Pathogenic Roles for RNASET2 in Clear Cell Renal Cell Carcinoma.

A specific splicing isoform of RNASET2 is associated with worse oncologic outcomes in clear cell renal cell carcinoma (ccRCC). However, the interplay between wild-type RNASET2 and its splice variant and how this might contribute to the pathogenesis of ccRCC remains poorly understood. We sought to better understand the relationship of RNASET2 in the pathogenesis of ccRCC and the interplay with a pathogenic splicing isoform (RNASET2-SV) and the tumor immune microenvironment. Using data from The Cancer Genome Atlas and Clinical Proteomic Tumor Analysis Consortium, we correlated clinical variables to RNASET2 expression and the presence of a specific RNASET2-SV. Immunohistochemical staining with matched RNA sequencing of ccRCC patients was then utilized to understand the spatial relationships of RNASET2 with immune cells. Finally, in vitro studies were performed to demonstrate the oncogenic role of RNASET2 and highlight its potential mechanisms. RNASET2 gene expression is associated with higher grade tumors and worse overall survival in The Cancer Genome Atlas cohort. The presence of the RNASET2-SV was associated with increased expression of the wild-type RNASET2 protein and epigenetic modifications of the gene. Immunohistochemical staining revealed increased intracellular accumulation of RNASET2 in patients with increased RNA expression of RNASET2-SV. In vitro experiments reveal that this accumulation results in increased cell proliferation, potentially from altered metabolic pathways. RNASET2 exhibits a tumor-promoting role in the pathogenesis of ccRCC that is increased in the presence of a specific RNASET2-SV and associated with changes in the cellular localization of the protein.

Increased spatial coupling of integrin and collagen IV in the immunoresistant clear cell renal cell carcinoma tumor microenvironment.

Background: Immunotherapy (IO) has improved survival for patients with advanced clear cell renal cell carcinoma (ccRCC), but resistance to therapy develops in most patients. We use cellular-resolution spatial transcriptomics in patients with IO naïve and IO exposed primary ccRCC tumors to better understand IO resistance. Spatial molecular imaging (SMI) was obtained for tumor and adjacent stroma samples. Spatial gene set enrichment analysis (GSEA) and autocorrelation (coupling with high expression) of ligand-receptor transcript pairs were assessed. Multiplex immunofluorescence (mIF) validation was used for significant autocorrelative findings and the cancer genome atlas (TCGA) and the clinical proteomic tumor analysis consortium (CPTAC) databases were queried to assess bulk RNA expression and proteomic correlates. Results: 21 patient samples underwent SMI. Viable tumors following IO harbored more stromal CD8+ T cells and neutrophils than IO naïve tumors. YES1 was significantly upregulated in IO exposed tumor cells. The epithelial-mesenchymal transition pathway was enriched on spatial GSEA and the associated transcript pair COL4A1-ITGAV had significantly higher autocorrelation in the stroma. Fibroblasts, tumor cells, and endothelium had the relative highest expression. More integrin αV+ cells were seen in IO exposed stroma on mIF validation. Compared to other cancers in TCGA, ccRCC tumors have the highest expression of both COL4A1 and ITGAV. In CPTAC, collagen IV protein was more abundant in advanced stages of disease. Conclusions: On spatial transcriptomics, COL4A1 and ITGAV were more autocorrelated in IO-exposed stroma compared to IO-naïve tumors, with high expression amongst fibroblasts, tumor cells, and endothelium. Integrin represents a potential therapeutic target in IO treated ccRCC.

Predicting Limited Survival Following Inguinal Lymph Node Dissection in Penile Cancer: Should We Revisit the Goals of Care?

OBJECTIVE: Patients with advanced penile squamous cell cancer have a poor prognosis and can benefit from early palliative care consultation. We built a model to identify those patients most likely to benefit. METHODS: Patients with penile squamous cell cancer undergoing inguinal lymph node dissection were identified from the National Cancer Database (NCDB) and a multi-institutional international dataset (INT). A multivariable Cox proportional hazards model for overall survival (OS) was developed using the NCDB and applied to the INT dataset. Parameters were used to make receiver operating characteristic (ROC) curves. ROC-related criteria were optimized to identify a predictive probability cut point and dichotomize patients from INT into risk groups for limited OS of <6 and <12 months. RESULTS: NCDB had 860 deaths; 105 (5%) at 6 months and 296 (15%) at 12 months. INT had 257 deaths; 56 (8%) at 6 months and 124 (18%) at 12 months. Limited OS was associated with older age, greater T and N stage, and fewer lymph nodes removed. Optimized ROC criteria using the OS <6 months curve best dichotomized INT patients into high-risk group with median OS of 24 months (95% CI 18-34) and low-risk group with median OS of 174 months (95% CI 120-NE). CONCLUSION: We developed a simple model that could be used as a screening tool for early palliative care referral.

Comparative Genomic Landscape of Urothelial Carcinoma of the Bladder Among Patients of East and South Asian Genomic Ancestry.

BACKGROUND: Despite the low rate of urothelial carcinoma of the bladder (UCB) in patients of South Asian (SAS) and East Asian (EAS) descent, they make up a significant portion of the cases worldwide. Nevertheless, these patients are largely under-represented in clinical trials. We queried whether UCB arising in patients with SAS and EAS ancestry would have unique genomic features compared to the global cohort. METHODS: Formalin-fixed, paraffin-embedded tissue was obtained for 8728 patients with advanced UCB. DNA was extracted and comprehensive genomic profiling was performed. Ancestry was classified using a proprietary calculation algorithm. Genomic alterations (GAs) were determined using a 324-gene hybrid-capture-based method which also calculates tumor mutational burden (TMB) and determines microsatellite status (MSI). RESULTS: Of the cohort, 7447 (85.3%) were EUR, 541 (6.2%) were AFR, 461 (5.3%) were of AMR, 74 (0.85%) were SAS, and 205 (2.3%) were EAS. When compared with EUR, TERT GAs were less frequent in SAS (58.1% vs. 73.6%; P = .06). When compared with non-SAS, SAS had less frequent GAs in FGFR3 (9.5% vs. 18.5%, P = .25). TERT promoter mutations were significantly less frequent in EAS compared to non-EAS (54.1% vs. 72.9%; P < .001). When compared with the non-EAS, PIK3CA alterations were significantly less common in EAS (12.7% vs. 22.1%, P = .005). The mean TMB was significantly lower in EAS vs. non-EAS (8.53 vs. 10.02; P = .05). CONCLUSIONS: The results from this comprehensive genomic analysis of UCB provide important insight into the possible differences in the genomic landscape in a population level. These hypothesis-generating findings require external validation and should support the inclusion of more diverse patient populations in clinical trials.

Cytoreductive Nephrectomy Following Immune Checkpoint Inhibitor Therapy Is Safe and Facilitates Treatment-free Intervals.

Patients with metastatic renal cell cancer (mRCC) who respond to upfront immune checkpoint inhibitor (ICI) combination therapies may be treated with cytoreductive nephrectomy (CN) to remove radiographically viable primary tumors. Early data for post-ICI CN suggested that ICI therapies induce desmoplastic reactions in some patients, increasing the risk of surgical complications and perioperative mortality. We evaluated perioperative outcomes for 75 consecutive patients treated with post-ICI CN at four institutions from 2017 to 2022. Our cohort of 75 patients had minimal or no residual metastatic disease but radiographically enhancing primary tumors after ICI and were treated with CN. Intraoperative complications were identified in 3/75 patients (4%) and 90-d postoperative complications in 19/75 (25%), including two patients (3%) with high-grade (Clavien ≥III) complications. One patient was readmitted within 30 d. No patients died within 90 d after surgery. Viable tumor was present in all but one specimen. Approximately half of the patients (36/75, 48%) remained off systemic therapy at last follow-up. These data suggest that CN following ICI therapy is safe and associated with low rates of major postoperative complications in appropriately selected patients at experienced centers. Post-ICI CN may facilitate observation without additional systemic therapy in patients without significant residual metastatic disease. Patient summary: Current first-line treatment for patients with kidney cancer that has spread to other sites (metastatic cancer) is immunotherapy. For cases in which metastatic sites respond to this therapy but primary tumor is still detected in the kidney, surgical treatment of the tumor is feasible and has a low rate of complications, and may delay the need for further chemotherapy.

Early return to continence and potency with use of dehydrated human umbilical cord graft at the time of robot-assisted radical prostatectomy: A case study and analysis of relevant literature.

INTRODUCTION: Robot-assisted radical prostatectomy often causes damage to the neurovascular bundle which results in erectile dysfunction and urinary incontinence. Recovery may take months; however, dehydrated umbilical cord allografts appear to offer an advantage in terms of a faster return to continence and potency. CASE PRESENTATION: A 67-year-old male, who presented with intermediate-risk prostate cancer, underwent a bilateral nerve-sparing radical prostatectomy and placement of dehydrated human umbilical cord graft. Four weeks post-prostatectomy, the patient reported minimal stress urinary incontinence and erections with 75% rigidity. Three months post-prostatectomy, the patient noted improved continence and erections with 100% rigidity. CONCLUSION: To our knowledge, this is the second experience reported in the literature evaluating the use of umbilical cord allograft during robot-assisted radical prostatectomy, with promising results, and it is the first reported case to analyze potency as an outcome.

Pathologic Complete Response to Neoadjuvant Nivolumab/Ipilimumab in a Patient with Metastatic Renal Cell Carcinoma.

Nivolumab plus ipilimumab represents an effective combination of checkpoint inhibitors that can lead to a durable response with minimal toxicity in patients with metastatic renal cell carcinoma (mRCC). We present a case of a pathologic complete response to neoadjuvant nivolumab plus ipilimumab in a patient with a 13.9 cm left renal mass and significant retroperitoneal and iliac lymphadenopathy, classified as intermediate-risk mRCC. We discuss and review the literature on complete responses after systemic therapy and the ability to predict who has undergone a complete response in the face of residual radiographic evidence of disease.

Mucinous adenocarcinoma of the prostatic urethra following a remote history of primary brachytherapy for prostate cancer.

Secondary malignancies are a known, albeit uncommon, complication of radiation for prostate cancer, either in the form of external beam radiotherapy or seed-implant brachytherapy. Of these secondary malignancies, mucinous adenocarcinoma of the prostatic urothelium is an extremely rare clinical entity that has only once been reported in the literature. We report the case of an 80-year-old gentleman who initially underwent low-dose brachytherapy for low-risk prostate cancer 18 years ago. He subsequently developed recurrent gross hematuria and obstructive voiding symptoms. He underwent cystoscopy and transurethral resection of a large tumor from within the prostate. Final pathology of the tumor revealed a mucinous adenocarcinoma. Further immunostaining revealed this is likely to have originated from the prostatic urothelium. Given his age, comorbidities, and no clear data demonstrating that aggressive extirpative surgery provides a clinical benefit, we elected to undergo surveillance. Clinicians should be aware of mucinous adenocarcinoma of the prostatic urethra as an extremely rare, radiation-induced malignancy. Once a diagnosis is made, extirpative surgery is an option for localized disease, although prognosis remains poor.

Long-term oncologic outcomes of positive surgical margins following robot-assisted partial nephrectomy.

BACKGROUND: Previous reports on positive surgical margin (PSM) after robot-assisted partial nephrectomy (RAPN) have reached inconsistent conclusions as to the impact of a PSM on oncologic outcomes. We sought to determine the effect of PSM on long-term cancer recurrence and survival outcomes. METHODS: We queried our renal oncology database for patients having undergone RAPN and compared recurrence-free survival (RFS) and overall survival (OS) between patients with PSM and negative surgical margin (NSM). Kaplan-Meier analysis was also performed for RFS and OS for PSM versus NSM. RESULTS: Of the 432 patients who underwent RAPN we identified 29 (6.7%) patients with PSM and 403 (93.3%) patients with NSM. Median follow-up for the overall cohort was 45.1 months. Three of the 29 patients with PSM and fourteen of the 403 patients with NSM had disease recurrence (P=0.09). RFS at 24, 48, and 72 months was 95.8%, 90%, and 85.5% for patients with NSM and 96.6%, 86.6%, and 80.4% for patients with PSM, respectively (log-rank P value =0.382). OS at 24, 48, and 72 months was 98%, 93.1%, and 89.7% for patients with NSM and 96.3%, 91.2%, and 85.2% for patients with PSM, respectively (log-rank P value =0.584). CONCLUSIONS: While PSM are relatively uncommon, their presence still serves as a potential risk factor for worse oncologic outcomes. In instances of PSM, immediate secondary intervention is most likely unnecessary and more attentive long-term clinical follow-up, especially in patients with high-risk features, may be more advisable.

A Case Report of an Obstructing Ureteral Nephrogenic Adenoma in a Child Managed With Open Ileal Ureter.

Nephrogenic adenoma is a rare, benign lesion that can be encountered anywhere along the urinary tract. It is associated with genitourinary trauma, chronic inflammation, genitourinary surgery, renal transplant, urolithiasis, and radiation. In children, these lesions are almost exclusively found in the bladder. However, we report an unusual case of a 15-year-old boy with no prior urologic history who presented with an obstructing right ureteral nephrogenic adenoma that required an ileal ureter interposition and right ureterectomy.

A novel Bayesian continuous piecewise linear log-hazard model, with estimation and inference via reversible jump Markov chain Monte Carlo.

We present a reversible jump Bayesian piecewise log-linear hazard model that extends the Bayesian piecewise exponential hazard to a continuous function of piecewise linear log hazards. A simulation study encompassing several different hazard shapes, accrual rates, censoring proportion, and sample sizes showed that the Bayesian piecewise linear log-hazard model estimated the true mean survival time and survival distributions better than the piecewsie exponential hazard. Survival data from Wake Forest Baptist Medical Center is analyzed by both methods and the posterior results are compared.

Partial cystectomy for muscle-invasive bladder cancer: a review of the literature.

The radical cystectomy (RC) for muscle-invasive bladder cancer is one of the most morbid and complex urologic procedures performed today. To avoid these complications, the partial cystectomy (PC) has been offered as an alternative in carefully selected patients as a means of achieving equal oncologic efficacy with less morbidity. Selection criteria should include solitary tumors without concomitant carcinoma in situ (CIS) and amenable to resection with 1-2 cm margins in a normally functioning bladder. In addition to the standard work-up, random bladder and prostatic biopsies may be performed. The PC can be performed through an open, laparoscopic, or robot-assisted approach, each with acceptable outcomes. A number of techniques have been developed to identify and resect the tumor completely with negative margins, while preventing tumor spillage within the abdomen. While there are no randomized trials, single institution series have demonstrated acceptable oncologic outcomes in appropriately selected patients. Therefore, offering PC in the appropriate candidate, including those patients who do not accept or are unfit for the associated morbidity of a RC, represents an acceptable alternative.

Syntaxin 6-mediated exosome secretion regulates enzalutamide resistance in prostate cancer.

Prostate cancer (PCa) deaths are typically the result of metastatic castration-resistant PCa (mCRPC). Recently, enzalutamide (Enz), an oral androgen receptor inhibitor, was approved for treating patients with mCRPC. Invariably, all PCa patients eventually develop resistance against Enz. Therefore, novel strategies aimed at overcoming Enz resistance are needed to improve the survival of PCa patients. The role of exosomes in drug resistance has not been fully elucidated in PCa. Therefore, we set out to better understand the exosome's role in the mechanism underlying Enz-resistant PCa. Results showed that Enz-resistant PCa cells (C4-2B, CWR-R1, and LNCaP) secreted significantly higher amounts of exosomes (2-4 folds) compared to Enz-sensitive counterparts. Inhibition of exosome biogenesis in resistant cells by GW4869 and dimethyl amiloride strongly decreased their cell viability. Mechanistic studies revealed upregulation of syntaxin 6 as well as its increased colocalization with CD63 in Enz-resistant PCa cells compared to Enz-sensitive cells. Syntaxin 6 knockdown by specific small interfering RNAs in Enz-resistant PCa cells (C4-2B and CWR-R1) resulted in reduced cell number and increased cell death in the presence of Enz. Furthermore, syntaxin 6 knockdown significantly reduced the exosome secretion in both Enz-resistant C4-2B and CWR-R1 cells. The Cancer Genome Atlas analysis showed increased syntaxin 6 expressions associated with higher Gleason score and decreased progression-free survival in PCa patients. Importantly, IHC analysis showed higher syntaxin 6 expression in cancer tissues from Enz-treated patients compared to Enz naïve patients. Overall, syntaxin 6 plays an important role in the secretion of exosomes and increased survival of Enz-resistant PCa cells.

Syntaxin 6: A novel predictive and prognostic biomarker in papillary renal cell carcinoma.

Syntaxin 6 is a SNARE family protein known to play an important role in intracellular trafficking. Here, we examined the tumorogenic role of syntaxin 6 in renal cell carcinoma (RCC). The Cancer Genome Atlas (TCGA) was queried for clinicopathologic data and syntaxin 6 expression. We found a significant difference in overall survival (OS) between groups, with high syntaxin 6 expression correlating with decreased survival. When stratifying the data based on histological subtype, the papillary RCC subtype exhibited a significant correlation between syntaxin 6 expression and survival. Using ROC curve, we calculated the area under the curve (AUC) to determine the ability of syntaxin 6 to predict 3-year overall survival. The AUC for syntaxin 6 was 0.73, significantly higher compared to 0.52 for T stage. Next, syntaxin 6 expression was evaluated in clear cell (786-O and Caki-1) and papillary (Caki-2 and ACHN) RCC cells. Syntaxin 6 expression was higher in Caki-1 and ACHN RCC cells. Silencing of syntaxin 6 in ACHN cells significantly decreased the cell viability (p < 0.001). Overall, syntaxin 6 could be a prognostic biomarker for patients with papillary RCC and syntaxin 6 inhibitors hold promise as a novel therapy against RCC.

Pioglitazone's beneficial effects on erectile function preservation after cavernosal nerve injury in the rat are negated by inhibition of the insulin-like growth factor-1 receptor: a preclinical study.

To determine if the insulin-like growth factor-1 (IGF-1) pathway is involved in the improvement in erectile function recovery in rats after nerve crush injury treated with pioglitazone (Pio). Sprague-Dawley rats were divided into four groups. The first group received sham operation (n = 5). The second group underwent bilateral cavernous nerve injury (BCNI, n = 7). The third group received BCNI and Pio treatment (BCNI + Pio, n = 7), whereas the fourth group underwent BCNI with Pio treatment and IGF-1 inhibition (BCNI + Pio + JB-1, n = 7). The IGF-1 receptor (IGF-1R) was inhibited by JB-1, a small molecular antagonist of the receptor. After 14 days of treatment, erectile function was measured via intracorporal pressure normalized to mean arterial pressure (ICP/MAP) and the major pelvic ganglion and cavernous nerve harvested for western blot and immunohistochemistry (IHC) of phosphorylated-IGF-1Rß (p-IGF-1Rß), phosphorylated-ERK1/2 (p-ERK1/2), and neuronal NOS (nNOS). BCNI + Pio animals exhibited improvements in ICP/MAP, similar to Sham animals, and BCNI + Pio + JB-1 rats demonstrated a reduced ICP/MAP similar to BCNI-only rats at all measured voltages. Western blot results showed upregulation of p-IGF-1Rß was observed in the BCNI + Pio group. Low levels of p-ERK1/2 were seen in the JB-1-treated animals. The immunoblot results were supported by IHC findings. Intense IHC staining of nNOS was detected in the BCNI + Pio group. The group treated with JB-1 showed minimal protein expression of p-ERK1/2, nNOS, and p-IGF-1Rß. Pio improves erectile function in rats undergoing BCNI via an IGF-1-mediated pathway.

A National Cancer Database-based nomogram to predict lymph node metastasis in penile cancer.

OBJECTIVE: To evaluate the predictive nature of several clinicopathological variables by developing a nomogram predictive for lymph node-positive disease using the National Cancer Database cohort of patients with squamous cell carcinoma of the penis. METHODS: Stepwise logistic regression was used to find the best-fit model; remaining clinical variables were used to create a nomogram to predict the probability of lymph node-positive disease. RESULTS: On multivariate analysis, high pathological grade (3-4 vs 1: odds ratio [OR] 3.27, 95% confidence interval [CI] 1.70-6.29; 2 vs 1: OR 2.58, 95% CI 1.39-4.79 [P = 0.002]), lymphovascular invasion (OR 2.49, 95% CI 1.61-3.84 [P < 0.001]), and positive clinical lymph node status (N1 vs N0: OR 20.0, 95% CI 11.4-35.7; N2 vs N0: OR 27.8, 95% CI 14.1-55.6; N3 vs N0: OR 49.2, 95% CI 14.8-162.8 [P < 0.001]) were predictors of lymph node metastasis in penile cancer. The bootstrap-corrected concordance index of this nomogram was 0.880. CONCLUSION: Using tumour grade, tumour lymphovascular invasion and clinical lymph node status, we developed a nomogram highly predictive of pathologial lymph node metastasis that, after further external validation, could be helpful in the surgical decision-making process.

Semi-competing risk model to predict perioperative and oncologic outcomes after radical cystectomy.

BACKGROUND: To utilize a semi-competing risk model to predict perioperative and oncologic outcomes after radical cystectomy and to compare the findings with the univariate Cox regression model. METHODS: We reviewed the Institutional Review Board approved database of radical cystectomy of 316 patients who had undergone robot-assisted radical cystectomy (RARC) or open radical cystectomy between 2006 and 2016. Demographic data, perioperative outcomes, complications, metastasis, and survival were analyzed. The Bayesian variable selection method was utilized to obtain models for each hazard function in the semi-competing risks. RESULTS: Of 316 patients treated, 48% and 18% experienced any or major complication respectively within 30 days. Intracorporeal RARC was associated with decreased metastasis risk. Extracorporeal RARC was associated with marginally decreased risks of overall complications or major complications. Patients with advanced cancer had an increased risk of metastasis, death after metastasis and death after complication. Positive nodes were associated with an increased risk of death without overall or major complications and increased risk of death after metastasis occurs. When a serious complication was taken into account there was no significant difference in mortality, irrespective of disease stage. CONCLUSIONS: A semi-competing risk model provides relatively more accurate information in comparison to Cox regression analysis in predicting risk factors for complications and metastasis in patients undergoing radical cystectomy.

Author Correction: Hypoxia-induced exosome secretion promotes survival of African-American and Caucasian prostate cancer cells.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Exosomes secreted by placental stem cells selectively inhibit growth of aggressive prostate cancer cells.

The current paradigm in the development of new cancer therapies is the ability to target tumor cells while avoiding harm to noncancerous cells. Furthermore, there is a need to develop novel therapeutic options against drug-resistant cancer cells. Herein, we characterized the placental-derived stem cell (PLSC) exosomes (PLSCExo) and evaluated their anti-cancer efficacy in prostate cancer (PCa) cell lines. Nanoparticle tracking analyses revealed the size distribution (average size 131.4 ±â€¯0.9 nm) and concentration of exosomes (5.23 × 1010±1.99 × 109 per ml) secreted by PLSC. PLSCExo treatment strongly inhibited the viability of enzalutamide-sensitive and -resistant PCa cell lines (C4-2B, CWR-R1, and LNCaP cells). Interestingly, PLSCExo treatment had no effect on the viability of a non-neoplastic human prostate cell line (PREC-1). Mass spectrometry (MS) analyses showed that PLSCExo are loaded with 241 proteins and mainly with saturated fatty acids. Further, Ingenuity Pathway Analysis analyses of proteins loaded in PLSCExo suggested the role of retinoic acid receptor/liver x receptor pathways in their biological effects. Together, these results suggest the novel selective anti-cancer effects of PLSCExo against aggressive PCa cells.