Citations

Abstract Background Percutaneous ablation of parathyroid adenomas provides a minimally invasive treatment option for primary hyperparathyroidism. However, the overall performance of this technique remains underexplored. This meta-analysis evaluates the effectiveness and safety of various ablation techniques for parathyroid adenomas. Methods Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, multiple databases, including Ovid MEDLINE and Cochrane, were systematically searched. Studies that provided separate data for radiofrequency (RF), microwave ablation (MWA), and ethanol ablation technique were included. Outcomes of interest were changes in serum calcium, PTH, and phosphorus levels, along with normocalcemia rates at 6 to 12 months after ablation. Safety outcomes included transient hoarseness, permanent hoarseness, severe hemorrhage, major complications, and severe hypocalcemia. Data were pooled using a random-effects model, with pooled prevalence and 95% CIs calculated. Also, the publication bias was assessed with Egger's test for each outcome measure. Results Twenty studies (815 patients) were included. The posttreatment normocalcemia rate at 6 to 12 months was 85.6% (95% CI, 80.48-90.72). Serum PTH and calcium levels significantly decreased, with mean differences of 101.49 pg/mL (95% CI, 73.50-129.48) and 0.39 mmol/L (95% CI, 0.34-.45), respectively. Permanent hoarseness and major complications were rare, with incidences of 0.28% (95% CI, 0.00-1.05) and 0.31% (95% CI, 0.00-1.09). The safety and efficacy outcomes of RF, MWA, and ethanol ablation were comparable. Conclusion Our findings indicate that percutaneous ablation of parathyroid adenomas is safe and effective within the first year of the treatment. Additionally, they suggest that RF, MWA, and ethanol ablation techniques can each be employed depending on patients' needs without particular limitations.

Background. The Fontan procedure has transformed the management of congenital heart defects characterized by single ventricle physiology, yet it predisposes individuals to Fontan-associated liver disease. Combined heart and liver transplantation (CHLT) emerges as a therapeutic option, but evidence of its efficacy and safety remains limited. This study aimed to comprehensively evaluate CHLT in Fontan patients, focusing on patient characteristics, perioperative outcomes, and posttransplant morbidity and mortality. Methods. Following Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines, a systematic search of PubMed, Embase, and the Cochrane Central Register of Controlled Trials was conducted. Studies meeting the intervention of CHLT in Fontan patients were included, and data were collected and synthesized using proportion meta-analysis techniques. Statistical analysis was carried out using R software. Results. Four studies met inclusion criteria, comprising 67 Fontan patients undergoing CHLT. All included studies were observational retrospective cohorts performed in the United States. The 1-y survival rate post-CHLT was 88% (95% confidence interval [CI], 70%-98%). Liver graft rejection rates were low, 4% (95% CI, 0%-22%), and no heart graft rejection greater than mild was reported. Postoperative complications included acute kidney injury 75% (95% CI, 50%-93%), temporary dialysis 27% (95% CI, 9%-51%), neurologic events 7% (95% CI, 0%-26%), infection 23% (95% CI, 3%-55%), and unplanned medical procedures 40% (95% CI, 23%-59%). Conclusions. CHLT in Fontan patients demonstrates promising survival rates, but graft rejection and postoperative complications pose challenges. The rate of renal complications is particularly notable and requires further evaluation. Future research should prioritize comparative different management strategies and long-term follow-up to refine protocols and optimize outcomes.

Abstract Robots have been used effectively in plastic and reconstructive surgery (PRS) for reconstruction. The utilization of robotics in all surgical specialties is expanding with the goal of offering the most appropriate patient-centered care possible, especially in complex multidisciplinary cases. Despite the safety, efficiency, and reproducibility of robotics in PRS, there is a paucity of required and formalized training in PRS residency programs. The ACGME and industry published guidelines were investigated. Robotic surgery case logs of Mayo Clinic Arizona General Surgery residents were analyzed with attention to equivalency certification (EQ). Over the past 5 years, the equivalency certification from Intuitive (Sunnyvale, CA) was obtained by 30% of all general surgery residents at our institution (range, 0–100). The case numbers to obtain the equivalence certification are industry recommendations, and proficiency is determined by the program director. The ACGME does not mandate robotics training in general surgery residency. According to the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES), trainees must complete 20 console cases and 10 bedside cases to become industry certified. With respect to training and advancing the field, PRS residents could successfully obtain certification in their residency programs. The minimum case requirement recommended by SAGES is not burdensome and can ensure robotic privileges in PRS practice immediately following graduation. By improving the training for minimally invasive robotic surgery in plastic surgery, patients and healthcare systems benefit from improved quality of life outcomes and decreased postoperative length of stay, which results in less strain on our entire medical system.

AbstractINTRODUCTIONPhosphorylated ubiquitin (p‐S65‐Ub) is generated during PINK1‐PRKN mitophagy as a specific marker of mitochondrial damage. Despite the widespread deposition of p‐S65‐Ub in aged and diseased human brain, the genetic contribution to its accumulation remains unclear.METHODSTo identify novel mitophagy regulators, we performed a genome‐wide association study using p‐S65‐Ub level as a quantitative trait in 1012 autopsy‐confirmed Lewy body disease (LBD) samples.RESULTSWe identified a significant genome‐wide association with p‐S65‐Ub for rs429358 (apolipoprotein E ε4 [APOE4]) and a suggestive association for rs6480922 (ZMIZ1). APOE4 was associated with higher p‐S65‐Ub levels and greater neuropathological burden. Functional validation in mouse and human induced pluripotent stem cell (iPSC) models confirmed APOE4‐mediated mitophagy alterations. Intriguingly, ZMIZ1 rs6480922 was associated with lower p‐S65‐Ub levels, reduced neuropathological load, and increased brain weight, indicating a potential protective role.DISCUSSIONOur findings underscore the importance of mitochondrial quality control in LBD pathogenesis and nominate regulators that may contribute to disease risk or resilience.Highlights p‐S65‐Ub levels were used as a quantitative marker of mitochondrial damage. A GWAS identified two genetic variants that modify mitophagy in LBD autopsy brain. APOE4 was associated with increased p‐S65‐Ub accumulation and neuropathology. APOE4 altered mitophagy via pathology‐dependent and pathology‐independent mechanisms. ZMIZ1 was linked to reduced p‐S65‐Ub and neuropathology indicative of protection.

Abstract Background The prevalence of delirium in intensive care units (ICUs) is high and has a major impact on patient outcomes. Aim To describe delirium assessment instruments, prevalence, interventions and barriers in delirium management in adult and paediatric ICUs; and to explore the association between delirium prevalence and reported interventions and barriers at unit level. Study Design A secondary analysis of the cross‐sectional World Delirium Awareness Day Delirium Survey on 15 March 2023. This was a prospective study to assess the one‐day point delirium prevalence, practices and quality improvement efforts across healthcare systems. Data was analysed descriptively and using multiple linear regression. Results Data of 1612 assessments in 123 ICUs from three German‐speaking countries were analysed. The most frequently used delirium assessment instrument was the Intensive Care Delirium Screening Checklist (43.9%, n = 54). The prevalence of delirium at 8 AM was 18.6% and at 8 PM 20.4% from the 94 ICUs included in the regression analyses. Prevalence for adult and paediatric and mixed ICUs are comparable. Main reported over all unit‐level interventions were ‘pain management’ (95.9%, n = 118), ‘mobilization’ (94.3%, n = 116) and ‘verbal re‐orientation’ (84.6%, n = 104). Main reported over all unit‐level barriers were ‘shortage of staff’ (53.7%, n = 66) and ‘patients who are difficult to assess’ (44.7%, n = 55). Interventions such as ‘avoidance of bladder tubes/catheters’ in all ICUs, ‘use of ear plugs and/or sleep glasses’ in adult ICUs and ‘mobilization’ in paediatric and mixed ICUs were associated with reduced delirium prevalence. Across all ICUs, as well as in both adult and paediatric ICUs, ‘lack of appropriate scores for delirium assessment’ was identified as a significant barrier. Conclusions One fifth of assessed ICU patients suffer from delirium. Several reported unit‐level interventions and barriers may have an impact on delirium prevalence, suggesting an approach for future studies and clinical practice. Relevance to Clinical Practice In clinical practice, unit‐level ‘avoidance of bladder tubes/catheters’, ‘use of ear plugs and/or sleep glasses’ and ‘mobilization’ may be used as delirium prevention and treatment interventions.

Objectives Traditionally, acute mesenteric ischemia studies are performed by utilizing an open superior mesenteric artery (SMA) occlusion, which is an invasive technique with potentially devastating effects. A new endovascular technique for SMA occlusion using a catheter-balloon system was designed and compared to the open SMA occlusion to test its efficacy and animal safety. Methods All animals underwent open instrumentation of the superior mesenteric vein (SMV) for blood flow monitoring. The animals were grouped into an open SMA occlusion technique group and an endovascular SMA occlusion group. The open SMA occlusion technique group involved exposure of the SMA via left medial visceral rotation with vascular clamping. In the endovascular group, an endovascular balloon was placed in the SMA and inflated to produce occlusion. Results Complete cessation of flow to the SMV was observed in the endovascular group, compared to the residual SMV flow in the open occlusion group. Following a 30-min post-occlusion period, the MAP in the endovascular group increased, compared to a decline of MAP in the open occlusion group. Conclusions This study indicates the endovascular technique provides a more potent SMA occlusion, with insignificant consequences on the overall health of the animal, in contrast to the open vascular clamping.

Abstract VSV-IFNβ-NIS (VV1) is a Vesicular Stomatitis Virus (VSV) that encodes the interferon beta (IFNβ) and the iodide symporter (NIS) gene. The IFNβ gene confers tumor selectivity and enhances host antitumor immunity while the NIS gene acts as an imaging biomarker, allowing noninvasive imaging of viral infection sites using PET/SPECT. Multiple myeloma (MM) is a cancer of plasma cells and poses a challenge for treatment due to its biological heterogeneity. As MM usually relapses and is refractory, current therapies face the issue of drug resistance and patients may have to turn to novel therapies. Therefore, we set out to understand the activity of VSV which could be a new approach for patients with relapsed refractory MM (RRMM). Our study utilized two unique bortezomib resistant Vk*MYC transplantable models, Vk12598 and Vk12653, with distinct genomic features. Upon re-transplantation of splenocytes from these mice, flow cytometry revealed that Vk12598 and Vk12653 mice had high MM populations in the spleen and bone marrow. To assess VV1 efficacy in tumor bearing mice, we performed a VV1 dose escalation study, showing efficacy in delaying MM development and prolonging survival in both mice models, with Vk12598 being the more responsive model. Later studies also showed that VV1 induces tumor remission in the Vk12598 model when treatment was initiated at low tumor burden (gamma/albumin ratio ∼0.2). IFNβ levels increased significantly post 24-72h of VV1 treatment, indicating targeted infection and replication of the virus in MM cells. However, high doses of VV1 led to toxicity, as observed from early mortality and weight loss. To determine the sites of MM metastasis and VV1 infection, timepoint harvests were carried out. Hematoxylin and eosin and immunostainings showed the onset of MM of Vk*MYC in the bone marrow and spleen first, then later in the liver. Immunofluorescent staining confirmed that the higher the tumor burden observed, the more VV1 was present in the tissues. To enhance VV1 efficacy, we performed in vivo combination therapies of VV1 with anti-PD-1, an inhibitor of PD-1 which is overexpressed on MM patient T cells; and bortezomib, which inhibits NF-κB which in turn prevents IFN pathway protein transcription, potentially enhancing the replication of VV1 virus. In Vk12598 mice, VV1 combined with both drugs induced tumor regression and doubled the median survival time compared to treatment with VV1 only or VV1 coupled with either of the drugs individually. Addition of VV1 to either anti-PD-1 or bortezomib alone also increased survival time significantly. Studies are still ongoing to understand the mechanisms of VSV and its combination treatments in Vk*MYC models. This translational study will allow us to gain the knowledge needed to refine VSV treatments and provide novel therapy combinations to improve MM patient survival. Citation Format: Yi Ying Ma, Lianwen Zhang, Rebecca A. Nace, Marta Chesi, Stephen J. Russell, Kah Whye Peng. Harnessing oncolytic virus VSV and combination therapy to advance treatments for relapsed refractory multiple myeloma using Vk*MYC models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 940.

Breast and ovarian cancer represent the most common and lethal cancers in women. Despite chemotherapy and targeted agents, recurrence is frequent and outcomes for patients with advanced disease are dismal, underscoring the need for novel therapeutic strategies. Using an unbiased approach with DepMap CRISPR screens across more than 1000 cancer cell lines, we identified six genes (CTPS1, RHOA, PRKRA, RAD9A, HUS1, and RAD1) that were essential for triple negative breast cancer (TNBC) cells, but not ERα+ breast cancer cells, that were also associated with poor outcomes. Validation of these effects by siRNA knockdown studies revealed that suppression of CTPS1 elicited the most potent inhibitory effects, characterized by S phase cell cycle arrest and apoptosis. Similar effects were also found in ovarian cancer cells which share many molecular features. CTPS1, along with CTPS2, is responsible for enzymatic conversion of UTP to CTP, an essential nucleoside triphosphate required for multiple cellular processes including DNA/RNA synthesis, phospholipid synthesis and glycosylation. CTPS1 was found to be highly expressed in tumor tissues, for both breast and ovarian cancer. RT-PCR assessment of CTPS1 expression in a panel of over 40 breast and ovarian cancer lines confirmed variable, but elevated expression relative to normal models. Notably, chemotherapy-resistant and PARP inhibitor (PARPi)-resistant models exhibited the highest levels of CTPS1 expression among all cells analyzed. In partnership with Step Pharma, which has developed a first-in-class highly selective CTPS1 inhibitor (STP938), we have demonstrated that STP938 elicits potent anti-proliferative effects at nM concentrations across many cell line and patient derived models, both in 2D and 3D culture systems. Furthermore, STP938 exhibited strong anti-cancer activity in chemotherapy- and PARPi-resistant ovarian cancer models, both as a monotherapy and in combination with standard-of-care treatments. RNA-seq analysis in cell models following STP938 treatment or CTPS1 knockdown/knockout showed significant dysregulation of DNA replication and cell cycle related genes, suggesting potential synergy with drugs targeting replication stress or DNA damage response pathways. Single-cell sequencing further revealed specific cell-cell interactions/cross talk/pathways that are disrupted by STP938 in vivo using ovarian cancer patient-derived xenograft. The first-in-human clinical trial for STP938 began in 2022 for relapsed/refractory B- and T-cell lymphomas (NCT05463263). In August 2024, a second phase I trial opened for advanced solid tumors, including an expansion cohort for CTPS2-null ovarian cancer (NCT06297525) at Mayo Clinic. These laboratory discoveries, and ongoing clinical studies, are expected to pave the way for a broader uptake of this novel therapeutic approach aimed at improving outcomes in patients with highly aggressive forms of these diseases. Citation Format: Xiyin Wang, Michael Emch, Lauren Voll, Rebecca Epp, Esther Rodman, Noa Odell, Nicole Pearson, Xiaonan Hou, Matthew Goetz, Scott Kaufmann, John Weroha, Philip Beer, John Hawse. Exploiting CTPS1 dependency for the treatment of breast and ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6388.

ABSTRACTVenous leg ulcers (VLUs) are traditionally managed with standard‐of‐care dressings, compression and appropriate adjunctive venous interventions for pathologic venous reflux. Due to pathophysiological complexity and underlying patient comorbidities, conducting randomised controlled trials to evaluate the comparative efficacy of advanced treatment modalities is difficult, as many patients would likely be excluded. This retrospective, pragmatic, real‐world evidence (RWE) study compared the healing outcomes of VLUs treated with either ovine forestomach matrix (OFM) (n = 312) or collagen/oxidised regenerated cellulose (ORC) (n = 239) in outpatient wound care centres. Unlike restrictive randomised controlled trials, minimal inclusion and exclusion criteria were applied to create two treatment cohorts that reflected the general VLU population. The incidence (%) of closure was greater in OFM‐treated VLUs at 12, 24 and 36 weeks, and this difference was significant at 24 and 36 weeks compared to collagen/ORC. Median time to wound closure was significantly faster (p = 0.045) in the OFM cohort (11.1 ± 0.6 weeks) compared to the collagen/ORC group (12.3 ± 1.0 weeks). Cox proportional hazards analysis demonstrated that OFM‐treated VLUs had a significantly greater probability of healing (up to ~40%). This RWE comparative efficacy study further substantiates the clinical benefit of OFM in the treatment of chronic wounds, such as VLU, in a real‐world patient cohort.