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The aim of this study was to develop a model to predict high-genomic-risk prostate cancer (PCa) according to Decipher score, a validated 22 gene prognostic panel. By doing so, one might select the individuals who are likely to benefit from genomic testing and improve pre-op counseling about the need for adjuvant treatments.We retrospectively reviewed IRB-approved databases at two institutions. All patients had preoperative magnetic resonance imaging (MRI) and Decipher prostate radical prostatectomy (RP), a validated 22 gene prognostic panel. We used binary logistic regression to estimate high-risk Decipher (Decipher score 0.60) probability on RP specimen. Area under the curve (AUC) and calibration were used to assess the accuracy of the model in the development and validation cohort. Decision curve analysis (DCA) was performed to assess the clinical benefit of the model.The development and validation cohort included 622 and 185 patients with 283 (35%) and 80 (43%) of those with high-risk Decipher. The multivariable model included PSA density, biopsy Gleason Grade Group, percentage of positive cores and MRI extracapsular extension. AUC was 0.73 after leave-one-out cross-validation. DCA showed a clinical benefit in a range of probabilities between 15 and 60%. In the external validation cohort, AUC was 0.70 and calibration showed that the model underestimates the actual probability of the outcome.The proposed model to predict high-risk Decipher score at RP is helpful to improve risk stratification of patients with PCa and to assess the need for additional testing and treatments.

Background Current European Association of Urology, American Urological Association, and National Comprehensive Cancer Network guidelines recommend active surveillance (AS) for selected intermediate-risk prostate cancer (PCa) patients. However, limited evidence exists regarding which men can be selected safely. Objective To externally validate the Gandaglia risk calculator (Gandaglia-RC), designed to predict adverse pathology (AP) at radical prostatectomy (RP) and thus able to improve selection of intermediate-risk PCa patients suitable for AS, and to assess whether addition of magnetic resonance imaging (MRI) findings (MAP model) improves the predictive ability of Gandaglia-RC. Design, setting, and participants This is a retrospective analysis of a single-center cohort of 1284 consecutive men with low- and intermediate-risk PCa treated with RP between 2013 and 2019. Outcome measurements and statistical analysis AP was defined as non–organ-confined disease and/or lymph node invasion and/or pathological grade group ≥ 3 at RP. Logistic regression was used to calculate the predictors of AP; calculated coefficients were used to develop a risk score. Receiver operating characteristic curve analysis and decision curve analysis were performed to evaluate the net benefit within models. Results and limitations At multivariable analysis, age at surgery, prostate-specific antigen, systematic and targeted biopsy Gleason grade group, MRI prostate volume, Prostate Imaging Reporting and Data System score, and MRI extraprostatic extension were significantly associated with AP. The model significantly improved the ability of Gandaglia-RC to predict AP (area under the curve 0.71 vs 0.63 [p Conclusions Compared with Gandaglia-RC, the MAP model significantly increased the number of patients eligible for AS without significantly increasing the risk of AP at RP. Patient summary In this report, we have developed a risk prediction tool to select men for conservative treatment of prostate cancer. Using the novel tool, more men could safely be allocated to conservative treatment rather than surgery or radiation.

Background A common side effect following radical prostatectomy is urinary incontinence. Here, we describe a novel surgical technique to reduce postoperative urinary incontinence and facilitate early return of continence. Objective To describe the novel “hood technique” for robotic-assisted radical prostatectomy (RARP). Design, setting, and participants This is an institutional review board–approved prospective study of 300 patients (median age 64 yr) with localized prostate cancer treated with the RARP hood technique at a major urban hospital between April 2018 and March 2019. The exclusion criteria were as follows: patients with anterior tumor location based on biopsy or multiparametric magnetic resonance imaging. All but one patient participated in follow-up over 12 mo after the procedure. Surgical procedure The RARP “hood technique” was performed to preserve the detrusor apron, puboprostatic ligament complex, arcus tendineus, endopelvic fascia, and pouch of Douglas. Measurements Clinical data collected included pre- and intraoperative variables, and postoperative functional and oncological outcomes and complications. Descriptive statistical analysis was performed. Results and limitations Continence rates at 1, 2, 4, 6 12, 24, and 48 wk after catheter removal were 21%, 36%, 83%, 88%, 91%, 94%, and 95%, respectively. Positive surgical margin rate was 6%. Thirty patients (9.7%) experienced complications after RARP: 17 (5.7%), 11 (3.6%), and one (0.4%) had Clavien-Dindo grade I, II, and III complications, respectively. This study was conducted within a single health system and may not be generalizable. The study lacked randomization and a comparative arm. Conclusions Results indicate that the hood technique spares musculofascial structures anterior to the urethral sphincter complex with early return of continence after surgery, without compromising positive surgical margin rates. Exclusion of anterior tumor location contributed to a reduction in positive surgical margins. Patient summary By better preservation of anatomical structures around the urethra, we were able to achieve early return of urinary continence without a negative impact on complications and cancer outcomes.

BACKGROUND Efforts are ongoing to try and find ways to reduce the number of unnecessary prostate biopsies without missing clinically significant prostate cancers (csPCa). The utility of multiparametric magnetic resonance imaging (mpMRI) in detecting prostate cancer (PCa) shows promise to be used as triage test for systematic prostate biopsy. Our aim is to Study clinical parameters and oncological outcomes in men with negative mpMRI (nMRI; PI-RADS v2 scores of ≤ 2) who underwent robot-assisted radical prostatectomy (RARP) to evaluate nMRI's practicality as a biopsy triage test. METHODS Retrospective analysis of 331 men with nMRI who underwent RARP between 2014 and 2020 compared with men with positive mpMRI (pMRI; PI-RADS v2 scores ≥ 3, N = 1770). csPCa was defined as Gleason score ≥ 3 + 4 and biochemical recurrence (BCR) was defined as PSA > 0.2 ng/ml on two occasions. Biopsies were graded with the International Society of Urologic Pathology [ISUP] grade. Descriptive statistics for nMRI and pMRI were performed. Mann-Whitney U test was used for continuous variables and χ 2 for categorical variables. Univariable and multivariable regression analyses were performed. RESULTS Univariable analysis shows statistically significant difference (p

The 2019 European Association of Urology guidelines recommend multiparametric magnetic resonance imaging (mpMRI) for biopsy-naive 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-naive 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) 1⿿2 lesions, the highest negative predictive value was observed for those with low or intermediate 4Kscore risk (96.9% and 97.1%), PSAd 7.5% and a subsequent biopsy if the mpMRI was positive (PI-RADS 3⿿5) or the 4Kscore was ⿥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 1⿿2) if the 4Kscore was ⿥18% or PSAd was ⿥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.

OBJECTIVES To evaluate if the blood biomarker, 4Kscore, in addition to multiparametric magnetic resonance imaging information could identify patients who would benefit from undergoing only a targeted biopsy. METHODS We retrospectively analyzed a population of 256 men with positive multiparametric magnetic resonance imaging who underwent standard + targeted biopsy at Mount Sinai Hospital, New York, NY, USA. 4Kscore (OPKO Health, Miami, FL, USA) was sampled from all patients before biopsy. Uni- and multivariable binary logistic regression analyses were carried out to predict clinically significant prostate cancer, defined as International Society of Urological Pathology grade group ≥2, in standard biopsy cores. The model with the best area under the curve was selected and internal validation was carried out using the leave-one-out cross-validation. RESULTS The developed model showed an area under the curve of 0.86. Carrying out only targeted biopsy in patients with a model-derived probability

PURPOSE Platinum-based chemotherapy for first-line treatment of metastatic urothelial cancer is typically administered for a fixed duration followed by observation until progression. “Switch maintenance” therapy with PD-1 blockade at the time of chemotherapy cessation may be attractive for mechanistic and pragmatic reasons. PATIENTS AND METHODS Patients with metastatic urothelial cancer achieving at least stable disease on first-line platinum-based chemotherapy were enrolled. Patients were randomly assigned double-blind 1:1 to switch maintenance pembrolizumab 200 mg intravenously once every 3 weeks versus placebo for up to 24 months. Patients with disease progression on placebo could cross over to pembrolizumab. The primary objective was to determine the progression-free survival. Secondary objectives included determining overall survival as well as treatment outcomes according to PD-L1 combined positive score (CPS). RESULTS Between December 2015 and November 2018, 108 patients were randomly assigned to pembrolizumab (n = 55) or placebo (n = 53). The objective response rate was 23% with pembrolizumab and 10% with placebo. Treatment-emergent grade 3-4 adverse events occurred in 59% receiving pembrolizumab and 38% of patients receiving placebo. Progression-free survival was significantly longer with maintenance pembrolizumab versus placebo (5.4 months [95% CI, 3.1 to 7.3 months] v 3.0 months [95% CI; 2.7 to 5.5 months]; hazard ratio, 0.65; log-rank P = .04; maximum efficiency robust test P = .039). Median overall survival was 22 months (95% CI, 12.9 months to not reached) with pembrolizumab and 18.7 months (95% CI, 11.4 months to not reached) with placebo. There was no significant interaction between PD-L1 CPS ≥ 10 and treatment arm for progression-free survival or overall survival. CONCLUSION Switch maintenance pembrolizumab leads to additional objective responses in patients achieving at least stable disease with first-line platinum-based chemotherapy and prolongs progression-free survival in patients with metastatic urothelial cancer.

Prostate biopsies are associated with infectious complications and approximately 80% are either benign or clinically insignificant prostate cancer. Our aim is to develop and independently validate prediction model to avoid unnecessary prostate biopsies by predicting clinically significant prostate cancer (csPCa) Materials and Methods: Retrospective analysis of single-center cohort (Mount Sinai Hospital, NY) of 1632 men who underwent systematic or combined systematic and Magnetic Resonance Imaging (MRI)/ultrasound fusion targeted prostate biopsy between 2014-2020. External cohort (University of Miami) included 622 men that underwent biopsy. Outcome for predicting csPCa was defined as International Society of Urologic Pathology (ISUP) Gleason grade ≥ 2 on biopsy. Multivariable logistic regression analysis was performed to build nomogram using coefficients of logit function. Nomogram validation was performed in external cohort by plotting receiver operating characteristics (ROC). We also plotted decision curve analysis (DCA) and compared nomogram-predicted probabilities with actual rates of csPCa probabilities in external cohort.Of 1632 men, 43% showed csPCa on biopsy. PSA density, prior negative biopsy, and Prostate Imaging and Reporting Data System (PI-RADS) scores 3, 4, and 5 were significant predictors for csPCa. ROC for prediction of csPCa was 0.88 in external cohort. There was agreement between predicted and actual rate of csPCa in external cohort. DCA demonstrated net benefit using the model. Using the prediction model at threshold of 30, 35% of biopsies and 46% of diagnosed indolent PCa could be avoided, while missing 5% of csPCa.Using our prediction model can help reduce unnecessary prostate biopsies with minimal impact on csPCa detection rates.

Background mpMRI can provide important information for surgical planning, yet its interpretation is not immediate and imaging consultation at the time of surgery can result in interruptions and delay. The use of 3D models based on mpMRI, might obviate these issues. We aimed to evaluate the role of the prospective integration of 3D models from mpMRI in the robotic console in reducing the rate of PSMs. Material and methods PSMs at our center are evaluated intraoperatively using the NeuroSAFE method. Based on the rate of PSMs on frozen section during the year prior to the implementation of 3D models during surgery (22.5%), we estimated that 151 subjects were needed to detect a statistically significant difference of at least 40%. Patients with biopsy-proven PCa who received a 3T mpMRI at our institution and had a PIRADS≥3 on mpMRI were included. Results 151 patients were included. Overall, 17(11.3%) patients had a PSM, 6(35%) of them had PSM in an area where the mpMRI did not demonstrate any lesions. The rates of PSMs on both frozen (22.5 vs. 11.3%) and permanent section (13.1 vs. 6.6%) were significantly lower (p≤0.03) compared to the cohort of patients operated during 2018(n=358). No significant differences among clinical characteristics were found between the study cohort and the 2018 cohort (all p>0.05). Conclusions The use of 3D models at the time of surgery was shown to reduce the PSM rate on both frozen and permanent section. Integrating 3D models in the robotic console could lead to improved PCa outcomes.

Active surveillance (AS) is the reference standard treatment for the management of low risk prostate cancer (PCa). Accurate assessment of tumor aggressiveness guides recruitment to AS programs to avoid conservative treatment of intermediate and higher risk patients. Nevertheless, underestimating the disease risk may occur in some patients recruited, with biopsy upgrading and the concomitant potential for delayed treatment.To evaluate the accuracy of mpMRI and GPS for the prediction of biopsy upgrading during active surveillance (AS) management of prostate cancer (PCa).A retrospective analysis was performed on 144 patients recruited to AS from October 2013 to December 2020. Median follow was 4.8 (IQR 3.6, 6.3) years. Upgrading was defined as upgrading to biopsy grade group ≥2 on follow up biopsies. Cox proportional hazard regression was used to investigate the effect of PSA density (PSAD), baseline Prostate Imaging-Reporting and Data System (PI-RADS) v2.1 score and GPS on upgrading. Time-to-event outcome, defined as upgrading, was estimated using the Kaplan-Meier method with log-rank test.Overall rate of upgrading was 31.9% (n = 46). PSAD was higher in the patients who were upgraded (0.12 vs. 0.08 ng/mlIn this study PSAD has higher accuracy over baseline PI-RADS score and GPS score for the prediction of PCa upgrading during AS. However, combined use of PSAD, GPS and PI-RADS Score yielded the highest predictive ability with a concordance index of 0.71.

Background Malignancy after transplantation is a leading cause of death among kidney transplant recipients. However, donor-derived malignancies are rare. We report a case of a high grade papillary urothelial carcinoma arising in a transplanted kidney. Case presentation A 62-year-old female who received a kidney transplantation more than 30 years ago presented with urinary tract infection, acute renal failure, and hydronephrosis of the transplant kidney. Anterograde nephrostogram showed a large filling defect in the lower pole of the transplant kidney and in the proximal 3–4 cm of the ureter. A biopsy from the renal pelvic mass showed a high grade urothelial carcinoma. She underwent an anterior exenteration, resection of both transplant and native kidneys and bilateral pelvic lymph node dissection. Pathologic examination showed a high grade papillary urothelial carcinoma which appeared to arise in the pelvis of the graft kidney, involve the graft ureter and native urinary bladder. The tumor had metastasized to one left obturator lymph node but spared the two native kidneys and ureters. Short tandem repeat (STR) analysis confirmed the tumor to be of donor origin. Next-generation sequencing identified amplification of TERT and loss of CDKN2A/CDKN2B in the primary tumor. Conclusion While it is known that transplant recipients have an increased risk of urothelial carcinoma compared to the general population, the lack of the well-documented risk factors, such as older age at transplantation, BK polyomavirus infection, and prolonged post-transplantation history and dissemination of the tumor in this case shed light on the de novo tumorigenesis of the graft kidney within the host microenvironment. Amplification of Telomerase reverse transcriptase (TERT) and loss of cyclin dependent kinase inhibitor 2A/2B (CDKN2A/CDKN2B) detected in the tumor by next gene sequencing suggests that they may play an important role in this case.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its associated clinical syndrome COVID-19 are causing overwhelming morbidity and mortality around the globe and disproportionately affected New York City between March and May 2020. Here, we report on the first 100 COVID-19-positive autopsies performed at the Mount Sinai Hospital in New York City. Autopsies revealed large pulmonary emboli in six cases. Diffuse alveolar damage was present in over 90% of cases. We also report microthrombi in multiple organ systems including the brain, as well as hemophagocytosis. We additionally provide electron microscopic evidence of the presence of the virus in our samples. Laboratory results of our COVID-19 cohort disclose elevated inflammatory markers, abnormal coagulation values, and elevated cytokines IL-6, IL-8, and TNFα. Our autopsy series of COVID-19-positive patients reveals that this disease, often conceptualized as a primarily respiratory viral illness, has widespread effects in the body including hypercoagulability, a hyperinflammatory state, and endothelial dysfunction. Targeting of these multisystemic pathways could lead to new treatment avenues as well as combination therapies against SARS-CoV-2 infection.

Objectives To create a model that predicts side-specific seminal vesicle invasion using clinical, biopsy and multiparametric magnetic resonance imaging data. Methods We analyzed data from 544 patients who underwent robot-assisted radical prostatectomy at a single institution. To develop a side-specific predictive model, we ultimately considered four variables: prostate-specific antigen, highest ipsilateral biopsy Gleason grade, highest ipsilateral percentage core involvement and seminal vesicle invasion on multiparametric magnetic resonance imaging. A binary multivariable logistic regression model was fitted to predict seminal vesicle invasion. A nomogram was then built based on the coefficients of the resulting logit function. The leave-one-out cross validation method was used for internal validation, and the decision curve analysis for the evaluation of the net clinical benefit. Results We relied on 804 side-specific cases after excluding negative biopsy observations (n = 284). Seminal vesicle invasion was reported on multiparametric magnetic resonance imaging in 41 (5%) cases, and on final pathology in 64 (8%) cases. All variables in the model emerged as predictors of seminal vesicle invasion (all P ≤ 0.001) and were subsequently considered to build a nomogram. The area under the curve of multiparametric magnetic resonance imaging alone in predicting seminal vesicle invasion was 59.1%; whereas one of the clinical variables only was 85.1%. The area under the curve of the nomogram resulting from their combination was 86.5%. After internal validation, this resulted in 84.7%. The model achieved good calibration and the decision curve analysis showed its clinical benefit, especially when compared with relying only on multiparametric magnetic resonance imaging prediction of seminal vesicle invasion. Conclusions A nomogram based on clinical and multiparametric magnetic resonance imaging data can predict seminal vesicle invasion and serve as a tool to urologists for surgical planning.

Multiparametric magnetic resonance imaging is a diagnostic tool for prostate cancer with limited data on prognostic use. We sought to determine whether multiparametric magnetic resonance could predict aggressive prostate cancer features.We retrospectively analyzed the records of 206 patients who underwent radical prostatectomy between 2013 and 2017. All patients had available RNA expression data on the final pathology specimen obtained from a location corresponding to a lesion location on multiparametric magnetic resonance imaging. The association between the PIRADS™ (Prostate Imaging Reporting and Data System) score and adverse pathology features were analyzed. We also performed differential transcriptomic analysis between the PIRADS groups. Factors associated with adverse pathology were analyzed using a multivariable logistic regression model.Lesion size (p = 0.03), PIRADS score (p = 0.02) and extraprostatic extension (p = 0.01) associated significantly with the Decipher® score. Multivariable analysis showed that the PIRADS score (referent PIRADS 3, OR 8.1, 95% CI 1.2-57.5, p = 0.04), the Gleason Grade Group (referent 3, OR 5.6, 95% CI 1.5-21.1, p = 0.01) and prostate specific antigen (OR 1.103, 95% CI 1.011-1.203) were risk factors for adverse pathology findings. The difference between PIRADS 4 and 5 did not reach significance (OR 1.9, 95% CI 0.8-4.5, p = 0.12). However, the PI3K-AKT-mTOR, WNT-β and E2F signaling pathways were more active in PIRADS 5 than in PIRADS 4 cases.The PIRADS score is associated with adverse pathology results, increased metastatic risk and differential genomic pathway activation.

Very few cases of villous adenomas of the bladder or urinary tract have been described. To our knowledge this is the first account of resection of an urachal villous adenoma via robotic laparoscopy, which is a safe and efficacious surgical approach. At this time, there is not enough evidence to suggest that progression of disease to carcinoma is the typical course. Nonetheless, follow-up cystoscopy is recommended after complete removal of the adenoma to monitor for recurrence. This case report reviews the current literature and describes a novel approach to treatment of this exceedingly rare entity.

Objective: Macrophages are critical in the pathogenesis of rheumatoid arthritis (RA). We recently demonstrated that FLIP (FLICE-like inhibitory protein) is necessary for the differentiation and/or survival of macrophages. We also identified that FLIP is highly expressed in RA synovial macrophages. This study was performed to determine if the reduction of Flip in macrophages would reduce synovial tissue macrophages and ameliorate serum transfer induced arthritis (STIA). Methods: Mice with Flip deleted in myeloid cells (Flipf/fLysMc/+ mice) and littermate controls were employed. STIA was induced by intraperitoneal injection of K/BxN serum. Arthritis was evaluated by clinical score and change in thickness of the ankles. Joints were examined by histology and immunohistochemistry. Cells were isolated from the ankles and bone marrow and examined by flow cytometry, qRT-PCR or Western blot. Results: In contrast to expectations, Flipf/fLysMc/+ mice developed more severe arthritis early in the clinical course, however the peak arthritis was attenuated and the resolution phase more complete. Prior to the induction of STIA, tissue resident macrophages were reduced. Further at day 9 post arthritis induction the number of F4/80hi macrophages in the joints of the Flipf/fLysMc/+ mice was not decreased, but increased. Flip was reduced in the F4/80hi macrophages in the ankles of the Flipf/fLysMc/+ mice, while F4/80hi population expressed an anti-inflammatory phenotype in both the Flipf/fLysMc/+ and control mice. Conclusions: These observations suggest that reduction of FLIP in macrophages, by increasing the number of anti-inflammatory macrophages, may be an effective therapeutic approach to suppress inflammation, depending upon the disease stage. This article is protected by copyright. All rights reserved.

Background Prediction of extra-prostatic extension (EPE) in men undergoing radical prostatectomy (RP) is of utmost importance. Great variability in the performance of multiparametric magnetic resonance imaging (mpMRI) has been reported for prediction of EPE. The present study aimed to determine the diagnostic performance of mpMRI for predicting EPE in different National Comprehensive Cancer Network (NCCN) risk categories. Methods Overall 664 patients who underwent radical prostatectomy with a staging mpMRI were enrolled in this single-center, retrospective study. Patients with mpMRI report non-compliant with PI-RADSv2.0, were excluded. Patients were stratified according to NCCN criteria: very low/low (VLR-LR) to High Risk (HR) in order to assess final pathology EPE rates (focal and established). Sensitivity, specificity, positive and negative predictive values of staging mpMRI were computed in each group. Univariable and multivariable analysis were used to evaluate predictors of positive surgical margins. Results Pathological evaluation demonstrated established and focal EPE in 60 (9%) and 106 (16%) patients, respectively, while mpMRI suspicion for EPE was present in 180 (27%) patients. Age, preoperative PSA, PSA density, number of positive cores, NCCN groups, prostate volume, mpMRI suspicion for EPE, PIRADSv2.0 and lesion size differed significantly between the patients with any EPE and without EPE (all P≤0.05). The sensitivity of mpMRI in detecting any EPE varied from 12% (95% CI: 0.6-53%) in VLR-LR to 83% (66-93%) in HR while the corresponding values for the specificity were 92% (85-96%) and 63% (45-78%), respectively. Patients with false-negative mpMRI EPE prediction were more likely to have positive surgical margins in univariable (OR: 2.14; CI: 1.18, 3.87) as well as multivariable analysis adjusting for NCCN risk categories (OR: 1.97; CI: 1.08, 3.60). Conclusions The performance of mpMRI for prediction of EPE varies greatly between different NCCN risk categories with a low positive predicting value in patients at low to favorable intermediate risk and a low negative predictive value in patients at Unfavorable intermediate to high risk PCa. Given that mpMRI EPE misdiagnosis could have a negative impact on oncological and functional outcomes, NCCN risk categories should be considered when interpreting mpMRI findings in PCa patients.

Introduction Presently, prostate biopsy (PBx) results report the highest Gleason Grade Group (GGG) as a single metric that gauges the overall clinical aggressiveness of cancer and dictates treatment. We hypothesized a PBx showing multiple cores of cancer with more volume cancer per core would represent more aggressive disease. We propose the Weighted Gleason Grade Group (WGGG), a novel scoring system that synthesizes all histopathologic data and cancer volume into a single numeric value representing the entire PBx, allowing for improved prediction of adverse pathology and risk of biochemical recurrence (BCR) following radical prostatectomy (RP). Methods We studied 171 men who underwent RP after standard PBx. The WGGG was calculated by summing each positive core using the formula: GGG + (GGG x %Ca/core). RP pathology was evaluated for extraprostatic extension (EPE), positive surgical margins (PSM), seminal vesicle invasion (SVI), and lymph node involvement (LNI), and patients were followed for BCR. We compared GGG vs. WGGG receiver operating characteristic curves for each outcome, and determined the predictive capability of GGG and WGGG to identify patients with BCR. Categorized WGGG groups were created based on risk of BCR using classification and regression tree analysis. We then sought to externally validate WGGG in a cohort of 389 patients in a separate institutional dataset. Results In the development cohort, area under the curves (AUCs) for the WGGG vs. GGG were significantly higher for predicting EPE (0.784 vs. 0.690, P = 0.002), SVI (AUC 0.823 vs. 0.721, P = .014), LNI (AUC 0.862 vs. 0.823, P = 0.039), and PSM (AUC 0.638 vs. 0.575, P = 0.031. Analysis of the validation cohort showed similar findings for EPE (AUC 0.764 vs. 0.729, P = 0.13), SVI (AUC 0.819 vs. 0.749, P = 0.01), LNI (AUC 0.939 vs. 0.867, P = 0.02), and PSM (AUC 0.624 vs. 0.547, P = 0.04). Patients with WGGG >30 (high-risk group) demonstrated ∼50% failure at 2 years in both cohorts. Conclusions The WGGG, by providing a metric reflecting the entirety of the PBx, is more informative than conventional single GGG alone in identifying adverse pathologic outcomes and risk of BCR following RP. This superior discriminatory capability has been achieved without any consideration of other commonly available clinical disease characteristics.

Neuroendocrine tumors (NETs) comprise 41.8% of small intestine malignancies. The NET nomogram is a 15-item prognostic tool that includes relevant factors for guiding management decisions. This is the first external validation of this tool among American patients at a tertiary treatment center.Patients who underwent surgical intervention from 2005 to 2017 were screened by retrospective chart review. Nomogram scores were calculated following the methods outlined by Modlin et al (Neuroendocrinology. 2010;92:143-157). Validation assessed the association between nomogram scores and survival using Wilcoxon test and Cox regression.Among the 121 patients selected, the NET nomogram significantly predicted survival as a continuous variable (P0.01) and when dichotomized using 83 points to distinguish low-risk versus high-risk groups (P0.01). However, the nomogram was not universally applicable as even at our specialty center, variables such as chromogranin A and urinary 5-hydroxyindoleacetic acid are not routinely collected, whereas others, like tumor grade, do not reflect the most recently updated classifications.The NET nomogram accurately identified patients at low and high risk of death. However, revision to update prognosticators could improve its usefulness for predicting survival of small intestine NETs.

INTRODUCTION AND OBJECTIVES:One of the major health related quality of life issues following radical prostatectomy (RP) is urinary incontinence. The detrusor apron (DA), although well described, is...

INTRODUCTION AND OBJECTIVES:The presence of tertiary pattern 5 (TP5) on radical prostatectomy specimens has been associated with worse long-term outcomes. However, the molecular underpinnings of TP...

Tsai et al. demonstrate that loss of Bim (BCL2L11) in myeloid cells in mice (LysMCreBimfl/fl) is sufficient to induce systemic autoimmunity. Kidney macrophages in LysMCreBimfl/fl mice possess a proinflammatory transcriptional signature and signal through TRIF to cause end-stage glomerulonephritis., The Bcl-2 family is considered the guardian of the mitochondrial apoptotic pathway. We demonstrate that Bim acts as a molecular rheostat by controlling macrophage function not only in lymphoid organs but also in end organs, thereby preventing the break in tolerance. Mice lacking Bim in myeloid cells (LysMCreBimfl/fl) develop a systemic lupus erythematosus (SLE)–like disease that mirrors aged Bim−/− mice, including loss of marginal zone macrophages, splenomegaly, lymphadenopathy, autoantibodies (including anti-DNA IgG), and a type I interferon signature. LysMCreBimfl/fl mice exhibit increased mortality attributed to glomerulonephritis (GN). Moreover, the toll-like receptor signaling adaptor protein TRIF (TIR-domain–containing adapter-inducing interferon-β) is essential for GN, but not systemic autoimmunity in LysMCreBimfl/fl mice. Bim-deleted kidney macrophages exhibit a novel transcriptional lupus signature that is conserved within the gene expression profiles from whole kidney biopsies of patients with SLE. Collectively, these data suggest that the Bim may be a novel therapeutic target in the treatment of SLE.

Primary squamous cell carcinoma (SCC) of the renal pelvis is exceedingly rare and is associated with advanced stage at diagnosis and a poor prognosis. Diagnosis is often difficult due to vague presenting symptoms and nonspecific radiologic findings. The mainstay of treatment is nephrectomy, with cisplatin based chemotherapy and palliative radiation reserved for metastatic disease. We report a SCC of the renal pelvis in a 72 year-old female who presented with abdominal pain. To date, this is the largest SCC originating from the renal pelvis reported in the literature, made even more exceptional by the lack of antecedent risk factors.

OBJECTIVE To investigate the genomic features of tertiary pattern 5 (TP5) on radical prostatectomy specimens in an effort to explain the poor clinical outcomes associated with this disease subtype. PATIENTS AND METHODS Data from 159 men with Gleason Grade Group (GGG) 3 or 4 were considered. All patients had Decipher diagnostic testing with transcript profiles and single-channel array normalisation (SCAN)-normalised expression of coding genes. The relationship between Decipher and TP5 was investigated by linear and binary logistic regressions. A differential transcriptomic analysis between patients with and without TP5 was performed. The prognostic role of these genes on progression-free survival (PFS) and overall survival (OS) was evaluated using The Cancer Genome Atlas. RESULTS In all, 52/159 (33%) patients had GGG 3-4 with TP5 disease. TP5 was associated with a higher Decipher score (β 0.07, 95% confidence interval [CI] 0.02-0.13; P = 0.04) and higher likelihood of falling within the intermediate- or high-risk categories (odds ratio 3.34, 95% CI 1.34-8.35; P = 0.01). Analysis of microarray data revealed an 18-gene signature that was differentially expressed in patients with TP5; 13 genes were over- and five under-expressed in the TP5 cohort. The overexpression of cyclin dependent kinase inhibitor 2B (CDKN2B), polo-like kinase 1 (PLK1), or cell division cycle 20 (CDC20) was associated with worse PFS. The group harbouring overexpression of at least one gene had a 5-year PFS rate of 50% vs 74% in the group without overexpression (P

Objectives To update the algorithm for performing incremental nerve sparing (NS) using our multiparametric magnetic resonance imaging (mpMRI)-based nomogram. Patients and methods We applied the coefficients of the nomogram to the observations extracted from our population of patients who underwent robot-assisted radical prostatectomy between February 2014 and October 2015 and who received preoperative mpMRI. The information considered were PSA level, highest side-specific biopsy Gleason grade group, highest ipsilateral percentage core involvement with the highest Gleason grade group, and extracapsular extension (ECE) on mpMRI. The nomogram-derived probability [P (%)], after internal validation, was used as the independent variable on a classification tree to identify the most significant thresholds for ECE prediction. Incremental NS was performed as follows: Grade 1 NS: intrafascial dissection between the peri-prostatic veins and the pseudocapsule of the prostate; Grade 2 NS: inter-fascial dissection along the peri-venous plane; Grade 3 NS: inter-fascial dissection through the outer compartment of the lateral prostatic fascia; Grade 4 NS: extrafascial dissection. Results Data from 561 patients were considered, and 829 prostatic lobes with biopsy-documented tumour were analysed. Overall, 142 lobes presented ECE that was focal in 27 (19%) cases. The classification tree identified four risk categories. In the low- [P (%) ≤10], intermediate- [P (%) 10-21], high [P (%) 21-73] and very-high-risk [P(%) >73] groups, the ECE rates were 3.3%, 16%, 61.6% and 90%, respectively. Amongst those, ECE was focal in 41.7%, 31.7%, 7.9% and 0%, respectively. Conclusion We suggest that Grade 1 NS (intrafascial) should be performed in the low-risk group. The inter-fascial approach, namely grades 2 and 3 NS, should be performed in the intermediate- and high-risk categories, respectively. Grade 4 NS (extrafascial) should be performed in the very-high-risk group. The current algorithm yields a better accuracy than the previous one; however, prospective validation is warranted.

Objectives To develop a nomogram for predicting side-specific extracapsular extension (ECE) for planning nerve-sparing radical prostatectomy. Materials and methods We retrospectively analysed data from 561 patients who underwent robot-assisted radical prostatectomy between February 2014 and October 2015. To develop a side-specific predictive model, we considered the prostatic lobes separately. Four variables were included: prostate-specific antigen; highest ipsilateral biopsy Gleason grade; highest ipsilateral percentage core involvement; and ECE on multiparametric magnetic resonance imaging (mpMRI). A multivariable logistic regression analysis was fitted to predict side-specific ECE. A nomogram was built based on the coefficients of the logit function. Internal validation was performed using 'leave-one-out' cross-validation. Calibration was graphically investigated. The decision curve analysis was used to evaluate the net clinical benefit. Results The study population consisted of 829 side-specific cases, after excluding negative biopsy observations (n = 293). ECE was reported on mpMRI and final pathology in 115 (14%) and 142 (17.1%) cases, respectively. Among these, mpMRI was able to predict ECE correctly in 57 (40.1%) cases. All variables in the model except highest percentage core involvement were predictors of ECE (all P ≤ 0.006). All variables were considered for inclusion in the nomogram. After internal validation, the area under the curve was 82.11%. The model demonstrated excellent calibration and improved clinical risk prediction, especially when compared with relying on mpMRI prediction of ECE alone. When retrospectively applying the nomogram-derived probability, using a 20% threshold for performing nerve-sparing, nine out of 14 positive surgical margins (PSMs) at the site of ECE resulted above the threshold. Conclusion We developed an easy-to-use model for the prediction of side-specific ECE, and hope it serves as a tool for planning nerve-sparing radical prostatectomy and in the reduction of PSM in future series.

L’IRM a 1,5T ou 3T de la prostate est l’imagerie la plus performante pour la detection du cancer de prostate. Nous avons travaille a des modeles experimentaux ex vivo d’IRM haute resolution a 7T permettant d’ameliorer la resolution spatiale et la detection tumorale.La premiere partie de ce travail a porte sur la mise au point de protocoles d’analyse IRM de tissus prostatiques ex vivo a 7T. Des coupes de tissus de pieces operatoires et cadaveriques avec et sans cancer ont ete etudiees. Les donnees obtenues ont permis de definir des parametres de sequence en turbo spin-echo pour obtenir des images avec resolution spatiale de 60 X 60 X 90 μm3. Cette resolution permettait d’identifier a l’imagerie IRM 7T des caracteristiques tissulaires comparables a celles obtenues par analyse histo-pathologique (X2).La seconde partie de ce travail a porte sur l’etude par IRM 7T de glandes prostatiques entieres chez 18 patients operes pour cancer de prostate. En utilisant les protocoles d’acquisition mis au point dans la premiere etude, l’imagerie a comporte des sequences T2, a la plus haute resolution de 130 X130 X195 μm3 et de diffusion avec cartographie ADC. Les resultats etaient interpretes par deux relecteurs en aveugle pour evaluer la qualite et la detection tumorale. La haute resolution spatiale des images, comparee a celle obtenue par analyse histo-pathologique, etait jugee comme bonne avec une concordance inter-relecteur elevee. Une etude de correlationanatomo-imagerie pour la detection du cancer avec analyse par secteur a montre une sensibilite de 70%, une specificite de 80%, une valeur predictive positive de 79% et une valeur predictive negative de 72%.Ces resultats ont permis de mesurer la resolution de l’imagerie IRM a 7T ex vivo et son interet pour la detection du cancer. Une semiologie IRM 7T du tissu prostatique doit etre decrite. Ces resultats serviront de base a la translation future de l’imagerie actuelle vers l’IRM 7T in vivo chez l’homme.

Objectives Angiogenesis plays a critical role in SSc (scleroderma). The aim of this study was to examine the expression of growth-regulated protein-γ (Gro-γ/CXCL3), granulocyte chemotactic protein 2 (GCP-2/CXCL6) and their receptor CXCR2 in endothelial cells (ECs) isolated from SSc skin and determine whether these cells mount an angiogenic response towards pro-angiogenic chemokines. The downstream signalling pathways as well as the pro-angiogenic transcription factor inhibitor of DNA-binding protein 1 (Id-1) were also examined. Methods Skin biopsies were obtained from patients with dcSSc. ECs were isolated via magnetic positive selection. Angiogenesis was measured by EC chemotaxis assay. Results Gro-γ/CXCL3 and GCP-2/CXCL6 were minimally expressed in both skin types but elevated in SSc serum. Pro-angiogenic chemokine mRNA was greater in SSc ECs than in normal ECs. SSc ECs did not migrate to vascular endothelial growth factor (VEGF), Gro-γ/CXCL3, GCP-2/CXCL6 or CXCL16. The signalling pathways stimulated by these chemokines were also dysregulated. Id-1 mRNA in SSc ECs was lower compared with normal ECs, and overexpression of Id-1 in SSc ECs increased their ability to migrate towards VEGF and CXCL16. Conclusion Our results show that SSc ECs are unable to respond to pro-angiogenic chemokines despite their increased expression in serum and ECs. This might be due to the differences in the signalling pathways activated by these chemokines in normal vs SSc ECs. In addition, the lower expression of Id-1 also decreases the angiogenic response. The inability of pro-angiogenic chemokines to promote EC migration provides an additional mechanism for the impaired angiogenesis that characterizes SSc.

Objective Polymorphisms in the transcription factor interferon regulatory factor 5 (IRF5) are associated with an increased risk of developing rheumatoid arthritis (RA). This study was undertaken to determine the role of IRF5 in a mouse model of arthritis development. Methods K/BxN serum–transfer arthritis was induced in mice deficient in IRF5, or lacking IRF5 only in myeloid cells, and arthritis severity was evaluated. K/BxN arthritis was also induced in mice deficient in TRIF, Toll-like receptor 2 (TLR2), TLR3, TLR4, and TLR7 to determine the pathways through which IRF5 might promote arthritis. In vitro studies were performed to determine the role of IRF5 in interleukin-1 (IL-1) receptor and TLR signaling. Results Arthritis severity was reduced in IRF5-deficient, TRIF-deficient, TLR3-deficient, and TLR7-deficient mice. The expression of multiple genes regulating neutrophil recruitment or function and bioactive IL-1β formation was reduced in the joints during active arthritis in IRF5-deficient mice. In vitro studies showed that TLR7 and the TRIF-dependent TLR3 pathway induce proinflammatory cytokine production in disease-relevant cell types in an IRF5-dependent manner. Conclusion Our findings indicate that IRF5 contributes to disease pathogenesis in inflammatory arthritis. This is likely due at least in part to the role of IRF5 in mediating proinflammatory cytokine production downstream of TLR7 and TLR3. Since TLR7 and TLR3 are both RNA-sensing TLRs, this suggests that endogenous RNA ligands present in the inflamed joint promote arthritis development. These findings may be relevant to human RA, since RNA capable of activating TLR7 and TLR3 is present in synovial fluid and TLR7 and TLR3 are up-regulated in the joints of RA patients.

Caspase-8 is a well-established initiator of apoptosis and suppressor of necroptosis, but maintains functions beyond cell death that involve suppression of receptor-interacting serine-threonine kinases (RIPKs). A genome-wide association study meta-analysis revealed an SNP associated with risk of rheumatoid arthritis (RA) development within the locus containing the gene encoding for caspase-8. Innate immune cells, like macrophages and dendritic cells, are gaining momentum as facilitators of autoimmune disease pathogenesis, and, in particular, RA. Therefore, we examined the involvement of caspase-8 within these antigen-presenting cell populations in the pathogenesis of an arthritis model that resembles the RA effector phase. Cre LysM Casp8 flox/flox and Cre CD11c Casp8 flox/flox mice were bred via a cross between Casp8 flox/flox and Cre LysM or Cre CD11c mice. RIPK3 –/– Cre LysM Casp8 flox/flox and RIPK3 –/– Cre CD11c Casp8 flox/flox mice were generated to assess RIPK3 contribution. Mice were subjected to K/BxN serum-transfer-induced arthritis. Luminex-based assays were used to measure cytokines/chemokines. Histological analyses were utilized to examine joint damage. Mixed bone marrow chimeras were generated to assess synovial cell survival. Flow cytometric analysis was employed to characterize cellular distribution. For arthritis, differences between the groups were assessed using two-way analysis of variance (ANOVA) for repeated measurements. All other data were compared by the Mann-Whitney test. We show that intact caspase-8 signaling maintains opposing roles in lysozyme-M- and CD11c-expressing cells in the joint; namely, caspase-8 is crucial in CD11c-expressing cells to delay arthritis induction, while caspase-8 in lysozyme M-expressing cells hinders arthritis resolution. Caspase-8 is also implicated in the maintenance of synovial tissue-resident macrophages that can limit arthritis. Global loss of RIPK3 in both caspase-8 deletion constructs causes the response to arthritis to revert back to control levels via a mechanism potentially independent of cell death. Mixed bone marrow chimeric mice demonstrate that caspase-8 deficiency does not confer preferential expansion of synovial macrophage and dendritic cell populations, nor do caspase-8-deficient synovial populations succumb to RIPK3-mediated necroptotic death. These data demonstrate that caspase-8 functions in synovial antigen-presenting cells to regulate the response to inflammatory stimuli by controlling RIPK3 action, and this delicate balance maintains homeostasis within the joint.

Background Rheumatoid arthritis (RA) is a common autoimmune disease characterized by chronic inflammation of the joints, leading to bone erosion and joint dysfunction. Despite the recent successes of disease-modifying anti-rheumatic drugs (DMARDs), there is still clinical need for understanding the development and molecular etiology of RA. Wnts are developmental morphogens whose roles in adult pathology are poorly characterized. Wnt5a is a member of the non-canonical family of Wnts that modulates a wide range of cell processes, including differentiation, migration, and inflammation. Wnt5a has been implicated as a possible contributor to arthritis and it is upregulated in synovial fibroblasts from RA patients. Methods We investigated the role of endogenous Wnt5a in RA. Tamoxifen-inducible, Wnt5a knockout (Wnt5a cKO) mice and littermate controls were monitored for arthritis development and joint pathology using the K/BxN serum transfer-induced arthritis (STIA) model. To explore a role of Wnt5a in osteoclast fusion, bone marrow-derived monocytes (BMDMs) were differentiated in vitro. Results Wnt5a cKO mice were resistant to arthritis development compared to control littermates as assessed by ankle thickness and histologic measurements. Some parameters of inflammation were reduced in the Wnt5a cKO mice, including the extent of polymononuclear cell infiltration and extra-articular inflammation. Wnt5a cKO mice also exhibited less cartilage destruction and a reduction in osteoclast activity with concomitant reduction in tartrate-resistant acid phosph atase (TRAP), cathepsin K (CTSK), macrophage colony-stimulating factor (MCSF), matrix metalloproteinase (MMP)2 and MMP9 in the arthritic joints. Treatment of BMDMs with Wnt5a enhanced osteoclast fusion and increased the expression of dendrocyte-expressed seven transmembrane protein (DCSTAMP) and MMP9, that are necessary for osteoclast formation and activity. Conclusions These data suggest that Wnt5a modulates the development of arthritis by promoting inflammation and osteoclast fusion, and provide the first mouse genetic evidence of a role for endogenous Wnt5a in autoimmune disease. Electronic supplementary material The online version of this article (doi:10.1186/s13075-017-1375-0) contains supplementary material, which is available to authorized users.

Cysteine-rich protein 61, connective tissue growth factor, and nephroblastoma overexpressed gene (CCN) comprise a family of matricellular proteins that have multiple physiologic functions including development, tissue repair, cell adhesion, migration, and proliferation. The expression of CCN1, cyclin D1, β-catenin, and p53 was explored by immunohistochemistry in different grades of ductal carcinoma in situ (DCIS) cases. These cases did not contain any infiltrating carcinoma components. In addition, all cysteine-rich protein 61 gene exons (encoding the CCN1 protein) were sequenced in 30 samples. Allred and H-scores were calculated for expression in both DCIS and the surrounding benign breast tissue. All cases of DCIS showed degrees of cytoplasmic CCN1 staining with median H-scores of 170, 160, and 60 in grades 3, 2, and 1, respectively (P = .043). Twelve of 28 DCIS 3, 1 of 15 DCIS 2, and 0 of 18 DCIS 1 also showed nuclear staining for CCN1. The cytoplasmic staining difference was preserved when the cases were divided into estrogen receptor (ER)+/DCIS grade 1, ER+/DCIS 2 and 3, and ER-/DCIS 2 and 3 by the H-score (P = .037). Cyclin D1 expression was positively correlated with the CCN1 cytoplasmic H-score in all DCIS samples (P = .038). Membranous β-catenin expression correlated with the grade of intraepithelial carcinoma by both H-score (P = .047) and Allred score (P = .026). Our results suggest that CCN1 has a role in the development of intraepithelial carcinoma. CCN1 expression correlates with grade of DCIS independent of ER status. It can induce cell cycle progression through cyclin D1. It is warranted to study high expression of CCN1 in DCIS as an independent risk factor in a larger cohort.

Polymorphisms in NOD2 confer risk for Crohn’s disease, characterized by intestinal inflammation. How NOD2 regulates both inflammatory and regulatory intestinal T cells, which are critical to intestinal immune homeostasis, is not well understood. Anti-CD3 mAb administration is used as therapy in human autoimmune diseases, as well as a model of transient intestinal injury. The stages of T cell activation, intestinal injury, and subsequent T tolerance are dependent on migration of T cells into the small intestinal (SI) lamina propria. Upon anti-CD3 mAb treatment of mice, we found that NOD2 was required for optimal small intestinal IL-10 production, in particular from CD8+ T cells. This requirement was associated with a critical role for NOD2 in SI CD8+ T cell accumulation and induction of the CXCR3 ligands CXCL9 and CXCL10, which regulate T cell migration. NOD2 was required in both the hematopoietic and nonhematopoietic compartments for optimal expression of CXCR3 ligands in intestinal tissues. NOD2 synergized with IFN-γ to induce CXCL9 and CXCL10 secretion in dendritic cells, macrophages, and intestinal stromal cells in vitro. Consistent with the in vitro studies, during anti-CD3 mAb treatment in vivo, CXCR3 blockade, CD8+ T cell depletion, or IFN-γ neutralization each inhibited SI CD8+ T cell recruitment, and reduced chemokine expression and IL-10 expression. Thus, NOD2 synergizes with IFN-γ to promote CXCL9 and CXCL10 expression, thereby amplifying CXCR3-dependent SI CD8+ T cell migration during T cell activation, which, in turn, contributes to induction of both inflammatory and regulatory T cell outcomes in the intestinal environment.

Objective A nonapoptotic role of Fas signaling has been implicated in the regulation of inflammation and innate immunity. This study was undertaken to elucidate the contribution of Fas signaling in macrophages to the development of arthritis. Methods K/BxN serum–transfer arthritis was induced in a mouse line in which Fas was conditionally deleted in the myeloid lineage (CreLysMFasflox/flox mice). The arthritis was assessed clinically and histologically. Expression of interleukin-1β (IL-1β), CXCL5, IL-10, IL-6, and gp96 was determined by enzyme-linked immunosorbent assay. Bone marrow–derived macrophages were activated with IL-1β and gp96. Cell phenotype and apoptosis were analyzed by flow cytometry. Results Arthritis onset in CreLysMFasflox/flox mice was comparable with that observed in control mice; however, resolution was accelerated during the chronic phase. The attenuated arthritis was associated with reduced articular expression of the endogenous Toll-like receptor 2 (TLR-2) ligand gp96 and the neutrophil chemotactic chemokine CXCL5, and enhanced expression of IL-10. Activation with IL-1β or gp96 induced increased IL-10 expression in Fas-deficient murine macrophages compared with control macrophages. IL-10 suppressed IL-6 and CXCL5 expression induced by IL-1β plus gp96. IL-1β–mediated activation of ERK, which regulates IL-10 expression, was increased in Fas-deficient mouse macrophages. Conclusion Taken together, our findings indicate that impaired Fas signaling results in enhanced expression of antiinflammatory IL-10 and reduced expression of gp96, and these effects are associated with accelerated resolution of inflammation during the chronic phase of arthritis. These observations suggest that strategies to reduce endogenous TLR ligands and increase IL-10 may be beneficial in the treatment of rheumatoid arthritis.