Suprita Krishna

Biomonitoring DNA Adducts of Cooked Meat Carcinogens in Human Prostate by Nano Liquid Chromatography–High Resolution Tandem Mass Spectrometry: Identification of 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine DNA Adduct

Epidemiologic studies have reported an association between frequent consumption of well-done cooked meats and prostate cancer risk. However, unambiguous physiochemical markers of DNA damage from carcinogens derived from cooked meats, such as DNA adducts, have not been identified in human samples to support this paradigm. We have developed a highly sensitive nano-LC-Orbitrap MS n method to measure DNA adducts of several carcinogens originating from well-done cooked meats, tobacco smoke, and environmental pollution, including 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), 2-amino-9H-pyrido[2,3-b]indole (AαC), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), benzo[a]pyrene (B[a]P), and 4-aminobiphenyl (4-ABP). The limit of quantification (LOQ) of the major deoxyguanosine (dG) adducts of these carcinogens ranged between 1.3 and 2.2 adducts per 10 9 nucleotides per 2.5 μg of DNA assayed. The DNA adduct of PhIP, N-(deoxyguanosin-8-yl)-PhIP (dG-C8-PhIP) was identified in 11 out of 35 patients, at levels ranging from 2 to 120 adducts per 10 9 nucleotides. The dG-C8 adducts of AαC and MeIQx, and the B[a]P adduct, 10-(deoxyguanosin-N 2 -yl)-7,8,9-trihydroxy-7,8,9,10-tetrahydrobenzo[a]pyrene (dG-N 2 -B[a]PDE) were not detected in any specimen, whereas N-(deoxyguanosin-8-yl)-4-ABP (dG-C8-4-ABP) was identified in one subject (30 adducts per 10 9 nucleotides). PhIP-DNA adducts also were recovered quantitatively from formalin fixed paraffin embedded (FFPE) tissues, signifying FFPE tissues can serve as biospecimens for carcinogen DNA adduct biomarker research. Our biomarker data provide support to the epidemiological observations implicating PhIP, one of the most mass-abundant heterocyclic aromatic amines formed in well-done cooked meats, as a DNA-damaging agent that may contribute to the etiology of prostate cancer.

Development of a Classification Scheme for Examining Adverse Events Associated with Medical Devices, Specifically the DaVinci Surgical System as Reported in the FDA MAUDE Database

OBJECTIVE To examine the Manufacturer and User Facility Device Experience Database (MAUDE) database to capture adverse events experienced with the Da Vinci Surgical System. In addition, to design a standardized classification system to categorize the complications and machine failures associated with the device. SUMMARY BACKGROUND DATA Overall, 1,057,000 DaVinci procedures were performed in the United States between 2009 and 2012. Currently, no system exists for classifying and comparing device-related errors and complications with which to evaluate adverse events associated with the Da Vinci Surgical System. METHODS The MAUDE database was queried for events reports related to the DaVinci Surgical System between the years 2009 and 2012. A classification system was developed and tested among 14 robotic surgeons to associate a level of severity with each event and its relationship to the DaVinci Surgical System. Events were then classified according to this system and examined by using Chi-square analysis. RESULTS Two thousand eight hundred thirty-seven events were identified, of which 34% were obstetrics and gynecology (Ob/Gyn); 19%, urology; 11%, other; and 36%, not specified. Our classification system had moderate agreement with a Kappa score of 0.52. Using our classification system, we identified 75% of the events as mild, 18% as moderate, 4% as severe, and 3% as life threatening or resulting in death. Seventy-seven percent were classified as definitely related to the device, 15% as possibly related, and 8% as not related. Urology procedures compared with Ob/Gyn were associated with more severe events (38% vs 26%, p < 0.0001). Energy instruments were associated with less severe events compared with the surgical system (8% vs 87%, p < 0.0001). Events that were definitely associated with the device tended to be less severe (81% vs 19%, p < 0.0001). CONCLUSIONS Our classification system is a valid tool with moderate inter-rater agreement that can be used to better understand device-related adverse events. The majority of robotic related events were mild but associated with the device.

Extended outpatient chemoprophylaxis reduces venous thromboembolism after radical cystectomy

PURPOSE Venous thromboembolism (VTE), including deep venous thrombosis (DVT) and pulmonary embolism, is a common cause of morbidity and mortality after radical cystectomy. The purpose of our study was to evaluate the utility of extended outpatient chemoprophylaxis against VTE after radical cystectomy-with a focus on any reduction in the incidence of VTE, including DVT and pulmonary embolism. MATERIALS AND METHODS Beginning in April 2013, we prospectively instituted a policy of extending inpatient VTE prophylaxis with subcutaneous heparin/enoxaparin for 30 days postoperatively. For this study, we reviewed the electronic medical records of all patients who underwent radical cystectomy at our institution from January 2012 through December 2015. The experimental group (n = 79) received extended outpatient chemoprophylaxis against VTE; the control group (n = 51) received no chemoprophylaxis after discharge. The primary outcome was the 90-day incidence of VTE. The secondary outcomes included the overall complication rate, the hemorrhagic complication rate, as well as the rate of readmission within 30 days of hospital discharge. RESULTS The experimental group experienced a significantly lower rate of DVT (5.06%), assessed as of 90 days postoperatively, than the control group (17.6%): a relative risk reduction of 71.3% (P = 0.021). We found no significant differences in secondary outcomes between the 2 groups, including the overall complication rate (54.4% vs. 68.6%), the hemorrhagic complication rate (3.7% vs. 2.0%), and the readmission rate (21.5% vs. 29.4%). CONCLUSION Extended outpatient chemoprophylaxis significantly reduced the incidence of VTE.

The current status of immunobased therapies for metastatic renal-cell carcinoma

The management of metastatic renal-cell carcinoma (mRCC) represents an important clinical challenge. Since being approved in the early 1990s, aspecific immunotherapy has been a mainstay of treatment for mRCC and the only therapy that has demonstrated long-term cures for mRCC. However, in recent times there have been landmark advances made in the field of specific immunotherapy for a number of malignancies, including kidney cancer. This review outlines the range of immunobased agents currently available for the treatment of mRCC.

Preoperative Incidence of Deep Venous Thrombosis in Patients With Bladder Cancer Undergoing Radical Cystectomy

OBJECTIVE To determine the preoperative incidence of subclinical lower-extremity deep vein thrombosis (DVT), as well as to evaluate the utility of preoperative DVT screening in patients with bladder cancer before undergoing radical cystectomy. MATERIALS AND METHODS Beginning in 2014, we prospectively instituted a policy of obtaining a screening lower-extremity duplex ultrasound on all patients within 7 days before undergoing radical cystectomy. We reviewed the electronic medical records of all patients at our institution who underwent radical cystectomy for bladder cancer from January 2012 through December 2015. The screened group (n = 65) underwent preoperative screening; the historical control group (n = 78) did not. Primary outcome was a lower-extremity duplex ultrasound positive screening. Secondary outcome measures included the development of symptomatic venous thromboembolism (VTE) postoperatively, and the rate and severity of complications. RESULTS DVT was identified in 13.9% of patients before undergoing cystectomy. Univariate analysis demonstrated an increased risk of subclinical DVT in patients who were exposed to neoadjuvant chemotherapy (35.3% vs 5.1%, P = .008). Postoperatively, there was a nonsignificant trend of lower DVT rate in the screened group compared to historical control. Overall complication rate and severity were similar between the groups. CONCLUSION Subclinical DVT is present in a significant number of pre-cystectomy patients, especially those exposed to neoadjuvant chemotherapy. Ultrasound screening in patients before undergoing radical cystectomy may identify opportunities for early intervention to reduce morbidity and mortality associated with perioperative DVT or venous thromboembolism in the cystectomy population.

Persistent muscle-invasive bladder cancer after neoadjuvant chemotherapy: an analysis of Surveillance, Epidemiology and End Results-Medicare data

To evaluate whether patients with persistent muscle‐invasive bladder cancer (MIBC) after undergoing neoadjuvant chemotherapy (NAC) and radical cystectomy (RC) have worse overall survival (OS) and cancer‐specific survival (CSS) than patients with similar pathology who undergo RC alone.

Racial Disparities in Surgical Outcomes Among Males Following Major Urologic Cancer Surgery

INTRODUCTION Disparities in healthcare outcomes between races have been extensively described; however, studies fail to characterize the contribution of differences in distribution of covariates between groups and the impact of discrimination. This study aims to characterize the degree to which clinicodemographic factors and unmeasured confounders are contributing to any observed disparities between non-Hispanic white and black males on surgical outcomes after major urologic cancer surgery. METHODS Non-Hispanic white and black males undergoing radical cystectomy, nephrectomy, or prostatectomy for cancer in the American College of Surgeons National Surgical Quality Improvement Program database from 2007 to 2016 were included in this analysis. The outcome of interest was Clavien III-V complications. Analysis was conducted in 2017 using the Peters-Belson method to compare the disparity in outcomes while adjusting for 13 important demographic and clinical characteristics. RESULTS Of the 15,693 cases included with complete data, 13.0% (n=2,040) were black. There was a significantly increased rate of unadjusted Clavien III and V complications between white versus black males for radical cystectomy (21.9% vs 10.1%, p=0.005); nephrectomy (6.4% vs 3.9%, p=0.028); and radical prostatectomy (2.3% vs 1.6%, p=0.046). Adjusting for differences in age, BMI, American Society of Anesthesiologists score, functional status, smoking history, and comorbidities including diabetes, chronic obstructive pulmonary disease, heart failure, renal failure, bleeding disorder, steroid use, unintentional weight loss, and hypertension between the groups could not explain the disparity in complications after radical cystectomy; the unexplained discrepancy was an absolute excess of 11.8% (p=0.01) in black males. There was an unexplained excess of complications in black males undergoing radical prostatectomy and nephrectomy but neither reached statistical significance. CONCLUSIONS Black males undergoing radical cystectomy for cancer experienced higher complication rates than white males. Unexplained differences between the black and white males significantly contributed to the disparity in outcomes, which suggests that unmeasured factors, such as the quality of surgical or perioperative care, are playing a considerable role in the observed inequality. SUPPLEMENT INFORMATION This article is part of a supplement entitled African American Mens Health: Research, Practice, and Policy Implications, which is sponsored by the National Institutes of Health.

MP28-02 PHYSIOLOGICAL EVIDENCE OF DNA DAMAGE BY CARCINOGENS KNOWN TO BE PRESENT IN CHARRED AND PROCESSED MEATS (PHIP DNA ADDUCTS), IN A SMALL COHORT OF PROSTATE CANCER PATIENTS.

INTRODUCTION AND OBJECTIVES: Epidemiologic studies have reported an association between frequent consumption of welldone cooked meats and prostate cancer (PC) risk. Charred red meat and cooked processed meats are known to contain heterocyclic aromatic amine (HAA) carcinogens, such as 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) the most mass abundant HAA, and are linked to PC development in a rodent model. However, unambiguous physiochemical markers of DNA damage from these meat-derived carcinogens have not been identified in human samples to support the paradigm of HAA induced human prostate carcinogenesis. METHODS: Thirty-five men with biopsy proven intermediate to high-risk PC underwent radical prostatectomy at University of Minnesota from Dec 2015-Aug 2016. After prostatectomy, both tumor bearing tissue and non-tumor bearing adjacent fresh tissue was analyzed for DNA adducts using a highly sensitive nano-LC-Orbitrap mass spectrometry method. We also analyzed formalin fixed paraffin embedded (FFPE) tissues from each patient. RESULTS: Median age of the men with PC was 65 (range 4578). Pathology demonstrated the following Gleason Scores (GS) and pathologic staging: GS1⁄4 6 in 1 patient (2.8%), GS1⁄47 in 28 patients (80%) and GS1⁄48-10 in 6 patients (17%) and 16 men (46%) were stage 2 and 19 men were stage 3 (54%). The PhIP DNA adduct was identified in 11 out of 35 patients, at levels ranging from 2 to 120 adducts per 109 nucleotides. PhIP DNA adducts also were recovered quantitatively from FFPE tissues. CONCLUSIONS: Our data provide support to the epidemiological observations implicating PhIP as a DNA damaging agent that may contribute to the etiology of PC in humans. FFPE tissues can be used as a tissue source in DNA-adduct biomarker research using our mass spectrometry method.

Current Concepts in the Management of Muscle Invasive Bladder Cancer

Bladder cancer is the ninth most common cancer in the world. Twenty to twenty-five percent of all newly diagnosed bladder cancers are muscle invasive in nature, and further, 20–25% of patients who are diagnosed with high-risk non-muscle invasive disease will eventually progress to muscle invasive disease in due course of time irrespective of adjuvant intravesical therapies. Availability of newer imaging modalities improves appropriate identification of patients with muscle invasive disease. Radical cystectomy remains the mainstay of treatment for management of muscle invasive disease. Availability of neoadjuvant chemotherapy has improved overall survival. Risk stratification systems are now in consideration to identify patients who benefit maximally from neoadjuvant chemotherapy. Urinary diversion is a major cause of morbidity in these patients, and several strategies are being employed to reduce morbidity. In this article, we review available literature on various aspects of management of muscle invasive disease.

The synergy between ionizing radiation and immunotherapy in the treatment of prostate cancer

There has been a surge in the use of immunotherapy for genitourinary malignancies. Immunotherapy is an established treatment for metastatic renal cell carcinoma and nonmuscle invasive bladder cancer, but its potential for treating prostate cancer (PCa) remains under investigation. Despite reported survival benefits, no published Phase III PCa trials using immunotherapy only as a treatment has demonstrated direct antitumor effects by reducing prostate-specific antigen levels. Subsequently, the thought of combining immunotherapy with other treatment modalities has gained traction as a way to achieving optimal results. Based on data from other malignancies, it is hypothesized that radiotherapy and immunotherapy can act synergistically to improve outcomes. We will discuss the clinical potential of combining immune-based treatments with radiotherapy as a treatment for advanced PCa.