The association between local atherosclerosis of the prostatic artery and benign prostatic enlargement in humans: Putative mechanism of chronic ischemia for prostatic enlargement.

BACKGROUND: To investigate the possible pathogenesis of the benign prostatic enlargement (BPE) induced by local atherosclerosis, the association between local atherosclerosis and prostatic enlargement was investigated, and molecular biological analyses were performed using human prostatectomy specimens. METHODS: A total of 69 consecutive patients who underwent robot-assisted radical prostatectomy (RARP) participated in this prospective study. To evaluate actual local atherosclerosis, prostatic arteries were removed during RARP. Microscopic assessment of local atherosclerosis was classified as one of three degrees of narrowing (minimal, moderate, and severe) according to the degree of obstruction of the inner cavity of the prostatic artery. The expressions of several mediators related to chronic ischemia and cell proliferation of the prostate were investigated by immunohistochemistry. RESULTS: The median age of the present cohort was 68 (range: 55-75) years. Although there was no relationship between local atherosclerosis and lower urinary symptoms evaluated by questionnaires, local atherosclerosis was significantly more severe in patients who had a history of treatment for benign prostatic hyperplasia (P = 0.02). Prostate size was significantly larger in the severe local atherosclerosis group than in the minimal and moderate local atherosclerosis groups (P < 0.001 and P = 0.03, respectively). Thepositive expression rates of hypoxia-inducible factor (HIF)-1α, malondialdehyde (MDA), transforming growth factor (TGF)-ß1 , and basic fibroblast growth factor (bFGF) in the prostate were significantly higher in patients with local atherosclerosis than in patients without local atherosclerosis (all P < 0.01, respectively). CONCLUSIONS: In human surgical specimens, there is evidence that local atherosclerosis of the prostatic artery is significantly associated with prostate size. Given the molecular evidence provided in this study, the putative mechanism for this relationship is that chronic ischemia induced upregulation of oxidative stress pathways, leading to BPE.

Effects of barbed suture during robot-assisted radical prostatectomy on postoperative tissue damage and longitudinal changes in lower urinary tract outcome.

OBJECTIVE: To compare the postoperative tissue damage and longitudinal changes in functional and patient-reported outcomes after vesicourethral anastomosis with barbed suture and nonbarbed suture in robot-assisted laparoscopic radical prostatectomy (RARP). MATERIALS AND METHODS: This was a prospective cohort study involving 88 consecutive patients who underwent RARP. These patients were categorized into the barbed suture group (n = 50) and the nonbarbed suture group (n = 38). Urethral and periurethral damages determined by magnetic resonance imaging at nine months after RARP were compared using generalized linear models. The International Prostate Symptom Score (IPSS), quality of life (QOL) index, uroflowmetry, and the 1-h pad test were measured at baseline and at 1, 3, 6, 9, and 12 months after RARP. The findings were analyzed using mixed-effects models. Confounding was adjusted for using propensity score covariate adjustment. RESULTS: The likelihood of having Grade 2/3 urethral and periurethral damages was greater in the barbed suture group than in the nonbarbed suture group (adjusted risk ratios: 2.98 and 3.85, respectively). IPSS, QOL index, and urinary leakage transiently increased at one month after RARP in both groups. QOL index was higher in the barbed suture group than in the nonbarbed suture group at 1, 9, and 12 months (P = 0.023, P = 0.025, and P = 0.011, respectively). The barbed suture group had significantly more cases of urinary incontinence than the nonbarbed suture group at 3 months (P = 0.041). Other outcomes were comparable between the two groups at all time points. CONCLUSIONS: This cohort study showed that, after RARP, barbed sutures during VUA induced more severe tissue damage as determined by MRI and greater transient aggravation of QOL and continence function than nonbarbed sutures. The present findings suggest that using nonbarbed sutures during VUA may facilitate earlier acquisition of urinary QOL and urinary continence.

Impact of Sulfatase-2 on cancer progression and prognosis in patients with renal cell carcinoma.

Heparan sulfate-specific endosulfatase-2 (SULF-2) can modulate the signaling of heparan sulfate proteoglycan-binding proteins. The involvement of SULF-2 in cancer growth varies by cancer type. The roles of SULF-2 expression in the progression and prognosis of renal cell carcinomas (RCC) have not yet been fully clarified. In the present study, the expression levels of SULF-2 mRNA and protein in 49 clinical RCC samples were determined by RT-PCR and immunostaining. The existence of RCC with higher SULF-2 expression and lower SULF-2 expression compared to the adjacent normal kidney tissues was suggested. High SULF-2 expression was correlated with an early clinical stage and less invasive pathological factors. Low SULF-2 expression was correlated with an advanced stage and higher invasive factors. Three-year cancer-specific survival (CSS) for high SULF-2 RCC and low SULF-2 RCC were 100% and 71.4%, respectively (log-rank P = 0.0019), with a significantly shorter CSS observed in low SULF-2 RCC patients. The influence of SULF-2 expression level on Wnt/VEGF/FGF signaling, cell viability and invasive properties was examined in three RCC cell lines, Caki-2, ACHN and 786-O, using a SULF-2 suppression model involving siRNA or a SULF-2 overexpression model involving a plasmid vector. High SULF-2 expression enhanced Wnt signaling and Wnt-induced cell viability, but not cell invasion. In contrast, low levels of SULF-2 expression significantly enhanced both cell invasion and viability through the activation of VEGF/FGF pathways. RCC with lower SULF-2 expression might have a higher potential for cell invasion and proliferation, leading to a poorer prognosis via the activation of VEGF and/or FGF signaling.

[Robot-assisted radical prostatectomy: surgical techniques].

Robot-assisted radical prostatectomy (RARP) for the patients with localized prostate cancer is increasingly being adopted around the world. The da Vinci surgical system (Intuitive Surgical, Sunnyvale, CA, USA) provides the advantages of simplification and precision of exposure and suturing because of allowing movements of the robotic arm in real time with increased degree of freedom and magnified 3-dimensional view. Therefore, RARP has been expected to provide superior therapeutic benefit to patients in terms of surgical outcome to open or laparoscopic radical prostatectomy. In this review, we provide our technical aspects and tips and tricks of RARP to improve surgical outcome and postoperative quality of life.

Expression and Function of LPA1 in Bladder Cancer.

PURPOSE: LPA is one of several physiologically active lipid mediators that promote cell proliferation and invasion, and are present in serum, ascites and urine. LPA receptor is a G-protein coupled receptor that is considered a potential therapeutic target for some malignant cancers. We evaluated the expression of LPA receptors in bladder cancer and the effect of LPA in bladder cancer invasion. MATERIALS AND METHODS: Using real-time polymerase chain reaction and immunohistochemical staining we determined LPA receptor expression in bladder cancer specimens from patients with bladder cancer, including 12 with Ta or T1 and 15 with T2-T4 disease. ROCK expression, myosin light chain phosphorylation and Matrigel™ invasion assays were done and morphological observations were made to assess LPA effects in T24 cells, which were derived from bladder cancer. RESULTS: Notably LPA1 mRNA expression was significantly higher in muscle invasive bladder cancer specimens than in nonmuscle invasive specimens. Strong LPA1 expression was evident on cell membranes in muscle invasive specimens. T24 cell invasion was increased by LPA treatment and invasiveness was decreased by LPA1 siRNA or LPA1 inhibitor. LPA treatment increased ROCK1 expression and myosin light chain phosphorylation, and induced morphological changes, including lamellipodia formation and cell rounding. CONCLUSIONS: Results indicate that LPA signaling via LPA1 activation promoted bladder cancer invasion. LPA1 might be useful to detect bladder cancer with highly invasive potential and become a new therapeutic target for invasive bladder cancer treatment.

The presence of antibodies against the AD2 epitope of cytomegalovirus glycoprotein B is associated with acute rejection after renal transplantation.

The aim of this study was to evaluate the association between antibodies against cytomegalovirus (CMV) glycoprotein B (gB) and acute rejection after transplantation. Seventy-seven consecutive renal transplant recipients in a D + /R+ setting were studied. Biopsy-proven rejection occurred in 35% of the recipients. Among these recipients, 85% had antibodies against CMV gB. The rate of acute rejection was significantly higher in recipients with antibodies against gB than in those without them. Antibodies against gB can be a useful predictor of acute rejection in renal transplant recipients in a D + /R+ setting.

Involvement of stretch-induced Rho-kinase activation in the generation of bladder tone.

AIMS: The present study investigated the role of the Rho-kinase (ROK) pathway in the maintenance of bladder tone during the storage phase, and its effects on bladder compliance. METHODS: Muscle strips from isolated rat bladder (detrusor strips) were used to evaluate the effects of the ROK inhibitors Y-27632 and HA-1077 on resting tension, which is independent of G-protein coupled pathways. Stretch-induced ROK activation was assessed by measuring phosphorylation of MYPT1 (myosin phosphatase targeting subunit) using Western blotting. The effect of ROK inhibitors on bladder compliance during bladder filling was assessed in an in vitro whole bladder model. RESULTS: Y-27632 and HA-1077 caused concentration-dependent relaxation of detrusor strips. Stretch increased MYPT1-p[Thr853] levels by approximately 1.5-fold in normal Krebs buffer. The ROK inhibitor Y-27632 abolished the stretch-induced increase and reduced the level of MYPT1-p[Thr853] to <50% of the basal values in normal Krebs buffer. Stretch-induced phosphorylation of MYPT1 was independent of Ca(2+) originating from either extracellular or intracellular stores. When tested in the isolated whole rat bladder model, HA-1077 significantly increased bladder compliance at both 3 and 10 µM. CONCLUSIONS: This study demonstrates that the ROK pathway is constitutively active and stretch further activates the ROK pathway, which contributes to the generation of bladder tone, thereby affecting bladder compliance.

Urinary incontinence after robot-assisted radical prostatectomy: pathophysiology and intraoperative techniques to improve surgical outcome.

Robot-assisted radical prostatectomy has been shown to have comparable and possibly improved postoperative continent rates compared with retropubic and laparoscopic radical prostatectomy. However, postoperative urinary incontinence has remained one of the most bothersome postoperative complications. The basic concept of the intraoperative technique to improve postoperative urinary continence is to maintain as normal anatomical and functional structure in the pelvis as possible. Therefore, improved knowledge of the normal structure in the pelvis should lead to a greater understanding of the pathophysiology of urinary incontinence, and further development of intraoperative techniques to improve the outcomes of urinary continence. It might be necessary to carry out three steps to realize improvement of the early return of urinary continence after robot-assisted radical prostatectomy: (i) preservation (bladder neck, neurovascular bundle, puboprostatic ligament, pubovesical complex, and/or urethral length, etc.); (ii) reconstruction (posterior and/or anterior reconstruction, and/or reattachment of the arcus tendineus to the bladder neck, etc.); and (iii) reinforcement (bladder neck plication and/or sling suspension, etc.). On the basis of these steps, further modifications during robot-assisted radical prostatectomy should be developed to improve urinary continence and quality of life after robot-assisted radical prostatectomy.

New classification for men with lower urinary tract symptoms: cluster analysis using the International Prostate Symptom Score.

SUBJECTS AND METHODS: • Secondary analysis of anonymous data from 10,434 patients enrolled in a postmarketing surveillance study of tamsulosin in Japan was performed. Data were prospectively collected through the central register from men diagnosed with LUTS in 1100 medical institutions between October 2004 and March 2005. • Those who had received an α1-adrenoceptor antagonist within 1 week before the initial visit were excluded. • The survey items were International Prostate Symptom Score (IPSS), quality of life (QOL) score, and patient characteristics including age, bodyweight, body mass index, and LUTS-related comorbid conditions. • Data on IPSS items were used in a hierarchical cluster analysis (Ward's method). RESULTS: • Of 10,434 men with LUTS, 9910 were included in the analysis after 5% data trimming (524 patients). Five symptom clusters were identified and the symptom types of each cluster were examined. • The largest cluster (27%) consisted of patients with multiple severe symptoms, i.e. complaining of six or more symptoms with a mean score ≥2.8. In contrast, the second smallest cluster (13%) consisted of patients with minimal symptoms, i.e. complaining of essentially one or two symptom with a mean score ≤2.1. • The other three clusters were labelled based on their dominant symptoms. The clusters were weak stream (27%), storage symptoms (21%) and voiding symptoms (12%). • The storage symptoms group was older, and had more comorbidities. • The distribution of the QOL score was different among the clusters, and the percentage of patients who were very dissatisfied was highest in the multiple severe symptoms group and lowest in the minimal symptoms group. CONCLUSIONS: • Cluster analysis using the IPSS showed that men with LUTS can be classified into five characteristic symptom groups. • A new approach to symptom-based classification may be useful to elucidate the pathology of male LUTS and individualize the therapeutic strategy for affected patients, but further studies are needed.

The effect of atherosclerosis-induced chronic bladder ischemia on bladder function in the rat.

AIMS: To develop a rat model of atherosclerosis-induced chronic bladder ischemia and investigate the effect of chronic bladder ischemia on voiding behavior and bladder function. METHODS: Adult male rats were divided into three groups. The arterial injury (AI) group underwent endothelial injury of the iliac arteries and received a 2% cholesterol diet. The sham group underwent sham operation and received a 2% cholesterol diet. The control group received a regular diet. After 8 weeks, a metabolic cage study and cystometry were performed without anesthesia. Bladder blood flow was measured using a laser Doppler blood flowmeter. Histological examination of the iliac arteries and the bladder was performed. The bladder was also processed for immunohistochemical staining of oxidative stress markers. RESULTS: The metabolic cage study showed that in the AI group, voiding frequency significantly increased while voided volume significantly decreased. Cystometry showed that the frequency of reflex bladder contractions was significantly higher in the AI group. Filling-induced decrease in bladder blood flow was the greatest in the AI group. Histological study showed that in the AI group alone, atherosclerotic occlusion occurred in the iliac arteries as well as in the downstream bladder microvessels. Oxidative stress marker positive cells were more prevalent in the AI bladder than in the other bladders. CONCLUSIONS: Combined with a high-cholesterol diet, endothelial injury of iliac arteries induced arterial occlusive disease in the downstream vessels and consequent bladder ischemia in rats. This model of chronic bladder ischemia showed detrusor overactivity manifested as an increase in voiding frequency.

Suppression of SOCS3 increases susceptibility of renal cell carcinoma to interferon-α.

Interferon (IFN)-α is one of the most commonly used agents in immunotherapy for patients with advanced stage renal cell carcinoma. However, because of the drug resistance to IFN-α, its benefits are limited. In this study, we examined whether repression of suppressor of cytokine signaling (SOCS) proteins, which are involved in the IFN-induced signaling pathway, can overcome the IFN resistance of renal cell carcinoma. The effect of IFN-α on SOCS3 expression and cell proliferation was examined using IFN-resistant 786-O and IFN-sensitive ACHN cell lines. The effects of SOCS3-targeted siRNA on 786-O xenografts were determined by SOCS3 expression, morphological observation, and tumor volume. The SOCS3 mRNA expression level was significantly increased by IFN-α stimulation in 786-O, but not in ACHN cells. The overexpression of SOCS3 by gene transfection in ACHN cells significantly inhibited the growth-inhibitory effect of IFN-α. Suppression of SOCS3 expression in 786-O cells by siRNA activated the IFN signaling pathway through signal transducer and activator of transcription 1 phosphorylation and recovered sensitivity to IFN-α. An in vivo study indicated that co-administration of SOCS3-targeted siRNA promoted IFN-α-induced cell death and growth suppression in 786-O cell xenograft in nude mice. Morphological observation of the tumors revealed the inhibition of SOCS3-induced apoptosis, invasion of inflammatory cells and fibrosis. SOCS3 could be a key component in the resistance to IFN treatment of renal cell carcinoma. Silencing SOCS3 gene expression could be an effective strategy to enhance the antitumor effect of IFN in human renal cell carcinoma cells.

Alpha1-adrenoceptor antagonists improve bladder storage function through reduction of afferent activity in rats with bladder outlet obstruction.

AIMS: Using a rat BOO model, we determined whether α1-adrenoceptor (AR) antagonists (silodosin, prazosin) improve the bladder storage function by reducing afferent input from the lower urinary tract. MATERIALS AND METHODS: Male rats received partial bladder outlet obstruction or sham surgery were used. Four weeks following surgery, their voiding behavior was measured in a metabolic cage. BOO-rats were administered silodosin, prazosin or vehicle for 2 weeks subcutaneously using osmotic pump. At the post-drug condition, voiding behavior was measured again. The L6 spinal cord was removed and immunostained using anti c-Fos antibody. The rats were also performed continuous cystometry with saline without anesthesia or restraint at the pre- and post-drug conditions. RESULTS: Metabolic cage study showed the voiding behavior of BOO-rats was characterized by increase in frequency of urination and decrease in volume voided. Cystometric evaluation also showed the significant increase both in the number of successive voiding contraction and in contraction pressure. The administration of silodosin or prazosin significantly decreased urinary frequency and the number of micturition reflex but affected neither bladder contraction pressure nor residual volume. The number of c-Fos-positive cell significantly increased in BOO-rats, while significantly decreased in those receiving αl-AR antagonists. CONCLUSIONS: The present study demonstrates that α1-AR antagonists silodosin and prazosin have an inhibitory effect on afferent input from the lower urinary tract independently of reducing urethral resistance, and thereby reduce the storage dysfunction secondary to BOO. This result suggests that αl-AR, particularly αlA-AR, may play an important role in the activation of the afferent pathway.

Effect of long-term prazosin and yohimbine administration on c-Fos expression in spinal neurons: inhibitory effect of alpha-1 and alpha-2 adrenoceptors on afferents from the lower urinary tract.

INTRODUCTION: To investigate the effects of long-term administration of the α(1)-adrenoceptor antagonist prazosin and the α(2)-adrenoceptor antagonist yohimbine on afferent inputs from the lower urinary tract by evaluating c-Fos expression in the spinal cord. MATERIALS AND METHODS: Prazosin or yohimbine was administered for 4 weeks in rats using an osmotic pump. Effects of these agents on urodynamic parameters were determined by continuous cystometry in conscious rats. After cystometry, c-Fos expression in the dorsal horn of the L6 spinal cord was measured by immunohistochemistry. RESULTS: The administration of prazosin (0.12 mg/kg/day) or yohimbine (0.10 mg/kg/day) significantly increased micturition interval and bladder capacity, but did not affect micturition pressure and residual urine volume. The numbers of c-Fos-positive neurons in the dorsal horn were significantly lower in rats that received prazosin than in controls. Yohimbine reduced the number of c-Fos-positive neurons in part of the dorsal horn. CONCLUSIONS: Long-term administration of prazosin and yohimbine at clinically recommended doses can exert inhibitory effects on afferent pathways from the lower urinary tract during the storage phase. These reductions of the afferent input result in the increased bladder capacity and increased micturition interval.

Long-term administration of prazosin improves bladder storage function: results from a study in spontaneously hypertensive rats.

OBJECTIVES: To investigate the effects of long-term administration of the α(1) -adrenoceptor antagonist prazosin on afferent inputs from the lower urinary tract (LUT). METHODS: Twenty female spontaneously hypertensive rats (SHR) were randomized to receive a 4-week course of prazosin (0.12 mg/kg per day) or vehicle; 10 female Wistar-Kyoto (WKY) rats were given vehicle. Prazosin or vehicle was administered via an osmotic pump. The effect of prazosin on urodynamic parameters was determined by continuous cystometry in conscious animals. After cystometry, rats were killed and c-fos expression in the dorsal horn of the L6 spinal cord was measured by immunohistochemistry. RESULTS: The bladder contraction interval was significantly shorter in untreated SHR compared with WKY rats (2.36 ± 0 vs 4.27 ± 0.12 min, respectively; P < 0.05) and cystometric capacity was decreased significantly in SHR compared with WKY rats. L6 spinal cord c-Fos expression was also significantly greater in SHR than WKY rats. The administration of prazosin significantly increased the micturition interval (4.07 ± 0.58 min; P < 0.05) and bladder capacity, but it did not affect micturition pressure. In SHR, the number of c-Fos-positive neurons was significantly lower following the administration of prazosin compared with vehicle. CONCLUSIONS: Increased afferent input from the LUT may induce an increase in urinary frequency in SHR. Furthermore, long-term administration of prazosin can exert inhibitory effects on afferent pathways from the LUT during the storage phase. Reductions of afferent input can result in increased bladder capacity and increased micturition interval.

The preoperative pad test as a predictor of urinary incontinence and quality of life after robot-assisted radical prostatectomy: a prospective, observational, clinical study.

PURPOSE: To assess whether the preoperative 1-h pad test could predict postoperative urinary incontinence and quality of life after robot-assisted radical prostatectomy. METHODS: A total of 329 patients who underwent robot-assisted radical prostatectomy between 2013 and 2016 were prospectively enrolled in this study. These patients were divided into the preoperative urinary continence group and the preoperative urinary incontinence group according to the 1-h pad test. The time to achieve urinary continence, lower urinary tract function evaluated by uroflowmetry and post-voided residual urine volume, and quality of life evaluated by King's Health Questionnaire and International Consultation on Incontinence Questionnaire-Short Form were compared between these two groups. RESULTS: There were 190 patients (58%) in the preoperative urinary continence group (1-h pad test ≤ 2 g) and 139 patients (42%) in the preoperative urinary incontinence group (1-h pad test > 2 g). In the preoperative urinary continence/incontinence groups, 83%/76% of patients achieved continence within 12 months, respectively, and urinary incontinence remained significantly longer in the preoperative incontinence group than in the preoperative continence group (P = 0.042). Although there were no significant differences in all quality of life items between the two groups before surgery, several items were significantly higher in the preoperative urinary continence group. CONCLUSION: Achievement of urinary continence and improvement of urinary quality of life are delayed in patients with preoperative urinary incontinence assessed by the 1-h pad test. The preoperative 1-h pad test could be a useful predictor of prolonged urinary incontinence and poor quality of life after robot-assisted radical prostatectomy.

Obstruction alters muscarinic receptor-coupled RhoA/Rho-kinase pathway in the urinary bladder of the rat.

AIMS: The present study investigated the effects of the bladder outlet obstruction (BOO) on the muscarinic receptor (MR)-coupled RhoA/Rho-kinase (ROK) pathway in the detrusor smooth muscle of the rat. METHODS: Detrusor muscle samples were obtained from bladders after 4 weeks of BOO and also from sham-operated control rats. Contractile responses to electrical field stimulation (EFS) and 1 microM carbachol (Cch) were determined in isolated detrusor strips. The effects of the ROK inhibitor Y-27632 on the Cch-induced phasic and sustained contractions were evaluated. Western blotting was used to determine the relative levels of RhoA expression and ROK isoform expression. RESULTS: Bladder weight increased significantly after 4 weeks of BOO. Contractile responses to EFS decreased significantly in detrusor muscle from the obstructed bladder. Cch (1 microM) induced a biphasic response consisting of an initial phasic contraction followed by a sustained contraction. Y-27632 attenuated the phasic and sustained contractions induced by Cch in both control and obstructed bladders. However, BOO caused a significant increase in contractile force during the sustained phase of the contractions induced by Cch. An inhibitory effect of Y-27632 on the sustained responses to Cch was significantly enhanced in the obstructed bladder. In accordance with the functional study, the expression of RhoA and ROK isoforms (both alpha and beta) at the protein level significantly increased in the obstructed bladder. CONCLUSIONS: These results suggest that the enhanced MR-coupled RhoA/ROK pathway contributes to the maintenance of contractile force in the obstructed bladder, as a compensatory mechanism for expelling the urine against the obstruction.

Strain-specific seroepidemiology and reinfection of cytomegalovirus.

Although there have been some reports describing the serostatus of cytomegalovirus, strain-specific antibody responses and their distribution remain unknown. In this study, ELISA using fusion proteins encompassing epitope of glycoprotein H from both AD169 and Towne strains was used to test 352 blood donors. Of these 352 donors, 207 were analyzed for strain-specific glycoprotein H antibodies. Of the 44 donors whose serum contained antibodies against both AD169 and Towne, 27 (60%) were aged 50 years or over (p = 0.0003). This may indicate serological evidence of reinfection with cytomegalovirus in the elder population. The nucleotide sequence analysis of cytomegalovirus glycoprotein H from the peripheral blood of the cytomegalovirus-positive renal transplant recipients showed that our strain-specific ELISA can reveal cytomegalovirus reinfection after transplantation.

Association of the outcome of renal transplantation with antibody response to cytomegalovirus strain-specific glycoprotein H epitopes.

BACKGROUND: Cytomegalovirus (CMV) is the most important pathogen affecting the outcome of renal transplantation. The combination of CMV-seronegative transplant recipients with CMV-seropositive transplant donors places recipients at the highest risk of CMV disease. In cases of congenital CMV infection, existing immunity only partially protected mothers from reinfection with a different genotypic strain. The effect of differences in infected CMV strains between CMV-seropositive transplant donors and CMV seropositive transplant recipients on the outcome of transplantation remains unclear. METHODS: In this prospective multicenter study, the presence of antibodies against strain-specific glycoprotein H epitopes in 84 CMV-seropositive transplant donor/CMV-seropositive transplant recipient renal transplantation cases were determined, and their relationships to acute transplant rejection, CMV infection, degree of antigenemia, and CMV disease were evaluated. RESULTS: Among the 84 donor/recipient pairs, 45 and 32 had matched and mismatched strain-specific glycoprotein H antibodies, respectively. Acute transplant rejection in the mismatched group was more frequent than it was in the matched group (63% vs. 22%; P=.005). CMV disease was also more frequently observed in the mismatched group (28% vs. 9%; P=.026). The mismatched group had a higher level of antigenemia (P=.019). CONCLUSIONS: Our results illustrate more adverse events in the cases with a CMV-seropositive transplant donor and a CMV-seropositive transplant recipient in which the glycoprotein H antibodies are mismatched, suggesting that reinfection with a different CMV strain results in more complications.

Overriding TKI resistance of renal cell carcinoma by combination therapy with IL-6 receptor blockade.

Metastatic renal cell carcinoma (RCC) is a tumor entity with poor prognosis due to limited therapy options. Tyrosine kinase inhibitors (TKI) represent the standard of care for RCCs, however a significant proportion of RCC patients develop resistance to this therapy. Interleukin-6 (IL-6) is considered to be associated with poor prognosis in RCCs. We therefore hypothesized that TKI resistance and IL-6 secretion are causally connected. We first analyzed IL-6 expression after TKI treatment in RCC cells and RCC tumor specimens. Cell proliferation and signal transduction activity were then quantified after co-treatment with tocilizumab, an IL-6R inhibitor, in vitro and in vivo. 786-O RCC cells secrete high IL-6 levels after low dose stimulation with the TKIs sorafenib, sunitinib and pazopanib, inducing activation of AKT-mTOR pathway, NFκB, HIF-2α and VEGF expression. Tocilizumab neutralizes the AKT-mTOR pathway activation and results in reduced proliferation. Using a mouse xenograft model we can show that a combination therapy with tocilizumab and low dosage of sorafenib suppresses 786-O tumor growth, reduces AKT-mTOR pathway and inhibits angiogenesis in vivo more efficient than sorafenib alone. Furthermore FDG-PET imaging detected early decrease of maximum standardized uptake values prior to extended central necrosis. Our findings suggest that a combination therapy of IL-6R inhibitors and TKIs may represent a novel therapeutic approach for RCC treatment.