Citations

Abstract Introduction Men with African ancestry have the highest incidence and mortality rates of prostate cancer (PCa) worldwide. Methods This study aimed to identify differentially methylated genes between tumor vs. adjacent normal and aggressive vs. indolent PCa in 121 African American patients. Epigenome‐wide DNA methylation patterns in tumor DNA were assessed using the human Illumina Methylation EPIC V1 array. Results Around 5,139 differentially methylated CpG‐sites (q < 0.01, lΔβl > 0.2) were identified when comparing normal vs. tumor, with an overall trend of hypermethylation in prostate tumors. Multiple representative differentially methylated regions (DMRs), including immune‐related genes, such as CD40 , Galectin3 , OX40L , and STING , were detected in prostate tumors when compared to adjacent normal tissues. Based on an epigenetic clock model, we observed that tumors’ total number of stem cell divisions and the stem cell division rate were significantly higher than adjacent normal tissues. Regarding PCa aggressiveness, 2,061 differentially methylated CpG‐sites (q < 0.05, lΔβl > .05) were identified when the grade group (GG)1 was compared with GG4/5. Among these 2,061 CpG sites, 155 probes were consistently significant in more than one comparison. Among these genes, several immune system genes, such as COL18A1 , S100A2 , ITGA4 , HLA‐C , and ADCYAP1 , have previously been linked to tumor progression in PCa. Conclusion Several differentially methylated genes involved in immune‐oncologic pathways associated with disease risk or aggressiveness were identified. In addition, 261 African American‐specific differentially methylated genes related to the risk of PCa were identified. These results can shedlight on potential mechanisms contributing to PCa disparities in the African American Population.

Abstract Background The exclusion/occlusion of the left atrial appendage (LAA) is a treatment option for atrial fibrillation (AF) patients who are at high risk of stroke and high risk of bleeding. As the role of the LAA is not well understood or explored, this study aims to assess its role on flow dynamics in the left atrium. Methods Computational fluid dynamics (CFD) simulations were carried out for nine AF patients before and after LAA exclusion. The flow parameters investigated included the LA velocities, Time Averaged Wall Shear Stress (TAWSS), Oscillatory Shear Index (OSI), Relative Residence Time (RRT), and Pressure in the LA. Results This study shows that, on average, a decrease in TAWSS (1.82 ± 1.85 Pa to 1.27 ± 0.96 Pa, p < 0.05) and a slight increase in OSI (0.16 ± 0.10 to 0.17 ± 0.10, p < 0.05), RRT (1.87 ± 1.84 Pa −1 to 2.11 ± 1.78 Pa −1 , p < 0.05), and pressure (−19.2 ± 6.8 mmHg to −15.3 ± 8.3 mmHg, p < 0.05) were observed in the LA after the exclusion of the LAA, with a decrease in low‐magnitude velocities. Conclusion The exclusion of the LAA seems to be associated with changes in LA flow dynamics. Further studies are needed to elucidate the clinical implications of these changes.

TPS3173 Background: ELU001, pasifolate exatecan, is an ultra-small nanoparticle drug conjugate, known as a CDC (~6 nm), designed to target and penetrate into solid tumors. Due to its size, ELU001 exhibits rapid renal elimination which is expected to reduce or eliminate the toxicities associated with many antibody drug conjugates. ELU001 has ~13 folic acid targeting moieties and ~21 cathepsin-B cleavable exatecan topoisomerase-1 inhibitor payloads covalently bound to short polyethylene glycol chains surrounding a silica core, the C’Dot. ELU001 binds to cancer cells expressing FRα and is internalized into the lysosome where it releases the exatecan payload. ELU001’s dose escalation study reported at ESMO Congress 2023 (1), examined weekly, bi-weekly (Q2W), and tri-weekly schedules over a range of doses in 42 patients. The study revealed that ELU001 could be administered safely and identified a dose level and schedule for the Expansion Studies described below. 22 of the patients with ovarian or endometrial cancers had >1 post-baseline scan(s), of these 2 had a PR and 19 had SD by RECIST v1.1 criteria. ELU001 demonstrated activity against tumors across a range of FRα expression levels, from low to high, retrospectively assessed using the VENTANA FOLR1 RxDx assay and the PS2+ scoring system. Methods: The current multicenter, Tumor Group Expansion open-label phase 1/2 clinical trial investigates ELU001 in patients with ovarian and endometrial cancers and is enrolling three cohorts; 1) ovarian cancer with high FRα expression, 2) ovarian cancer with moderate and low expression and 3) endometrial cancer with low to high expression with assessments based upon the PS2+ scoring system (high = ≥ 75%, moderate = ≥ 50% to < 75%, low = 25% to < 50%, negative = <25% of tumor cells with 2+ or 3+ staining intensity). An initial exploratory dose of 2.0 mg/m2 Q2W was employed in all three cohorts and a second dose of 1.7 mg/m2 Q2W will be studied in the ovarian cancer cohorts. Patients will ultimately be randomized to one of two or more doses to optimize dosing for registration. Primary endpoint: Objective Response Rate (ORR); secondary endpoints include DOR, PFS, TFST, PFS2, OS, adverse events, PK, and ADA assessments. Approximately 20 patients per tumor group will be recruited in the U.S. 1. Ann. Oncol. (2023) 34 (suppl_2): S458-S497. Clinical trial information: NCT05001282 .

Abstract Background Delirium is a common complication of older people in hospitals, rehabilitation and long-term facilities. Objective To assess the worldwide use of validated delirium assessment tools and the presence of delirium management protocols. Design Secondary analysis of a worldwide one-day point prevalence study on World Delirium Awareness Day, 15 March 2023. Setting Cross-sectional online survey including hospitals, rehabilitation and long-term facilities. Methods Participating clinicians reported data on delirium, the presence of protocols, delirium assessments, delirium-awareness interventions, non-pharmacological and pharmacological interventions, and ward/unit-specific barriers. Results Data from 44 countries, 1664 wards/units and 36 048 patients were analysed. Validated delirium assessments were used in 66.7% (n = 1110) of wards/units, 18.6% (n = 310) used personal judgement or no assessment, and 10% (n = 166) used other assessment methods. A delirium management protocol was reported in 66.8% (n = 1094) of wards/units. The presence of protocols for delirium management varied across continents, ranging from 21.6% (on 21/97 wards/units) in Africa to 90.4% (235/260) in Australia, similar to the use of validated delirium assessments with 29.6% (29/98) in Africa to 93.5% (116/124) in North America. Wards/units with a delirium management protocol [n = 1094/1664, 66.8%] were more likely to use a validated delirium test than those without a protocol [odds ratio 6.97 (95% confidence interval 5.289–9.185)]. The presence of a delirium protocol increased the chances for valid delirium assessment and, likely, evidence-based interventions. Conclusion Wards/units that reported the presence of delirium management protocols had a higher probability of using validated delirium assessments tools to assess for delirium.

Abstract Aim Recent evidence challenges the current standard of offering surgery to patients with ileocaecal Crohn's disease (CD) only when they present complications of the disease. The aim of this study was to compare short‐term results of patients who underwent primary ileocaecal resection for either inflammatory (luminal disease, earlier in the disease course) or complicated phenotypes, hypothesizing that the latter would be associated with worse postoperative outcomes. Method A retrospective, multicentre comparative analysis was performed including patients operated on for primary ileocaecal CD at 12 referral centres. Patients were divided into two groups according to indication of surgery for inflammatory (ICD) or complicated (CCD) phenotype. Short‐term results were compared. Results A total of 2013 patients were included, with 291 (14.5%) in the ICD group. No differences were found between the groups in time from diagnosis to surgery. CCD patients had higher rates of low body mass index, anaemia (40.9% vs. 27%, p < 0.001) and low albumin (11.3% vs. 2.6%, p < 0.001). CCD patients had longer operations, lower rates of laparoscopic approach (84.3% vs. 93.1%, p = 0.001) and higher conversion rates (9.3% vs. 1.9%, p < 0.001). CCD patients had a longer hospital stay and higher postoperative complication rates (26.1% vs. 21.3%, p = 0.083). Anastomotic leakage and reoperations were also more frequent in this group. More patients in the CCD group required an extended bowel resection (14.1% vs. 8.3%, p : 0.017). In multivariate analysis, CCD was associated with prolonged surgery (OR 3.44, p = 0.001) and the requirement for multiple intraoperative procedures (OR 8.39, p = 0.030). Conclusion Indication for surgery in patients who present with an inflammatory phenotype of CD was associated with better outcomes compared with patients operated on for complications of the disease. There was no difference between groups in time from diagnosis to surgery.

BACKGROUND: Narrative operative reports may omit or obscure data from an operation. OBJECTIVE: To develop a synoptic operative report for rectal prolapse that includes core descriptors as developed by an international consensus of expert pelvic floor surgeons. DESIGN: Descriptors for patients undergoing rectal prolapse surgery were generated through review. Members of the Pelvic Floor Disorders Consortium were recruited to participate in a 3-round Delphi process using a 9-point Likert scale. Descriptors that achieved 70% agreement were kept from the first round, and descriptors scoring 40% to 70% agreement were recirculated in subsequent rounds. A final list of operative descriptors was determined at a consensus meeting, with a final consensus meeting more than 70% agreement. SETTINGS: This survey was administered to members of the Pelvic Floor Disorders Consortium. PATIENTS: No patient data are included in this study. MAIN OUTCOME MEASURES: Descriptors meeting greater than 70% agreement were selected. RESULTS: One hundred seventy-six surgeons representing colorectal surgeons, urogynecologists, and urologists distributed throughout North America (56%), Latin America (4%), Western Europe (29%), Asia (4%), and Africa (1%) participated in the first round of Delphi voting. After 2 additional rounds and a final consensus meeting, 16 of 30 descriptors met 70% consensus. Descriptors that met consensus were surgery type, posterior dissection, ventral dissection, mesh used, type of mesh used, mesh location, sutures used, suture type, pouch of Douglas and peritoneum reclosed, length of rectum imbricated, length of bowel resected, levatoroplasty, simultaneous vaginal procedure, simultaneous gynecologic procedure, simultaneous enterocele repair, and simultaneous urinary incontinence procedure. LIMITATIONS: The survey represents the views of members of the Delphi panel and may not represent the viewpoints of all surgeons. CONCLUSIONS: This Delphi survey establishes international consensus descriptors for intraoperative variables that have been used to produce a synoptic operative report. This will help establish defined operative reporting to improve clinical communication, quality measures, and clinical research. See Video Abstract. DESARROLLO DE UN PROTOCOLO OPERATORIO SINÓPTICO DERIVADO DE CONSENSO PARA EL PROLAPSO RECTAL: UN INFORME DEL CONSORCIO DE TRASTORNOS DEL PISO PÉLVICO ANTECEDENTES: Los protocolos operativos narrativos frecuentemente pueden omitir u oscurecer datos de un procedimiento. OBJETIVO: Nuestro objetivo es desarrollar un protocolo operatorio sinóptico para el prolapso rectal que incluya descriptores básicos desarrollados por un consenso internacional de cirujanos expertos en piso pélvico. DISEÑO: Los descriptores para pacientes sometidos a cirugía de prolapso rectal se generaron mediante revisión. Se reclutó a miembros del Consorcio de Trastornos del Piso Pélvico para participar en un proceso Delphi de 3 rondas utilizando una escala Likert de 9 puntos. Los descriptores que lograron un 70% de acuerdo se mantuvieron en la primera ronda, los descriptores que obtuvieron un 40-70% de acuerdo se recircularon en rondas posteriores. Se determinó una lista final de descriptores operativos en una reunión de consenso, con una reunión de consenso final de más del 70% de acuerdo. ESCENARIO: Esta fue una encuesta administrada a miembros del Consorcio de Trastornos del Piso Pélvico. PRINCIPALES MEDIDAS DE RESULTADO: Se seleccionaron los descriptores que cumplieron más del 70% de acuerdo. RESULTADOS: Ciento setenta y seis cirujanos en representación de cirujanos colorrectales, uroginecólogos y urólogos distribuidos en América del Norte (56%), América Latina (4%), Europa Occidental (29%), Asia (4%) y África (1%) participaron en la primera ronda de votación Delphi. Después de dos rondas adicionales y una reunión de consenso final, 16 de 30 descriptores alcanzaron un 70% de consenso. Los descriptores que alcanzaron consenso fueron: tipo de cirugía, disección posterior, disección ventral, malla utilizada, tipo de malla utilizada, ubicación de la malla, suturas utilizadas, tipo de sutura, cierre del fondo de saco de Douglas y peritoneo, longitud del recto superpuesto, longitud del intestino resecado, plastía de los elevadores , procedimiento vaginal simultáneo, procedimiento ginecológico simultáneo, reparación simultánea de enterocele y procedimiento simultáneo de incontinencia urinaria. LIMITACIONES: La encuesta representa las opiniones de los miembros del panel Delphi y puede no representar los puntos de vista de todos los cirujanos. CONCLUSIONES/DISCUSIÓN: Esta encuesta Delphi establece descriptores de consenso internacional para las variables intraoperatorias que se han utilizado para producir un protocolo operatorio sinóptico. Esto ayudará a establecer protocolos operativos definidos para mejorar la comunicación clínica, las medidas de calidad y la investigación clínica. (Traducción—Dr. Felipe Bellolio)

Abstract Neuromuscular blocking agents (NMBAs) are commonly used to induce skeletal muscle relaxation during surgery. While muscle relaxation facilitates surgical procedures and tracheal intubation, adequate recovery of muscle function after surgery is required to support pulmonary function, and even mild residual neuromuscular block increases the risk of severe postoperative pulmonary complications. While recovery of muscle function after surgery involving NMBAs can be monitored and, in addition, be accelerated by use of current antagonists (reversal agents), there is a clear clinical need for a safe drug to antagonize all types of NMBAs. Here we show that inhibition of the skeletal muscle-specific chloride ion (Cl-) channel, the ClC-1 channel, markedly accelerates recovery of both single contraction (twitch) and physiologically important sustained contractions (tetanic) in a novel rat model mimicking NMBA-induced muscle block used during surgery. ClC-1 inhibition was found to reverse any NMBA with superior properties to existing reversal agents. This suggests ClC-1 inhibition as a novel mechanism for fast and efficacious reversal from neuromuscular block.

Background: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a well-established treatment for the motor symptoms of Parkinson’s disease (PD). While PD is primarily characterized by motor symptoms such as tremor, rigidity, and bradykinesia, it also involves a range of non-motor symptoms, and anxiety is one of the most common. The relationship between PD and anxiety is complex and can be a result of both pathological neural changes and the psychological and emotional impacts of living with a chronic progressive condition. Managing anxiety in PD is critical for improving the patients’ quality of life. However, patients undergoing STN DBS can occasionally experience increased anxiety. Methods: This study investigates changes in risk-avoidant behavior following STN DBS in a pre-motor animal model of PD under chronic and acute unilateral high frequency stimulation. Results: No significant changes in risk-avoidant behaviors were observed in rats who underwent STN DBS compared with sham stimulation controls. Chronic stimulation prevented sensitization in the elevated zero maze. Conclusions: These results suggest that unilateral stimulation of the STN may have minimal effects on risk-avoidant behaviors in PD. However, additional research is required to fully understand the mechanisms responsible for changes in anxiety during STN DBS for PD.