Robotic or open superficial inguinal lymph node dissection as staging procedures for clinically node negative high risk penile cancer.

OBJECTIVE: To evaluate perioperative and oncologic outcomes of a cohort of clinically node negative high-risk penile cancer patients undergoing robotic assisted inguinal lymph node dissection (RAIL) compared to patients undergoing open superficial inguinal lymph node dissection (OSILND). PATIENTS AND METHODS: We retrospectively reviewed the clinical characteristics and outcomes of clinically node negative high-risk penile cancer patients undergoing RAIL at MDACC from 2013-2019. We sought to compare this to a contemporary open cohort of clinically node negative patients treated from 1999 to 2019 at MDACC and Moffit Cancer Center (MCC) with an OSILND. Descriptive statistics were used to characterize the study cohorts. Comparison analysis between operative variables was performed using Fisher's exact test and Wilcoxon's rank-sum test. The Kaplan-Meier method was used to estimate survival endpoints. RESULTS: There were 24 patients in the RAIL cohort, and 35 in the OSILND cohort. Among the surgical variables, operative time (348.5 minutes vs. 239.0 minutes, P < 0.01) and the duration of operative drain (37 vs. 22 days P = 0.017) were both significantly longer in the RAIL cohort. Complication incidences were similar for both cohorts (34.3% for OSILND vs. 33.3% for RAIL), with wound complications making up 33% of all complications for RAIL and 31% of complications for OSILND. No inguinal recurrences were noted in either cohort. The median follow-up was 40 months for RAIL and 33 months for OSILND. CONCLUSIONS: We observed similar complication rates and surgical variable outcomes in our analysis apart from operative time and operative drain duration. Oncological outcomes were similar between the two cohorts. RAIL was a reliable staging and potentially therapeutic procedure among clinically node negative patients with penile squamous cell carcinoma with comparable outcomes to an OSILND cohort.

Long-Term Oncological Outcomes in Patients Diagnosed With Nonmetastatic Plasmacytoid Variant of Bladder Cancer: A 20-Year University of Texas MD Anderson Cancer Center Experience.

PURPOSE: The treated natural history of nonmetastatic plasmacytoid variant of bladder cancer (PV-BCa) is poorly understood owing to its rarity. We sought to examine the disease recurrence and metastasis patterns in this select group of patients in order to identify opportunities for intervention. MATERIALS AND METHODS: We conducted a natural language processing algorithm-augmented retrospective chart review of 56 consecutive patients who were treated with curative intent for nonmetastatic PV-BCa at our institution between 1998 and 2018. Kaplan-Meier and multivariable Cox regression methods were used for survival analyses. RESULTS: The stage at presentation was: ≤ cT2N0 in 22 (39.3%), cT3N0 in 15 (26.8%), cT4N0 in 13 (23.2%), and ≥ cN1 in 6 patients (10.7%). Forty-nine patients (87.5%) received chemotherapy, and 42 (75%) were able to undergo the planned surgery. Notably, only 4 patients (7.2%) had pT0 stage, while 22 (52.4%) had pN+ disease at the time of surgery. At 36-month follow-up, 28.4% of patients (95% CI: 22.1%-34.5%) were alive and 22.2% (95% CI: 16.1%-28.5%) were free of metastatic disease. The benefit of surgical extirpation was stage specific: successful completion of surgery was associated with improved metastasis-free survival (at 36 months 32.4% vs 0%, log-rank P < .001) in patients with localized or locally advanced disease (≤cT2N0/cT3N0); however, in patients with regionally advanced disease (cT4N0/≥cN1), consolidative surgery following chemotherapy was not associated with improved metastasis-free survival (12.5% vs 10% at 36 months, log-rank P = .49). The median time to metastasis from primary treatment end was 6.5 months (IQR: 2.9-14.7). The predominant site of recurrence/metastasis was the peritoneum (76.1%), either in isolation or along with extraperitoneal lesions. Salvage immunotherapy in these patients significantly reduced the risk of death (HR = 0.11, P = .001). CONCLUSIONS: PV-BCa is a disease with high lethality. Despite multimodal treatment, a vast majority of patients develop atypical intraperitoneal metastasis soon after therapy and rapidly succumb to it. Clinical trials evaluating utility of hyperthermic intraperitoneal chemotherapy and/or immunotherapy may be warranted in this high-risk population.

15-year biochemical failure, metastasis, salvage therapy, and cancer-specific and overall survival rates in men treated with robotic radical prostatectomy for PSA-screen detected prostate cancer.

BACKGROUND: An informed decision regarding a treatment option requires data on its long-term efficacy and side-effect profile. While the side-effects of robotic radical prostatectomy have been well-quantified, the data on its long-term efficacy are lacking. We here provide 15-year oncological outcomes of clinically-localized prostate cancer (CLPCa) patients treated with robot-assisted laparoscopic prostatectomy (RALP). METHODS: We treated 1,807 men with CLPCa with RALP between 2001 and 2005 and prospectively collected follow-up data through 2020. We examined the rates of biochemical failure (BCF), metastatic progression, secondary therapy use, PCa-specific mortality (PCSM), and overall survival (OS) using Kaplan-Meier and competing-risk cumulative incidence methods as appropriate. RESULTS: The median follow-up was 14.1 years. Six hundred eight and 312 men had D'Amico intermediate- and high-risk disease, respectively. Overall, the 15-year rates of BCF, metastasis, secondary therapy use, PCSM, and OS were 28.1%, 4.0%, 16.3%, 2.5%, and 82.1%, respectively. The rates of oncologic failure increased with increasing D'Amico (preoperative) and Diaz (postoperative) risk scores - BCF, metastasis, and PCSM rates in D'Amico low-, intermediate-, and high-risk groups at 15-years were 15.2%, 38.3%, and 44.1% [BCF], 1.1%, 4.1%, and 13.0% [metastasis], and 0.5%, 3.4%, and 6.6% [PCSM], respectively, and in Diaz risk groups 1, 2, 3, 4, and 5 were 5.5%, 20.6%, 41.8%, 66.9%, and 89.2% [BCF], 0%, 0.5%, 3.2%, 20.5%, and 60.0% [metastasis], and 0%, 0.8%, 0.6%, 13.5%, and 37.5% [PCSM], respectively. The OS rates in D'Amico low-to-high and Diaz 1-to-5 risk groups at 15-years were 85.9%, 78.6%, and 75.2%, and 89.4%, 83.2%, 80.6%, 67.2%, and 23.4%, respectively. CONCLUSIONS: Men diagnosed with clinically-localized prostate cancer in the contemporaneous PSA-screening era and treated with RALP achieve durable long-term oncological control. The data reported here (in a risk-stratified manner) represent the longest follow-up after robotic radical prostatectomy, and as such, should be of value when counseling patients regarding expected oncologic outcomes from RALP.

The Acute Complications After Surgery for Penile Carcinoma and Strategies for Their Management: A Systematic Review of the Literature.

OBJECTIVES: To investigate the contemporary rates of 30-day complications after surgery for penile cancer and to discuss the currently used preventative and therapeutic practices aimed at mitigation of these postoperative adverse events. DATA SOURCES: A systematic review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was performed, and studies reporting on the contemporary rates, nature, or management of acute complications following primary penile surgery or inguinal lymph node dissection for penile cancer were abstracted. Medline (PubMed) and EMBASE libraries were used to retrieve the articles published between January 1984 and December 2021 (n = 170 articles). Ultimately, 38 articles were included. The primary outcome of interest was 30-day (acute) postoperative complications, stratified by those associated with treatment of the primary penile lesion and those with inguinal lymph node dissection. Risk of bias assessment was undertaken. Special attention was paid to studies reporting management strategies for these complications. CONCLUSION: This comprehensive review revealed that the quality of existing studies reporting on complications is poor and the risk of bias is high. Within these studies, the rates of acute complications following primary penile surgery and inguinal lymph node dissection ranged between 0% and 29.4% and 6% and 90%, respectively. More than 50% of these complications were wound related. Over the past two decades, several studies have reported on improved surgical techniques and protocolized postsurgical care pathways. Although the newer techniques have been associated with improved outcomes, the absolute rates of complications have remained high even in the most contemporary series. Therefore, there is an urgent need for health care providers and stakeholders to reach consensus regarding preoperative workup and medical optimization goals, stage appropriate therapies, and postoperative care pathways, as has been done for other malignancies associated with high morbidity. IMPLICATIONS FOR NURSING PRACTICE: Penile cancer is a disease of the elderly, and surgical management of the primary lesion or the groins is associated with a high rate of complications. Most complications are wound related. Meticulous surgical technique and careful postoperative monitoring with early intervention are keys to mitigating surgery-related morbidity. However, equally important is dissemination and adoption of these principles by all health care workers universally.

Platelets stimulate programmed death-ligand 1 expression by cancer cells: Inhibition by anti-platelet drugs.

BACKGROUND: Platelets facilitate hematogenous metastasis in part by promoting cancer cell immunoevasion, although our understanding of platelet function in modulating the adaptive immune system in cancer is limited. A major negative regulator of the adaptive response is the immune checkpoint protein Programmed Death Ligand 1 (PD-L1). OBJECTIVES: As platelets secrete factors that may increase PD-L1 expression, we investigated whether they up-regulate cancer cell PD-L1, thus promoting immunoevasion, and whether common anti-platelet drugs inhibit this process. METHODS: Platelets were isolated from human volunteers. A549 lung, PD-L1 null A549, and 786-O renal cancer cells were incubated with and without platelets, and cancer cell PD-L1 expression was measured by qPCR and flow cytometry. Additionally, platelet-cancer cell incubations were performed in the presence of common anti-platelet drugs, and with growth factor neutralizing antibodies. Following incubation with platelets, A549 were co-cultured with T-cells and interleukin-2 (IL-2) levels were measured by flow cytometry as a marker of T-cell activation. RESULTS: Platelets increased PD-L1 mRNA and surface protein expression by A549 and 786-0 cells. Combined neutralization of VEGF and PDGF prevented the platelet-induced up-regulation of PD-L1 by A549, as did the anti-platelet drug eptifibatide. A549 incubated with platelets demonstrated a reduced ability to activate human T-cells, an effect reversed by eptifibatide. CONCLUSIONS: As platelets promote immunoevasion of the adaptive immune response by increasing cancer cell PD-L1 expression and as anti-platelet drugs prevent this immunoevasive response, the investigation of anti-platelet drugs as adjuvant therapy to immune checkpoint inhibitors may be warranted in the treatment of cancer.

Preferential interaction of platelets with prostate cancer cells with stem cell markers.

BACKGROUND: Prostate cancer (PCa) may be initiated by CD133+/CD44+ expressing stem cell-like cells (PCSC), which are also thought to drive metastasis. Platelets also contribute to metastasis via tumor cell-induced platelet aggregation (TCIPA), which in part enhances cancer cell invasion. Moreover, activated platelets secrete stromal derived growth factor-1α (SDF-1α) that can mobilize CSCs via the CXCR4 receptor. However, the potential reciprocal interactions between CSCs and platelets have not been investigated. OBJECTIVE: To characterize the mechanisms behind PCSC-platelet interaction. METHODS: Fluorescence Activated Cell Sorting was utilized to separate DU145 and PC3 PCa cells into CD133+/CD44+, CD133+/CD44-, CD44+/CD133-, and CD133-/CD44- subpopulations and to measure their CXCR4 surface expression. PCa subpopulation TCIPA experiments were performed using aggregometry and immunoblot was used to measure prothrombin. Platelet SDF-1α secretion was measured by ELISA. Modified-Boyden chamber assays were used to assess the role of SDF-1α:CXCR4 pathway in platelet-PCSC interactions. RESULTS: DU145 and PC3 expressing both CD133 and CD44 stem cell markers accounted for only small fractions of total cells (DU145: CD133+/CD44+ 3.44 ± 1.45% vs. CD133+/CD44- 1.56 ± 0.45% vs. CD44+/CD133- 68.19 ± 6.25% vs. CD133-/CD44- 20.36 ± 4.51%). However, CD133+ subpopulations induced the greatest amount of aggregation compared to CD44+/CD133- and double-negative DU145, and this aggregation potency of CD133+ PCa cells corresponded with high levels of prothrombin expression. Additionally, CD133+ subpopulations expressed significantly higher level of CXCR4 compared to CD133-/CD44- and CD44+/CD133-. Disruption of SDF-1α:CXCR4 pathway reduced platelet-induced PCSC invasion. CONCLUSIONS: CD133+/CD44+ and CD133+/CD44- PCSCs have highest platelet aggregation potency, which could be attributed to their increased prothrombin expression. Reciprocally, platelet-derived SDF-1α stimulates PCSC invasion.

Active surveillance for low-risk prostate cancer - in pursuit of a standardized protocol.

INTRODUCTION: Active surveillance (AS) is a management option recommended by most guidelines for low risk clinically-localized prostate cancer (LR-CLPC). Data shows that AS is being increasingly adopted into clinical practice worldwide. Our aim was to review the up-to date guidelines and observational studies in regards to AS in LR-CLRPC to gain insight into principles of contemporary clinical practice. MATERIAL AND METHODS: Several guidelines on the management of low-risk prostate cancer were reviewed for evidence-based recommendations regarding the protocol of AS. We reviewed the available literature for most recent studies on AS in LR-CLPC. RESULTS: No uniform protocol of AS in LR-CLPC has been recommended up to date and available guidelines significantly differ in terms of protocol schedules and the role of particular tools in monitoring for disease progression. Nevertheless, recent studies on AS in LR-CLPC, in which various protocols were adopted, have demonstrated promising outcomes in regards to cancer-specific survival (99-100% at 5 years, 98.1-99.9% at 10 years, and 94.3-96% at 15 years), with high rates of men remaining within the protocols (23-39% at 10 years). CONCLUSIONS: This article is a call for focusing further research on development and recommending a precise and standardized, evidence-based protocol for AS in LR-CLPC.

The role of the androgen receptor in prostate cancer-induced platelet aggregation and platelet-induced invasion.

BACKGROUND: Metastatic prostate cancer progresses from a hormone sensitive androgen receptor expressing phenotype to a hormone insensitive androgen receptor-independent subtype with low overall survival. Human platelets contribute to metastasis via tumor cell-induced platelet aggregation, which in part enhances cancer cell invasion. Given the more aggressive nature of hormone insensitive prostate cancer, we hypothesized that androgen receptor-negative prostate cancer cells exhibit higher platelet aggregation potency and invasive response compared to cells with androgen receptor. OBJECTIVE: To characterize the role of androgen receptors in prostate cancer-induced platelet aggregation and platelet-induced invasion. METHODS: Tumor cell-induced platelet aggregation experiments were performed with platelets from healthy human donors and benign prostate (RWPE-1) and prostate cancer cell lines positive (LNCaP) and negative for androgen receptor (DU145 and PC3). Immunoblot measured prostate cancer prothrombin. Modified Boyden chamber invasion assays and zymography were performed to assess the effects of platelets on prostate cancer cell invasion and matrix metalloproteinase (MMP) expression, respectively. RESULTS: Androgen receptor-positive prostate cancer cell lines failed to induce platelet aggregation. However, androgen receptor-inhibited and -negative cell lines all induced platelet aggregation, which was abolished by dabigatran. Androgen receptor-inhibited and -negative cell lines demonstrated greater expression of prothrombin than androgen receptor-positive cells. Platelets enhanced invasion and MMP-2 and -9 expression by androgen receptor-inhibited and negative prostate cancer cells, but not that of the androgen receptor-positive cells. CONCLUSIONS: Androgen receptor loss within prostate cancer results in increased thrombogenicity due to upregulation of prothrombin expression. Reciprocally, platelets enhance invasion of androgen receptor-negative prostate cancer cells via increased MMP expression.

Are urologic surgeons performing robot-assisted radical prostatectomy at the University of Alberta meeting surgical quality performance benchmarks? The PROCURE-02 quality assurance study.

INTRODUCTION: Robot-assisted radical prostatectomy (RARP) is a standard of care primary treatment for men with clinically localized prostate cancer (CLPC). The 2010 Canadian Urological Association (CUA) consensus guideline examining surgical quality performance for radical prostatectomy suggested benchmarks for surgical performance. To date, no study has examined whether Canadian surgeons are achieving these benchmarks. We determined the proportion of University of Alberta (UA) urologic surgeons achieving the CUA surgical quality performance outcome (SQPO) benchmarks. METHODS: A retrospective quality assurance analysis of prospectively collected data from the PROstate Cancer Urosurgery Repository of Edmonton (PROCURE) was performed. Men who underwent RARP for CLPC between September 2007 and May 2018 by one of seven surgeons were analyzed. SQPO were an unadjusted pT2-R1 resection rate <25%, blood transfusion rate <10%, rectal injury rate <1%, and 90-day mortality rate <1%. Descriptive statistics were used to determine the proportion of surgeons achieving the benchmarks. RESULTS: Data were evaluable for 2821 men. Seven of seven (100%) surgeons achieved a blood transfusion rate <10%, rectal injury rate <1%, and 90-day mortality rate <1%. However, only six of seven surgeons achieved an unadjusted pT2-R1 resection rate <25%; one surgeon had an unadjusted pT2-R1 resection rate of 27.9%. Limitations include the lack of centralized pathology review for surgical margin status by a dedicated genitourinary pathologist. CONCLUSIONS: UA surgeons are achieving the CUA SQPO benchmarks for blood transfusion, rectal injury, and perioperative mortality. However, not all UA urologists are achieving a pT2-R1 resection rate <25%. Surgical quality performance initiatives designed to improve cancer control may be warranted.

Perioperative chemotherapy for muscle invasive bladder cancer.

PURPOSE OF REVIEW: Radical cystectomy with or without systemic chemotherapy is considered a standard of care for patients with muscle invasive bladder cancer (MIBC). The purpose of this review is to provide an update on current and recent literature published within the last 12 months reviewing the evidence for use of perioperative chemotherapy for patients with MIBC. RECENT FINDINGS: In the neoadjuvant chemotherapy (NAC) setting, the evidence demonstrates clinical efficacy and lower rate of toxicity with the use of high-dose methotrexate, vinblastine, doxorubicin, and cyclophosphamide (MVAC) compared with standard MVAC. Higher quality evidence for the use of gemcitabine with cisplatin is not yet available. Meta-analysis of cisplatin-based regimens in the adjuvant setting demonstrates significant benefit in overall survival and disease-free survival specifically in patients with lymph-node-positive disease. SUMMARY: The available evidence suggests that along with radical cystectomy, cisplatin-based perioperative chemotherapy should be the standard of care in patients with MIBC with a higher quality and quantity of literature in support of the NAC approach. Adoption of perioperative chemotherapy for MIBC is on the rise in North America, which is reassuring. Novel therapeutic approaches for cisplatin-ineligible patients are currently being investigated.

Assessment of antibiotic prophylaxis prescribing patterns for TURP: A need for Canadian guidelines?

BACKGROUND: While antibiotic prophylaxis is recommended to all patients undergoing transurethral resection of prostate (TURP), little data exist regarding prescribing patterns of urologists prior to this procedure. Here, we sought to determine real-world antibiotic prophylaxis prescribing patterns at a high volume Canadian institution and determine compliance rates to recommendations put forth by the American Urological Association's (AUA) Best Practice Statement (BPS) on antimicrobial prophylaxis. METHODS: A retrospective chart review of 488 patients undergoing TURP was conducted. Electronic medical records were reviewed to determine antibiotics prescribed 3 hours preoperatively and 24 hours postoperatively. For patients without a catheter, compliance was defined as those receiving an antibiotic prior to TURP. In patients with an indwelling catheter, compliance was defined as those receiving antibiotics from two different classes prior to surgery. RESULTS: Overall, a total of 30 antibiotic regimens were utilized. The most common single antibiotic regimens prescribed were ciprofloxacin (32%), cefazolin (25%) and gentamicin (3%). In those patients with indwelling Foley catheters prior to TURP, a significant increase in gentamicin, as well as combination antibiotic regimens, was noted. The compliance rate with the AUA BPS in patients without a preoperative catheter was 81%, while the compliance rate for patients with an indwelling catheter prior to TURP was 37%. INTERPRETATION: Collectively, our results demonstrate that prescribing patterns vary significantly prior to TURP, with compliance to AUA BPS being lower than anticipated. Overall, these results support educational efforts in this area, and the development of Canadian recommendations to improve uptake by practicing urologists.

Does routine ultrasound change management in the follow-up of patients with vesicoureteral reflux?

INTRODUCTION: Children with vesicoureteral reflux (VUR) usually need a renal ultrasound (RUS). There is little data on the role of follow-up RUS in VUR. We evaluated the impact of follow-up RUS on the change in clinical management in patients with VUR. METHODS: We prospectively analyzed children with a previous diagnosis of VUR seen in the outpatient clinic with a routine follow-up RUS within 4 months. Variables collected included: demographic data, VUR history, dysfunctional voiding symptoms and concurrent ultrasound findings. Change in management was defined as addition of new medication, nurse counselling, surgery or further investigations. RESULTS: The study included 114 consecutive patients. The mean patient age was 4.5 years old, mean age of VUR diagnosis was 1.7 years, with average follow-up of 2.8 years. A change in management with stable RUS occurred in 14 patients, in which the change included ordering a DMSA in 9, nurse counselling for dysfunctional voiding in 3, and booking surgery in 2 patients. Change on RUS was seen in 4 patients. Multivariable analysis showed that history of urinary tract infection (UTI) since the last follow-up visit was more significant than RUS findings. CONCLUSIONS: The RUS findings in most patients followed for VUR remain stable or with minimal changes. The variable showing a significant effect on change in management in our study was history of UTI since the last follow-up visit rather than RUS findings. The value of follow-up RUS for children with VUR may need to be revisited.

Epithelial cell extrusion leads to breaches in the intestinal epithelium.

BACKGROUND: Two distinct forms of intestinal epithelial cell (IEC) extrusion are described: 1 with preserved epithelial integrity and 1 that introduced breaches in the epithelial lining. In this study, we sought to determine the mechanism underlying the IEC extrusion that alters the permeability of the gut epithelium. METHODS: IEC extrusions in polarized T84 monolayer were induced with nigericin. Epithelial permeability was assessed with transepithelial electrical resistance and movements of latex microspheres and green fluorescent protein-transfected Escherichia coli across the monolayer. In vivo IEC extrusion was modulated in wild-type and a colitic (interleukin-10 knock-out) mouse model with caspase-1 activation and inhibition. Luminal aspirates and mucosal biopsies from control patients and patients with inflammatory bowel disease were analyzed for caspase-1 and caspase-3&7 activation. RESULTS: Caspase-1-induced IEC extrusion in T84 monolayers resulted in dose-dependent and time-dependent barrier dysfunction, reversible with caspase-1 inhibition. Moreover, the movements of microspheres and microbes across the treated epithelial monolayers were observed. Increased caspase-1-mediated IEC extrusion in interleukin-10 knock-out mice corresponded to enhanced permeation of dextran, microspheres, and translocation of E. coli compared with wild type. Caspase-1 inhibition in interleukin-10 knock-out mice resulted in a time-dependent reduction in cell extrusion and normalization of permeability to microspheres. Increased IEC extrusion in wild-type mice was induced with caspase-1 activation. In human luminal aspirates, the ratio of positively stained caspase-1 to caspase-3&7 cells were 1:1 and 2:1 in control patients and patients with inflammatory bowel disease, respectively; these observations were confirmed by cytochemical analysis of mucosal biopsies. CONCLUSIONS: IEC extrusion mediated by caspase-1 activation contributes to altered intestinal permeability in vitro and in vivo.