A Comprehensive Review on Upper Tract Urothelial Carcinoma: An Update in 2023.

It is our pleasure to serve as the guest editors for the Cancers journal for this Special Issue, titled "Comprehensive Review on Upper Tract Urothelial Carcinoma: An Update in 2023" [...].

Prophylactic Use of Biologic Mesh in Ileal Conduit (PUBMIC): A Randomized Clinical Trial.

PURPOSE: We assessed the effect of prophylactic biologic mesh on parastomal hernia (PSH) development in patients undergoing cystectomy and ileal conduit (IC). MATERIALS AND METHODS: This phase 3, randomized, controlled trial (NCT02439060) included 146 patients who underwent cystectomy and IC at the University of Southern California between 2015 and 2021. Follow-ups were physical exam and CT every 4 to 6 months up to 2 years. Patients were randomized 1:1 to receive FlexHD prophylactic biological mesh using sublay intraperitoneal technique vs standard IC. The primary end point was time to radiological PSH, and secondary outcomes included clinical PSH with/without surgical intervention and mesh-related complications. RESULTS: The 2 arms were similar in terms of baseline clinical features. All surgeries and mesh placements were performed without any intraoperative complications. Median operative time was 31 minutes longer in patients who received mesh, yet with no statistically significant difference (363 vs 332 minutes, P = .16). With a median follow-up of 24 months, radiological and clinical PSHs were detected in 37 (18 mesh recipients vs 19 controls) and 16 (8 subjects in both arms) patients, with a median time to radiological and clinical PSH of 8.3 and 15.5 months, respectively. No definite mesh-related adverse events were reported. Five patients (3 in the mesh and 2 in the control arm) required surgical PSH repair. Radiological PSH-free survival rates in the mesh and control groups were 74% vs 75% at 1 year and 69% vs 62% at 2 years. CONCLUSIONS: Implementation of biologic mesh at the time of IC construction is safe without significant protective effects within 2 years following surgery.

Racial Differences in the Detection Rate of Bladder Cancer Using Blue Light Cystoscopy: Insights from a Multicenter Registry.

The use of blue light cystoscopy (BLC) has been shown to improve bladder tumor detection. However, data demonstrating the efficacy of BLC across different races are limited. Herein, we aim to evaluate heterogeneity in the characteristics of BLC for the detection of malignant lesions among various races. Clinicopathologic information was collected from patients enrolled in the multi-institutional Cysview® registry (2014-2021) who underwent transurethral resection or biopsy of bladder tumors. Outcome variables included sensitivity and negative and positive predictive values of BLC and white light cystoscopy (WLC) for the detection of malignant lesions among various races. Overall, 2379 separate lesions/tumors were identified from 1292 patients, of whom 1095 (85%) were Caucasian, 96 (7%) were African American, 51 (4%) were Asian, and 50 (4%) were Hispanic. The sensitivity of BLC was higher than that of WLC in the total cohort, as well as in the Caucasian and Asian subgroups. The addition of BLC to WLC increased the detection rate by 10% for any malignant lesion in the total cohort, with the greatest increase in Asian patients (18%). Additionally, the positive predictive value of BLC was highest in Asian patients (94%), while Hispanic patients had the highest negative predictive value (86%). Our study showed that regardless of race, BLC increases the detection of bladder cancer when combined with WLC.

Surveillance of non-muscle-invasive bladder cancer with blue-light cystoscopy: a meta-analysis.

OBJECTIVE: To compare the value of flexible blue-light cystoscopy (BLC) vs flexible white-light cystoscopy (WLC) in the surveillance setting of non-muscle-invasive bladder cancer (NMIBC). METHODS: All major databases were searched for articles published before May 2023 according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The primary outcome was the accuracy of flexible BLC vs WLC in detecting bladder cancer recurrence among suspicious bladder lesions. RESULTS: A total of 10 articles, comprising 1634 patients, were deemed eligible for the quantitative synthesis. In the meta-analysis focusing on the detection of disease recurrence, there was no difference between flexible BLC and WLC (odds ratio [OR] 1.08, 95% confidence interval [CI] 0.82-1.41)]; the risk difference (RD) showed 1% of flexible BLC, corresponding to a number needed to treat (NNT) of 100. In the subgroup meta-analysis of detection of carcinoma in situ (CIS) only, there was again no significant difference between flexible BLC and WLC (OR 1.19, 95% CI 0.82-1.69), BLC was associated with a RD of 2% (NNT = 50). The positive predictive values for flexible BLC and WLC in detecting all types of recurrence were 72% and 66%, respectively, and for CIS they were 39% and 29%, respectively. CONCLUSION: Surveillance of NMIBC with flexible BLC could detect more suspicious lesions and consequently more tumour recurrences compared to flexible WLC, with a increase in the rate of false positives leading to overtreatment. A total of 100 and 50 flexible BLC procedures would need to be performed to find on additional tumor and CIS recurences, respectively. A risk-stratified strategy for patient selection could be considered when using flexible BLC for the surveillance of NMIBC patients.

The effect of enhanced recovery after surgery on oncologic outcome following radical cystectomy for urothelial bladder carcinoma.

INTRODUCTION: Limited data are available regarding the effect of enhanced recovery after surgery (ERAS) protocols on the long-term outcomes of radical cystectomy (RC) in bladder cancer patients. The aim of this study is to evaluate the oncological outcomes in patients who underwent RC with ERAS protocol. METHODS: We reviewed the records of patients who underwent RC for primary urothelial bladder carcinoma with curative intent from January 2003 to August 2022. The primary and secondary outcomes were recurrence-free (RFS) and overall survival (OS). Multivariable Cox regression analysis was performed to evaluate the effect of ERAS on oncological outcomes. RESULTS: A total of 967 ERAS patients and 1144 non-ERAS patients were included in this study. The RFS rates at 1, 3, and 5 years after RC were 81%, 71.5%, and 69% in the ERAS cohort, respectively. This rate in the non-ERAS group was 81%, 71%, and 67% at 1, 3, and 5 years after RC, respectively (P = 0.50). However, ERAS patients had significantly better OS with 86%, 73%, and 67% survival rates at 1, 3, and 5 years compared to 84%, 68%, and 59.5% survival rates in the non-ERAS group, respectively (P = 0.002). In multivariable analysis adjusting for other relevant factors, ERAS was no longer independently associated with recurrence-free (HR = 0.96, 95% CI 0.76-1.22, P = 0.75) or overall survival (HR = 0.84, 95% CI 0.66-1.09, P = 0.28) following RC. CONCLUSION: ERAS protocols are associated with a shorter hospital stay, yet with no impact on long-term oncologic outcomes in patients undergoing RC for bladder cancer.

Reply to Jue et al. Overcoming Understaging and Undergrading in Upper Tract Urothelial Carcinoma. Comment on "Ghoreifi et al. Modern Kidney-Sparing Management of Upper Tract Urothelial Carcinoma. Cancers 2023, 15, 4495".

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Blood-based liquid biopsy: A promising noninvasive test in diagnosis, surveillance, and prognosis of patients with upper tract urothelial carcinoma.

OBJECTIVES: To assess the efficacy of blood-based liquid biopsy in the diagnosis, surveillance, and prognosis of upper tract urothelial carcinoma (UTUC). METHODS AND MATERIALS: In this prospective study, peripheral blood samples were collected from patients with primary UTUC before surgery with curative intent and follow-up visits at University of Southern California between May 2021 and September 2022. The samples were analyzed using the third-generation comprehensive high-definition single-cell assay (HDSCA3.0) to detect rare events, including circulating tumor cells (CTCs) and oncosomes, based on the immunofluorescence signals of DAPI (D), cytokeratin (CK), CD45/CD31 (CD), and vimentin (V). The findings of pre-surgery liquid biopsies were compared with those of blood samples from normal donors (NDs) and matched follow-up liquid biopsies. The association between liquid biopsy findings and clinical data, including recurrence-free survival (RFS), was also assessed. RESULTS: Twenty-eight patients with UTUC were included, of whom 21 had follow-up samples. Significant differences in specific rare analytes were detected in the preoperative samples compared to the NDs. In the post- vs. presurgery matched analysis, a significant decrease was detected in total-, CK-, and CK|V oncosomes, as well as in D-, D|V-, and D|V|CD cells. With a median follow-up of 11 months, 8 patients had disease recurrence. Survival analysis demonstrated that patients with >1.95 preoperative CK|V oncosomes (p = 0.020) and those with >4.18 D|CK|V cells (p = 0.050) had worse RFS compared to other patients. CONCLUSIONS: This study demonstrated promising initial evidence for the biomarker role of CTCs and oncosomes in the diagnosis and surveillance of patients with UTUC.

Oncologic Outcomes in Patients with Residual Upper Tract Urothelial Carcinoma Following Neoadjuvant Chemotherapy.

BACKGROUND AND OBJECTIVE: Growing evidence supports the use of neoadjuvant chemotherapy (NAC) for upper tract urothelial carcinoma (UTUC). However, the implications of residual UTUC at radical nephroureterectomy (RNU) after NAC are not well characterized. Our objective was to compare oncologic outcomes for pathologic risk-matched patients who underwent RNU for UTUC who either received NAC or were chemotherapy-naïve. METHODS: We retrospectively identified 1993 patients (including 112 NAC recipients) who underwent RNU for nonmetastatic, high-grade UTUC between 1985 and 2022 in a large, international, multicenter cohort. We divided the cohort into low-risk and high-risk groups defined according to pathologic findings of muscle invasion and lymph node involvement at RNU. Recurrence-free survival (RFS), overall survival (OS), and cancer-specific survival (CSS) estimates were calculated using the Kaplan-Meier method. Multivariable analyses were performed to determine clinical and demographic factors associated with these outcomes. KEY FINDINGS AND LIMITATIONS: Among patients with low-risk pathology at RNU, RFS, OS, and CSS were similar between the NAC and chemotherapy-naïve groups. Among patients with high-risk pathology at RNU, the NAC group had poorer RFS (hazard ratio [HR] 3.07, 95% confidence interval [CI] 2.10-4.48), OS (HR 2.06, 95% CI 1.33-3.20), and CSS (subdistribution HR 2.54, 95% CI 1.37-4.69) in comparison to the pathologic risk-matched, chemotherapy-naïve group. Limitations include the lack of centralized pathologic review. CONCLUSIONS AND CLINICAL IMPLICATIONS: Patients with residual invasive disease at RNU after NAC represent a uniquely high-risk population with respect to oncologic outcomes. There is a critical need to determine an optimal adjuvant approach for these patients. PATIENT SUMMARY: We studied a large, international group of patients with cancer of the upper urinary tract who underwent surgery either with or without receiving chemotherapy beforehand. We identified a high-risk subgroup of patients with residual aggressive cancer after chemotherapy and surgery who should be prioritized for clinical trials and drug development.

Immune Checkpoint Inhibitor Therapy Before Nephrectomy for Locally Advanced and Metastatic Renal Cell Carcinoma: A Review.

Importance: The therapeutic landscape of advanced renal cell carcinoma (RCC) has rapidly evolved in the past 2 decades, with the advent of cytokines therapy followed by targeted therapies and novel immune checkpoint inhibitors (ICI). This article aims to review the current evidence and ongoing trials of neoadjuvant or prenephrectomy ICI therapy in patients with locally advanced and metastatic RCC. Observations: A literature search was performed using the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and PubMed as well as relevant medical society meetings for English-language studies, articles, and abstracts published before January 31, 2023. Currently, level I evidence supports the use of ICI-based combination therapy as the first-line treatment of patients with metastatic RCC with the potential option of deferred nephrectomy in those who respond to treatment. Nevertheless, limited prospective data are available regarding the role and outcomes of nephrectomy (cytoreductive or consolidative) in conjunction with ICI therapy in both metastatic and locally advanced RCC. Although data from retrospective case series confirmed the feasibility and safety of deferred nephrectomy in this setting, the sequence of nephrectomy and whether it should be considered in patients with metastatic RCC is a common clinical dilemma. However, although neoadjuvant targeted therapy for nonmetastatic RCCs has been associated with some advantages yet not accepted as a standard, current data from a phase 3 randomized clinical trial failed to demonstrate the oncologic benefit of neoadjuvant nivolumab for locally advanced RCC. Conclusion and Relevance: The findings of this review suggest that ICI-based combination therapy is the standard of care as the first-line treatment of patients with metastatic RCC. However, the role of neoadjuvant ICIs in locally advanced RCC is an active area of investigation. Deferred nephrectomy after ICI-based immunotherapy for metastatic RCC is feasible and safe yet should be performed in high-volume health centers by experienced surgeons. The multidisciplinary and careful approach is critical for treatment decisions.

Survival of Patients with Chronic Kidney Disease Treated with Radical Cystectomy and Risk Factors of Glomerular Filtration Rate Loss Following Radical Cystectomy: Two Systematic Reviews and Meta-analyses of Interplay Between Radical Cystectomy and Renal Function.

CONTEXT: There is no high-level evidence regarding the risk factors of glomerular filtration rate (GFR) loss following radical cystectomy (RC) and survival outcomes of patients with chronic kidney disease (CKD) undergoing RC. OBJECTIVE: To identify the risk factors of CKD in patients treated with RC for bladder cancer and to assess overall and oncological survival of patients with CKD who underwent RC. EVIDENCE ACQUISITION: According to the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement, two systematic reviews were performed for studies published before September 30, 2022, assessing (1) risk factors of renal function (RF) decline following RC and (2) overall and oncological outcomes of CKD patients treated with RC. EVIDENCE SYNTHESIS: A total of 21 and 17 studies were included for qualitative and quantitative syntheses, respectively. The first meta-analysis of ten studies (15 502 patients) identified these factors to be significantly associated with GFR loss following RC: advanced age, lower baseline RF, higher Charlson Comorbidity Index (CCI), diabetes mellitus, hypertension, postoperative hydronephrosis, ureteroenteric stricture, and locally advanced disease (hazard ratios [HRs] 1.03, 1.22, 1.5, 1.27, 1.24, 1.69, 1.92, and 5.13, respectively), while sex, preoperative hydronephrosis, perioperative chemotherapy, and diversion type were not. The second meta-analysis of seven studies (6900 patients) demonstrated significantly worse metastasis-free, cancer-specific, and overall survival in patients with higher CKD stages than in those with lower stages (HRs 1.54, 2.09, and 1.47, respectively). CONCLUSIONS: Current evidence suggests that older age, lower baseline RF, higher CCI, diabetes mellitus, hypertension, postoperative hydronephrosis, ureteroenteric stricture, and locally advanced disease are associated with long-term GFR loss following RC. In addition, patients with higher stages of CKD have worse long-term overall and oncological outcomes following RC. These data may help in counseling and decision-making regarding therapy and preventive measures. PATIENT SUMMARY: Several factors have been identified that can help identify patients at risk for glomerular filtration rate loss after radical cystectomy (RC). Chronic kidney disease is associated with poor cancer- and non-cancer-specific outcomes following RC.

Therapeutic Effects of Low-Level Laser on Male Infertility: A Systematic Review.

Introduction: The objective of this study was to assess the effectiveness and safety of photobiomodulation (PBM) in the treatment of male infertility. Methods: We searched Google Scholar, PubMed, and the reference sections of relevant papers published from January 1, 2000 to September 23, 2022. We retrieved all publications related to the impact of PBM on male infertility. After reviewing the titles, abstracts, and full texts, we included fifteen papers in the research. The studies involved 477 semen samples (in vitro studies) and 70 male participants (randomized clinical trials). Results: All 14 in vitro studies that evaluated effectiveness reported that PBM was successful in increasing the proportion of progressive sperms in semen samples. Various methods were used to evaluate the safety. One study with a sample size of 58 concluded that PBM was not a safe treatment, whereas the other ten studies confirmed its safety. Only one clinical trial evaluated the effect of laser acupuncture on male infertility and found improvements in sperm progressive motility without any serious adverse effects. Conclusion: All 15 studies evaluating effectiveness reported that the low-level laser was effective for increasing the proportion of progressive sperm in semen samples and that it was safe to use. However, due to the heterogeneity of population characteristics, source characteristics, duration of exposure, sample size, and instruments for measuring safety and efficacy, we cannot conclude that the positive results obtained from the reviewed studies are solely attributable to the low-level laser on the sperm samples.

Modern Kidney-Sparing Management of Upper Tract Urothelial Carcinoma.

PURPOSE: To review the latest evidence on the modern techniques and outcomes of kidney-sparing surgeries (KSS) in patients with upper tract urothelial carcinoma (UTUC). METHODS: A comprehensive literature search on the study topic was conducted before 30 April 2023 using electronic databases including PubMed, MEDLINE, and EMBASE. A narrative overview of the literature was then provided based on the extracted data and a qualitative synthesis of the findings. RESULTS: KSS is recommended for low- as well as select high-risk UTUCs who are not eligible for radical treatments. Endoscopic ablation is a KSS option that is associated with similar oncological outcomes compared with radical treatments while preserving renal function in well-selected patients. The other option in this setting is distal ureterectomy, which has the advantage of providing a definitive pathological stage and grade. Data from retrospective studies support the superiority of this approach over radical treatment with similar oncological outcomes, albeit in select cases. Novel chemoablation agents have also been studied in the past few years, of which mitomycin gel has received FDA approval for use in low-risk UTUCs. CONCLUSION: KSSs are acceptable approaches for patients with low- and select high-risk UTUCs, which preserve renal function without compromising the oncological outcomes.

Impact of Variant Histology on Oncological Outcomes in Upper Tract Urothelial Carcinoma: Results From the ROBUUST Collaborative Group.

INTRODUCTION: Oncologic implications of variant histology (VH) have been extensively studied in bladder cancer; however, further investigation is needed in upper tract urothelial carcinoma (UTUC). Our study aims to evaluate the impact of VH on oncological outcomes in UTUC patients treated with radical nephroureterectomy (RNU). METHODS: A retrospective analysis was performed on patients who underwent a robotic or laparoscopic RNU for UTUC using the ROBUUST database, a multi-institutional collaborative including 17 centers worldwide. Logistic regression was used to assess the effect of VH on urothelial recurrence (bladder, contralateral upper tract), metastasis, and survival following RNU. RESULTS: A total of 687 patients were included in this study. Median (IQR) age was 71 (64-78) years and 470 (68%) had organ confined disease. VH was present in 70 (10.2%) patients. In a median follow-up of 16 months, the incidence of urothelial recurrence, metastasis, and mortality was 26.8%, 15.3%, and 11.8%, respectively. VH was associated with increased risk of metastasis (HR 4.3, P <.0001) and death (HR 2.0, P =.046). In multivariable analysis, VH was noted to be an independent risk factor for metastasis (HR 1.8, P =.03) but not for urothelial recurrence (HR 0.99, P =.97) or death (HR 1.4, P =.2). CONCLUSION: Variant histology can be found in 10% of patients with UTUC and is an independent risk factor for metastasis following RNU. Overall survival rates and the risk of urothelial recurrence in the bladder or contralateral kidney are not affected by the presence of VH.

Perioperative mortality for radical cystectomy in the modern Era: experience from a tertiary referral center

ABSTRACT Purpose To evaluate the perioperative mortality and contributing variables among patients who underwent radical cystectomy (RC) for bladder cancer in recent decades, with comparison between modern (after 2010) and premodern (before 2010) eras. Materials and Methods Using our institutional review board-approved database, we reviewed the records of patients who underwent RC for primary urothelial bladder carcinoma with curative intent from January 2003 to December 2019. The primary and secondary outcomes were 90- and 30-day mortality. Univariate and multivariable logistic regression models were applied to assess the impact of perioperative variables on 90-day mortality. Results A total of 2047 patients with a mean±SD age of 69.6±10.6 years were included. The 30- and 90-day mortality rates were 1.3% and 4.9%, respectively, and consistent during the past two decades. Among 100 deaths within 90 days, 18 occurred during index hospitalization. Infectious, pulmonary, and cardiac complications were the leading mortality causes. Multivariable analysis showed that age (Odds Ratio: OR 1.05), Charlson comorbidity index ≥ 2 (OR 1.82), blood transfusion (OR 1.95), and pathological node disease (OR 2.85) were independently associated with 90-day mortality. Nevertheless, the surgical approach and enhanced recovery protocols had no significant effect on 90-day mortality. Conclusion The 90-day mortality for RC is approaching five percent, with infectious, pulmonary, and cardiac complications as the leading mortality causes. Older age, higher comorbidity, blood transfusion, and pathological lymph node involvement are independently associated with 90-day mortality.

Sarcopenia and body fat change as risk factors for radiologic incisional hernia following robotic nephrectomy.

OBJECTIVE: To assess the effect of body muscle and fat metrics on the development of radiologic incisional hernia (IH) following robotic nephrectomy. MATERIALS AND METHODS: We retrospectively reviewed the records of patients who underwent robotic nephrectomy for kidney tumors between 2011 and 2017. All pre- and postoperative CTs were re-reviewed by experienced radiologists for detection of radiologic IH and calculation of the following metrics using Synapse 3D software: cross-sectional psoas muscle mass at the level of L3 and L4 as well as subcutaneous and visceral fat areas. Sarcopenia was defined as psoas muscle index below the lowest quartile. Cox proportional hazard model was constructed to examine the association between muscle and fat metrics and the risk of developing radiologic IH. RESULTS: A total of 236 patients with a median (IQR) age of 64 (54-70) years were included in this study. In a median (IQR) follow-up of 23 (14-38) months, 62 (26%) patients developed radiologic IH. On Cox proportional hazard model, we were unable to detect an association between sarcopenia and risk of IH development. In terms of subcutaneous fat change from pre-op, both lower and higher values were associated with IH development (HR (95% CI) 2.1 (1.2-3.4), p = 0.01 and 2.4 (1.4-4.1), p < 0.01 for < Q1 and ≥ Q3, respectively). Similar trend was found for visceral fat area changes from pre-op with a HR of 2.8 for < Q1 and 1.8 for ≥ Q3. CONCLUSION: Both excessive body fat gain and loss are associated with development of radiologic IH in patients undergoing robotic nephrectomy.

Perioperative Complications and Oncologic Outcomes of Nephrectomy Following Immune Checkpoint Inhibitor Therapy: A Multicenter Collaborative Study.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are now a mainstay of metastatic renal cell carcinoma (RCC) management with five current Food and Drug Administration-approved regimens. However, data regarding nephrectomy outcomes following an ICI are limited. OBJECTIVE: To evaluate the safety and outcomes of nephrectomy following an ICI. DESIGN, SETTING, AND PARTICIPANTS: A retrospective review was performed of patients with primary locally advanced or metastatic RCC undergoing nephrectomy following an ICI in five US academic centers between January 2011 and September 2021. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Clinical data, perioperative outcomes, and 90-d complications/readmissions were recorded and evaluated by univariate and logistic regression models. Recurrence-free and overall survival probabilities were estimated by the Kaplan-Meier method. RESULTS AND LIMITATIONS: A total of 113 patients with a median (interquartile range) age of 63 (56-69) yr were included. The main ICI regimens were nivolumab ± ipilimumab (n = 85) and pembrolizumab ± axitinib (n = 24). Risk groups included 95% intermediate- and 5% poor-risk patients. Surgical procedures were 109 radical and four partial nephrectomies, including 60 open, 38 robotic, and 14 laparoscopic with five (10%) conversions. Two intraoperative complications were reported (bowel and pancreatic injury). The median operative time, estimated blood loss, and hospital stay were 3 h, 250 ml, and 3 d, respectively. A complete pathologic response (ypT0N0) was noted in six (5%) patients. The 90-d complication rate was 24%, with 12 (11%) patients requiring readmission. On a multivariable analysis, two or more risk factors (odds ratio [OR] 2.91, 95% confidence interval [CI]: 1.09, 7.42) and pathologic T stage ≥T3 (OR 4.21, 95% CI: 1.13-15.8) were independently associated with a higher 90-d complication rate. The 3-yr estimated overall survival and recurrence-free survival rates were 82% and 47%, respectively. Limitations include the retrospective nature and heterogeneous cohort in terms of clinicopathologic characteristics and ICI regimens received. CONCLUSIONS: Nephrectomy following ICI therapy is feasible and a potential consolidative therapy option in select patients. Further research in the neoadjuvant setting is also warranted. PATIENT SUMMARY: This study evaluates the outcomes of kidney surgery following immune checkpoint inhibitor therapy (mainly nivolumab and ipilimumab or pembrolizumab and axitinib) for patients with advanced kidney cancer. We utilized data from five academic centers across the USA and found that surgery in this setting did not have more complications or returns to the hospital than similar surgeries, indicating that it is a safe and feasible procedure at this time.