Local and distant tumor dormancy during early stage breast cancer are associated with the predominance of infiltrating T effector subsets.

BACKGROUND: Although breast cancer mortality is a result of distant recurrences associated with the establishment of tumor dormancy, current clinical practice guidelines recommend a wait and watch approach for tumor recurrences. This is because of our limited understanding of tumor dormancy and insufficient evidence in support of immunological control of tumor dormancy. METHODS: We used FVBN202 transgenic mice expressing rat neu oncogene in the mammary glands, and their parental FVB strain lacking neu expression. These models allowed the detection of tumor dormancy at distant sites using the rat neu protein as a tumor marker. We also used Ki67 for the detection of the indolent and quiescent types of tumor dormancy. Multicolor flow cytometry was used to detect dormant tumor cells and T cell subsets. Co-culture studies were performed to determine the role of T cells in preventing regrowth of dormant cells. RESULTS: We demonstrated that dormant tumor cells were present at the site of primary breast cancer and at distant sites in the lungs and in the liver very early in the course of early stage breast cancer when no distant metastasis was evident. Dormant tumor cells were characterized as neu expressing Ki67- and Ki67low fractions associated with the induction of local immune responses predominated by CD4+ and CD8+ T effector cell subsets. The presence of neu-autoreactive T cells from FVBN202 mice only prevented regrowth of dormant cells. On the other hand, presence of neu-alloreactive anti-tumor T cells in FVB mice prior to tumor challenge resulted in the protection of mice from the dissemination of dormant tumor cells to distant organs. CONCLUSION: Our results suggest that immunotherapeutic targeting of semi-allogeneic mutant neoantigens during tumor dormancy might prevent distant recurrence of the disease.

Robotic versus other nephroureterectomy techniques: a systematic review and meta-analysis of over 87,000 cases.

PURPOSE: To perform a systematic review and meta-analysis of the literature inherent robotic nephroureterectomy (RNU) and to compare its outcomes with those of other nephroureterectomy (NU) techniques. METHODS: A systematic literature search was performed up to April 2019 using PubMed, Embase®, and Web of Science. The Preferred Reporting Items for Systematic Review and Meta-analysis Statement was followed for study selection. The following data were extracted for each study: baseline features, surgical outcomes, oncological outcomes, and survival outcomes. Stata® 15.0 was used for statistical analysis. RESULTS: Literature search identified 80 studies eligible for the meta-analysis and overall 87,291 patients were included in the analysis: open NU (ONU; n = 45,601), hand-assisted laparoscopic NU (HALNU; n = 442), laparoscopic NU (LNU n = 31,093), and RNU (n = 10,155). RNU was more likely to be performed in those patients with multifocal tumor location (proportion: 0.19; 95% CI 0.14, 0.24) and high-grade disease (proportion: 0.70; 95% CI 0.53, 0.68). The lowest EBL was recorded in the RNU group (weighted mean (WM) 163.31 mL; 95% CI 88.94, 237.68), whereas the highest was in the ONU group (414.99 mL; 95% CI 378.52, 451.46). Operative time was shorter for ONU (224.98 mL; 95% CI 212.26, 237.69). RNU had lower rate of intraoperative complications (0.02; 95% CI 0.01, 0.05). ONU showed higher odds of transfusions (0.20; 95% CI 0.15, 0.25). LOS was statistically significantly shorter for the RNU group (5.35 days; 95% CI 4.97, 5.82). HALNU seemed to present lower risk of PSM (0.02; 95% CI - 0.01, 0.05), and lower risk of recurrence (0.22; 95% CI 0.15, 0.30), metastasis (0.07; 95% CI 0.05, 0.10), and cancer-related death (0.03; 95% CI 0.01, 0.06). ONU showed the lowest 5 years cancer specific survival (proportion: 0.77; 95% CI 0.74, 0.80). No correlation was found between the surgical technique and recurrence-free and cancer-specific survival. CONCLUSIONS: Evidence regarding RNU for the treatment of UTUC is increasing but it remains quite sparse and of low quality. Despite this, RNU seems to be safe, and to offer the advantages of a minimally invasive approach without impairing the oncological outcomes. Nevertheless, ONU, HALNU, and LNU still represent a valid, and commonly used surgical treatment option. As RNU becomes more popular, and concerns related to its use remain, the best surgical technique for NU remains to be determined.

Ureteral location is associated with survival outcomes in upper tract urothelial carcinoma: A population-based analysis.

OBJECTIVES: To evaluate the prognostic value of tumor location in patients with upper tract urothelial carcinoma. METHODS: Within the Surveillance, Epidemiology and End Results Incidence Database, 6619 upper tract urothelial carcinoma cases were identified, including 3719 confined to the renal pelvis and 2971 to the ureter. Predictors of surgical technique (kidney sparing surgery versus radical nephroureterectomy), as well as 2- and 5-year cancer-specific survival and overall survival were evaluated. RESULTS: Median follow-up time was 29 months (interquartile range 0-126 months) for both groups. Multivariate logistic analysis showed tumor dimension as the only factor associated with radical nephroureterectomy (odds ratio 1.02; P < 0.001). Ureteral 2- and 5-year overall survival were lower (log-rank P = 0.001) compared with renal pelvis. When stratifying tumor location according to dimensions, a ureteral carcinoma >3 cm was associated with the worst 2- and 5-year cancer-specific mortality (Pepe-Mori P < 0.001), and overall survival (log-rank P < 0.001). The 2- and 5-year cancer-specific mortality (Pepe-Mori P < 0.001) and overall survival were the worst for ureteral ≥T3 tumors (log-rank P < 0.001). The 2- and 5-year cancer-specific mortality (Pepe-Mori P < 0.001) and overall survival (log-rank P < 0.001) were the worst for ureteral grade III-IV cancers. Ureteral tumor location (subdistribution hazard ratio 1.18, P < 0.001), tumor dimension ≥3 (subdistribution hazard ratio 1.25, P < 0.001), T staging (T2-4 all P < 0.001), grading (grade III subdistribution hazard ratio 2.20, P = 0.001; grade IV subdistribution hazard ratio 2.39, P < 0.001) were found to be associated with higher cancer mortality. CONCLUSIONS: Ureteral tumor location in upper tract urothelial carcinoma seems to be associated with worse oncological outcomes, especially in the case of advanced disease. Although the type of surgical treatment does not seem to impact survival, surgeons should use caution in adopting a kidney-sparing surgery for patients with ureteral upper tract urothelial carcinoma.

Adherence to EAU guidelines on penile cancer translates into better outcomes: a multicenter international study.

INTRODUCTION: We aimed to evaluate adherence to the EAU guidelines (GL) on penile cancer (PC) with regard to primary surgical treatment and management of lymph nodes and to estimate the influence of adherence to GL on clinical outcome. MATERIALS AND METHODS: This is a retrospective multicenter study (PEnile Cancer ADherence study, PECAD Study) on PC patients treated at 12 European and American centers between 2010 and 2016. Adherence to the EAU GL on the surgical management of the primary penile tumor and lymphadenectomy was evaluated. Descriptive analyses were performed, and survival curves were estimated. RESULTS: Data on 425 patients were considered for the analysis. The EAU GL on surgical treatment of the primary tumor and lymphadenectomy were respected in 74.8% and 73.7% of cases, respectively. Survival analysis showed that adherence to the GL on primary penile surgery was significantly associated with a good overall survival [adjusted HR 0.40 (95% CI 0.20-0.83, p value = 0.014)]. Also, the adherence to the GL on lymphadenectomy was statistically significantly associated with overall survival [adjusted HR 0.48 (95% CI 0.24-0.96, p value = 0.038)]. Limited follow-up and retrospective design represent limitations of this study. CONCLUSIONS: Our findings suggest that there is a good adherence to the EAU GL on PC. However, this should be further reinforced, endorsed and encouraged as it might translate into better clinical outcomes for PC patients.

Dendritic cell trafficking in tumor-bearing mice.

Prostate cancer is one of the leading causes of cancer deaths, with no curative treatments once it spreads. Alternative therapies, including immunotherapy, have shown limited efficacy. Dendritic cells (DC) have been widely used in the treatment of various malignancies. DC capture antigens and move to the lymphoid organs where they prime naive T cells. Interaction between DC and T cells are most active in lymph nodes and suppression of DC trafficking to lymph nodes impairs the immune response. In this work, we aimed to study trafficking of DC in vivo via various routes of delivery, to optimize the effectiveness of DC-based therapy. A DC labeling system was developed using 1,1'-dioctadecyltetramethyl indotricarbocyanine Iodine for in vivo fluorescent imaging. DC harvested from C57B/6 mice were matured, labeled, and injected intravenously, subcutaneously, or intratumorally, with or without antigen loading with whole tumor lysate, into C57B/6 mice inoculated with RM-1 murine prostate tumor cells. Signal intensity was measured in vivo and ex vivo. Signal intensity at the tumor site increased over time, suggesting trafficking of DC to the tumor with all modes of injection. Subcutaneous injection showed preferential trafficking to lymph nodes and tumor. Intravenous injection showed trafficking to lungs, intestines, and spleen. Subcutaneous injection of DC pulsed with whole tumor lysate resulted in the highest increase in signal intensity at the tumor site and lymph nodes, suggesting subcutaneous injection of primed DC leads to highest preferential trafficking of DC to the immunocompetent organs.

Role of Epigenetic Modification and Immunomodulation in a Murine Prostate Cancer Model.

INTRODUCTION: Decreased expression of highly immunogenic cancer-testis antigens (CTA) might help tumor to achieve low immunogenicity, escape immune surveillance and grow unimpeded. Our aim was to evaluate CTA expression in tumor and normal tissues and to investigate possible means of improving the immune response in a murine prostate cancer (CaP) model by using the combination of epigenetic modifier 5-azacitidine (5-AzaC) and immunomodulator lenalidomide. No study to date has examined the effect of this combination on the prostate cancer or its impact on antigen-presenting cells (APC). MATERIALS AND METHODS: Gene microarrays were performed to compare expression of several CTA in murine prostate cancer (RM-1 cells) and normal prostate. RM-1 cells were treated with 5-AzaC and real-time PCR was performed to investigate the expression of several CTA. Western blotting was used to determine whether expression of CTA-specific mRNA induced by 5-AzaC resulted in increase in the corresponding protein. Effect of the epigenetic agents and immunomodulators was assessed on dendritic cells (DC) using flow cytometry, ELISA and T-cell proliferation assay. RESULTS: Gene arrays demonstrated decreased expression of 35 CTA in CaP tissue compared to normal prostate. 5-AzaC treatment of RM-1 prostate cancer cells upregulated the expression of all 13 CTA tested in a dose-dependent fashion. DC were treated with 5-AzaC and lenalidomide and the expression of surface markers MHC Class I, MHC Class II, CD80, CD86, CD 205, and CD40 was increased. Combination of 5-AzaC and lenalidomide enhances the ability of DC to stimulate T-cell proliferation in mixed leukocyte reaction. Secretion of IL-12 and IL-15 by DC increased significantly with addition of 5-AzaC or 5-AzaC and lenalidomide. CONCLUSIONS: Decreased expression of CTA by prostate cancer may be a means of escaping immune monitoring. Combination of epigenetic modifications and immunomodulation by 5-AzaC and lenalidomide increased tumor immunogenicity and enhanced DC function and may be used in the treatment of advanced prostate cancer. Prostate 77: 361-373, 2017. © 2016 Wiley Periodicals, Inc.

Impact of diagnostic ureteroscopy on intravesical recurrence in patients undergoing radical nephroureterectomy for upper tract urothelial cancer: a systematic review and meta-analysis.

Aim of this study was to analyse the association between the use of diagnostic ureteroscopy (URS) and the development of intravesical recurrence (IVR) in patients undergoing radical nephroureterectomy (RNU) for high-risk upper tract urothelial carcinoma. A systematic review of the published data was performed up to December 2016, using multiple search engines to identify eligible studies. A formal meta-analysis was conducted of studies comparing patients who underwent URS before RNU with those who did not. Hazard ratios (HRs), with their 95% confidence intervals (CIs), from each study were used to calculate pooled HRs. Pooled estimates were calculated using a fixed-effects or random-effects model according to heterogeneity. Statistical analyses were performed using RevMan, version 5. Seven studies were included in the systematic review, but only six of these were deemed fully eligible for meta-analysis. Among the 2 382 patients included in the meta-analysis, 765 underwent diagnostic URS prior to RNU. All examined studies were retrospective, and the majority examined Asian populations. The IVR rate ranged from 39.2% to 60.7% and from 16.7% to 46% in patients with and without prior URS, respectively. In the pooled analysis, a statistically significant association was found between performance of URS prior to RNU and IVR (HR 1.56, 95% CI 1.33-1.88; P < 0.001). There was no heterogeneity in the observed outcomes, according to the I2 statistic of 2% (P = 0.40). Within the intrinsic limitations of this type of analysis, these findings suggest a significant association between the use of diagnostic URS and higher risk of developing IVR after RNU. Further research in this area should be encouraged to further investigate the possible causality behind this association and it potential clinical implications.

Low amplitude rhythmic contraction frequency in human detrusor strips correlates with phasic intravesical pressure waves.

PURPOSE: Low amplitude rhythmic contractions (LARC) occur in detrusor smooth muscle and may play a role in storage disorders such as overactive bladder and detrusor overactivity. The purpose of this study was to determine whether LARC frequencies identified in vitro from strips of human urinary bladder tissue correlate with in vivo LARC frequencies, visualized as phasic intravesical pressure (p ves) waves during urodynamics (UD). METHODS: After IRB approval, fresh strips of human urinary bladder were obtained from patients. LARC was recorded with tissue strips at low tension (<2 g) and analyzed by fast Fourier transform (FFT) to identify LARC signal frequencies. Blinded UD tracings were retrospectively reviewed for signs of LARC on the p ves tracing during filling and were analyzed via FFT. RESULTS: Distinct LARC frequencies were identified in 100% of tissue strips (n = 9) obtained with a mean frequency of 1.97 ± 0.47 cycles/min (33 ± 8 mHz). Out of 100 consecutive UD studies reviewed, 35 visually displayed phasic p ves waves. In 12/35 (34%), real p ves signals were present that were independent of abdominal activity. Average UD LARC frequency was 2.34 ± 0.36 cycles/min (39 ± 6 mHz) which was similar to tissue LARC frequencies (p = 0.50). A majority (83%) of the UD cohort with LARC signals also demonstrated detrusor overactivity. CONCLUSIONS: During UD, a subset of patients displayed phasic p ves waves with a distinct rhythmic frequency similar to the in vitro LARC frequency quantified in human urinary bladder tissue strips. Further refinements of this technique may help identify subsets of individuals with LARC-mediated storage disorders.

A Panel of MicroRNAs as Diagnostic Biomarkers for the Identification of Prostate Cancer.

Prostate cancer is the most common non-cutaneous cancer among men; yet, current diagnostic methods are insufficient, and more reliable diagnostic markers need to be developed. One answer that can bridge this gap may lie in microRNAs. These small RNA molecules impact protein expression at the translational level, regulating important cellular pathways, the dysregulation of which can exert tumorigenic effects contributing to cancer. In this study, high throughput sequencing of small RNAs extracted from blood from 28 prostate cancer patients at initial stages of diagnosis and prior to treatment was used to identify microRNAs that could be utilized as diagnostic biomarkers for prostate cancer compared to 12 healthy controls. In addition, a group of four microRNAs (miR-1468-3p, miR-146a-5p, miR-1538 and miR-197-3p) was identified as normalization standards for subsequent qRT-PCR confirmation. qRT-PCR analysis corroborated microRNA sequencing results for the seven top dysregulated microRNAs. The abundance of four microRNAs (miR-127-3p, miR-204-5p, miR-329-3p and miR-487b-3p) was upregulated in blood, whereas the levels of three microRNAs (miR-32-5p, miR-20a-5p and miR-454-3p) were downregulated. Data analysis of the receiver operating curves for these selected microRNAs exhibited a better correlation with prostate cancer than PSA (prostate-specific antigen), the current gold standard for prostate cancer detection. In summary, a panel of seven microRNAs is proposed, many of which have prostate-specific targets, which may represent a significant improvement over current testing methods.

Follow the Stream: Imaging of Urinary Diversions.

Urinary diversion is a surgical technique to redirect the stream of urine, most often after cystectomy. Cystectomy may be performed both for benign and for malignant conditions. Bladder cancer is the most common indication for cystectomy, and most patients who undergo radical cystectomy and urinary diversion have muscle-invasive or high-risk non-muscle-invasive bladder cancer. There are two major surgical approaches for urinary diversions performed after radical cystectomy: continent and incontinent diversions. For incontinent urinary diversions, a cutaneous ostomy is used for continuous urine drainage (eg, ileal conduit). With a continent diversion procedure, the patient may void through the native urethra or self-catheterize through a surgically created stoma. The goals of imaging after urinary diversion are to assess postoperative anatomy, detect postoperative complications, evaluate for residual or recurrent tumor and metastatic disease, and monitor for upper tract distention and/or deterioration. Multiple imaging modalities and techniques may be used to evaluate urinary diversions, including computed tomographic and magnetic resonance urography, intravenous pyelography, ultrasonography, pouchography, loopography, and nephrostomy studies. Knowledge of the expected postoperative appearance after urinary diversions and potential postoperative complications is crucial because many complications may be clinically silent. Radiologists must be able to recognize the expected postoperative appearance as well as complications to facilitate appropriate diagnosis and treatment of patients after cystectomy and urinary diversion. (©)RSNA, 2016.

Acute length adaptation and adjustable preload in the human detrusor.

AIMS: The biomechanical properties of length adaptation and adjustable preload have been previously identified in detrusor smooth muscle in animal models. This in vitro study aims to show that human detrusor smooth muscle exhibits length adaptation and adjustable preload tension which could play an important role in both overactive bladder and detrusor underactivity. METHODS: In order to demonstrate length adaptation, human detrusor smooth muscle strips are stretched and contracted beyond an optimum length and then contracted three times at the previous optimum length to determine if maximum active tension could be re-established. To demonstrate adjustable preload (Tap ), human detrusor smooth muscle strips are subjected to a pre-defined loading-unloading (strain softening) sequence to reduce preload. Then, tissues are contracted and the sequence is repeated to determine if this active process restored preload. RESULTS: Nine patients (average age, 62) provide tissue: 89% are men with urothelial carcinoma and a minority (22%) also have neurogenic bladder dysfunction. In the length adaptation protocol, contractions show progressive increases in active tension (P < 0.05). In the Tap protocol, a significant amount of preload is lost to strain softening (P < 0.05) and is restored after active contraction (P = 0.50). Exposure to the rho-kinase inhibitor, H-1152, prevents the restoration of preload (P < 0.05). CONCLUSIONS: This study demonstrates that human detrusor smooth muscle displays both length adaptation and Tap . Furthermore, Tap may be regulatable through a rho-kinase pathway. These biomechanical processes may be important in the pathophysiology of both overactive bladder and detrusor underactivity. Neurourol. Urodynam. 35:792-797, 2016. © 2015 Wiley Periodicals, Inc.

Cancer detection in dogs using rapid Raman molecular urinalysis.

Introduction: The presence of cancer in dogs was detected by Raman spectroscopy of urine samples and chemometric analysis of spectroscopic data. The procedure created a multimolecular spectral fingerprint with hundreds of features related directly to the chemical composition of the urine specimen. These were then used to detect the broad presence of cancer in dog urine as well as the specific presence of lymphoma, urothelial carcinoma, osteosarcoma, and mast cell tumor. Methods: Urine samples were collected via voiding, cystocentesis, or catheterization from 89 dogs with no history or evidence of neoplastic disease, 100 dogs diagnosed with cancer, and 16 dogs diagnosed with non-neoplastic urinary tract or renal disease. Raman spectra were obtained of the unprocessed bulk liquid urine samples and were analyzed by ISREA, principal component analysis (PCA), and discriminant analysis of principal components (DAPC) were applied using the Rametrix®Toolbox software. Results and discussion: The procedure identified a spectral fingerprint for cancer in canine urine, resulting in a urine screening test with 92.7% overall accuracy for a cancer vs. cancer-free designation. The urine screen performed with 94.0% sensitivity, 90.5% specificity, 94.5% positive predictive value (PPV), 89.6% negative predictive value (NPV), 9.9 positive likelihood ratio (LR+), and 0.067 negative likelihood ratio (LR-). Raman bands responsible for discerning cancer were extracted from the analysis and biomolecular associations were obtained. The urine screen was more effective in distinguishing urothelial carcinoma from the other cancers mentioned above. Detection and classification of cancer in dogs using a simple, non-invasive, rapid urine screen (as compared to liquid biopsies using peripheral blood samples) is a critical advancement in case management and treatment, especially in breeds predisposed to specific types of cancer.

Proposal for a Two-Tier Re-classification of Stage IV/M1 domain of Renal Cell Carcinoma into M1 ("Oligometastatic") and M2 ("Polymetastatic") subdomains: Analysis of the Registry for Metastatic Renal Cell Carcinoma (REMARCC).

Purpose: We hypothesized that two-tier re-classification of the "M" (metastasis) domain of the Tumor-Node-Metastasis (TNM) staging of Renal Cell Carcinoma (RCC) may improve staging accuracy than the current monolithic classification, as advancements in the understanding of tumor biology have led to increased recognition of the heterogeneous potential of metastatic RCC (mRCC). Methods: Multicenter retrospective analysis of patients from the REMARCC (REgistry of MetAstatic RCC) database. Patients were stratified by number of metastases into two groups, M1 (≤3, "Oligometastatic") and M2 (>3, "Polymetastatic"). Primary outcome was overall survival (OS). Secondary outcomes were cancer-specific survival (CSS). Cox-regression and Kaplan-Meier (KMA) analysis were utilized for outcomes, and receiver operating characteristic analysis (ROC) was utilized to assess diagnostic accuracy compared to current "M" staging. Results: 429 patients were stratified into proposed M1 and M2 groups (M1 = 286/M2 = 143; median follow-up 19.2 months). Cox-regression revealed M2 classification as an independent risk factor for worsened all-cause mortality (HR=1.67, p=0.001) and cancer-specific mortality (HR=1.74, p<0.001). Comparing M1-oligometastatic vs. M2-polymetastatic groups, KMA revealed significantly higher 5-year OS (36% vs. 21%, p<0.001) and 5-year CSS (39% vs. 17%, p<0.001). ROC analyses comparing OS and CSS, for M1/M2 reclassification versus unitary M designation currently in use demonstrated improved c-index for OS (M1/M2 0.635 vs. unitary M 0.500) and CSS (M1/M2 0.627 vs. unitary M 0.500). Conclusion: Subclassification of Stage "M" domain of mRCC into two clinical substage categories based on metastatic burden corresponds to distinctive tumor groups whose oncological potential varies significantly and result in improved predictive capability compared to current staging.

Current Management of Urachal Carcinoma: An Evidence-based Guide for Clinical Practice.

Urachal carcinoma is a rare urological disease. The shortage of data about diagnosis and surgical treatment in literature makes it hard for clinicians to make a decision. Indeed, urachal carcinoma is an aggressive disease that requires prompt staging and treatment to ensure the best outcome for patients. We reviewed the last evidence about the management of urachal carcinoma to provide an easy-to-use guide for clinical practice. Patient summary: Urachal carcinoma is a rare malignancy. The literature on this challenging disease remains limited. Herein, we provide a practical guide for its management from diagnosis to treatment, which in most cases requires surgical intervention or chemotherapy.

Alterations in the molecular composition of COVID-19 patient urine, detected using Raman spectroscopic/computational analysis.

We developed and tested a method to detect COVID-19 disease, using urine specimens. The technology is based on Raman spectroscopy and computational analysis. It does not detect SARS-CoV-2 virus or viral components, but rather a urine 'molecular fingerprint', representing systemic metabolic, inflammatory, and immunologic reactions to infection. We analyzed voided urine specimens from 46 symptomatic COVID-19 patients with positive real time-polymerase chain reaction (RT-PCR) tests for infection or household contact with test-positive patients. We compared their urine Raman spectra with urine Raman spectra from healthy individuals (n = 185), peritoneal dialysis patients (n = 20), and patients with active bladder cancer (n = 17), collected between 2016-2018 (i.e., pre-COVID-19). We also compared all urine Raman spectra with urine specimens collected from healthy, fully vaccinated volunteers (n = 19) from July to September 2021. Disease severity (primarily respiratory) ranged among mild (n = 25), moderate (n = 14), and severe (n = 7). Seventy percent of patients sought evaluation within 14 days of onset. One severely affected patient was hospitalized, the remainder being managed with home/ambulatory care. Twenty patients had clinical pathology profiling. Seven of 20 patients had mildly elevated serum creatinine values (>0.9 mg/dl; range 0.9-1.34 mg/dl) and 6/7 of these patients also had estimated glomerular filtration rates (eGFR) <90 mL/min/1.73m2 (range 59-84 mL/min/1.73m2). We could not determine if any of these patients had antecedent clinical pathology abnormalities. Our technology (Raman Chemometric Urinalysis-Rametrix®) had an overall prediction accuracy of 97.6% for detecting complex, multimolecular fingerprints in urine associated with COVID-19 disease. The sensitivity of this model for detecting COVID-19 was 90.9%. The specificity was 98.8%, the positive predictive value was 93.0%, and the negative predictive value was 98.4%. In assessing severity, the method showed to be accurate in identifying symptoms as mild, moderate, or severe (random chance = 33%) based on the urine multimolecular fingerprint. Finally, a fingerprint of 'Long COVID-19' symptoms (defined as lasting longer than 30 days) was located in urine. Our methods were able to locate the presence of this fingerprint with 70.0% sensitivity and 98.7% specificity in leave-one-out cross-validation analysis. Further validation testing will include sampling more patients, examining correlations of disease severity and/or duration, and employing metabolomic analysis (Gas Chromatography-Mass Spectrometry [GC-MS], High Performance Liquid Chromatography [HPLC]) to identify individual components contributing to COVID-19 molecular fingerprints.

Impact of Metastasectomy on Cancer Specific and Overall Survival in Metastatic Renal Cell Carcinoma: Analysis of the REMARCC Registry.

BACKGROUND: Treatment paradigms for management of metastatic renal cell carcinoma (mRCC) are evolving. We examined impact of surgical metastasectomy on survival across in mRCC stratified by risk-group. METHODS: Multicenter retrospective analysis from the Registry of Metastatic RCC database. The cohort was subdivided utilizing Motzer criteria (favorable-, intermediate-, high-risk). Primary outcome was all-cause mortality (ACM)/overall survival (OS); secondary outcome was cancer-specific mortality (CSM)/cancer-specific survival (CSS). Impact of metastasectomy was analyzed via Cox-Regression analysis adjusting for potential prognostic variables and Kaplan-Meier analysis (KMA) within each risk-group. RESULTS: Four hundred thirty-one patients (59 favorable-risk, 274 intermediate-risk, 98 high-risk; median follow-up 27.2 months) were analyzed. Metastasectomy was performed in 22 (37%), 66 (24%), and 32 (16%) of favorable-, intermediate- and high-risk groups (P = .012). Median number of metastases at diagnosis differed significantly (favorable-risk 2, intermediate-risk 3.4, high-risk 5.1, P < .001). On Cox-regression, high-risk (HR = 1.72, P = .002) was associated with worsened ACM, while metastasectomy was associated with improved ACM (HR = 0.56, P = .005). On KMA, median OS (months) was longer with metastasectomy in favorable- (92.7 vs. 25.8, P = .003) and intermediate-risk (26.3 vs. 20.1, P = .038), but not high-risk (P = .911) groups. Metastasectomy was associated with longer CSS in favorable- (76.1 vs. 32.8, P = .004) but not intermediate- (P = .06) and high-risk (P = .595) groups. CONCLUSIONS: Metastasectomy was independently associated with improved ACM and CSM, as well as improved CSS and OS in favorable- and intermediate-risk mRCC patients. Metastasectomy may be considered as component of multimodal management strategy in favorable and intermediate-risk subgroups. In high-risk patients, metastasectomy should be deferred except in select circumstances.

A Preoperative Nomogram to Predict Renal Function Insufficiency for Cisplatin-based Adjuvant Chemotherapy Following Minimally Invasive Radical Nephroureterectomy (ROBUUST Collaborative Group).

BACKGROUND: Postoperative renal function impairment represents a main limitation for delivering adjuvant chemotherapy after radical nephroureterectomy (RNU). OBJECTIVE: To create a model predicting renal function decline after minimally invasive RNU. DESIGN, SETTING, AND PARTICIPANTS: A total of 490 patients with nonmetastatic UTUC who underwent minimally invasive RNU were identified from a collaborative database including 17 institutions worldwide (February 2006 to March 2020). Renal function insufficiency for cisplatin-based regimen was defined as estimated glomerular filtration rate (eGFR) <50 ml/min/1.73 m2 at 3 mo after RNU. Patients with baseline eGFR >50 ml/min/1.73 m2 (n = 361) were geographically divided into a training set (n = 226) and an independent external validation set (n = 135) for further analysis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Using transparent reporting of a multivariable prediction model for individual prognosis or diagnosis (TRIPOD) guidelines, a nomogram to predict postoperative eGFR <50 ml/min/1.73 m2 was built based on the coefficients of the least absolute shrinkage and selection operation (LASSO) logistic regression. The discrimination, calibration, and clinical use of the nomogram were investigated. RESULTS AND LIMITATIONS: The model that incorporated age, body mass index, preoperative eGFR, and hydroureteronephrosis was developed with an area under the curve of 0.771, which was confirmed to be 0.773 in the external validation set. The calibration curve demonstrated good agreement. Besides, the model was converted into a risk score with a cutoff value of 0.583, and the difference between the low- and high-risk groups both in overall death risk (hazard ratio [HR]: 4.59, p < 0.001) and cancer-specific death risk (HR: 5.19, p < 0.001) was statistically significant. The limitation mainly lies in its retrospective design. CONCLUSIONS: A nomogram incorporating immediately available clinical variables can accurately predict renal insufficiency for cisplatin-based adjuvant chemotherapy after minimally invasive RNU and may serve as a tool facilitating patient selection. PATIENT SUMMARY: We have developed a model for the prediction of renal function loss after radical nephroureterectomy to facilitate patient selection for perioperative chemotherapy.

Novel Classification for Upper Tract Urothelial Carcinoma to Better Risk-stratify Patients Eligible for Kidney-sparing Strategies: An International Collaborative Study.

BACKGROUND: The European Association of Urology risk stratification dichotomizes patients with upper tract urothelial carcinoma (UTUC) into two risk categories. OBJECTIVE: To evaluate the predictive value of a new classification to better risk stratify patients eligible for kidney-sparing surgery (KSS). DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective study including 1214 patients from 21 centers who underwent ureterorenoscopy (URS) with biopsy followed by radical nephroureterectomy (RNU) for nonmetastatic UTUC between 2000 and 2017. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: A multivariate logistic regression analysis identified predictors of muscle invasion (≥pT2) at RNU. The Youden index was used to identify cutoff points. RESULTS AND LIMITATIONS: A total of 811 patients (67%) were male and the median age was 71 yr (interquartile range 63-77). The presence of non-organ-confined disease on preoperative imaging (p < 0.0001), sessile tumor (p < 0.0001), hydronephrosis (p = 0.0003), high-grade cytology (p = 0.0043), or biopsy (p = 0.0174) and higher age at diagnosis (p = 0.029) were independently associated with ≥pT2 at RNU. Tumor size was significantly associated with ≥pT2 disease only in univariate analysis with a cutoff of 2 cm. Tumor size and all significant categorical variables defined the high-risk category. Tumor multifocality and a history of radical cystectomy help to dichotomize between low-risk and intermediate-risk categories. The odds ratio for muscle invasion were 5.5 (95% confidence interval [CI] 1.3-24.0; p = 0.023) for intermediate risk versus low risk, and 12.7 (95% CI 3.0-54.5; p = 0.0006) for high risk versus low risk. Limitations include the retrospective design and selection bias (all patients underwent RNU). CONCLUSIONS: Patients with low-risk UTUC represent ideal candidates for KSS, while some patients with intermediate-risk UTUC may also be considered. This classification needs further prospective validation and may help stratification in clinical trial design. PATIENT SUMMARY: We investigated factors predicting stage 2 or greater cancer of the upper urinary tract at the time of surgery for ureter and kidney removal and designed a new risk stratification. Patients with low or intermediate risk may be eligible for kidney-sparing surgery with close follow-up. Our classification scheme needs further validation based on cancer outcomes.

Robot-Assisted Ureteral Reimplantation: A Single-Center Comparative Study.

Background: Aim of this study was to report a single-center experience with robot-assisted ureteral reimplantation (RAUR) and to compare its outcomes with those of open ureteral reimplantation (OUR). Materials and Methods: Patients who underwent RAUR or OUR for ureteral disease between 2016 and 2020 were identified. Data collected included baseline, pathologic, perioperative, and postoperative features. The RAUR outcomes were compared with those of OUR. Results: Overall, 21 (42.8%) patients underwent RAUR, and 28 (57.2%) underwent OUR. The two groups were similar in terms of baseline and pathologic characteristics. There was a statistically significant difference in favor of RAUR for median operative time (216 vs 317 minutes, p = 0.01) and median blood loss (35 vs 175 mL, p = 0.001). No difference was observed in overall complication rate (33.3% vs 46.4%, p = 0.9), as well as major complications (Clavien-Dindo≥III grade) rate between RAUR and OUR groups. Median length of stay was shorter for RAUR (2 vs 6 days; p = 0.001), as well as median catheterization time (16 vs 28 days; p = 0.005). Conclusions: RAUR is a safe and effective minimally invasive surgical procedure for the management of mid to distal ureteral strictures. It can recapitulate the success rate of the gold standard OUR while offering a benefit in terms of lower surgical morbidity and faster postoperative recovery.