Factors predicting outcomes of penile rehabilitation with udenafil 50 mg following radical prostatectomy.

Udenafil is a selective phosphodiesterase type 5 inhibitor made available in recent years for the treatment of erectile dysfunction. Herein, we evaluated independent predictors of potency recovery in radical prostatectomy (RP) patients who underwent penile rehabilitation with udenafil 50 mg. One hundred and forty-three men who underwent RP were enrolled in a penile rehabilitation program using udenafil 50 mg every other day. The rate of regained potency in the study group was significantly higher compared with the recovery rate seen in patients who were not part of the penile rehabilitation program (41.3% vs 13.0%; P<0.001). On the multivariate Cox analyses, preoperative International Index of Erectile Function-5 scores (hazard ratio (HR), 1.049; P=0.040), alcohol consumption (HR, 2.043; P=0.020) and Gleason biopsy score (HR, 0.368; P=0.024) were independent preoperative predictors for potency recovery. Among post-RP variables, the use of robotic procedures (HR, 2.287; P=0.030) and pathologic stage (HR, 0.506; P=0.038) were significantly associated with potency recovery. This study identified predictive factors for the recovery of potency in patients undergoing penile rehabilitation with udenafil following RP. Our results could provide physicians with useful information for counseling RP patients and selecting optimal candidates for penile rehabilitation.

Pathologic findings in patients who underwent robot-assisted radical prostatectomy following active surveillance: a prospective study in a single center.

AIM: Active surveillance is the recommended treatment of option for men with very low-risk prostate cancer. In this study, the clinicopathological results of patients who were initially treated with active surveillance and subsequently underwent robot-assisted radical prostatectomy during follow-up are described. METHODS: A prospective cohort of 106 men enrolled in active surveillance was reviewed. Pathologic specimens for patients who ultimately underwent robot-assisted radical prostatectomy for progression or personal preference were analyzed. RESULTS: After exclusion of 14 patients who were lost to follow-up or with incomplete data collection, 92 men were included in the present analyses. Median follow-up was 27.6 months (range 3.3 to 193.1). Twenty-nine patients underwent robot-assisted radical prostatectomy. Progression occurred in 32 patients (34.8%), of which 23 men elected to undergo surgery. Robot-assisted radical prostatectomy was performed in 6 additional patients who chose definitive intervention due to anxiety. Pathologic analyses revealed organ-confined disease in 24 patients (82.8%), and Gleason score was ≥ 7 in nine (31%). Fourteen (48.3%) specimens were identified as having an advanced disease (Gleason score ≥ 7 and/or T3). In comparison to the patients with low-risk disease post-operatively (Gleason score <7 and T2), patients with advanced disease had significantly higher PSA density level and lower prostate volume. CONCLUSION: In this prospective active surveillance cohort, the progression rate was 34.8% over the follow-up period of 27.6 months. In specimens of patients who underwent robot-assisted radical prostatectomy, 48.3% displayed advanced pathologic features. Therefore we recommend that patients considering active surveillance should be counseled on risk of advanced disease as a possible hazard.

Prostate cancer bone metastases acquire resistance to androgen deprivation via WNT5A-mediated BMP-6 induction.

BACKGROUND: Androgen ablation is the first-line therapy for patients with metastatic prostate cancer (CaP). However, castration resistance will eventually emerge. In the present study, we have investigated the role of bone morphogenetic protein-6 (BMP-6) in the development of castration-resistant prostate cancer (CRPC) in the context of bone metastases. METHODS: We initially investigated the clinical course of 158 men with advanced CaP who were treated with primary androgen deprivation therapy. To elucidate the underlying mechanism of CRPC in the context of bone metastases, we examined the impact of bone stromal cells on CaP in the absence of androgens using a co-culture model. RESULTS: In the 158 patients, we found that the median time to prostate-specific antigen progression was significantly shorter when bone metastases were present (14 months (95% CI, 10.2-17.8 months) vs 57 months (95% CI, 19.4-94.6 months)). These results suggest that bone-tumour interactions may accelerate castration resistance. Consistent with this hypothesis, in vitro co-cultures demonstrated that CaP cells proliferated under an androgen-depleted condition when incubated with bone stromal cells. Mechanistically, gene expression analysis using quantitative polymerase chain reaction arrays showed a dramatic induction of BMP-6 by CaP cell lines in the presence of bone stromal cells. Further studies revealed that WNT5A derived from bone stromal cells induced the expression of BMP-6 by CaP cells; BMP-6 in turn stimulated cellular proliferation of CaP cells in an androgen-deprived media via a physical interaction between Smad5 and ß-catenin. Intracellularly, WNT5A increased BMP-6 expression via protein kinase C/NF-κB pathway in CaP cell lines. CONCLUSIONS: These observations suggest that bone-CaP interaction leads to castration resistance via WNT5A/BMP-6 loop.

Factors related to patient-perceived satisfaction after robot-assisted radical prostatectomy based on the expanded prostate cancer index composite survey.

BACKGROUND: Few studies have analyzed factors that influence longitudinal changes in patient-perceived satisfaction during the recovery period following robot-assisted radical prostatectomy (RARP) for prostate cancer. We investigated variables that were associated with patient-perceived satisfaction after RARP using the expanded prostate cancer index composite (EPIC) survey. METHODS: Of 175 men who underwent RARP between 2010 and 2011, 140 men completed the EPIC questionnaire preoperatively and 3, 6 and 12 months postoperatively. On the basis of the EPIC question no. 32 (item number 80), patients were divided into four groups according to the pattern of satisfaction change at postoperative 3 and 12 months: satisfied to satisfied (group 1); satisfied to dissatisfied (group 2); dissatisfied to satisfied (group 3); and dissatisfied to dissatisfied (group 4). Longitudinal changes in EPIC scores over time in each group and differences in EPIC scores of each domain subscale between groups at each follow-up were analyzed. A linear mixed model with generalized estimating equation approach was used to identify independent factors that influence overall satisfaction among repeated measures from same patients. RESULTS: On the basis of the pattern of satisfaction change, groups 1, 2, 3 and 4 had 103 (74.3%), 21 (15.0%), 11 (7.9%) and 5 (2.9%) patients, respectively. The factor that was associated with overall satisfaction was urinary bother (UB) (ß=0.283, 95% confidence interval (0.024, 0.543 ); P=0.033) adjusted for other factors under consideration. CONCLUSIONS: UB was the independent factor influencing patient-perceived satisfaction after RARP. During post-RARP follow-up, physician should have the optimal management for the patient's UB.

Radium Ra 223 dichloride in castration-resistant prostate cancer.

Radium Ra 223 dichloride (Xofigo®, formerly Alpharadin) is one of the representative α-particle-emitting isotopes that delivers radiation with a higher biological effect to a more localized area. Preclinical studies in mouse, rat and canine models have demonstrated that radium Ra 223 dichloride has a definite skeletal affinity and antitumor effect with a relatively low toxicity on bone marrow. More recently, in a large randomized phase III trial (ALSYMPCA), patients with bone metastasis and castration-resistant prostate cancer (CRPC) received six cycles of 50 kBq/kg of radium Ra 223 dichloride in 4-week intervals. In these men, radium Ra 223 dichloride improved the median overall survival by 3.6 months when compared to the placebo group. Collectively, these results suggest that radium Ra 223 dichloride is a promising candidate for managing bone metastases in patients with CRPC.

Incidence, nature, and etiology of metabolic alkalosis in dogs and cats.

BACKGROUND: The incidence and causes of metabolic alkalosis in dogs and cats have not been fully investigated. OBJECTIVES: To describe the incidence, nature, and etiology of metabolic alkalosis in dogs and cats undergoing blood gas analysis at a veterinary teaching hospital. ANIMALS: Dogs and cats at a veterinary medical teaching hospital. METHODS: Acid-base and electrolyte results for dogs and cats measured during a 13-month period were retrospectively collected from a computer database. Only the first measured (venous or arterial) blood gas analyzed in a single hospitalization period was included. Animals with a base excess above the reference range for the species were included. RESULTS: A total of 1,805 dogs and cats were included. Of these, 349 (19%) were identified as having an increased standardized base excess, 319 dogs and 30 cats. The mixed acid-base disorder of metabolic alkalosis with respiratory acidosis was the most common abnormality identified in both dogs and cats. Hypokalemia and hypochloremia were more common in animals with metabolic alkalosis compared to animals without metabolic alkalosis. The 4 most commonly identified underlying diseases were respiratory disease, gastrointestinal tract obstruction, furosemide administration, and renal disease. CONCLUSIONS AND CLINICAL IMPORTANCE: Metabolic alkalosis was less common than metabolic acidosis in the same population of animals. Evidence of contraction alkalosis was present in many patients in this study. Hypokalemia and hypochloremia were more frequent in patients with metabolic alkalosis and suggest the importance of evaluation of acid-base status in conjunction with serum electrolyte concentrations.

Enzalutamide for the treatment of castration-resistant prostate cancer.

Castration-resistant prostate cancer (CRPC) remains a major clinical challenge, given the mechanistic heterogeneity due to a complex signal transduction network. Enzalutamide (MDV-3100), recently approved by the U.S. Food and Drug Administration (FDA) at a dose of 160 mg/day for the treatment of CRPC, blocks androgen signaling by directly binding to the androgen receptor (AR) and inhibiting nuclear translocation and coactivator recruitment of the ligand-receptor complex. In preclinical studies, enzalutamide has been shown to block the binding of AR to DNA, resulting in apoptosis and retardation of tumor growth. Clinically, a phase I/II study (N = 140) revealed that enzalutamide had an optimal safety profile and significant antitumor activity in patients with CRPC regardless of prior chemotherapy. In the AFFIRM phase III trial (N = 1,199), oral enzalutamide significantly improved survival in men with metastatic CRPC after chemotherapy. Currently, a phase III trial (PREVAIL) is under way to determine the effectiveness of enzalutamide in patients who have not received prior docetaxel chemotherapy.

Paradoxical embolism as a cause of silent brain infarctions in healthy subjects: the ICONS study (Identification of the Cause of Silent Cerebral Infarction in Healthy Subjects).

BACKGROUND: In healthy elderly people, silent brain infarctions (SBIs) have been recognized as common lesions. In this study, we evaluated the association between SBI located outside the perforating artery territory (PAT) and paradoxical embolism detected by agitated saline transcranial Doppler (TCD) monitoring in healthy subjects. METHODS: This was a prospective observational study undertaken by a university health promotion center for healthy subjects and by a university stroke center for acute stroke patients. We defined SBI as evidence on fluid-attenuation inversion recovery (FLAIR) magnetic resonance imaging (MRI) of one or more infarcts, without history of corresponding stroke or transient ischaemic attack. We also evaluated in all subjects the neuroimaging indicator of microangiopathy leukoaraiosis (LA). This study is registered with ClinicalTrials.gov, number NCT01429948. RESULTS: Amongst 1103 consecutive healthy adults who underwent MRI, 347 (31%) had one or more SBIs located outside the PAT, suggesting embolism. Amongst them, 253 subjects underwent agitated saline TCD monitoring and 128 (51%) had right-to-left shunts (RLS). The prevalence of RLS was similar to cryptogenic embolic stroke (62.0%, P = 0.056), but higher than in patients with other stroke subtypes (36.2%, P = 0.021). Amongst subjects with SBI, absence of LA was the only factor associated with RLS (OR 1.78; 95% CI 1.01-3.14; P = 0.046). CONCLUSION: Our results suggest that paradoxical embolism may play an important role in the development of SBI outside the PAT in apparently healthy adults.

Development of the deep flexor tendons and lumbricalis muscle in the hand and foot: a histological study using human mid-term foetuses.

To revisit foetal development of the deep flexor tendons of the hand and foot, we examined the paraffin-embedded histology of 20 mid-term foetuses at 8-15 weeks of estimated gestational age (35-118 mm crown-rump length or CRL). At 8-9 weeks, in front of the metacarpal bones, the flexor pollicis longus and flexor digitorum profundus (FDP) muscles provided a plate-like, common tendon from which the lumbricalis muscles originated. However, in the foot, we had no evidence of such a common tendon. The flexor pollicis tendon was separated from the common tendon at 9-10 weeks possibly due to mechanical stress from the laterally growing thumb. Notably, at the lumbricalis muscle origins at 10-12 weeks, the FDP and flexor digitorum longus tendons remained undifferentiated and the primitive tenocytes were dispersed from them. The dispersed cells seemed to develop into an interface tissue between the lumbricalis muscle fibre and the deep tendon. In 3 of 5 specimens at 15 weeks, we found an excess number of the FDP tendons (5-7) in the proximal side of the lumbricalis muscle origin. However, the excess tendons dispersed in the lumbricalis muscle origin. The development of the lumbricalis muscle origin might follow the tendon splitting for four fingers. However, conversely, we hypothesised that the developing lumbricalis muscles re-arranged the deep flexor tendons to provide a configuration of one deep tendon per one finger (or toe). The quadrates plantae muscle seemed not to contribute on the re-arrangement.

RUNX3 methylation in normal surrounding urothelium of patients with non-muscle-invasive bladder cancer: potential role in the prediction of tumor progression.

PURPOSE: Previously, we reported a causal relationship between RUNX3 methylation and bladder tumor development. Thus, in order to clarify its role in tumorigenesis, this study aims to identify the function of RUNX3 methylation in normal adjacent urothelium of patients with non-muscle invasive bladder cancer (NMIBC). METHODS: Tumor tissue and donor-matched normal adjacent tissue from 55 patients who underwent transurethral resection (TUR) were selected for the study, and RUNX3 promoter methylation was assessed using methylation-specific polymerase chain reaction (MS-PCR). RESULTS: RUNX3 promoter methylation occurred more frequently in tumor samples than in histologically normal urothelium in patients with NMIBC (P = 0.02). The methylation rates for the RUNX3 promoter in normal adjacent urothelium and tumor tissue were 47% and 69%, respectively. Interestingly, RUNX3 methylation in normal adjacent urothelium was associated with tumor number (P = 0.022) and progression (P = 0.035). Kaplan-Meier estimates revealed that RUNX3 methylation in normal urothelium showed a significant association with time to progression (P = 0.017) in NMIBC patients. Stratifying the patients into 'both methylation', 'one methylation' and 'no methylation' groups for tumors and normal urothelium revealed that no progression occurred in the 'no methylation' group during follow-up. Multivariate Cox regression analysis demonstrated that RUNX3 methylation in normal urothelium [hazards ratio (HR): 5.692, P = 0.042] was an independent predictor of progression. CONCLUSIONS: RUNX3 methylation was associated with transition from normal urothelium to bladder tumor. More importantly, RUNX3 methylation in normal adjacent urothelium may predict progression in NMIBC patients who have undergone TUR.

The hOGG1 mutant genotype is associated with prostate cancer susceptibility and aggressive clinicopathological characteristics in the Korean population.

BACKGROUND: The gene encoding human 8-oxoguanine glycosylase 1 (hOGG1) is involved in DNA base excision repair from oxidatively damaged DNA. A case-control study was conducted to evaluate the correlation between the susceptibility and clinicopathological outcomes of prostate cancer (CaP) and hOGG1 genotype. PATIENTS AND METHODS: Subjects were recruited from 266 CaP patients and 266 age-matched benign prostatic hyperplasia patients. The hOGG1 codon 326 genotype was determined by peptide nucleic acid-mediated PCR clamping and compared with Gleason score and tumor stage. RESULTS: The Cys allele at codon 326 of hOGG1 was associated with an increased risk of CaP in comparison with the Ser allele (P = 0.005). Gleason scores of 8 or higher were observed more often in patients with the mutant genotypes Ser/Cys and Cys/Cys than in those with a wild-type genotype (P = 0.045), and the Cys/Cys homozygous genotype was associated with a significantly higher risk of metastatic disease in comparison with the Ser/Ser genotype (P = 0.017). CONCLUSIONS: These results suggest that hOGG1 is associated with the susceptibility to CaP and its aggressive clinicopathological characteristics.

Unusual findings in cerebral abscess: report of two cases.

Markedly restricted water diffusion is a characteristic of purulent fluid in brain abscesses. We report two cases of brain abscesses with unusual diffusion findings.

A protein kinase from Colletotrichum trifolii is induced by plant cutin and is required for appressorium formation.

When certain phytopathogenic fungi contact plant surfaces, specialized infection structures (appressoria) are produced that facilitate penetration of the plant external barrier; the cuticle. Recognition of this hydrophobic host surface must be sensed by the fungus, initiating the appropriate signaling pathway or pathways for pathogenic development. Using polymerase chain reaction and primers designed from mammalian protein kinase C sequences (PKC), we have isolated, cloned, and characterized a protein kinase from Colletotrichum trifolii, causal agent of alfalfa anthracnose. Though sequence analysis indicated conserved sequences in mammalian PKC genes, we were unable to induce activity of the fungal protein using known activators of PKC. Instead, we show that the C. trifolii gene, designated LIPK (lipid-induced protein kinase) is induced specifically by purified plant cutin or long-chain fatty acids which are monomeric constituents of cutin. PKC inhibitors prevented appressorium formation and, to a lesser extent, spore germination. Overexpression of LIPK resulted in multiple, abnormally shaped appressoria. Gene replacement of lipk yielded strains which were unable to develop appressoria and were unable to infect intact host plant tissue. However, these mutants were able to colonize host tissue following artificial wounding, resulting in typical anthracnose lesions. Taken together, these data indicate a central role in triggering infection structure formation for this protein kinase, which is induced specifically by components of the plant cuticle. Thus, the fungus is able to sense and use host surface chemistry to induce a protein kinase-mediated pathway that is required for pathogenic development.

Synthesis of (R)- and (S)-10,16-dihydroxyhexadecanoic acid: cutin stereochemistry and fungal activation.

The first asymmetric syntheses of the cutin monomers (R)- and (S)-10,16-dihydroxyhexadecanoic acid (10,16-DHPA) and confirmation of (S)(+)-absolute configuration for 10,16-DHPA derived from tomato are reported. The individual DHPA stereoisomers display differences in their ability to activate the fungal pathogen Colletotrichum trifolii.

Clinical analysis of 34 diffuse axonal injured (DAI) patients below GCS 8.

A consecutive series of 34 severe head-injured patients (DAI) were studied prospectively. Patients were categorized according to a new, simple classification system comprised of four lesion types according to the compression or obliteration of the ventricles or cisterns. Five patients belonged to type II and 19 patients to type IV. Each type was further subdivided into two GCS score ranges (5 to 8 and below 5). The distribution of the posttraumatic infarction was mainly in the frontal and temporal lobes (60% of all cases). Our data demonstrated that the ICP was significantly lower at a 30 degrees head elevation than at 0 degree (18.6 +/- 7.21 mmHg vs 23.0 +/- 10.60 mmHg. t = 4.22 P < 0.001), but head position did not statistically affect CPP (69.4 +/- 19.86 mmHg vs 68.2 +/- 19.87 mmHg. t = -0.54, P < 0.59). The effect of intensive therapy on ICP, CPP and AVDO2 was studied in all cases, employing steroids and diuretics in a modified intensive care scale. In cases where barbiturates were employed, there were statistically significant changes in ICP and AVDO2 (P < 0.001), but CPP was not affected (P < 0.59). Surviving patients were analyzed by using the GOS and the neurological grading score (NGS, Nihon University) of the persistent vegetative state. Our data suggests that head elevation of 30 degrees and barbiturate therapy are more effective on ICP and AVDO2, and NGS more exact than GOS in vegetative patients.

Intraventricular or epidural injection of morphine for severe pain.

Intraventricular or epidural injection of morphine through implantable infusion devices was used for severe pain in 50 patients with advanced cancer, arachnoiditis, or spinal injury. Intraventricular catheter was inserted for injection of morphine in 21 patients, 29 were treated through epidural infusion. For the evaluation of results the multimodal evoked potential (MEP) has been obtained before and after each treatment. 80% of the patients experienced good results. No significant side effects have been noted in patients with either epidural or intraventricular injection of morphine. These may be excellent methods for pain control in well selected patients.