Citations

Abstract Background Full-thickness lower eyelid defects after Mohs micrographic surgery are frequently referred out to oculoplastic surgery for reconstruction. Reconstructive options include wedge closure with or without canthotomy/cantholysis and tarsoconjunctival sliding flaps. Defects >50% of the eyelid margin have traditionally required the two-stage Hughes flap, leaving the patient with monocular vision for 3-6 weeks until pedicle division. Objective To demonstrate single-stage periosteal flaps performed by dermatologic surgeons can result in safe, functional, and cosmetically acceptable repairs for large full thickness eyelid defects. Materials and Methods An institutional review board-approved retrospective study of repairs performed by two dermatologic surgeons between January 2017 and July 2021 at the University of Minnesota. Patient demographics, operative notes, and follow-up notes were reviewed. Defect and follow up photos were scored using a visual analogue scale to assess aesthetic results. Results Ten cases were included in the analysis. Six patients were male and the average age was 62 years old. 8/10 were basal cell carcinoma and 2/10 were melanoma. The mean defect was 9.5 cm2, with a range of 1 cm2 to 24 cm2. The median cosmetic score was 85.8 +/- 10.7. There were no serious complications reported. Conclusion Mohs micrographic surgeons can safely and successfully reconstruct large, full thickness eyelid defects by periosteal flap.

PURPOSE Erb-B2 receptor tyrosine kinase 2 ( ERBB2)–positive breast cancer (BC) is particularly common in young women. Genomic features of ERBB2-positive tumors before and after chemotherapy and trastuzumab (chemo + H) have not been described in young women and are important for guiding study of therapeutic resistance in this population. METHODS From a large prospective cohort of women age 40 years or younger with BC, we identified patients with ERBB2-positive BC and tumor tissue available before and after chemo + H. Whole-exome sequencing (WES) was performed on each tumor and on germline DNA from blood. Tumor-normal pairs were analyzed for mutations and copy number (CN) changes. RESULTS Twenty-two women had successful WES on samples from at least one time point; 12 of these had paired sequencing results from before and after chemo + H and 10 had successful sequencing from either time point. TP53 was the only significantly recurrently mutated gene in both pre- and post-treatment samples. MYC gene amplification was observed in four post-treatment tumors. Seven of 12 patients with paired samples showed acquired and/or clonally enriched alterations in cancer-related genes. One patient had an increased clonality putative activating mutation in ERBB2. Another patient acquired a clonal hotspot mutation in TP53. Other genomic changes acquired in post-treatment specimens included alterations in NOTCH2, STIL, PIK3CA, and GATA3. There was no significant change in median ERBB2 CN (20.3 v 22.6; Wilcoxon P = .79) between paired samples. CONCLUSION ERBB2-positive BCs in young women displayed substantial genomic evolution after treatment with chemo + H. Approximately half of patients with paired samples demonstrated acquired and/or clonally enriched genomic changes in cancer genes. ERBB2 CN changes were uncommon. We identified several genes warranting exploration as potential mechanisms of resistance to therapy in this population.

Abstract Background: There are conflicting data on whether nonalcoholic fatty liver disease (NAFLD) is associated with susceptibility to pancreatic cancer. Using Mendelian randomization (MR), we investigated the relationship between genetic predisposition to NAFLD and risk for pancreatic cancer. Methods: Data from genome-wide association studies (GWAS) within the Pancreatic Cancer Cohort Consortium (PanScan; cases n = 5,090, controls n = 8,733) and the Pancreatic Cancer Case Control Consortium (PanC4; cases n = 4,163, controls n = 3,792) were analyzed. We used data on 68 genetic variants with four different MR methods [inverse variance weighting (IVW), MR-Egger, simple median, and penalized weighted median] separately to predict genetic heritability of NAFLD. We then assessed the relationship between each of the four MR methods and pancreatic cancer risk, using logistic regression to calculate ORs and 95% confidence intervals (CI), adjusting for PC risk factors, including obesity and diabetes. Results: No association was found between genetically predicted NAFLD and pancreatic cancer risk in the PanScan or PanC4 samples [e.g., PanScan, IVW OR, 1.04; 95% confidence interval (CI), 0.88–1.22; MR-Egger OR, 0.89; 95% CI, 0.65–1.21; PanC4, IVW OR, 1.07; 95% CI, 0.90–1.27; MR-Egger OR, 0.93; 95% CI, 0.67–1.28]. None of the four MR methods indicated an association between genetically predicted NAFLD and pancreatic cancer risk in either sample. Conclusions: Genetic predisposition to NAFLD is not associated with pancreatic cancer risk. Impact: Given the close relationship between NAFLD and metabolic conditions, it is plausible that any association between NAFLD and pancreatic cancer might reflect host metabolic perturbations (e.g., obesity, diabetes, or metabolic syndrome) and does not necessarily reflect a causal relationship between NAFLD and pancreatic cancer.

PURPOSEThere are numerous barriers to enrollment in oncology biomarker-driven studies.METHODSThe ELAINE 2 study (ClinicalTrials.gov identifier: NCT04432454 ) is an open-label phase 2 study of lasofoxifene combined with abemaciclib in patients with advanced or metastatic estrogen receptor–positive/human epidermal growth factor receptor 2–negative breast cancer with an ESR1 mutation. ELAINE 2 opened clinical sites by using a Traditional approach, which activated a site before patient identification, and the Tempus TIME Trial network, which opened a site only after identifying an eligible patient. This manuscript presents the operational metrics comparing the Traditional and TIME Trial site data.RESULTSThe study enrolled patients over 34 weeks and 16 sites (six Traditional and 10 TIME Trial) participated. Duration for full clinical trial agreement execution for Traditional sites and TIME Trial sites averaged 200.5 (range, 142-257) and 7.6 days (range, 2-14), respectively. Institutional review board approval time for Traditional sites and TIME Trial sites was 27.5 (range, 12-71) and 3.0 days (range, 1-12), respectively. Duration from study activation to first consent was 33.3 (range, 18-58) and 8.8 days (range, 1-35) for Traditional and TIME Trial sites, respectively. The first patient on study was at a TIME Trial site 115 days before a Traditional site and the first seven patients enrolled were at TIME Trial sites. Traditional sites consented 23 and enrolled 16 patients, while TIME Trial sites consented 16 and enrolled 13. The trial enrolled 29 patients in 8.5 months with the anticipated enrollment duration being 12-18 months.CONCLUSIONThe TIME Trial network opened earlier and enrolled the first study patients. These results demonstrate that the Just-in-TIME model, along with a Traditional model, can improve enrollment in biomarker-driven studies.

Abstract Pulmonary embolization in donor lungs is a common finding and found in up to 38% of cases. To expand the pool of organs, transplant centers now utilize lungs, from increased risk donors, that may have pulmonary embolic disease. Modalities of clearing pulmonary artery embolisms are critical to reduce the prevalence of primary graft dysfunction post transplantation. There have been anecdotal cases of pulmonary embolectomy pre and post organ procurement or in vivo and ex vivo thrombolytic therapy performed in donors with massive pulmonary emboli. We report for the first time therapeutic ex vivo thrombolysis on the back table without Ex Vivo Lung Perfusion (EVLP), followed by successful transplantation.

Introduction Decision aids (DAs) are helpful instruments used to support shared decision making (SDM). Patients with atrial fibrillation (AF) face complex decisions regarding stroke prevention strategies. While a few DAs have been made for AF stroke prevention, an encounter DA (EDA) and patient DA (PDA) have not been created to be used in conjunction with each other before. Design Using iterative user-centered design, we developed 2 DAs for anticoagulation choice and stroke prevention in AF. Prototypes were created, and we elicited feedback from patients and experts via observations of encounters, usability testing, and semistructured interviews. Results User testing was done with 33 experts (in AF and SDM) and 51 patients from 6 institutions. The EDA and PDA underwent 1 and 4 major iterations, respectively. Major differences between the DAs included AF pathophysiology and a preparation to meet with the clinician in the PDA as well as different language throughout. Content areas included personalized stroke risk, differences between anticoagulants, and risks of bleeding. Based on user feedback, developers 1) addressed feelings of isolation with AF, 2) improved navigation options, 3) modified content and flow for users new to AF and those experienced with AF, 4) updated stroke risk pictographs, and 5) added structure to the preparation for decision making in the PDA. Limitations These DAs focus only on anticoagulation for stroke prevention and are online, which may limit participation for those less comfortable with technology. Conclusions Designing complementary DAs for use in tandem or separately is a new method to support SDM between patients and clinicians. Extensive user testing is essential to creating high-quality tools that best meet the needs of those using them. Highlights First-time complementary encounter and patient decision aids have been designed to work together or separately. User feedback led to greater structure and different experiences for patients naïve or experienced with anticoagulants in patient decision aids. Online tools allow for easier dissemination, use in telehealth visits, and updating as new evidence comes out.

AbstractBackgroundWhite matter signal abnormalities (WMSA) are frequently observed on magnetic resonance imaging (MRI) scans of people with frontotemporal dementia (FTD). We hypothesized that carriers of mutations in progranulin (GRN+), chromosome 9 open reading frame 72 (C9orf72+) and microtubule associated protein tau (MAPT+) have increased rates of progression of WMSA compared to non‐carrier individuals prior to onset of dementia, and that different mutations may have different rates of WMSA accumulation.MethodParticipants were recruited through the ARTFL‐LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) Study. We selected participants with Clinical Dementia Rating scale (CDR) scores of 0 and 0.5. If a participant developed FTD during the follow‐up, we only analyzed observations collected before the conversion. WMSA were defined as hyperintensities on FLAIR MRI. Total WMSA volumes were normalized to the respective intracranial volumes. We used a linear mixed effects model, with random intercepts and slopes, to compare the baseline burden and the longitudinal progression of total WMSA volumes between mutation carriers and controls. The model was adjusted for baseline age, sex, education, baseline Montreal Cognitive Assessment (MoCA) scores, and MRI acquisition sites.ResultWe analyzed MRI data from 199 participants who had at least two MRI visits (46 C9orf72+, 17 GRN+, 35 MAPT+, 101 non‐carrier controls; up to five years of follow‐up). We did not find significant group differences in baseline demographic features, except that MAPT+ was younger than non‐carrier controls (average age: C9orf72+ = 47, GRN+ = 56, MAPT+ = 40, controls = 47). Baseline WMSA volumes were not significantly different between mutation carriers and controls. Longitudinally, the rates of WMSA volume increase in C9orf72+ and MAPT+ were comparable to controls; whereas, GRN+ had higher rates of WMSA volume increases compared to controls (p = 0.01).ConclusionWMSA may accumulate at higher rates in GRN+ prior to the onset of FTD, which is consistent with the frequent presence of white matter diseases observed in symptomatic FTD patients with GRN mutations. Future work is warranted to investigate the association between white matter structural changes and cognitive/psychiatric changes in FTD mutation carriers.

AbstractBackgroundNeuropsychiatric symptoms (NPS) often occur during the prodromal stage of frontotemporal dementia (FTD), as evidenced by the presence of early psychiatric diagnosis in approximately 50% of bvFTD patients prior to their dementia diagnosis. We hypothesized that carriers of mutations in progranulin (GRN+), chromosome 9 open reading frame 72 (C9orf72+) and microtubule associated protein tau (MAPT+) have increased baseline burden and rates of progression of NPS compared to non‐carrier individuals prior to onset of dementia symptoms based on the Clinical Dementia Rating (CDR) scale.MethodParticipants were recruited through the ARTFL‐LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) Study. NPS were assessed with Neuropsychiatric Inventory‐Questionnaire (NPI‐Q), Geriatric Depression Scale (GDS), Interpersonal Reactivity Index (IRI), Social Behaviour Checklist (SBOCL), and Behavioral Inhibition Scale (BIS) annually for up to five years. We selected participants with CDR scores of 0 and 0.5. If a participant’s CDR changed to above 0.5 during the follow‐up, we only analyzed observations collected before the conversion. We used mixed effects models to compare the baseline burden and the longitudinal progression of NPS measures between carriers and controls, adjusted for baseline age, sex, education, and baseline Montreal Cognitive Assessment (MoCA) scores.ResultWe analyzed data from 607 participants (111 C9orf72+, 47 GRN+, 67 MAPT+ and 382 non‐carrier controls). There were no significant group differences in baseline demographic features, except that MAPT+ was significantly younger than other groups (average age: C9orf72+ = 45, GRN+ = 53, MAPT+ = 41, controls = 54). Baseline NPS scores were not significantly different between carriers and controls, except that C9orf72+ had significantly lower GDS compared to controls (p = 0.002). Longitudinally, GRN+ (p = 0.02) and MAPT+ (p = 0.009) had significantly higher rates of NPI‐Q increases compared to controls, while the progression of NPI‐Q in C9orf72+ was comparable to controls. The rates of GDS, IRI, SBOCL and BIS progression were not significantly different between carriers and controls.ConclusionPrior to the onset of dementia, GRN+ and MAPT+ have a faster progression of NPS, as measured by NPI‐Q, compared to controls. Future work will investigate whether different mutation carriers are affected by specific type/cluster of symptoms.

Introduction: Shared decision-making (SDM) about anticoagulant treatment in patients with atrial fibrillation (AF) is widely recommended but its effectiveness is unclear. We assessed the extent to which using an SDM tool promotes high-quality SDM. Hypothesis: SDM will improve communication quality, knowledge, and decisional conflict and will translate to improved medication adherence and outcomes. Methods: In this multicentre encounter-randomized trial, we included patients with nonvalvular AF considering starting/reviewing anticoagulation, and their clinicians. We compared usual care with or without ANTICOAGULATION CHOICE, an SDM conversation tool for use during the clinical encounter that presents individualized risk estimates and compares anticoagulation options across patient important issues. Results: We enrolled and video-recorded 922 patient-clinician encounters. So far, our data have shown that participants in both arms reported near-optimal communication quality, knowledge, and decisional conflict (JAMA IM-2020). Patients in intervention-arm estimated their stroke risks more accurately and were more involved in decision-making (JAMA IM-2020), clinicians were more satisfied (JAMA IM-2020), and cost conversation were more common (JAMA NO-2021). Use of the intervention had no effect on treatment decisions, encounter duration (JAMA IM-2020), treatment adherence, clinical outcomes (JAHA-epub) or patient-perceived sense of the care plan (PEC-epub). New analyses have shown that compared to eligible white participants, black participants more frequently did not enrol to the study. Enrolment of Black, indigenous, and people of colour benefited most form including and prioritizing practices most likely to care for them. We found no evidence of contamination (tool use, functional, or learned) between study arms. Conclusions: Use of an SDM tool improved some measures of SDM quality, without affecting treatment decisions and their sensibility, encounter duration, patient adherence, or clinical outcomes. Our results should calibrate expectations as to what could be accomplished by implementing SDM tools about anticoagulation in the care of patients with AF