Comparison of lateral flank approach and low anterior access for single port (SP) retroperitoneal partial nephrectomy: an analysis from the single port advanced research consortium (SPARC).

Single Port (SP) robotic partial nephrectomy (RPN) can be performed via retroperitoneal and transperitoneal approach. We aim to compare outcomes of two commonly described incisions for retroperitoneal SP RPN: lateral flank approach (LFA) and low anterior access (LAA). We performed a retrospective study of patients who underwent SP retroperitoneal RPN from 2018 to 2023 as part of a large multi-institute collaboration (SPARC). Baseline demographic, clinical, tumor-specific characteristics, and perioperative outcomes were compared using χ2, t test, Fisher exact test, and Mann-Whitney U test. Multivariable analyses were conducted using robust and logistic regressions. A total of 70 patients underwent SP retroperitoneal RPN, with 44 undergoing LAA. Overall, there were no significant differences in baseline characteristics between the two groups. The LAA group exhibited significantly lower median RENAL scores (8 vs. 5, p < 0.001) and more varied tumor locations (p = 0.002). In the bivariate analysis, there were no statistically significant differences in ischemia time, estimated blood loss, or complication rates between the groups. However, the LAA group had longer operative times (101 vs. 134 min, p < 0.001), but was more likely to undergo a same-day discharge (p < 0.001). When controlling for other variables, LAA was associated with shorter ischemia time (p = 0.005), but there was no significant difference in operative time (p = 0.348) and length of stay (p = 0.122). Both LFA and LAA are acceptable approaches for SP retroperitoneal RPN with comparable perioperative outcomes. This early data suggests the LAA is more versatile for varying tumor locations; however, larger cohort studies are needed to ascertain whether there is an overall difference in patient recovery.

Assessing Functional Outcomes of Partial Versus Radical Nephrectomy for T1b-T2 Renal Masses: Results from a Multi-institutional Collaboration.

BACKGROUND: Deterioration of renal function is associated with increased all-cause mortality. In renal masses larger than 4 cm, whether partial versus radical nephrectomy (PN vs. RN) might affect long-term functional outcomes is unknown. This study tested the association between PN versus RN and postoperative acute kidney injury (AKI), recovery of at least 90% of the preoperative estimated glomerular filtration rate (eGFR) at 1 year, upstaging of chronic kidney disease (CKD) one stage or more at 1 year, and eGFR decline of 45 ml/min/1.73 m2 or less at 1 year. METHODS: Data from 23 high-volume institutions were used. The study included only surgically treated patients with single, unilateral, localized, clinical T1b-2 renal masses. Multivariable logistic regression analyses were performed. RESULTS: Overall, 968 PN patients and 325 RN patients were identified. The rate of AKI was lower in the PN versus the RN patients (17% vs. 58%; p < 0.001). At 1 year after surgery, for the PN versus the RN patients, the rate for recovery of at least 90% of baseline eGFR was 51% versus 16%, the rate of CKD progression of ≥ 1 stage was 38% versus 65%, and the rate of eGFR decline of 45 ml/min/1.73 m2 or less was 10% versus 23% (all p < 0.001). Radical nephrectomy independently predicted AKI (odds ratio [OR], 7.61), 1-year ≥ 90% eGFR recovery (OR, 0.30), 1-year CKD upstaging (OR, 1.78), and 1-year eGFR decline of 45 ml/min/1.73 m2 or less (OR, 2.36) (all p ≤ 0.002). CONCLUSIONS: For cT1b-2 masses, RN portends worse immediate and 1-year functional outcomes. When technically feasible and oncologically safe, efforts should be made to spare the kidney in case of large renal masses to avoid the hazard of glomerular function loss-related mortality.

AI-powered real-time annotations during urologic surgery: The future of training and quality metrics.

INTRODUCTION AND OBJECTIVE: Real-time artificial intelligence (AI) annotation of the surgical field has the potential to automatically extract information from surgical videos, helping to create a robust surgical atlas. This content can be used for surgical education and qualitative initiatives. We demonstrate the first use of AI in urologic robotic surgery to capture live surgical video and annotate key surgical steps and safety milestones in real-time. SUMMARY BACKGROUND DATA: While AI models possess the capability to generate automated annotations based on a collection of video images, the real-time implementation of such technology in urological robotic surgery to aid surgeon and training staff it is still pending to be studied. METHODS: We conducted an educational symposium, which broadcasted 2 live procedures, a robotic-assisted radical prostatectomy (RARP) and a robotic-assisted partial nephrectomy (RAPN). A surgical AI platform system (Theator, Palo Alto, CA) generated real-time annotations and identified operative safety milestones. This was achieved through trained algorithms, conventional video recognition, and novel Video Transfer Network technology which captures clips in full context, enabling automatic recognition and surgical mapping in real-time. RESULTS: Real-time AI annotations for procedure #1, RARP, are found in Table 1. The safety milestone annotations included the apical safety maneuver and deliberate views of structures such as the external iliac vessels and the obturator nerve. Real-time AI annotations for procedure #2, RAPN, are found in Table 1. Safety milestones included deliberate views of structures such as the gonadal vessels and the ureter. AI annotated surgical events included intraoperative ultrasound, temporary clip application and removal, hemostatic powder application, and notable hemorrhage. CONCLUSIONS: For the first time, surgical intelligence successfully showcased real-time AI annotations of 2 separate urologic robotic procedures during a live telecast. These annotations may provide the technological framework for send automatic notifications to clinical or operational stakeholders. This technology is a first step in real-time intraoperative decision support, leveraging big data to improve the quality of surgical care, potentially improve surgical outcomes, and support training and education.

Robotic nephroureterectomy supplanting open and laparoscopic approach for upper tract urothelial carcinoma management: a narrative review.

Background and Objective: The use of robotic surgery for managing upper tract urothelial carcinoma (UTUC) has increased significantly over the years. Minimally invasive techniques (MIS) are now used for approximately half of all robot-assisted laparoscopic nephroureterectomy (RAL-NU) performed in the USA. However, there are currently no specific management guidelines that recommend the use of a robotic approach, and the available literature on this topic is limited. For this reason, we reviewed the history and current literature regarding this technique. Methods: We searched Web of Science and PubMed for articles between 1934 to 2023 using 20 different search terms and combinations. We restricted our selection to only publications in English language. Key Content and Findings: Comparative retrospective studies between techniques [open nephroureterectomy (ONU), laparoscopic nephroureterectomy (LNU), and RAL-NU] and case series of surgical groups, mostly at short- and mid-term follow-up, were included. Conclusions: Robotic surgery for UTUC is on the rise and is predicted to become the preferred method for nephroureterectomy. A comparison of RAL-NU to LNU and ONU shows several advantages, including less blood loss, pain, and hospital stay, as well as a quicker recovery time. The safety and effectiveness of robotic surgery for lymphadenectomy also supports its use in RAL-NU. As more medical facilities adopt the technique and further studies support its benefits, it is likely that robotic surgery will become the preferred method for NU.

One-year healthcare costs after robotic-assisted and laparoscopic partial and radical nephrectomy: a cohort study.

OBJECTIVE: Despite the wide-spread adoption of robotic-assisted surgery (RAS), the cost-benefit implications for partial (PN) and radical nephrectomy (RN) versus laparoscopic surgery (Lap) is not well established. We sought to examine the trend of adoption and 1-year healthcare expenditure of PN and RN, and compare 1-year expenditures of RAS versus Lap for PN and RN. PATIENTS AND METHODS: This cohort study used the MerativeTM MarketScan® Databases between 2013 and 2020. A total of 5,353 patients with kidney cancer undergoing PN (2,980, 55.7%) or RN (2,373, 44.3%). We compared open-conversion, length of stay (LOS), index expenditure, 1-year healthcare expenditure and utilization, and missed work-days between RAS and Lap for PN and RN. RESULTS: Adoption of PN increased overtime (47.0% to 55.8%), mainly driven by robotic PN increase. Among PN, RAS had lower open-conversion, shorter LOS and lower index expenditure than Lap. Among RN, RAS had shorter LOS, and similar open-conversion and index expenditures. During 1-year post-discharge, RAS had lower hospital outpatient visits (IRR = 0.92, 95% CI = 0.85, 0.99, p = 0.029) and office-based visits (IRR = 0.91, 95% CI = 0.86, 0.96, p = 0.002) for PN, translating to a 1-day less (95% CI = 0.25, 1.75, p = 0.008) missed from work for RAS. Following RN, RAS had lower 1-year readmission than Lap (O.R = 0.72, 95% CI = 0.55, 0.94, p = 0.018). RAS and Lap had comparable 1-year post-discharge expenditures for both PN (mean difference, MD = -$475, 95% CI = -$4362, $3412, p = 0.810) and RN (MD = -$4,204, 95% CI = -$13,837, $5430, p = 0.404). CONCLUSION: At index surgery, RAS was associated with shorter LOS for both PN and RN, and lower open-conversion and expenditures for PN. RAS and Lap had comparable 1-year total expenditures, despite lower healthcare visits for RAS.

Trends in the surgical management of kidney cancer by tumor stage, treatment modality, facility type, and location.

Partial nephrectomy (PN) is an alternative to radical nephrectomy (RN) in the appropriate localized renal tumor. The scope of PN has expanded over time and, since the advent and proliferation of minimally invasive surgery, more surgeons have access to and have been trained in laparoscopic and robotic technology. Amid the changing surgical landscape, we sought to characterize the trends in management by cancer stage, institution type, and geographic location using the National Cancer Database (NCDB). We queried the NCDB for patients with kidney cancer from 2004 to 2019. Overall, 241,311 patients who underwent PN or RN were included in the study. The nephrectomy approach was categorized as robotic partial (RPN), robotic radical (RRN), laparoscopic partial (LPN), laparoscopic radical (LRN), open or unspecified partial (OPN), and open or unspecified radical (ORN). The categorical variables were presented as frequency and percentages. Overall, there was an increase in the utilization of robotic approaches from 2010 to 2019. For cT1 tumors, the use of RPN and RRN increased from 14.27 to 33.06% and 5.24% to 19.63%, respectively. The use of ORN for cT2 and cT3 tumors declined, with rates dropping from 54.71 to 10.76% and 64.71 to 46.64%, respectively. Conversely, the utilization of RRN rose during this period. However, ORN remained the most common approach for cT3 tumors. The use of RPN increased across different facility types, with the highest utilization observed in academic/research programs. The use of ORN for cT2 and cT3 tumors declined across facility types, although it remained most prevalent in community cancer programs. The use of robot-assisted surgery to treat localized renal cancer increased in the US between 2010 and 2019 across all stages of disease. RPN became the most used approach for cT1 disease, while LRN was preferred for cT2 disease. ORN remained the approach of choice for cT3 disease throughout the study period. Trends in facility type and geographic location largely mirrored the overall trends.

Low Risk of Postoperative Hernia Following Single-port Robot-assisted Radical Prostatectomy: A Report From the Single-port Advanced Research Consortium (SPARC).

OBJECTIVE: To evaluate the risk of postoperative hernia following different approaches of single-port robot-assisted radical prostatectomy (SP-RARP). METHODS: A retrospective review was performed on patients who underwent SP-RARP between February 2019 and December 2022. Demographic and clinical information was collected from the multi-institutional, prospectively-maintained Single-Port Advanced Research Consortium (SPARC) database. Data were analyzed using IBM Statistical Packaging for Social Sciences (SPSS) version 29.0 with descriptive statistics as presented. RESULTS: A total of 1103 patients were identified, consisting of 244 (22.1%), 712 (64.6%), and 147 (13.3%) cases performed via transperitoneal, extraperitoneal (EP), and transvesical (TV) approaches, respectively. During a median follow-up time of 11 months (interquartile range 5.7-17.1 months), only two cases of incisional hernia were reported. Both cases occurred following transperitoneal SP-RARP with one patient requiring surgical repair. There remains no evidence of postoperative hernia following EP and TV SP-RARP at the completion of our review. CONCLUSION: SP-RARP was associated with low risk for postoperative hernia. The risk was lower following TV and EP SP-RARP where the peritoneum is preserved.

Effects of increased grazing intensity during the early and late grazing periods on the welfare of spring-calving, pasture-based dairy cows.

The objective of this study was to identify potential effects of increased grazing intensity, characterized by differing pasture availability and stocking rate, on indicators of welfare during both early and late grazing periods. Seventy spring-calving, pasture-based Holstein-Friesian and cross-bred dairy cows, averaging 35 ± 16 d in milk on the first day of data collection, were assigned to 3 treatments (20-26 cows/treatment) representing a range in grazing intensity: LO (high pasture availability, 980 kg DM/ha opening cover, 2.75 cows/ha, 90:10% pasture:concentrate diet), MOD (medium pasture availability, 720 kg DM/ha opening cover, 2.75 cows/ha, 90:10% pasture:concentrate diet), and HI (low pasture availability, 570 kg DM/ha opening cover, 3.25 cows/ha, 80:20% pasture:concentrate diet); representative of current, best practice and proposed production levels respectively for this system. Welfare indicators were locomotion score, digital dermatitis and white line disease, rumen fill, ocular and nasal discharge, integument damage to the neck-back and hock regions, and lying time. Data were collected during a 5-wk early grazing period in spring (EG) and a 7-wk late grazing period in autumn (LG). Average daily lying time was recorded for 8 to 10 focal cows per treatment. Results demonstrated only minor treatment effects. Cows on MOD [odds ratio (OR) = 3.11] and HI (OR = 1.95) were more likely to display nasal discharge compared with LO. Cows on MOD tended to have more damage to the skin on the neck-back region than LO (OR = 4.26). Total locomotion score (maximum = 25) was greater on LOW (7.1 ± 0.20) compared with HI (6.5 ± 0.19). Average lame cow prevalence for EG and LG respectively was 15.3 ± 3.12% and 39.2 ± 3.00% (LO), 20.0 ± 2.58% and 24.2 ± 5.69% (MOD), and 14.9 ± 4.79% and 17.0 ± 3.44% (HI). Cows on HI were less likely to have impaired walking speed than either LO (OR = 0.24) or MOD (OR = 0.29). Cows on both HI (OR = 0.36) and MOD (OR = 0.40) were less likely to display impaired abduction or adduction compared with those on LO. An interaction between treatment and period revealed longer lying times for cows on LO (10.6 h/d ± 0.39) compared with both MOD and HI (8.7 ± 0.43 and 8.4 ± 0.41 h/d) during EG only. The greatest effects were across grazing periods, with all indicators except rumen fill and locomotion score demonstrating improvements from EG to LG. This suggests cows were able to cope well with increasing levels of grazing intensity, and that regardless of treatment, a greater number of days on pasture led to improvements in welfare indicators.

Transperitoneal Versus Retroperitoneal Single-port Robotic-assisted Partial Nephrectomy: An Analysis from the Single Port Advanced Research Consortium.

BACKGROUND: In the surgical management of kidney tumors, such as in multiport technology, single-port (SP) robotic-assisted partial nephrectomy (RAPN) can be performed using the transperitoneal (TP) or retroperitoneal (RP) approach. However, there is a dearth of literature on the efficacy and safety of either approach for SP RAPN. OBJECTIVE: To compare the peri- and postoperative outcomes of the TP and RP approaches for SP RAPN. DESIGN, SETTING, AND PARTICIPANTS: This is a retrospective cohort study using data from the Single Port Advanced Research Consortium (SPARC) database of five institutions. All patients underwent SP RAPN for a renal mass between 2019 and 2022. INTERVENTION: TP versus RP SP RAPN. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Baseline characteristics, and peri- and postoperative outcomes were compared between both the approaches using χ2 test, Fisher exact test, Mann-Whitney U test, and Student t test. RESULTS AND LIMITATIONS: A total of 219 patients (121 [55.25%] TP, 98 [44.75%] RP) were included in the study. Of them, 115 (51.51%) were male, and the mean age was 60 ± 11 yr. RP had a significantly higher proportion of posterior tumors (54 [55.10%] RP vs 28 [23.14%] TP, p < 0.001), while other baseline characteristics were comparable between both the approaches. There was no statistically significant difference in ischemia time (18 ± 9 vs 18 ± 11 min, p = 0.898), operative time (147 ± 67 vs 146 ± 70 min, p = 0.925), estimated blood loss (p = 0.167), length of stay (1.06 ± 2.25 vs 1.33 ± 1.05 d, p = 0.270), overall complications (5 [5.10%] vs 7 [5.79%]), and major complication rate (2 [2.04%] vs 2 [1.65%], p = 1.000). No difference was observed in positive surgical margin rate (p = 0.472) or delta eGFR at median 6-mo follow-up (p = 0.273). Limitations include retrospective design and no long-term follow-up. CONCLUSIONS: With proper patient selection based on patient and tumor characteristics, surgeons can opt for either the TP or the RP approach for SP RAPN, and maintain satisfactory outcomes. PATIENT SUMMARY: The use of a single port (SP) is a novel technology for performing robotic surgery. Robotic-assisted partial nephrectomy (RAPN) is a surgery to remove a portion of the kidney due to kidney cancer. Depending on patient characteristics and surgeons' preference, SP can be performed via two approaches for RAPN: through the abdomen or through the space behind the abdominal cavity. We compared outcomes between these two approaches for patients receiving SP RAPN, finding that they were comparable. We conclude that with proper patient selection based on patient and tumor characteristics, surgeons can opt for either the TP or the RP approach for SP RAPN, and maintain satisfactory outcomes.

Transperitoneal Versus Retroperitoneal Robotic-Assisted Partial Nephrectomy in Patients with Obesity.

Introduction: We aim to compare transperitoneal (TP) and retroperitoneal (RP) robotic partial nephrectomy (RPN) in obese patients. Obesity and RP fat can complicate RPN, especially in the RP approach where working space is limited. Materials and Methods: Using a multi-institutional database, we analyzed 468 obese patients undergoing RPN for a renal mass (86 [18.38%] RP, 382 [81.62%] TP). Obesity was defined as body mass index ≥30 kg/m2*. A 1:1 propensity score matching was performed adjusting for age, previous abdominal surgery, tumor size, R.E.N.A.L nephrometry score, tumor location, surgical date, and participating centers. Baseline characteristics and perioperative and postoperative data were compared. Results: In the propensity score-matched cohort, 79 (50%) TP patients were matched with 79 (50%) RP patients. The RP group had more posterior tumors (67 [84.81%], RP versus 23 [29.11%], TP; P < .001), while the other baseline characteristics were comparable. Warm ischemia time (interquartile range; 15 [10, 12], RP versus 14 [10, 17] minutes, TP; P = .216), operative time (129 [116, 165], RP versus 130 [95, 180] minutes, TP; P = .687), estimated blood loss (50 [50, 100], RP versus 75 [50, 150] mL, TP; P = .129), length of stay (1 [1, 1], RP versus 1 [1, 2] day, TP; P = .319), and major complication rate (1 [1.27%], RP versus 3 [3.80%], TP; P = .620) were similar. No significant difference was observed in positive surgical margin rate and delta estimated glomerular filtration at follow-up. Conclusion: TP and RP RPN yielded similar perioperative and postoperative outcomes in obese patients. Obesity should not be a factor in determining optimal approach for RPN.

Robot-assisted partial nephrectomy for complex renal tumors: Analysis of a large multi-institutional database.

INTRODUCTION: Highly complex renal masses pose a challenge to urologic surgeons' ability to perform robotic partial nephrectomy (RPN). Given the increased utilization of the robotic approach for small renal masses, we sought to characterize the outcomes and determine the safety and feasibility of RPN for complex renal masses from our large multi-institutional cohort. METHODS: We performed a retrospective analysis of patients with R.E.N.A.L. Nephrometry Scores ≥10 who underwent RPN in our multi-institutional cohort (N = 372). Baseline demographic, clinical and tumor related characteristics were evaluated with the primary endpoint of trifecta achievement (defined as negative surgical margin, no major complications, and warm ischemia time ≤25 min). Relationships between variables were assessed using the chi-square test of independence, Fisher exact test, Mann-Whitney U test, and Kruskal Wallis test. Logistic regression was used to evaluate the relationship between baseline characteristics and trifecta achievement. RESULTS: Of 372 patients in the study, mean age was 58 years, and median BMI was 30.49 kg/m2. The median tumor size was 4.3 cm (3.0-5.9 cm). Most of the patients had R.E.N.A.L. scores of 10 (n = 253; 67.01%). Overall, trifecta was achieved in 72.04% of patients. Stratifying intraoperative and postoperative outcomes by R.E.N.A.L. scores, there was no significant difference in trifecta achievement, operative time, warm ischemia time (WIT), open conversion, major complication, or positive margin rates. Length of hospital stay was significantly longer for higher R.E.N.A.L. scores (median days 2 vs. 1, P = 0.012). Multivariate analyses for factors associated with trifecta achievement concluded that age and baseline eGFR were independently associated with trifecta achievement. CONCLUSION: RPN is a safe and reproducible procedure for complex tumors with R.E.N.A.L. Nephrometry scores ≥10. Our results suggest excellent rates of trifecta achievement and short-term functional outcomes when performed by experienced surgeons. Long-term oncological and functional evaluation are needed to further support this conclusion.

Staphylococcus aureus persisters are associated with reduced clearance in a catheter-associated biofilm infection.

Background: Staphylococcus aureus causes a wide variety of infections, many of which are chronic or relapsing in nature. Antibiotic therapy is often ineffective against S. aureus biofilm-mediated infections. Biofilms are difficult to treat partly due to their tolerance to antibiotics, however the underlying mechanism responsible for this remains unknown. One possible explanation is the presence of persister cells-dormant-like cells that exhibit tolerance to antibiotics. Recent studies have shown a connection between a fumC (fumarase C, a gene in the tricarboxylic acid cycle) knockout strain and increased survival to antibiotics, antimicrobial peptides, and in a Drosophila melanogaster model. Objective: It remained unclear whether a S. aureus high persister strain would have a survival advantage in the presence of innate and adaptive immunity. To further investigate this, a fumC knockout and wild type strains were examined in a murine catheter-associated biofilm model. Results: Interestingly, mice struggled to clear both S. aureus wild type and the fumC knockout strains. We reasoned both biofilm-mediated infections predominantly consisted of persister cells. To determine the persister cell population within biofilms, expression of a persister cell marker (Pcap5A::dsRED) in a biofilm was examined. Cell sorting of biofilms challenged with antibiotics revealed cells with intermediate and high expression of cap5A had 5.9-and 4.5-fold higher percent survival compared to cells with low cap5A expression. Based on previous findings that persisters are associated with reduced membrane potential, flow cytometry analysis was used to examine the metabolic state of cells within a biofilm. We confirmed cells within biofilms had reduced membrane potential compared to both stationary phase cultures (2.5-fold) and exponential phase cultures (22.4-fold). Supporting these findings, cells within a biofilm still exhibited tolerance to antibiotic challenge following dispersal of the matrix through proteinase K. Conclusion: Collectively, these data show that biofilms are largely comprised of persister cells, and this may explain why biofilm infections are often chronic and/or relapsing in clinical settings.

Translation of circHGF RNA encodes an HGF protein variant promoting glioblastoma growth through stimulation of c-MET.

INTRODUCTION: HGF/c-MET signaling is a significant driver of glioblastoma (GBM) growth and disease progression. Unfortunately, c-MET targeted therapies have been found to be largely ineffective suggesting additional redundant mechanisms of c-MET activation. METHODS: Utilizing RNA-sequencing (RNA-seq) and ribosome profiling analyses of circular RNAs, circ-HGF (hsa_circ_0080914) was identified as markedly upregulated in primary GBM and found to potentially encode an HGF protein variant (C-HGF) 119 amino acids in length. This candidate HGF variant was characterized and evaluated for its ability to mediate c-MET activation and regulate PDX GBM cell growth, motility and invasive potential in vitro and tumor burden in intracranial xenografts in mice. RESULTS: An internal ribosome entry site (IRES) was identified within the circ-HGF RNA which mediated translation of the cross-junctional ORF encoding C-HGF and was observed to be highly expressed in GBM relative to normal brain tissue. C-HGF was also found to be secreted from GBM cells and concentrated cell culture supernatants or recombinant C-HGF activated known signaling cascades downstream of c-MET. C-HGF was shown to interact directly with the c-MET receptor resulting in its autophosphorylation and activation in PDX GBM lines. Knockdown of C-HGF resulted in suppression of c-MET signaling and marked inhibition of cell growth, motility and invasiveness, whereas overexpression of C-HGF displayed the opposite effects. Additionally, modulation of C-HGF expression regulated tumor growth in intracranial xenografted PDX GBM models. CONCLUSIONS: These results reveal an alternative mechanism of c-MET activation via a circular RNA encoded HGF protein variant which is relevant in GBM biology. Targeting C-HGF may offer a promising approach for GBM clinical management.

Corruption of DNA end-joining in mammalian chromosomes by progerin expression.

Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare genetic condition characterized by features of accelerated aging and a life expectancy of about 14 years. HGPS is commonly caused by a point mutation in the LMNA gene which codes for lamin A, an essential component of the nuclear lamina. The HGPS mutation alters splicing of the LMNA transcript, leading to a truncated, farnesylated form of lamin A termed "progerin." Progerin is also produced in small amounts in healthy individuals by alternative splicing of RNA and has been implicated in normal aging. HGPS is associated with an accumulation of genomic DNA double-strand breaks (DSBs), suggesting alteration of DNA repair. DSB repair normally occurs by either homologous recombination (HR), an accurate, templated form of repair, or by nonhomologous end-joining (NHEJ), a non-templated rejoining of DNA ends that can be error-prone; however a good portion of NHEJ events occurs precisely with no alteration to joined sequences. Previously, we reported that over-expression of progerin correlated with increased NHEJ relative to HR. We now report on progerin's impact on the nature of DNA end-joining. We used a model system involving a DNA end-joining reporter substrate integrated into the genome of cultured thymidine kinase-deficient mouse fibroblasts. Some cells were engineered to express progerin. Two closely spaced DSBs were induced in the integrated substrate through expression of endonuclease I-SceI, and DSB repair events were recovered through selection for thymidine kinase function. DNA sequencing revealed that progerin expression correlated with a significant shift away from precise end-joining between the two I-SceI sites and toward imprecise end-joining. Additional experiments revealed that progerin did not reduce HR fidelity. Our work suggests that progerin suppresses interactions between complementary sequences at DNA termini, thereby shifting DSB repair toward low-fidelity DNA end-joining and perhaps contributing to accelerated and normal aging through compromised genome stability.

A Multi-Institutional Matched-Pair Analysis of Robotic Partial Nephrectomy for Single vs Multiple Ipsilateral Renal Masses.

Introduction: Nephron-sparing surgery is important in patients with multiple renal tumors, especially if associated with a solitary kidney or hereditary syndrome. Prior studies have shown partial nephrectomy (PN) of multiple ipsilateral renal masses to have good oncologic and renal function outcomes. We aim to compare renal function changes, complications, and warm ischemia time (WIT) of partial nephrectomy of a single renal mass (sPN) vs those of partial nephrectomy of multiple ipsilateral renal masses (mPN). Materials and Methods: We retrospectively reviewed our multi-institutional PN database. We matched robotic sPN and mPN patients ∼3:1 using "nearest neighbor" propensity score matching based on age, Charlson comorbidity index (CCI), total tumor size, and nephrometry score. Univariate analysis was performed, and multivariable models were fit controlling for age, gender, CCI, and tumor size. Results: Fifty mPN and 146 sPN patients were matched. The mean total tumor size was 3.3 and 3.2 cm, respectively (p = 0.363). The mean nephrometry score in both groups was 7.3 and 7.2, respectively (p = 0.772). Estimated blood loss (EBL) was 137.6 and 117.8 mL, respectively (p = 0.184). The mPN group had higher operative time (174.6 vs 156.4 minutes, p = 0.008) and WIT (17.0 vs 15.3 minutes, p = 0.032). There was no significant difference in the change in glomerular filtration rate (mPN -6.4% vs sPN -8.7%, p = 0.712). Complications (Clavien 2+) occurred in 10.2% of mPN and 11.3% of sPN patients (p = 0.837). A multivariable linear model predicts a nonstatistically significant difference of 1.4 minutes of additional WIT in the mPN group (p = 0.242). There was no statistical difference in complication rates between groups in a multivariable model (odds ratio 1.00, p = 0.991). Conclusions: Robotic PN in our multi-institutional matched comparison of mPN and sPN showed no difference in complications, renal functional outcomes, or EBL. mPN was associated with increased operative time and WIT, though the WIT difference was not significant on multivariable analysis.

m6A-modification of cyclin D1 and c-myc IRESs in glioblastoma controls ITAF activity and resistance to mTOR inhibition.

A major mechanism conferring resistance to mTOR inhibitors is activation of a salvage pathway stimulating internal ribosome entry site (IRES)-mediated mRNA translation, driving the synthesis of proteins promoting resistance of glioblastoma (GBM). Previously, we found this pathway is stimulated by the requisite IRES-trans-acting factor (ITAF) hnRNP A1, which itself is subject to phosphorylation and methylation events regulating cyclin D1 and c-myc IRES activity. Here we describe the requirement for m6A-modification of IRES RNAs for efficient translation and resistance to mTOR inhibition. DRACH-motifs within these IRES RNAs upon m6A modification resulted in enhanced IRES activity via increased hnRNP A1-binding following mTOR inhibitor exposure. Inhibitor exposure stimulated the expression of m6A-methylosome components resulting in increased activity in GBM. Silencing of METTL3-14 complexes reduced IRES activity upon inhibitor exposure and sensitized resistant GBM lines. YTHDF3 associates with m6A-modified cyclin D1 or c-myc IRESs, regulating IRES activity, and mTOR inhibitor sensitivity in vitro and in xenograft experiments. YTHDF3 interacted directly with hnRNP A1 and together stimulated hnRNP A1-dependent nucleic acid strand annealing activity. These data demonstrate that m6A-methylation of IRES RNAs regulate GBM responses to this class of inhibitors.

Operative and oncological outcomes of salvage robotic radical and partial nephrectomy: a multicenter experience.

We aim to describe the perioperative and oncological outcomes for salvage robotic partial nephrectomy (sRPN) and salvage robotic radical nephrectomy (sRRN). Using a prospectively maintained multi-institutional database, we compared baseline clinical characteristics and perioperative and postoperative outcomes, including pathological stage, tumor histology, operative time, ischemia time, estimated blood loss (EBL), length of stay (LOS), postoperative complication rate, recurrence rate, and mortality. We identified a total of 58 patients who had undergone robotic salvage surgery for a recurrent renal mass, of which 22 (38%) had sRRN and 36 (62%) had sRPN. Ischemia time for sRPN was 14 min. The median EBL was 100 mL in both groups (p = 0.581). One intraoperative complication occurred during sRRN, while three occurred during sRPN cases (p = 1.000). The median LOS was 2 days for sRRN and 1 day for sRPN (p = 0.039). Postoperatively, one major complication occurred after sRRN and two after sRPN (p = 1.000). The recurrence reported after sRRN was 5% and 3% after sRPN. Among the patients who underwent sRRN, the two most prevalent stages were pT1a (27%) and pT3a (27%). Similarly, the two most prevalent stages in sRPN patients were pT1a (69%) and pT3a (6%). sRRN and sRPN have similar operative and perioperative outcomes. sRPN is a safe and feasible procedure when performed by experienced surgeons. Future studies on large cohorts are essential to better characterize the importance and benefit of salvage partial nephrectomies.

Single Port Versus Multiport Robot-assisted Simple Prostatectomy: A Multi-institutional Study From the Single-port Advanced Research Consortium (SPARC).

OBJECTIVE: To compare robot-assisted simple prostatectomy intraoperative and postoperative.ßoutcomes between single-port (SP) and multiport (MP) robotic systems in a multi-institutional setting. METHODS: We analyzed all-consecutive robot-assisted simple prostatectomy cases done in 5 centers from January 2017 to October 2022. Data were analyzed with descriptive statistics and compared with appropriate tests depending on the type of variable and distribution. Statistical significance was considered when P.ß<.05. RESULTS: A total of 405 cases were analyzed:.ß249 and 156 were MP and SP, respectively. Operative times were similar between groups (P.ß=.ß.62). Estimated blood loss during surgery was significantly lower with the SP robot (P.ß<.001). Postoperatively, the SP approach required a significantly shorter hospital stay, less use of opioids, and a shorter duration of Foley catheter (P.ß<.001). There was no significant difference between the post-operative Clavien-Dindo ...3 complication rate (P.ß=.ß.30). The 30-day readmission rate of MP (10.8%) was significantly higher than for SP (0%) (P.ß<.001). De novo urge incontinence was more common in the MP group (P.ß=.ß.02). CONCLUSION: The SP robotic approach to simple prostatectomy is advantageous when it comes to postoperative comfort for patients. Specifically, it requires a shorter hospital stay, less use of opioids, and a shorter Foley catheter duration.