supported. We report that we were able to perform stoma-free surgical treatment for prostate cancer extensively infiltrating rectum.

Predictive model for recurrence of renal cell carcinoma by comparing pre- and postoperative urinary metabolite concentrations.

To improve treatment outcomes in real practice, useful biomarkers are desired when predicting postoperative recurrence for renal cell carcinoma (RCC). We collected data from patients who underwent definitive surgery for RCC and for benign urological tumor at our department between November 2016 and December 2019. We evaluated the differences in pre- and postoperative urinary metabolites with our precise quantitative method and identified predictive factors for RCC recurrence. Additionally, to clarify the significance of metabolites, we measured the intracellular metabolite concentration of three RCC cell lines. Among the 56 patients with RCC, nine had a recurrence (16.0%). When comparing 27 patients with T1a RCC and 10 with benign tumor, a significant difference was observed between pre- and postoperative concentrations among 10 urinary metabolites. In these 10 metabolites, multiple logistic regression analysis identified five metabolites (lactic acid, glycine, 2-hydroxyglutarate, succinic acid, and kynurenic acid) as factors to build our recurrence prediction model. The values of area under the receiver operating characteristic curve, sensitivity, and specificity in this predictive model were 0.894%, 88.9%, and 88.0%, respectively. When stratified into low and high risk groups of recurrence based on this model, we found a significant drop of recurrence-free survival rates among the high risk group. In in vitro studies, intracellular metabolite concentrations of metastatic tumor cell lines were much higher than those of primary tumor cell lines. By using our quantitative evaluation of urinary metabolites, we could predict postoperative recurrence with high sensitivity and specificity. Urinary metabolites could be noninvasive biomarkers to improve patient outcome.

Metabolomic Analysis to Elucidate Mechanisms of Sunitinib Resistance in Renal Cell Carcinoma.

Metabolomics analysis possibly identifies new therapeutic targets in treatment resistance by measuring changes in metabolites accompanying cancer progression. We previously conducted a global metabolomics (G-Met) study of renal cell carcinoma (RCC) and identified metabolites that may be involved in sunitinib resistance in RCC. Here, we aimed to elucidate possible mechanisms of sunitinib resistance in RCC through intracellular metabolites. We established sunitinib-resistant and control RCC cell lines from tumor tissues of RCC cell (786-O)-injected mice. We also quantified characteristic metabolites identified in our G-Met study to compare intracellular metabolism between the two cell lines using liquid chromatography-mass spectrometry. The established sunitinib-resistant RCC cell line demonstrated significantly desuppressed protein kinase B (Akt) and mesenchymal-to-epithelial transition (MET) phosphorylation compared with the control RCC cell line under sunitinib exposure. Among identified metabolites, glutamine, glutamic acid, and α-KG (involved in glutamine uptake into the tricarboxylic acid (TCA) cycle for energy metabolism); fructose 6-phosphate, D-sedoheptulose 7-phosphate, and glucose 1-phosphate (involved in increased glycolysis and its intermediate metabolites); and glutathione and myoinositol (antioxidant effects) were significantly increased in the sunitinib-resistant RCC cell line. Particularly, glutamine transporter (SLC1A5) expression was significantly increased in sunitinib-resistant RCC cells compared with control cells. In this study, we demonstrated energy metabolism with glutamine uptake and glycolysis upregulation, as well as antioxidant activity, was also associated with sunitinib resistance in RCC cells.

Expression of Ganglioside Disialosyl Globopentaosyl Ceramide in Prostate Biopsy Specimens as a Predictive Marker for Recurrence after Radical Prostatectomy.

Carbohydrate antigens are associated with carcinogenesis, cancer invasion, and metastasis and their expression reflect biological activities of various cancers. We previously reported that expression of disialosyl globopentaosyl ceramide (DSGb5), one of carbohydrate antigens, in radical prostatectomy specimens independently predicted biochemical recurrence (i.e., elevating serum prostate specific antigen without recurrent lesions in the image) after radical prostatectomy. However, it is important to evaluate the prognosis at the diagnosis. In this study we investigated DSGb5 expression in prostate biopsy specimens to develop a novel biomarker for providing appropriate management. Between 2005 and 2011, patients who underwent both prostate biopsy and radical prostatectomy in our institution were included. The median follow-up period was 88 months. DSGb5 expression was assessed by immunohistochemical staining and defined 116 patients as high DSGb5 expression (42 patients) or low DSGb5 expression (74 patients). High DSGb5 expression was significantly associated with lymphovascular invasion in radical prostatectomy specimens on both univariate and multivariable analyses (p = 0.028, 0.027). On multivariable analysis, Gleason Score in prostatectomy specimen, positive resection margin, and DSGb5 expression in the biopsy specimen were independently associated with biochemical recurrence-free survival following radical prostatectomy (p = 0.004, 0.008, 0.024). When targeting only patients with negative resection margin, DSGb5 expression was significantly associated with biochemical recurrence-free survival on both univariate and multivariable analyses (p = 0.006, 0.007). DSGb5 expression in prostate biopsy specimens is predictive of lymphovascular invasion and biochemical recurrence-free survival following radical prostatectomy. DSGb5 is a potential biomarker for preoperatively predicting oncological outcomes of prostate cancer.

Familial testicular germ cell tumors in two brothers.

INTRODUCTION: Two percent of testicular germ cell tumors occur in family clusters. Here, we report metachronous testicular germ cell tumors in two brothers. CASE PRESENTATION: An elder brother was diagnosed at the age of 30 years old and the pathological diagnosis was mixed testicular germ cell tumor. A tumor in the younger brother was suspected during testicular self-examination. It was confirmed by ultrasound examination at the age of 30 years old, 3 years and 6 months after the diagnosis of the testicular tumor in elder brother. The pathological diagnosis was pure seminoma. Both brothers had stage 1 testicular germ cell tumors and no recurrence was observed during the follow-up period of 4 years and 4 months and 10 months, respectively. CONCLUSION: Various histological types of tumor can occur in members of one family. Besides genetic predisposition, shared diet, environmental exposure and other factors can contribute to the familial testicular cancer. Testicular self-examination is recommended for family members of a person with testicular germ cell tumor.

Accurate quantification of urinary metabolites for predictive models manifest clinicopathology of renal cell carcinoma.

Using surgically resected tissue, we identified characteristic metabolites related to the diagnosis and malignant status of clear cell renal cell carcinoma (ccRCC). Specifically, we quantified these metabolites in urine samples to evaluate their potential as clinically useful noninvasive biomarkers of ccRCC. Between January 2016 and August 2018, we collected urine samples from 87 patients who had pathologically diagnosed ccRCC and from 60 controls who were patients with benign urological conditions. Metabolite concentrations in urine samples were investigated using liquid chromatography-mass spectrometry with an internal standard and adjustment based on urinary creatinine levels. We analyzed the association between metabolite concentration and predictability of diagnosis and of malignant status by multiple logistic regression and receiver operating characteristic (ROC) curves to establish ccRCC predictive models. Of the 47 metabolites identified in our previous study, we quantified 33 metabolites in the urine samples. Multiple logistic regression analysis revealed 5 metabolites (l-glutamic acid, lactate, d-sedoheptulose 7-phosphate, 2-hydroxyglutarate, and myoinositol) for a diagnostic predictive model and 4 metabolites (l-kynurenine, l-glutamine, fructose 6-phosphate, and butyrylcarnitine) for a predictive model for clinical stage III/IV. The sensitivity and specificity of the diagnostic predictive model were 93.1% and 95.0%, respectively, yielding an area under the ROC curve (AUC) of 0.966. The sensitivity and specificity of the predictive model for clinical stage were 88.5% and 75.4%, respectively, with an AUC of 0.837. In conclusion, quantitative analysis of urinary metabolites yielded predictive models for diagnosis and malignant status of ccRCC. Urinary metabolites have the potential to be clinically useful noninvasive biomarkers of ccRCC to improve patient outcomes.

Intraoperative hypothermia is a significant prognostic predictor of radical cystectomy especially for stage II muscle-invasive bladder cancer.

The objective of this study was to evaluate intraoperative hypothermia as a predictor of complication and prognosis in patients with muscle-invasive bladder cancer treated with radical cystectomy.The data of 124 patients treated with radical cystectomy for muscle-invasive bladder cancer in our department, from 2003 to 2016, were retrospectively collected. The patients were divided into 2 groups according to the lowest intraoperative deep body temperature, that is, the hypothermia group (<96.8°F) and the normothermia group (≥96.8°F). Preoperative and intraoperative variables were compared among the 2 groups, and factors associated with complications, recurrences, and survivals were analyzed.Sixty-eight (54.8%) of the 124 patients presented intraoperative hypothermia. There was no significant difference in the patient's characteristics between the 2 groups. Postoperative complications (Clavien-Dindo ≤III) of any types occurred in 15 patients (22.1%) in the hypothermia group, as compared with 8 patients (14.3%) in the normothermia group (P = .27). The hypothermia group had a higher pathologic stage (P = .029) and a higher recurrence rate within 12 months (P = .013), as compared with the normothermia group. Intraoperative hypothermia was an independent prognostic factor for overall survival in all patients (hazard ratio [HR] 2.47; 95% confidence interval [CI], 1.01-2.85; P = .047). When stratified by disease stage, stage II intraoperative hypothermia was an independent prognostic factor for disease-free survival (HR 3.35; 95% CI, 1.27-8.83; P = .015) and overall survival (HR 4.24; 95% CI, 1.38-12.9; P = .011).This study suggests that intraoperative hypothermia could be a significant predictor for recurrence and survival in muscle-invasive bladder cancer treated with radical cystectomy.

[PHEOCHROMOCYTOMA CRISIS WITH MIBG SCINTIGRAPHY NEGATIVE: A CASE REPORT].

We report a case of pheochromocytoma crisis with negative MIBG scintigraphy. A 48-year-old man was admitted for hypertension crisis. Computed tomographic scan revealed a 60 mm right adrenal mass. The MIBG scintigraphy was negative, but we diagnosed pheochromocytoma crisis because of high blood catecholamine levels. We successfully managed the patient's hemodynamics through medical treatment and the patient was able to recover from the crisis. After appropriate preparation, the tumor was removed via laparotomy. SDHB mutation, related to the negative MIBG scintigraphy, was also denied pathologically by immunostaining procedures. Histopathologically, it showed a wide range of necrotic images. So the cause of the crisis was thought to be the release of a large amount of catecholamine from necrotic tumor cells. It was thought that scintigraphy became negative due to the decreased MIBG uptake of tumor cells with extensive necrosis.

Bladder cancer metastasis producing beta-human chorionic gonadotropin, squamous cell carcinoma antigen, granulocyte-colony stimulating factor, and parathyroid hormone-related protein.

INTRODUCTION: In urothelial cancer, several paraneoplastic syndromes can be triggered by the aberrant expression of hormones, growth factors or lymphokines by tumor cells. CASE PRESENTATION: A 71-year-old female patient underwent radical cystectomy for muscle-invasive urothelial cancer. Shortly after the operation, the patient presented with a leukemoid reaction and hypercalcemia. Computed tomography scans revealed a rapidly progressing tumor on the left pelvic side, and serum levels of granulocyte-colony stimulating factor, parathyroid hormone-related protein, and beta human chorionic gonadotropin were elevated. The patient also tested positive for serum squamous cell carcinoma antigen. Hypercalcemia was successfully treated with denosumab. However, the patient's leukocyte counts steadily increased, her condition deteriorated and she passed away. CONCLUSION: To the best of our knowledge, this is the first report of urothelial cancer that tested positive for four tumor markers. The findings support the idea that poorly differentiated bladder carcinomas can ectopically secrete multiple proteins causing pleiotropic paraneoplastic syndromes.

Newly Identified t(2;17)(p15;q24.2) Chromosomal Translocation Is Associated with Dysgenetic Gonads and Multiple Somatic Anomalies.

Campomelic dysplasia (CD) is a skeletal dysplasia characterized by shortened and bowed long bones, airway instability, the potential for disorders of sexual differentiation (DSD), and Pierre Robin Sequence (PRS) with cleft palate, midface hypoplasia and laryngotrachemomalacia. CD is caused by alterations in the Sex-determining region of the Y chromosome (SRY)-related-box 9 (SOX9), which has important roles in tissue and sexual differentiation. The SOX9 gene and the enhancer regions of SOX9 are located at chromosome 17q24.3. We report a 6-year-old phenotypically female referred to our department because of precocious puberty. The patient was born with Tetralogy of Fallot (TOF) and PRS. Skeletal X-ray examination showed only 11 pairs of ribs and bilateral bowed radiuses. Endocrine evaluations showed that increased levels of serum testosterone, and chromosomal analysis revealed a 46, XY, t(2;17)(p15;q24.2) karyotype. The patient was diagnosed with peripheral precocious puberty caused by over-secretion of testosterone by gonadoblastoma originating from dysgenetic gonads with Y-chromosome-related DSD. Multiple somatic abnormalities and DSD indicated that the patient might have CD. Laparoscopy revealed bilateral dysgenetic gonads, and these were removed in the successive operation to prevent malignant transformation and virilization, caused by dysgenetic gonads with Y chromosomal materials. It is highly suggestive that the chromosomal translocation of 17q 24.2 may cause DSD and multiple somatic abnormalities, including CD, although the identified 17q breakpoint was located outside of known SOX9 enhancer regions. Thus, a hitherto unknown enhancer may be present at 17q24.2. This is the first reported case of CD with a translocation breakpoint at 17q24.2.

[High Orchidectomy and Histopathology to Differentiate Granulomatous Orchitis from Testicular Malignancy : Case Report and Literature Review].

A 59-year-old man presented with pain and swelling of the right scrotum. Magnetic resonance imaging revealed a mass withsignal intensity similar to background on an apparent diffusion coefficient (ADC)-map of the upper region of the right testis. Inflammation was considered, but a testicular tumor could not be ruled out. Right high orchidectomy and histopathological assessment revealed granulomatous orchitis. The cause, clinical course and treatment of rare granulomatous orchitis remain unknown. Granulomatous orchitis and testicular tumor are difficult to discriminate, and high orchidectomy is usually applied along with histopathological assessment to achieve a definitive diagnosis. On the other hand, some patients who were only medically treated for granulomatous orchitis have recovered. We recently found that diffusionweighted imaging and ADC values derived from magnetic resonance images can differentiate testicular tumor from orchitis. We suggest an algorithm for the diagnosis and treatment of granulomatous orchitis considering the present patient and previous reports.

[Two Cases of Urachal Carcinoma Treated by TS-1/CDDP as Adjuvant Chemotherapy].

Case 1 : A 48-year-old man presenting with gross hematuria was suspected to have a tumor located in the bladder dome. He was referred to our department for further examination and treatment. Cystoscopy showed a dome-shaped mass in the supravesical region. Computed tomography and magnetic resonance imaging indicated the possibility of urachal carcinoma and peritoneal dissemination. Therefore, partial cystectomy with urachal resection was performed. The intraoperative findings were disseminated peritoneal nodules and mucus entering the peritoneal cavity from the tumor. On pathological examination, the tumor was classified as a mucinous-type adenocarcinoma, and 6 courses of TS-1/cisplatin (CDDP) therapy were administered to the patient as adjuvant chemotherapy. To date (10 months since the surgery), there has been no disease progression. Case 2 : A 76-year-old woman was referred to our department with a finding of a tumor in the bladder dome during her detailed examination for lung tumors. Cystoscopy showed nodular tumors, indicating lung metastases of the urachal carcinoma. Therefore, partial cystectomy with urachal resection was performed. On pathological examination, the tumor was classified as an enteric-type adenocarcinoma, and 2 courses of TS-1/CDDP therapy were administered to the patient as adjuvant chemotherapy. However, due to the development of marked bone marrow depression, the drugs had to be discontinued. Nonetheless, the lung metastases markedly diminished in size. To date (9 months since the discontinuation of chemotherapy), there has been no disease progression.

Dedifferentiated Liposarcoma in the Spermatic Cord Finally Diagnosed at 7th Resection of Recurrence: A Case Report and Bibliographic Consideration.

Liposarcoma in the spermatic cord is infrequent, and accurate diagnosis of histopathological subtype is often difficult in spite of the importance of differential diagnosis for adequate treatment. A 54-year-old man underwent left-sided high orchiectomy with inguinal lymphadenectomy for a spermatic cord tumor in July 2006. The initial histopathological report diagnosed leiomyosarcoma in the spermatic cord. He then underwent surgeries for repeated recurrences a further 6 times between July 2008 and May 2014. Pathological finding at the 7th resection of the recurrent tumor was osteosarcoma, which was uncommon in the spermatic cord. With a thorough overview of all specimens, the histopathological diagnosis was finally confirmed as dedifferentiated liposarcoma because of a biphasic pattern in the specimen of high orchiectomy at the first resection. A biphasic pattern represents high-grade sarcoma like osteosarcoma and well-differentiated liposarcoma, and is characteristic of dedifferentiated liposarcoma. Although the dedifferentiated type is one of poor prognosis, the diagnosing of liposarcoma histopathologically was found to be difficult throughout this case. In this report we discuss the accurate histopathological diagnosis of liposarcoma in the spermatic cord in order to prevent repeated recurrences based on a review of the literature, as well as the difficulty in recognizing dedifferentiated liposarcoma macroscopically and morphologically. Our experience suggests that, after much difficulty, accurate histopathological diagnosis of liposarcoma in the spermatic cord is still clinically challenging.

Serum G-CSF May Be a More Valuable Biomarker than Image Evaluation in G-CSF-Producing Urothelial Carcinoma: A Case Report.

Granulocyte colony-stimulating factor (G-CSF)-producing urothelial carcinomas (UCs) are rare and have a poor prognosis. According to the literature, treatment for G-CSF-producing UCs is very difficult. We experienced 2 cases of UC presenting with leukocytosis. In these cases, serum G-CSF levels were higher than the reference value with leukocytosis at diagnosis, and the resected specimens were positive for anti-G-CSF immunostaining. One case had a good prognosis and the other case died after 9 months from diagnosis. A change in serum G-CSF levels was reportedly an effective tumor marker in several reports. In the present cases, evaluation of serum G-CSF levels was found to be more sensitive than computerized tomography. The treatment and outcomes of UC-producing G-CSFs and the efficacy of serum G-CSF as a tumor marker are discussed based on our cases and a review of the literature.

[Availability of Local Therapy to Castration-Resistant Prostate Cancer for M0 Patients with Initial Prostate Specific Antigen 100 ng/ml or Higher].

Prostate cancer patients with initial PSA 100 ng/ml or greater who received transrectal ultrasoundguided prostate biopsy and were staged as M0 by imaging studies from 2011 to 2014 in seven hospitals, were enrolled in the study. Castration-resistant prostate cancer (CRPC)-free survival was compared between the two treatment groups : androgen deprivation therapy (ADT) alone and ADT plus local therapy. Of 142 prostate cancer patients with initial PSA 100 ng/ml or greater, 49 (34.5%) had no metastases and final analysis was performed on 46 patients. Thirty one M0 patients received ADT alone, and 15 received ADT plus local therapy. During follow-up (median 31 months, range 1-56 months) 13 patients (42%) in the ADT alone group progressed to CRPC. One- and two-year CRPC-free survival rates were 72.5 and 53%, respectively. No patients with ADT plus local therapy developed CRPC, and time to CRPC was prolonged significantly (p=0.002). On multivariate analysis for the group with ADT alone, PSA nadir of more than 0. 2 ng/ml and cN1 were independent predictors for progression to CRPC (p=0.009, 0.031). About one third of prostate cancer patients with initial PSA 100 ng/ml or greater had clinically no metastases. Local therapy to prostate combined with ADT may prolong time to CRPC compared with ADT alone. A subset of men with a PSA nadir of more than 0.2 ng/ml after ADT and cN1 could benefit from local therapy.