Citations

Device infection is associated with increased mortality in cardiovascular implantable electronic device (CIED) recipients. However, published data regarding clinical predictors of mortality in patients with CIED infection are limited. In current investigation, we sought to identify patient and device-related factors associated with mortality in CIED infection cases. We performed a retrospective review of all cases of CIED infection admitted to Mayo Clinic Rochester from 1991 to 2008. Survival data were obtained from hospital medical records and United Sates Social Security Index. Key data regarding patient demographics, device features, comorbid conditions, clinical presentation, echocardiographic findings and management strategies were abstracted. Potential risk factors for short (30-day) and long-term mortality were analyzed using univariate and multivariable logistic and Cox proportional hazards regression models, respectively. 415 cases of CIED infection were identified from the institutional database. The mean duration of follow-up for the 243 patients who were alive at last follow-up was 6.9 years. In multivariable model, congestive heart failure (CHF, Odds ratio 9.31, 95% CI 2.08-41.67), chronic corticosteroid use (OR 4.04, 1.40-11.60) and presentation with CIED-related infective endocarditis (CIED-IE), (OR 5.6, 2.25-13.92) were associated with increased odds of short-term mortality. Independent predictors of long-term mortality on multivariable model included patients' age (hazard ratio for 10-year increase 1.2, 95% CI 1.06-1.36), CHF (HR 2.01, 1.42-2.86), metastatic malignancy (HR 5.99, 1.67-21.53), corticosteroid use (HR 1.97, 1.22-3.18), renal failure (HR 1.94, 1.37-2.74) and CIED-IE (HR 1.68, 1.17-2.41). Our investigation provides some novel insights into predictors of short- and long-term mortality in CIED infection cases. While comorbid conditions and immunocompromised host status were primary determinants of both short- and long-term mortality, complicated device infection (CIED-IE) is the only predictor that presents an opportunity for intervention where mortality may be reduced by early diagnosis and expedited device removal.

Abstract One striking clinical hallmark in patients with autoantibodies to leucine-rich glioma inactivated 1 (LGI1) is the very frequent focal seizure semiologies, including faciobrachial dystonic seizures (FBDS), in addition to the amnesia. Polyclonal serum IgGs have successfully modelled the cognitive changes in vivo but not seizures. Hence, it remains unclear whether LGI1-autoantibodies are sufficient to cause seizures. We tested this with the molecularly precise monoclonal antibodies directed against LGI1 [LGI1-monoclonal antibodies (mAbs)], derived from patient circulating B cells. These were directed towards both major domains of LGI1, leucine-rich repeat and epitempin repeat, and infused intracerebroventricularly over 7 days into juvenile male Wistar rats using osmotic pumps. Continuous wireless EEG was recorded from a depth electrode placed in hippocampal CA3 plus behavioural tests for memory and hyperexcitability were performed. Following infusion completion (Day 9), post-mortem brain slices were studied for antibody binding and effects on Kv1.1. The LGI1-mAbs bound most strongly in the hippocampal CA3 region and induced a significant reduction in Kv1.1 cluster number in this subfield. By comparison to control-Ab injected rats video-EEG analysis over 9 days revealed convulsive and non-convulsive seizure activity in rats infused with LGI1-mAbs, with a significant number of ictal events. Memory was not impaired in the novel object recognition test. Peripherally-derived human LGI1-mAbs infused into rodent CSF provide strong evidence of direct in vivo epileptogenesis with molecular correlations. These findings fulfill criteria for LGI1-antibodies in seizure causation.

Abstract Vascular graft infection (VGI) is one of the most serious complications following arterial reconstructive surgery. VGI has received increasing attention over the past decade, but many questions remain regarding its diagnosis and management. In this review, we describe our approach to VGI through multidisciplinary collaboration and discuss decision-making for challenging presentations. This document will concentrate on VGI that impacts both aneurysms and pseudoaneurysms excluding the ascending thoracic aorta.

Study Design. Retrospective cohort study of prospectively accrued data. Objective. To evaluate a large, prospective, multicentre dataset of surgically treated degenerative cervical myelopathy (DCM) cases on the contemporary risk of C5 palsy with surgical approach. Summary of Background Data. The influence of surgical technique on postoperative C5 palsy after decompression for DCM is intensely debated. Comprehensive, covariate-adjusted analyses are needed using contemporary data. Methods. Patients with moderate to severe DCM were prospectively enrolled in the multicenter, randomized, Phase III CSM-Protect clinical trial and underwent either anterior or posterior decompression between Jan 31, 2012 and May 16, 2017. The primary outcome was the incidence of postoperative C5 palsy, defined as the onset of muscle weakness by at least one grade in manual muscle test at the C5 myotome with slight or absent sensory disruption after cervical surgery. Two comparative cohorts were made based on the anterior or posterior surgical approach. Multivariate hierarchical mixed-effects logistic regression was used to estimate odds ratios (OR) with 95% confidence intervals (CI) for C5 palsy. Results. A total of 283 patients were included, and 53.4% underwent posterior decompression. The total incidence of postoperative C5 palsy was 7.4% and was significantly higher in patients who underwent posterior decompression compared with anterior decompression (11.26% vs. 3.03%, P=0.008). After multivariable regression, the posterior approach was independently associated with greater than four times the likelihood of postoperative C5 palsy (P=0.017). Rates of C5 palsy recovery were comparable between the two surgical approaches. Conclusion. The odds of postoperative C5 palsy are significantly higher after posterior decompression compared to anterior decompression for DCM. This may influence surgical decision-making when there is equipoise in deciding between anterior and posterior treatment options for DCM. Level of Evidence. Therapeutic Level—II

Abstract Colorectal cancer is the second leading cause of cancer-related mortality in adults in the United States. Despite compelling evidence of improved outcomes in colorectal cancer, screening rates are not optimal. This study aimed to characterize colorectal cancer screening trends over the last two decades and assess the impact of various screening modalities on overall colorectal cancer screening rates. Using National Health Interview Survey data from 2005 to 2021, we examined colorectal cancer screening [colonoscopy, multitarget stool DNA (mt-sDNA), fecal occult blood test (FOBT)/fecal immunochemical test, sigmoidoscopy, CT colonography] rates among adults ages 50–75 years (n = 85,571). A pseudo-time-series cross-sectional (pseudo-TSCS) analysis was conducted including a random effects generalized least squares regression model to estimate the relative impact of each modality on changes in colorectal cancer screening rates. Among 50 to 75 year olds, the estimated colorectal cancer screening rate increased from 47.7% in 2005 to 69.9% in 2021, with the largest increase between 2005 and 2010 (47.7%–60.7%). Rates subsequently plateaued until 2015 but increased from 63.5% in 2015 to 69.9% in 2018. This was primarily driven by the increased use of mt-sDNA (2.5% in 2018 to 6.6% in 2021). Pseudo-TSCS analysis results showed that mt-sDNA contributed substantially to the increase in overall screening rates (77.3%; P < 0.0001) between 2018 and 2021. While colorectal cancer screening rates increased from 2005 to 2021, they remain below the 80% goal. The introduction of mt-sDNA, a noninvasive screening test may have improved overall rates. Sustained efforts are required to further increase screening rates to improve patient outcomes and offering a range of screening options is likely to contribute to achieving this goal. Prevention Relevance: This retrospective study highlights the importance of convenient stool-based colorectal cancer screening options to achieve the national goal of 80% for overall colorectal cancer screening rates. Empowering screening-eligible individuals with a choice for their colorectal cancer screening tests is imperative.

AimsDislocation remains a leading cause of failure following revision total hip arthroplasty (THA). While dual-mobility (DM) bearings have been shown to mitigate this risk, options are limited when retaining or implanting an uncemented shell without modular DM options. In these circumstances, a monoblock DM cup, designed for cementing, can be cemented into an uncemented acetabular shell. The goal of this study was to describe the implant survival, complications, and radiological outcomes of this construct.MethodsWe identified 64 patients (65 hips) who had a single-design cemented DM cup cemented into an uncemented acetabular shell during revision THA between 2018 and 2020 at our institution. Cups were cemented into either uncemented cups designed for liner cementing (n = 48; 74%) or retained (n = 17; 26%) acetabular components. Median outer head diameter was 42 mm. Mean age was 69 years (SD 11), mean BMI was 32 kg/m2 (SD 8), and 52% (n = 34) were female. Survival was assessed using Kaplan-Meier methods. Mean follow-up was two years (SD 0.97).ResultsThere were nine cemented DM cup revisions: three for periprosthetic joint infection, three for acetabular aseptic loosening from bone, two for dislocation, and one for a broken cup-cage construct. The two-year survivals free of aseptic DM revision and dislocation were both 92%. There were five postoperative dislocations, all in patients with prior dislocation or abductor deficiency. On radiological review, the DM cup remained well-fixed at the cemented interface in all but one case.ConclusionWhile dislocation was not eliminated in this series of complex revision THAs, this technique allowed for maximization of femoral head diameter and optimization of effective acetabular component position during cementing. Of note, there was only one failure at the cemented interface.Cite this article: Bone Joint J 2024;106-B(4):352–358.

Abstract PARP inhibitors (PARPis) have now become a standard of care for high-grade serous ovarian cancer (HGSOC), especially for those with defects in homologous recombination (HR) DNA repair. However, the innate and acquired PARPi resistance in HGSOC poses a significant concern, necessitating the exploration of novel treatment options and strategies. Here we investigated the potential of combining brigatinib—a second-generation anaplastic lymphoma kinase (ALK) inhibitor approved for treating lung cancer—with PARPis as way to enhance PARPi activity in HGSOC. Clonogenic cell survival assays revealed that brigatinib synergizes with PARPis in HR-proficient and -deficient HGSOC cell lines. In subsequent proteomics approaches and cell-based confirmatory studies, we found that brigatnib suppressed tyrosine kinases FAK and EphA2 with reduction in downstream signaling. Follow-up pharmacologic and gene-silencing techniques demonstrated that dual FAK and EphA2 inhibition additively reduces PI3K/Akt and MAPK/ERK cell survival signaling to levels conferring PARPi sensitivity. Additionally, the efficacy of this therapeutic approach on tumor size reduction was assessed in HGSOC patient-derived xenograft (PDX) models, with combination treatment inducing tumor regression more effectively than either agent alone. Overall, our studies unveil a beneficial ALK-independent effect of brigatinib that may offer new avenues for considering its repurposing as a HGSOC therapy. Citation Format: Julie R. Duffield, Xiaonan Hou, Iman K. McKeon-Makki, Amelia M. Huehls, Benjamin W. Wilson, Anjali Prasad, Xinyan Wu, Scott H. Kaufmann, Larry M. Karnitz, John J. Weroha, Arun Kanakkanthara. Brigatinib induces synergy with PARP inhibitors through dual inhibition of FAK and EphA2 in high-grade serous ovarian carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4538.

Abstract Triple negative breast cancer (TNBC) represents an aggressive and therapeutically challenging breast cancer subtype with higher incidence and mortality rates in non-Hispanic Black (NHB) women. This disparity persists even after adjusting for socioeconomic factors, tumor biology, and quality of care. The study aims to unravel specific molecular mechanisms underlying this disparity, with a focus on Hedgehog signaling pathways in premenopausal NHB women. Understanding these mechanisms is vital for developing targeted therapies and personalized medicine approaches to address these health disparities. Our research utilized a unique cohort of NHB and non-Hispanic White (NHW) women who underwent breast reduction surgery at the Mayo Clinic and donated breast tissue samples for our study. We isolated RNA from whole tissue sections from a cohort of 12 NHB and 40 NHW women who were parous and premenopausal at time of surgery. We performed gene expression profiling using NanoString BC360 and IO360 assays. This allowed us to identify a distinct gene expression signature characteristic of basal-like/TNBC and indicative of heightened activity in the Hedgehog signaling pathway. We also employed advanced cell culture techniques to generate tissue organoids and subculture human mammary epithelial cells (HMECs) that preserve the intrinsic characteristics of the original tissue samples. We found that significantly differential expression of IL20RA and SOX10, principal factors in the gene expression signature, were preserved in both the derived organoids and the HMECs. These results suggest a potential intrinsic difference in the activation of the Hedgehog pathway in the breast epithelial cells of NHB women. This activation may contribute to increased proliferation and transformation of basal stem cells within the breast, possibly fueling the development and progression of TNBC. The implication of activated Hedgehog signaling in NHB women opens new avenues for understanding TNBC disparities. IL20RA and SOX10 represent potential biomarkers for TNBC risk that may serve as a stratification tool for NHB women. The results of this study have the potential to improve assessment and management of TNBC risk among NHB women, thereby contributing significantly to reducing health disparities in breast cancer outcomes. Citation Format: Jennifer Vanessa Cabezas, Savanna Touré, Matthew Wilson, Melody L. Stallings Mann, Laura M. Pacheco-Spann, Joshua W. Ogony, Mark E. Sherman, Derek C. Radisky. Identifying molecular mechanisms in triple negative breast cancer disparities: Unveiling the role of Hedgehog signaling in non-Hispanic Black women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2139.