Favorable Response of Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma with Only Small Lesions to not be Considered Measurable by RECIST.

PURPOSE: Pembrolizumab is currently considered the standard second-line treatment for advanced urothelial carcinoma (UC). This study aimed to investigate the efficacy and safety of pembrolizumab in patients with advanced UC in real-world data, which is not well-reported. MATERIALS AND METHODS: The study included 97 patients with advanced UC whose lesions were classified according to the Response Evaluation Criteria in Solid Tumors (RECIST). The median age was 73 years. Nineteen patients (20%) with performance status (PS) 2-4 were included. The percentages of liver, lung, bone, and lymph node metastasis were 18%, 27%, 19%, and 76%, respectively. The efficacy, safety, and risk factors for prognosis were evaluated for patients with and without measurable lesions. RESULTS: The best response was complete response in nine patients (9%) and partial response in 16 patients (17%). The median progression-free survival and overall survival were 3.7 months (95% confidence interval [CI]: 2.8-4.7) and 11.8 months (95% CI: 6.7-17.0), respectively. Twenty-one (22%) patients had no measurable lesions per RECIST. In univariate and multivariate analysis, PS 2-4 and lesions by RECIST were identified as factors associated with short overall survival (OS). The median OS of 18.3 months in patients without lesions by RECIST was significantly longer than the median OS of 6.7 months in patients with lesions by RECIST (p = .012). CONCLUSION: We demonstrated that good PS 0-1 and no measurable lesions, especially small lesions, by RECIST were favorable prognostic factors in patients with advanced UC treated by pembrolizumab.

Blood Cell Count Biomarkers Predicting Efficacy of Pembrolizumab as Second-line Therapy for Advanced Urothelial Carcinoma.

BACKGROUND/AIM: To investigate the blood markers for predicting pembrolizumab efficacy in advanced urothelial carcinoma (UC). PATIENTS AND METHODS: This study included 91 advanced UC patients. The relationship between prognosis and markers from peripheral blood cell counts, including the neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), monocyte-lymphocyte ratio (MLR), and systemic inflammation response index (SIRI=monocytes × neutrophils/lymphocytes), was evaluated. RESULTS: Multivariate analysis indicated that pretreatment NLR and the 1-month-change NLR were both significantly associated with overall survival (OS) after pembrolizumab initiation. When the patients were divided into four groups according to calculated cutoffs using Cox proportional hazard model, the pretreatment NLR <2.9 and 1-month change NLR <+43% groups had a significantly better OS than the pretreatment NLR ≥2.9 and 1-month-change NLR ≥+43% groups. CONCLUSION: NLR, MLR, PLR and SIRI before pembrolizumab and 1-month-change NLR in advanced UC correlated with OS after pembrolizumab treatment.

Stone Attenuation Values Measured by Average Hounsfield Units and Stone Volume as Predictors of Total Laser Energy Required During Ureteroscopic Lithotripsy Using Holmium:Yttrium-Aluminum-Garnet Lasers.

OBJECTIVE: To evaluate the predictors of the total laser energy (TLE) required during ureteroscopic lithotripsy (URS) using the holmium:yttrium-aluminum-garnet (Ho:YAG) laser for a single ureteral stone. MATERIALS AND METHODS: We retrospectively analyzed the data of 93 URS procedures performed for a single ureteral stone in our institution from November 2011 to September 2015. We evaluated the association between TLE and preoperative clinical data, such as age, sex, body mass index, and noncontrast computed tomographic findings, including stone laterality, location, maximum diameter, volume, stone attenuation values measured using average Hounsfield units (HUs), and presence of secondary signs (severe hydronephrosis, tissue rim sign, and perinephric stranding). RESULTS: The mean maximum stone diameter, volume, and average HUs were 9.2 ± 3.8 mm, 283.2 ± 341.4 mm3, and 863 ± 297, respectively. The mean TLE and operative time were 2.93 ± 3.27 kJ and 59.1 ± 28.1 minutes, respectively. Maximum stone diameter, volume, average HUs, severe hydronephrosis, and tissue rim sign were significantly correlated with TLE (Spearman's rho analysis). Stepwise multiple linear regression analysis defining stone volume, average HUs, severe hydronephrosis, and tissue rim sign as explanatory variables showed that stone volume and average HUs were significant predictors of TLE (standardized coefficients of 0.565 and 0.320, respectively; adjusted R2 = 0.55, F = 54.7, P <.001). CONCLUSION: Stone attenuation values measured by average HUs and stone volume were strong predictors of TLE during URS using Ho:YAG laser procedures.

Numerical studies on critical properties of the Kosterlitz-Thouless phase for the gauge glass model in two dimensions.

The critical exponents are estimated for the gauge glass model in two dimensions, in which only the Kosterlitz-Thouless (KT) phase appears in the low-temperature regime. The nonequilibrium relaxation method is applied to estimate the transition temperature and critical exponents: the static exponent η and the dynamical exponent z. Since the system exhibits criticality in the whole KT phase, we estimate the exponents on the boundary as well as inside the KT phase. The static exponent η depends on both the temperature and the strength of randomness, while the dynamical one z is almost constant throughout the KT phase, including the boundary.

The effectiveness of interferon-alpha subtypes alternation for metastasis from renal cell carcinoma.

Interferon-alpha (IFN-α) has been used in systemic treatment for metastatic renal cell carcinoma (mRCC). IFN-α has at least 14 subtypes, each of which has different biological activity. There have been reports that mRCC resistant to an IFN-α treatment responded to another IFN-α subtype. This study was performed to evaluate the effectiveness of alternation of different IFN-α subtypes for mRCC that did not respond to initial IFN-α treatment. In our department and associated institutions, alternating therapy of IFN-α was provided for 15 initial IFN-α refractory mRCC cases from June 2005 to September 2008. Among the 15 patients, the effects of alternating IFN-α therapy were as follows: complete response (CR), 0 cases; partial response (PR), 1 case; stable disease (SD), 3 cases; progressive disease (PD), 11 cases. The response rate (CR+PR) was 7% and disease control rate (CR+PR+SD) was 27%. No severe side effects were observed in any of these cases. The PR case is still in PR 21 months after alternating IFN-α therapy. Among the three SD cases, one has continued SD for 14 months and the other for 12 months. Alternating IFN-α therapy for mRCC can be attempted even if other cytokines are not effective.

Effects of discreteness on gauge glass models in two and three dimensions.

The q-state clock gauge glass model is studied to see the effect of discreteness on the Kosterlitz-Thouless (KT) transition and the ferromagnetic (FM) critical phenomenon in random systems. The nonequilibrium relaxation analysis is applied. In two dimensions, the successive transitions of paramagnetic (PM), KT, and FM phases are investigated along the Nishimori line for q=6, 8, 10, 12, 14, 16, and 1024 (recognized as infinity) cases. For the upper critical temperature, it is found that the transition temperature is almost the same as in the continuous case for all q values. The lower transition temperature is found to be proportional to 1/q2. In three dimensions, the critical behavior of the PM-FM transition is studied along the Nishimori line for q=6, 8, 16, and 1024 cases. It is found that the spin discreteness is irrelevant, and the transition belongs to the same universality class as in the (continuous) XY case.

Mild brain ischemia produces bladder hyperactivity without brain damage in rats.

INTRODUCTION: The influence of brain ischemia without cerebral infarction on voiding function is unknown. To investigate the effects of a reduction in cerebral blood flow on voiding function, the influence of chronic cerebral hypoperfusion (CH) on bladder activity was examined in rats. MATERIALS AND METHODS: CH was induced in each of 11 female Sprague-Dawley rats by anastomosis between the right external jugular vein and the right common carotid artery with partial obstruction of the left common carotid artery. Twelve intact animals comprised a control group. Voided volume per micturition was assessed in a metabolic cage for 24 h on weeks 2, 4, and 8. Eight weeks after the operation, the rats were tested in a hippocampus-related learning paradigm, the Morris water maze. Bladder activity was monitored in 13 rats with continuous infusion cystometrography (CMG) at 2 weeks. After evaluation, the rats' brains were stained by perfusion with 2% 2,3,5-triphenyltetrazolium chloride (TTC). RESULTS: Voided volume per micturition was significantly reduced and voiding frequency was significantly increased in CH rats 2 weeks after CH as compared to the control group (p < 0.05). Bladder capacity on CMG of CH rats was significantly reduced 14 days after CH as compared to the controls (p < 0.05). Although TTC staining of the CH rat brain did not show cerebral infarction, CH induced impairment of water maze learning. CONCLUSIONS: These results indicate that mild forebrain ischemia without infarction results in the development of bladder hyperactivity and impairment of memory. Mild brain ischemia with aging may induce bladder overactivity in humans. Further studies of the nervous system related to bladder hyperactivity using this animal model may lead to pharmacological therapy or prevention of bladder overactivity in the aging individual with an unidentified origin of voiding dysfunction.

Dehydroepiandrosterone alleviates copulatory disorder induced by social stress in male rats.

INTRODUCTION: Social stress induces sexual dysfunction and reduces serum testosterone (T) level in rats. Stressful events exert an influence on a variety of behaviors and physiology through hormonal changes. The mechanism of stress-induced sexual dysfunction is unknown. AIM: To investigate the role of dehydroepiandrosterone (DHEA) in copulatory behavior induced by social stress in rats. METHODS: Stress-induced male rats were subjected to social stress in which the males lived in a wire-mesh siege located in a colony of male and female rats and were exposed daily to a brief defeat by the colony of males for five consecutive days. After the stress period, copulatory behavior and serum concentrations of DHEA and T were measured. MAIN OUTCOME MEASURES: The effects of DHEA, T, and NE-100, a selective sigma 1 receptor antagonist, on copulatory behavior following social stress were examined. RESULTS: The males exhibited a marked suppression of copulatory behavior (elongation of intromission and ejaculation latencies). Serum concentrations of DHEA and T were significantly lower than those in nonstressed control males. Another three groups of social stressed males were injected daily with DHEA, T, or DHEA + NE-100 during the stress period. Injections of DHEA attenuated the stress-induced suppression of copulatory behavior, whereas T had no effect. The combined treatment of NE-100 made DHEA ineffective at restoring copulatory behavior. CONCLUSIONS: These results indicate that DHEA, but not its conversion to T, alleviates the suppressive effect of social stress on copulatory behavior via sigma 1 receptors. We suggest that the decreased endogenous DHEA is involved in copulatory disorders induced by social stress in rats.

Role of cyclooxygenase-2 in the development of bladder overactivity after cerebral infarction in the rat.

PURPOSE: We investigated the role of cyclooxygenase (COX) isoforms in bladder overactivity induced by cerebral infarction (CI) in rats. MATERIALS AND METHODS: CI was induced by left middle cerebral artery occlusion (MCAO) in female Sprague-Dawley rats. Bladder activity was monitored with continuous infusion cystometrography of conscious rats. Specimens were obtained from the pontine tegmental area (PTA) 1, 3, 5, 12 and 24 hours after CI or sham operation (SO). The effects of MK-801 (0.1 mg/kg intravenously), an NMDA (N-methyl-D-aspartate) glutamatergic receptor antagonist, on bladder activity, and on COX-1 and 2 mRNA expression following MCAO were examined. Real-time quantitative reverse transcriptase-polymerase chain reaction was performed to evaluate the effects of CI on gene expression in the PTA. The effects of the COX-2 inhibitor NS398 (0.01 to 10 mg/kg intravenously) on bladder activity were examined. RESULTS: The bladder capacity of CI rats was significantly decreased 1 to 24 hours after MCAO compared with that of SO rats (p <0.05 or 0.01). One and 3 hours after MCAO mean COX-2 mRNA expression +/- SE had increased significantly to 22.4 +/- 3.5 in terms of its expression relative to the outer control in a sample obtained immediately after MCAO, in contrast to that in SO rats (p <0.01). The expression level returned to the control level within 12 hours after MCAO. COX-1 expression was not influenced by MCAO. Pretreatment with MK-801 inhibited the development of bladder overactivity and significantly decreased the expression of COX-2 mRNA in the PTA (p <0.01). Treatment with NS398 before MCAO prevented the development of bladder overactivity in a dose dependent manner and did not influence infarct volume. CONCLUSIONS: These results indicate that the development of bladder overactivity following MCAO is accompanied by an increase in COX-2 mRNA expression in the PTA and is mediated by NMDA receptor activity. COX-2 in the brain may be a new target for the treatment of neurogenic voiding dysfunction after cerebral infarction.

RNA synthesis in pons necessary for maintenance of bladder overactivity after cerebral infarction in rat.

PURPOSE: The maintenance of long lasting bladder overactivity caused by cerebral infarction is believed to require transcription in the pontine micturition center. Therefore, we examined the influence of the RNA synthesis inhibitor actinomycin D (Banyu Pharmaceutical Co., Ltd., Tokyo, Japan) on bladder overactivity induced by left middle cerebral artery occlusion. MATERIALS AND METHODS: Rats under halothane anesthesia were injected with actinomycin D or vehicle (mannitol) into the bilateral dorsal pontine tegmentum, followed by middle cerebral artery occlusion. Awake rats were cystometrically examined for 12 hours. The expression of c-fos and zif268 mRNA in the dorsal pontine tegmentum was monitored with real-time polymerase chain reaction. RESULTS: Injection of actinomycin D produced a significant decrease in bladder capacity in sham operated rats but bladder capacity returned to control levels before sham operation within 6 hours. In cerebral infarcted rats pretreated with vehicle bladder capacity was significantly decreased after middle cerebral artery occlusion and it remained consistently below half of pre-occlusion capacity. Actinomycin D blocked the decrease in bladder capacity in cerebral infarcted rats. In actinomycin D treated cerebral infarcted rats bladder capacity gradually recovered and returned to the control level before middle cerebral artery occlusion within 10 hours. Actinomycin D suppressed an increase in c-fos mRNA expression 1 hour after middle cerebral artery occlusion as well as in zif268 3 hours after occlusion. Administering actinomycin D 0.5 or 1 hour after middle cerebral artery occlusion also suppressed bladder overactivity until at least 10 hours after occlusion but injection 3 hours after occlusion did not. CONCLUSIONS: These results indicate that an RNA synthesis inhibitor can prevent a late stage of bladder overactivity. Transcription in the dorsal pontine tegmentum was found to be necessary to maintain the long lasting bladder overactivity caused by cerebral infarction.

Overactive bladder--experimental aspects.

Supra-pontine lesions resulting from neurological disorders such as vascular disease, Parkinson's disease, or Alzheimer type senile dementia lead to an increase in bladder activity. This is due in part to the removal at the cortical inhibitory control of the micturition center in the brain stem - i.e. the pontine micturition center (PMC) - and in part to facilitation of excitatory control. These inhibitory or excitatory controls consist of several neurotransmitter systems, including glutamate, dopamine, gamma-aminobutyric acid (GABA), and acetylcholine. Bladder overactivity caused by cerebral infarction is mediated by upregulation of N-methyl-D-aspartate (NMDA) glutamatergic and D2 dopaminergic excitatory mechanisms, and by downregulation of NMDA glutamatergic and Ml muscarinic inhibitory mechanisms in the brain. Bladder overactivity associated with Parkinson's disease is reportedly induced by a loss of input to the D1 dopaminergic receptor. Furthermore, bladder overactivity caused by Alzheimer type dementia is thought to be mediated by downregulation of M1 muscarinic inhibitory mechanisms. Development of bladder overactivity following cerebral infarction is mediated by activation of the NMDA receptor and accompanied by an increase in c-fos, zif268 and COX-2 mRNA expression in the dorsal pontine tegmentum.

A causative factor of copulatory disorder in rats following social stress.

PURPOSE: We investigated the causative role of testosterone in copulatory disorder and the expression of c-fos messenger (m)RNA in the medial preoptic area in rats after social stress. MATERIALS AND METHODS: To generate copulatory disorder rats in the experimental defeated group were attacked by residents for 10 minutes daily for 7 consecutive days (social stress). We then investigated the effect of repeat defeat on the frequency of mounting behavior and plasma testosterone levels. The effects of testosterone replacement and/or apomorphine (100 microg./kg. subcutaneously), a dopamine receptor agonist, on the frequency of mounting behavior were also studied. After experiencing social stress the brain area within the medial preoptic area was removed for analysis of c-fos and androgen receptor mRNA expression. Real-time reverse transcription-polymerase chain reaction was done to analyze gene expression. RESULTS: Rats in the defeated group showed a reduced frequency of mounting behavior and a decrease in plasma testosterone levels compared with values in control rats (p <0.01). After testosterone replacement the frequency of mounting behavior became significantly higher than that of socially stressed rat (p <0.05) but did not achieve control levels. The frequency of mounting behavior by socially stressed rats after apomorphine treatment was significantly higher than that of vehicle treated rats (p <0.05) but the frequency produced by the combination of testosterone replacement and apomorphine injection did not achieve control levels. After the social stress experience c-fos mRNA expression was significantly increased compared with that in control rats (p <0.05). The expression of androgen receptor mRNA was not affected by social stress. Testosterone replacement significantly reduced the expression of c-fos mRNA in the medial preoptic area (p <0.05). CONCLUSIONS: Our results indicate that a reduction in plasma testosterone may have a causative role in copulatory disorder induced by social stress. Changes in c-fos mRNA expression in the medial preoptic area correlated with copulatory disorder and, thus, they are suitable for monitoring that disorder.

Contribution of cerebral nitric oxide to bladder overactivity after cerebral infarction in rats.

PURPOSE: We investigated the contribution of cerebral nitric oxide to neurogenic voiding dysfunction after cerebral infarction. MATERIALS AND METHODS: The left mid cerebral artery in female Sprague-Dawley rats was occluded with 4-zero monofilament nylon thread. Bladder activity was monitored during infusion cystometrography. Time or dose dependent effects of intracerebral ventricular administration of the nonselective nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME), were investigated in conscious, sham operated and cerebral infarcted rats. The selective neuronal nitric oxide synthase inhibitor 1-(2-trifluoromethylphenyl) imidazole was also administered to determine the participation of nitric oxide synthase subtypes. Cross-sectional infarct area was measured and infarct volume was calculated 12 hours after mid cerebral artery occlusion. RESULTS: Bladder capacity was reduced by 54% 30 minutes after mid cerebral artery occlusion. L-NAME significantly increased bladder capacity in a dose and time dependent manner in cerebral infarcted rats but had no effect on sham operated rats. L-NAME (50 microg./kg.) administered 3 or 5 hours after occlusion significantly increased bladder capacity. This effect of L-NAME was reversed by injecting 250 microg. L-arginine per rat, which alone did not produce any significant change in bladder capacity in cerebral infarcted rats. Administration of 1-(2-trifluoromethylphenyl) imidazole also significantly increased bladder capacity in these rats. On the other hand, 5 microg. of the nitric oxide donor FK-409 per rat reduced bladder capacity for 10 to 15 minutes. None of the drugs affected infarct volume. CONCLUSIONS: These results indicate that supraspinal nitric oxide has an important role in bladder overactivity after cerebral infarction but it does not affect normal micturition in rats. This finding suggests a central mechanism sensitive to nitric oxide for bladder overactivity after cerebral infarction.