Kavalactone Kawain Impedes Urothelial Tumorigenesis in UPII-Mutant Ha-Ras Mice via Inhibition of mTOR Signaling and Alteration of Cancer Metabolism.

UPII-mutant Ha-ras transgenic mice develop urothelial hyperplasia and low-grade papillary carcinoma, which mimics human non-muscle invasive bladder cancer (NMIBC). We investigated the effects and mechanisms of kawain, a main kavalactone in the kava plant, on oncogenic Ha-ras-driven urothelial carcinoma in these mice. The mice were fed at six weeks of age with vehicle control or kawain (6 g/kg) formulated food for approximately five months. Seventy-eight percent of the mice or more fed with kawain food survived more than six months of age, whereas only 32% control food-fed male mice survived, (p = 0.0082). The mean wet bladder weights (a surrogate for tumor burden) of UPII-mutant Ha-ras transgenic mice with kawain diet was decreased by approximately 56% compared to those fed with the control diet (p = 0.035). The kawain diet also significantly reduced the occurrence of hydronephrosis and hematuria in UPII-mutant Ha-ras transgenic mice. Histological examination and immunohistochemistry analysis revealed that vehicle control-treated mice displayed more urothelial carcinoma and Ki67-positive cells in the bladder compared to kawain treated mice. Global metabolic profiling of bladder tumor samples from mice fed with kawain food showed significantly more enrichment of serotonin and less abundance of xylulose, prostaglandin A2, D2 and E2 compared to those from control diet-fed mice, suggesting decreased shunting of glucose to the pentose phosphate pathway (PPP) and reduced inflammation. In addition, kawain selectively inhibited the growth of human bladder cancer cell lines with a significant suppression of 4E-BP1 expression and rpS6 phosphorylation. These observations indicate a potential impact of kawain consumption on bladder cancer prevention by rewiring the metabolic programs of the tumor cells.

Systemic and tumor-directed therapy for oligometastatic prostate cancer: study protocol for a phase II trial for veterans with de novo oligometastatic disease.

BACKGROUND: The treatment paradigm for metastatic hormone-sensitive prostate cancer (mHSPC) patients is evolving. PET/CT now offers improved sensitivity and accuracy in staging. Recent randomized trial data supports escalated hormone therapy, local primary tumor therapy, and metastasis-directed therapy. The impact of combining such therapies into a multimodal approach is unknown. This Phase II single-arm clinical trial sponsored and funded by Veterans Affairs combines local, metastasis-directed, and systemic therapies to durably render patients free of detectable disease off active therapy. METHODS: Patients with newly-diagnosed M1a/b prostate cancer (PSMA PET/CT staging is permitted) and 1-5 radiographically visible metastases (excluding pelvic lymph nodes) are undergoing local treatment with radical prostatectomy, limited duration systemic therapy for a total of six months (leuprolide, abiraterone acetate with prednisone, and apalutamide), metastasis-directed stereotactic body radiotherapy (SBRT), and post-operative fractionated radiotherapy if pT ≥ 3a, N1, or positive margins are present. The primary endpoint is the percent of patients achieving a serum PSA of < 0.05 ng/mL six months after recovery of serum testosterone ≥150 ng/dL. Secondary endpoints include time to biochemical progression, time to radiographic progression, time to initiation of alternative antineoplastic therapy, prostate cancer specific survival, health related quality-of-life, safety and tolerability. DISCUSSION: To our knowledge, this is the first trial that tests a comprehensive systemic and tumor directed therapeutic strategy for patients with newly diagnosed oligometastatic prostate cancer. This trial, and others like it, represent the critical first step towards curative intent therapy for a patient population where palliation has been the norm. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT03298087 (registration date: September 29, 2017).

Ureteroenteric anastomotic revision as initial management of stricture after urinary diversion.

OBJECTIVE: To report our experience with ureteroenteric anastomotic revision as initial treatment of stricture after urinary diversion. METHODS: An institutional review board-approved retrospective study was carried out. A total of 41 patients who underwent primary ureteroenteric anastamotic revision were identified between 2007 and 2015. Data analyzed included patient characteristics, type of diversion, estimated blood loss, operative time, change in renal function, length of stay, postoperative complications and time with nephrostomy/stent. Success of revision was defined as an improvement in hydronephrosis on radiographic imaging and/or reflux during pouchogram. Predictors of length of stay and complications were analyzed using analysis of covariance. RESULTS: A total of 50 renal units were revised with a success rate of 100%. The median length of stay was 6 days (2-16 days). There were a total of 15 complications (one major, 14 minor) in 14 patients (33% 30-day complication rate). The most common were wound infection (n = 4) and arrhythmia (n = 4). Robotic revision (n = 5) had a median length of stay of 3 days (2-4) with no complications. CONCLUSIONS: Primary ureteroenteric anastomotic revisions have an excellent success rate at an experienced center and might obviate the need for multiple interventions. Open revision is associated with mostly minor complications. Robotic revision might reduce the morbidity of open revision in select cases.

Utility of noninvasive biomarker testing and MRI to predict a prostate cancer diagnosis.

PURPOSE: To assess the diagnostic performance and utility of the ExoDx IntelliScore and an OPKO4K score to predict prostate cancer in men presenting with elevated PSA-both as independent predictors and in combination with clinical/MRI characteristics. METHODS: Patients with elevated PSA were retrospectively reviewed. Abnormal tests were defined as an OPKO4K score ≥ 7.5% and an ExoDx IntelliScore ≥ 15.6. Four regression models and ROC curves were generated based on: (1) age, PSA, and DRE, (2) model 1 + OPKO4K 4Kscore ≥ 7.5%, (3) model 2 + ExoDx IntelliScore ≥ 15.6, and (4) model 3 + MRI PIRADS 4-5. RESULTS: 359 men received an OPKO4K test, 307 had MRI and 113 had ExoDx tests. 163 men proceeded to prostate biopsy and 196 (55%) were saved from biopsy. Mean age was 65.0 ± 8.7 years and mean PSA was 7.1 ± 6.1 ng/mL. Positive biopsies were found in 84 (51.5%) men. The sensitivity and negative predictive value of an OPKO4K score were 86.7% and 72.3%; values for an ExoDx test were 76.5% and 77.1%, respectively. On regression analysis, clinical markers (Age, PSA, DRE) generated an AUC of 0.559. The addition of an OPKO4K score raised the AUC to 0.653. The stepwise addition of an ExoDx score raised the AUC to 0.766. The combined use of both biomarkers, patient characteristics, and MRI yielded an AUC of 0.825. CONCLUSION: This analysis demonstrates the high negative predictive value of both the OPKO4K score and ExoDX IntelliScore independently while demonstrating that the combination of an OPKO4K score, an ExoDX IntelliScore, and MRI increases predictive capability for biopsy confirmed prostate cancer.

Kawain Inhibits Urinary Bladder Carcinogenesis through Epigenetic Inhibition of LSD1 and Upregulation of H3K4 Methylation.

Epidemiological evidence suggests that kava (Piper methysticum Forst) drinks may reduce the risk of cancer in South Pacific Island smokers. However, little is known about the anti-carcinogenic effects of kava on tobacco smoking-related bladder cancer and its underlying mechanisms. Here we show that dietary feeding of kawain (a major active component in kava root extracts) to mice either before or after hydroxy butyl(butyl) nitrosamine (OH-BBN) carcinogen exposure slows down urinary bladder carcinogenesis and prolongs the survival of the OH-BBN-exposed mice. OH-BBN-induced bladder tumors exhibit significantly increased expression of lysine-specific demethylase 1 (LSD1), accompanied by decreased levels of H3K4 mono-methylation compared to normal bladder epithelium, whereas dietary kawain reverses the effects of OH-BBN on H3K4 mono-methylation. Human bladder cancer tumor tissues at different pathological grades also show significantly increased expression of LSD1 and decreased levels of H3K4 mono-methylation compared to normal urothelium. In addition, kava root extracts and the kavalactones kawain and methysticin all increase the levels of H3K4 mono- and di-methylation, leading to inhibitory effects on cell migration. Taken together, our results suggest that modification of histone lysine methylation may represent a new approach to bladder cancer prevention and treatment and that kavalactones may be promising agents for bladder cancer interception in both current and former smokers.

Comparison of Perioperative Outcomes for Radical Nephrectomy Based on Surgical Approach for Masses Greater Than 10 cm.

Introduction and Objective: Robot-assisted radical nephrectomy (RRN) is increasingly utilized as an alternative to laparoscopic radical nephrectomy (LRN), but there are concerns over costs and objective benefit. In the setting of very large renal masses (>10 cm), comparison between techniques is limited and it is unclear whether a robotic approach confers any perioperative benefit over LRN or open radical nephrectomy (ORN). In this study, perioperative outcomes of RRN, LRN, and ORN for very large renal masses are compared. Methods: Using the National Cancer Database, patients were identified who underwent radical nephrectomy for kidney tumors >10 cm diagnosed from 2010 to 2015. Patients were analyzed according to surgical approach. Perioperative outcomes, including conversion to open, length of stay, readmission rates, positive surgical margins, and 30- and 90-day mortality were compared among cohorts. Results: A total of 9288 patients met inclusion criteria (RRN = 842, LRN = 2326, ORN = 6120). Compared with ORN, recipients of RRN or LRN had similar rates of 30-day readmission and 30- and 90-day mortality. Length of hospital stay was significantly shorter in RRN (-1.73 days ±0.19; p < 0.0001) and LRN (-1.40 days ±0.12; p < 0.0001) compared with ORN. LRN had a higher rate of conversion to open compared with RRN (odds ratio 1.48; 95% confidence interval 1.10-1.98; p = 0.0087). Conversion to open from RRN or LRN added 1.3 additional days of inpatient stay. Over the study period, RRN use increased from 4.1% to 14.8%, LRN from 20.9% to 25.6%, whereas ORN use decreased from 75% to 59.6%. Conclusions: Minimally invasive approaches are increasingly utilized in very large renal masses. RRN has lower rates of conversion to open but produces comparable perioperative outcomes to LRN. Minimally invasive approaches have a shorter length of inpatient stay but otherwise report similar surgical margin status, readmission rates, and mortality rates compared with ORN.

Black race may be associated with worse overall survival in renal cell carcinoma patients.

OBJECTIVE: To examine socio-demographic and treatment variables in an attempt to identify factors associated with survival differences between black and white patients with renal cell carcinoma (RCC). PATIENTS AND METHODS: We identified 79,618 white and 10,604 black patients diagnosed with RCC in the National Cancer Database. We compared the distribution of socio-demographic, presentation and treatment variables between Blacks and Whites and then utilized a multivariable cox proportion hazards regression model to evaluate the contribution of differences in these variables to disparities in overall survival (OS). RESULTS: Black patients were younger (60 vs. 63 years, P< 0.001) and with a lower stage (12.0% vs. 18.8% Stage III-IV P< 0.001). Blacks presented with a higher Charlson-Deyo score (P< 0.001), lower income (P< 0.001), lower education (P< 0.001) and were less likely to receive radical nephrectomy and systemic therapy for stage IV RCC (29.9% vs. 38.8%, P< 0.001). Unadjusted OS was lower for Whites (5-year survival 79% for Blacks and 77% for Whites). However, OS was lower for Blacks when adjusted for all variables (5-year survival 89% for Blacks and 93% for Whites). On multivariable analysis, black race was independently associated with worse OS, HR: 1.09 (95% confidence interval: 1.03, 1.14, P= 0.002). A sensitivity analysis including patients with complete data on tumor grade confirmed our results. CONCLUSION: Our study indicates that black patients present at a younger age and with lower stage RCC, but have worse OS. Blacks experienced disparities in socio-demographic characteristics, clinical presentation, treatment-related factors, and had an independently increased hazard of death.

Complications of cranioplasty following decompressive craniectomy: analysis of 62 cases.

OBJECT: Decompressive craniectomy is a potentially life-saving procedure used in the treatment of medically refractory intracranial hypertension, most commonly in the setting of trauma or cerebral infarction. Once performed, surviving patients are obligated to undergo a second procedure for cranial reconstruction. The complications following cranial reconstruction are not well described in the literature and may very well be underreported. A review of the complications would suggest measures to improve the care of these patients. METHODS: A retrospective chart review was undertaken of all patients who had undergone cranioplasty during a 7-year period. Demographic data, indications for craniectomy, as well as preoperative, intraoperative, and postoperative parameters following cranioplasty, were recorded. Perioperative and postoperative complications were also recorded. Patients were classified as having no complications, any complications, and complications requiring reoperation. The groups were compared to identify risk factors predictive of poor outcomes. RESULTS: The authors identified 62 patients who had undergone cranioplasty. The immediate postoperative complication rate was 34%. Of these, 46 patients did not require reoperation and 16 did. Of those requiring reoperation, 7 were due to infection, 2 from wound breakdown, 2 from intracranial hemorrhage, 3 from bone resorption, and 1 from a sunken cranioplasty, and 1 patient's cranioplasty procedure was prematurely ended due to intraoperative hypotension and bradycardia. The only factor statistically associated with need for reoperation was the presence of a bifrontal cranial defect (bifrontal: 8 [67%] of 12, requiring reoperation; unilateral: 8 [16%] of 49 requiring reoperation; p < 0.01) CONCLUSIONS: Cranioplasty following decompressive craniectomy is associated with a high complication rate. Patients undergoing a bifrontal craniectomy are at significantly increased risk for postcranioplasty complications, including the need for reoperation.

A delay ≥8 weeks to neoadjuvant chemotherapy before radical cystectomy increases the risk of upstaging.

OBJECTIVES: To investigate delays to neoadjuvant chemotherapy (NAC) and radical cystectomy (RC) and their effect on outcomes in a large national registry of patients with localized muscle invasive bladder cancer. PATIENTS AND METHODS: Within the National Cancer Database (2004-2014), we identified 2,227 patients who underwent NAC and RC for cT2-T4aN0M0 urothelial carcinoma of the bladder. Times from diagnosis to treatments were tested for association with overall survival and pathologic outcomes, using Cox models, and restricted cubic splines regression. RESULTS: Median times from diagnosis to NAC and RC were 39 days (interquartile range: 26-56) and 155 days (interquartile range: 131-185), respectively. Time to NAC and time to RC were not associated with overall survival in the complete cohort, as well as in subgroups of responders and nonresponders to NAC. Overall, 916 patients (41%) were upstaged after RC, including 485 patients (22%) with positive lymph nodes. We identified delay to NAC ≥8 weeks as a significant cut-off point to predict the risk of upstaging in multivariable analysis (odds ratio: 1.27; 95% confidence interval: 1.02-1.59; P = 0.031). Black race, Medicaid insurance, and academic facilities were associated with a higher risk of delayed treatment. CONCLUSION: After diagnosis of muscle invasive bladder cancer, NAC should be initiated as soon as possible and no more than 8 weeks to prevent upstaging. There is no evidence to support avoiding NAC due to concerns of delayed RC that was generated from surgery alone studies, as long as RC is performed within 7 months from initial diagnosis.

Risk factors and prognostic implications for pathologic upstaging to T3a after partial nephrectomy.

BACKGROUND: Performing partial nephrectomy (PN) on a cT1 tumor, which postoperatively is upgraded to pT3a can possibly lead to compromise of cancer specific mortality. We therefore aimed to identify risk factors for pathologic T3a upstaging of cT1 tumors and to analyze the association between upstaging, positive surgical margins (PSM) and overall survival (OS). METHODS: The present study included patients who underwent PN for a clinically localized T1 renal mass from two datasets: 1) 1298 patients from a prospectively maintained multi-center database (MCDB); and 2) 7940 patients from the National Cancer Database (NCDB). Multivariable logistic regression models within each cohort were used to identify predictors of cT1 to pT3a upstaging and its association with PSM. Cox proportion hazards regression models were used to compare overall survival in the NCDB cohort. RESULTS: The rate of pT3a upstaging was 5.7% (N.=74) in the MCDB and 1.9% (N.=156) in the NCDB cohort. Older age (MCDB OR=1.04, P=0.001; NCDB OR=1.04, P=0.001) and larger tumor size (MCDB OR=1.89, P<0.001; NCDB OR=1.38, P<0.001) increased the likelihood of upstaging. PSM was found to be more likely for pT3a upstaged patients in both cohorts (MCDB 14.9% vs. 3.5%, P<0.001; NCDB 14.8% vs. 8.3%, P=0.006), even when adjusting for tumor size. At short term follow-up (NCDB median follow-up 27.3 months), pT3a upstaging was associated with worse OS in univariable (HR=1.89; 95% CI=1.00, 3.55; P=0.049) but not multivariable analysis (HR=1.63; 95% CI=0.86, 3.08; P=0.131). OS was 93.0% vs. 95.8% at 3 years for those with and without pT3a upstaging, respectively. CONCLUSIONS: Larger tumor size and increased age are associated with pathological upstaging to T3a for clinical T1 tumors treated with partial nephrectomy. Steps to improve identification of occult pT3a disease are necessary as its occurrence significantly increased the likelihood of a PSM, both in a high-volume multicenter cohort, as well as, a national data registry.

Utilization of perioperative systemic chemotherapy in upper tract urothelial carcinoma.

INTRODUCTION: Evidence for the use of perioperative chemotherapy (PC) in upper tract urothelial carcinoma (UTUC) is largely derived from level I evidence for invasive urothelial carcinoma of the bladder (UCB). There has been an increase in PC for urothelial carcinoma of the bladder, as it has disseminated into clinical practice. Therefore, we sought to not only analyze trends in the utilization of PC in UTUC, but also assess factors associated with its use in a large cancer registry database. METHODS: The National Cancer Database was queried for patients with UTUC who underwent extirpative surgery from 2004 to 2013. Predictors of receiving PC were identified using univariate and multivariate logistic regression. Temporal trends in the utilization of PC were also analyzed using a general analysis of variance linear model. RESULTS: From 2004 to 2013, there was significant increase in PC for UTUC from 9.6% to 13.8% (P = 0.0003). Neoadjuvant chemotherapy increased from 0.7% to 2.1% (P = 0.0018), whereas adjuvant chemotherapy remained relatively stable at 11.3%. Significant predictors of receiving PC on multivariate analysis were private insurance, ureter as the primary site, poorly differentiated and undifferentiated grade, lymphovascular invasion, positive margins, clinical T3 or T4 disease, nodal metastasis, and reporting from an academic research program. Patients who were≥70 years old,>50 miles to treatment center, had tumor in the kidney, or had an increased Charlson-Deyo Score were significantly less likely to receive PC. CONCLUSIONS: Over the time period studied, there has been an increase in the use of PC, primarily from increased administration of neoadjuvant chemotherapy. Its use is mostly associated with advanced pathologic characteristics. The study also highlights key demographic and socioeconomic differences that can help identify barriers to receiving PC and aid in making improvements in delivery of health care to patients with UTUC.

Trends in management of the small renal mass in renal transplant recipient candidates: A multi-institutional survey analysis.

INTRODUCTION: Patients with end-stage renal disease are under increased risk for renal cell carcinoma development, and radical nephrectomy is the preferred treatment in this setting. Owing to the increased surgical morbidity and mortality, active surveillance (AS) may be a valid option for treatment of small renal masses (SRM). As there is a lack of high-level evidence for treatment recommendations, we performed a survey analysis to analyze the treatment patterns of transplant surgeons. MATERIAL AND METHODS: A 21-question online survey designed to analyze the practice patterns to treat SRM in renal transplant recipient candidates was sent to active transplant centers in the United States. The list of recipients to whom the survey was distributed was obtained with permission from the American Society of Transplant Surgeons. RESULTS: We received 62 responses. All regions of United Network of Organ Sharing were represented. Radical nephrectomy was the preferred treatment (59%, n = 61), followed by AS (21.3%, n = 13), partial nephrectomy (14.8%, n = 9), and focal ablative therapy (4.9%, n = 3). Among the responders whose institutions did not allow AS, 77.4% indicated that if presented with long-term data showing safety of AS, they would perform immediate transplantation and monitor SRM. Responders were more likely to allow immediate transplantation after radical nephrectomy (77.4%), as opposed to partial nephrectomy (58.1%) and focal ablation (45.2%). CONCLUSION: Though radical nephrectomy is the preferred treatment, most transplant surgeons would consider AS if long-term safety data were available.

Prostate-specific antigen screening and prostate cancer treatment in renal transplantation candidates: A survey of U.S. transplantation centers.

INTRODUCTION: Renal transplantation candidates are a highly screened population. There are currently no guidelines or consensus on prostate cancer (CaP) screening in these patients. In light of the recent United States Preventive Services Task Force recommendations against prostate-specific antigen (PSA) screening, we conducted a survey of transplantation surgeons to gain a better understanding of practice patterns among U.S. centers. MATERIALS AND METHODS: A 14-question multiple-choice online survey was e-mailed to 195 U.S. renal transplantation centers. The questionnaire assessed CaP screening and treatment practices. The survey also evaluated characteristics of the respondent's institution. Descriptive statistics were used for each of the responses, and associations were made with program characterization using logistic or linear regression models. RESULTS: A total of 90 surgeons responded, representing 65 of 195 programs (33% response rate). Overall, 89% of respondents reported routinely screening for CaP in renal transplantation candidates and 71% had set guidelines for PSA screening. The most common age to start PSA screening was 50 years (51%) and 79% of respondents reported no age limit to stop PSA screening. Definitive treatment of CaP was required before proceeding to transplantation in 45% of respondents. Active surveillance was a viable option in 67% of responders. Most respondents (73%) replied that the waiting time for eligibility after treatment depended on the CaP stage and risk. CONCLUSIONS: Although most programs have guidelines on PSA screening in renal transplantation candidates, there is still variation nationwide in screening and treatment practices. AS is a viable treatment option in most of the programs. Our results suggest a benefit of a consensus panel to recommend guidelines in this population.

Comparison of perioperative outcomes of retroperitoneal and transperitoneal minimally invasive partial nephrectomy after adjusting for tumor complexity.

OBJECTIVE: To evaluate and compare perioperative outcomes of transperitoneal and retroperitoneal (RP) laparoscopic and robotic partial nephrectomies (LPNs) while adjusting for tumor complexity. MATERIALS AND METHODS: Retrospective review was conducted of 191 patients who underwent transperitoneal (n = 116) or RP (n = 75) LPN. To adjust for tumor complexity, individual components of the radius, exophytic or endophytic properties, nearness to the collecting system or sinus, anterior or posterior location, and location in reference to polar lines (R.E.N.A.L.) nephrometry score were used in multivariate linear and logistic regression models to compare perioperative outcomes between the 2 groups. A propensity approach was also used to adjust for multiple covariates. Investigated outcomes included estimated blood loss (EBL), ischemia and operative times, length of hospital stay, margin status, opioid use, postoperative estimated glomerular filtration rate, complications within 30 days, and readmission rates. RESULTS: Tumors resected by RPLPN were more likely to have lower complexity score by nephrometry (P = .04). Four of the 5 components of the R.E.N.A.L. nephrometry score were significantly different between the groups. After adjustment for these factors, a lower EBL was noted in the RP group (ß, -97; 95% confidence interval, -156 to -39; P = .001). Risk of readmission for the RP group was significantly lower (odds ratio, 0.15; P = .024) using propensity analysis. CONCLUSION: Using adjustment for tumor complexity, RPLPN was associated with lower EBL and readmission rates supporting the potential clinical advantage for this approach when feasible.