DNA-dependent protein kinase catalytic subunit (DNA-PKcs, herein referred as DNA-PK) is a multifunctional kinase of high cancer relevance. DNA-PK is deregulated in multiple tumor types, including ...prostate cancer, and is associated with poor outcomes. DNA-PK was previously nominated as a therapeutic target and DNA-PK inhibitors are currently undergoing clinical investigation. Although DNA-PK is well studied in DNA repair and transcriptional regulation, much remains to be understood about the way by which DNA-PK drives aggressive disease phenotypes.
Here, unbiased proteomic and metabolomic approaches in clinically relevant tumor models uncovered a novel role of DNA-PK in metabolic regulation of cancer progression. DNA-PK regulation of metabolism was interrogated using pharmacologic and genetic perturbation using in vitro cell models, in vivo xenografts, and ex vivo in patient-derived explants (PDE).
Key findings reveal: (i) the first-in-field DNA-PK protein interactome; (ii) numerous DNA-PK novel partners involved in glycolysis; (iii) DNA-PK interacts with, phosphorylates (in vitro), and increases the enzymatic activity of glycolytic enzymes ALDOA and PKM2; (iv) DNA-PK drives synthesis of glucose-derived pyruvate and lactate; (v) DNA-PK regulates glycolysis in vitro, in vivo, and ex vivo; and (vi) combination of DNA-PK inhibitor with glycolytic inhibitor 2-deoxyglucose leads to additive anti-proliferative effects in aggressive disease.
Findings herein unveil novel DNA-PK partners, substrates, and function in prostate cancer. DNA-PK impacts glycolysis through direct interaction with glycolytic enzymes and modulation of enzymatic activity. These events support energy production that may contribute to generation and/or maintenance of DNA-PK-mediated aggressive disease phenotypes.
3D printing has been growing in many surgical fields including Urology. The primary use has been to print kidneys with tumors to better understand anatomy and to assist with surgical planning and ...education. Previous studies that utilized 3D printing of kidneys for partial nephrectomies have been limited by the cost and complexity of model creation, rendering them highly impractical to be used on a routine basis. Using a simpler and more cost-effective design and materials allow the 3D kidney models to be used in a wider range and number of patients. We describe our streamlined process to create 3D kidney models costing $30 on average and we believe this process can be repeated by others.
Purpose of Review
This study aims to make the reader be aware of recent trends regarding the endoscopic management of upper tract urothelial carcinoma (UTUC) via review of the urologic literature ...over the past 5 years. Given the rare incidence of this disease, and the lack of level 1 evidence, systematic reviews and meta-analyses were also evaluated. Studies of importance are also considered and outlined in the annotated reference section.
Recent Findings
The PubMed database was queried using the following medical subject headings (MeSH terms): “carcinoma, transitional cell,” “ureter,” “ureteral neoplasms,” “kidney pelvis,” “endoscopy,” “laser therapy,” “ureteroscopy,” “urologic surgical procedures,” and “ureteroscopes.” MeSH terms were linked together in varying combinations and limited to human studies in English. Given the relatively rare nature of upper tract urothelial carcinoma (UTUC), level 1 evidence regarding the efficacy of endoscopic treatment does not exist, even after 30+ years of experience. Rather, the literature available mostly is in the form of single institutional retrospective series consisting of relatively small numbers of patients with short to intermediate follow-up. Only within the last 3 years have published series with larger numbers of patients and mean follow-up over 5 years been made available. Even with these more robust experiences, comparisons among series are difficult given variable treatment and follow-up approaches.
Summary
Most endoscopically managed UTUC will locally recur, especially with longer follow-up. Renal preservation rate is high, however, approaching 80% with follow-up well over 3 years. Patients with high-grade disease often fare poorly regardless of treatment modality. As such, endoscopic management for high-grade urothelial carcinoma should only be used in exceptional circumstances (i.e., in those patients medically unfit for NU or those with solitary kidneys wishing to avoid the morbidity of dialysis). No level 1 evidence exists for the routine use of intraluminal adjuvant therapy for UTUC (i.e., BCG and Mitomycin C) and multiple retrospective observational series claim there is no overt benefit. The recent formation of multiple international groups with interest in UTUC may eventually lead to the production of level 1 studies regarding optimal treatment; however, uniformity in treatment approach will likely still offer challenges.
Radical cystectomy (RC) is standard of care for muscle-invasive bladder cancer, but it comes with significant perioperative risk, with half of the patients experiencing major postoperative ...complications. Robot-assisted radical cystectomies (RARCs) have aimed to decrease patient morbidity and been increasingly adopted in North America. Currently, both open radical cystectomies (ORCs) and RARCs are frequently performed. The aim of this study is to contribute to the existing literature using newly available data from the American College of Surgeons National Surgical Quality Improvement Project (NSQIP), representing one of the most recent, largest multi-institutional studies, while uniquely accounting for a variety of factors, including type of urinary diversion, cancer staging, and neoadjuvant chemotherapy.
RC procedures performed between 2019 and 2021 were identified in NSQIP and the corresponding cystectomy-targeted database. Cases in the ORC group were planned open procedures, and cases in the RARC group were robot assisted, including unplanned conversion to open cases for intention to treat. Chi-square and t-tests were performed to compare baseline demographics and operative parameters. Multivariate analysis was performed for outcomes, including major complications, minor complications, and 30-day mortality rates, while adjusting for baseline differences significant on univariate analysis.
Five thousand three hundred forty-three RC cases were identified. Of these, 70% underwent planned ORC, while 30% received RARC. RARC was associated with longer operative times and shorter hospital length of stay compared with ORC. On multivariate analysis, there was no difference between the cohorts in 30-day rates of major complications, hospital readmissions, need for reoperation, or mortality. ORC was, however, associated with higher rates of minor complications, bleeding, superficial surgical site infections, and anastomotic leak.
In the NSQIP database, ORC is associated with higher rates of 30-day minor complications, most notably bleeding, compared with RARC. However, there is no difference in regard to perioperative major morbidity or mortality rates. This study is unique in the size of the cohorts compared, timeliness of data (2019-2021), applicability to a variety of different practice settings across the country, and ability to control for factors, such as type of urinary diversion and pathological bladder cancer staging, as well as use of neoadjuvant chemotherapy. This study was approved by the Institutional Review Board (IRB) specific to Thomas Jefferson University.
Radiation for primary pelvic malignancies increases the risk of secondary malignancy development. However, outside of malignancies, with excellent cancer-specific survival, the impact of radiation on ...latency between primary and secondary malignancies is likely not enough to change practice patterns.
Radiation therapy has increasingly been used in the management of pelvic malignancies. However, the use of radiation continues to pose a risk of a secondary malignancy to its recipients. This study investigates the risk of secondary malignancy development following radiation for primary pelvic malignancies.
A retrospective cohort review of the Surveillance, Epidemiology, and End Results database from 1975 to 2016 was performed. Primary pelvic malignancies were subdivided based on the receipt of radiation, and secondary malignancies were stratified as pelvic or nonpelvic to investigate the local effect of radiation.
A total of 2102192 patients were analyzed (1189108 with prostate, 315026 with bladder, 88809 with cervical, 249535 with uterine, and 259714 with rectal/anal cancer). The incidence rate (defined as cases per 1000 person years) of any secondary malignancies (including but not limited to secondary pelvic malignancies) was higher in radiation patients than in nonradiation patients (incidence rate ratio IRR 1.04, confidence interval CI 1.03-1.05), with significantly greater rates noted in radiation patients with prostate (IRR 1.22, CI 1.21-1.24), uterine (IRR 1.34), and cervical (IRR 1.80, CI 1.72-1.88) cancer. While the overall incidence rate of any secondary pelvic malignancy was lower in radiation patients (IRR 0.79, CI 0.78-0.81), a greater incidence was still noted in the same cohorts including radiation patients with prostate (IRR 1.42, CI 1.39-1.45), uterine (IRR 1.15, CI 1.08-1.21), and cervical (IRR 1.72, CI 1.59-1.86) cancer.
Except for localized cervical cancer, when put in the context of median overall survival, the impact of radiation likely does not carry enough weight to change practice patterns. Radiation for pelvic malignancies increases the risk for several secondary malignancies, and more specifically, secondary pelvic malignancies, but with a relatively low absolute risk of secondary malignancies, the benefits of radiation warrant continued use for most pelvic malignancies. Practice changes should be considered for radiation utilization in malignancies with excellent cancer-specific survival such as cervical cancer.
The use of radiation for the management of pelvic malignancies induces a risk of secondary malignancies to its recipients. However, the absolute risk being low, the benefits of radiation warrant its continued use, and a change in practice patterns is unlikely.
•Goal: Evaluate real-world accuracy of multiparametric magnetic resonance imaging in staging localized prostate cancer.•Key outcomes: organ confined disease, extracapsular extension, seminal vesicle ...invasion, lymph node involvement, bladder neck invasion.•Demonstrated poor sensitivity, positive predictive value, and negative predictive value in predicting key pathologic outcomes.•Demonstrated better specificity in predicting above pathologic outcomes.•multiparametric magnetic resonance imaging should be used cautiously as a staging tool for prostate cancer and should be interpreted considering individual patient risk strata.
Multiparametric magnetic resonance imaging (mpMRI) has been increasingly utilized in prostate cancer (CaP) diagnosis and staging. While Level 1 data supports MRI utility in CaP diagnosis, there is less data on staging utility. We sought to evaluate the real-world accuracy of mpMRI in staging localized CaP.
Men who underwent radical prostatectomy (RP) for CaP in 2021 at our institution were identified. Sensitivity, specificity, positive predictive value and negative predictive value of mpMRI in predicting pT2N0 organ confined disease , extracapsular extension , seminal vesicle invasion , lymph node involvement, and bladder neck invasion were evaluated. Associations between MRI accuracy and AUA risk stratification (AUA RS), MRI institution (MRI-I), MRI strength (1.5 vs. 3T) (MRI-S), and MRI timing (MRI-T) were assessed. These analyses were repeated using Pennsylvania Urologic Regional Collaborative (PURC) data.
Institutional and community mpMRI CaP staging data demonstrated poor sensitivity (2.9%−49.2%% vs. 16.8%−24.4%), positive predictive value (40%−100% vs. 35.8%−68.2%), and negative predictive value (56.3%−94.3% vs. 68.4%−96.2%) in predicting surgical pathologic features – in contrast, specificity (89.1%−100% vs. 93.9%−98.6%) was adequate. mpMRI accuracy for extracapsular extension, seminal vesicle invasion, and lymph node involvement was significantly (p < 0.001) associated with AUA RS. There was no association between mpMRI accuracy and MRI-I, MRI-S, and MRI-T.
Despite enthusiasm for its use, in a real-world setting, mpMRI appears to be a poor staging study for localized CaP and is unreliable as the sole means of staging patients prior to prostatectomy. mpMRI should be used cautiously as a staging tool for CaP, and should be interpreted considering individual patient risk strata.
Active Stat5a/b predicts early recurrence and disease-specific death in prostate cancer (PC), which both typically are caused by development of metastatic disease. Herein, we demonstrate that ...Stat5a/b induces epithelial-to-mesenchymal transition (EMT) of PC cells, as shown by Stat5a/b regulation of EMT marker expression (Twist1, E-cadherin, N-cadherin, vimentin, and fibronectin) in PC cell lines, xenograft tumors in vivo , and patient-derived PCs ex vivo using organ explant cultures. Jak2-Stat5a/b signaling induced functional end points of EMT as well, indicated by disruption of epithelial cell monolayers and increased migration and adhesion of PC cells to fibronectin. Knockdown of Twist1 suppressed Jak2-Stat5a/b–induced EMT properties of PC cells, which were rescued by re-introduction of Twist1, indicating that Twist1 mediates Stat5a/b-induced EMT in PC cells. While promoting EMT, Jak2-Stat5a/b signaling induced stem-like properties in PC cells, such as sphere formation and expression of cancer stem cell markers, including BMI1. Mechanistically, both Twist1 and BMI1 were critical for Stat5a/b induction of stem-like features, because genetic knockdown of Twist1 suppressed Stat5a/b-induced BMI1 expression and sphere formation in stem cell culture conditions, which were rescued by re-introduction of BMI1. By using human prolactin knock-in mice, we demonstrate that prolactin-Stat5a/b signaling promoted metastases formation of PC cells in vivo . In conclusion, our data support the concept that Jak2-Stat5a/b signaling promotes metastatic progression of PC by inducing EMT and stem cell properties in PC cells.
Objectives Minimally invasive surgical techniques have many benefits, including reduced postoperative pain. Despite this, most patients require opioid analgesia, which can have significant side ...effects and toxicity. We report the first urologic study using multimodal analgesia with pregabalin, a gabapentinoid. Methods The present retrospective study included 60 patients who underwent robotic-assisted laparoscopic radical prostatectomy. Of the 60 patients, 30 received multimodal treatment with pregabalin 150 mg, acetaminophen 975 mg, and celecoxib 400 mg orally 2 hours before the start of the procedure and continued postoperatively. These patients were compared with 30 consecutive previous patients, who had received a standard postoperative analgesic regimen with intravenous ketorolac 15 mg every 6 hours with oxycodone 5 mg and acetaminophen 325 mg, 1 to 2 tablets, every 4 hours as needed for pain. Results The patients in the multimodal treatment group had a significantly reduced intraoperative opioid requirement, as measured by the mean morphine equivalent dose administered (38.4 ± 2.73 mg vs 49.1 ± 2.65 mg; P < .01). The mean postoperative opioid use was also significantly reduced (10.7 ± 2.82 mg vs 26.2 ± 6.56 mg; P = .034), as was the mean total morphine equivalent dose administered (49.1 ± 2.7 mg vs 75.3 ± 4.6 mg; P < .001). The operative time, estimated operative blood loss, antiemetic use, postoperative creatinine and hemoglobin levels, and length of stay were similar in the 2 groups. No operative or treatment complications occurred in either group. Conclusions The present retrospective review has indicated that a multimodal analgesic approach with pregabalin and celecoxib administered preoperatively decreases intraoperative and postoperative opioid use in patients undergoing robotic-assisted laparoscopic radical prostatectomy.
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