Angelica gigas: Signature Compounds, In Vivo Anticancer, Analgesic, Neuroprotective and Other Activities, and the Clinical Translation Challenges.

Angelica gigas Nakai (AGN) root is a medicinal herbal widely used in traditional medicine in Korea. AGN root ethanolic extract dietary supplements are marketed in the United States for memory health and pain management. We comprehensively reviewed the anticancer, analgesic, pro-memory and other bio-activities of AGN extract and its signature phytochemicals decursin, decursinol angelate, and decursinol a decade ago in 2012 and updated their anticancer activities in 2015. In the last decade, significant progress has been made for understanding the pharmacokinetics (PK) and metabolism of these compounds in animal models and single dose human PK studies have been published by us and others. In addition to increased knowledge of the known bioactivities, new bioactivities with potential novel health benefits have been reported in animal models of cerebral ischemia/stroke, anxiety, sleep disorder, epilepsy, inflammatory bowel disease, sepsis, metabolic disorders, osteoporosis, osteoarthritis, and even male infertility. Herein, we will update PK and metabolism of pyranocoumarins, review in vivo bioactivities from animal models and human studies, and critically appraise the relevant active compounds, the cellular and molecular pharmacodynamic targets, and pertinent mechanisms of action. Knowledge gaps include whether human pyranocoumarin PK metrics are AGN dose dependent and subjected to metabolic ceiling, or metabolic adaptation after repeated use. Critical clinical translation challenges include sourcing of AGN extracts, product consistency and quality control, and AGN dose optimization for different health conditions and disease indications. Future research directions are articulated to fill knowledge gaps and address these challenges.

Diagnostic Imaging in Low-Risk Prostate Cancer: More Harm Than Good?

INTRODUCTION: Despite guidelines recommending that staging imaging is not needed in very low-risk (VLR) and low-risk (LR) prostate cancer (PCa), there is concern for overutilization in these risk groups. We investigate utilization of staging imaging and implications of findings in newly diagnosed VLR and LR PCa patients. METHODS: A total of 493 patients diagnosed with PCa between 2011 and 2017 were stratified according to American Urological Association and National Comprehensive Cancer Network® VLR and LR groups. Computerized tomography (CT), magnetic resonance imaging and bone scan performed at diagnosis was captured and guidelines compliance was evaluated. The significance of radiologist interpreted imaging findings, by imaging type, were classified as normal, nonurological, nonsignificant urological and PCa significant. RESULTS: Greater than 75% of patients in the VLR and LR groups underwent imaging at time of diagnosis. Bone scan was performed in 30% of patients, none of which noted PCa-significant findings, and the majority were normal. CT was utilized in 38% of patients, with only 3 showing PCa-significant findings. Ten CTs showed nonurological/nonsignificant urological findings causing further evaluation. Magnetic resonance imaging was the most utilized scan in low-risk groups, occurring in 70% of patients. Although the majority were normal, 25 scans showed nonsignificant urological findings while only 7 showed PCa-significant findings. CONCLUSIONS: Among VLR and LR PCa patients, there is high overutilization of imaging with most studies yielding minimal PCa-significant findings and further evaluation for incidental observations. This exploratory analysis gives awareness that staging imaging in VLR and LR PCa patients may do more harm than good.

Is pelvic MRI imaging sufficient cross-sectional imaging for staging intermediate and high-risk prostate cancer?

OBJECTIVES: The American Urological Association's (AUA) and National Comprehensive Cancer Network's (NCCN) provide highly recognized guidelines for staging prostate cancer (CaP). However, both are vague as to specific type of cross-sectional imaging (CT vs. MRI) and extent (abdominal vs. pelvis), thereby raising concern for overlapping imaging. We investigated if current AUA and NCCN CaP staging guidelines can become more specific yet maintain sufficient staging. METHODS: We identified 493 patients diagnosed with CaP between 2011 and 2017 and focused analysis on those with AUA and NCCN Intermediate risk (IR) and High risk (HR) groups. Type of staging imaging was recorded and frequency of overlapping (CT + MRI) and abdominal imaging determined. Significance of radiologist findings, for both overlapping and abdominal imaging, were classified as nonurologic, nonsignificant urologic, and CaP significant. RESULTS: Among IR and HR AUA and NCCN risk groups, 82 (35.7%) and 95 (37.3%) patients, respectively, experienced overlapping imaging, of which only 7 patients in AUA and 9 patients in NCCN risk groups had an abnormal CT with normal MRI. However, only 3 of these CTs had CaP significant findings, of which 2 identified bone metastases, which were subsequently detected on bone scan. In regard to the extent of imaging, a total of 157 (68.2%) AUA and 178 (69.8%) NCCN IR and HR patients received abdominal scans, of which only 46 (20.0%) and 49 (19.2%) were abnormal among AUA and NCCN risk groups, respectively. Among these abnormal abdominal scans, only 10 showed CaP significant findings, of which half were suspected bone metastases, and confirmed on recommended bone scan. CONCLUSIONS: Due to nonspecific staging guidelines in IR and HR CaP regarding type and extent of cross-sectional imaging, patients are frequently receiving imaging of overlapping locations. Based on low occurrences of unique CaP significant findings on CT and abdominal imaging, our exploratory analysis suggests that narrowing cross-sectional imaging recommendations to pelvic MRI may reduce imaging overlap while maintaining sufficient staging.

Active Surveillance as Initial Management of Newly Diagnosed Prostate Cancer: Data from the PURC.

PURPOSE: We describe contemporary active surveillance utilization and variation in a regional prostate cancer collaborative. We identified demographic and disease specific factors associated with active surveillance in men with newly diagnosed prostate cancer. MATERIALS AND METHODS: We analyzed data from the PURC (Pennsylvania Urologic Regional Collaborative), a cooperative effort of urology practices in southeastern Pennsylvania and New Jersey. We determined the rates of active surveillance among men with newly diagnosed NCCN® (National Comprehensive Cancer Network®) very low, low or intermediate prostate cancer and compared the rates among participating practices and providers. Univariate and multivariable analyses were used to identify factors associated with active surveillance utilization. RESULTS: A total of 1,880 men met inclusion criteria. Of the men with NCCN very low or low risk prostate cancer 57.4% underwent active surveillance as the initial management strategy. Increasing age was significantly associated with active surveillance (p <0.001) while adverse clinicopathological variables were associated with decreased active surveillance use. Substantial variation in active surveillance utilization was observed among practices and providers. CONCLUSIONS: More than 50% of men with low risk disease in the PURC collaborative were treated with active surveillance. However, substantial variation in active surveillance rates were observed among practices and providers in academic and community settings. Advanced age and favorable clinicopathological factors were strongly associated with active surveillance. Analysis of regional collaboratives such as the PURC may allow for the development of strategies to better standardize treatment in men with prostate cancer and offer active surveillance in a more uniform and systematic fashion.

Preoperative urine culture is unnecessary in asymptomatic men prior to prostate needle biopsy.

PURPOSE: To determine the clinical utility of preoperative urine cultures in asymptomatic men undergoing prostate needle biopsy (PNB). METHODS: One hundred fifty asymptomatic men had urine cultures obtained 14-days prior to PNB. As per study protocol, positive cultures were not treated. Antibiotic prophylaxis prior to PNB included ciprofloxacin 500 mg the night before and morning of the biopsy. Repeat urine cultures were obtained immediately prior to PNB with colony-forming units (CFUs) annotated. Infectious complications post-biopsy were recorded. RESULTS: Of the 150 men, six patients (4%) had evidence of asymptomatic bacteriuria with > 10,000 CFU/mL on office urine culture. Repeat urine cultures on morning of biopsy in all 150 patients noted a mean bacterial count of 55 CFU/mL (range 0-1000). All six patients with positive office urine cultures had < 100 CFU/mL at time of PNB. Following biopsy, four patients (2.7%) developed an infectious complication including two with sepsis and two with culture-positive UTIs. The causative organism in all cases was quinolone-resistant E. coli. None of the six patients with preoperative positive urine cultures developed an infectious complication following PNB. CONCLUSIONS: In this prospective observational study, under 5% of asymptomatic men had positive office cultures prior to PNB. Furthermore, repeat urine culture on the morning of biopsy showed resolution in these patients, and none developed post-biopsy infectious complications. Routine office urine culture in the asymptomatic male prior to PNB was unnecessary.

Empiric antibiotics for an elevated prostate-specific antigen (PSA) level: a randomised, prospective, controlled multi-institutional trial.

OBJECTIVE: To determine the impact of empiric antibiotics on men with an elevated prostate-specific antigen (PSA) level. SUBJECTS/PATIENTS AND METHODS: Men of any age with a PSA level of >2.5 ng/mL and normal digital rectal examination undergoing their first prostate biopsy were recruited from five medical centres. Patients with previous biopsy, prostate cancer, urinary tract infection (UTI) or prostatitis within the prior year, antibiotic use within 1 month, 5α-reductase inhibitor use, allergy to fluoroquinolones or clinical suspicion of UTI were excluded. Men were randomised to 2 weeks of ciprofloxacin or no antibiotic. A PSA measurement was obtained 21-45 days after randomisation immediately before prostate biopsy. The primary endpoint was the change in PSA level between baseline and immediately before biopsy. RESULTS: Complete data were available for 77 men with a mean (interquartile range) age of 60.6 (53-66) years. In the control group of men not receiving antibiotic (39 men), the mean baseline and pre-biopsy PSA levels were 6.5 and 6.9 ng/mL, respectively (P = 0.8). In men receiving ciprofloxacin (38 men), the mean baseline PSA level was 7.6 ng/mL and after 2 weeks of ciprofloxacin was 8.5 ng/mL (P = 0.7). Compared with controls not receiving antibiotic, use of ciprofloxacin was not associated with a statistically significant change in PSA level (P = 0.33). Prostate cancer was detected in 36 (47%) men, 23 (59%) in the control group and 13 (34%) in the antibiotic group (P = 0.04). Detection rates were not significantly associated with the change in PSA level between baseline and biopsy. The primary limitation of the study is early stoppage due to an interim futility analysis and poor accrual. CONCLUSION: Despite not meeting the target accrual goal, empiric use of antibiotics for asymptomatic men with an elevated PSA level does not appear to be of clinical benefit.