Citations

8549 Background: First-line treatment of early stage non-small cell lung cancer (NSCLC) is surgical resection, but with a 5-year survival of only 54%, rates of future relapse are high. Identifying patients at high risk of relapse can help guide adjuvant treatment decisions. Deep convolutional neural network (DCNN) AI models trained on tumor histology have shown incredible flexibility as potential biomarkers, both in lung cancer and more generally across many malignancies. While DCNN models can obtain extremely accurate results when used for routine purposes such as diagnosis, subtyping, and grading of malignancies, most models trained for prognostication or treatment response prediction do not reach performance sufficient for clinical application. Uncertainty quantification (UQ) – a family of techniques that give DCNN models the ability to report confidence alongside predictions – is an underexplored avenue in cancer AI that may help further improve performance and clinical application of models designed to provide clinicians with estimations of risk. Methods: To explore the potential use of UQ in clinically-oriented DCNN models, we trained models on a single-institution, retrospective digital tumor histology slide cohort from patients with Stage I-III NSCLC who underwent surgical resection to predict risk of future relapse. Estimation of uncertainty was performed using dropout as a Bayesian approximation, and uncertainty thresholds were calculated from training sets using a novel method to identify and remove low-confidence predictions. For comparison, a separate multivariate logistic regression was trained in cross-validation using known clinical risk factors. Results: We trained DCNN models on slides from 198 patients (40 relapsed, 158 without relapse). In this cohort, 130 patients had stage I disease (65.6%), 42 had stage II (21.2%), and 26 had stage III (13.2%). The average age was 69 years, 85% were current or previous smokers, and 38 received guideline-concordant adjuvant chemotherapy. Without UQ, a DCNN model predicted risk of future relapse with an average area under receiver operator curve (AUROC) of 0.74 across three-fold cross-validation. Using UQ estimation, 63% of slides were reported with high confidence. Relapse prediction was significantly improved in the high-confidence cohort, with an average AUROC of 0.83 in cross-validation. With a specificity of 70%, this corresponds to an average sensitivity of 86.8% across the three cross-folds (79.1%, 85.5%, and 95.7%). In comparison, a clinical-only multivariate regression model predicted relapse with a cross-validated AUROC of 0.67. Conclusions: This method of uncertainty quantification appears to be a powerful tool to predict lung cancer recurrence risk from digital histopathology while simultaneously providing clinicians with a measurement of algorithm trustworthiness.

Abstract Introduction Advanced Practice Providers (APPs; Advanced practice registered nurses, physician assistants) and physicians-in-training (residents, fellows) receive inadequate education on obstructive sleep apnea (OSA)/perioperative OSA risks. However, they are front-line providers assessing these patients. Failure to mitigate this risk has led to significant postoperative morbidity/mortality. We assessed these providers’ perceptions to OSA/perioperative OSA training. Methods Surveys were sent to three provider roles, APPs, residents, and fellows, in four categories of practice at nine academic institutions between May 9-June 30, 2021. Chi-square and Fisher’s exact tests assessed association between survey responses and participant characteristics. False discovery rate adjustment accounted for multiple comparisons, threshold of q<0.05 for statistical significance. Cochran-Mantel-Haenzsel tests evaluated associations stratified by institution. Results 2236 of 6724 (33.3%) participants responded: 48.4% APPs, 11% Fellows and 40.6% Residents. Primary category of practice included: 20.3% Anesthesiology, 8.9% Family Medicine, 34.1%, Internal Medicine (IM)/IM subspecialties, 6.7% Obstetrics/Gynecology/Gynecologic Oncology, 25.9% Surgery/Surgery subspecialties, 4.1% Other.While 93.2% of respondents believed OSA is a risk factor for perioperative complications, fewer respondents reported that they felt adequately trained to assess for OSA (50.9%) in general, with significant differences noted by provider role (range 42-70%, q=0.001) and across the categories of practice (range 12-82%, q=0.001). Even fewer felt adequately trained to assess for OSA in perioperative patients (38.2%) with significant differences noted by provider role (range 31-52%, q=0.001) and across the categories of practice (range 15-84%, q=0.001).Across all categories of practice, respondents indicated that they would like additional educational training about OSA (76.7%). This varied by clinical role (range 64-82%, q=0.003), but not categories of practice (range 73-84%, q=0.13). Furthermore, respondents indicated they also desired additional education about OSA in the perioperative patient (75.5%). This extended across all clinical roles (range 68-77%, q=0.09) and categories of practice (range 72-80%, q=0.09). Conclusion We found significant differences in APP and physician-in-training perceptions of the adequacy of their current training and desire for further OSA/perioperative OSA education. Our study identifies a critical gap and opportunity to improve provider understanding and patient care. Support (If Any) American Academy of Sleep Medicine Foundation (AASMF) award.

Abstract COVID-19 vaccines are effective, but breakthrough infections have been increasingly reported. We conducted a test-negative case-control study to assess the durability of protection against symptomatic infection after vaccination with mRNA-1273. We fit conditional logistic regression (CLR) models stratified on residential county and calendar date of SARS-CoV-2 PCR testing to assess the association between the time elapsed since vaccination and the odds of symptomatic infection, adjusted for several covariates. There were 2,364 symptomatic individuals who had a positive SARS-CoV-2 PCR test after full vaccination with mRNA-1273 (“cases”) and 12,949 symptomatic individuals who contributed 15,087 negative tests after full vaccination (“controls”). The odds of symptomatic infection were significantly higher 250 days after full vaccination compared to the date of full vaccination (Odds Ratio [OR]: 2.47, 95% confidence interval [CI]: 1.19–5.13). The odds of non-COVID-19 associated hospitalization and non-COVID-19 pneumonia (negative control outcomes) remained relatively stable over the same time interval (Day 250 ORNon-COVID Hospitalization: 0.68, 95% CI: 0.47–1.0; Day 250 ORNon-COVID Pneumonia: 1.11, 95% CI: 0.24–5.2). The odds of symptomatic infection remained significantly lower almost 300 days after the first mRNA-1273 dose as compared to 4 days after the first dose, when immune protection approximates the unvaccinated state (OR: 0.26, 95% CI: 0.17–0.39). Low rates of COVID-19 associated hospitalization or death in this cohort precluded analyses of these severe outcomes. In summary, mRNA-1273 robustly protected against symptomatic SARS-CoV-2 infection at least 8 months after full vaccination, but the degree of protection waned over this time period.

Abstract We diagnosed 66 peripheral nerve injuries in 34 patients who survived severe coronavirus disease 2019 (COVID-19). We combine our latest data with published case series re-analyzed here (117 nerve injuries; 58 patients) to provide a comprehensive accounting of lesion sites. The most common are ulnar (25.1%), common fibular (15.8%), sciatic (13.1%), median (9.8%), brachial plexus (8.7%) and radial (8.2%) nerves at sites known to be vulnerable to mechanical loading. Protection of peripheral nerves should be prioritized in the care of COVID-19 patients. To this end, we report proof of concept data of a wearable, wireless pressure sensor to provide real time monitoring in the intensive care unit setting.

Abstract BACKGROUND AND AIMS NEK8/NPHP9 encodes a protein that localizes to the primary cilium. Biallelic NEK8 variants are known to cause multiorgan developmental defects, including kidney cystic dysplasia and extensive extra-renal defects, with heterozygous carrier parents being asymptomatic [1]. This autosomal recessive inheritance is the most common inheritance mode for ciliopathies. Complementary to this, we now propose a dominant negative effect for specific heterozygous NEK8 missense variants in the kinase domain resulting in an autosomal-dominant ciliopathy. METHOD We performed genetic testing in patients from several medical centers. To explore the consequences of the identified NEK8 variants, we are performing cilia staining assays in patients' skin fibroblast and kidney cells, as well as in mIMCD3 cells overexpressing the identified variants. Furthermore, we are examining the impact of the NEK8 variants on replication stress response. RESULTS We identified three distinct heterozygous NEK8 variants in 12 families (Table 1), all leading to missense alterations in the kinase domain. Interestingly the p.Arg45Trp variant is a recurrent variant we detected in 10 unrelated families. All patients have a kidney phenotype that varies from mild focal segmental glomerulosclerosis to prenatal presentation with polycystic kidneys. Most patients have kidney failure needing kidney replacement therapy at varying ages of onset. In all patients, we thoroughly checked whether a second variant could be found. Furthermore, the large symptomatic family and de novo occurrences favor a dominant inheritance mode. Our preliminary results from functional studies show abnormal primary cilia formation in serum-starved cells as well as increased replication stress. CONCLUSION We present the first evidence for a pathogenic effect of heterozygous NEK8 variants. Remarkably our patients present with a kidney limited phenotype as compared to the multiorgan defects found in patients with biallelic variants. This reveals a new mode of inheritance for NEK8 variants and expands genotype-phenotype correlations for this gene.

Abstract Cardiac hemangioma is a rare, benign primary tumor characterized by endothelial proliferation. While reports of cardiac hemangiomas demonstrating 18 F FDG avidity and other forms of hemangiomas showing 68 Ga Dotatate avidity have been published, we present a rare case of primary cardiac hemangioma demonstrating 68 Ga Dotatate avidity, mimicking a primary neuroendocrine tumor.

Abstract As of 2021 November 29, booster vaccination against SARS-CoV-2 infection has been recommended for all individuals aged 18 years and older in the United States. A key reason for this recommendation is the expectation that a booster vaccine dose can alleviate observed waning of vaccine effectiveness (VE). Although initial reports of booster effectiveness have been positive, the level of protection from booster vaccination is unclear. We conducted two studies to assess the impact of booster vaccination, with BNT162b2 or mRNA-1273, on the incidence of SARS-CoV-2 infection between August and December 2021. We first compared SARS-CoV-2 infection incidence in cohorts of 3-dose vaccine recipients to incidence in matched cohorts of 2-dose vaccine recipients (cohort size = 24,539 for BNT162b2 and 14,004 for mRNA-1273). Additionally, we applied a test-negative study design to compare the level of protection against symptomatic infection in 3-dose recipients to that observed in recent 2-dose primary vaccine series recipients. The 3-dose recipients experienced a significantly lower incidence rate of SARS-CoV-2 infection than the matched 2-dose cohorts (BNT162b2 Incidence Rate Ratio: 0.11, 95% CI: 0.09 to 0.13 and mRNA-1273 IRR: 0.11, 95% CI: 0.08 to 0.15). Results from the test-negative study showed the third vaccine dose mitigated waning of VE, with the risk of symptomatic infection in 3-dose recipients being comparable to that observed 7 to 73 days after the primary vaccine series. These results show that 3-dose vaccine regimens with BNT162b2 or mRNA-1273 are effective at reducing SARS-CoV-2 infection and support the widespread administration of booster vaccine doses.

Abstract Background Management of pulmonary hypertension (PH) in the setting of heart failure with preserved ejection fraction (HFpEF) can be challenging. Herein, we describe the case of a patient with HFpEF and combined pre- and post-capillary PH who showed striking improvement with sildenafil. Case summary A 74-year-old man presented with exertional dyspnea and near-syncope. He underwent a hemodynamic exercise study that showed evidence of HFpEF with pre- and post-capillary PH. Right ventricular endomyocardial biopsy showed interstitial fibrosis and mild hypertrophy, with no evidence of infiltrative or storage diseases. The patient was treated with sildenafil 20 mg three times daily, which resulted in significant symptomatic and functional improvement in 12 years of follow-up. Discussion Phosphodiesterase 5 inhibitors are currently not approved by the United States Food and Drug Administration for treatment of PH in heart failure and are used off-label in patients with heart failure. This case illustrates the importance of unloading the right ventricle to improve cardiac output in patients with diastolic dysfunction and combined pre- and post-capillary PH. Although promising, future studies are needed to validate these findings.

Abstract Objective Cystic adrenal mass is a rare imaging presentation of pheochromocytoma. We aimed to describe the clinical, biochemical and imaging characteristics of patients with cystic pheochromocytoma. Design Single‐centre, retrospective study, 2000−2020. Patients Consecutive patients with cystic pheochromocytoma were identified from our institutional pathology and adrenal tumour database. Results Of the 638 patients with pheochromocytomas, 21 (3.2%) had cystic pheochromocytomas (median age: 57 years, 57% women). Most pheochromocytomas were discovered incidentally (57%) or due to symptoms of catecholamine excess (24%). The median tumour size was 6.4 cm. On imaging, cystic pheochromocytomas were round or oval (90%), heterogeneous lesions (86%) with a thick solid rim (median rim thickness 13.9 mm, unenhanced computed tomography (CT) attenuation 40 Hounsfield units (HU), venous‐phase CT attenuation 83 HU), and a median cystic component of 40% (unenhanced CT attenuation 17.6 HU, venous‐phase CT attenuation 20.4 HU), and rarely with calcifications (15%). All 20 patients with biochemical testing had functioning tumours (adrenergic in 80%, noradrenergic in 20%). Total urinary metanephrine excretion correlated with the volume of the solid component ( R 2 = .75, p < .0001) but not the cystic component ( R 2 = .04, p = .4386). All patients underwent adrenalectomy (48% laparoscopic, 52% open), and the median duration of hospital stay was 4 days. Conclusions Cystic pheochromocytomas are rare, large tumours with a phenotypic appearance that can masquerade as other adrenal cystic lesions. The degree of biochemical abnormality in cystic pheochromocytomas is associated with the volume of the solid component. All patients with adrenal cysts that have a solid component or an unenhanced attenuation >10 HU should undergo biochemical testing for pheochromocytoma.

Abstract Aims Influence of atrial fibrillation (AF) type on outcomes seen with catheter ablation vs. drug therapy is incompletely understood. This study assesses the impact of AF type on treatment outcomes in the Catheter Ablation vs. Antiarrhythmic Drug Therapy for Atrial Fibrillation Trial (CABANA). Methods and results CABANA randomized 2204 patients ≥65 years old or &lt;65 with at least one risk factor for stroke to catheter ablation or drug therapy. Of these, 946 (42.9%) had paroxysmal AF (PAF), 1042 (47.3%) had persistent AF (PersAF), and 215 (9.8%) had long-standing persistent AF (LSPAF) at baseline. The primary endpoint was a composite of death, disabling stroke, serious bleeding, or cardiac arrest. Symptoms were measured with the Mayo AF-Specific Symptom Inventory (MAFSI), and quality of life was measured with the Atrial Fibrillation Effect on Quality of Life (AFEQT). Comparisons are reported by intention to treat. Compared with drug therapy alone, catheter ablation produced a 19% relative risk reduction in the primary endpoint for PAF {adjusted hazard ratio [aHR]: 0.81 [95% confidence interval (CI): 0.50, 1.30]}, and a 17% relative reduction for PersAF (aHR: 0.83, 95% CI: 0.56, 1.22). For LSPAF, the ablation relative effect was a 7% reduction (aHR: 0.93, 95% CI: 0.36, 2.44). Ablation was more effective than drug therapy at reducing first AF recurrence in all AF types: by 51% for PAF (aHR: 0.49, 95% CI: 0.39, 0.62), by 47% for PersAF (aHR: 0.53, 95% CI: 0.43,0.65), and by 36% for LSPAF (aHR 0.64, 95% CI 0.41,1.00). Ablation was associated with greater improvement in symptoms, with the mean difference between groups in the MAFSI frequency score favouring ablation over 5 years of follow-up in all subgroups: PAF had a clinically significant −1.9-point difference (95% CI: −1.2 to −2.6); PersAF a −0.9 difference (95% CI: −0.2 to −1.6); LSPAF a clinically significant difference of −1.6 points (95% CI: −0.1 to −3.1). Ablation was also associated with greater improvement in quality of life in all subgroups, with the AFEQT overall score in PAF patients showing a clinically significant 5.3-point improvement (95% CI: 3.3 to 7.3) over drug therapy alone over 5 years of follow-up, PersAF a 1.7-point difference (95% CI: 0.0 to 3.7), and LSPAF a 3.1-point difference (95% CI: -1.6 to 7.8). Conclusion Prognostic treatment effects of catheter ablation compared with drug therapy on the primary and major secondary clinical endpoints did not differ consequentially by AF subtype. With regard to decreases in AF recurrence and improving quality of life, ablation was more effective than drug therapy in all three AF type subgroups. ClinicalTrials.gov Identifier NCT00911508