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Purpose : To evaluate the prognostic value of prostate-specific antigen nadir (nPSA) after high-dose-rate (HDR) brachytherapy in clinically non-metastatic high-risk prostate cancer patients. Material and methods : Data from 216 patients with high-risk or locally advanced prostate cancer who underwent HDR brachytherapy and external beam radiation therapy with long-term androgen deprivation therapy (ADT) between 2003 and 2008 were analyzed. The median prostate-specific antigen (PSA) level at diagnosis was 24 ng/ml (range: 3-338 ng/ml). The clinical stage was T1c-2a in 55 cases (26%), T2b-2c in 48 (22%), T3a in 75 (35%), and T3b-4 in 38 (17%). The mean dose to 90% of the planning target volume was 6.3 Gy/fraction of HDR brachytherapy. After 5 fractions, external beam radiation therapy with 10 fractions of 3 Gy was administered. All patients initially underwent neoadjuvant ADT for at least 6 months, and adjuvant ADT was continued for 36 months. The median follow-up was 7 years from the start of radiotherapy. Results : The 7-year PSA relapse-free rate among patients with a post-radiotherapy nPSA level of ≤ 0.02 ng/ml was 94%, compared with 23% for patients with higher nPSA values (HR = 28.57; 95% CI: 12.04-66.66; p < 0.001). Multivariate analysis revealed that the nPSA value after radiotherapy was a significant independent predictor of biochemical failure, whereas pretreatment predictive values for worse biochemical control including higher level of initial PSA, Gleason score ≥ 8, positive biopsy core rate ≥ 67%, and T3b-T4, failed to reach independent predictor status. The 7-year cancer-specific survival rate among patients with a post-radiotherapy nPSA level of ≤ 0.02 ng/ml was 99%, compared with 82% for patients with higher nPSA values (HR = 32.25; 95% CI: 3.401-333.3; p = 0.002). Conclusions : A post-radiotherapy nPSA value of ≤ 0.02 ng/ml was associated with better long-term biochemical tumor control even if patients had pretreatment predictive values for worse control.

Background We evaluated a five-tiered Gleason grade groups arising from the 2014 International Society of Urological Pathology consensus conference on prognostic prediction in clinical stage T3a (extracapsular invasion) and T3b (seminal vesicle involvement) prostate cancer undergoing high-dose-rate brachytherapy (HDR-BT). Methods From November 2003 to December 2012, 283 patients with stage T3 prostate cancer received HDR-BT and external beam radiation therapy (EBRT) with long-term androgen deprivation therapy (ADT). Of these, 203 (72%) and 80 (28%) patients had stage T3a and T3b disease, respectively. The mean dose to 90% of the planning target volume was 7.5 Gy/fraction of HDR-BT. After five fractions, EBRT with 10 fractions of 3 Gy was administered. All patients first underwent ≥6 months of neoadjuvant ADT, and adjuvant ADT continued for 36 months. Median follow-up was 74 months from the start of radiotherapy. Results The 10-year biochemical recurrence (BCR) -free rate for stage T3a and T3b disease was 79% and 64%, respectively (P = 0.0083). The 10-year cancer-specific survival (CSS) rate for stage T3a and T3b was 96% and 91%, respectively (P = 0.0305). Although grade groups ≥4 were independent predictors for BCR in cT3a patients (P = 0.0270), they failed to significantly predict prostate cancer-specific mortality (PCSM) among cT3a patients. Among cT3b patients, grade group 5 was a significant predictor of both BCR (P = 0.0017) and PCSM (P = 0.0233). Among stage T3a patients, no significant difference existed in 10-year CSS between grade groups 5 and 4 (94% vs 97%, P = 0.3960). In contrast, grade group 5 had a significantly worse outcome in 10-year CSS than grade group 4 among stage T3b patients (74% vs 100%, P = 0.0350). Conclusions Stage T3a patients with grade groups 4/5 and stage T3b with grade group 4 had fairly low PCSM risk. Approximately one of four patients among stage T3b patients with grade group 5 showed PCSM after combined HDR-BT and EBRT with long-term ADT. Stage T3b patients with grade group 5 may have a greater risk for PCSM.

Purpose: The purpose of this work was to report measured catheter displacement prior to the delivery of highdose-rate brachytherapy (HDR) in the treatment of prostate cancer. Material and methods: Data from 30 prostate cancer patients treated with HDR brachytherapy were analyzed retrospectively. Eighteen transperineal hollow catheters were inserted under transrectal ultrasound guidance. Gold marker seeds were also placed transperineally into the base and apex of the prostate gland. Five treatment fractions of 7.5 Gy each were administered over 3 days. The patient underwent CT scanning prior to each treatment fraction. Catheter displacement was measured from the pre-treatment CT dataset reconstructed at 1.25 mm slice thickness. Results: Most of catheters were displaced in the caudal direction. Variations of 18 catheters for each patient were small (standard deviations < 1 mm for all but one patient). Mean displacements relative to the apex marker were 6 ± 4 mm, 12 ± 6 mm, 12 ± 6 mm, 12 ± 6 mm, and 12 ± 6 mm from plan to 1 st , 2 nd , 3 rd , 4 th , and 5 th fractions, respectively. Conclusions: Our results indicate that catheter positions must be confirmed and if required, adjusted, prior to every treatment fraction for the precise treatment delivery of HDR brachytherapy, and to potentially reduce over-dosage to the bulbo-membranous urethra. J Contemp Brachytherapy 2014; 6, 2: 161–166 DOI: 10.5114/jcb.2014.43619

Introduction Treating adrenal metastases from primary malignancies with laparoscopic adrenalectomy (LA) remains controversial. The aim of this study was to evaluate the feasibility, effectiveness and efficiency of LA for solitary adrenal metastasis. Methods From November 2003 to September 2012, eight consecutive patients with adrenal metastasis were treated with LA. A retrospective study was conducted, and clinical and histological data were analyzed. Results All LA were successfully performed. There were no major complications, blood transfusions or conversions to open adrenalectomy. The patients included seven men and one woman with a median age of 59 years at the time of operation. Adrenal metastases were most commonly noted to be from non-small-cell lung cancer (four patients) and renal cell carcinoma (four patients). The majority of adrenal metastases were unilateral (right: one patient; left: seven patients). One patient had bilateral metastases. The median overall survival was 14 months. Four patients (two with non-small-cell lung cancer; two with renal cell carcinoma) were alive with no evidence of metastatic disease as of October 2013. Conclusion LA is a safe and effective procedure for patients with isolated metastases. Surgical resection with LA for a solitary adrenal metastasis from primary malignancy can achieve a good prognosis.

The purpose of this study was to report the outcomes of high-dose-rate (HDR) brachytherapy and hypofractionated external beam radiotherapy (EBRT) combined with long-term androgen deprivation therapy (ADT) for National Comprehensive Cancer Network (NCCN) criteria-defined high-risk (HR) and very high-risk (VHR) prostate cancer. Data from 178 HR (n = 96, 54%) and VHR (n = 82, 46%) prostate cancer patients who underwent (192)Ir-HDR brachytherapy and hypofractionated EBRT with long-term ADT between 2003 and 2008 were retrospectively analyzed. The mean dose to 90% of the planning target volume was 6.3 Gy/fraction of HDR brachytherapy. After five fractions of HDR treatment, EBRT with 10 fractions of 3 Gy was administered. All patients initially underwent ≥ 6 months of neoadjuvant ADT, and adjuvant ADT was continued for 36 months after EBRT. The median follow-up was 61 months (range, 25-94 months) from the start of radiotherapy. The 5-year biochemical non-evidence of disease, freedom from clinical failure and overall survival rates were 90.6% (HR, 97.8%; VHR, 81.9%), 95.2% (HR, 97.7%; VHR, 92.1%), and 96.9% (HR, 100%; VHR, 93.3%), respectively. The highest Radiation Therapy Oncology Group-defined late genitourinary toxicities were Grade 2 in 7.3% of patients and Grade 3 in 9.6%. The highest late gastrointestinal toxicities were Grade 2 in 2.8% of patients and Grade 3 in 0%. Although the 5-year outcome of this tri-modality approach seems favorable, further follow-up is necessary to validate clinical and survival advantages of this intensive approach compared with the standard EBRT approach.

GLIPR1 is a p53 target gene known to be downregulated in prostate cancer, and increased endogenous GLIPR1 expression has been associated with increased production of reactive oxygen species, increased apoptosis, decreased c-Myc protein levels and increased cell cycle arrest. Recently, we found that upregulation of GLIPR1 in prostate cancer cells increases mitotic catastrophe through interaction with heat shock cognate protein 70 (Hsc70) and downregulation of Aurora kinase A and TPX2. In this study, we evaluated the mechanisms of recombinant GLIPR1 protein (glioma pathogenesis-related protein 1-transmembrane domain deleted [GLIPR1-ΔTM]) uptake by prostate cancer cells and the efficacy of systemic GLIPR1-ΔTM administration in a prostate cancer xenograft mouse model. GLIPR1-ΔTM was selectively internalized by prostate cancer cells, leading to increased apoptosis through reactive oxygen species production and to decreased c-Myc protein levels. Interestingly, GLIPR1-ΔTM was internalized through clathrin-mediated endocytosis in association with Hsc70. Systemic administration of GLIPR1-ΔTM significantly inhibited VCaP xenograft growth. GLIPR1-ΔTM showed no evidence of toxicity following elimination from mouse models 8 hr after injection. Our results demonstrate that GLIPR1-ΔTM is selectively endocytosed by prostate cancer cells, leading to increased reactive oxygen species production and apoptosis, and that systemic GLIPR1-ΔTM significantly inhibits growth of VCaP xenografts without substantial toxicity.

Introduction The objective of this study is to clarify whether symphysiotomy is an essential procedure combined with the laparoscopic pyeloplasty for the surgical treatment of ureteropelvic junction obstruction related to horseshoe kidney. Methods We retrospectively reviewed five horseshoe kidney patients with symptomatic hydronephrosis who underwent laparoscopic transperitoneal Anderson–Hynes pyeloplasty without symphysiotomy between July 2002 and October 2011. Results All procedures were completed successfully without open conversion. Mean operative time and estimated blood loss were 209 min and 40 mL, respectively. Anterior crossing vessels were observed in all cases, and four of them were defined as a principle cause of the obstruction. In the remaining case, intrinsic stenosis of the ureteropelvic junction was noted. Crossing vessels were transposed behind the ureter with ureteropelvic anastomosis at the anterior aspect of these structures. Preoperative symptoms were absent postoperatively in all cases. Diuretic renogram showed that renal function of the side with hydronephrosis was unchanged, but diuretic excretion half-time was diminished in all cases. Conclusion The present data suggest that symphysiotomy can be avoided in many, if not all, cases of hydronephrosis related to horseshoe kidney. Laparoscopic Anderson-Hynes pyeloplasty with transposition of anterior crossing vessels seems effective, especially if aberrant vessels are strongly suspected to be present from the preoperative imaging examination.

Aims: Inflammatory myofibroblastic tumor (IMT) of the urinary bladder is a clinically and histologically uncommon benign tumor that can be easily mistaken for a malignant neoplasm. We sought to determine whether immunohistochemical staining would be evaluated IMT of the urinary bladder. We have also shown the literatures that imminohistochemical staining of IMT was investigated to distinguish malignant lesions using PubMed data base. Methods: Immunohistochemical staining, including anaplastic lymphoma kinase (ALK), p53, cytokeratin, vimentin, desmin, alpha-smooth muscle actin, myoglobin, smooth muscle myosin and S100, was carried out on serial sections from archival specimens of three patients who underwent transurethral resection and partial cystectomy. Results: Immunohistchemical staining in all patients was positive for ALK and weak positive for p53 protein. In the literatures, positive rates of ALK and p53 inthe IMT of the urinary bladder were 60.9% and 53.1%, respectively. Sarcoma and carcinosarcoma were shown in the pathological specimens with negative ALK and strongly positive p53 inthe same data base. Conclusions: Both ALK and p53 were potentially useful protein markers to distinguish between IMT and sarcoma. However, this study was small sample size. Further study was warranted an investigation of the availability of these proteins in IMT.

Approximately 80% of patients with prostate cancer will develop bone metastases, which often lead to bone pain and skeletal-related events. Sr-89 is an established alternative for the palliation of bone pain in prostate cancer. We aimed to assess the effect of Sr-89 radionuclide therapy on quality of life (QOL) in prostate cancer patients with painful bone metastases.Thirteen patients received a single intravenous injection of Sr-89 at a dose of 2.0 MBq/kg. All patients underwent QOL evaluation prior to Sr-89 treatment and 1, 2, and 3 months afterward using the Japanese version of the EORTC QLQ-BM22, EORTC QLQ-C30, a VAS, and face scale. We also evaluated PSA and ALP response and toxicity of the Sr-89 therapy.The pain characteristics subscale of the EORTC QLQ-BM22 was significantly reduced from 1 month onward compared with the baseline. The functional interference and psychosocial aspects subscales were significantly higher than baseline from 2 months onward. At 2 months, VAS indicated a significant reduction in pain as compared to the baseline. Sr-89 therapy caused a nonsignificant reduction in PSA and ALP levels. No patients had leukocyte toxicity, and one patient had grade 3 platelet toxicity.Sr-89 radionuclide therapy can provide not only reduced pain characteristics but also better psychosocial aspects and functional interference in patients with painful bone metastases of prostate cancer.

AIM: To investigate the time course of testosterone (T) recovery after cessation of androgen deprivation therapy (ADT) in patients treated with brachytherapy. METHODS: One-hundred and seventy-four patients treated between June 1999 and February 2009 were studied. Patients were divided into a short-term usage group (≤ 12 mo, n = 91) and a long-term usage group (≥ 36 mo, n = 83) according to the duration of gonadotropin-releasing hormone agonist therapy. Median follow-up was 29 mo in the short-term group and was 60 mo in the long-term group. RESULTS: Cumulative incidence rates of T recovery to normal and supracastrate levels at 24 mo after cessation were 28.8% and 74.6%, respectively, in the long-term usage group, whereas these values were 96.4% and 98.8% in the short-term usage group. T recovery to normal and supracastrate levels occurred significantly more rapidly in the short-term than in the long-term usage group (P < 0.001 and P < 0.001, respectively). Five years after cessation, 22.6% of patients maintained a castrate T level in the long-term usage group. On multivariate analysis, lower T levels (< 10 ng/dL) at cessation of ADT was significantly associated with prolonged T recovery to supracastrate levels in the long-term usage group (P = 0.002). CONCLUSION: Lower T levels at cessation of ADT were associated with prolonged T recovery in the long-term usage group. Five years after cessation of long-term ADT, approximately one-fifth of patients still had castrate T levels. When determining the therapeutic effect, especially biochemical control, we should consider this delay in T recovery.

Background Docetaxel is the first chemotherapy agent approved for treatment of metastatic castration-resistant prostate cancer (mCRPC). The limited survival benefit associated with the quick emergence of resistance and systemic toxicity diminished its efficacy. JNK-mediated apoptosis is one of the mechanisms of docetaxel activity whereas ERK1/2-c-Myc-CXCR4 signaling is implicated in the development of resistance and induction of migration. The aim of this study was to evaluate the hypothesis that the combination treatment with docetaxel and GLIPR1-ΔTM will synergistically induce greater cell death and inhibit the emergence of resistance and development of metastatic potential in prostate cancer (PCa) cells. Methods The synergistic effects of the docetaxel and GLIPR1-ΔTM were evaluated with DNA fragmentation, DAPI staining and MTS using paired t-test and isobologram study. The effects of the drugs on JNK and ERK1/2-c-Myc-CXCR4 signaling were evaluated with Western blot, DNA fragmentation, and MTS assays using the JNK inhibitor SP600125, and CXCR4 siRNA. The results of docetaxel and GLIPR1-ΔTM combination on migration were examined with scratch assay using the CXCR4 inhibitor AMD3100 while our hypothesis was examined in vivo using VCaP orthotopic xenograft model. Results We found that GLIPR1-ΔΤΜ synergized with docetaxel to induce apoptosis in VCaP and PC-3 PCa cells through induction of JNK signaling and concomitant inhibition of ERK1/2-c-Myc-CXCR4 signaling. We showed that JNK activation mediates the apoptotic effects of the drug combination and that CXCR4 knockdown increases its efficacy. We also found that the addition of GLIPR1-ΔΤΜ to docetaxel decreases the migration of VCaP and PC-3 cells. The combination treatment with docetaxel and GLIPR1-ΔTM inhibited tumor growth and decreased metastatic potential in VCaP xenografts more than single agents did. Conclusions Our data suggested that addition of GLIPR1-ΔTM treatment in PCa cells increases the efficacy of docetaxel and may inhibit the emergence of drug resistance; potentially permitting a decrease of docetaxel dose for patients with mCRPC eliminating its systemic toxicities. Electronic supplementary material The online version of this article (doi:10.1186/s12943-015-0395-0) contains supplementary material, which is available to authorized users.

Venous vascular extension is one of the aggressive tumor behaviors especially for renal cell carcinoma (RCC). It has been reported that 4% to 10% have tumor thrombus extending into the venous system among patients with newly diagnosed RCC (Marshall et al., 1970; Hoehn & Hermanek, 1983; Casanova & Zingg, 1991; Hatcher et al., 1991; Pagano et al., 1992). Compared with conservative treatment regimens, surgical resection remains the most effective treatment for these patients (Staehler & Brkovic, 2000). The mean 5-year survival rates of such patients with inferior vena cava involvement undergoing radical surgery for RCC have been reported as 32% to 64% (Neves & Zincke, 1987; Skinner et al., 1989; Montie et al., 1991; Swierzewski et al., 1994; Glazer & Novick, 1996).

Multiple studies have demonstrated overexpression of caveolin-1 (Cav-1) in prostate cancer (PCa) cells and its association with disease progression. In PCa cells, Cav-1 serves multiple diverse functions that appear to be unique in tumor biology. Within those, elevated Cav-1 may lead to the formation of aberrant signaling scaffolds and may actively participate as a signaling molecule. In addition, overexpression of Cav-1 can induce mRNA levels for specific growth factors (GFs), including vascular endothelial GF, transforming GF-β1, and fibroblast GF2, through Akt activities. Importantly, these specific GFs can, in turn, stimulate expression of Cav-1. It is notable that Cav-1 is secreted by PCa cells and that secreted Cav-1 can be taken up by adjacent PCa cells and tumor-associated endothelial cells, through which the tumor-promoting activities of Cav-1 “spread” throughout the tumor microenvironment. Because secreted Cav-1 can enter the blood, the tumor-promoting effects of Cav-1 also manifest at distant sites of metastasis. The pervasive effects of Cav-1 lead to the establishment of a positive-feedback loop that promotes PCa progression through unprecedented effects on the local and metastatic tumor microenvironments. This chapter is a brief discussion of the complex, context-dependent activities of Cav-1, and delineation of its oncogenic functions within the context of PCa.

Background: GLIPR1 is upregulated by p53 in prostate cancer cells and has preclinical antitumor activity. A phase I clinical trial was conducted to evaluate the safety and activity of the neoadjuvant intraprostatic injection of GLIPR1 expressing adenovirus for intermediate or high-risk localized prostate cancer before radical prostatectomy (RP). Methods: Eligible men had localized prostate cancer (T1-T2c) with Gleason score greater than or equal to 7 or prostate-specific antigen 10 ng/mL or more and were candidates for RP. Patients received the adenoviral vector expressing the GLIPR1 gene by a single injection into the prostate followed four weeks later by RP. Six viral particle (vp) dose levels were evaluated: 1010, 5 × 1010, 1011, 5 × 1011, 1012, and 5 × 1012 vp. Results: Nineteen patients with a median age of 64 years were recruited. Nine men had T1c, 4 had T2a, and 3 had T2b and T2c clinical stage. Toxicities included urinary tract infection (n = 3), flu-like syndrome (n = 3), fever (n = 1), dysuria (n = 1), and photophobia (n = 1). Laboratory toxicities were grade 1 elevated AST/ALT (n = 1) and elevations of PTT (n = 3, with 1 proven to be lupus anticoagulant). No pathologic complete remission was seen. Morphologic cytotoxic activity, induction of apoptosis, and nuclear p27Kip1 upregulation were observed. Peripheral blood CD8+, CD4+, and CD3+ T-lymphocytes were increased, with upregulation of their HLA-DR expression and elevations of serum IL-12. Conclusions: The intraprostatic administration of GLIPR1 tumor suppressor gene expressed by an adenoviral vector was safe in men, with localized intermediate or high-risk prostate cancer preceding RP. Preliminary evidence of biologic antitumor activity and systemic immune response was documented. Clin Cancer Res; 17(22); 7174–82. ©2011 AACR.

We analyzed the effects of castration on epididymal white adipose tissue (WAT) in C57BL/6J mice which were fed a regular or high-fat diet. Fourteen days following surgical castration profound effects on WAT tissue such as reductions in WAT wet weight and WAT/body weight ratio, induction of lipolysis and morphologic changes characterized by smaller adipocytes, and increased stromal cell compartment were documented in both dietary groups. Castrated animals had decreased serum leptin levels independent of diet but diet-dependent decreases in serum adiponectin and resistin. The castrated high-fat group had dramatically lower serum triglyceride levels. Immunohistochemical analysis revealed higher staining for smooth muscle actin, macrophage marker Mac-3, and Cxcl5 in the castrated than in the control mice in both dietary groups. We also detected increased fatty-acid synthase expression in the stromal compartment of WAT in the regular-diet group. Castration also reduces the expression of androgen receptor in WAT in the regular-diet group. We conclude that that castration reduces tissue mass and affects biologic function of WAT in mice.

Migration of surgical materials into the urinary tract is very rare. We present a case of spontaneous migration of a metal clip into renal pelvis after laparoscopic pyeloplasty. A 44-year-old woman who had a long history of multiple sclerosis presented with symptomatic left hydronephrosis due to ureteropelvic junction (UPJ) obstruction. Since antegrade endopyelotomy was unsuccessful, the patient underwent laparoscopic Anderson-Hynes pyeloplasty. The UPJ was wrapped with thick inflammatory tissue and a crossing vessel that firmly adhered to the UPJ was found and dissected. Metal clips were used for hemostasis. Although the hydronephrosis was improved and flank pain was completely dissolved, a stone was identified in the pelvis 22 months after the surgery. The stone was formed around a metal clip that had been possibly migrated into the renal pelvis. Transureteral lithotripsy was performed using an 8F ureterofiberscope and a clip was removed.

A 52-year-old woman was referred to our institute for the evaluation of a tumor in her pelvic cavity. The tumor seemed to have arisen from the bladder or urethra, and bilateral iliac lymphadenopathy was seen. Her urethral mucosa looked intact according to the results of cystourethroscopy. Histopathological examination of the biopsy specimens showed clear-cell adenocarcinoma. She underwent radical cystourethrectomy with complete pelvic lymph node dissection and the construction of a bilateral ureterocutaneostomy. Macroscopically, the tumor had arisen from the trigone of the bladder, and histopathological examination of the tumor revealed adenocarcinoma exhibiting solid clear cells with glandular and papillary patterns. The tumor had infiltrated perivesical structure (pT3a), and metastases in multiple pelvic lymph nodes were recognized (pN3). Postoperatively, three courses of systemic combination chemotherapy with 5-fluouracil (FU) and cisplatin, along with a total of 45 Gy of irradiation during the second course of chemotherapy, were conducted. No evidence of the disease has been seen 28 months after the surgery.

Few reports have described port site tumor recurrence following laparoscopic or retroperitoneoscopic radical nephrectomy for renal cell carcinoma. We report a case in which recurrence in the lumbar musculature developed 39 months after retroperitoneoscopic radical nephrectomy. CASE REPORT A 56-year-old male who had been maintained on hemodialysis for 6 years due to chronic renal failure (CRF) had a 6 cm solid mass discovered incidentally on ultrasonography of the left kidney. Computerized tomography (CT) revealed a 5 6 cm solid tumor arising in an atrophic kidney (fig. 1). Findings were consistent with stage T1bN0M0 renal cell carcinoma. The patient underwent retroperitoneoscopic radical nephrectomy via a posterior lumbar approach as described previously. 1 The kidney was evacuated though a posterior skin incision without using an organ entrapment sac. Pathological examination showed grade 2, pT3a clear cell carcinoma of the kidney. The margin was negative for malignant cells. At 39 months postoperatively the patient presented complaining of left lumbar pain around the operation scar. CT demonstrated an enhancing tumor in the lumbar muscles along the evacuation route of the kidney (fig. 2). Needle biopsy followed by pathological examination revealed metastatic renal cell carcinoma. Since the patient refused surgical resection, radiation therapy was administered to control the local symptoms. DISCUSSION

e15026 Background: GLIPR1/RTVP-1 is up-regulated by p53 in prostate cancer (PCa) cells and has preclinical pro-apoptotic, anti- angiogenic, immunostimulatory and metastasis-suppressing activity. A ...