Incidence and location of positive surgical margin among open, laparoscopic and robot-assisted radical prostatectomy in prostate cancer patients: a single institutional analysis.

OBJECTIVE: To evaluate the positive surgical margin rates and locations in radical prostatectomy among three surgical approaches, including open radical prostatectomy, laparoscopic radical prostatectomy and robot-assisted radical prostatectomy. METHODS: We retrospectively reviewed clinical outcomes at our institution of 450 patients who received radical prostatectomy. Multiple surgeons were involved in the three approaches, and a single pathologist conducted the histopathological diagnoses. Positive surgical margin rates and locations among the three approaches were statistically assessed, and the risk factors of positive surgical margin were analyzed. RESULTS: This study included 127, 136 and 187 patients in the open radical prostatectomy, laparoscopic radical prostatectomy and robot-assisted radical prostatectomy groups, respectively. The positive surgical margin rates were 27.6% (open radical prostatectomy), 18.4% (laparoscopic radical prostatectomy) and 13.4% (robot-assisted radical prostatectomy). In propensity score-matched analyses, the positive surgical margin rate in the robot-assisted radical prostatectomy was significantly lower than that in the open radical prostatectomy, whereas there was no significant difference in the positive surgical margin rates between robot-assisted radical prostatectomy and laparoscopic radical prostatectomy. In the multivariable analysis, PSA level at diagnosis and surgical approach (open radical prostatectomy vs robot-assisted radical prostatectomy) were independent risk factors for positive surgical margin. The apex was the most common location of positive surgical margin in the open radical prostatectomy and laparoscopic radical prostatectomy groups, whereas the bladder neck was the most common location in the robot-assisted radical prostatectomy group. The significant difference of positive surgical margin locations continued after the propensity score adjustment. CONCLUSIONS: Robot-assisted radical prostatectomy may potentially achieve the lowest positive surgical margin rate among three surgical approaches. The bladder neck was the most common location of positive surgical margin in robot-assisted radical prostatectomy and apex in open radical prostatectomy and laparoscopic radical prostatectomy. Although robot-assisted radical prostatectomy may contribute to the reduction of positive surgical margin, dissection of the bladder neck requires careful attention to avoid positive surgical margins.

Impact of early changes in serum biomarkers following androgen deprivation therapy on clinical outcomes in metastatic hormone-sensitive prostate cancer.

BACKGROUND: Less evidence is known about the role of early changes in serum biomarker after androgen deprivation therapy (ADT) in patients with metastatic hormone-sensitive prostate cancer (mHSPC). Here we evaluated the impact of pre-treatment prognostic factors and early changes in serum biomarkers on prostate specific antigen (PSA) progression-free and overall survival rates in mHSPC. METHODS: We retrospectively reviewed the medical records of 60 mHSPC patients (median age 72 years) treated with ADT whose laboratory data at baseline and following 12 weeks were available. RESULTS: Forty-four patients (73%) had PSA progression and 27 patients (45.0%) died during a median follow-up of 34 months. The multivariable Cox hazard model demonstrated that a log-transformed baseline PSA level (p = 0.003) and an extent of bone disease (EOD) score of ≥3 (p = 0.004) were statistically associated with an increased risk for PSA progression whereas one unit increase in a log-transformed PSA change (baseline-12 weeks) was associated with a decreased risk for PSA progression (p = 0.004). For overall survival, a high level of alkaline phosphatase (ALP) at 12 weeks was associated with increased risk (p = 0.030) whereas a one-unit increase in the log-transformed PSA change was associated with decreased risk (p = 0.001). CONCLUSIONS: An increased level of PSA at baseline, or an EOD score of ≥3 may be a good predictor of PSA progression, and a high level of ALP at 12 weeks may be a risk predictor of death. A larger decline in PSA at 12 weeks from the baseline was associated with both PSA progression-free and overall survival time. Early changes in serum biomarkers may be useful in predicting poor outcomes in patients with mHSPC who are initially treated with ADT.

Altered miRNA expression in high-fat diet-induced prostate cancer progression.

Recent evidence suggests that a high-fat diet (HFD) plays an important role in prostate carcinogenesis; however, underlying mechanisms largely remain unknown. Here, we investigated microRNA (miRNA) expression changes in murine prostate cancer (PCa) xenografts using two different diets: HFD and control diet. We then assessed the roles and targets of altered miRNAs in HFD-induced PCa progression. We identified 38 up- and 21 downregulated miRNAs in xenografts under HFD conditions using the miRCURY LNA™ microRNA array. The differences in 10 candidate miRNAs were validated using quantitative RT-PCR. We focused on miR-130a because the expression levels were significantly lower in the three PCa cell lines in comparison with benign prostate PINT1B cells. PCa cells cultured in a medium containing HFD mouse serum were associated with significantly higher cell proliferation rates and lower miR-130a expression levels. Further, miR-130a modulated MET expression in PCa cells, and MET was overexpressed in in vitro and in vivo HFD-induced PCa progression models. Moreover, ectopic miR-130a downregulated AR in LNCaP cells and DICER1 in PC-3 and DU145 cells, respectively. In human tissues, as elucidated using laser capture microdissection, the mean miR-130a expression level in cancer epithelium was significantly lower than that in normal epithelium. Furthermore, cytoplasmic MET in PCa tissues was overexpressed in patients with higher body mass index. In conclusion, a substantial number of miRNAs was altered in HFD-induced PCa growth. Specifically, miR-130a was attenuated in HFD-induced PCa progression with MET overexpression. miRNAs thus have implications in the mechanism, prevention and treatment of HFD-induced PCa progression.

[Clinical Outcomes of Anteroposterior Dissection Holmium Laser Enucleation of the Prostate for Benign Prostatic Hyperplasia].

Holmium laser enucleation of the prostate (HoLEP) is a standard surgical procedure for treatment of benign prostatic hyperplasia (BPH). A low incidence of postoperative urinary incontinence in association with anteroposterior dissection HoLEP was recently reported. We evaluated 66 patients with BPH who underwent anteroposterior dissection HoLEP from March 2013 to November 2014. The International Prostate Symptom Score (IPSS), quality of life (QOL) index, maximum flow rate (Qmax), and post-void residual urine volume (PVR) were assessed preoperatively and at 1 and 3 months after treatment. The incidence of postoperative urinary incontinence, which was defined as the requirement of more than one pad per day, was compared between the first and second half of the patient population. Postoperative urination parameters (IPSS, QOL index, Qmax, and PVR) were significantly improved. The incidence of urinary incontinence at 3 months was significantly lower in the second half (4%) than first half (28%) of the patient population (p＝0.020). In conclusion, anteroposterior dissection HoLEP is an effective procedure for the treatment of BPH and can reduce the rate of postoperative urinary incontinence, even in low-volume institutes.

[Extrarenal Retroperitoneal Angiomyolipoma Masquerading as Retroperitoneal Liposarcoma : A Report of Two Cases].

We report two patients with extrarenal retroperitoneal angiomyolipoma masquerading as perinephric liposarcoma. Patient 1 : A 66-year-old man was diagnosed with a retroperitoneal tumor near the right renal hilum on an abdominal computed tomography (CT) performed before surgery for gastric cancer. A diagnosis of extrarenal retroperitoneal angiomyolipoma was made on the basis of negative uptake of fluorine- 18 2-deoxy-2-fluoro-D-glucose positron emission tomography (18F-FDG PET)/CT. However, because the tumor was found to have gradually enlarged at 18 months afterward, he underwent resection of the extrarenal fat tissue together with the right kidney. Patient 2 : A 56-year-old man underwent abdominal ultrasound during a periodic medical examination, which revealed a right retroperitoneal tumor. Because of the findings in the contrast-enhanced CT and positive uptake of 18F-FDG PET/CT, he underwent resection of the extrarenal fat tissue together with the right kidney. The pathological examination of the two tumors confirmed extrarenal angiomyolipoma. The differential diagnosis of extrarenal retroperitoneal angiomyolipoma from retroperitoneal liposarcoma is difficult even with the use of 18F-FDG PET/CT.

[Outcome of Resection of Inferior Vena Cava Superior to the Renal Vein in Renal Cell Carcinoma with Vena Caval Tumor Thrombus].

Surgical management with radical nephrectomy and thrombectomy has often been performed in renal cell carcinoma (RCC) with tumor thrombus infiltrating the inferior vena cava (IVC). We retrospectively reviewed the outcomes of IVC resection without venous reconstruction in patients with RCC and IVC thrombus at our institution. Eight patients with right RCC underwent radical nephrectomy and IVC resection superior to the level of the renal vein without venous reconstruction from August 2005 to February 2015. Thoracotomy, liver mobilization, and extracorporeal circulation were performed based on the IVC thrombus level. We assessed surgical outcomes, perioperative complications, and survival. At presentation, four patients had level IIIa IVC thrombus, three had level IIIb IVC thrombus, and one had level IV IVC thrombus. Perioperative imaging showed that three of the four patients who underwent neoadjuvant molecular targeting therapy achieved down-staging of the tumor thrombus level. The median operative time was 406 min, and the median estimated blood loss was 3,135 ml. With regard to IVC resectionassociated perioperative complications, one patient needed extracorporeal circulation with IVC ligation and Pringle maneuver owing to low blood pressure. Another patient underwent temporary hemodialysis for 8 days after surgery. There were no perioperative deaths, and none of the patients required permanent hemodialysis. Three patients survived the mean observation period of 25 months, including one patient with no recurrence. Three patients achieved long-term survival of more than 2 years. IVC resection without venous reconstruction may be a feasible option for patients with RCC and IVC tumor thrombus. Further study is needed to determine the most appropriate candidates for this procedure.

[Current status of castration-resistant prostate cancer translational research].

Recently, new drugs including abiraterone and enzalutamide have been able to be used for castration resistant prostate cancer(CRPC) patients. However, a subset of these patients who receive the new drugs does not response to the therapies. Furthermore, most patients who initially response to the drugs, progress to secondary resistance eventually. Therefore, it is important to investigate a novel therapeutic target and a novel treatment-selection marker for CRPC. In this review, we focused on AR-V7, TMPRSS2-ERG fusion gene and EP4 antagonist as representative translational researches.

[Scrotal desmoid tumor in a patient with familial adenomatous polyposis].

A 46-year-old man presented to our hospital for further examination following a positive fecal occult blood test. He also had a painless, palpable scrotal mass that had been present for several years, but he had not previously sought treatment. Colonoscopy demonstrated multiple adenomatous polyps and colon cancer ; when taken together with his family history, these findings led to the diagnosis of familial adenomatous polyposis. A computed tomography scan revealed a right intrascrotal tumor, and the patient was referred to our department. Together with digestive surgeons, we carried out scrotal mass resection and colectomy under general anesthesia. On scrotal exploration, a large, solid mass was identified ; it was separate from the testis and epididymis. Although the mass was adhered to the surface of the corpus cavernosum penis, we were able to completely resect the mass along with part of the corpus cavernosum penis. The tumor was composed of abundant collagen fibers and mature fibroblasts. Histopathology revealed the right scrotal mass to be a desmoid tumor. The patient is alive with no evidence of disease 24 months after surgery.

Up-regulation of miR-582-5p regulates cellular proliferation of prostate cancer cells under androgen-deprived conditions.

BACKGROUND: MicroRNAs are noncoding small RNA that negatively regulate target gene expression by binding to the 3'-UTR of mRNA. Previous studies have shown that several microRNAs play a pivotal role in prostate cancer by acting as oncogenes or tumor suppressors. This study was aimed at identifying microRNAs that contribute to the progression to castration resistant prostate cancer. METHODS: MicroRNAs expression profiles of a xenograft model and cell lines were examined by microarray analysis and real-time PCR. Functional analysis of miR-582-5p in cellular proliferation was examined by cell counting. Furthermore, in order to investigate a candidate target of miR-582-5p, microarray analysis and analysis in silico were utilized. RESULTS: MiR-582-5p was identified to be up-regulated at the castration resistant stage of a xenograft model, KUCaP2 and in castration resistant cell line, AILNCaP#1. Overexpression of miR-582-5p increased the number and the percentage of S phase of LNCaP cells under androgen deprived condition. Moreover, suppression of miR-582-5p decreased the number and the percentage of S phase of AILNCaP#1 cells. Furthermore, we identified that miR-582-5p down-regulates EFNB2 expression, which is down-regulated at the castration resistant stage of a xenograft model, KUCaP2 and in castration resistant cell line, AILNCaP#1. CONCLUSIONS: Our results suggest that up-regulation of miR-582-5p contributes to an increase in the proliferation of prostate cancer cells under androgen deprived conditions.

[Clinical outcomes after non-ischemic partial nephrectomy for clinical T1 renal tumors using soft coagulation versus microwave tissue coagulation].

PURPOSE: We have performed non-ischemic partial nephrectomy for clinical T1 renal tumors using microwave tissue coagulation (MTC group) or soft coagulation (soft coagulation group). The clinical outcomes were retrospectively compared between the two groups. MATERIALS AND METHODS: A total of 36 patients were analyzed in this study (22 in the MTC group and 14 in the soft coagulation group). The anatomical characteristics of the renal tumors were assessed using the R.E.N.A.L Nephrometry Score. Renal function was assessed by the estimated glomerular filtration rate. RESULTS: The preoperative estimated glomerular filtration rate was 72.1 ml/min in the MTC group and 65.6 ml/min in the soft coagulation group (p = 0.05). The R.E.N.A.L Nephrometry Score was not significantly different between the two groups. Clavian grade > or = 2 postoperative complications occurred in one patient (4.5%) in the MTC group and one patient (7.1%) in the soft coagulation group. Postoperative local recurrence and distant metastasis occurred in one patient (8.3%) in the soft coagulation group and no patients in the MTC group, which was not a significant difference between the two groups. The median postoperative decrease in estimated glomerular filtration rate was 11.5% in the MTC group and 3.6% in the soft coagulation group. Postoperative renal preservation tended to be better in the soft coagulation group than in the MTC group, but this difference was not significant. CONCLUSION: The use of soft coagulation in non-ischemic partial nephrectomy for the treatment of clinical T1 renal tumors is as effective as that of MTC.

SPA-1 controls the invasion and metastasis of human prostate cancer.

Recent studies suggest that SIPA1 encoding a Rap GTPase-activating protein SPA-1 is a candidate metastasis efficiency-modifying gene in human breast cancer. In this study, we investigated the expression and function of SPA-1 in human prostate cancer (CaP). Immunohistochemical studies of tumor specimens from CaP patients revealed a positive correlation of SPA-1 expression with disease progression and metastasis. The correlation was recapitulated in human CaP cell lines; LNCaP that rarely showed metastasis in SCID mice expressed an undetectable level of SPA-1, whereas highly metastatic PC3 showed abundant SPA-1 expression. Moreover, SIPA1 transduction in LNCaP caused prominent abdominal lymph node metastasis without affecting primary tumor size, whereas shRNA-mediated SIPA1 knockdown or expression of a dominant-active Rap1 mutant (Rap1V12) in PC3 suppressed metastasis. LNCaP transduced with SPA-1 (LNCaP/SPA-1) showed attenuated adhesion to the precoated extracellular matrices (ECM) including collagens and fibronectin, due to defective ECM-medicated Rap1 activation. In addition, LNCaP/SPA-1 showed a diminished level of nuclear Brd4, which is known to bind SPA-1, resulting in reduced expression of a series of ECM-related genes. These results suggest that SPA-1 plays an important role in controlling metastasis efficiency of human CaP by regulating the expression of and interaction with ECM in the primary sites.

Antiandrogen withdrawal syndrome and alternative antiandrogen therapy associated with the W741C mutant androgen receptor in a novel prostate cancer xenograft.

BACKGROUND: The mechanisms underlying antiandrogen withdrawal syndrome (AWS) and alternative antiandrogen therapy (AAT) effectiveness were assumed to be mutations in the androgen receptor (AR), which resulted in an altered response to antiandrogens. The aim of the present study was to test this assumption using the novel prostate cancer xenograft model KUCaP-1 harboring the W741C mutant AR (Yoshida et al., Cancer Res 2005; 65(21): 9611-9616). METHODS: Mice bearing xenograft tumors were castrated, and the long-term sequential changes in tumor volume were observed. To determine whether AWS was observed in this model, bicalutamide (BCL) was orally administered to the castrated mice and then withdrawn. The effect of flutamide (FLT) on the W741C mutant AR was examined with transactivation assays in vitro and with the oral administration of FLT to non-castrated mice harboring KUCaP-1 in vivo. The AAT efficacy against KUCaP-1 was evaluated by changing BCL with FLT. RESULTS: KUCaP-1 regressed significantly after castration and did not re-grow. KUCaP-1 treated with BCL continued to grow even after castration and started regressing 2 months after BCL withdrawal, replicating clinically recognized AWS. The antagonistic effect of FLT against the W741C mutant AR was revealed in vitro and in vivo. AAT with FLT suppressed tumor growth after BCL withdrawal. CONCLUSIONS: KUCaP-1 was an entirely androgen-dependent xenograft and mimicked the clinical phenomena of AWS and AAT caused by the agonistic and antagonistic activity of BCL and FLT, respectively. KUCaP-1 could be an in vivo model for screening novel antiandrogens for the treatment of BCL resistant prostate cancer harboring the W741C mutation in the AR.

A patient with synchronous bilateral low-grade upper tract urothelial carcinoma who underwent nephroureterectomy and total ureterectomy with ileal ureteric replacement.

We present the case of a synchronous bilateral low-grade upper-tract urothelial carcinoma patient who underwent left nephroureterectomy and right total ureterectomy with ileal ureteric replacement resulting in a favorable prognosis. A 66-year-old male presented with bilateral hydronephrosis. Computed tomography revealed left pelvic and right upper-middle ureteral tumors with no lymph node swelling or distant metastasis. The patient underwent a left nephroureterectomy with a bladder cuff, and histopathology revealed a low-grade urothelial carcinoma. Considering the contralateral low-grade nature as revealed in histopathology and the right retrograde ureterography being noninvasive, he underwent a right total ureterectomy with ileal ureteric replacement. Histopathology of the right ureter revealed a low-grade urothelial carcinoma. The patient successfully avoided an anephric status without renal function deterioration for 4 years with a transurethral resection for a recurrent small papillary bladder tumor on 18 months after the total ureterectomy.

Purine-rich element binding protein (PUR) alpha induces endoplasmic reticulum stress response, and cell differentiation pathways in prostate cancer cells.

BACKGROUND: Following androgen ablation treatment for advanced prostate cancer, almost all men relapse after a period of initial response to therapy, which eventually is life threatening. We have previously found that purine-rich element binding protein, PURalpha, was significantly repressed in androgen-independent prostate cancer cell lines in comparison to an androgen-dependent line. Moreover, over-expressing PURalpha in androgen-independent prostate cancer cells attenuated their cell proliferation. The aim of the studies described here was to uncover some of the mechanisms by which over-expression of PURalpha attenuates cell proliferation. METHODS: A set of common genes induced by over-expressing PURalpha both in PC3 and LNCaP cells was analyzed by DNA microarray. The results were then validated utilizing quantitative reverse transcription-PCR. Using a 5.3-kb region of the PSA promoter containing androgen response elements, the participation of PURalpha in androgen regulated gene expression was determined. RESULTS: Genes involved in stress response and cell differentiation were induced in cells over-expressing PURalpha. Some of the genes that are targets of androgen regulation are also induced. Most strikingly, ectopic expression of PURalpha induced transcriptional activity of the 5.3-kb PSA promoter containing androgen response elements, without androgen stimulation. CONCLUSION: Based upon the consideration that some of the genes involved in cell stress and differentiation are also regulated by androgens our data suggest that PURalpha shares some common pathways regulated by the androgen receptor. These findings suggest that regulation of PURalpha expression in prostate cancer cells may serve as a therapeutic target for hormone refractory prostate cancer.

Restoration of cyclin D2 has an inhibitory potential on the proliferation of LNCaP cells.

Despite well known oncogenic function of G1-S cell-cycle progression, cyclin D2 (CCND2) is often silenced epigenetically in prostate cancers. Here we show that CCND2 has an inhibitory potential on the proliferation of androgen receptor (AR)-dependent prostate cancer LNCaP cells. Forced expression of CCND2 suppressed the proliferative ability and induced cell death in LNCaP cells in a cdk-independent manner. Knocking down CCND2 restored the proliferation of LNCaP subclones with relatively high CCND2 expression and low proliferative profiles. Immunoprecipitation using deletion mutants of CCND2 indicated that a central domain of CCND2 is required for binding to AR. A deletion mutant lacking the central domain failed to hinder LNCaP cells. Collectively, our results indicated that CCND2 inhibits cell proliferation of AR-dependent prostate cancer through the interaction with AR. Our study suggests that restoration of CCND2 expression potentially prevents the carcinogenesis of prostate cancer, which is mostly AR-dependent in the initial settings.

Clinical implications of pharmacokinetics of sunitinib malate and N-desethyl-sunitinib plasma concentrations for treatment outcome in metastatic renal cell carcinoma patients.

In this study, we examined the association between the pharmacokinetics (PK) level of sunitinib malate (SU) and its metabolite N-desethyl-sunitinib (DSU) in terms of adverse events (AEs) and clinical outcomes in patients with metastatic renal cell carcinoma (mRCC). The PK of sunitinib (SU and DSU) was examined in 26 patients (20 men and 6 women) with mRCC. The associations between SU/DSU C0 and AE occurrence, best response rate, time to treatment failure, progression-free survival (PFS), and overall survival (OS) were investigated. Occurrence of grade 1 or higher hand-foot syndrome and thrombocytopenia (p = 0.002 and 0.024, respectively) was associated with a high concentration before morning intake (C0) level of SU. Low C0 levels of DSU were significantly associated with drug discontinuation due to disease progression (p = 0.035). Patients with DSU C0 level higher than 15.0 ng/mL showed a tendency toward increased PFS (61 weeks vs 12 weeks, p = 0.004) and OS (36 months vs 8 months, p = 0.040). The C0 level of SU and SU + DSU were not associated with prognosis. The higher level of C0 of SU may predict developing AEs and DSU C0 >15.0 ng/mL may lead to better prognosis of patients treated with sunitinib. PK of sunitinib may be useful for determining adequate dosages and prevention of severe AEs. Further studies are required to establish the utility of the PK of sunitinib in patients with mRCC.

The impact of obesity and adiponectin signaling in patients with renal cell carcinoma: A potential mechanism for the "obesity paradox".

Although obesity increases the risk of renal cell carcinoma (RCC), obese patients with RCC experience longer survival than non-obese patients. However, the mechanism of this "obesity paradox" is unknown. We examined the impact of preoperative BMI, serum total adiponectin (sAd) level, total adiponectin secretion from perinephric adipose tissue, and intratumoral expression of adiponectin receptors on RCC aggressiveness and survival. We also investigated the mechanism underlying enhanced cancer aggressiveness in RCC cells stimulated with exogenous adiponectin. Overweight and obese patients had significantly lower grade cancers than normal patients in all patients and in those without metastasis (p = 0.003 and p = 0.027, respectively). Cancer-specific survival was significantly longer in overweight and obese patients than in normal patients in all patients (p = 0.035). There was a weak inverse correlation between sAd level and BMI in RCC patients (r = -0.344, p = 0.002). Tumor size was slightly correlated with sAd level, and high sAd was significantly associated with poor overall survival rates in patients with non-metastatic RCC (p = 0.035). Adiponectin levels in perinephric adipose tissue and intratumoral AdipoR1/R2 expression were not correlated with RCC aggressiveness or survival. Proliferation significantly increased in 786-O and Caki-2 cells exposed to exogenous adiponectin, whereas cell invasion and migration were unaffected. In addition, exogenous adiponectin significantly inhibited starvation- and metformin-induced apoptosis, and up-regulated p-AMPK and Bcl-xL levels. In summary, low BMI and high adiponectin levels are associated with aggressive cell behaviors and poor survival in surgically-treated RCC patients. The effects of adiponectin on proliferation and apoptosis might underlie the "obesity paradox" of RCC.

Host-related Risk Factors for Adherent Perinephric Fat in Healthy Individuals Undergoing Laparoscopic Living-donor Nephrectomy.

PURPOSE: The purpose of this study is to assess the risk factors and characteristics of adherent perinephric fat (APF) in healthy individuals. PATIENTS AND METHODS: Men who underwent laparoscopic donor nephrectomy were included. Video review was used to divide patients on the basis of APF severity. Relationship between APF scores and clinical and radiographic features was evaluated. RESULTS: Of the 92 patients, 43 (46.7%) and 8 (8.7%) were categorized as APF and severe APF, respectively. The median total operative time was significantly associated with APF severity. Sex, body mass index, and perinephric fat area, stranding, and thickness were significantly associated with severe APF. In the multivariate analysis, perinephric fat areas and stranding were independent risk factors for severe APF (HR, 1.189 and 14.450, respectively). In the 44 analyzed cytokines, levels of sIL-6R in the perinephric adipose tissue-conditioned medium were significantly higher for APF group than that for non-APF group (P=0.049). CONCLUSIONS: Host-related risk factors for APF could predict surgical difficulty in patients undergoing partial nephrectomy.

Inhibition of the RANK/RANKL signaling with osteoprotegerin prevents castration-induced acceleration of bone metastasis in castration-insensitive prostate cancer.

Androgen deprivation therapy (ADT) for patients with metastatic or locally advanced prostate cancer reduces bone mineral density by stimulating receptor activator of nuclear factor kappa-B (RANK) signaling in osteoclasts. The involvement of the RANK/RANKL signaling in ADT-induced acceleration of bone metastasis in castration-insensitive prostate cancer was examined in a murine model using osteoprotegerin (OPG). Male Balb/c nude mice were divided into three groups: the non-castration, castration, and castration + OPG groups. PC-3M-luc-C6 was injected into the left ventricle of the mice. Recombinant OPG was injected intravenously twice weekly in the castration + OPG group. In-vivo imaging system (IVIS®) determined that the prevalence and photon counts of bone metastasis in the castration group were significantly higher than that in the non-castration and castration + OPG groups. The mean number of RANKL-positive osteoblasts and the mean serum RANKL level in the castration group were significantly higher than those in the non-castration group. RANKL-enhanced activation of osteoclasts was attenuated in the castration + OPG group. These results suggest that the mechanisms of RANK/RANKL signaling are involved in the ADT-induced acceleration of bone metastasis in castration-insensitive prostate cancer.

Inverse relationship between insulin receptor expression and progression in renal cell carcinoma.

We investigated the relationship among serum insulin level, insulin receptor (IR) expression in renal cell carcinoma (RCC), and outcomes in patients with RCC who underwent nephrectomy. We also explored the role of insulin signaling in RCC progression in a murine RCC allograft RENCA model using metformin to treat hyperinsulinemia induced by a high-carbohydrate diet. Clinically, the IR expression level in RCC tissue was significantly lower in patients with tumor stage pT2-4 and/or distant metastases. The IR expression level in RCC tissue was significantly lower in patients with preoperative serum C-peptide levels greater than or equal to the median than in patients with levels less than the median. High IR expression level was significantly associated with better disease-free and overall survival after nephrectomy. The IR expression level was significantly higher in murine subcutaneous flank tumors of the low-carbohydrate diet group and high-carbohydrate diet plus metformin group than of the high­carbohydrate diet group. In vivo progression of murine tumors was not significantly enhanced by hyperinsulinemia induced by a high-carbohydrate diet and was significantly inhibited by metformin in both the low- and high­carbohydrate diet groups. IR expression in RCC tissue was inversely associated with cancer progression in the clinical and murine experimental model studies. The clinical and murine allograft model study results suggested that hyperinsulinemia does not promote RCC progression. Decreased IR expression in high­stage RCC tumors with poor prognosis may be the result of downregulation induced by the host's hyperinsulinemia.