Leilei Xia

Systematic Review and Meta-Analysis of Comparative Studies Reporting Perioperative Outcomes of Robot-Assisted Partial Nephrectomy Versus Open Partial Nephrectomy

BACKGROUND Robot-assisted partial nephrectomy (RAPN) is increasingly being used for the surgical management of renal masses. The comparison of RAPN with open partial nephrectomy (OPN) has not yet led to a unified conclusion with regard to perioperative outcomes. PURPOSE To conduct a systematic review and meta-analysis of the literature on the perioperative outcomes of RAPN compared with OPN. METHODS We searched PubMed and EMBASE through January 31, 2016, to identify randomized controlled trials (RCTs) and observational comparative studies assessing the comparison of the two approaches (RAPN vs OPN). Primary outcomes were intraoperative complication rate and postoperative complication rate (including minor and major). Secondary outcomes were perioperative transfusion rate, positive surgical margin (PSM) rate, operative time (OT), warm ischemia time (WIT), estimated blood loss (EBL), length of hospital stay (LOS), and estimated glomerular filtration rate (eGFR) change. RESULTS A total of 19 cohort studies with at least 3551 patients (RAPN, 1216; OPN, 2335) were included. Compared with OPN, RAPN had the advantages of (a) lower rates of postoperative complication (risk ratio [RR] = 0.60, 95% confidence interval [CI] = 0.46, 0.78, p = 0.0002), postoperative minor complication (RR = 0.73, 95% CI = 0.56, 0.96, p = 0.02), and postoperative major complication (RR = 0.50, 95% CI = 0.30, 0.84, p = 0.01); (b) lower need for transfusion (RR = 0.64, 95% CI = 0.41, 0.98, p = 0.04); (c) less EBL (weighted mean difference [WMD] = -98.82, 95% CI = -125.64, -72.01, p < 0.00001); and (d) shorter LOS (WMD = -2.64, 95% CI = -3.27, -2.00, p < 0.00001). Sensitivity analyses excluding studies with obvious selection bias based on tumor complexity confirmed all these advantages. RAPN had longer OT (WMD = 18.56, 95% CI = 2.13, 35.00, p = 0.03) and WIT (WMD = 3.65, 95% CI = 0.75, 6.56, p = 0.01) in the primary analyses. Sensitivity analyses, however, showed no differences between RAPN and OPN regarding OT and WIT. Intraoperative complication rate (RR = 0.61, 95% CI = 0.29, 1.27, p = 0.19), PSM rate (RR = 0.87, 95% CI = 0.56, 1.34, p = 0.52), and short-term eGFR change, including absolute eGFR change (WMD = -1.56, 95% CI = -3.41, 0.28, p = 0.10) and percentage eGFR change (WMD = 0.99, 95% CI = -0.52, 2.50), did not differ between the two approaches. CONCLUSIONS Compared with OPN, RAPN appears to have lower morbidity and achieves similar short-term functional outcomes. However, evidence is limited regarding the long-term oncologic outcomes even though the PSM rate is similar between the two groups. Well-designed RCTs with large sample sizes and long-term follow-up are needed to confirm and update the findings of our study.

Intraoperative Molecular Imaging Combined With Positron Emission Tomography Improves Surgical Management of Peripheral Malignant Pulmonary Nodules

Objective: To determine if intraoperative molecular imaging (IMI) can improve detection of malignant pulmonary nodules. Background: 18-Fluorodeoxyglucose positron emission tomography (PET) is commonly utilized in preoperative assessment of patients with solid malignancies; however, false negatives and false positives remain major limitations. Using patients with pulmonary nodules as a study model, we hypothesized that IMI with a folate receptor targeted near-infrared contrast agent (OTL38) can improve malignant pulmonary nodule identification when combined with PET. Methods: Fifty patients with pulmonary nodules with imaging features suspicious for malignancy underwent preoperative PET. Patients then received OTL38 before pulmonary resection. During resection, IMI was utilized to evaluate known pulmonary nodules and identify synchronous lesions. Tumor size, PET standardized uptake value, and IMI tumor-to-background ratios were compared for known and synchronous nodules via paired and unpaired t tests, when appropriate. Test characteristics of PET and IMI with OTL38 were compared. Results: IMI identified 56 of 59 (94.9%) malignant pulmonary nodules identified by preoperative imaging. IMI located an additional 9 malignant lesions not identified preoperatively. Nodules only detected by IMI were smaller than nodules detected preoperatively (0.5 vs 2.4 cm; P < 0.01), but displayed similar fluorescence (tumor-to-background ratio 3.3 and 3.1; P = 0.50). Sensitivity of IMI and PET were 95.6% and 73.5% (P = 0.001), respectively; and positive predictive values were 94.2% and 89.3%, respectively (P > 0.05). Additionally, utilization of IMI clinically upstaged 6 (12%) subjects and improved management of 15 (30%) subjects. Conclusions: These data suggest that combining IMI with PET may provide superior oncologic outcomes for patients with resectable lung cancer.

Preoperative Anemia and Low Hemoglobin Level Are Associated With Worse Clinical Outcomes in Patients With Bladder Cancer Undergoing Radical Cystectomy: A Meta-Analysis

Micro‐Abstract A meta‐analysis was performed to synthesize currently available evidence and determine the association between preoperative anemia/hemoglobin level and prognosis of patients undergoing radical cystectomy. Seventeen studies were included, and the results showed that preoperative anemia and low hemoglobin level are associated with increased all‐cause mortality, cancer‐specific mortality, and disease recurrence. Purpose: The aim of this study was to determine the effect of preoperative anemia status and hemoglobin level on clinical outcomes in patients with bladder cancer undergoing radical cystectomy. Materials and Methods: A systematic review of literature with meta‐analyses of predefined outcomes based on a search of PubMed and EMBASE was performed. Hazard ratios (HRs) measuring the association between preoperative anemia/hemoglobin and all‐cause mortality, cancer‐specific mortality, and disease recurrence were calculated with random effects model. Study heterogeneities were quantified by I2 tests. Publication bias was assessed with funnel plots. Results: A total of 17 studies evaluating the impact of preoperative anemia status (categorical, 11 studies) and hemoglobin level (continuous, 7 studies) on clinical outcomes were included. The cutoff value of anemia varied among studies (10.5‐13.5 g/dL for male, 10.5‐13.4 g/dL for female). Meta‐analyses showed that compared with non‐anemia, anemia was associated with increased all‐cause mortality (HR, 1.75; 95% confidence interval [CI], 1.48‐2.05; P < .00001; I2 = 30%), cancer‐specific mortality (HR, 1.80; 95% CI, 1.45‐2.25; P < .00001; I2 = 26%), and disease recurrence (HR, 1.37; 95% CI, 1.16‐1.62; P = .0002; I2 = 9%). Meta‐analyses showed that higher level of hemoglobin was associated with decreased all‐cause mortality (HR, 0.90; 95% CI, 0.87‐0.92; P < .00001; I2 = 13%), cancer‐specific mortality (HR, 0.90; 95% CI, 0.85‐0.95; P = .0003; I2 = 61%), and disease recurrence (HR, 0.95; 95% CI, 0.91‐0.99; P = .01; I2 = 53%). No obvious publication bias was observed. Conclusions: Preoperative anemia and low hemoglobin level are associated with earlier recurrence and shorter survival of patients with bladder cancer undergoing radical cystectomy. However, well‐designed prospective studies with large sample size and limited confounding factors are needed to confirm and update our findings.

Early Discharge and Post-Discharge Outcomes in Patients Undergoing Radical Cystectomy for Bladder Cancer

To assess whether discharging patients early after radical cystectomy (RC) is associated with an increased risk of readmission and post‐discharge complications.

Associations Between Travel Distance, Hospital Volume, and Outcomes Following Radical Cystectomy in Patients With Muscle-invasive Bladder Cancer

OBJECTIVE To explore the associations between travel distance, hospital volume, and outcomes following radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC). METHOD The 2006 to 2013 National Cancer Database was queried to identify patients with MIBC who underwent RC. Multivariable regressions alternately including travel distance, hospital volume, and both in the models were used. Travel distances and hospital volumes were categorized by quartiles. Outcomes of interest were overall survival and quality-of-care indicators. RESULT A total of 6551 patients were included in the final cohort. When only travel distance or hospital volume was included in the multivariable regression model, fourth quartiles of both variables were associated with improved overall survival. When both travel distance and hospital volume were included in the model, only hospital volume was found to be associated with overall survival. Sensitivity analyses with both travel distance and hospital volume considered as continuous variables showed similar results. Patients who underwent RC in high-volume hospitals were more likely to receive neoadjuvant chemotherapy, have 10 or more lymph nodes removed, but also had higher odds of surgical delay (>3 months) in the full models adjusting for travel distance. CONCLUSION This National Cancer Database-based study suggests that the association between longer travel distance and improved overall survival (distance bias effect) after RC for MIBC is mainly mediated by higher hospital volume. The benefits of having RC at high-volume hospitals may outweigh the potential disadvantages of longer travel distance, which further supports the continued regionalization of RC and cancer care for MIBC.

An open label trial of folate receptor-targeted intraoperative molecular imaging to localize pulmonary squamous cell carcinomas

Background Clinical applicability of folate receptor-targeted intraoperative molecular imaging (FR-IMI) has been established for surgically resectable pulmonary adenocarcinoma. A role for FR-IMI in other lung cancer histologies has not been studied. In this study, we evaluate feasibility of FR-IMI in patients undergoing pulmonary resection for squamous cell carcinomas (SCCs). Methods In a human clinical trial (NCT02602119), twelve subjects with pulmonary SCCs underwent FR-IMI with a near-infrared contrast agent that targets the folate receptor-α (FRα), OTL38. Near-infrared signal from tumors and benign lung was quantified to calculate tumor-to-background ratios (TBR). Folate receptor-alpha expression was characterized, and histopathologic correlative analyses were performed to evaluate patterns of OTL38 accumulation. An exploratory analysis was performed to determine patient and histopathologic variables that predict tumor fluorescence. Results 9 of 13 SCCs (in 9 of 12 of subjects) displayed intraoperative fluorescence upon NIR evaluation (median TBR, 3.9). OTL38 accumulated within SCCs in a FRα-dependent manner. FR-IMI was reliable in localizing nodules as small as 1.1 cm, and prevented conversion to thoracotomy for nodule localization in three subjects. Upon evaluation of patient and histopathologic variables, in situ fluorescence was associated with distance from the pleural surface, and was independent of alternative variables including tumor size and metabolic activity. Conclusions This work demonstrates that FR-IMI is potentially feasible in 70% of SCC patients, and that molecular imaging can improve localization during minimally invasive pulmonary resection. These findings complement previous data demonstrating that ∼98% of pulmonary adenocarcinomas are localized during FR-IMI and suggest broad applicability for NSCLC patients undergoing resection.

Hospital volume and outcomes of robot‐assisted partial nephrectomy

To evaluate the impact of hospital volume on outcomes of robot‐assisted partial nephrectomy (RAPN).

Near-infrared Intraoperative Molecular Imaging Can Identify Metastatic Lymph Nodes in Prostate Cancer

OBJECTIVE To propose a novel method to perform indocyanine green (ICG) based near-infrared (NIR) fluorescence imaging during pelvic lymph node dissection (PLND) for prostate cancer patients with lymph node metastasis (LNM). MATERIALS AND METHODS A prostate cancer cell line PC3 was used to establish xenograft model in NOD/SCID mice. After tumor growth, the mice were injected with ICG through the tail vein. Xenografts and surrounding tissues were imaged with NIR camera 24 hours after intravenous ICG, and tumor-to-background ratios were calculated. We then performed a pilot human study to evaluate the role of NIR imaging in robotic PLND after systemic ICG in 4 patients with prostate cancer and preoperative lymphadenopathy. RESULTS ICG localized to PC3 xenografts in the mice and all xenografts were highly fluorescent compared with surrounding tissues, with a median tumor-to-background ratio of 2.85 (interquartile range = 2.64-3.90). In the human study, intraoperative in vivo NIR imaging identified 3 of the 4 preoperative lymphadenopathies as fluorescence-positive, and back table ex vivo NIR imaging identified all 4 lymphadenopathies as fluorescence-positive. All the lymphadenopathies were found to be LNMs by pathologic examination. Two of the four cases had additional LNMs, all of which were fluorescence-positive with intraoperative in vivo NIR imaging. CONCLUSION Intravenously administered ICG accumulates in prostate cancers in both a murine model and human patients. NIR fluorescence based on intravenous ICG may serve as a useful tool to facilitate the identification of positive nodes during PLND in patients with higher risk of LNMs.

Reporting and methodological quality of meta-analyses in urological literature

Purpose To assess the overall quality of published urological meta-analyses and identify predictive factors for high quality. Materials and Methods We systematically searched PubMed to identify meta-analyses published from January 1st, 2011 to December 31st, 2015 in 10 predetermined major paper-based urology journals. The characteristics of the included meta-analyses were collected, and their reporting and methodological qualities were assessed by the PRISMA checklist (27 items) and AMSTAR tool (11 items), respectively. Descriptive statistics were used for individual items as a measure of overall compliance, and PRISMA and AMSTAR scores were calculated as the sum of adequately reported domains. Logistic regression was used to identify predictive factors for high qualities. Results A total of 183 meta-analyses were included. The mean PRISMA and AMSTAR scores were 22.74 ± 2.04 and 7.57 ± 1.41, respectively. PRISMA item 5, protocol and registration, items 15 and 22, risk of bias across studies, items 16 and 23, additional analysis had less than 50% adherence. AMSTAR item 1, “a priori” design, item 5, list of studies and item 10, publication bias had less than 50% adherence. Logistic regression analyses showed that funding support and “a priori” design were associated with superior reporting quality, following PRISMA guideline and “a priori” design were associated with superior methodological quality. Conclusions Reporting and methodological qualities of recently published meta-analyses in major paper-based urology journals are generally good. Further improvement could potentially be achieved by strictly adhering to PRISMA guideline and having “a priori” protocol.

The second window ICG technique demonstrates a broad plateau period for near infrared fluorescence tumor contrast in glioblastoma

Introduction Fluorescence-guided surgery has emerged as a powerful tool to detect, localize and resect tumors in the operative setting. Our laboratory has pioneered a novel way to administer an FDA-approved near-infrared (NIR) contrast agent to help surgeons with this task. This technique, coined Second Window ICG, exploits the natural permeability of tumor vasculature and its poor clearance to deliver high doses of indocyanine green (ICG) to tumors. This technique differs substantially from established ICG video angiography techniques that visualize ICG within minutes of injection. We hypothesized that Second Window ICG can provide NIR optical contrast with good signal characteristics in intracranial brain tumors over a longer period of time than previously appreciated with ICG video angiography alone. We tested this hypothesis in an intracranial mouse glioblastoma model, and corroborated this in a human clinical trial. Methods Intracranial tumors were established in 20 mice using the U251-Luc-GFP cell line. Successful grafts were confirmed with bioluminescence. Intravenous tail vein injections of 5.0 mg/kg (high dose) or 2.5 mg/kg (low dose) ICG were performed. The Perkin Elmer IVIS Spectrum (closed field) was used to visualize NIR fluorescence signal at seven delayed time points following ICG injection. NIR signals were quantified using LivingImage software. Based on the success of our results, human subjects were recruited to a clinical trial and intravenously injected with high dose 5.0 mg/kg. Imaging was performed with the VisionSense Iridium (open field) during surgery one day after ICG injection. Results In the murine model, the NIR signal-to-background ratio (SBR) in gliomas peaks at one hour after infusion, then plateaus and remains strong and stable for at least 48 hours. Higher dose 5.0 mg/kg improves NIR signal as compared to lower dose at 2.5 mg/kg (SBR = 3.5 vs. 2.8; P = 0.0624). Although early (≤ 6 hrs) visualization of the Second Window ICG accumulation in gliomas is stronger than late (≥24 hrs) visualization (SBR = 3.94 vs. 2.32; p<0.05) there appears to be a long plateau period of stable ICG NIR signal accumulation within tumors in the murine model. We call this long plateau period the “Second Window” of ICG. In glioblastoma patients, the delayed visualization of intratumoral NIR signal was strong (SBR 7.50 ± 0.74), without any significant difference within the 19 to 30 hour visualization window (R2 = 0.019). Conclusion The Second Window ICG technique allows neurosurgeons to deliver NIR optical contrast agent to human glioblastoma patients, thus providing real-time tumor identification in the operating room. This nonspecific tumor accumulation of ICG within the tumor provides strong signal to background contrast, and is not significantly time dependent between 6 hours to 48 hours, providing a broad plateau for stable visualization. This finding suggests that optimal imaging of the “Second Window of ICG” may be within this plateau period, thus providing signal uniformity across subjects.