Current Standard Of Care Research Articles

Lead-in calorie restriction enhances the weight-lowering efficacy of incretin hormone-based pharmacotherapies in mice

ObjectivesThe potential benefits of combining lifestyle changes with weight loss pharmacotherapies for obesity treatment are underexplored. Building on recent clinical observations, this study aimed to determine whether “lead-in” calorie restriction before administering clinically approved weight loss medications enhances the maximum achievable weight loss in preclinical models. MethodsDiet-induced obese mice (DIO) were exposed to 7 or 14 days of calorie restriction before initiating treatment with semaglutide (a glucagon-like peptide-1 receptor (GLP-1R) agonist), tirzepatide (a GLP-1R/glucose insulinotropic peptide receptor (GIPR) co-agonist), or setmelanotide (a melanocortin-4 receptor (MC4R) agonist). Follow-up assessments using indirect calorimetry determined the contributions of energy intake and expenditure linked to consecutive exposure to dieting followed by pharmacotherapy. ResultsCalorie restriction prior to treatment with semaglutide or tirzepatide enhanced the weight loss magnitude of both incretin-based therapies in DIO mice, reflected by a reduction in fat mass and linked to reduced energy intake and a less pronounced adaptive drop in energy expenditure. These benefits were not observed with the MC4R agonist, setmelanotide. ConclusionsOur findings provide compelling evidence that calorie restriction prior to incretin-based therapy enhances the achievable extent of weight loss, as reflected in a weight loss plateau at a lower level compared to that of treatment without prior calorie reduction. This work suggests that more intensive lifestyle interventions should be considered prior to pharmacological treatment, encouraging further exploration and discussion of the current standard of care.

The effect of epidermal growth factor receptor mutation on adjuvant chemotherapy with tegafur/uracil for patients with completely resected, non-lymph node metastatic non-small cell lung cancer (> 2cm): a multicenter, retrospective, observational study as exploratory analysis of the CSPOR-LC03 study.

The use of adjuvant osimertinib for epidermal growth factor receptor (EGFR) mutants is expected to expand to earlier stage I in the future, potentially competing with the current standard of care, oral tegafur/uracil (UFT), in Japan. However, the effect of EGFR mutation status on the therapeutic effect of UFT remains unclear. This study was conducted as an exploratory analysis of a retrospective observational study that investigated the real-world data of postoperative adjuvant chemotherapy in Japan (CSPOR-LC03). Between 2008 and 2013, 1812 patients with completely resected adenocarcinoma diagnosed as pathologic stage I (T1>2cm, TNM classification, sixth edition) who have maintained organ function, and no history of other cancers were included. The primary endpoint was the 5-year disease-free survival (DFS) rate, and we compared this rate between four groups classified based on the administration of adjuvant UFT and EGFR mutation status. Of the 933 (51%) patients with EGFR mutations, 394 underwent adjuvant UFT therapy. Of the 879 (49%) patients without EGFR mutations, 393 underwent adjuvant UFT therapy. The 5-year DFS of UFT+/EGFR+ and UFT-/EGFR+ patients were 82.0 and 87.1%, respectively, and those of UFT+/EGFR- and UFT-/EGFR- patients were 80.0 and 86.9%, respectively. DFS was significantly worse in the UFT+ group than in the UFT- group (P=0.015). Adjuvant UFT therapy was not an independent prognostic factor for DFS, regardless of the EGFR mutation status. In pathologic stage I (>2cm) lung adenocarcinomas with EGFR mutation, the survival benefit of adjuvant UFT was not observed.

Clinical Interest in Exome-Based Analysis of Somatic Mutational Signatures for Non-Small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality. This study investigates the clinical interest of whole exome sequencing (WES) for analyzing somatic mutational signatures in patients with advanced or metastatic NSCLC treated with the current standard of care. Exome sequencing data and clinical characteristics from 132 patients with advanced or metastatic NSCLC were analyzed. Somatic mutational signatures including single base substitutions (SBSs), double base substitutions (DBSs), and copy number signatures were evaluated. Structural variations including tumor mutational burden (TMB), the number of neoantigens, TCR clonality, homologous recombination deficiency (HRD), copy number alterations (CNAs), and microsatellite instability (MSI) score were determined. The association between these genomic features, NSCLC subtypes, and patient outcomes (progression-free and overall survival) was evaluated. Exome sequencing offers valuable insights into somatic mutational signatures in NSCLC. This study identified specific signatures associated with a poor response to immune checkpoint inhibitor (ICI) therapy and chemotherapy, potentially aiding treatment selection and identifying patients unlikely to benefit from these approaches.

SP4.14 - Mild acute biliary pancreatitis: still a surgical disease. A post-hoc analysis of the MANCTRA-1 international study

Abstract Aims The current standard of care for mild acute biliary pancreatitis (MABP) involves early laparoscopic cholecystectomy (ELC) reducing the risk of early recurrence. The MANCTRA-1 project disclosed a discrepancy in translating this evidence into clinical practice, estimating a 35 to 70% probability of narrowing this gap within 2025. This study assesses the safety of suboptimal ELC implementation in MABP, looking for risk factors for recurrent acute biliary pancreatitis (ABP) in patients awaiting interval cholecystectomy after an uneventful episode of MABP. Methods We conducted a post hoc analysis of the MANCTRA-1 registry. Clinicaltrials.gov ID NCT04747990. We included MABP patients who did not undergo ELC during the index hospitalization, excluding those who experienced disease-related complications. The primary outcome was the 30-day hospital readmission rate due to ABP recurrence. We performed univariable and multivariable logistic regression to identify risk factors for 30-day ABP recurrence. Results Between January 2019 and December 2020, a total of 2,253 MABP patients from 150 centres were included. The 30-day readmission rate due to ABP recurrence was 6%. The multivariable logistic regression showed that admission to a medical ward (internal medicine or gastroenterology) odds ratio (OR) 1.62 (95%[CI] 1.1;2.37), p=0.01 was an independent risk factor for 30-day ABP recurrence. Conclusion Our real-world analysis provides valuable insights to manage MABP, particularly in centres where ELC strategies cannot be fully implemented due to organizational and clinical constraints. Despite the admitting ward, it underscores the importance of timely access to surgical care in reducing the risk of early recurrence, disclosing the need to implement surgical consultation pathways in ABP care bundles.

ThP6.9 - Endoluminal vacuum-assisted closure (EndoVAC) therapy in spontaneous duodenal perforation: a novel approach to an undertreated problem

Abstract Introduction Duodenal perforation is a rare but critical condition, with management ranging from conservative to surgical depending on timing of presentation, patient status, and clinician preference. In recent years, minimally invasive techniques have been emerging alternatives for their safety and efficacy. Notably, there have been cases promoting endoluminal vacuum-assisted closure (EndoVAC) therapy as a viable alternative for use among patients with iatrogenic oesophageal perforations. To our knowledge, there has been no reported use of this novel approach specifically in spontaneous duodenal perforations. Case presentation A 55-year-old female with no history of trauma, surgery, NSAID use, or gastrointestinal conditions presented with epigastric pain and vomiting. A CT scan revealed a contained duodenal perforation at the D2/3 junction, accompanied by a complex retroperitoneal collection unsuitable for imaging-guided drainage. Initial management was conservative with intravenous hydration, antibiotics, proton pump inhibitors, and nasogastric tube decompression. She underwent oesophagoduodenoscopy and EndoVAC therapy resulting in complete resolution of collection and a small diverticulum on repeat CT. Discussion Current standard of care for duodenal perforations would be conservative management, though this carries the risk of deterioration due to biliopancreatic leakage and slow resolution of sepsis. Surgical management, when needed, is often technically challenging with high morbidity. EndoVAC gives the benefit of providing targeted drainage and negative pressure therapy to the site of perforation, reducing ongoing contamination, and promoting wound granulation. Conclusion EndoVAC therapy offers a minimally invasive alternative to treatment of duodenal perforations and has the potential for broader application in specialist and tertiary healthcare settings.

Eduardo Slatopolsky: A Pioneer in the Field of Mineral and Bone Disorders in Kidney Disease.

Eduardo Alberto Slatopolsky (1934-2024), Washington University Joseph Friedman Professor Emeritus of Medicine, a prominent physician-scientist, was born in Buenos Aires, Argentina. The impact of his research in the area of mineral and bone disorders in kidney disease has been profound for over 50 years starting in the 1960s. He was a global authority on secondary hyperparathyroidism. He was instrumental in illustrating the role of hyperphosphatemia in chronic kidney disease (CKD) and in developing the first reliable parathyroid hormone (PTH) assay. His research led to the utilization of calcium salts as phosphate binders replacing the toxic aluminum salts. Moreover, he illustrated the role of vascular calcifications in CKD patients, paving the way for non-calcium phosphate binders. He proposed the use of calcitriol and later vitamin D analogs in the management of secondary hyperparathyroidism, which is the current standard of care. He demonstrated the decreased expression of the calcium-sensing receptor in parathyroid tissue in CKD patients. Dr. Slatopolsky's global legacy will last for generations.

Sparsentan improves glomerular hemodynamics, cell functions, and tissue repair in a mouse model of FSGS.

Dual endothelin-1 (ET-1) and angiotensin II (AngII) receptor antagonism with sparsentan has strong antiproteinuric actions via multiple potential mechanisms that are more pronounced, or additive, compared with current standard of care using angiotensin receptor blockers (ARBs). Considering the many actions of ET-1 and AngII on multiple cell types, this study aimed to determine glomeruloprotective mechanisms of sparsentan compared to the ARB losartan by direct visualization of its effects in the intact kidney in focal segmental glomerulosclerosis (FSGS) using intravital multiphoton microscopy. In both healthy and FSGS models, sparsentan treatment increased afferent/efferent arteriole diameters; increased or preserved blood flow and single-nephron glomerular filtration rate; attenuated acute ET-1 and AngII-induced increases in podocyte calcium; reduced proteinuria; preserved podocyte number; increased both endothelial and renin lineage cells and clones in vasculature, glomeruli, and tubules; restored glomerular endothelial glycocalyx; and attenuated mitochondrial stress and immune cell homing. These effects were either not observed or of smaller magnitude with losartan. The pleiotropic nephroprotective effects of sparsentan included improved hemodynamics, podocyte and endothelial cell functions, and tissue repair. Compared with losartan, sparsentan was more effective in the sustained preservation of kidney structure and function, which underscores the importance of the ET-1 component in FSGS pathogenesis and therapy.

Artificial intelligence guided screening for cardiomyopathies in an obstetric population: a pragmatic randomized clinical trial.

Nigeria has the highest reported incidence of peripartum cardiomyopathy worldwide. This open-label, pragmatic clinical trial randomized pregnant and postpartum women to usual care or artificial intelligence (AI)-guided screening to assess its impact on the diagnosis left ventricular systolic dysfunction (LVSD) in the perinatal period. The study intervention included digital stethoscope recordings with point of-care AI predictions and a 12-lead electrocardiogram with asynchronous AI predictions for LVSD. The primary end point was identification of LVSD during the study period. In the intervention arm, the primary end point was defined as the number of identified participants with LVSD as determined by a positive AI screen, confirmed by echocardiography. In the control arm, this was the number of participants with clinical recognition and documentation of LVSD on echocardiography in keeping with current standard of care. Participants in the intervention arm had a confirmatory echocardiogram at baseline for AI model validation. A total of 1,232 (616 in each arm) participants were randomized and 1,195 participants (587 intervention arm and 608 control arm) completed the baseline visit at 6 hospitals in Nigeria between August 2022 and September 2023 with follow-up through May 2024. Using the AI-enabled digital stethoscope, the primary study end point was met with detection of 24 out of 587 (4.1%) versus 12 out of 608 (2.0%) patients with LVSD (intervention versus control odds ratio 2.12, 95% CI 1.05-4.27; P = 0.032). With the 12-lead AI-electrocardiogram model, the primary end point was detected in 20 out of 587 (3.4%) versus 12 out of 608 (2.0%) patients (odds ratio 1.75, 95% CI 0.85-3.62; P = 0.125). A similar direction of effect was observed in prespecified subgroup analysis. There were no serious adverse events related to study participation. In pregnant and postpartum women, AI-guided screening using a digital stethoscope improved the diagnosis of pregnancy-related cardiomyopathy. ClinicalTrials.gov registration: NCT05438576.

Cost-effectiveness of early vs delayed use of abemaciclib combination therapy for patients with high-risk hormone receptor-positive/human epidermal growth factor receptor 2-negative early breast cancer.

Abemaciclib was newly approved for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) high-risk early breast cancer (EBC). Clinical guidelines recommended abemaciclib as the first-line treatment for HR+/ HER2- EBC (early use) or HR+/ HER2- metastatic breast cancer (MBC) (delayed use). To compare the cost-effectiveness of early vs delayed use of abemaciclib for treatment of HR+/HER2- high-risk EBC. Early use was defined as combined abemaciclib and endocrine therapy as first-line therapy for EBC, followed by treatment with fulvestrant for MBC. Delayed use was defined as endocrine therapy for EBC, followed by combined abemaciclib and fulvestrant therapy for MBC. A 5-state model was developed to estimate lifetime costs, life-years (LYs), and quality-adjusted life-years (QALYs) of hypothetical patients with HR+/ HER2- EBC from a third-party US payer's perspective. Key clinical and safety data were derived from the monarchE and MONARCH 2 clinical trials. Costs, utilities, and disutility values of adverse events were obtained from the literature. We calculated the incremental cost-effectiveness ratio (ICER) of early vs delayed abemaciclib use and compared it with a willingness-to-pay (WTP) threshold of $100,000 per LY or QALY. Deterministic and probabilistic sensitivity analyses (PSAs) were performed to test the robustness of the base-case model. Base-case analysis showed early use yielded 21.08 LYs and 17.93 QALYs for $586,213 and delayed use yielded 11.14 LYs and 9.38 QALYs for $157,576. The ICER of early vs delayed use was $43,136/LY and $50,104/QALY, which was cost-effective at the WTP threshold of $100,000. The PSA result indicated that a 94.6% likelihood of early use (vs delayed use) was cost-effective at the WTP threshold of $100,000 per QALY. This study suggests that giving abemaciclib in the early stage rather than waiting until patients develop metastatic disease (current standard of care in MBC) is a cost-effective strategy.

521. SHORT-TERM PROPHYLACTIC STENTING FOR HIGH-RISK ESOPHAGEAL ANASTOMOSIS: A CASE SERIES

Abstract Background Anastomotic leak after esophagectomy is a cause of major morbidity, increases surgical mortality and can affect long-term survival outcomes. Early recognition and treatment of anastomotic leaks has greatly improved the rescue rates for this catastrophic complication. However, for some patients, successful rescue is not sufficient to prevent major morbidity and worse long-term outcomes. Prevention of esophageal anastomotic leaks would benefit these patients. Prophylactic stenting after esophagectomy can be one of the tools used in addition to all other factors that are implemented to improve surgical outcomes in this complex cohort of patients. Methods We present a series of seven patients who underwent esophagectomy for malignant disease at our institution. They had insertion of prophylactic esophageal stents at the time of esophagectomy due to a combination of patient factors and intraoperative complications. All anastomoses were carried out using the modified Orringer technique of linear stapled esophagogastric anastomosis. All patients underwent insertion of an 18mm diameter, fully covered EGIS (S&G Biotech, Korea) esophageal stent with antireflux valve. This was fixed to the esophagus / gastric tube using two 2-0 Vicryl Rapide (Polyglactin 910) sutures. The stents were removed endoscopically between postoperative day 14 and 28. Results None of the seven patients who underwent prophylactic esophageal stenting had any clinical or radiological evidence of anastomotic leak. In one patient, at the time of stent removal, a possible anastomotic defect was noted but it was not possible to enter the cavity. A new stent was inserted, and the patient was clinically observed. He remained clinically well throughout. Another patient developed a severe hospital acquired pneumonia requiring ventilatory support without evidence of anastomotic leak. Median length of stay was 13 days. There was no mortality within 90 days of surgery. Conclusion Short term prophylactic esophageal stenting is possible and safe. The technique of stent fixation and early removal helps to mitigate the risks of stent migration and erosion. In our small series, the stents were effective in preventing anastomotic leaks with no stent related complications. This provides optimism for patients and surgeons that morbidity from anastomotic leaks can be minimised, enabling patients to recover from surgery and proceed to adjuvant treatment if indicated. The safety profile of prophylactic esophageal stents should be investigated further and both short- term and long-term outcomes compared to current standards of care by randomised studies.

754. PATHOLOGICAL RESPONSE PREDICTS EFFICACY OF ADJUVANT FLOT CHEMOTHERAPY IN GASTROESOPHAGEAL CANCER: AN INTERNATIONAL COHORT STUDY

Abstract Background Perioperative FLOT-based chemotherapy is the current standard of care for all patients with locally-advanced gastroesophageal cancer. However, many patients are unable to complete all planned adjuvant FLOT cycles due to treatment related toxicity and diminished performance status after radical surgery. Within this context, it is unclear whether adjuvant FLOT will improve oncological outcomes for patients with cancers that either don’t respond or respond exceptionally well to neoadjuvant FLOT. To facilitate clinical decision-making, we examined whether pathological response to neoadjuvant FLOT can guide its adjuvant use. Methods Prospectively collected data from 43 centres across 12 countries was analysed. Patients with non-metastatic gastroesophageal adenocarcinoma who received neoadjuvant FLOT followed by radical surgery between 2017-2022 were included. Pathological response was assessed using validated tumour regression grading (TRG) systems. All TRG were trichotomized into minimal responders (MR=worse TRG category), complete responders (CR=pathological complete response), and partial responders (PR=all TRG categories between MR and CR). Survival outcomes of patients who did and did not receive adjuvant FLOT within these cohorts were compared using Kaplan Meier and Cox regression analysis. These findings were validated using propensity score matched analysis. Results 1887 patients (MR n=459, CR n=221, PR n=1207) were evaluated. The median follow-up was 25.5 months. In the MR group, there was no DFS (HR=1.03, 95%CI 0.78-1.36) or adjusted-OS (HR=0.96, 95%CI 0.70-1.30) difference between those who did (n=272) and did not (n=187) receive adjuvant FLOT. In the CR group, there was no DFS (HR=0.88, 95%CI 0.41-1.85) or OS (HR=0.69, 95%CI 0.31-1.54) difference between those who did (n=136) and did not (n=85) receive adjuvant FLOT. In the PR group (adjuvant FLOT n=847, no adjuvant FLOT n=360), adjuvant FLOT conferred a significant DFS (HR=0.68, 95%CI 0.55-0.86) and OS (HR=0.55, 95%CI 0.44-0.69) benefit. Conclusions Pathological response to neoadjuvant FLOT predicts therapeutic efficacy to adjuvant FLOT. Only partial responders benefit from adjuvant treatment. Our findings challenge the current doctrine that perioperative FLOT should be applied to all patients regardless of pathological tumour response.

Novel systemic treatment options for advanced bladder cancer

Systemic treatment of urothelial carcinoma of the bladder requires complex approaches and is constantly evolving. Neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy remains the current standard of care for muscle-invasive advanced bladder cancer. For patients ineligible for cisplatin, adjuvant treatment with nivolumab is recommended. Innovative perioperative combinations could transform the treatment landscape in the future. First-line treatment for metastatic urothelial carcinoma has long been dominated by platinum-based combinations, recently followed by the immune checkpoint inhibitor avelumab as maintenance therapy; however, recent results on the use of enfortumab vedotin and pembrolizumab in the first-line setting are expected to fundamentally change the treatment options. In subsequent lines of treatment, the not yet approved erdafitinib, as the first targeted therapy for advanced urothelial carcinoma, offers an important alternative and underscores the need for molecular testing.

Treatment Outcomes and Toxicity Profiles with PORTEC-3 Trial Regimen in South Asian Cohort of High-Risk Endometrial Cancer Patients: A Single-Center Ambispective Analysis

Objectives Adjuvant chemoradiation followed by chemotherapy is the current standard of care in high-risk endometrial cancer after the PORTEC-3 trial. There is a lack of data on this treatment regimen in the South Asian patient cohort. The present study aims to assess toxicity profiles and outcomes in this cohort of patients. Materials and Methods High-risk endometrial cancer patients planned for adjuvant chemoradiation followed by chemotherapy were included. Toxicity was graded using the Radiation Therapy Oncology Group and Common Terminology Criteria for Adverse Events criteria. Disease-free survival (DFS) and overall survival (OS) were estimated using the Kaplan–Meier method. Survival curves were compared using the log-rank test. Cox regression analysis was done to find out the predictors of DFS. Results This study included 58 patients treated from October 2016 to August 2022. Median age was 61 years (interquartile range [IQR] 56–66), with Fédération Internationale de Gynécologie et d'Obstétrique Stages I = 26 (44.8%), II = 5 (8.6%), and III = 27 (46.6%). p53 positivity was seen in 38 (65.5%) patients. Intensity-modulated radiotherapy was used in 44 (79.3%) patients. There was no treatment discontinuation during chemoradiation. Acute Grade 2 and above toxicity during chemoradiation were diarrhea in 10 (17.2%) and hematological in 2 (3.4%). For the planned adjuvant chemotherapy in 55 patients, 51 (92.7%) completed four cycles. Grade 2 or above neuropathy was seen in 11 (20%), with 5 (9%) having persisting neuropathy at 1-year follow-up. At a median follow-up of 31 months, 15 (25.8%) patients recurred; distant = 13 and isolated para-aortic = 2. The median time to recurrence was 16 months (IQR 12–22), with 80% (12 out of 15) of recurrence within the first 2 years of follow-up. The actuarial 5-year DFS and OS were 63.8 and 76.5%, respectively. In univariate analysis, p53 positivity and lymphovascular space invasion were predictors for DFS, with p-values 0.031 and 0.027, respectively. There was no significant predictor identified in multivariate analysis. Conclusion There is good tolerance and compliance to adjuvant chemoradiation and chemotherapy in this South Asian cohort of patients with high-risk endometrial cancer, with no toxicity-related treatment breaks during radiation. The majority of the recurrences were seen at distant sites and within the first 2 years of follow-up. These findings are in line with the outcomes of the PORTEC-3 trial.

BRD-810 is a highly selective MCL1 inhibitor with optimized in vivo clearance and robust efficacy in solid and hematological tumor models

The MCL1 gene is frequently amplified in cancer and codes for the antiapoptotic protein myeloid cell leukemia 1 (MCL1), which confers resistance to the current standard of care. Therefore, MCL1 is an attractive anticancer target. Here we describe BRD-810 as a potent and selective MCL1 inhibitor and its key design principle of rapid systemic clearance to potentially minimize area under the curve-driven toxicities associated with MCL1 inhibition. BRD-810 induced rapid cell killing within 4 h in vitro but, in the same 4-h window, had no impact on cell viability or troponin I release in human induced pluripotent stem cell-derived cardiomyocytes, even at suprapharmacologic concentrations. In vivo BRD-810 induced efficacy in xenograft hematological and solid tumor models despite the short residence time of BRD-810 in plasma. In totality, our data support the hypothesis that short-term inhibition of MCL1 with BRD-810 can induce apoptosis in tumor cells while maintaining an acceptable safety profile. We, therefore, intend to advance BRD-810 to clinical trials.

Comparative Analysis of Learning Curves in Robotic Versus Laparoscopic Cholecystectomy: A Systematic Review.

Robotic surgery has undergone much development and increased use over the years;it has offered many benefits for the operating surgeon compared to the more restrictive nature of conventional laparoscopic surgery (CLS) which is the current standard of care. However, to the best of our knowledge, no studies have attempted to draw a comparison between the two in terms of the cases required for the learning curve to be achieved. The systematic review was performed at Barts Cancer Institute. A search of Cochrane, PubMed and Embase was made on 15 March 2024. Screening and risk of bias were done by two reviewers. Screening was done via the eligibility criteria by two reviewers. Data collection was done using Excel (Microsoft® Corp., Redmond, USA) and information was double-checked by another reviewer and transferred into a tabulated format. Seventeenstudies were included, with the learning curve reported in 14 studies. The cases required to achieve the learning curve for multiport robotic cholecystectomy (MRC) ranged from 16 to 134 and for single-site robotic cholecystectomy (SSRC), itranged from 10 to over 102 cases.Conventional laparoscopic cholecystectomy (CLC) was from 7 to 200. The improvement in operating times was measured in very different ways and was reported in 10 of the 17 studies. The studies that were available had a high level of heterogeneity making it difficult for comparisons to be made between studies. Several studies included only one surgeon resulting in the sample size of surgeons being too small and vulnerable to bias. As robotic surgery is still relatively novel, higher-quality studies have to be made in order for more conclusive conclusions to be made on the benefits of the learning curve of MRC and SSRC.

Tenecteplase Versus Alteplase: A Comparison of Bleeding Outcomes in Massive Pulmonary Embolism (TACO-PE).

Thrombolysis is recommended in the setting of massive pulmonary embolism (PE) for reperfusion of vessels but carries a serious concern for increased bleed risk. In October 2022, our institution adopted tenecteplase as the formulary thrombolytic. Previous literature is unclear regarding the bleed risk of tenecteplase in massive PE, and no study has yet compared safety outcomes with the current standard of care, alteplase. The objective of this study was to compare the incidence of bleeding with tenecteplase versus alteplase in massive PE patients. This was a retrospective, observational cohort study that included adults who received tenecteplase or alteplase for massive PE. The primary outcome was major bleeding as defined by the International Society on Thrombosis and Hemostasis (ISTH). Secondary outcomes included incidence of symptomatic intracranial hemorrhage (ICH), in-hospital mortality, administration of reversal agents, and length of stay. A total of 44 patients met inclusion criteria with 20 patients in the alteplase cohort and 24 in the tenecteplase cohort. Seventeen percent of tenecteplase patients compared with 5% of alteplase patients experienced bleeding. The mortality rate was 83% vs 75%, respectively. In addition, 1 patient in the tenecteplase cohort experienced a symptomatic ICH and 2 patients required initiation of massive transfusion protocol. Although this study was limited in sample size, these results suggest that there may be reason for concern of higher bleeding rates in patients treated with tenecteplase in the setting of massive PE.

Pretreatment with oleuropein protects the neonatal brain from hypoxia-ischemia by inhibiting apoptosis and neuroinflammation.

Hypoxic-ischemic (HI) encephalopathy is a cerebrovascular injury caused by oxygen deprivation to the brain and remains a major cause of neonatal mortality and morbidity worldwide. Therapeutic hypothermia is the current standard of care but it does not provide complete neuroprotection. Our aim was to investigate the neuroprotective effect of oleuropein (Ole) in a neonatal (seven-day-old) mouse model of HI. Ole, a secoiridoid found in olive leaves, has previously shown to reduce damage against cerebral and other ischemia/reperfusion injuries. Here, we administered Ole as a pretreatment prior to HI induction at 20 or 100 mg/kg. A week after HI, Ole significantly reduced the infarct area and the histological damage as well as white matter injury, by preserving myelination, microglial activation and the astroglial reactive response. Twenty-four hours after HI, Ole reduced the overexpression of caspase-3 and the proinflammatory cytokines IL-6 and TNF-α. Moreover, using UPLC-MS/MS we found that maternal supplementation with Ole during pregnancy and/or lactation led to the accumulation of its metabolite hydroxytyrosol in the brains of the offspring. Overall, our results indicate that pretreatment with Ole confers neuroprotection and can prevent HI-induced brain damage by modulating apoptosis and neuroinflammation.

MIXED-REALITY GUIDANCE FOR PELVIC OSTEOTOMY AND ACETABULAR REALIGNMENT: PROOF OF CONCEPT

Mixed Reality has the potential to improve accuracy and reduce required dissection for the performance of peri-acetabular osteotomy. The current work assesses initial proof of concept of MR guidance for PAO.A PAO planning module, based on preoperative computed tomography (CT) imaging, allows for the planning of PAO cut planes and repositioning of the acetabular fragment. 3D files (holograms) of the cut planes and native and planned acetabulum positions are exported with the associated spatial information. The files are then displayed on mixed reality head mounted device (HoloLens2, Microsoft) following intraoperative registration using an FDA-cleared mixed reality application designed primary for hip arthroplasty (HipInsight). PAO was performed on both sides of a bone model (Pacific Research). The osteotomies and acetabular reposition were performed in accordance with the displayed holograms. Post-op CT imaging was performed for analysis. Cutting plane-accuracy was evaluated using a best-fit plane and 2D angles (°) between the planned and achieved supra (SA)- and retroacetabular (RA) osteotomy and retroacetabular and ischial osteotomies (IO) were measured.To evaluate the accuracy of acetabular reorientation, we digitized the acetabular rim and calculated the acetabular opening plane. Absolute errors of planned and achieved operative inclination and anteversion (°) of the acetabular fragment, as well as 3D lateral-center-edge (LCE) angles were calculated.The mean absolute difference between the planned and performed osteotomy angles was 3 ± 3°.The mean absolute error between planned and achieved operative anteversion and inclination was 1 ± 0° and 0 ± 0° respectively. Mean absolute error between planned and achieved 3D LCE angle was 0.5 ± 0.7°.Mixed-reality guidance for the performance of pelvic osteotomies and acetabular fragment reorientation was feasible and highly accurate. This solution may improve the current standard of care by enabling reliable and precise reproduction of the desired acetabular realignment.

Spatial computational modelling illuminates the role of the tumour microenvironment for treating glioblastoma with immunotherapies

Glioblastoma is the most common and deadliest brain tumour in adults, with a median survival of 15 months under the current standard of care. Immunotherapies like immune checkpoint inhibitors and oncolytic viruses have been extensively studied to improve this endpoint. However, most thus far have failed. To improve the efficacy of immunotherapies to treat glioblastoma, new single-cell imaging modalities like imaging mass cytometry can be leveraged and integrated with computational models. This enables a better understanding of the tumour microenvironment and its role in treatment success or failure in this hard-to-treat tumour. Here, we implemented an agent-based model that allows for spatial predictions of combination chemotherapy, oncolytic virus, and immune checkpoint inhibitors against glioblastoma. We initialised our model with patient imaging mass cytometry data to predict patient-specific responses and found that oncolytic viruses drive combination treatment responses determined by intratumoral cell density. We found that tumours with higher tumour cell density responded better to treatment. When fixing the number of cancer cells, treatment efficacy was shown to be a function of CD4 + T cell and, to a lesser extent, of macrophage counts. Critically, our simulations show that care must be put into the integration of spatial data and agent-based models to effectively capture intratumoral dynamics. Together, this study emphasizes the use of predictive spatial modelling to better understand cancer immunotherapy treatment dynamics, while highlighting key factors to consider during model design and implementation.

Milvexian: An Oral, Bioavailable Factor XIa Inhibitor.

Direct oral anticoagulants have a dose-dependent increased bleeding risk which limits use in certain populations. Studies in both animals and humans with inherited variations in factor XI levels provide a theoretical basis for a drug target capable of addressing current unmet needs. Milvexian is an oral factor XIa inhibitor that has the potential to provide robust anticoagulant effect without increased bleeding compared with current standard of care. Several key studies in the preclinical, phase I, and phase II stages have reported promising safety data in venous thromboembolism and stroke prevention without compromising hemostasis. The planned phase III trials will examine the efficacy of milvexian for prevention of thrombotic events in patients with acute stroke, acute coronary syndrome, and atrial fibrillation.