Publications by authors named "Peter E Clark"

203 Publications

Genomic analysis of response to bacillus Calmette-Guérin (BCG) treatment in high-grade stage 1 bladder cancer patients.

Transl Androl Urol 2021 Jul;10(7):2998-3009

Department of Urology, Levine Cancer Institute/Atrium Health, Charlotte, NC, USA.

Background: Intravesical bacillus Calmette-Guérin (BCG) therapy is standard treatment for high-risk non-muscle invasive bladder cancer (NMIBC) but overall efficacy is low, and no reliable predictive biomarkers currently exist to refine patient selection. We performed genomic analysis on high-grade (HG) T1 NMIBCs to determine if response to therapy is predicted by certain mutational and/or expressional changes.

Methods: Patients with HG T1 NMIBC treated with induction BCG were stratified by response into durable and non-durable responders. Baseline tumor samples were subjected to targeted DNA sequencing and whole-exome RNAseq. Genomic variants differing significantly between response groups were analyzed using Ingenuity Pathway Analysis (IPA) software. Variant selection was refined to target potential biomarker candidates for responsiveness to BCG.

Results: Among 42 patients, the median follow-up was 51.7 months and 40.5% (n=17) were durable BCG responders. Deleterious mutations in the RNA sequence of , , , and were more common in non-durable responders. Mutations in and detected on targeted sequencing were more commonly found in durable responders. Of all deleterious DNA and RNA mutations identified, only was significantly associated with longer recurrence free survival (RFS) (P=0.031).

Conclusions: Differences in the genomic profiles of HG T1 NMIBC tumors exist between those who show durable response to BCG and those who do not. Using pathway analysis, those differences imply upregulation of several interconnected inflammatory pathways among responders. Specific variants identified here, namely , are candidates for further study and, if clinically validated, may serve as useful biomarkers in the future.
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http://dx.doi.org/10.21037/tau-21-158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8350238PMC
July 2021

Differential effect of body mass index by gender on oncological outcomes in patients with renal cell carcinoma.

J Cancer Res Ther 2021 Apr-Jun;17(2):420-425

Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.

Objectives: To investigate the relationship between gender, body mass index (BMI), and prognosis in renal cell carcinoma (RCC) patients.

Materials And Methods: We retrospectively reviewed 1353 patients with RCC who underwent a partial or radical nephrectomy between 1988 and 2015. The association among sex, BMI, stage, grade, overall survival (OS), and recurrence-free survival (RFS) was analyzed.

Results: The median age of the patients was 59.4 ± 11.9 years. Female patients had proportionally lower grade tumors than male patients (Grade I-II in 75.5% vs. 69.3% in women and men, respectively, P = 0.022). There was no relationship between Fuhrman grade and BMI when substratified by gender (p > 0.05). There was a nonsignificant trend toward more localized disease in female patients (p = 0.058). There was no relationship between T stage and BMI when stratified by gender (p > 0.05). Patients with higher BMI had significantly better OS (p = 0.0004 and P = 0.0003) and RFS (P = 0.0209 and P =0.0082) whether broken out by lower 33 or 25 percentile. Male patients with higher BMI had significantly better OS and RFS rates. However, there was no relationship between BMI and OS or RFS for female patients (P > 0.05). Multivariate analysis of the entire cohort demonstrated that a BMI in the lower quartile independently predicts OS (hazard ratio 1.604 [95% confidence interval: 1.07-2.408], P = 0.022) but not RFS (P > 0.05). When stratified by gender, there was no relationship between BMI and either OS or RFS (P > 0.05).

Conclusions: Increasing BMI was associated with RCC prognosis. However, the clinical association between BMI and oncologic outcomes may be different between men and women.
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http://dx.doi.org/10.4103/jcrt.JCRT_546_18DOI Listing
June 2021

Renal Mass and Localized Renal Cancer: Evaluation, Management, and Follow-Up: AUA Guideline: Part I.

J Urol 2021 Aug 11;206(2):199-208. Epub 2021 Jul 11.

Fox Chase Cancer Center, Philadelphia, Pennsylvania.

Purpose: This AUA Guideline focuses on evaluation/counseling/management of adult patients with clinically-localized renal masses suspicious for cancer, including solid-enhancing tumors and Bosniak 3/4 complex-cystic lesions.

Materials/methods: The Renal Mass and Localized Renal Cancer guideline underwent an update literature review which resulted in the 2021 amendment. When sufficient evidence existed, the body of evidence was assigned a strength rating of A (high), B (moderate), or C (low) for support of Strong, Moderate, or Conditional Recommendations. In the absence of sufficient evidence, additional information is provided as Clinical Principles and Expert Opinions (table 1[Table: see text]).

Results: Great progress has been made regarding the evaluation/management of clinically-localized renal masses. These guidelines provide updated, evidence-based recommendations regarding evaluation/counseling including the evolving role of renal-mass-biopsy (RMB). Given great variability of clinical/oncologic/functional characteristics, index patients are not utilized and the panel advocates individualized counseling/management. Options for intervention (partial-nephrectomy (PN), radical-nephrectomy (RN), and thermal-ablation (TA)) are reviewed including recent data about comparative-effectiveness/potential morbidities. Oncologic issues are prioritized while recognizing the importance of functional-outcomes for survivorship. Granular criteria for RN are provided to help reduce overutilization of RN while also avoiding imprudent PN. Priority for PN is recommended for clinical T1a lesions, along with selective utilization of TA, which has good efficacy for tumors≤3.0 cm. Recommendations for genetic-counseling have been revised and considerations for adjuvant-therapies are addressed. Active-surveillance and follow-up after intervention are discussed in an adjunctive article.

Conclusion: Several factors require consideration during counseling/management of patients with clinically-localized renal masses including general health/comorbidities, oncologic-considerations, functional-consequences, and relative efficacy/potential morbidities of various management-strategies.
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http://dx.doi.org/10.1097/JU.0000000000001911DOI Listing
August 2021

Renal Mass and Localized Renal Cancer: Evaluation, Management, and Follow-up: AUA Guideline: Part II.

J Urol 2021 Aug 11;206(2):209-218. Epub 2021 Jul 11.

Consultant Methodologist, Ontario, Canada.

Purpose: This AUA Guideline focuses on active surveillance (AS) and follow-up after intervention for adult patients with clinically-localized renal masses suspicious for cancer, including solid enhancing tumors and Bosniak 3/4 complex cystic lesions.

Materials And Methods: In January 2021, the Renal Mass and Localized Renal Cancer guideline underwent additional amendment based on a current literature-search. This literature search retrieved additional studies published between July 2016 to October 2020 using the same Key Questions and search criteria from the Renal Mass and Localized Renal Cancer guideline. When sufficient evidence existed, the body of evidence was assigned strength-rating of A (high), B (moderate), or C (low) for support of Strong, Moderate, or Conditional Recommendations. In the absence of sufficient evidence, additional information is provided as Clinical Principles and Expert Opinions (table 1[Table: see text]).

Results: AS with potential delayed intervention should be considered for patients with solid, enhancing renal masses <2cm or Bosniak 3-4 lesions that are predominantly-cystic. Shared decision-making about AS should consider risks of intervention/competing mortality versus the potential oncologic benefits of intervention. Recommendations for renal mass biopsy and considerations for periodic clinical/imaging-based surveillance are discussed. After intervention, risk-based surveillance protocols are defined incorporating clinical/laboratory evaluation and abdominal/chest imaging designed to detect local/systemic recurrences and possible treatment-related sequelae, such as progressive renal-insufficiency.

Conclusion: AS is a potential management strategy for some patients with clinically-localized renal masses that requires careful risk-assessment, shared decision-making and periodic-reassessment. Follow-up after intervention is designed to identify local/systemic recurrences and potential treatment-related sequelae. A risk-based approach should be prioritized with selective use of laboratory/imaging resources.
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http://dx.doi.org/10.1097/JU.0000000000001912DOI Listing
August 2021

Racial Disparities in Prostate Specific Antigen Screening and Referral to Urology in a Large, Integrated Health Care System: A Retrospective Cohort Study.

J Urol 2021 08 1;206(2):270-278. Epub 2021 Apr 1.

Atrium Health, Carolinas Medical Center, Department of Urology, Charlotte, North Carolina.

Purpose: Contemporary trends and racial disparities in prostate cancer screening and referral to urology for prostate cancer risk are not well characterized, despite consensus that Black men are at higher risk for poor prostate cancer outcomes. The objective of this study was to characterize current racial disparities in prostate cancer screening and referral from primary care to urology for prostate cancer concern within our large, integrated health care system.

Materials And Methods: This retrospective cohort study used data from Atrium Health's enterprise data warehouse, which includes patient information from more than 900 care locations across North Carolina, South Carolina and Georgia. We included all men seen in the ambulatory or outpatient setting between 2014 and 2019 who were ≥40 years old. Clinical and demographic data were collected for all men, including age and race. Racial outcomes were reported for all groups with >2% representation in the population. Between-group comparisons were determined using chi-squared analysis, Wilcoxon rank sum testing and multivariable logistic regression, with significance defined as p <0.05.

Results: We observed a significant decrease in prostate specific antigen testing across all age and racial groups in a cohort of 606,985 men at Atrium Health, including 87,189 Black men, with an overall relative decline of 56%. As compared to White men, Black men were more likely to undergo prostate specific antigen testing (adjusted OR 1.24, 95% CI 1.22-1.26) and be referred to urology for prostate cancer (adjusted OR 1.94, 95% CI 1.75-2.16).

Conclusions: There was a continued significant decline in prostate cancer screening between 2014 and 2019. Despite having modestly elevated odds of being screened for prostate cancer compared to White men, Black men are relatively underscreened when considering that those who undergo prostate specific antigen screening are more likely to be referred by primary care to urology for additional prostate cancer diagnostic evaluation.
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http://dx.doi.org/10.1097/JU.0000000000001763DOI Listing
August 2021

Diagnostic renal mass biopsy is associated with individual categories of PADUA and RENAL nephrometry scores: Analysis of diagnostic and concordance rates with surgical resection.

Urol Oncol 2021 06 26;39(6):371.e7-371.e15. Epub 2021 Mar 26.

Vanderbilt University Medical Center, Department of Pathology, Immunology, and Microbiology; Nashville, TN. Electronic address:

Background: Renal mass biopsy (RMB) is a safe and accurate method for diagnosis and clinical management of renal masses. However, the non-diagnostic rate is a limiting factor. We tested the hypothesis that imaging characteristics and anatomic complexity of the mass may impact RMB diagnostic outcome using the preoperative aspects and dimensions used for an anatomical (PADUA) classification and radius-exophytic/endophytic-nearness-anterior/posterior-location (RENAL) score.

Material And Methods: Single institution, retrospective study of 490 renal masses from 443 patients collected from 2001 to 2018. Outcome measurements include (1) diagnostic and concordance rates amongst RMB types and RMB with surgical resection specimens; (2) association between diagnostic RMB and anatomical complexity of renal masses. The analysis was conducted in unselected masses and small renal masses (SRMs).

Results: RMB was performed by fine needle aspiration (FNA), core needle biopsy (CNB), or both (FNA+CNB). Non-diagnostic rate was significantly higher for FNA compared to CNB and FNA+CNB in both unselected and SRMs. Subset analysis in the FNA+CNB group showed similar diagnostic rates for FNA and CNB. In unselected masses, specificity for FNA, CNB, and FNA+CNB was 100%. Sensitivity was higher for CNB (90.1%, P = 0.002) and FNA+CNB (96.3%, P = 0.004) compared to FNA (66.7%). For unselected masses, endophytic growth predicted a non-diagnostic CNB. R.E.N.A.L location entirely between the polar lines (central) and entirely above the upper polar line predicted a diagnostic CNB. Sonography-guidance predicted a diagnostic FNA. For SRMs, non-diagnostic CNB was associated with endophytic growth, while diagnostic CNB was associated with renal sinus invasion and operator experience. More cystic masses were sampled by FNA, but diagnostic results were similar for FNA and CNB.

Conclusions: Endophytic growth consistently predicted a non-diagnostic CNB in unselected and SRMs, whereas sonography-guidance predicted a diagnostic FNA. Cystic masses could be adequately sampled by FNA.
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http://dx.doi.org/10.1016/j.urolonc.2021.02.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205938PMC
June 2021

Claudin-2 inhibits renal clear cell carcinoma progression by inhibiting YAP-activation.

J Exp Clin Cancer Res 2021 Feb 23;40(1):77. Epub 2021 Feb 23.

Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE, 68198-5870, USA.

Background: Claudin-2 expression is upregulated in multiple cancers and promotes cancer malignancy. Remarkably, the regulation of claudin-2 expression in kidney cell lines contrasts its reported regulation in other organs. However, claudin-2 role in renal clear cell carcinoma (RCC) remains unknown despite its predominant expression in the proximal tubular epithelium (PTE), the site of RCC origin.

Methods: Publicly available and independent patient databases were examined for claudin-2 association with RCC. The novel protein function was validated in vitro and in vivo by gain or loss of function assays. Mechanistic results were concluded by Mass spectroscopy, immunoprecipitation and mutational studies, and functional evaluations.

Results: We show that the significant decrease in claudin-2 expression characterized PTE cells and Ex-vivo cultured mouse kidney subjected to dedifferentiation. Inhibition of claudin-2 was enough to induce mesenchymal plasticity and invasive mobility in these models. Further, a progressive loss of claudin-2 expression associated with the RCC progression and poor patient survival. Overexpression of claudin-2 in RCC-derived cancer cells inhibited tumorigenic abilities and xenograft tumor growth. These data supported a novel tumor-suppressive role of claudin-2 in RCC. Mechanistic insights further revealed that claudin-2 associates with YAP-protein and modulates its phosphorylation (S127) and nuclear expression. The tumor suppressive effects of claudin-2 expression were lost upon deletion of its PDZ-binding motif emphasizing the critical role of the PDZ-domain in claudin-2 interaction with YAP in regulating RCC malignancy.

Conclusions: Our results demonstrate a novel kidney specific tumor suppressive role for claudin-2 protein and further demonstrate that claudin-2 co-operates with the YAP signaling in regulating the RCC malignancy.
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http://dx.doi.org/10.1186/s13046-021-01870-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901196PMC
February 2021

Demographic and Socioeconomic Factors Associated with Urinary Stone Disease Management in a Large Urban US Population.

Urology 2021 Jul 30;153:93-100. Epub 2021 Jan 30.

Department of Urology, Atrium Health, Charlotte, NC.

Objective: To determine the influence of socioeconomic parameters on urinary stone surgeries.

Methods: A retrospective cohort study analyzed patients undergoing urolithiasis surgery in our community network hospital in North Carolina from 2005-2018.

Results: Of 7731 patients, 2160 (28%), 5,174 (67%), and 397 (5%) underwent SWL, URS, and PCNL, respectively. A higher proportion of Whites underwent URS (67%) and SWL (74%) than PCNL (56%); whereas a larger percentage of Blacks underwent PCNL (24%) than URS (20%) and SWL (15%) groups (P <.001). Private insurance payers were greater in the SWL (95%) group than URS (80%) and PCNL (81%) (P <.001). The distribution of median income was significantly different amongst the 3 surgeries with higher income classes overutilizing SWL and underutilizing PCNL compared to lower income classes (P <.001). In linear regression modeling, the proportion of SWL in a postal code was positively associated with median income (R=0.55, P <.001); URS and PCNL were negatively associated with median income (R=0.40, P <.001 and R=0.41, P <.001, respectively). On multivariate logistic regression modeling, Blacks were significantly more likely to undergo PCNL than Whites (aOR 1.32, 95% CI 1.01-1.74 P <.050). Private insurance payers were more likely to undergo SWL (aOR 11.0, 95% CI 7.26-16.8, P <.0001) than public insurance payers. Patients in higher median income brackets are significantly less likely to undergo PCNL than those in the <$40,000 income bracket (P <.0001).

Conclusion: Our study suggests that socioeconomic status impacts urolithiasis surgical management, underscoring disparity recognition importance in endourologic care and ensuring appropriate surgical care regardless of socioeconomic status.
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http://dx.doi.org/10.1016/j.urology.2021.01.036DOI Listing
July 2021

Epidemiology and survival outcome of adult kidney, bladder, and prostate rhabdomyosarcoma: A SEER database analysis.

Rare Tumors 2020 4;12:2036361320977401. Epub 2020 Dec 4.

Department of Urology, Atrium Health, Charlotte, NC, USA.

Rhabdomyosarcoma (RMS) is rare in adulthood, accounting for 2%-5% of adult soft tissue tumors, and less than 20% occur in genitourinary organs. Given its rarity, survival data on adult kidney, bladder, and prostate RMSs is limited. In this population-based analysis, we performed an analysis of all adult RMS cases reported in Surveillance, Epidemiology, and End Results (SEER) database to understand prognostic factors among kidney, bladder, and prostate RMS. A query of the SEER database was performed from 1973 to 2016 for patients >18 of age with RMS. The final cohort consisted of 14 kidney, 35 bladder, and 21 prostate RMS cases in the adult population. Demographic, treatment, and survival data were obtained. Analysis was performed using Fisher's exact test, survival analysis, and model. The median (range) age of diagnosis for adult bladder RMS was 65 years old (19-84) compared to 52.5 (28-68) and 42 (19-87) for kidney and prostate ( = 0.007). About 78.6% of patients underwent surgical intervention. Five-year overall survival (OS) for adult kidney, bladder, and prostate RMS are 17.1% (2.9-41.6%), 22.2% (9.4-38.4%), and 33.0 (12.8-55.0%), respectively. OS was not statistically associated with primary site ( = 0.209). On multivariable analysis, compared to adult bladder RMS, kidney RMS had a higher incidence of mortality (HR: 2.16, 95% CI 1.03-4.53,  = 0.041). Incidence of mortality from prostate RMS was not significantly different from bladder RMS (HR: 0.70, 95% CI 0.30-1.65,  = 0.411). Extent of disease (HR: 5.17, 95% CI 2.09-12.79,  < 0.001) and older age (HR 1.03, 95% CI 1.01-1.04,  = 0.002) were adverse prognostic factors for OS. Overall survival at 5 years for adult kidney, bladder, and prostate RMS is poor. Localized disease and younger age are prognostic factors for improved outcomes in adult RMS. Hence, early diagnosis and intervention appear paramount to improved survival for this rare malignancy in adulthood.
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http://dx.doi.org/10.1177/2036361320977401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720312PMC
December 2020

Identification of Genes Required for Enzalutamide Resistance in Castration-Resistant Prostate Cancer Cells .

Mol Cancer Ther 2021 02 9;20(2):398-409. Epub 2020 Dec 9.

Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio.

Castration-resistant prostate cancer can be treated with the antiandrogen enzalutamide, but responses and duration of response are variable. To identify genes that support enzalutamide resistance, we performed a short hairpin RNA (shRNA) screen in the bone-homing, castration-resistant prostate cancer cell line, C4-2B. We identified 11 genes ( and ) whose loss resulted in decreased cell survival in response to enzalutamide. To validate our screen, we performed transient knockdowns in C4-2B and 22Rv1 cells and evaluated cell survival in response to enzalutamide. Through these studies, we validated three genes ( and ) as supporters of enzalutamide resistance Although expression is lower in metastatic castration-resistant prostate cancer samples versus primary prostate cancer samples, knockdown of was sufficient to reduce cell survival in C4-2B and 22Rv1 cells. expression increases with Gleason grade, and the highest expression is observed in metastatic castration-resistant disease. Knockdown of reduced cell survival, and pharmacologic inhibition of MAP3K11 with CEP-1347 in combination with enzalutamide resulted in a dramatic increase in cell death. This was associated with decreased phosphorylation of AR-Serine650, which is required for maximal AR activation. Finally, although expression did not change during disease progression, knockdown of resulted in decreased AR and AR splice variant expression, likely contributing to the C4-2B and 22Rv1 decrease in cell survival. Our study has therefore identified at least three new supporters of enzalutamide resistance in castration-resistant prostate cancer cells .
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http://dx.doi.org/10.1158/1535-7163.MCT-20-0244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867613PMC
February 2021

Human epidermal growth factor receptor 2 overexpression is frequently discordant between primary and metastatic urothelial carcinoma and is associated with intratumoral human epidermal growth factor receptor 2 heterogeneity.

Hum Pathol 2021 01 26;107:96-103. Epub 2020 Oct 26.

Levine Cancer Institute, Atrium Health, Charlotte, NC, 28204, USA. Electronic address:

Human epidermal growth factor receptor 2 (HER2) overexpression occurs in 5-10% of primary urothelial carcinomas (UCs) but has not reliably predicted benefit from HER2-targeted agents in the metastatic setting. HER2 testing of primary tumors may not reflect the HER2 status of distant metastases. We assessed the concordance of HER2 expression in paired primary and distant metastatic UC lesions. Specimens from 149 patients with metastatic UC underwent immunohistochemical staining for HER2, including 79 paired primary and distant metastatic tumors. HER2 status was defined using 2018 ASCO/CAP guidelines. HER2 intratumoral heterogeneity (ITH) was defined as HER2 3+ expression in 5-50% of tumor cells. The HER2-positive, -equivocal, and -negative rates observed were 10.6%, 24.7%, and 64.7% for primary tumors and 9.8%, 12.6%, and 77.6% for metastatic tumors, respectively. HER2 ITH occurred in 44% of HER2-positive primary tumors. Low agreement of HER2-positive status between primary and metastatic tumors was observed (к = 0.193, P = 0.079). Loss of HER2 overexpression in the metastatic lesion was observed in 55% (5 of 9 cases) of HER2-positive primary cases and was associated with the presence of HER2 ITH in the primary tumor (Fisher's exact P = 0.048). Change from negative primary to positive metastasis was seen in 2% (1 of 50) of cases. No differences in metastasis-free survival or overall survival were observed in accordance with HER2 status defined by either the primary or metastatic lesion. These findings are likely to impact patient selection for HER2 targeted therapies in UC. Confirmation and evaluation of the clinical significance of HER2 discordance is warranted, preferably in the context of a clinical trial.
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http://dx.doi.org/10.1016/j.humpath.2020.10.006DOI Listing
January 2021

Safety and effectiveness of percutaneous renal cryoablation with conscious sedation.

Arab J Urol 2020 Mar 23;18(3):163-168. Epub 2020 Mar 23.

Department of Urology, Atrium Health, Charlotte, NC, USA.

Objective: To investigate complications and treatment failure rates of percutaneous renal cryoablation (PRC) for small renal masses under local anaesthesia and conscious sedation (LACS), to assess the safety and effectiveness of this approach, as PRC is typically performed under general anaesthesia (GA).

Patients And Methods: We retrospectively reviewed PRC under LACS from 2003 to 2017. We analysed perioperative parameters between patients who successfully underwent PRC under LACS and patients with post-procedural complications or treatment failure (renal mass enhancement after successful intraoperative tumour ablation). Two-sided non-parametric and Fisher's exact tests were performed to compare uncomplicated or disease-free PRC with the complication or treatment failure group, respectively.

Results: A total of 100 PRCs under LACS were performed during the study period. Of these patients, six patients had at least one postoperative complication (6%), and treatment failure was diagnosed in nine patients (9%) after PRC [mean (SD) follow-up of 42.7 (26.6) months]. The procedural failure rate was 1%. No ablations were converted to GA. The mean tumour size was smaller in patients who had no complications during PRC compared to those who did, at a mean (SD) of 2.2 (0.6) cm vs 3.0 (1.0) cm ( = 0.039). The use of more intraoperative probes during the PRC was also associated with complications, at a mean (SD) 3.0 (1.4) vs 1.8 (0.8) ( = 0.021).

Conclusions: PRC under LACS is an effective and safe procedural approach for managing small renal masses with low complication, treatment failure, and procedural failure rates. Larger renal masses and intraoperative use of multiple probes is associated with an increased risk of PRC complications.

Abbreviations: BMI: body mass index; CCI: Charlson Comorbidity Index; GA: general anaesthesia; LACS: local anaesthesia and conscious sedation; PRC: percutaneous renal cryoablation; R.E.N.A.L.: Radius, Exophytic/Endophytic, Nearness, Anterior/Posterior, Location.
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http://dx.doi.org/10.1080/2090598X.2020.1739382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473112PMC
March 2020

Management changes for patients with endocrine-related cancers in the COVID-19 pandemic.

Endocr Relat Cancer 2020 09;27(9):R357-R374

Departments of Solid Tumor Oncology, Endocrinology, and Urologic Oncology, Levine, Cancer Institute, Charlotte, North Carolina, USA.

Substantial management changes in endocrine-related malignancies have been required as a response to the COVID-19 pandemic, including a draconian reduction in the screening of asymptomatic subjects, delay in planned surgery and radiotherapy for primary tumors deemed to be indolent, and dose reductions and/or delays in initiation of some systemic therapies. An added key factor has been a patient-initiated delay in the presentation because of the fear of viral infection. Patterns of clinical consultation have changed, including a greater level of virtual visits, physical spacing, masking, staffing changes to ensure a COVID-free population and significant changes in patterns of family involvement. While this has occurred to improve safety from COVID-19 infection, the implications for cancer outcomes have not yet been defined. Based on prior epidemics and financial recessions, it is likely that delayed presentation and treatment of high-grade malignancy will be associated with worse cancer outcomes. Cancer patients are also at increased risk from COVID-19 infection compared to the general population. Pandemic management strategies for patients with tumors of breast, prostate, thyroid, parathyroid and adrenal gland are reviewed.
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http://dx.doi.org/10.1530/ERC-20-0229DOI Listing
September 2020

EDITORIAL COMMENT.

Authors:
Peter E Clark

Urology 2020 Aug;142:131-132

Department of Urology at Atrium Health, Chair, Urologic Oncology at Levine Cancer Institute, Charlotte, NC.

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http://dx.doi.org/10.1016/j.urology.2020.03.055DOI Listing
August 2020

Increased nuclear factor I/B expression in prostate cancer correlates with AR expression.

Prostate 2020 09 21;80(13):1058-1070. Epub 2020 Jul 21.

Department of Urology, Case Western Reserve University, Cleveland, Ohio.

Background: Most prostate cancers express androgen receptor (AR), and our previous studies have focused on identifying transcription factors that modify AR function. We have shown that nuclear factor I/B (NFIB) regulates AR activity in androgen-dependent prostate cancer cells in vitro. However, the status of NFIB in prostate cancer was unknown.

Methods: We immunostained a tissue microarray including normal, hyperplastic, prostatic intraepithelial neoplasia, primary prostatic adenocarcinoma, and castration-resistant prostate cancer tissue samples for NFIB, AR, and synaptophysin, a marker of neuroendocrine differentiation. We interrogated publically available data sets in cBioPortal to correlate NFIB expression and AR and neuroendocrine prostate cancer (NEPCa) activity scores. We analyzed prostate cancer cell lines for NFIB expression via Western blot analysis and used nuclear and cytoplasmic fractionation to assess where NFIB is localized. We performed co-immunoprecipitation studies to determine if NFIB and AR interact.

Results: NFIB increased in the nucleus and cytoplasm of prostate cancer samples versus matched normal controls, independent of Gleason score. Similarly, cytoplasmic AR and synaptophysin increased in primary prostate cancer. We observed strong NFIB staining in primary small cell prostate cancer. The ratio of cytoplasmic-to-nuclear NFIB staining was predictive of earlier biochemical recurrence in prostate cancer, once adjusted for tumor margin status. Cytoplasmic AR was an independent predictor of biochemical recurrence. There was no statistically significant difference between NFIB and synaptophysin expression in primary and castration-resistant prostate cancer, but cytoplasmic AR expression was increased in castration-resistant samples. In primary prostate cancer, nuclear NFIB expression correlated with cytoplasmic NFIB and nuclear AR, while cytoplasmic NFIB correlated with synaptophysin, and nuclear and cytoplasmic AR. In castration-resistant prostate cancer samples, NFIB expression correlated positively with an AR activity score, and negatively with the NEPCa score. In prostate cancer cell lines, NFIB exists in several isoforms. We observed NFIB predominantly in the nuclear fraction of prostate cancer cells with increased cytoplasmic expression seen in castration-resistant cell lines. We observed an interaction between AR and NFIB through co-immunoprecipitation experiments.

Conclusion: We have described the expression pattern of NFIB in primary and castration-resistant prostate cancer and its positive correlation with AR. We have also demonstrated AR interacts with NFIB.
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http://dx.doi.org/10.1002/pros.24019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7434711PMC
September 2020

Implementation of a Dedicated Enhanced Recovery after Surgery (ERAS) Program for Radical Cystectomy Patients is Associated With Decreased Postoperative Inpatient Opioid Usage and Pain Scores.

Urology 2020 Sep 28;143:186-193. Epub 2020 May 28.

Department of Urology, Carolinas Medical Center/Atrium Health/Levine Cancer Institute, Charlotte, NC.

Objective: To measure differences in post-operative opioid usage and pain scores between pre- and post-Enhanced Recovery after Surgery (ERAS) radical cystectomy (RC) patients in an effort to optimize outcomes.

Study Design: We performed a retrospective cohort study from a single institution from January 1, 2015 to July 31, 2018 among 86 and 108 pre- and post-ERAS RC patients. The primary endpoints were total mean opioid usage (morphine equivalent daily dosing or MEDD) and mean pain scores (Visual Analog Scale) on postoperative days (POD) 1-3. Secondary endpoints were number of opioid pills prescribed at discharge and within 30 days of discharge. Multivariable model selection was carried out with forward selection and backward elimination to identify variables associated with key outcomes.

Results: Total mean usage of opioids and mean pain scores were significantly lower in post-ERAS vs pre-ERAS patients across POD 1-3, respectively (32.90 MEDD vs 99.86 MEDD, P ≤ .001; 3.51 vs 4.17, P = .003). The median number of opioid pills prescribed at discharge was significantly lower in the post-ERAS group compared to pre-ERAS (30 pills vs 45 pills, P = .046) as well as the median number opioid pills prescribed within 30 days of discharge (40 pills vs 50 pills, P = .001).

Conclusion: Our study suggests that a dedicated ERAS protocol following RC might be superior to traditional, non-ERAS methods in reducing postoperative opioid use and pain scores.
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http://dx.doi.org/10.1016/j.urology.2020.04.110DOI Listing
September 2020

Comparison of venous thromboembolic complications following urological surgery between patients with or without cancer.

Turk J Urol 2020 May 8. Epub 2020 May 8.

Department of Urology, Odense University Hospital, Odense, Denmark.

Objective: Guidelines recommend 4 weeks of thromboembolic prophylaxis in patients who undergo major surgery for solid malignancies. However, there are limited head-to-head comparisons of risk of venous thromboembolic complications in patients with and without cancer undergoing similar surgical procedures. The purpose of this study was to compare risk of venous thromboembolic complications following major renal surgery and cystectomy between patients with and without cancer at the time of surgery.

Material And Methods: In the nationwide Danish National Patient Registry, which captures all hospital contacts, including surgical procedures, we identified 8,645 patients who underwent major renal surgery (4,273 without cancer and 4,372 with cancer) and 2,164 patients who underwent cystectomy (359 without cancer and 1,805 with cancer) in 2000-2009. The rate of venous thromboembolic events within 6 months from surgery was compared for patients with and without cancer after stratification on organ using Chi-squared test.

Results: There was no difference in the rate of venous thromboembolic complications within the first 6 months after major renal surgery (0.4% and 0.3% [p=0.91]) or cystectomy (1.3% and 0.8% [p=0.44]) for patients with and without cancer. The cost for 28 days of Tinzaparin 4.500 IE administered by the patient was €112, whereas the cost if administered by a community nurse was €1.988.

Conclusions: Our study questions the different recommendations in thromboembolic prophylaxis between patients with and without cancer after major renal surgery and cystectomy.
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http://dx.doi.org/10.5152/tud.2020.20030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360159PMC
May 2020

A Germline Variant at 8q24 Contributes to Familial Clustering of Prostate Cancer in Men of African Ancestry.

Eur Urol 2020 09 12;78(3):316-320. Epub 2020 May 12.

Department of Surgery, Center for Prostate Disease Research, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.

Although men of African ancestry have a high risk of prostate cancer (PCa), no genes or mutations have been identified that contribute to familial clustering of PCa in this population. We investigated whether the African ancestry-specific PCa risk variant at 8q24, rs72725854, is enriched in men with a PCa family history in 9052 cases, 143 cases from high-risk families, and 8595 controls of African ancestry. We found the risk allele to be significantly associated with earlier age at diagnosis, more aggressive disease, and enriched in men with a PCa family history (32% of high-risk familial cases carried the variant vs 23% of cases without a family history and 12% of controls). For cases with two or more first-degree relatives with PCa who had at least one family member diagnosed at age <60 yr, the odds ratios for TA heterozygotes and TT homozygotes were 3.92 (95% confidence interval [CI] = 2.13-7.22) and 33.41 (95% CI = 10.86-102.84), respectively. Among men with a PCa family history, the absolute risk by age 60 yr reached 21% (95% CI = 17-25%) for TA heterozygotes and 38% (95% CI = 13-65%) for TT homozygotes. We estimate that in men of African ancestry, rs72725854 accounts for 32% of the total familial risk explained by all known PCa risk variants. PATIENT SUMMARY: We found that rs72725854, an African ancestry-specific risk variant, is more common in men with a family history of prostate cancer and in those diagnosed with prostate cancer at younger ages. Men of African ancestry may benefit from the knowledge of their carrier status for this genetic risk variant to guide decisions about prostate cancer screening.
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http://dx.doi.org/10.1016/j.eururo.2020.04.060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805560PMC
September 2020

Safety of decreasing ureteral stent duration following radical cystectomy.

World J Urol 2021 Feb 17;39(2):473-479. Epub 2020 Apr 17.

Department of Urology, Carolinas Medical Center/Atrium Health, 1000 Blythe Ave, Suite 163, Medical Education Building, Charlotte, NC, 28203, USA.

Purpose: We aim to assess the safety of decreasing ureteral stenting duration following Radical Cystectomy with Urinary Diversion (RCUD).

Materials And Methods: We analyzed a prospectively and retrospectively collected dataset for cystectomy patients at our tertiary center. Adult patient who underwent RCUD for malignancy from January 2013 to February 2018 were included. Patients with a history of abdominal/pelvic radiation and continent diversions were excluded. The patient population was divided to late stent removal group (LSR-POD 14) and early stent removal group (ESR-POD5). Our endpoints were total stent duration, 90-day readmission, 90-day total-UTI, 90-day urinary-readmissions, complications and Ureteroenteric Stricture (UES) rates. Statistical methods included t test, Chi-squared test and multivariate logistic regression.

Results: One hundred and seventy-eight patients were included in the final analysis after inclusion/exclusion criteria were applied. The LSR (n = 74) and ESR (n = 104) groups were similar in preoperative characteristics except higher intracorporeal ileal conduit formation in ESR. The duration of stenting decreased significantly from approximately 15.5-5 days (P < 0.001). The LSR had higher 90-day overall readmission rates (OR = 2.57, 95% CI 1.19-5.53, P = 0.016) and total-UTIs (OR = 2.36, 95%CI 1.11-5.04, P = 0.026). With a median follow-up of 9.8 months, UES was similar between the two groups.

Conclusion: Shorter ureteral stent duration is a safe and non-inferior option following RCUD. It allows for stent removal prior to discharge and less outpatient visits. In addition, decreasing stent duration was linked decreased readmissions and total-UTIs without increased risk of UES. However, future studies are needed to establish causality and promote stent duration change.
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http://dx.doi.org/10.1007/s00345-020-03191-2DOI Listing
February 2021

High aurora kinase expression identifies patients with muscle-invasive bladder cancer who have poor survival after neoadjuvant chemotherapy.

Urol Oncol 2019 12 6;37(12):900-906. Epub 2019 Oct 6.

Levine Cancer Institute, Atrium Health, Charlotte, NC.

Objectives: Overexpression of aurora kinase A (AURKA) confers a poor prognosis in patients with urothelial carcinoma of the bladder. The prognostic value of high aurora kinase B (AURKB) expression in local bladder cancer is not well defined, and whether the prognostic value of either AURKA or AURKB is affected by the use of chemotherapy is unknown. We sought to characterize the impact of high AURKA and AURKB expression on clinical outcome in patients with muscle-invasive bladder cancer (MIBC) who received neoadjuvant chemotherapy (NAC).

Materials And Methods: Immunohistochemistry for AURKA and AURKB was performed on pretreatment diagnostic transurethral resection of bladder tumor (TURBT) and matched cystectomy specimens in 50 subjects with MIBC who received NAC. Receiver operator characteristic curves (ROC) were calculated to assess the impact of AURKA and AURKB expression on pathologic response rate. Kaplan-Meier techniques and Cox proportional hazards models were used to assess the association with relapse-free survival (RFS) and overall survival (OS).

Results: Twenty-two of 50 [44%] patients had residual muscle-invasive (ypT2-4) urothelial carcinoma after NAC. Neither baseline tumor expression of AURKA (ROC = 0.57, P = 0.46) nor AURKB (ROC = 0.56, P = 0.87) predicted for ypT2-4 status. However, baseline expression of AURKA above the 75th percentile for this cohort was associated with an inferior RFS, (HR = 3.88, P = 0.008) and OS, (HR = 6.10, P < 0.001). Similar trends for worse survival outcomes were also observed for high AURKB levels (RFS, [HR = 2.2, P = 0.13] and OS, (HR = 2.25, P = 0.09).

Conclusions: High baseline tumor AURKA and AURKB expression identified MIBC patients with inferior RFS and OS despite the use of NAC and may identify patients who should be prioritized for clinical trial enrollment rather than standard cisplatin-based chemotherapy.
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http://dx.doi.org/10.1016/j.urolonc.2019.09.009DOI Listing
December 2019

Sex specific associations in genome wide association analysis of renal cell carcinoma.

Eur J Hum Genet 2019 10 23;27(10):1589-1598. Epub 2019 Jun 23.

Russian N.N. Blokhin Cancer Research Centre, Moscow, Russian Federation.

Renal cell carcinoma (RCC) has an undisputed genetic component and a stable 2:1 male to female sex ratio in its incidence across populations, suggesting possible sexual dimorphism in its genetic susceptibility. We conducted the first sex-specific genome-wide association analysis of RCC for men (3227 cases, 4916 controls) and women (1992 cases, 3095 controls) of European ancestry from two RCC genome-wide scans and replicated the top findings using an additional series of men (2261 cases, 5852 controls) and women (1399 cases, 1575 controls) from two independent cohorts of European origin. Our study confirmed sex-specific associations for two known RCC risk loci at 14q24.2 (DPF3) and 2p21(EPAS1). We also identified two additional suggestive male-specific loci at 6q24.3 (SAMD5, male odds ratio (OR) = 0.83 [95% CI = 0.78-0.89], P = 1.71 × 10 compared with female odds ratio (OR) = 0.98 [95% CI = 0.90-1.07], P = 0.68) and 12q23.3 (intergenic, OR = 0.75 [95% CI = 0.68-0.83], P = 1.59 × 10 compared with OR = 0.93 [95% CI = 0.82-1.06], P = 0.21) that attained genome-wide significance in the joint meta-analysis. Herein, we provide evidence of sex-specific associations in RCC genetic susceptibility and advocate the necessity of larger genetic and genomic studies to unravel the endogenous causes of sex bias in sexually dimorphic traits and diseases like RCC.
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http://dx.doi.org/10.1038/s41431-019-0455-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777615PMC
October 2019

Discordance of high PD-L1 expression in primary and metastatic urothelial carcinoma lesions.

Urol Oncol 2019 05 17;37(5):299.e19-299.e25. Epub 2019 Jan 17.

Levine Cancer Institute, Atrium Health, Charlotte, NC.

Immune checkpoint inhibitors (ICI) targeting PD-(L)1 are effective in select patients with advanced urothelial carcinoma (UC). High PD-L1 expression enriches for response to ICIs; however, the predictive value of PD-L1 expression is limited, which may be due in part to dynamic expression of PD-L1 in the tumor environment. We sought to characterize PD-L1 expression in primary UC and paired metastatic lesions to gain insight into the potential discordance of tumor PD-L1 expression during the metastatic process.

Materials And Methods: Immunohistochemical staining for PD-L1 using the SP-142 antibody was performed on primary tumors and matched metastatic specimens in 77 evaluable subjects with advanced UC. Immunohistochemical staining was scored for the percentage of cells positive (<5%, ≥5%) in tumor cell (TC) and immune cell (IC) compartments. Correlation of PD-L1 expression in TCs and ICs was estimated using Spearman's correlation coefficients (rho, ρ). Cohen's kappa statistics (κ) were utilized to assess the agreement in PD-L1 expression between groups.

Results: High (≥5%) PD-L1 expression in primary and metastatic biopsies, respectively, was observed in 6.0% and 7.7% of TCs and in 14.5% and 11.5% of ICs. IC PD-L1 expression in primary tumors was not correlated with IC PD-L1 expression in paired metastatic lesions (ρ = 0.05, P = 0.67) and there was poor agreement in high expression rates between primary and metastatic lesions in the IC compartment (κ= 0.086).

Conclusion: High PD-L1 IC expression is temporally and spatially discordant between primary and metastatic UC lesions. Future studies of PD-(L)1 targeted therapies in patients with metastatic UC may benefit from use of fresh biopsies of metastatic lesions to define PD-L1 expression when feasible.
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http://dx.doi.org/10.1016/j.urolonc.2019.01.002DOI Listing
May 2019

The influence of obesity-related factors in the etiology of renal cell carcinoma-A mendelian randomization study.

PLoS Med 2019 01 3;16(1):e1002724. Epub 2019 Jan 3.

National Institute of Public Health, Bucharest, Romania.

Background: Several obesity-related factors have been associated with renal cell carcinoma (RCC), but it is unclear which individual factors directly influence risk. We addressed this question using genetic markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian randomization (MR) framework. This methodology limits bias due to confounding and is not affected by reverse causation.

Methods And Findings: Genetic markers associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose were initially identified as instrumental variables, and their association with RCC risk was subsequently evaluated in a genome-wide association study (GWAS) of 10,784 RCC patients and 20,406 control participants in a 2-sample MR framework. The effect on RCC risk was estimated by calculating odds ratios (ORSD) for a standard deviation (SD) increment in each risk factor. The MR analysis indicated that higher body mass index increases the risk of RCC (ORSD: 1.56, 95% confidence interval [CI] 1.44-1.70), with comparable results for waist-to-hip ratio (ORSD: 1.63, 95% CI 1.40-1.90) and body fat percentage (ORSD: 1.66, 95% CI 1.44-1.90). This analysis further indicated that higher fasting insulin (ORSD: 1.82, 95% CI 1.30-2.55) and diastolic blood pressure (DBP; ORSD: 1.28, 95% CI 1.11-1.47), but not systolic blood pressure (ORSD: 0.98, 95% CI 0.84-1.14), increase the risk for RCC. No association with RCC risk was seen for lipids, overall type 2 diabetes, or fasting glucose.

Conclusions: This study provides novel evidence for an etiological role of insulin in RCC, as well as confirmatory evidence that obesity and DBP influence RCC risk.
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http://dx.doi.org/10.1371/journal.pmed.1002724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6317776PMC
January 2019

Higher Incidence of Hemorrhagic Cystitis Following Haploidentical Related Donor Transplantation Compared with Matched Related Donor Transplantation.

Biol Blood Marrow Transplant 2019 04 20;25(4):785-790. Epub 2018 Dec 20.

Department of Cancer Biostatistics, Levine Cancer Research, Atrium Health, Charlotte, North Carolina.

Hemorrhagic cystitis (HC) is a common and important complication of allogeneic hematopoietic cell transplantation (HCT). Reactivation of BK virus is its most common cause. The more intense immunosuppressive regimens administered to recipients of grafts from alternative donors have been reported to account for the increased susceptibility to HC in this population. This study compares patients undergoing HCT with either a haploidentical donor or a matched related donor, all of whom received identical immunosuppression with a post-transplantation cyclophosphamide-based regimen. The incidence of HC was significantly higher in the patients receiving a haploidentical graft (P = .01). The higher incidence of HC in haploidentical graft recipients is therefore directly related to the inherent immune deficiency that follows HLA-mismatched transplantation, independent of the intensity of pharmacologic immunosuppression. This finding carries significant clinical impact for the prevention and treatment of HC in haploidentical graft recipients.
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http://dx.doi.org/10.1016/j.bbmt.2018.12.142DOI Listing
April 2019

Use of venous-thrombotic-embolic prophylaxis in patients undergoing surgery for renal tumors: a questionnaire survey in the Nordic countries (The NORENCA-2 study).

Res Rep Urol 2018 25;10:181-187. Epub 2018 Oct 25.

Department of Urology, Haukeland University Hospital.

Purpose: To examine the variation in venous thromboembolism prophylactic treatment (VTEP) among renal cancer patients undergoing surgery.

Materials And Methods: An Internet-based questionnaire on renal tumor management before and after surgery was mailed to all Nordic departments of urology. The questions focused on the use of VTEP and were subdivided into different surgical modalities.

Results: Questionnaires were mailed to 91 institutions (response rate 53%). None of the centers used VTEP before surgery, unless the patient had a vena caval tumor thrombus. Overall, the VTEP utilized during hospitalization for patients undergoing renal surgery included early mobilization (45%), compression stockings (52%) and low-molecular-weight heparin (89%). In patients undergoing open radical Nx, 80% of institutions used VTEP during their hospitalization (23% compression stockings and 94% low-molecular-weight heparin). After leaving the hospital, the proportion and type of VTEP received varied considerably across institutions. The most common interval, used in 60% of the institutions, was for a period of 4 weeks. The restriction to the Nordic countries was a limitation and, therefore, may not reflect the practice patterns elsewhere. It is a survey study and, therefore, cannot measure the behaviors of those institutions that did not participate.

Conclusion: We found variation in the type and duration of VTEP use for each type of local intervention for renal cancer. These widely disparate variations in care strongly argue for the establishment of national and international guidelines regarding VTEP in renal surgery.
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http://dx.doi.org/10.2147/RRU.S177774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6209070PMC
October 2018

Perioperative Oral Nutrition Supplementation Reduces Prevalence of Sarcopenia following Radical Cystectomy: Results of a Prospective Randomized Controlled Trial.

J Urol 2019 03;201(3):470-477

Tennessee Valley Health Care System, Nashville, Tennessee.

Purpose: We designed a prospective randomized, controlled pilot trial to investigate the effects of an enriched oral nutrition supplement on body composition and clinical outcomes following radical cystectomy.

Materials And Methods: A total of 61 patients were randomized to an oral nutrition supplement or a multivitamin multimineral supplement twice daily during an 8-week perioperative period. Body composition was determined by analyzing abdominal computerized tomography images at the L3 vertebra. Sarcopenia was defined as a skeletal muscle index of less than 55 cm/m in males and less than 39 cm/m in females. The primary outcome was the difference in 30-day hospital free days. Secondary outcomes included hospital length of stay, complications, readmissions and mortality.

Results: The oral nutrition supplement group lost less weight (-5 vs -6.5 kg, p = 0.04) compared to the multivitamin multimineral supplement group. The proportion of patients with sarcopenia did not change in the oral nutrition supplement group but increased 20% in the multivitamin multimineral supplement group (p = 0.01). Mean length of stay and 30-day hospital free days were similar in the groups. The oral nutrition supplement group had a lower rate of overall and major (Clavien grade 3 or greater) complications (48% vs 67% and 19% vs 25%, respectively) and a lower readmission rate (7% vs 17%) but the differences did not reach statistical significance.

Conclusions: Patients who undergo radical cystectomy after consuming an oral nutrition supplement perioperatively have a reduced prevalence of sarcopenia and may also experience fewer and less severe complications and readmissions. A larger blinded, randomized, controlled trial is necessary to determine whether oral nutrition supplement interventions can improve outcomes following radical cystectomy.
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http://dx.doi.org/10.1016/j.juro.2018.10.010DOI Listing
March 2019

Epidemiology, prevention, screening, diagnosis, and evaluation: update of the ICUD-SIU joint consultation on bladder cancer.

World J Urol 2019 Jan 13;37(1):3-13. Epub 2018 Aug 13.

Department of Urology, Unit 1373, The University of Texas MD Anderson Cancer Center, 1155 Pressler, Houston, TX, 77030, USA.

Purpose: To update current recommendations on prevention, screening, diagnosis, and evaluation of bladder cancer (BC) based on a thorough assessment of the most recent literature on these topics.

Methods: A non-systematic review was performed, including articles until June 2017. A variety of original articles, reviews, and editorials were selected according to their epidemiologic, demographic, and clinical relevance. Assessment of the level of evidence and grade of recommendations was performed according to the International Consultation on Urological Diseases grading system.

Results: BC is the ninth most common cancer worldwide with 430,000 new cases in 2012. Currently, approximately 165,000 people die from the disease annually. Absolute incidence and prevalence of BC are expected to rise significantly during the next decades because of population ageing. Tobacco smoking is still the main risk factor, accounting for about 50% of cases. Smoking cessation is, therefore, the most relevant recommendation in terms of prevention, as the risk of developing BC drops almost 40% within 5 years of cessation. BC screening is not recommended for the general population. BC diagnosis remains mainly based on cystoscopy, but development of new endoscopic and imaging technologies may rapidly change the diagnosis algorithm. The same applies for local, regional, and distant staging modalities.

Conclusions: A thorough understanding of epidemiology, risk factors, early detection strategies, diagnosis, and evaluation is essential for correct, evidence-based management of BC patients. Recent developments in endoscopic techniques and imaging raise the hope for providing better risk-adopted approaches and thereby improving clinical outcomes.
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http://dx.doi.org/10.1007/s00345-018-2436-yDOI Listing
January 2019

MAGI2 is an independent predictor of biochemical recurrence in prostate cancer.

Prostate 2018 06 14;78(8):616-622. Epub 2018 Mar 14.

Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee.

Background: Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 2 (MAGI2) promotes the activity of phosphatase and tensin homolog (PTEN). Recent studies suggest that dysregulation of this signaling pathway has a role in prostate carcinogenesis. Our study aims to determine the prognostic significance of MAGI2 expression in prostate cancer.

Methods: Tissue microarrays from 51 radical prostatectomy cases including benign prostatic tissue, high grade prostatic intraepithelial neoplasia (HGPIN), and adenocarcinoma were constructed. Immunohistochemistry with double staining for MAGI2 and p63 was performed and analyzed by image analysis as percent of analyzed area (%AREA). Multivariable logistic regression was used to correlate MAGI2 expression with clinical outcomes. Generalized Estimating Equations (GEE) with linear and logistic regression was used to correlate MAGI2 with intrapatient histology.

Results: MAGI2 %AREA was inversely associated with progression from HGPIN to adenocarcinoma of low to high Gleason score (OR, 0.980; slope, -0.02; P = 0.005) and HGPIN to cancer of any Gleason score (OR, 0.969; P = 0.007). After adjusting for grade, stage, and margin status, MAGI2 %AREA was a significant independent predictor of biochemical recurrence (BCR) (OR, 0.936; 95%CI, 0.880-0.996; P = 0.037; bootstrap P = 0.017). The addition of MAGI2 %AREA to these standard clinical parameters improved accuracy of predicting BCR by 2.9% (91.0% vs 88.1%).

Conclusions: These results reveal that MAGI2 expression is reduced during prostate cancer progression and that retention of MAGI2 signal reduces odds of BCR. The study results further suggest a possible role of MAGI2 in prostate neoplasia. Decreased MAGI2 expression may help predict prostate cancer aggressiveness and provide new insight for treatment decisions and post-operative surveillance intervals.
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http://dx.doi.org/10.1002/pros.23506DOI Listing
June 2018

Editorial Comment.

Authors:
Peter E Clark

J Urol 2018 05 13;199(5):1317-1318. Epub 2018 Feb 13.

Department of Urology, Carolinas HealthCare System Levine Cancer Institute, Charlotte, North Carolina.

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http://dx.doi.org/10.1016/j.juro.2017.11.141DOI Listing
May 2018
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