Displacement of Lower Pole Stones During Retrograde Intrarenal Surgery Improves Stone-free Status: A Prospective Randomized Controlled Trial.

PURPOSE: Lower pole renal stones are associated with the lowest stone-free status of any location in the urinary tract during retrograde intrarenal surgery. Prior work has suggested displacing lower pole stones to a more accessible part of the kidney to improve stone-free status. We sought to prospectively compare the efficacy of laser lithotripsy in situ vs after displacement during retrograde intrarenal surgery for lower pole stones. MATERIALS AND METHODS: Between July 2017 and May 2022 patients undergoing retrograde intrarenal surgery for lower pole stones were randomized into an in situ or displacement group. Demographics, comorbidities, and operative parameters were documented. Primary outcome was stone-free status, determined by combination of abdominal x-ray and renal ultrasound at 30-day follow-up. Secondary outcomes included operative time, 30-day complications, emergency department visits, and readmissions. RESULTS: A total of 138 patients (69 per group) were enrolled and analyzed. Baseline characteristics were similar between groups. Stone-free status significantly favored the displacement group over the in situ group (95% vs 74%, P = .003, n=62 in each group). Operative time, total laser energy usage, 30-day complications, and 30-day emergency department visits or hospital readmissions were similar between groups. On multivariate analysis only study group allocation was significantly associated with stone-free status (P = .024). CONCLUSIONS: Basket displacement of lower pole stones results in a significantly higher stone-free status compared to in situ lithotripsy. The technique is simple, atraumatic, and requires no additional equipment costs and little additional operative time, making it a practical tool in the treatment of lower pole stones.

Gold nanoshell-localized photothermal ablation of prostate tumors in a clinical pilot device study.

Biocompatible gold nanoparticles designed to absorb light at wavelengths of high tissue transparency have been of particular interest for biomedical applications. The ability of such nanoparticles to convert absorbed near-infrared light to heat and induce highly localized hyperthermia has been shown to be highly effective for photothermal cancer therapy, resulting in cell death and tumor remission in a multitude of preclinical animal models. Here we report the initial results of a clinical trial in which laser-excited gold-silica nanoshells (GSNs) were used in combination with magnetic resonance-ultrasound fusion imaging to focally ablate low-intermediate-grade tumors within the prostate. The overall goal is to provide highly localized regional control of prostate cancer that also results in greatly reduced patient morbidity and improved functional outcomes. This pilot device study reports feasibility and safety data from 16 cases of patients diagnosed with low- or intermediate-risk localized prostate cancer. After GSN infusion and high-precision laser ablation, patients underwent multiparametric MRI of the prostate at 48 to 72 h, followed by postprocedure mpMRI/ultrasound targeted fusion biopsies at 3 and 12 mo, as well as a standard 12-core systematic biopsy at 12 mo. GSN-mediated focal laser ablation was successfully achieved in 94% (15/16) of patients, with no significant difference in International Prostate Symptom Score or Sexual Health Inventory for Men observed after treatment. This treatment protocol appears to be feasible and safe in men with low- or intermediate-risk localized prostate cancer without serious complications or deleterious changes in genitourinary function.

A cohort of transperineal electromagnetically tracked magnetic resonance imaging/ultrasonography fusion-guided biopsy: assessing the impact of inter-reader variability on cancer detection.

OBJECTIVE: To evaluate the ability to detect clinically significant prostate cancer (PCa) using a novel electromagnetically (EM) tracked transperineal magnetic resonance imaging (MRI)/ultrasonography (US) fusion-guided targeted biopsy (transperineal TBx) platform and the impact of inter-reader variability on cancer detection. MATERIALS AND METHODS: A total of 176 patients with suspicious lesions detected on multiparametric MRI (mpMRI) underwent a systematic modified Barzel template biopsy (12-core) transperineal biopsy (transperineal SBx) and transperineal TBx with EM tracking (UroNav; Philips Healthcare, Best, the Netherlands) in the same setting. Cancer detection rates (CDRs) were stratified by Prostate Imaging Reporting and Data System (PI-RADS) v2 scores and compared with Fisher's exact test. Area under the curve (AUC) was calculated for prostate-specific antigen (PSA), PSA density (PSAD), PI-RADS score, and subgroup analysis of individual readers' PI-RADS scores with respect to overall CDR and clinically significant CDR. RESULTS: The overall CDR was 76.7% (135/176), of which 76.3% (103/135) was clinically significant PCa. Among the 135 patients with PCa, transperineal TBx detected 90.4% of cases (122/135), either alone or in combination with transperineal SBx. The remaining 9.6% of cases (13/135) missed by transperineal TBx were diagnosed by transperineal SBx alone, of which three were clinically significant. Conversely, transperineal SBx missed 14% of cases (19/135), 14 of which were clinically significant PCa. Sensitivities for transperineal TBx and transperineal SBx were 90.4% and 85.9%, respectively. On a per-lesion basis, PI-RADS score (AUC 0.74) outperformed both PSA (AUC 0.59) and PSAD (AUC 0.63) in discriminating clinically significant from non-clinically significant PCa on transperineal TBx. Although not formally statistically tested, AUCs amongst different mpMRI readers appeared to display considerable variability. There were no adverse events, including sepsis. CONCLUSIONS: Electromagnetically tracked transperineal TBx of MRI-visible lesions enhanced the ability of transperineal SBx to detect PCa, with greater sensitivity for clinically significant disease. These findings suggest transperineal TBx is a safe, alternative fusion platform for patients with a suspicious lesion on prostate MRI. The assessment of inter-reader variability, in conjunction with prediction of clinically significant PCa and CDR, is an important first step for quality control in implementing an MRI-based screening programme.

Immune phenotype of peripheral blood mononuclear cells in patients with high-risk non-muscle invasive bladder cancer.

PURPOSE: To explore the immune phenotype of peripheral blood mononuclear cells (PBMC) in patients with high-risk non-muscle invasive bladder cancer (NMIBC). METHODS: We prospectively collected blood samples from patients with high-risk NMIBC treated at our institution. PBMC were analyzed by flow cytometry to determine the frequency of T cells and NK cells and the expression of immunoregulatory molecules (Tim-3, TIGIT and PD-1). PBMC from healthy donors (HD) were included for comparison, and associations with response to BCG were investigated. RESULTS: A total of 38 patients were included, 19 BCG responders and 19 BCG refractory. Compared to 16 PBMC from HD, the frequency of total NK cells was significantly higher in patients with NMIBC [15.2% (IQR: 11.4, 22.2) vs. 5.72% (IQR: 4.84, 9.79); p = 0.05], whereas the frequency of T cells was not statistically different. Both Tim-3 and TIGIT expressions were significantly higher in NMIBC compared to HD, particularly in NK cells [13.8% (11.0; 22.4) vs. 5.56% (4.20; 10.2) and 34.9% (18.9; 53.5) vs. 1.82% (0.63; 5.16), respectively; p < 0.001]. Overall, the expression of PD-1 in all cell types was low in both NMIBC patients and HD. The immune phenotype was not significantly different before and after initiation of BCG. However, the proportion of CD8+ T cells before BCG was significantly higher in responders. CONCLUSION: The immune phenotype of PBMC from patients with high-risk NMIBC was significantly different from HD, regardless of the presence of disease or the initiation of BCG. Peripheral CD8+ T cells could play a role in response to BCG.

Targeted Ablative Therapies for Prostate Cancer.

Men diagnosed with low- to intermediate-risk, clinically localized prostate cancer (PCa) often face a daunting and difficult decision with respect to treatment: active surveillance (AS) or radical therapy. This decision is further confounded by the fact that many of these men diagnosed, by an elevated PSA, will have indolent disease and never require intervention. Radical treatments, including radical prostatectomy and whole-gland radiation, offer greater certainty for cancer control, but at the risk of significant urinary and/or sexual morbidity. Conversely, AS preserves genitourinary function and quality of life in exchange for burdensome surveillance and the psychological impact of living with cancer.

Cell death under epithelial-mesenchymal transition control in prostate cancer therapeutic response.

Prostate cancer is a widespread problem among men, with >160 000 new cases in 2017 alone. Androgen deprivation therapy is commonly used in prostate cancer treatment to block androgens required for cancer growth, but disease relapse after androgen deprivation therapy is both common and severe. Changes in androgen receptor signaling from androgen deprivation therapy have been linked to therapeutic resistance and tumor progression. Resistant cells can become reprogrammed to undergo epithelial-mesenchymal transition, a phenotypic switch from benign, epithelial cells to a mobile cell with mesenchymal traits. In these cells, attachment to their epithelial cell layer is no longer required for survival. Anoikis is a form of cell death that occurs when detachment from other cells and the basement membrane occurs. Epithelial cells have been shown to undergo epithelial-mesenchymal transition, avoid anoikis induction and progress to a metastatic phenotype. In prostate cancer progression to advanced disease, epithelial-mesenchymal transition induction (characterized by loss of epithelial cellular attachment protein E-cadherin) correlates with a higher Gleason score, tumor progression, increased metastasis and higher biochemical recurrence. The concept of interfacing epithelial-mesenchymal transition with anoikis in the tumor microenvironment landscape will be discussed here, with focus on the significance of the functional exchange between the two processes in therapeutic targeting of advanced disease. The current evidence on the impact of loss of cell-cell contact, acquisition of chemoresistance, immune escape and metastatic spread in advanced tumors in response to transforming growth factor-ß on prostate cancer metastasis will be also discussed. The signaling cross-talk between transforming growth factor-ß and androgen receptor signaling will be interrogated as a new therapeutic platform for the development of combination strategies to impair prostate cancer metastasis.

Predicting Complications Following Robot-Assisted Partial Nephrectomy with the ACS NSQIP® Universal Surgical Risk Calculator.

PURPOSE: We evaluated the predictive value of the ACS NSQIP® (American College of Surgeons National Surgical Quality Improvement Program®) surgical risk calculator in a tertiary referral cohort of patients who underwent robot-assisted partial nephrectomy. MATERIALS AND METHODS: We queried our prospectively maintained, multi-institutional database of patients treated with robot-assisted partial nephrectomy and input the preoperative details of 300 randomly selected patients into the calculator. Accuracy of the calculator was assessed by the ROC AUC and the Brier score. RESULTS: The observed rate of any complication in our cohort was 14% while the mean predicted rate of any complication using the calculator was 5.42%. The observed rate of serious complications (Clavien score 3 or greater) was 3.67% compared to the predicted rate of 4.89%. Low AUC and high Brier score were calculated for any complication (0.51 and 0.1272) and serious complications (0.55 and 0.0352, respectively). The calculated AUC was low for all outcomes, including venous thromboembolism (0.67), surgical site infection (0.51) and pneumonia (0.44). CONCLUSIONS: The ACS NSQIP risk calculator poorly predicted and discriminated which patients would experience complications after robot-assisted partial nephrectomy. These findings suggest the need for a more tailored outcome prediction model to better assist urologists risk stratify patients undergoing robot-assisted partial nephrectomy and counsel them on individual surgical risks.

Natural Killer Cell Dysfunction In Human Bladder Cancer Is Caused By Tissue-Specific Suppression of SLAMF6 Signaling.

NK cells are innate lymphocytes critical for surveillance of viruses and tumors, however the mechanisms underlying NK cell dysfunction in cancer are incompletely understood. We assessed the effector function of NK cells from bladder cancer patients and found severe dysfunction in NK cells derived from tumors versus peripheral blood. While both peripheral and tumor-infiltrating NK cells exhibited conserved patterns of inhibitory receptor over-expression, this did not explain the observed defects in NK surveillance in bladder tumors. Rather, TME-specific TGF-ß and metabolic perturbations such as hypoxia directly suppressed NK cell function. Specifically, an oxygen-dependent reduction in signaling through SLAMF6 was mechanistically responsible for poor NK cell function, as tumor-infiltrating NK cells cultured ex vivo under normoxic conditions exhibited complete restoration of function, while deletion of SLAMF6 abrogated NK cell cytolytic function even under normoxic conditions. Collectively, this work highlights the role of tissue-specific factors in dictating NK cell function, and implicates SLAMF6 signaling as a rational target for immuno-modulation to improve NK cell function in bladder cancer.

Factors that influence preference for male or female urologist among underserved patients in New York City.

Objective: To examine the prevalence of patient preference for male or female urologic provider and explore which patient characteristics influence this preference. Materials and Methods: After obtaining hospital Institutional Review Board approval, a 14-question survey in English and Spanish was administered across four general urology clinic sites in a single hospital system in New York City. The survey asked demographic questions and preference for a male or a female urologist. The survey included questions pertaining to the nature of the clinic visit and subsequent provider preference as well. Statistics were performed using Stata 16 (StataCorp, College Station, TX). Results: A total of 540 patients completed the 14-question survey. The vast majority of survey respondents identified as male (90%). The largest proportion demographic groups were those aged 41-60 (47%), Hispanic or Latino (43%), Catholic (47%), unemployed (40%) and those with a high school level of education (34%). Most patients (60%) did not have a preference for a specific gender provider, whereas 37% preferred a male provider, and 3% preferred a female provider. On univariate analysis, patient age 25-40, less than high school education level and lack of employment were significant predictors of provider gender preference (p < 0.05), with most patients indicating a male provider preference. On multivariate analysis of gender, age, education level and employment status, gender and education level were not significant predictors of preference, whereas age 25-40 and being unemployed were significant predictors (p < 0.05). Conclusion: Patient gender, race and religion do not appear to influence their preference to be seen by a male or a female urologist in the clinic setting. However, patient age, unemployment and potentially educational attainment were significantly associated with a provider gender preference.

Reverse Trendelenburg Positioning Minimizes Stone Retropulsion During Ureteroscopic Laser Lithotripsy: A Prospective Randomized Study.

Purpose: Retropulsion of stone fragments during ureteroscopic laser lithotripsy (URSLL) remains a challenge for urologists and is associated with increased operative time and reduced stone-free rate (SFR). In this study, we compared the rate of retropulsion of ureteral stones during URSLL between the standard dorsal lithotomy (SDL) position and dorsal lithotomy position with reverse Trendelenburg (RT). Materials and Methods: Patients with ureteral stones requiring surgical intervention between May 2019 and January 2022 were randomized to undergo URSLL in either SDL or RT positions. The primary outcome of this study was stone retropulsion. Secondary outcomes included retropulsion to the kidney, SFR, operative time, 30-day emergency department visits and complications, and the need for conversion from semirigid to flexible ureteroscope. Differences between groups were evaluated using the chi-square test, Fisher exact test, Kruskal-Wallis test, or t-test. Results: A total of 114 patients were included in the study, with 57 patients in each group. There were no differences between groups in terms of baseline demographics or stone characteristics. Retropulsion was significantly less frequent in the RT group (68.4% vs 10.5%, p < 0.01). Similarly, the RT group was favored for lower risk of retropulsion into the kidney (40.4% vs 5.3%, p < 0.01), operative time (43.5 vs 33.0 minutes, p = 0.02), and need for ureteroscope conversion (16.7% vs 2.2%, p = 0.04). There was no difference in the SFR (100% vs 95%, p = 0.49). Conclusions: RT positioning during URSLL for ureteral stones significantly decreases the rate of stone retropulsion, operative time, and the need for conversion from semirigid to flexible ureteroscope.

TIM-3 and TIGIT are possible immune checkpoint targets in patients with bladder cancer.

The resurgence of immunotherapy as an effective anticancer strategy has been coupled with more mature understandings of the underlying immune pathways and the development of novel immune checkpoint targets. The clinical development of antibodies first directed against cytotoxic T-lymphocyte-associated antigen 4, and later against program death 1, achieved durable disease control in a subset of patients across a large number of tumor types. Previous work demonstrates that targeting the programmed death 1 pathway alone does not result in complete restoration of T cell function and in some cancers, targeting this axis does not restore T cell function at all, suggesting a need to identify other molecules and inhibitory pathways that are involved in T cell exhaustion. In a comprehensive immune profiling study of patients with bladder cancer, we demonstrate T-cell immunoglobulin domain and mucin domain-containing molecule and T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain as possible targets as perhaps monotherapy or in combination with other immune checkpoint inhibitors.

Black race may be associated with worse overall survival in renal cell carcinoma patients.

OBJECTIVE: To examine socio-demographic and treatment variables in an attempt to identify factors associated with survival differences between black and white patients with renal cell carcinoma (RCC). PATIENTS AND METHODS: We identified 79,618 white and 10,604 black patients diagnosed with RCC in the National Cancer Database. We compared the distribution of socio-demographic, presentation and treatment variables between Blacks and Whites and then utilized a multivariable cox proportion hazards regression model to evaluate the contribution of differences in these variables to disparities in overall survival (OS). RESULTS: Black patients were younger (60 vs. 63 years, P< 0.001) and with a lower stage (12.0% vs. 18.8% Stage III-IV P< 0.001). Blacks presented with a higher Charlson-Deyo score (P< 0.001), lower income (P< 0.001), lower education (P< 0.001) and were less likely to receive radical nephrectomy and systemic therapy for stage IV RCC (29.9% vs. 38.8%, P< 0.001). Unadjusted OS was lower for Whites (5-year survival 79% for Blacks and 77% for Whites). However, OS was lower for Blacks when adjusted for all variables (5-year survival 89% for Blacks and 93% for Whites). On multivariable analysis, black race was independently associated with worse OS, HR: 1.09 (95% confidence interval: 1.03, 1.14, P= 0.002). A sensitivity analysis including patients with complete data on tumor grade confirmed our results. CONCLUSION: Our study indicates that black patients present at a younger age and with lower stage RCC, but have worse OS. Blacks experienced disparities in socio-demographic characteristics, clinical presentation, treatment-related factors, and had an independently increased hazard of death.

Epithelial plasticity can generate multi-lineage phenotypes in human and murine bladder cancers.

Tumor heterogeneity is common in cancer, however recent studies have applied single gene expression signatures to classify bladder cancers into distinct subtypes. Such stratification assumes that a predominant transcriptomic signature is sufficient to predict progression kinetics, patient survival and treatment response. We hypothesize that such static classification ignores intra-tumoral heterogeneity and the potential for cellular plasticity occurring during disease development. We have conducted single cell transcriptome analyses of mouse and human model systems of bladder cancer and show that tumor cells with multiple lineage subtypes not only cluster closely together at the transcriptional level but can maintain concomitant gene expression of at least one mRNA subtype. Functional studies reveal that tumor initiation and cellular plasticity can initiate from multiple lineage subtypes. Collectively, these data suggest that lineage plasticity may contribute to innate tumor heterogeneity, which in turn carry clinical implications regarding the classification and treatment of bladder cancer.

Avoiding Unnecessary Magnetic Resonance Imaging (MRI) and Biopsies: Negative and Positive Predictive Value of MRI According to Prostate-specific Antigen Density, 4Kscore and Risk Calculators.

The 2019 European Association of Urology guidelines recommend multiparametric magnetic resonance imaging (mpMRI) for biopsy-naïve patients with clinical suspicion of prostate cancer (PC) and avoiding biopsy in patients with negative mpMRI and low clinical suspicion. However, consensus on the optimal definition of low clinical suspicion is lacking. We evaluated 266 biopsy-naïve patients who underwent mpMRI, the 4Kscore test, and prostate biopsy to define the best strategy to avoid unnecessary testing and biopsies. The European Randomized Study of Screening for Prostate Cancer risk calculator (ERSPC-RC) and prostate-specific antigen density (PSAd) were also considered. For men with Prostate Imaging-Reporting and Data System v2.0 (PI-RADS) 1â¿¿2 lesions, the highest negative predictive value was observed for those with low or intermediate 4Kscore risk (96.9% and 97.1%), PSAd <0.10ng/ml/cm3 (98.7%), and ERSPC-RC <2% (98.7%). For men with PI-RADS 3â¿¿5 lesions the lowest positive predictive value was observed for those with low 4Kscore risk (0%), PSAd <0.10ng/ml/cm3 (13.2%), and ERSPC-RC <2% (12.3%). The best biopsy strategy was an initial 4Kscore followed by mpMRI if the 4Kscore was>7.5% and a subsequent biopsy if the mpMRI was positive (PI-RADS 3â¿¿5) or the 4Kscore was â¿¥18%. This would result in missing 2.7% (2/74) of clinically significant PCs (csPCs) and avoiding 34.2% of biopsies. Initial mpMRI followed by biopsy for negative mpMRI (PI-RADS 1â¿¿2) if the 4Kscore was â¿¥18% or PSAd was â¿¥0.10ng/ml/cm3 resulted in a similar percentage of csPC missed (2.7% [2/74] and 1.3% [1/74]) but slightly fewer biopsies avoided (25.2% and 28.1%). Physicians should consider clinical risk screening tools when ordering and interpreting mpMRI results to avoid unnecessary testing and diagnostic errors. PATIENT SUMMARY: Performing the 4Kscore test in conjunction with multiparametric magnetic resonance imaging for men with a clinical suspicion of prostate cancer may help to reduce unnecessary biopsies.

Clinicopathological and survival analysis of clinically advanced papillary and chromophobe renal cell carcinoma.

INTRODUCTION: Clinically, the papillary (pRCC) and chromophobe (chRCC) histologic subtypes of renal cell carcinoma (RCC) are viewed as more indolent compared to the more-common clear cell histology (ccRCC). However, there remain advanced cases of these purportedly less-aggressive histologies that lead to significant mortality. We therefore sought to evaluate outcomes of advanced pRCC and chRCC compared to ccRCC utilizing the National Cancer Database's registry of RCC patients. MATERIALS AND METHODS: A total of 115,365 ccRCC patients, 28,344 pRCC patients, and 11,942 chRCC patients met eligibility criteria. Overall survival (OS) was estimated using the Kaplan-Meier method (median follow-up 3.6 years). OS was compared between stage III and IV ccRCC, pRCC, and chRCC using multivariable Cox proportional hazards model adjusted for clinical and treatment characteristics. RESULTS: A total of 25.7% of ccRCC patients, 14.1% of pRCC patients, and 14.8% of chRCC patients had stage III to IV disease. The 5-year OS for stage III ccRCC, pRCC, and chRCC was 66.9%, 63.6%, and 80.5%, respectively. The 5-year OS for stage IV ccRCC, pRCC and chRCC was 19.7%, 13.3%, and 22.0%, respectively. The hazard of death was significantly higher for stage IV pRCC vs. ccRCC (hazard ratio = 1.29; 95% confidence interval = 1.19, 1.39; P < 0.01) and similar for stage IV chRCC vs. ccRCC (hazard ratio = 1.01; 95% confidence interval = 0.85, 1.21; P = 0.885). CONCLUSIONS: pRCC and chRCC are rare but similarly fatal compared to ccRCC when advanced or metastatic. With most clinical trials devoted toward ccRCC, greater efforts to identify aggressive variants and treatment strategies for metastatic pRCC and chRCC are necessary.

Demographic and socioeconomic predictors of treatment delays, pathologic stage, and survival among patients with penile cancer: A report from the National Cancer Database.

OBJECTIVES: To evaluate whether socioeconomic factors affect pathologic stage, treatment delays, pathologic upstaging, and overall survival (OS) in patients with penile cancer (PC). PATIENTS AND METHODS: A total of 13,283 eligible patients diagnosed with PC from 1998 to 2012 were identified from the National Cancer Database. Socioeconomic, demographic and pathologic variables were used in multivariable regression models to identify predictors of pathologic T stage ≥2, pathologic lymph node positivity, cT to pT upstaging, treatment delays, and OS. RESULTS: A 5-year OS was 61.5% with a median follow-up of 41.7 months. Pathologic T stage ≥2 was identified in 3,521 patients (27.2%), 1,173 (9.2%) had ≥pN1 and 388 (7.9%) experienced cT to pT upstaging. Variables associated with a higher likelihood of pathologic T stage ≥2 included no insurance (OR = 1.79, P<0.001), lower higher education based on zip code (OR = 1.13, P = 0.027), black race (OR = 1.17, P = 0.046) and Hispanic ethnicity (OR = 1.66, P<0.001). Patients with Hispanic ethnicity (OR = 1.46; P<0.001) or living in nonmetropolitan areas were more likely to have ≥pN1 (P = 0.001). Lack of insurance was associated with cT to pT upstaging (OR = 2.05, P = 0.001) as was living in an urban vs. metropolitan area (OR = 1.35, P = 0.031). In addition to TNM stage, black vs. white race (HR = 1.56, P<0.001), living in an urban vs. metropolitan area (hazard ratio [HR] = 1.18, P = 0.022), age (HR = 1.04, P<0.001) and Charlson score (HR = 1.49, P<0.001) were associated with lower OS. CONCLUSION: Socioeconomic variables including no insurance, lower education, race, Hispanic ethnicity, and nonmetropolitan residence were found to be poor prognostic factors. Increased educational awareness of this rare disease may help reduce delays in diagnosis, improve prognosis and ultimately prevent deaths among socioeconomically disadvantaged men with PC.