Prediction of clinically significant prostate cancer through urine metabolomic signatures: A large-scale validated study.

PURPOSE: Currently, there are no accurate markers for predicting potentially lethal prostate cancer (PC) before biopsy. This study aimed to develop urine tests to predict clinically significant PC (sPC) in men at risk. METHODS: Urine samples from 928 men, namely, 660 PC patients and 268 benign subjects, were analyzed by gas chromatography/quadrupole time-of-flight mass spectrophotometry (GC/Q-TOF MS) metabolomic profiling to construct four predictive models. Model I discriminated between PC and benign cases. Models II, III, and GS, respectively, predicted sPC in those classified as having favorable intermediate risk or higher, unfavorable intermediate risk or higher (according to the National Comprehensive Cancer Network risk groupings), and a Gleason sum (GS) of ≥ 7. Multivariable logistic regression was used to evaluate the area under the receiver operating characteristic curves (AUC). RESULTS: In Models I, II, III, and GS, the best AUCs (0.94, 0.85, 0.82, and 0.80, respectively; training cohort, N = 603) involved 26, 24, 26, and 22 metabolites, respectively. The addition of five clinical risk factors (serum prostate-specific antigen, patient age, previous negative biopsy, digital rectal examination, and family history) significantly improved the AUCs of the models (0.95, 0.92, 0.92, and 0.87, respectively). At 90% sensitivity, 48%, 47%, 50%, and 36% of unnecessary biopsies could be avoided. These models were successfully validated against an independent validation cohort (N = 325). Decision curve analysis showed a significant clinical net benefit with each combined model at low threshold probabilities. Models II and III were more robust and clinically relevant than Model GS. CONCLUSION: This urine test, which combines urine metabolic markers and clinical factors, may be used to predict sPC and thereby inform the necessity of biopsy in men with an elevated PC risk.

Efficacy evaluation of Chinese herbal medicine, VGH-BPH1, for patients with benign prostatic hyperplasia: A randomized, double-blind, placebo-controlled, and crossover study.

BACKGROUND: Benign prostatic hyperplasia (BPH) can affect quality of life and cause various complications. Previous studies have suggested that Chinese herbal medicine can alleviate symptoms in patients with BPH. This study aimed to investigate whether the Chinese herbal medicine prescription VGH-BPH1 can alleviate BPH symptoms when used as an add-on treatment. METHODS: In this crossover, randomized, double-blind, placebo-controlled trial, patients with BPH were randomly segregated into two groups: group A received VGH-BPH1, and group B received a placebo for 8 weeks. Subsequently, after a 2-week wash-out period, the two groups were switched to the opposite treatment for another 8 weeks. The International Prostate Symptoms Score and Aging Male Symptoms Score were adopted as the primary outcomes to assess improvement in BPH and patient quality of life. The secondary outcomes were the International Index of Erectile Function, Constitution Chinese Medicine Questionnaire, uroflowmetry results, and postvoid residual urine volume. RESULTS: VGH-BPH1 treatment significantly decreased the International Prostate Symptoms Score total score (p = 0.027); however, no significant difference was observed between the treatment and placebo groups. The Aging Male Symptoms Score "joint pain and muscular ache" score in the VGH-BPH1 group was significantly lower than that of the placebo group (p = 0.022). The "physical exhaustion" score also exhibited a decreasing trend when both groups were compared (p = 0.057). CONCLUSION: Although VGH-BPH1 treatment did not outperform the placebo in terms of improving BPH symptoms, it resulted in improvement in several quality of life indicators when relative to the placebo. Future research using a larger sample size with appropriate amendments to the protocol should be conducted to further investigate the effects of VGH-BPH1.

Risk factors for pharmacotherapy for storage symptoms after transurethral resection of the prostate in patients with benign prostatic hyperplasia.

OBJECTIVES: Postoperative persistence of storage symptoms after transurethral resection of the prostate (TURP) is bothersome, and evidence of its cause is sparse. We sought to analyze risk factors for using antimuscarinics or beta-3 agonists after TURP in benign prostatic hyperplasia (BPH) patients. METHODS: BPH patients who underwent TURP and were followed up for >6 months after surgery were retrospectively enrolled. Postoperative pharmacotherapy for storage symptoms was defined as the prescription of antimuscarinics or beta-3 agonists within 3 months after TURP for >3 months. Preoperative and perioperative variables were evaluated for their effect on the postoperative prescription of antimuscarinics or beta-3 agonists. RESULTS: Of the 376 patients, 45 (12.0%) received postoperative pharmacotherapy for storage symptoms. Patients who underwent bipolar TURP were significantly more likely to receive postoperative pharmacotherapy than those who underwent monopolar TURP (15.7% vs 6.9%; P = 0.01). Significantly more patients with intravesical prostatic protrusions >1 cm used postoperative pharmacotherapy than those with protrusions of ≤1 cm (14.4% vs 5.2% respectively; P = 0.02). Multivariate logistic regression analysis revealed age >75 years (odds ratio [OR] 3.04; 95% CI 1.29-7.16; P = 0.011), intravesical prostatic protrusion >1 cm (OR, 3.48; 95% CI, 1.32-9.15; P = 0.012), and bipolar transurethral resection (OR 4.25; 95% CI 1.53-11.80; P = 0.005) as significant risk factors for postoperative pharmacotherapy. CONCLUSIONS: Advanced age, intravesical prostatic protrusion, and bipolar TURP were significantly associated with postoperative pharmacotherapy for storage symptoms after TURP in BPH patients. Therefore, patients with these risk factors might be informed about the risk of postoperative storage symptoms that may require medications after TURP.

Evaluating Teaching Effectiveness of Medical Humanities in an Integrated Clerkship Program by a Novel Prospective Propensity Score Matching Framework.

BACKGROUND: This study aims to rigorously compare the effectiveness of the educational programs of a new integrated clinical clerkship in medicine (3 months) and surgery (3 months) at a cancer center with the conventional subspecialty-based rotations at a tertiary teaching hospital, by this prospective, pre-post comparative method. METHODS: Between 2013-2016, we compared 69 students who had selected the integrated clerkship that emphasized clinical competency and medical humanities training with 138 matched peers who had completed conventional clerkships during the same period. Outcome measures for medical humanities included empathy, patient-centeredness, and other values and skills related to holistic health care professionalism by introducing prospective propensity score matching (PSM). RESULTS: At baseline, no significant between-group differences existed. At the completion of the core clerkships, students receiving the integrative clerkship had significantly higher scores on the Patient-Practitioner Orientation Scale (PPOS) and the Professionalism Climate in Clinical Teaching Environment (PCI), and similar Jefferson Scale of Physician Empathy Student Version (JSPE) scores, as compared with the comparison group. We also found that the students in this program did not perform worse than those in the traditional internship group in the comprehensive and formative OSCE medical clinical skills test. CONCLUSIONS: Our study develops an empirical basis for rigorous evaluation to design medical education to improve the medical humanities values and skills of interns. Features of the new integrated clerkship program that we developed include substantial participation by the students in patient-centered in-hospital culture, as well as reflection, discussion, and feedback on actual clinical cases.

The effects of a Chinese herbal medicine (VGHBPH0) on patients with benign prostatic hyperplasia: A pilot study.

BACKGROUND: The current Western medicine treatment options for benign prostatic hyperplasia (BPH) have various degrees of documented effectiveness. However, the uses of these interventions are limited to specific patient populations or have certain side effects that interfere with patient quality of life. This study evaluated the clinical effects of a Chinese herbal medicine (CHM) on patients with BPH. METHODS: This was a single-arm pilot study. Twenty BPH patients were enrolled, and they were required to take the investigated CHM three times a day for 8 weeks, along with their Western medicine. Patients returned to clinics as scheduled and completing international prostate symptoms scores (IPSS), aging male symptoms score, international index of erectile function, and body constitution questionnaire of traditional Chinese medicine. Uroflowmetry and sonography were also applied to evaluate the changes in urinary velocity and post-voiding residual urine volume from the baseline to the end of the study. RESULTS: The mean IPSS total score was significantly decreased by 2.5 points after 8 weeks of treatment with the CHM (from 17.5 to 15.0, p = 0.03). The mean IPSS voiding subscore was decreased by 1.7 points (from 10.1 to 8.4, p = 0.02), and the mean incomplete emptying subscore was decreased by 0.8 points (from 2.9 to 2.1, p = 0.02), with both decreases being statistically significant. A descending trend in the post-voiding residual urine volume was also observed (from 52.9 to 30.8 mL, p = 0.07). CONCLUSION: This trial indicated that the add-on CHM treatment (VGHBPH0) might be a potential treatment for improving the lower urinary tract symptoms of BPH patients.

Is intravesical prostatic protrusion a risk factor for hydronephrosis and renal insufficiency in benign prostate hyperplasia patients?

BACKGROUND: Some patients with benign prostatic hyperplasia (BPH) and lower urinary tract symptoms hesitate to undergo surgical treatment until acute urinary retention (AUR) occurs. Some of these patients have been found to have hydronephrosis or even renal insufficiency. This study aimed to analyze the risk factors for hydronephrosis in patients with AUR who needed to receive transurethral resection of the prostate (TURP). METHODS: We retrospectively analyzed 91 patients from January 2014 to June 2015, who had BPH and received TURP for AUR. Patients with urolithiasis, prostate cancer, bladder cancer, gross hematuria, previous bladder radiation therapy, or urinary tract surgery were excluded. Parameters of intravesical prostatic protrusion (IPP), serum prostatic specific antigen (PSA), total prostate volume (PV), age, body mass index (BMI), hypertension (HTN), diabetes mellitus (DM), coronary artery disease (CAD), and serum creatinine (Cr) were compared between the hydronephrosis and non-hydronephrosis groups. RESULTS: There were significant differences in IPP (p < 0.001) and Serum Cr (p < 0.001) between the hydronephrosis and non-hydronephrosis groups. For IPP, the cut-off values of the highest risk of hydronephrosis was 1.95 cm. There were no significant differences in age, BMI, DM, HTN, CAD, total PV, and PSA between the two groups. IPP was not correlated with total PV (p = 0.423). Most of the patients with hydronephrosis had renal function improvement after TURP. CONCLUSION: IPP was a significant risk factor for hydronephrosis in BPH patients. If the patients' IPP exceeded 1.95 cm, they had a higher risk of having hydronephrosis when AUR occurred. Hydronephrosis is a risk factor for renal insufficiency, and Serum Cr levels decreased significantly in the patients of our study.

Vapoenucleation of the prostate using a high-power thulium laser: a one-year follow-up study.

BACKGROUND: Prostate vaporization and enucleation is a novel treatment option for bladder outlet obstruction caused by benign prostate enlargement. This surgical technique, however, has not yet been standardized. We present our findings of using a high-power thulium laser to accomplish vapoenucleation of the prostate (ThuVEP). METHODS: We prospectively collected and analyzed data from 29 patients who underwent ThuVEP between August 2010 and May 2012. The control group included 30 patients who underwent traditional transurethral resection of the prostate (TURP). Operative variables, patient profiles, preoperative and postoperative urine flow rates, prostate volume (measured using transrectal ultrasonography), and the international prostate symptom score (IPSS) were recorded and analyzed using a two-tailed Student's t-test and analysis of variance. RESULTS: The ages (mean ± SD) of the patients were 76.1 ± 9.4 and 72.6 ± 7.4 years (p = 0.28) in the ThuVEP and TURP groups, respectively. The average urinary flow rates before and 12 months after the operation (volume/maximum flow/average flow) were 243.3/10.5/5.0 and 302.8/17.6/9.4 (in mL, mL/s, mL/s, respectively) in the ThuVEP group and 247.2/10.8/4.6 and 369.9/20.8/12.0, respectively, in the TURP group. Preoperative and postoperative IPSSs were 17.1 ± 5.0 and 6.5 ± 3.8, respectively, in the ThuVEP group and 18.2 ± 4.5 and 6.2 ± 3.3, respectively, in the TURP group. The mean ratio of the estimated postoperative residual prostate volume to the preoperative total volume was 0.47 (p = 0.449) in both groups. The overall complication rate was 20.7% in the ThuVEP group and 30.0% in the TURP group. CONCLUSIONS: One year of follow-up showed that ThuVEP and TURP effectively alleviated subjective and objective voiding symptoms with a low rate of complications. Thus, vapoenucleation using a high-power laser is feasible in elderly patients. TRIAL REGISTRATION: ISRCTN registry with study ID ISRCTN52339705 . Date assigned: 06/03/2015.

Diagnosis of prostate cancer: repeated transrectal prostate biopsy or transurethral resection.

BACKGROUND: Transrectal ultrasound-guided biopsy of the prostate is the major method by which prostate cancer is diagnosed. However, many patients might be overlooked with the initial biopsy. Not uncommonly, patients need repeated biopsies when they continue to exhibit suspicious clinical signs. This may cause psychological stress to both patients and doctors. The purpose of this study was to determine how many repeat transrectal biopsies are adequate for prostate cancer detection and when to switch to transurethral resection. METHODS: We retrospectively studied a cohort of 2,996 patients who had undergone prostate biopsy. If the biopsy specimen was negative for malignancy, patients were given the choice of either being managed with observation or undergoing transurethral resection of the prostate (TURP) if indicated. If there was a high suspicion of cancer, patients were advised to undergo additional biopsies. The primary endpoint of this study was a diagnosis of cancer. RESULTS: The cancer detection rate was 22.9% (685 of 2,996 patients) in specimens taken during the first transrectal biopsy, 8.7% in those taken during the second biopsy (32 of 336 patients), and 6.1% in those taken during the third biopsy (6 of 98 patients). The cancer detection rate of TURP after 1 negative biopsy result was 9.3% (35 of 375 patients), and that after 2 negative biopsy results was 17.1% (6 of 35 patients). TURP-derived specimens that were pathologically diagnosed as malignant had lower Gleason grade on average, no matter how many repeat biopsies there were in patients whose previous transrectal biopsy specimens were negative for malignancy (p=0.002 for 2 negative biopsy results and p=0.007 for 3 negative biopsy results). CONCLUSION: The chance of detecting malignancy beyond a third transrectal biopsy procedure is low. TURP, therefore, might be an alternative procedure for obtaining tissue for pathologic diagnosis, especially in patients with rising prostate-specific antigen levels and comorbid illnesses such as obstructive symptoms.

Inhibitory effects of evodiamine on the growth of human prostate cancer cell line LNCaP.

Evodiamine, isolated from a Chinese herbal drug named Wu-Chu-Yu, possesses many biological functions. Recently, it has been reported that Wu-Chu-Yu exerts an antiproliferative effect on several cancers. Prostate carcinoma initially occurs as an androgen-dependent tumor and is the second leading cause of cancer death in American males. In the present study, the effect of evodiamine on the growth of androgen-dependent prostate cancer cell line LNCaP in vitro was examined. Based on [3-(4,5-dimethylthiazol-2-yle)2,5-diphenyltetrazolium bromide] (MTT) assay, evodiamine significantly inhibited the growth of LNCaP cells in a concentration-dependent manner. A significant and concentration-dependent inhibitory effect of evodiamine on LNCaP cell growth was observed at 24 hr and persisted for 96 hr. The examination of lactate dehydrogenase (LDH) assay showed that the cytotoxic effects of evodiamine on LNCaP cells were concentration dependent. Furthermore, we examined the influences of evodiamine on cell death and cell cycle. The flow cytometric analysis of evodiamine-treated cells indicated a block of G2/M phase and an elevated level of DNA fragmentation. The G2/M arrest reached a maximum at 24 hr after evodiamine treatment. The G2/M arrest was accompanied by an elevated p34(cdc2) kinase activity and an increase in the protein expression of cyclin B1 and phosphorylated form of p34(cdc2) (Thr 161). Examination of TUNEL showed that evodiamine-induced apoptosis was observed at 24 hr and extended for 72 hr. Evodiamine elevated caspase-3, and caspase-9 activities and the processing of caspase-3 and caspase-9. These results suggested that evodiamine inhibits the growth of prostate cancer cell line, LNCaP, through an accumulation of cell cycle at G2/M phase and an induction of apoptosis.

H1-A extracted from Cordyceps sinensis suppresses the proliferation of human mesangial cells and promotes apoptosis, probably by inhibiting the tyrosine phosphorylation of Bcl-2 and Bcl-XL.

H1-A, a pure compound used in traditional Chinese medicine, is effective in the treatment of autoimmune disorders of MRL lpr/lpr mice. We have previously reported that after 8 weeks of oral therapy with H1-A, 40 microg/kg/day, MRL lpr/lpr mice demonstrated significantly less proteinuria, lower serum creatinine levels, and less renal mesangial proliferation than mice in an untreated group. To clarify the pharmacologic properties of H1-A, we studied its cellular and subcellular effects in cultured human mesangial cells. Our results show that H1-A inhibits cell proliferation and promotes the apoptosis of interleukin (IL)-1- and platelet-derived growth factor (PDGF)-BB-activated human mesangial cells in vitro. Uptake of tritiated thymidine was nearly totally suppressed by the addition of 12.5 micromol/L H1-A (counts per minute decreased from 3905 +/- 70 to 141 +/- 5). The population of S-phase cells decreased from 15.5% +/- 1.7% to 10.0% +/- 0.3%, and G0 + G1 phase cells increased from 68.8% +/- 0.07% to 74.6% +/- 0.05%. This suppression was not a result of cytotoxicity. Apoptosis of human mesangial cells was detectable after treatment with 12.5 or 25 micromol/L H1-A. Using immunoprecipitation and immunoblotting, we found that H1-A inhibits tyrosine phosphorylation of human mesangial proteins and that Bcl-2 and Bcl-XL were probably among these proteins. These findings suggest that H1-A modulates some subcellular signal-transduction pathways and changes the balance between proliferation and apoptosis of mesangial cells in vitro or in vivo. H1-A may be effective in the management of autoimmune disorders, and the modulation of the signal transduction proteins Bcl-2 and Bcl-XL may represent a target for future pharmacologic interventions.

Effects of bufalin and cinobufagin on the proliferation of androgen dependent and independent prostate cancer cells.

BACKGROUND: Cardiac glycosides may induce oncolytic effects in cancers. This study was to evaluate bufalin and cinobufagin effects on the proliferation of prostate cancer cell lines named LNCaP, DU145, and PC3. METHODS: Cell proliferation was measured by MTT assay. The cytotoxic effects were determined by lactate dehydrogenase measurements. The intracellular calcium concentration ([Ca(2+)](i)) was measured by a dual-wavelength spectrometer system. TUNEL assay and flow cytometry were performed to measure percentage of apoptotic cells. A colorimetric assay was to measure caspases activities. RESULTS: Bufalin and cinobufagin inhibited proliferation of cancer cells at doses of 0.1, 1, or 10 microM after 2-4 days of culture. Cytotoxicity of bufalin and cinobufagin on the DU145 and LNCaP cells was dose-dependent. Bufalin or cinobufagin increased [Ca(2+)](i) and apoptosis in cancer cells after a 24-hr culture as well as caspase 3 activities in DU145 and PC3 cells and caspase 9 activities in LNCaP cells. CONCLUSIONS: Bufalin and cinobufagin may inhibit the proliferation of prostate cancer cell lines associated with sustained elevation of the [Ca(2+)](i) and that of apoptosis.