Joseph Renzulli

Diffusion-Weighted MRI of Peripheral Zone Prostate Cancer: Comparison of Tumor Apparent Diffusion Coefficient With Gleason Score and Percentage of Tumor on Core Biopsy

OBJECTIVE The objective of our study was to determine the relationship between the apparent diffusion coefficient (ADC) value on diffusion-weighted imaging (DWI) and Gleason score of prostate cancer and percentage of tumor involvement on prostate core biopsy. MATERIALS AND METHODS We performed a retrospective study of 57 patients with biopsy-proven prostate cancer who underwent endorectal MRI with DWI between July 2007 and March 2008. Regions of interest (ROIs) were drawn on ADC maps at sites of visible tumor on DW images and ADC maps. A hierarchic mixed linear model was used to compare the ADC value of prostate cancer with the Gleason score and the percentage of tumor on core biopsy. RESULTS Eighty-one sites of biopsy-proven prostate cancer were visible on DW images and ADC maps. The least-squares mean ADC for disease with a Gleason score of 6 was 0.860 x 10(-3) mm(2)/s (standard error of the mean [SEM], 0.036); Gleason score of 7, 0.702 x 10(-3) mm(2)/s (SEM, 0.030); Gleason score of 8, 0.672 x 10(-3) mm(2)/s (SEM, 0.057); and Gleason score of 9, 0.686 x 10(-3) mm(2)/s (SEM, 0.067). Differences between the mean ADC values for a prostate tumor with a Gleason score of 6 and one with a Gleason score of 7 (p = 0.0096) and for a prostate tumor with a Gleason score of 6 and one with a Gleason score of 8 (p = 0.0460) were significant. Comparison between the ADC and percentage of tumor on core biopsy showed a mean ADC decrease of 0.006 (range, 0.004-0.008 x 10(-3) mm(2)/s) for every 1% increase in tumor in the core biopsy specimen. CONCLUSION DWI may help differentiate between low-risk (Gleason score, 6) and intermediate-risk (Gleason score, 7) prostate cancer and between low-risk (Gleason score, 6) and high-risk (Gleason score > 7) prostate cancer. There is an inverse relationship between the ADC and the percentage of tumor involvement on prostate core biopsies.

Microvesicle Induction of Prostate Specific Gene Expression in Normal Human Bone Marrow Cells

PURPOSE Transfer of genetic material from cancer cells to normal cells occurs via microvesicles. Cell specific phenotypes can be induced in normal cells by the transfer of material in microvesicles, leading to genetic changes. We report the identification and expression of prostate specific genes in normal human marrow cells co-cultured with human prostate cancer cells. MATERIALS AND METHODS We harvested prostate tissue from 11 patients with prostate cancer. In 4 cases prostate tissue was co-cultured across from human marrow for 2 or 7 days but separated from it by a 0.4 μM polystyrene membrane. In 5 cases conditioned medium from patient cancer tissue was collected and ultracentrifuged, and microvesicles were collected for co-culture (3) and vesicle characterization (3). Explanted human marrow was harvested from cultures and RNA extracted. Real-time reverse transcriptase-polymerase chain reaction was done for select prostate specific genes. RESULTS Marrow exposed to human prostate tumor or isolated microvesicles in culture in 4 and 3 cases, respectively, showed at least 2-fold or greater prostate gene expression than control marrow. In 1 case in which normal prostate was co-cultured there were no prostate gene increases in normal marrow. CONCLUSIONS Prostate cancer tumor cells co-cultured with human bone marrow cells induce prostate specific gene expression. The proposed mechanism of transfer of genetic material is via microvesicles. This represents an opportunity for novel therapeutic agents, such as antibodies, to block microvesicle release from cancer cells or for agents that may block cells from accepting microvesicles.

Rectal swab culture-directed antimicrobial prophylaxis for prostate biopsy and risk of postprocedure infection: a cohort study.

OBJECTIVE To examine the effect of rectal swab culture-directed prophylaxis on the incidence of prostate biopsy-associated infections. Secondary objectives were to determine the rate of fluoroquinolone resistance and extended-spectrum beta-lactamase production in local rectal flora. METHODS All men receiving prostate biopsies from February 2013 to February 2014 were included in a retrospective institutional review board-approved study. All received either a preprocedural rectal swab and culture-directed antimicrobial prophylaxis or routine fluoroquinolone antibiotics. Clinical information was collected on infectious complications treated within 30 days of biopsy. Chi-square test, Fisher exact test, and Welch t test were used for statistical analysis. Confounding variables were included in a multivariate logistic regression model. RESULTS Of 487 total patients, 314 received preprocedure rectal cultures and 173 did not. Average ages were 62.7 and 64.1 years, respectively (P = .07). There was no difference in mean prostate-specific antigen value (P = .9), Charlson comorbidity score (P = .8), or ethnicity (P = .1). The rectal swab group was more likely to receive supplemental gentamicin (P < .001) and had fewer infectious complications (1.9% vs 2.9%; P = .5). On multivariate analysis, decreased odds of infection was associated with culture-directed antibiotics (odds ratio, 0.70; 95% confidence interval, 0.20-2.50; P = .6). However, the study was only powered to detect a 97% reduction in infections. The incidence of fluoroquinolone resistance and extended-spectrum beta-lactamase production was 12.1% and 0.64%, respectively. CONCLUSION Our study was underpowered but suggests that there are lower odds of infection with rectal swab-directed antimicrobial prophylaxis. The local incidence of fluoroquinolone resistance is high. A prospective, randomized, controlled trial is warranted to further evaluate this intervention.

An unbiased prospective report of perioperative complications of robot-assisted laparoscopic radical prostatectomy.

OBJECTIVES To analyze and classified our single-institution experience with the perioperative complications associated with robot-assisted laparoscopic radical prostatectomy (RALRP). METHODS A total of 239 patients with a mean age of 60.6 years were evaluated (January 2007 to June 2008). Data were collected through an institutional review board-approved blinded prospective database by an independent third party committee. The data-points accrued were set forth by a 5-member panel including 3 robotic urological surgeons (J. R., G. H., G. P.), the chief of general surgery (H. S.), and a member of the hospitals outcomes committee. The Modified Clavien system was used to grade complications, with grade I and II representing minor and grade III, IV, and V major complications. RESULTS Of our 239 patients, 198 (82.9%) had an uneventful postoperative course, defined as discharged home from the hospital within 2 days postoperatively with no unscheduled procedures/studies/hospital admissions or emergency room visits. On review of the remaining 41 patients, 55 complications were found. Of these, 24 were grade I, 17 grade II, 7 grade IIIa, 5 grade IIIb, 1 grade IVa, and 1 grade V complications. There was 1 perioperative mortality (0.4%) attributed to a pulmonary embolism on autopsy. Blood loss data revealed 1 (0.4%) intraoperative transfusion and 9 (3.8%) postoperative transfusions. CONCLUSIONS RALRP is associated with major and minor complication rates of 5.0% and 14.6%, respectively. Prospective and blinded data on complications associated with RALRP are lacking in the published data. Our prospective, unbiased data provide an important tool to help counsel patients on complications associated with robot-assisted laparoscopic radical prostatectomy.

Reversal of chemosensitivity and induction of cell malignancy of a non-malignant prostate cancer cell line upon extracellular vesicle exposure

BackgroundExtracellular vesicle (EV) trafficking is a fundamental cellular process that occurs in cells and is required for different aspects of pathophysiology. EV trafficking leads to changes in cellular function including apoptosis, angiogenesis and proliferation required for increased tumor formation.ResultsWe report several phenotypic changes mediated by EVs isolated from non-malignant and malignant prostate cells as well as patient biopsied prostate tumor samples. EVs can reverse the resistance of prostate cancer cells to camptothecin EVs isolated from non-malignant PrECs (Prostate Epithelial Cells) can reverse soft agar colony formation of malignant DU145 cells, with the reciprocal effect observed. Isolation of EVs from 2 Gleason grade 8 prostate cancer patients significantly induced soft agar colony formation of non-malignant PrECs. We have identified proteins via antibody and Mass spectrometry analysis that may be responsible for the phenotypic changes. Mass spectrometry analysis of protein lysates using ProteoIQ revealed protein candidates associated with gene ontology annotations that may be responsible for this phenotypic change. Ingenuity Pathway Analysis was used to identify statistically relevant canonical pathways and functions associated the protein IDs and expression values obtained using ProteoIQ. Western blot analysis confirmed the increase of 14-3-3 zeta, pRKIP and prohibitin protein levels in PrEC cells co-cultured with patient EVs. 14-3-3 proteins were also found as common proteins of 3 other Gleason grade 8 patients.ConclusionOur study provides a rational basis to further investigate putative proteins, such as 14-3-3 and prohibitin and genetic factors that may be responsible for phenotypic changes that are associated with prostate cancer progression.

Nanostructured polyurethane-poly-lactic-co-glycolic acid scaffolds increase bladder tissue regeneration: an in vivo study.

Although showing much promise for numerous tissue engineering applications, polyurethane and poly-lactic-co-glycolic acid (PLGA) have suffered from a lack of cytocompatibility, sometimes leading to poor tissue integration. Nanotechnology (or the use of materials with surface features or constituent dimensions less than 100 nm in at least one direction) has started to transform currently implanted materials (such as polyurethane and PLGA) to promote tissue regeneration. This is because nanostructured surface features can be used to change medical device surface energy to alter initial protein adsorption events important for promoting tissue-forming cell functions. Thus, due to their altered surface energetics, the objective of the present in vivo study was to create nanoscale surface features on a new polyurethane and PLGA composite scaffold (by soaking the polyurethane side and PLGA side in HNO3 and NaOH, respectively) and determine bladder tissue regeneration using a minipig model. The novel nanostructured scaffolds were further functionalized with IKVAV and YIGSR peptides to improve cellular responses. Results provided the first evidence of increased in vivo bladder tissue regeneration when using a composite of nanostructured polyurethane and PLGA compared with control ileal segments. Due to additional surgery, extended potentially problematic healing times, metabolic complications, donor site morbidity, and sometimes limited availability, ileal segment repair of a bladder defect is not optimal and, thus, a synthetic analog is highly desirable. In summary, this study indicates significant promise for the use of nanostructured polyurethane and PLGA composites to increase bladder tissue repair for a wide range of regenerative medicine applications, such as regenerating bladder tissue after removal of cancerous tissue, disease, or other trauma.

Insulin resistance and glucose transporter expression during the euglycemic hyperinsulinemic clamp in the lamb

Three- to six-day-old lambs infused with 100 mU ⋅ kg-1 ⋅ min-1insulin required greater amounts of glucose to maintain euglycemia during a euglycemic hyperinsulinemic clamp compared with 31- to 35-day-old insulin-infused lambs (15.87 ± 3.47 vs. 4.30 ± 1.11 mg ⋅ kg-1 ⋅ min-1, P < 0.05, respectively). Endogenous glucose production persisted in both groups; however, the percent decrease compared with age-matched lambs receiving no insulin was greater in the younger group compared with the older group (53%, P < 0.001, vs. 34%, P < 0.01). The younger animals showed greater glucose utilization compared with the older animals (215 vs. 96%, respectively, P < 0.01). No effect of insulin was noted on GLUT-4 protein expression in either group. GLUT-2 expression was increased in older vs. younger lambs. Older insulin-infused lambs showed lower GLUT-2 expression than older 0 insulin-infused lambs [0.94 ± 0.07 vs. 1.64 ± 0.10 (OD) units, P < 0.005]. Increased sensitivity to insulin in the younger animals was not related to acute changes in GLUT-4 expression. Increased GLUT-2 expression with age, as well as decreased expression with hyperinsulinemia, is consistent with the development of an insulin-resistant state in the adult.Three- to six-day-old lambs infused with 100 mU x kg(-1) x min(-1) insulin required greater amounts of glucose to maintain euglycemia during a euglycemic hyperinsulinemic clamp compared with 31- to 35-day-old insulin-infused lambs (15.87 +/- 3.47 vs. 4.30 +/- 1.11 mg x kg(-1) x min(-1), P < 0.05, respectively). Endogenous glucose production persisted in both groups; however, the percent decrease compared with age-matched lambs receiving no insulin was greater in the younger group compared with the older group (53%, P < 0.001, vs. 34%, P < 0.01). The younger animals showed greater glucose utilization compared with the older animals (215 vs. 96%, respectively, P < 0.01). No effect of insulin was noted on GLUT-4 protein expression in either group. GLUT-2 expression was increased in older vs. younger lambs. Older insulin-infused lambs showed lower GLUT-2 expression than older 0 insulin-infused lambs [0.94 +/- 0.07 vs. 1.64 +/- 0.10 (OD) units, P < 0.005]. Increased sensitivity to insulin in the younger animals was not related to acute changes in GLUT-4 expression. Increased GLUT-2 expression with age, as well as decreased expression with hyperinsulinemia, is consistent with the development of an insulin-resistant state in the adult.

Dedicated robotics team reduces pre-surgical preparation time.

Context: Robot-Assisted Laparoscopic Radical Prostatectomy (RALRP) requires significant preoperative setup time for the room, staff, and surgical platform. The utilization of a dedicated robotics operating room (OR) staff may facilitate efficiency and decrease costs. Aims: We sought to determine the degree to which preoperative time decreased as experience was gained. Materials and Methods: A total of 476 patients with a mean age of 60.2 years were evaluated (11/2006 to 1/2010). Data was assimilated through an institutional review board approved blinded, prospective database. Utilizing time from patient arrival in the OR to robot docking as preoperative preparation, our experience was evaluated. Age, body mass index (BMI), and American Society of Anesthesiologists risk scores (ASA) were compared. Statistical Analysis Used: Analysis of variance; Two-sample t-test for unequal variances. Results: The first and last 100 cases were found to have similar age (P=0.27), BMI (P=0.11), and ASA (P=0.09). The average preoperative times were 66. 4 and 53.4 min, respectively (P<0.05). The second 100 patients treated were found to have a significantly shorter preoperative time when compared to the first 100 patients (P<0.05). When the first 100 cases were divided into cohorts of 10 cases the mean preoperative time for the first through fourth cohorts were 80.5, 69.3, 78.8, and 64.7 min, respectively. After treatment of our first 30 patients we found a significant drop in preoperative time. This persisted throughout the remainder of our experience. Conclusions: From the time of patient arrival a number of tasks are accomplished by the non-physician operating room staff during RALRP. The use of a consistent staff can decrease preoperative setup times and, therefore, the overall length of surgery.

The emergence of extracellular vesicles in urology: fertility, cancer, biomarkers and targeted pharmacotherapy

Extracellular vesicles (EV) are small membrane-bound vesicles enriched in a selective repertoire of mRNA, miRNA, proteins and cell surface receptors from parental cells and are actively involved in the transmission of inter and intracellular signals. Cancer cells produce EV that contain cargo including DNA, mRNA, miRNA and proteins that allow EV to create epigenetic changes in target cells both locally and systemically. Cancer-derived EV play critical roles in tumorigenesis, cancer cell migration, metastasis, evasion of host immune defense, chemoresistance, and they promote a premetastatic niche favourable to micrometastatic seeding. Their unique molecular profiles acquired from originator cells and their presence in numerous body fluids, including blood and urine, make them promising candidates as biomarkers for prostate, renal and bladder cancers. EV may ultimately serve as targets for therapy and as platforms for personalized medicine in urology. As urologic malignancy comprises 28% of new solid tumour diagnoses and 15% of cancer-related deaths, EV-related research is rapidly emerging and providing unique insights into disease progression. In this report, we review the current literature on EV in the setting of genitourinary fertility and malignancy.

Radium-223 dichloride: illustrating the benefits of a multidisciplinary approach for patients with metastatic castration-resistant prostate cancer

Improving options for patients with metastatic castration-resistant prostate cancer (mCRPC) provide latitude in designing treatment plans that meet patients’ medical needs and personal goals. The field’s rapid evolution opens avenues for contributions by multiple medical specialties and requires considering more options to ensure that each patient receives the most appropriate care. A multidisciplinary clinic (MDC) focusing on patients with cancers of the genitourinary tract demonstrates an efficient and cost-effective means of integrating the diverse professional knowledge and skills needed to develop an optimal patient treatment plan. As a guide to establishing an MDC for patients with mCRPC, this article describes the operation of the Genitourinary MDC at The Miriam Hospital in Providence, RI – specifically, the successful incorporation of radium-223 dichloride (radium-223) into the treatment algorithm for men with mCRPC and symptomatic bone metastases. Radium-223 is a new treatment that, unlike earlier radionuclide therapies, has shown a survival advantage in a large randomized phase 3 trial (ALSYMPCA). The overall survival benefit was comparable to that of newer immuno-and hormonal therapies in similar populations. Radium-223 treatment also delayed onset of symptomatic skeletal events. Both benefits were independent of prior docetaxel therapy or concurrent bisphosphonate use. In our clinic, radium-223 is used primarily to extend patient survival. Patient selection, patient management, and treatment sequencing are discussed here in the context of a multidisciplinary environment.