CD8+ T cell activation in cancer comprises an initial activation phase in lymph nodes followed by effector differentiation within the tumor.

Improvements in tumor immunotherapies depend on better understanding of the anti-tumor T cell response. By studying human tumor-draining lymph nodes (TDLNs), we found that activated CD8+ T cells in TDLNs shared functional, transcriptional, and epigenetic traits with TCF1+ stem-like cells in the tumor. The phenotype and TCR overlap suggested that these TDLN cells were precursors to tumor-resident stem-like CD8+ T cells. Murine tumor models revealed that tumor-specific CD8+ T cells were activated in TDLNs but lacked an effector phenotype. These stem-like cells migrated into the tumor, where additional co-stimulation from antigen-presenting cells drove effector differentiation. This model of CD8+ T cell activation in response to cancer is different from that of canonical CD8+ T cell activation to acute viruses, and it proposes two stages of tumor-specific CD8+ T cell activation: initial activation in TDLNs and subsequent effector program acquisition within the tumor after additional co-stimulation.

Prospective Randomized Trial Comparing the Safety and Clarity of Water Versus Saline Irrigant in Ureteroscopy.

BACKGROUND: Water irrigant is discouraged in ureteroscopy due to risks demonstrated in more invasive endoscopic procedures. However, water is not well studied in ureteroscopy and may provide better visualization than standard saline. OBJECTIVE: To determine whether water irrigant increases the risk of hyponatremia compared with saline and provides better visualization in ureteroscopy. DESIGN, SETTING, AND PARTICIPANTS: A randomized, prospective, double-blinded trial was conducted. In 2017, eligible adult ureteroscopy patients at a university hospital were recruited for the study. INTERVENTION: Participants randomized to water or saline irrigant in ureteroscopy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Serum sodium and osmolality, body temperature, subjective surgeon visualization, and objective turbidity clarity were analyzed. Chi-square or Fisher's exact tests for categorical variables and analysis of variance test for continuous variables were performed. RESULTS AND LIMITATIONS: A total of 121 individuals (mean age 57 ± 15 yr) underwent ureteroscopy (mean time 35 ± 18 min) with a mean irrigation volume of 839 ± 608 ml. For the 101 (83%) patients who had nephrolithiasis, the mean number of stones was 2 ± 1 and the mean stone burden was 13 ± 7 mm. There were no significant differences in demographic, clinical, and intraoperative variables between water and saline groups, except for a higher body mass index in the saline group (p = 0.01). There was no significant difference between groups in the incidence of hyponatremia, hypo-osmolality, or hypothermia. The median surgeon visualization score was significantly higher using water (p < 0.01). The mean turbidity was significantly lower with water (p = 0.02). Limitations were not objectively assessing hemolysis or fluid absorption. CONCLUSIONS: Water irrigant does not increase the incidence of hyponatremia in uncomplicated ureteroscopy and provides clearer visualization than saline. PATIENT SUMMARY: We compared safety and clarity of water and saline irrigation, which aid surgeon visualization, in ureteroscopy, which can treat kidney stones. We found that water irrigant does not reduce blood sodium levels significantly compared with saline in ureteroscopy and provides better visualization.

Overall survival comparison between androgen deprivation therapy (ADT) plus external beam radiation therapy (EBRT) vs ADT plus EBRT with brachytherapy boost in clinically node-positive prostate cancer.

PURPOSE: Optimal therapy for clinically node-positive, nonmetastatic (cN1) prostate cancer (PC) patients remains controversial, ranging from aggressive local therapy to palliative systematic therapy alone. Despite guideline support, it is unclear if a brachytherapy (BT) boost should be considered for cN1 patients as these patients were excluded from randomized trials establishing its benefit. Herein, we compare definitive radiation therapy (RT) with or without a BT boost in cN1 PC. METHODS AND MATERIALS: The National Cancer Database was used to identify men with cN1 PC treated with definitive RT and concomitant androgen deprivation therapy between 2004 and 2013. Overall survival (OS) was compared between those who received external beam RT (EBRT) or combination EBRT plus BT boost (EBRT + BT) using Kaplan-Meier with propensity score matching and Cox proportional hazards. RESULTS: With a median followup of 48.5 months, 1,650 patients were eligible for this analysis, 103 (6.2%) of whom received EBRT + BT. Younger age, no medical comorbidities, and Gleason score of six were associated with higher likelihood of receiving EBRT + BT over EBRT alone. The mean (median) OS for EBRT and EBRT + BT was 99.0 (110.6) months vs 109.2 (not reached) months, respectively (p = 0.048). However, no significance difference in OS was observed between the groups after propensity score matching. On multivariable analysis, EBRT + BT was not significantly associated with improved OS (adjusted HR 0.67, 95% CI, 0.41-1.07, p = 0.098). CONCLUSIONS: In this retrospective, observational study of patients with cN1 PC treated with definitive RT and concomitant androgen deprivation therapy, EBRT + BT had an unadjusted improvement in OS compared with EBRT alone that lost statistical significance after multivariable adjustment and propensity score matching.

High-dose-rate prostate brachytherapy appears safe in patients with high baseline International Prostate Symptom Scores.

PURPOSE: The purpose of the study was to report our institutional quality of life data for those undergoing high-dose-rate brachytherapy with an International Prostate Symptom Score (IPSS) ≥15 compared with those with an IPSS <15. METHODS AND MATERIALS: The charts of 95 patients with localized adenocarcinoma of the prostate treated with high-dose-rate as monotherapy or as a boost after external beam radiation therapy at a single institution between 2012 and 2015 were reviewed. All patients completed the IPSS and Expanded Prostate Index for Prostate Cancer-Clinical Practice quality of life assessments before treatment and at least one followup survey. Linear mixed models were performed to test for significant changes and differences in each outcome over time. RESULTS: Median followup in the IPSS <15 group was 23 months and 16 months in the IPSS ≥15 group. Median prostate volume was 46.3 cc and 45.4 cc, respectively (p = 0.901). IPSS, incontinence, and urinary irritation/obstruction scores were significantly higher in the IPSS ≥15 group compared with the IPSS <15 group at baseline (all p ≤ 0.05). By the >24 months time point, these scores had decreased below baseline and were not significantly different from those with a baseline IPSS <15 (all p > 0.1). 12.5% in the IPSS ≥15 group developed a new Grade 2 genitourinary toxicity requiring an alpha blocker compared with 26.5% in the IPSS <15 group (p = 0.34). No patients required emergency placement of a foley catheter within 30 days of treatment. CONCLUSIONS: Given the low rates of genitourinary toxicity, this technique appears appropriate even for those with high baseline urinary symptoms.

MicroRNA Expression Profile Identifies High Grade, Non-Muscle-Invasive Bladder Tumors at Elevated Risk to Progress to an Invasive Phenotype.

The objective of this study was to identify a panel of microRNAs (miRNAs) differentially expressed in high-grade non-muscle invasive (NMI; TaG3-T1G3) urothelial carcinoma that progress to muscle-invasive disease compared to those that remain non-muscle invasive, whether recurrence happens or not. Eighty-nine high-grade NMI urothelial carcinoma lesions were identified and total RNA was extracted from paraffin-embedded tissue. Patients were categorized as either having a non-muscle invasive lesion with no evidence of progression over a 3-year period or as having a similar lesion showing progression to muscle invasion over the same period. In addition, comparison of miRNA expression levels between patients with and without prior intravesical therapy was performed. Total RNA was pooled for microarray analysis in each group (non-progressors and progressors), and qRT-PCR of individual samples validated differential expression between non-progressive and progressive lesions. MiR-32-5p, -224-5p, and -412-3p were associated with cancer-specific survival. Downregulation of miR-203a-3p and miR-205-5p were significantly linked to progression in non-muscle invasive bladder tumors. These miRNAs include those implicated in epithelial mesenchymal transition, previously identified as members of a panel characterizing transition from the non-invasive to invasive phenotype in bladder tumors. Furthermore, we were able to identify specific miRNAs that are linked to postoperative outcome in patients with high grade NMI urothelial carcinoma of the bladder (UCB) that progressed to muscle-invasive (MI) disease.

Gaps in Patient Knowledge About Risks and Benefits of Testosterone Replacement Therapy.

OBJECTIVE: To assess patient knowledge of the symptoms of testosterone deficiency, and the benefits and risks associated with testosterone replacement therapy (TRT). METHODS: An anonymous, 10-question multiple choice survey was administered to consecutive patients presenting for urologic evaluation at an academic medical center, from December 2015 to April 2016. The survey included questions about perceived symptoms of testosterone deficiency, perceived benefits and risks associated with TRT, whether respondents had a diagnosis of testosterone deficiency, and whether they were interested in receiving TRT. RESULTS: The survey response rate was 88% (97/110). The median age group was 41-50 years. Although 43% of all respondents reported an interest in TRT, only half of them had a clinical diagnosis of hypogonadism. The most commonly reported symptoms of low testosterone were "low energy" (54%), "decreased libido" (51%), "weak erections" (52%), and "decreased strength" (42%). Of the perceived benefits of TRT, the most commonly reported were "improved sexual function" (54%), "increased energy" (53%), and "feeling better" (51%). Half of the respondents were unsure of the risks of TRT. Of the respondents, 16%, 10%, and 8% acknowledged the association between TRT and heart attack, TRT and stroke, and TRT and blood clots, respectively. CONCLUSION: There is disproportionate knowledge about the benefits vs the risks associated with TRT among patients. Although 43% of the respondents were interested in receiving TRT, half of the respondents were unsure of the associated risks. These findings indicate an ongoing need for patient education regarding TRT.

Biopsy is contraindicated in the management of penile calciphylaxis.

INTRODUCTION: Calciphylaxis, a rare obliterative small vessel vasculopathy associated with diabetes mellitus (DM), end-stage renal disease (ESRD), portends a poor prognosis. Because penile involvement is rare, agreement on appropriate diagnosis and management is unclear. AIM: To determine the role and effect of penile biopsy for diagnosis and management of penile calciphylaxis. METHODS: Medical records of three penile calciphylaxis patients from our institution were evaluated. Data collected included age, history of DM, ESRD, and hemodialysis (HD) status, serum calcium (Ca), Ca × phosphorous product (C × P), parathyroid hormone (PTH), performance of biopsy, presence of non-penile cutaneous lesions, intervention, survival, and time from diagnosis to death. PubMed Search for relevant publications from 1995 to 2012 was performed to identify case reports of penile calciphylaxis that provided the same clinical data obtained from the 3 patients from our institution. MAIN OUTCOME MEASURES: Clinical evidence for outcomes in patients with penile calciphylaxis after biopsy of penile lesion compared to those without biopsy. RESULTS: A total of sixteen patients were identified in the literature and in our institution with clinical data of interest. Overall, 10/16 (62.5%) patients identified with penile calciphylaxis had a penile biopsy, and 7/10 (70%) experienced disease progression, while only 3/10 (30%) stabilized. Mean time to death in this patient population was short, approximately 6.5 months, regardless of type of intervention. CONCLUSION: Based on the results of our study, we argue that conservative measures should be employed as first line therapy for penile calciphylaxis. More importantly, secondary to likely resultant progression of necrosis, penile biopsy is not only unnecessary for diagnosis of penile calciphylaxis, but is also harmful and contraindicated.