CNPY2 promoted the proliferation of renal cell carcinoma cells and increased the expression of TP53.

Renal cell carcinoma (RCC) is the most common type of kidney cancer. However, the mechanisms underlying the progression of the disease are not well understood. The data in this report suggest that canopy FGF signaling regulator 2 (CNPY2) is a promoter of RCC progression. We found that CNPY2 significantly promoted growth of RCC cells and upregulated TP53 gene expression. Although TP53 is widely known as a tumor suppressor, in RCC TP53 promoted tumor cell growth. A typical p53 target gene, CDKN1A, was upregulated by both p53 and CNPY2 in RCC cells, suggesting that CNPY2 increased the expression level of TP53. Consistent with these results, CNPY2 and TP53 expression levels were positively correlated in RCC patients. These findings suggested that CNPY2 promoted cancer cell growth in RCC through regulating TP53 gene expression.

Morphometric analysis of prostate zonal anatomy using magnetic resonance imaging: impact on age-related changes in patients in Japan and the USA.

OBJECTIVES: To evaluate the impact of morphometric magnetic resonance imaging (MRI) analysis of the prostate zonal anatomy on aging, prostatic hypertrophy and lower urinary tract symptoms in patients from Japan and the USA. SUBJECTS AND METHODS: A retrospective analysis of 307 men, including 156 men from Japan and 151 from the USA, who consecutively underwent 3-Tesla MRI and International Prostate Symptom Score (IPSS) assessment because of elevated PSA levels. Using Synapse-Vincent (Fujifilm), the prostatic zones were segmented in each axial step-section of the T2-weighted MRI to reconstruct a three-dimensional model of the prostate, which was used to calculate: zonal volumes (whole-gland prostate, transition zone and peripheral zone volumes); the presumed circle area ratio (PCAR); and PZ thickness. Bivariate associations were quantified using Spearman's rank correlation coefficients. RESULTS: The USA subgroup had a greater prostate volume (49 vs 42 mL; P = 0.003) and TZ volume (26 vs 20 mL; P < 0.001) than the Japan subgroup, with no difference in PZ volume (19 vs 20 mL; P = 0.2). There was no age-related increase in PZ volume in either of the subgroups or in the entire cohort (P = 0.9, P = 0.2, P = 0.3, respectively). PZ thickness had a significant negative correlation with PCAR (P < 0.001) and TZ volume (P < 0.001). The greater the increase in the TZ volume with the increase in PCAR, which probably correlates with obstructive pressure, the thinner the PZ became. PCAR had a significant positive correlation with IPSS (P = 0.003) and obstructive symptoms (P = 0.007), while PZ thickness had a significant negative correlation (P = 0.018). CONCLUSIONS: No age-related increases and no differences between the Japanese and the US subgroups were found with regard to PZ volume. The more TZ volume increased, the higher the obstructive pressure and the thinner the PZ became; these changes were associated with increased obstructive symptoms. MRI analysis of prostate zonal anatomy enhanced our understanding of age-related changes in morphology and urinary symptoms.

A novel technique using three-dimensionally documented biopsy mapping allows precise re-visiting of prostate cancer foci with serial surveillance of cell cycle progression gene panel.

BACKGROUND: Conventional systematic biopsy has the shortcoming of sampling error and reveals "no evidence of cancer" with a rate of >50% on active surveillance (AS). The objective of this study is to report our initial experience of applying a 3D-documented biopsy-mapping technology to precisely re-visit geographically documented low-risk prostate cancer and to perform serial analysis of cell-cycle-progression (CCP) gene-panel. METHODS: Over a period of 40 months (1/2010-4/2013), the 3D-biopsy-mapping technique, in which the spatial location of biopsy-trajectory was digitally recorded (Koelis), was carried out. A pair of diagnostic (1st-look) and surveillance (2nd-look) biopsy were performed per subject (n = 25), with median interval of 12 months. The documented biopsy-trajectory was used as a target to guide the re-visiting biopsy from the documented cancer focus, as well as the targeted field-biopsy from the un-sampled prostatic field adjacent to negative diagnostic biopsies. The accuracy of re-visiting biopsy and biopsy-derived CCP signatures were evaluated in the pair of the serial biopsy-cores. RESULTS: The 1st-look-biopsy revealed a total of 43 cancer lesions (1.7 per patient). The accuracy of re-visiting cancer was 86% (37/43) per lesion, 76% (65/86) per core, and 80% (20/25) per patient. This technology also provided an opportunity for 3D-targeted field-biopsy in order to potentially minimize sampling errors. The CCP gene-panel of the 1st-look (-0.59) versus 2nd-look (-0.37) samples had no significant difference (P = 0.4); which suggested consistency in the molecular signature of the known cancer foci during the short-time interval of median 12 months. Any change in CCP of the same cancer foci would be likely due to change in sampling location from the less to more significant portion in the cancer foci rather than true molecular progression. The study limitations include a small number of the patients. CONCLUSION: The 3D-documented biopsy-mapping technology achieved an encouraging re-sampling accuracy of 86% from the known prostate cancer foci, allowing the serial analysis of biopsy-derived CCP signatures.

Assessment of lower urinary tract function in pediatrics using ultrasonography.

Ultrasound imaging is a less invasive imaging modality without radiation exposure and is available for repeated tests. It is the gold standard examination for diagnosing and managing disorders of the urinary tract, including lower urinary tract dysfunction (LUTD) in pediatric urology. Ultrasound imaging is effective for screening underlying diseases and determining treatment strategies. Ultrasound examination at the bedside should focus on post-voided residual urine (PVR), bladder wall thickening, renal morphology, and rectal diameter. Since PVR must be tested immediately after voiding, examining infants who cannot complain of the urge to void is difficult. PVR measurement combined with a 4-h voiding observation or alarm system activated by urine is recommended for these infants. Early diagnosis is important because LUTD is associated with the risk of morbid residual urine and high voiding pressure, which can result in renal deterioration, urinary leakage, and febrile urinary tract infection.

Transrectal ultrasound navigation during minilaparotomy retropubic radical prostatectomy: impact on positive margin rates and prediction of earlier return to urinary continence.

OBJECTIVES: To assess the impact of transrectal ultrasound (TRUS) navigation on positive margin rates and membranous urethral length (MUL) after minilaparotomy radical retropubic prostatectomy (MRP). METHODS: Rates of positive distal margins prior to and after the application for TRUS navigation during MRP were assessed. Of the 189 men undergoing MRP at our institution, 70 were evaluated for the clinical usefulness of preoperative and postoperative MUL. Patients filled out self-administrated questionnaires concerning continence status at 1, 3, 6, 9, and 12 months after the MRP. Surgery-related factors including MUL were analyzed for the prediction of urinary continence after MRP. RESULTS: With the application of TRUS, the rate of positive distal margins decreased by 14%. Postoperative MUL was an independent variable predictive of urinary continence 1 month after surgery. Patients with a MUL longer than 12 mm showed a significantly more favorable recovery from urinary incontinence after surgery. CONCLUSION: Application of TRUS results in a lower rate of positive margins, and a longer postoperative MUL is associated with an earlier return to urinary continence after MRP.

Efficacy of the combination use of aprepitant and palonosetron for improving nausea in various moderately emetogenic chemotherapy regimens.

BACKGROUND: Nausea is more difficult to control than vomiting in chemotherapy. We therefore analyzed the efficacy of a strong supportive treatment with aprepitant, palonosetron, and dexamethasone against nausea for various moderately emetogenic chemotherapy (MEC). METHODS: A total of 312 cases treated by palonosetron with or without aprepitant receiving MEC regimens using oxaliplatin, carboplatin, and irinotecan from 2014 to 2016 in our outpatient center for digestive organ cancers, lung cancers, and gynecological cancers were analyzed. Through propensity score matching analysis, cases were divided into 97 cases receiving 2 drugs (palonosetron+dexamethasone) and 97 receiving 3 drugs (aprepitant+palonosetron+dexamethasone). We examined the control rates of nausea for the first two consecutive courses in the both groups. Additionally, risk factors for acute and delayed nausea were analyzed using a multivariate analysis among overall 312 cases. RESULTS: The control rates of nausea in the two- and the three-drug groups were as follows: acute, 92.8 and 95.9% (p = 0.35); and delayed, 83.5 and 81.4% (p = 0.85), although the control rates of vomiting exceeded 95% in both groups. A multivariate analysis showed that significant risk factors for acute nausea (odds ratio, 95% confidence interval) were elevation of serum creatinine (12.601, 2.437-65.157), general fatigue (3.728, 1.098-12.661), and performance status (PS) 2 (19.829, 3.200-122.865). The significant risk factors for delayed nausea were elevation of alanine aminotransferase (2.397, 1.153-4.984), general fatigue (2.652, 1.380-5.097), and PS 2 (5.748, 1.392-23.740). CONCLUSIONS: The control for nausea in MEC was insufficient even with palonosetron and aprepitant, and we should pay attention to risk factors for preventing nausea.

Naftopidil versus tamsulosin hydrochloride for lower urinary tract symptoms associated with benign prostatic hyperplasia with special reference to the storage symptom: a prospective randomized controlled study.

OBJECTIVES: In order to compare the clinical efficacy of naftopidil (Naf) and tamsulosin hydrochloride (Tam), which differ in their selectivity to alpha receptor subtypes, we performed a multi-center prospective randomized controlled study. METHODS: Men complaining of lower urinary tract symptoms due to benign prostatic hypertrophy, were randomized into two treatment groups: one receiving 50 mg Naftopidil daily (Naf group, n = 31 pts), and one receiving 0.2 mg Tam once daily (Tam group, n = 28 pts). Baseline symptom scores were compared to those at 2 weeks and at the end of the observation period (6-8 weeks). RESULTS: In the Naf group at 2 weeks, the score of the daytime frequency significantly improved from 3.5 to 2.2 (P = 0.03), and the score of nocturia improved significantly from 3.5 to 2.2 (P = 0.0004), respectively. In the Tam group at 2 weeks, however, no significant improvement was noted in the increased score of daytime frequency (P = 0.1) or nocturia (P = 0.2). At 2 weeks, the storage symptom score of the frequency to the combined score of daytime frequencies and the score of nocturia was better in the Naf group (improved from 7.0 to 4.4, P = 0.0017) than in the Tam group (from 6.8 to 4.9, P = 0.08) (P < 0.05). At 6-8 weeks, the effects of the two drugs on lower urinary tract symptoms were comparable. CONCLUSIONS: Naf demonstrated a significant early response to improve storage symptoms at 2 weeks, including daytime frequency and nocturia, compared with Tam.

[Continuous intravenous administration of fentanyl reduces tenesmus after transurethral resection of the prostate (TUR-P)].

BACKGROUND: The relief from tenesmus is important after transurethral resection of the prostate (TUR-P). We evaluated the effect of continuous intravenous administration of fentanyl on the tenesmus. METHODS: Eleven patients receiving fentanyl infusion (fentanyl group) were compared with fourteen patients without fentanyl infusion (control group) retrospectively. All patients underwent TUR-P under spinal anesthesia with hyperbaric 0.5% bupivacaine 2.2-2.8 ml. In the fentanyl group, fentanyl infusion 25 microg x hr(-1) was started followed by fentanyl 50 microg administration postoperatively. RESULTS: In the fentanyl group, NSAIDs were needed in only one patient. Eleven patients in the control group, however, required NSAIDs and three of them needed additional pentazocine administration. The required amount of NSAIDs per patient was significantly smaller in the fentanyl group (Mann-Whitney U test, P < 0.01). In the fentanyl group, one patient had slight nausea but needed no care. Other side effects, such as respiratory depression, hypotension, bradycardia and somnolence were not observed. CONCLUSIONS: Continuous intravenous administration of fentanyl was very effective and safe enough for the tenesmus after TUR-EP.

Randomized study of intravesical pirarubicin chemotherapy with low and intermediate-risk nonmuscle-invasive bladder cancer in Japan: Comparison of a single immediate postoperative intravesical instillation with short-term adjuvant intravesical instillations after transurethral resection.

PURPOSE: The objective of this study was to evaluate the efficacy, defined by the 3-year tumor recurrence-free survival rate, of intravesical chemotherapy using pirarubicin (THP) in patients with low or intermediate-risk nonmuscle-invasive bladder cancer (NMIBC). PATIENTS AND METHODS: Between October 2010 and January 2015, 206 patients were enrolled, and finally 113 were randomized to receive either a single immediate postoperative intravesical instillation of THP (30 mg) (Group A), or 8 additional weekly intravesical instillations of THP (30 mg) after a single postoperative instillation (Group B). The patients were examined by performing cystoscopy and urine cytology every 3 months after transurethral resection to determine bladder tumor recurrence. The primary endpoint was 3-year-recurrence-free survival rate. RESULTS: All 113 patients were bacillus Calmette-Guérin (BCG)-naïve. The 3-year recurrence free survival rate was 63.7% for Group A and 85.3% for Group B (log-rank test, P = .0070). In patients with intermediate recurrence risk, the 3-year recurrence-free survival rate was 63.4% in Group A and 86.1% in Group B (log-rank test, P = .0036). Cox regression analysis revealed that only additional instillation of THP was a significant independent factor for recurrence-free rate in patients with intermediate risk. No patient with progression was noted during this period. Frequent adverse effects (AEs) were frequent urination and micturition pain, and no severe AEs (Grade 3 or more) occurred. CONCLUSION: Additional instillation of THP (30 mg) weekly for 8 weeks reduced the risk of tumor recurrence without severe AEs in BCG-naïve NMIBC patients with intermediate risk.

Predictive factors in patients eligible for pegfilgrastim prophylaxis focusing on RDI using ordered logistic regression analysis.

Although pegfilgrastim prophylaxis is expected to maintain the relative dose intensity (RDI) of chemotherapy and improve safety, information is limited. However, the optimal selection of patients eligible for pegfilgrastim prophylaxis is an important issue from a medical economics viewpoint. Therefore, this retrospective study identified factors that could predict these eligible patients to maintain the RDI. The participants included 166 cancer patients undergoing pegfilgrastim prophylaxis combined with chemotherapy in our outpatient chemotherapy center between March 2015 and April 2017. Variables were extracted from clinical records for regression analysis of factors related to maintenance of the RDI. RDI was classified into four categories: 100% = 0, 85% or < 100% = 1, 60% or < 85% = 2, and < 60% = 3. Multivariate ordered logistic regression analysis was performed to identify predictive factors in patients eligible for pegfilgrastim prophylaxis to maintain the RDI. Threshold measures were examined using a receiver operating characteristic (ROC) analysis curve. Age [odds ratio (OR) 1.07, 95% confidence interval (CI) 1.04-1.11; P < 0.0001], anemia (grade) (OR 1.77, 95% CI 1.10-2.84; P = 0.0184), and administration 24-72 h after chemotherapy (OR 0.44, 95% CI 0.22-0.89; P = 0.0224) were factors that significantly correlated with RDI maintenance. ROC curve analysis of the group that failed to maintain the RDI indicated that the threshold for age was 70 years and above, with a sensitivity of 60.0% and specificity of 80.2% (area under the curve: 0.74). In conclusion, younger age, anemia (less), and administration of pegfilgrastim 24-72 h after chemotherapy were significant factors for RDI maintenance.

Predictive factors for the development of irinotecan-related cholinergic syndrome using ordered logistic regression analysis.

Cholinergic syndrome is an acute adverse reaction associated with irinotecan. Development of cholinergic syndrome can be ameliorated or prevented by administering various anticholinergics, including atropine sulfate or scopolamine butylbromide. Although many of the side effects are transient and non-life-threatening, their onset is painful and can lower a patient's quality of life (QoL). This retrospective study was performed to identify predictive factors of the development of irinotecan-related cholinergic syndrome in order to develop future strategies for improving the QoL of patients undergoing chemotherapy. We enrolled 150 cancer patients who underwent chemotherapy, which included irinotecan, in our outpatient chemotherapy center between October 2014 and January 2017. For regression analysis, variables related to the development of irinotecan-related cholinergic syndrome were extracted from the patient's clinical records. The degree of cholinergic syndrome was classified as follows: grade 0 = not developed; grade 1 = developed but did not require anticholinergic drugs; and grade 2 = developed and required anticholinergic drugs or stopping the chemotherapy due to cholinergic syndrome. Multivariate ordered logistic regression analysis was performed to identify predictive factors for the development of irinotecan-related cholinergic syndrome. Threshold measurements were determined using a receiver operating characteristic analysis (ROC) curve. Significant factors identified for the development of cholinergic syndrome included female sex [odds ratio (OR) 2.183, 95% confidence interval (CI) 1.010-4.717; P = 0.0471] and irinotecan dose (OR 1.014, 95% Cl 1.007-1.021; P = 0.0001). ROC curve analysis of the group likely to develop cholinergic syndrome indicated that the threshold for the irinotecan dose was 175 mg or above (area under the curve = 0.69). In conclusion, female sex and irinotecan dose were identified as significant predictors of the development of cholinergic syndrome.

Validity of the Short Nutritional Assessment Questionnaire for Japanese Patients with Cancer Undergoing Outpatient Chemotherapy.

PURPOSE: To investigate the utility of the Short Nutritional Assessment Questionnaire (SNAQ) in the nutritional evaluation of patients with cancer undergoing outpatient chemotherapy. METHODS: We included 229 patients with cancer who were undergoing outpatient chemotherapy between October 2015 and April 2016. The SNAQ and the revised SNAQ (addition of age and body mass index) were implemented, and their relationships with Controlling Nutritional Status (CONUT), an indicator of bionutritional assessment, were examined. RESULTS: The cutoff value of the SNAQ score corresponding to moderate-to-severe undernourishment in CONUT values was 0.5, with a sensitivity of 87.5% and a specificity of 65.9%, and the corresponding values for the revised SNAQ score were 2.5, 91.7%, and 62.9%, respectively. This cutoff value and the corresponding positive prediction value for the revised SNAQ were superior to those of SNAQ. Binary logistic regression analysis with the revised SNAQ and sex as independent variables and the CONUT value as the dependent variable revealed that the higher the SNAQ score, the more likely it was that CONUT moderate-to-severe undernourishment would be identified (odds ratio, 1.48;, 1.34-1.96). CONCLUSION: Nutritional evaluation with the revised SNAQ can predict moderate-to-severe undernourishment according to CONUT in patients with cancer undergoing outpatient chemotherapy. J. Med. Invest. 64: 117-121, February, 2017.

Androgen suppresses testicular cancer cell growth in vitro and in vivo.

Silencing of androgen receptor (AR)-meditated androgen signaling is thought to be associated with the development of testicular germ cell tumors (TGCTs). However, the role of the androgen/AR signal in TGCT development has not been investigated. In this study, we show that the androgen/AR signal suppressed the cell growth of seminomas (SEs), a type of TGCT, in vitro and in vivo. Growth of SE cells was suppressed by DHT treatment and reduction of androgen levels by surgical castration promoted cancer cell growth in an in vivo xenograft model. Tryptophan hydroxylase 1 (TPH1), the rate limit enzyme in serotonin synthesis, was one of the genes which expression was reduced in DHT-treated SE cells. TPH1 was highly expressed in SE cancer tissues compared with adjacent normal tissues. Activation of androgen/AR signaling in SE cells reduced the expression of TPH1 in SE cells, followed by the reduction of serotonin secretion in cell culture supernatant. These results suggested that silencing of androgen/AR signaling may cause initiation and progression of SE through increase in TPH1 gene expression level.

Genistein induces Gadd45 gene and G2/M cell cycle arrest in the DU145 human prostate cancer cell line.

Genistein is the most abundant isoflavone of soybeans and has been shown to cause growth arrest in various human cancer cell lines. However, the precise mechanism for this is still unclear. We report here that the growth arrest and DNA damage-inducible gene 45 (gadd45) gene is induced by genistein via its promoter in a DU145 human prostate cancer cell line. The binding of transcription factor nuclear factor-Y to the CCAAT site of the gadd45 promoter appears to be important for this activation by genistein.

Preoperative administration of chlormadinone acetate reduces blood loss associated with transurethral resection of the prostate: a prospective randomized study.

OBJECTIVES: To assess the effects of giving chlormadinone acetate (CMA) before surgery on blood loss associated with transurethral resection of the prostate (TURP), in a prospective randomized controlled study. PATIENTS AND METHODS: Candidates for TURP among patients with benign prostatic hyperplasia were randomized to either treatment with CMA (CMA+) or not (CMA-). In principle, CMA was started at least 28 days before TURP and continued until just before surgery. RESULTS: In all, 33 patients in the CMA+ (median duration of treatment 34.5 days) and 38 in the CMA- group were evaluable. The mean blood loss during TURP was less in the CMA+ (237.3 mL) than in the CMA- group (263.1 mL), but the difference was not significant. There was significantly less blood loss per gram of resected prostate tissue in the CMA+ (9.6 mL/g) than in the CMA- group (13.3 mL/g) (P < 0.05). Haematuria on the day of and the day after TURP was also significantly less severe in the CMA+ than in the CMA- group (P < 0.001 and P < 0.05, respectively). The mean microvessel density of resected prostate tissue was significantly less after CMA treatment (P < 0.001). CONCLUSIONS: CMA given for 1 month before TURP could reduce blood loss to some extent during and after TURP, and this may be related to a decrease in microvessel density.

Isoliquiritigenin inhibits the growth of prostate cancer.

OBJECTIVE: Isoliquiritigenin, one of the components in the root of Glycyrrhiza glabra L., is a member of the flavonoids, which are known to have an anti-tumor activity in vitro and in vivo. In this study, we investigated the anti-tumor effect of isoliquiritigenin on prostate cancer in vitro. METHODS: DU145 and LNCaP prostate cancer cell lines were used as targets. We examined the effects of isoliquiritigenin on cell proliferation, cell cycle regulation and cell cycle-regulating gene expression. Further, we investigated the effects of isoliquiritigenin on the GADD153 mRNA and protein expression, and promoter activity. RESULTS: Isoliquiritigenin significantly inhibited the proliferation of prostate cancer cell lines in a dose-dependent and time-dependent manner. Fluorescence-activated cell sorting (FACS) analysis indicated that isoliquiritigenin induced S and G2/M phase arrest. Isoliquiritigenin enhanced the expression of GADD153 mRNA and protein associated with cell cycle arrest. Further, isoliquiritigenin stimulated transcriptional activity of GADD153 promoter dose-dependently. CONCLUSION: These findings suggest that isoliquiritigenin is a candidate agent for the treatment of prostate cancer and GADD153 may play an important role in isoliquiritigenin-induced cell cycle arrest and cell growth inhibition.

Carotenoids in cancer chemoprevention.

Various natural carotenoids, besides beta-carotene, were proven to have anticarcinogenic activity, and some of them showed more potent activity than beta-carotene. Thus, these carotenoids (alpha-carotene, lutein, zeaxanthin, lycopene, beta-cryptoxanthin, fucoxanthin, astaxanthin, capsanthin, crocetin and phytoene), as well as beta-carotene, may be useful for cancer prevention. In the case of phytoene, the concept of 'bio-chemoprevention', which means biotechnology-assisted method for cancerchemoprevention, may be applicable. In fact, establishment of mammalian cells producing phytoene was succeeded by the introduction of crtB gene, which encodes phytoene synthase, and these cells were proven to acquire the resistance against carcinogenesis. Antioxidative phytoene-containing animal foods may be classified as a novel type of functional food, which has the preventive activity against carcinogenesis, as well as the ability to reduce the accumulation of oxidative damages, which are hazardous for human health.