Citations

AbstractBackgroundCervical artery dissection (CAD) is a common cause of ischemic stroke in young adults. Local blood clot formation and distal emboli are the key mechanisms for the development of stroke in patients with CAD. Microemboli distal to the dissection point can be detected as high‐intensity transient signals (HITS) using transcranial Doppler (TCD). Despite this unique capability, TCD is used inconsistently in the management of CAD. In this international survey, we aim to explore the frequency and potential barriers to TCD use in CAD.MethodThis study was an international electronic survey, based on the Antithrombotic Treatment for Stroke Prevention in Cervical Artery Dissection (STOP‐CAD) study, aiming at evaluating the use of TCD in diagnosing and managing CAD patients. A comprehensive questionnaire was developed to gather insights into the current practices, perceptions, and potential barriers to the effective use of TCD in participating centers. The collected data was then analyzed.ResultsFifty‐eight medical centers with advanced stroke care capabilities from Europe and United States participated in this study. Half (29 out of 58) of the sites routinely perform TCD on CAD patients, particularly in the presence of carotid or vertebral artery stenosis, complete carotid occlusion, and early neurologic deterioration. The primary reason for participating institutions not performing TCD was because its results would not change their practice. The protocol for TCD monitoring and managing HITS‐positive CAD patients varied among centers but transitioning from antiplatelet to anticoagulant was the most common practice in this patient population.ConclusionHalf of the stroke centers in our survey routinely perform TCD monitoring for CAD patients. The detection of HITS in CAD patients is a warning sign for providers, which may prompt a change in secondary stroke prevention management. However, a standard protocol for performing TCD in CAD and treatment recommendations for HITS‐positive CAD are not currently available, which warrants further research.

AbstractIntroductionPulsed field ablation (PFA) has emerged as an innovative therapy for cardiac arrhythmias. Drawing parallels with PFA's application in solid tumors, calcium chloride (CaCl2) as an adjuvant therapy, known as calcium electroporation, may amplify PFA's apoptotic effects. We propose that PFA in the atrium could enhance calcium uptake through PFA‐created pores, thereby increasing ablation efficacy even at reduced power levels by exploiting PFA's permeabilization effects.MethodsWe conducted in vivo ablations on the atria of seven pigs using low PFA power (250 V, 20 μs for 50 pulses at 200 ms intervals). Post‐PFA, we randomly administered an infusion of either 200 mg/2 ml CaCl2 (calcium group) or saline (control) directly to the ablation site via the catheter tip. We evaluated reduction in electrogram voltage amplitude, electrocardiography (ECG) parameters, ablation lesion parameters, and histology after PFA.ResultsNineteen lesions from control and calcium groups were examined. Control lesions showed no voltage decrease post‐PFA, whereas calcium‐treated lesions exhibited a significant voltage reduction. Gross pathology indicated marked differences in maximum lesion surface diameter, depth, and volume between the lesion groups. Histologically, calcium group lesions were characterized by a more severe acute PFA response with contraction band necrosis, myocytolysis and nuclear pyknosis in adjacent myocardium, in addition to microhemorrhages.ConclusionInfusing calcium chloride locally after PFA markedly improves the immediate efficacy of electroporation in porcine atria. This study suggests that calcium electroporation could bolster PFA outcomes without higher energy levels, potentially diminishing associated risks. These preliminary findings warrant further research into the long‐term efficacy and potential clinical application of calcium electroporation in PFA.

Post-hepatectomy liver failure (PHLF) remains a significant risk for patients undergoing partial hepatectomy (PHx). Reliable prognostic markers and treatments to enhance liver regeneration are lacking. Plasma nanoparticles, including lipoproteins, exosomes, and extracellular vesicles (EVs), can reflect systemic and tissue-wide proteostasis and stress, potentially aiding liver regeneration. However, their role in PHLF is still unknown. Methods: Our study included nine patients with hepatocellular carcinoma (HCC) undergoing PHx: three patients with PHLF, three patients undergoing the associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) procedure, and three matched controls without complications after PHx. Patient plasma was collected before PHx as well as 1 and 5 days after. EVs were isolated by ultracentrifugation, and extracted proteins were subjected to quantitative mass spectrometry using a super-SILAC mix prepared from primary and cancer cell lines. Results: We identified 2625 and quantified 2570 proteins in the EVs of PHx patients. Among these, 53 proteins were significantly upregulated and 32 were downregulated in patients with PHLF compared to those without PHLF. Furthermore, 110 proteins were upregulated and 78 were downregulated in PHLF patients compared to those undergoing ALPPS. The EV proteomic signature in PHLF indicates significant disruptions in protein translation, proteostasis, and intracellular vesicle biogenesis, as well as alterations in proteins involved in extracellular matrix (ECM) remodelling and the metabolic and cell cycle pathways, already present before PHx. Conclusions: Longitudinal proteomic analysis of the EVs circulating in the plasma of human patients undergoing PHx uncovers proteomic signatures associated with PHLF, which reflect dying hepatocytes and endothelial cells and were already present before PHx.

AbstractObjectivesInterpatient variability in bipolar I depression (BP‐D) symptoms challenges the ability to predict pharmacotherapeutic outcomes. A machine learning workflow was developed to predict remission after 8 weeks of pharmacotherapy (total score of ≤8 on the Montgomery Åsberg Depression Rating Scale [MADRS]).MethodsSupervised machine learning models were trained on data from BP‐D patients treated with olanzapine (N = 168) and were externally validated on patients treated with olanzapine/fluoxetine combination (OFC; N = 131) and lamotrigine (LTG; N = 126). Top predictors were used to develop a prognosis rule informing how many symptoms should change and by how much within 4 weeks to increase the odds of achieving remission.ResultsAn AUC of 0.76 (NIR:0.59; p = 0.17) was established to predict remission in olanzapine‐treated subjects. These trained models achieved AUCs of 0.70 with OFC (NIR:0.52; p < 0.03) and 0.73 with LTG (NIR:0.52; p < 0.003), demonstrating external replication of prediction performance. Week‐4 changes in four MADRS symptoms (reported sadness, reduced sleep, reduced appetite, and concentration difficulties) were top predictors of remission. Across all pharmacotherapies, three or more of these symptoms needed to improve by ≥2 points at Week‐4 to have a 65% chance of achieving remission at 8 weeks (OR: 3.74, 95% CI: 2.45–5.76; p < 9.3E‐11).ConclusionMachine learning strategies achieved cross‐trial and cross‐drug replication in predicting remission after 8 weeks of pharmacotherapy for BP‐D. Interpretable prognoses rules required only a limited number of depressive symptoms, providing a promising foundation for developing simple quantitative decision aids that may, in the future, serve as companions to clinical judgment at the point of care.

AbstractPatients in delirium require trustful communication and re‐orientation. We developed a flyer with positive, re‐orientating suggestions for families of delirious patients in intensive care units. Suggestions include creating a safe environment, interpreting unusual behaviours positively and fostering mental resilience. Additionally, families are encouraged to prioritize their own well‐being, recognizing their crucial role in supporting their loved ones. This flyer offers practical strategies across four key areas: ensuring security and orientation, reframing noises and body experiences, managing agitation and reshaping perceptions. By equipping families with knowledge and tools, this resource aims to promote understanding, resilience and strength to humanize delirium care.

Abstract Genome-wide association studies (GWAS) have identified over 300 loci associated with the inflammatory bowel diseases (IBD), but putative causal genes for most are unknown. We conducted the largest disease-focused expression quantitative trait loci (eQTL) analysis using colon tissue from 252 IBD patients to determine genetic effects on gene expression and potential contribution to IBD. Combined with two non-IBD colon eQTL studies, we identified 194 potential target genes for 108 GWAS loci. eQTL in IBD tissue were enriched for IBD GWAS loci colocalizations, provided novel evidence for IBD-associated genes such as ABO and TNFRSF14, and identified additional target genes compared to non-IBD tissue eQTL. IBD-associated eQTL unique to diseased tissue had distinct regulatory and functional characteristics with increased effect sizes. Together, these highlight the importance of eQTL studies in diseased tissue for understanding functional consequences of genetic variants, and elucidating molecular mechanisms and regulation of key genes involved in IBD.

6026 Background: We examined a large patient dataset based on E1305, a completed phase III randomized trial of platinum-based chemotherapy with or without bevacizumab (Argiris et al. JCO 2019), to evaluate prognostic factors in the first-line treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck (RM SCCHN) and expand on our previous observations in cooperative group trials (Argiris et al. Cancer 2004). Methods: All 403 patients enrolled in E1305 were analyzed. Overall survival (OS) was the outcome of interest. Clinical and tumor characteristics were examined using Cox proportional hazards models. Variables which were significant in the univariate setting at a level of ≤ 0.10 were included in a multivariable model, and backwards selection was performed (threshold of p ≤ 0.05). The final multivariable model was then applied to the two treatment arms, separately. Variables for which the hazards ratio (HR) within an arm was more than 10% different than that for the whole cohort, were removed from the final cohort model. Results: The median OS in the whole study cohort was 11.8 months. A prognostic score model for OS was built, using the 4 independent prognostic factors identified in the multivariable model: ECOG performance status (1 vs 0), prior radiation, primary region (non-oropharynx vs oropharynx), and metastatic disease bone or liver (vs other sites/no metastases). Prognostic score was dichotomized (0-2 and > 2). Patients with 0-2 risk factors (n = 249) had a median OS of 15.2 months (90% CI: 13.8, 18.1), while patients with > 2 risk factors (n = 154) had a median OS of 7.6 months (90% CI: 6.5, 9.3); HR of 2.14 (95% CI: 1.73, 2.66), p < 0.0001. Compared to our previous 5-factor model from analysis of older trials in a similar setting, the variable “bone/liver metastasis” is new, but “tumor cell differentiation” and “weight loss” were not significant and not included in the new model for OS. Conclusions: The new proposed model includes 4 prognostic factors for OS (performance status, primary site, prior radiation, presence of bone/liver metastasis) in the first-line treatment of RM SCCHN.

6041 Background: Human papillomavirus (HPV) E6/E7 oncoproteins mediate immune evasion by down-regulating Type 1 interferons, TLR9, MHC Class I/II as well as other mechanisms, resulting in persistent infection and initiation of ̃5% of all cancers globally. Similarly, established cancers evade immune surveillance utilizing parallel mechanisms including the expression of checkpoint proteins. PDS0101 is a molecularly targeted immunotherapeutic based on an enantiospecific cationic lipid nanoparticle platform containing HPV16 neoantigens that exhibits anti-tumor activity with checkpoint inhibitors (CPIs) by upregulating Type I interferons and promoting antigen processing and cross presentation. This allows generation of high levels of polyfunctional HPV16-specific CD8 and CD4 T cells in vivo as well as immune memory. VERSATILE-002 (NCT04260126) is a phase 2 study of the combination of PDS0101 and pembrolizumab in treatment of CPI naïve and refractory patients with recurrent or metastatic HPV16-related HNSCC. Herein, we report preliminary safety and efficacy data for CPI naïve patients at a prespecified interim analysis. Methods: Subjects are treated with pembrolizumab 200mg IV every three weeks plus SC PDS0101 following pembrolizumab on days one of Cycles1-4 and Cycle12; pembrolizumab continues up until 35 cycles, disease progression or intolerance to therapy. Results: Eighteen CPI naïve subjects with confirmed HPV16 tumors and a CPS score > = 1, median age 62 yrs (range 46-71), all male, 17 (94%) of whom were White and 16 (88.9%) not Hispanic or Latino, received at least one cycle of combination therapy. At the time of analysis, 17 (94%) subjects had received > = 4 doses of PDS0101 (median 4, range 1-5) and pembrolizumab (median 7, range 1-14). There were no Grade 3 or greater treatment-related toxicities and no drug discontinuation related to toxicity or immune-related AEs. Clinical activity (CR+PR+SD) was seen in 13 (72.2%) of 18 subjects, with best overall reponse per RECIST1.1 documenting: OR in 7 (38.9%; 2 CR, 5PR); stable disease (SD) in 6 (33.3%) and progressive disease in 3 (16.7%); 2 subjects had missing data. Tumor reduction was seen in 4 of 6 (67%) subjects with SD. Nine-month PFS and OS rates (95% CI) were 52% (22.5, 74.7) and 81% (37.8, 95.5) respectively; median PFS and OS have not been reached. Conclusions: The combination of PDS0101 and pembrolizumab demonstrates an excellent safety profile with preliminary evidence of clinical activity in the majority of CPI naïve patients with HPV-related HNSCC. Clinical trial information: NCT04260126.

Abstract Background A retrospective review was performed of 15 adult patients who underwent arthroscopic suture anchor scapholunate capsuloligamentous repair between 2021 and 2023. Materials and Methods There were 12 male and 3 female patients, with a mean age of 44.9 years. Eight patients had European Wrist Arthroscopy Society (EWAS) II (Geissler II), four patients had EWAS IIIC (Geissler III), and three patients had EWAS IV (Geissler IV). After a follow-up of 12 months (12–26), the mean grip strength significantly improved by 131% compared with presurgery. There was a significant improvement in the visual analog scale score from 6 to 1.2, the Mayo Wrist Score from 43.5 to 86.5, and the Quick Disabilities of the Arm, Shoulder, and Hand questionnaire score from 65.9 to 6.5. Two EWAS IV patients had recurrent symptomatic scapholunate diastasis requiring scapholunate ligamentoplasty. Conclusion The arthroscopic dorsal scapholunate capsuloligamentous repair with suture anchors is a reliable and safe technique with minimal complications. It is recommended for reducible acute or chronic injury to the scapholunate ligament complex with suspected avulsion injury. Level of Evidence Level IV