Impact of frozen section on long-term outcomes in robot-assisted laparoscopic prostatectomy.

OBJECTIVES: To compare 1-year functional and 5-year oncological outcomes of men undergoing robot-assisted laparoscopic prostatectomy (RALP) with neurovascular structure-adjacent frozen-section examination (NeuroSAFE) with those in men undergoing RALP without NeuroSAFE (standard of care [SOC]). SUBJECTS AND METHODS: Men undergoing RALP in our centre between 1 January 2009 and 30 June 2018 were enrolled from a prospectively maintained database. Patients were excluded if they had undergone preoperative therapy or postoperative adjuvant therapy or were enrolled in clinical trials. Patients were grouped based on use of NeuroSAFE. Follow-up was censored at 5 years. The primary outcome was difference in time to biochemical recurrence (BCR) on multivariable analysis, defined as prostate-specific antigen (PSA) >0.2 ng/L on two consecutive measurements. Secondary outcomes were difference in 1-year erectile dysfunction and incontinence. RESULTS: In the enrolment period, 1199 consecutive men underwent RALP, of whom 1140 were eligible, including 317 with NeuroSAFE and 823 with SOC. The median PSA follow-up was 60 months in both groups. Rates of 5-year BCR were similar on Kaplan-Meier survival curve analysis (11% vs 11%; P = 0.9), as was time to BCR on multivariable Cox proportional hazards modelling (hazard ratio 1.2; P = 0.6). Compared with the SOC group at 1 year, the NeuroSAFE group had similar unadjusted rates of incontinence (5.1% vs 7.7%) and lower unadjusted impotence (57% vs 80%). On multivariable analysis, NeuroSAFE patients had equivalent risk of incontinence (odds ratio [OR] 0.59, 95% CI 0.17-1.6; P = 0.4) but significantly reduced risk of erectile dysfunction (OR 0.37, 95% CI 0.22-0.60; P < 0.001). CONCLUSIONS: For men undergoing RALP, compared with SOC, NeuroSAFE patients had equivalent time to BCR and risk of 1-year incontinence, and significantly lower risk of 1-year erectile dysfunction.

Concordance between renal tumour biopsy and robotic-assisted partial and radical nephrectomy histology: a 10-year experience.

We aimed to assess concordance between renal tumour biopsy (RTB) and surgical pathology from robotic-assisted partial nephrectomy (RAPN) or robotic-assisted radical nephrectomy (RARN). Patients with preoperative RTB undergoing RAPN or RARN for suspected malignancy (9 September 2013-9 September 2023) were enrolled retrospectively from three sites. Patients were excluded if the tumour had prior cryotherapy or if biopsy or nephrectomy histology were unavailable or inconclusive. The primary outcome was concordance with the presence/absence of malignancy. Secondary outcomes were concordance with tumour subtype, World Health Organisation nuclear grade (patients with RTB clear cell or papillary RCC only), false-negative rate, false-positive rate, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). In the enrolment period, 332 and 132 patients underwent RAPN and RARN, respectively. Of these, 160 received preoperative RTB, with nine patients excluded, leaving 151 eligible patients. Median age was 63 years, and 49 (32%) were female. On surgical specimens, 144 patients had malignant histology. RTB was highly concordant with presence/absence of malignancy (147/151, 97%). Concordance with tumour subtype occurred in 141 patients (93%), while concordance with nuclear grade was seen in 42/66 patients (64%, RTB grade missing in 53 patients). False-negative rate, false-positive rate, sensitivity, specificity, PPV, and NPV were 2%, 14%, 98%, 86%, 99%, and 67%, respectively. Limitations include absence of complication data and exclusion of patients biopsied without surgery. In patients undergoing RAPN or RARN, preoperative RTB has high concordance with surgical pathology, both in the presence of malignancy and RCC subtype.

AI-Generated Information for Vascular Patients: Assessing the Standard of Procedure-Specific Information Provided by the ChatGPT AI-Language Model.

Introduction Ensuring access to high-quality information is paramount to facilitating informed surgical decision-making. The use of the internet to access health-related information is increasing, along with the growing prevalence of AI language models such as ChatGPT. We aim to assess the standard of AI-generated patient-facing information through a qualitative analysis of its readability and quality. Materials and methods We performed a retrospective qualitative analysis of information regarding three common vascular procedures: endovascular aortic repair (EVAR), endovenous laser ablation (EVLA), and femoro-popliteal bypass (FPBP). The ChatGPT responses were compared to patient information leaflets provided by the vascular charity, Circulation Foundation UK. Readability was assessed using four readability scores: the Flesch-Kincaid reading ease (FKRE) score, the Flesch-Kincaid grade level (FKGL), the Gunning fog score (GFS), and the simple measure of gobbledygook (SMOG) index. Quality was assessed using the DISCERN tool by two independent assessors. Results The mean FKRE score was 33.3, compared to 59.1 for the information provided by the Circulation Foundation (SD=14.5, p=0.025) indicating poor readability of AI-generated information. The FFKGL indicated that the expected grade of students likely to read and understand ChatGPT responses was consistently higher than compared to information leaflets at 12.7 vs. 9.4 (SD=1.9, p=0.002). Two metrics measure readability in terms of the number of years of education required to understand a piece of writing: the GFS and SMOG. Both scores indicated that AI-generated answers were less accessible. The GFS for ChatGPT-provided information was 16.7 years versus 12.8 years for the leaflets (SD=2.2, p=0.002) and the SMOG index scores were 12.2 and 9.4 years for ChatGPT and the patient information leaflets, respectively (SD=1.7, p=0.001). The DISCERN scores were consistently higher in human-generated patient information leaflets compared to AI-generated information across all procedures; the mean score for the information provided by ChatGPT was 50.3 vs. 56.0 for the Circulation Foundation information leaflets (SD=3.38, p<0.001). Conclusion We concluded that AI-generated information about vascular surgical procedures is currently poor in both the readability of text and the quality of information. Patients should be directed to reputable, human-generated information sources from trusted professional bodies to supplement direct education from the clinician during the pre-procedure consultation process.

Colectomy rates in ulcerative colitis: A systematic review and meta-analysis.

BACKGROUND: Surgical management in Ulcerative Colitis (UC) is typically utilised in medically refractory cases and, therefore, it is a useful marker for efficacy of medical management. AIMS: To understand the changing prevalence of colectomy in UC over time. METHODS: A systematic review was conducted using MEDLINE (1946-2021), EMBASE and EMBASE classic (1947-2021) to identify studies with a population of n>500 that reported colectomy rates in UC patients >18 years old. The primary outcome was the prevalence of colectomy at 1-, 5- and 10-years post-diagnosis. Secondary outcomes included colectomy rates in the pre-biologics (defined as pre-2004) and post-biologics eras (defined as post-2004). RESULTS: Thirty-one studies with 294,359 patients with UC were included for review and meta-analysis. The prevalence of colectomy at 1-, 5- and 10-years post-diagnosis were 3% (95% CI 2%-6%), 5% (95% CI 2%-9%), 10% (95% CI 6%-16%) respectively. The pooled relative risk for colectomy in the post-biologics era was 0.68 (95% CI 0.42 to 1.09, p=0.10) at 1-year and 0.71 (95% CI 0.56 to 0.91, p<0.01) at 5-years post-diagnosis. CONCLUSION: The overall colectomy rate has decreased over the past three decades. Biologics may have played a role in reducing the risk of colectomy, however the relative risk reduction is likely to be modest.

Pro-inflammatory Cytokines Drive Deregulation of Potassium Channel Expression in Primary Synovial Fibroblasts.

The synovium secretes synovial fluid, but is also richly innervated with nociceptors and acts as a gateway between avascular joint tissues and the circulatory system. Resident fibroblast-like synoviocytes' (FLS) calcium-activated potassium channels (K Ca) change in activity in arthritis models and this correlates with FLS activation. OBJECTIVE: To investigate this activation in an in vitro model of inflammatory arthritis; 72 h treatment with cytokines TNFα and IL1ß. METHODS: FLS cells were isolated from rat synovial membranes. We analyzed global changes in FLS mRNA by RNA-sequencing, then focused on FLS ion channel genes and the corresponding FLS electrophysiological phenotype and finally modeling data with ingenuity pathway analysis (IPA) and MATLAB. RESULTS: IPA showed significant activation of inflammatory, osteoarthritic and calcium signaling canonical pathways by cytokines, and we identified ∼200 channel gene transcripts. The large K Ca (BK) channel consists of the pore forming Kcnma1 together with ß-subunits. Following cytokine treatment, a significant increase in Kcnma1 RNA abundance was detected by qPCR and changes in several ion channels were detected by RNA-sequencing, including a loss of BK channel ß-subunit expression Kcnmb1/2 and an increase in Kcnmb3. In electrophysiological experiments, there was a decrease in over-all current density at 20 mV without change in chord conductance at this potential. CONCLUSION: TNFα and IL1ß treatment of FLS in vitro recapitulated several common features of inflammatory arthritis at the transcriptomic level, including increase in Kcnma1 and Kcnmb3 gene expression.

Involvement of ER stress and activation of apoptotic pathways in fisetin induced cytotoxicity in human melanoma.

The prognosis of malignant melanoma remains poor in spite of recent advances in therapeutic strategies for the deadly disease. Fisetin, a dietary flavonoid is currently being investigated for its growth inhibitory properties in various cancer models. We previously showed that fisetin inhibited melanoma growth in vitro and in vivo. Here, we evaluated the molecular basis of fisetin induced cytotoxicity in metastatic human melanoma cells. Fisetin treatment induced endoplasmic reticulum (ER) stress in highly aggressive A375 and 451Lu human melanoma cells, as revealed by up-regulation of ER stress markers including IRE1α, XBP1s, ATF4 and GRP78. Time course analysis indicated that the ER stress was associated with activation of the extrinsic and intrinsic apoptotic pathways. Fisetin treated 2-D melanoma cultures displayed autophagic response concomitant with induction of apoptosis. Prolonged treatment (16days) with fisetin in a 3-D reconstituted melanoma model resulted in inhibition of melanoma progression with significant apoptosis, as evidenced by increased staining of cleaved Caspase-3 in the treated constructs. However, no difference in the expression of autophagic marker LC-3 was noted between treated and control groups. Fisetin treatment to 2-D melanoma cultures resulted in phosphorylation and activation of the multifunctional AMP-activated protein kinase (AMPK) involved in the regulation of diverse cellular processes, including autophagy and apoptosis. Silencing of AMPK failed to prevent cell death indicating that fisetin induced cytotoxicity is mediated through both AMPK-dependent and -independent mechanisms. Taken together, our studies confirm apoptosis as the primary mechanism through which fisetin inhibits melanoma cell growth and that activation of both extrinsic and intrinsic pathways contributes to fisetin induced cytotoxicity.

YB-1 expression promotes epithelial-to-mesenchymal transition in prostate cancer that is inhibited by a small molecule fisetin.

Epithelial-to-mesenchymal transition (EMT) plays an important role in prostate cancer (PCa) metastasis. The transcription/translation regulatory Y-box binding protein-1 (YB-1) is known to be associated with cancer metastasis. We observed that YB-1 expression increased with tumor grade and showed an inverse relationship with E-cadherin in a human PCa tissue array. Forced YB-1 expression induced a mesenchymal morphology that was associated with down regulation of epithelial markers. Silencing of YB-1 reversed mesenchymal features and decreased cell proliferation, migration and invasion in PCa cells. YB-1 is activated directly via Akt mediated phosphorylation at Ser102 within the cold shock domain (CSD). We next identified fisetin as an inhibitor of YB-1 activation. Computational docking and molecular dynamics suggested that fisetin binds on the residues from ß1 - ß4 strands of CSD, hindering Akt's interaction with YB-1. Calculated free binding energy ranged from -11.9845 to -9.6273 kcal/mol. Plasmon Surface Resonance studies showed that fisetin binds to YB-1 with an affinity of approximately 35 µM, with both slow association and dissociation. Fisetin also inhibited EGF induced YB-1 phosphorylation and markers of EMT both in vitro and in vivo. Collectively our data suggest that YB-1 induces EMT in PCa and identify fisetin as an inhibitor of its activation.