Mayo Clinic Rochester Research Articles

Substratification of Patients with Newly Diagnosed Standard-Risk Multiple Myeloma

Background:Despite the absence of cytogenetic high-risk abnormalities on fluorescence in situ hybridization (FISH) evaluation, a subset of patients with newly diagnosed multiple myeloma does experience poor overall survival. We aimed to identify demographic, clinical, and cytogenetic characteristics predicting poor three-year overall survival in patients with newly diagnosed standard-risk multiple myeloma.Methods: We studied 428 patients who were diagnosed with multiple myeloma between July 2004 and July 2014 at Mayo Clinic Rochester, underwent FISH evaluation within six months of diagnosis, and received treatment with novel agents. Patients with high- and intermediate-risk cytogenetics as well as patients lost to follow-up within three years were excluded. High-risk cytogenetics were defined as del(17p), t(14;16), and t(14;20). Intermediate-risk cytogenetics were defined as t(4;14) and dup(1q). A multivariable-adjusted logistic regression model was used to assess the associations between the parameters of interest and three-year overall survival. The identified predictors were used to derive a numerical scoring system. Receiver operating characteristic analysis was used to determine the optimal cut-off and associated score performance characteristics. Cox regression models were used to compare the derived scoring system to the established International Scoring System (ISS).Results: The median overall survival was 7.4 years (6.1-8.6) for the entire cohort (n=428), 10.5 years (8.3-NR) for those who survived at least three years (n=327, 76%), and 1.6 years (1.3 - 1.7) for those who did not survive three years after diagnosis (n=101, 24%). The prediction model had good discrimination (c=0.75) and adequate calibration (p=0.538). Scores were assigned based on the factors independently associated with poor three-year overall survival (Table 1): Advanced age (+8), advanced stage (+6), thrombocytopenia (+6), the absence of trisomies on FISH (+4), and low bone marrow plasma cells (+4). The scoring system had identical discrimination (c=0.75, 95% CI 0.70-0.81; internal cross-validation c=0.76, 95% CI 0.70-0.82). A cut-off of ≥8 (75% of the patients) yielded a sensitivity of 94% (95% CI 88-98) translating into a negative predictive value of 94% (95% CI 88-97). Risk strata based on the scores had better predictive power than the International Staging System alone (p=0.009, Figure 1).Conclusions: Patients with standard-risk multiple myeloma are a heterogeneous population. One fourth of the patients are experiencing less than three years of overall survival after diagnosis. Five readily available factors were helpful in identifying patients at risk for early death. These findings emphasize the importance of further risk stratification in this patient population and warrant external validation. [Display omitted] DisclosuresDispenzieri:Celgene, Millenium, Pfizer, Janssen: Research Funding. Lacy:Celgene: Research Funding. Gertz:Millennium: Consultancy, Honoraria; Celgene, Novartis, Smith-Kline, Prothena, Ionis, Amgen: Honoraria. Leung:Prothena: Consultancy. Kapoor:Takeda, Celgene and Amgen: Research Funding. Kumar:Celgene, Millennium/Takeda, Onyx, AbbVie, Janssen, Sanofi, Novartis, Amgen, Genentech, Merck, Oncopeptides, Roche, Skyline Diagnostics: Research Funding; Celgene, Millennium, BMS, Onyx, Janssen, Noxxon, AbbVie, Amgen, Merck, Oncopeptides, Skyline Diagnostics, Takeda: Consultancy; Skyline: Honoraria.

Presence of Immunoglobulin Heavy Chain Gene (IGH) Translocations in Chronic Lymphocytic Leukemia Is Related to Poor Prognosis.

Background: Genetic analysis has an important role in the diagnosis, classification, and management of patients with CLL. Although translocations involving the IGH locus are well characterized in B-cell malignancies such as follicular cell lymphoma, their frequency in CLL are less well defined and little is known about their prognostic significance. We studied a series of CLL patients using a FISH probe set which included an IGH probe and reviewed clinical data and disease course of CLL patients with IGH translocations.Methods: FISH was performed on blood using a DNA probe set designed to detect common chromosome anomalies associated with CLL and translocations involving IGH. Patients with an IGH abnormality were further studied using FISH probes sets for IGH and cyclin D1, BCL-2, BCL-3, BCL-6, BCL-11a, c-MYC, MALT-1, c-MAF, FGFR-3 or PAX-5. Between 5/15/03 and 5/15/07, samples from 4,976 patients with a presumed lymphoproliferative disorder were analyzed by FISH. Of these, 316 patients (6.3%) had translocations involving the IGH locus. Sixty-three (21%) of the 316 patients with IGH translocations had been seen at Mayo Clinic Rochester and had clinical and laboratory data for detailed review and analysis of associations to the FISH results.Results: We identified 39 patients with CLL and IGH translocations. Identified partner genes were: BCL-2 (n=22), BCL-3 (n=7), CMYC (n=2), MALT-1 (n=1). The partner gene was not identified despite using above mentioned panel of partner gene probes in 7 patients. Median age at time of diagnosis of patients with IGH translocations was 62 (45-82), 29 patients were males. The median time to initial treatment (TTT) of all 39 patients with IGH translocations was 3.1 years. The median TTT for patients with IGH/BCL-2 was 3.6 years; 70% of patients required treatment by 5 years. The median TTT for IGH/BCL-3 patients was significantly shorter, 1.5 years, p=0.017, with all patients requiring therapy 3 years from diagnosis (see Figure 1).Conclusion: The presence of IGH translocations in CLL appears to be associated with rapid disease progression and the need for an early initiation of therapy. The IGH partner gene seems to be important; IGH/BCL-3 fusion is associated with a worse prognosis than IGH/BCL-2. Further studies on the biological significance of IGH translocations in CLL are warranted and continue at our institution. [Display omitted]

Management of externally manufactured cell therapy products: the Mayo Clinic approach

BackgroundThe rise of investigative and commercially available cell therapy products adds a new dynamic to academic medical centers; that is, the management of patient-specific cell products. The scope of cell therapy has rapidly expanded beyond in-house collection and infusion of cell products such as bone marrow and peripheral blood transplant. The complexities and volumes of cell therapies are likely to continue to become more demanding. As patient-specific “living drugs,” cell therapy products typically require material collection, product provenance, transportation and maintenance of critical quality attributes, including temperature and expiration dates. These requirements are complicated by variations in product-specific attributes, reporting requirements and interactions with industry not required of typical pharmaceuticals. MethodsTo manage these requirements, the authors set out to establish a framework within the Immune, Progenitor and Cell Therapeutics Lab, the Current Good Manufacturing Practice facility responsible for cell manufacturing at Mayo Clinic Rochester housed within the Division of Transfusion Medicine. The authors created a work unit (biopharmaceutical unit) dedicated to addressing the specialized procedures required to properly handle these living drugs from collection to delivery and housing the necessary processes to more easily integrate externally manufactured cell therapies into clinical practice. ResultsThe result is a clear set of expectations defined for each step of the process, with logical documentation of critical steps that are concise and easy to follow. ConclusionsThe authors believe this system is scalable for addressing the promised growth of cell therapy products well into the future. Here the authors describe this system and provide a framework that could be used by other centers to manage these important new therapies.

Single institution toxicity of definitive chemoradiation and maintenance durvalumab in locally advanced non-small cell lung cancer.

e20554 Background: The paradigm for locally advanced non-small cell lung cancer has been markedly altered to include maintenance durvalumab (D) post completion of definitive chemoradiation (CRT) following the publication of the Pacific trial in 2018. The toxicity of this treatment has not been well evaluated in the real-world setting. Methods: We identified 42 patients (pts) with Stage IIB-IIIC NSCLC treated at Mayo Clinic Rochester between 6/1/2018 and 10/1/2020 who received definitive CRT followed by maintenance D. Data were abstracted by retrospective chart review under an IRB approved protocol. Results: Median age was 66 yrs (range 47-90) and 62% were women. Primary lung cancer histology included 19 adenocarcinoma, 20 squamous cell, and 3 adenosquamous. The distribution of stages was: IIB (4/42), IIIA (15/42), IIIB (19/42), IIIC (4/42). Approximately half of patients had PDL1 expression > 25% (20/42). With a median follow up of 12.2 months (calculated from first cycle of D; range 4.2-30.5 months), 14 had completed one year of maintenance D, 16 were receiving ongoing D, and 10 stopped D early with 6/12 discontinuing due to disease progression (4/6 local progression, 2/6 distant progression). Other reasons for discontinuation (5/10) included grade 3 colitis, grade 2 hepatitis, aspergillus lung infection, and flare of autoimmune disorders. One quarter of patients experienced grade 2 radiation pneumonitis (RP; 10/42) with median time to development of RP 78 days from end of CRT and 45 days from start of D. RP was determined by multidisciplinary review of imaging and treatment fields. 17/42 patients developed immune related adverse events (see Table for details). There was minimal overlap between the patients who experienced pneumonitis and immune related toxicity; 2/17 had both pneumonitis and immune related toxicity (hepatitis, thyroiditis). Conclusions: In our early experience with the Pacific regimen, 29% of patients did not complete D due to either toxicity or progression during D administration. Pneumonitis was common (10/42 patients) although there were no grade 3 events. Nearly half of the patients developed an immune-related adverse event. Further analysis is needed to evaluate the real-world toxicity of this treatment as well as oncologic outcomes.[Table: see text]

Symptom identification and management in epithelial ovarian cancer.

5554 Background: A better understanding regarding the burden of treatment side effects in patients with gynecological malignancies could help guide symptom interventions and oncologic therapy decision-making. We aim to inform understanding of symptom burden in epithelial ovarian cancer (EOC) by analyzing patient-reported symptom data from patients treated for this condition over a 16-month period. Methods: Patients receiving medical oncology care at Mayo Clinic Rochester and at Midwest Mayo Clinic Health System community sites have received symptom-focused surveys prior to each medical oncology visit since March 28, 2019 through the Enhanced Electronic Health Record Facilitated Cancer Symptom Control Study (E2C2). These surveys, administered either through the electronic medical record portal or on a clinic tablet prior to each oncology office visit, no more frequently than every 2 weeks, include six linear analogue scales measuring sleep disturbance, pain, anxiety, emotional distress, and fatigue (SPADE), as well as physical dysfunction on a scale of 0 (none) to 10 (as bad as you can imagine). Scores of 0-3 were considered mild symptoms, 4-6 moderate symptoms, and 7-10 severe symptoms. We collected survey results from March 28, 2019 to July 20, 2020 for patients with EOC and reviewed the number of surveys per patient in addition to the average symptom scores. Results: From March 2019 to July 2020, for patients with EOC, there were 2974 encounter-based surveys from 762 patients. The number of surveys completed by each patient ranged from 1-20. The following number of patients returned the correlating number of surveys: 1 survey:240 patients; 2 surveys:145; 3 surveys:79; 4 surveys:56; 5 surveys:58; 6 surveys:45; 7 surveys:38; 8 surveys:27; 9 surveys:22; ≥10 surveys:52. The average score from all surveys for each symptom was: 2.41 for sleep disturbance, 2.03 for pain, 2.32 for anxiety, 1.97 for emotional distress, 3.26 for fatigue, and 2.50 for physical dysfunction. Please see the table for the proportion of surveys that reported symptoms as mild, moderate, or severe. Conclusions: Fatigue and physical dysfunction were reported most frequently in patients with EOC, while emotional distress and pain were reported least frequently. 20% of surveys reported moderate to severe emotional distress, while 40% reported moderate to severe fatigue. A targeted approach to symptom management is needed for patients undergoing EOC evaluation and treatment. Our next steps in this analysis include an assessment of potential predictors of greater symptom burden (e.g., specific treatments, age, and other clinical and sociodemographic characteristics). Clinical trial information: NCT03892967. [Table: see text]

Outpatient practice pattern and remote patient monitoring for axicabtagene ciloleucel CAR-T therapy in patients with aggressive lymphoma.

7554 Background: Chimeric antigen receptor T-cell therapy (CAR-T) are commonly administered inpatient due to concern for early onset cytokine release syndrome (CRS), especially with axicabtagene ciloleucel (axi-cel). We report Mayo Clinic Rochester experience for hospital-based outpatient (HBO) management of patients (pts) receiving axi-cel and identify opportunities for improvement. HBO is closely integrated with inpatient practice and includes the same specialty trained clinical team. It is the first point of contact 24/7 for pts and triage evaluations. Lymphodepletion chemotherapy and CAR-T infusion is given on HBO followed by daily monitoring till day 8 and thereafter, as clinically needed until admission criteria is met. Methods: We retrospectively analyzed database of pts who received axi-cel between 1/2018 and 1/2021. After 06/2020, remote patient monitoring (RPM) tools were implemented to collect patient-reported neurologic symptoms and vital signs via bluetooth-enabled devices 4 times daily through month 1. Adverse data trends are addressed by the HBO team. Results: Among 72 recipients, 89% received their cells outpatient; 8% remained outpatient for the entire month. CRS and neurotoxicity incidence were comparable to those reported from CIBMTR. Median time to first admission was 2 days (Table). Use of bridging therapy, increased CRP and LDH were associated with early admission (≤3 days). Median time to tocilizumab, steroid, oxygen support, vasopressor was 4 days after admission. Half of HBO visits required intervention such as blood transfusions, IV medications through the first month. Nine pts had enrolled in RPM to date; with 8 having evaluable data. With 4 scheduled entries/day, a median of 1 entry/day was skipped and 2 entries/day were answered incompletely. An average of 57 additional unscheduled entries were generated per pt. Among a median of 373 (range 91-522) readings per pt over the first month, 4% (2%-20%) of the readings generated alerts. An average of 4 alerts were seen within 48 hours prior to admission. Data including additional subjects will be presented at ASCO meeting. Conclusions: We report a feasible outpatient care model for management of axi-cel recipients with safe outcomes. Clinical characteristics associated with more aggressive disease are associated with likelihood of early admission. Early RPM experience suggest use of digital tools could improve monitoring compliance and may predict evolution to symptoms requiring escalation of care.[Table: see text]

Oral Midodrine Administration During the First 24 Hours of Sepsis to Reduce the Need of Vasoactive Agents: Placebo-Controlled Feasibility Clinical Trial.

Objectives:Our preliminary data and observational studies suggested an increasing “off label” use of oral midodrine as a vasopressor sparing agent in various groups of critically ill patients, including those with sepsis. We designed this clinical trial to evaluate the feasibility of use of midodrine hydrochloride in early sepsis to reduce the duration for IV vasopressors and decrease ICU and hospital length of stay.Design:Pilot, two-center, placebo-controlled, double blinded randomized clinical trial.Setting:Medical ICUs at Mayo Clinic Rochester and Cleveland Clinic Abu Dhabi were the study sites.Patients and Methods:Adult patients (≥ 18 yr old) were included within 24 hours of meeting the Sepsis-3 definition if the mean arterial pressure remained less than 70 mm Hg despite receiving timely antibiotics and initial IV fluid bolus of 30 cc/kg.Intervention:Three doses of 10 mg midodrine versus placebo were administered.Measurements and Main Results:Total 32 patients were randomized into midodrine (n = 17) and placebo groups (n = 15). There were no major differences in baseline variables between the groups except for higher baseline creatinine in the midodrine group (2.0 ± 0.9 mg/dL) versus placebo group (1.4 ± 0.6 mg /dL), p = 0.03. The median duration of IV vasopressor requirement was 14.5 ± 8.1 hours in midodrine group versus 18.8 ± 7.1 hours in the placebo group, p value equals to 0.19. Patients in the midodrine group needed 729 ± 963 norepinephrine equivalent compared with 983 ± 1,569 norepinephrine equivalent in the placebo group, p value equals to 0.59. ICU length of stay was 2.29 days (interquartile range, 1.65–3.9 d) in the midodrine group, compared with 2.45 days (interquartile range, 1.6–3.2 d) in the placebo group, p value equals to 0.36. No serious adverse events were observed in either group.Conclusions:Phase II clinical trial powered for clinical outcomes (duration of vasopressor use, need for central venous catheter, and ICU and hospital length of stay) is justified.

Utility of Transbronchial Biopsy in the Immunocompromised Host With New Pulmonary Radiographic Abnormalities

ObjectiveTo assess how often transbronchial biopsy (TBBx) added unique positive findings apart from other synchronous bronchoscopic sampling techniques including the bronchoalveolar lavage–immunocompromised host (BAL-ICH) panel that justified changes in management in an array of immunocompromised patients with new pulmonary radiographic abnormalities. MethodsWe retrospectively reviewed all bronchoscopies performed at Mayo Clinic Rochester between January 2012 and December 2017; on the basis of the physician’s selection of a BAL-ICH panel, we identified 192 immunocompromised patients who underwent bronchoscopy with both a BAL-ICH panel and TBBx. The results of the BAL-ICH panel and TBBx were compared and subsequent management decisions analyzed from clinical notes. We identified changes in immunosuppressive agents, antibiotics, chemotherapy, goals of care, and decisions on further evaluation and procedures. We assessed whether the TBBx findings added information not identified on the BAL-ICH panel and other bronchoscopic sampling methods performed during the same procedure that justified subsequent management changes. ResultsOf 192 bronchoscopic procedures performed on immunocompromised patients with acute and subacute pulmonary radiographic abnormalities, management changes justified by the unique positive results of the TBBx occurred 28% (51/192) of the time. Those immunocompromised by solid malignant neoplasms and receiving active immunosuppressive therapy had management changes justified 62.1% (18/29) of the time by the TBBx results. No additional fungal organisms were identified on TBBx that were accounted for on the BAL-ICH panel. ConclusionTransbronchial biopsy may add information to other bronchoscopic findings in immunocompromised patients, especially those with solid malignant neoplasms receiving active immunosuppressive treatment. These potential benefits must be weighed against the risks inherent to the procedure.

Cancer Patients Have a Higher Risk of Thrombotic and Ischemic Events After Percutaneous Coronary Intervention.

This study sought to define the risk of stent thrombosis (ST) and myocardial infarction (MI) in cancer patients compared with noncancer patients after percutaneous coronary intervention (PCI). Cancer patients are considered to be at high thrombotic risk, but data on whether this is the case after PCI remain inconclusive. Cancer patients undergoing PCI at Mayo Clinic Rochester from January 1, 2003, to December 31, 2013, were identified by cross-linking institutional cancer and PCI databases and by propensity score matching to noncancer patients. The combined primary endpoint was all-cause mortality, MI, and revascularization rate at 5-year follow-up. Secondary endpoints were the individual primary endpoint components, cause of mortality, ST, and Bleeding Academic Research Consortium 2+ bleeding. The primary endpoint occurred in 48.6% of 416 cancer and in 33.0% of 768 noncancer patients (p<0.001). In competing risk analyses, cancer patients had a higher rate of noncardiac death (24.0% vs. 10.5%; p<0.001) and a lower rate of cardiac death (5.0% vs. 11.7%; p<0.001). Cancer patients had a higher rate of MI (16.1% vs. 8.0%; p<0.001), ST (6.0% vs. 2.3%; p<0.001), repeat revascularization (21.2% vs. 10.0%; p<0.001), and bleeding (6.7% vs. 3.9%; p=0.03). The most critical period for ST in cancer patients was in the first year after PCI. The dual antiplatelet therapy score was predictive of thrombotic and ischemic events in both groups. Cancer patients have a higher risk of thrombotic and ischemic events after PCI, identifiable by a high dual antiplatelet therapy score. These findings have important implications for antiplatelet therapy decisions.

Alpha-Synuclein Oligomers and Neurofilament Light Chain Predict Phenoconversion of Pure Autonomic Failure.

To explore the role of alpha-synuclein (αSyn) oligomers and neurofilament light chain (NfL) in cerebrospinal fluid (CSF) of patients with pure autonomic failure (PAF) as markers of future phenoconversion to multiple system atrophy (MSA). Well-characterized patients with PAF (n=32) were enrolled between June 2016 and February 2019 at Mayo Clinic Rochester and followed prospectively with annual visits to determine future phenoconversion to MSA, Parkinson's disease (PD), or dementia with Lewy bodies (DLB). ELISA was utilized to measure NfL and protein misfolding cyclic amplification (PMCA) to detect αSyn oligomers in CSF collected at baseline. Patients were followed for a median of 3.9 years. Five patients converted to MSA, 2 to PD, and 2 to DLB. NfL at baseline was elevated only in patients who later developed MSA, perfectly separating those from future PD and DLB converters as well as non-converters. ASyn-PMCA was positive in all but two cases (94%). The PMCA reaction was markedly different in five samples with maximum fluorescence and reaction kinetics previously described in MSA patients; all of these patients later developed MSA. αSyn-PMCA is almost invariably positive in the CSF of patients with PAF establishing this condition as α-synucleinopathy. Both NfL and the magnitude and reaction kinetics of αSyn PMCA faithfully predict which PAF patients will eventually phenoconvert to MSA. This finding has important implications not only for prognostication, but also for future trials of disease modifying therapies, allowing for differentiation of MSA from Lewy body synucleinopathies before motor symptoms develop. ANN NEUROL 2021;89:1212-1220.

Cost and clinical outcomes of postoperative intensive care unit versus general floor management in head and neck free flap reconstructive surgery patients

PurposeTo compare clinical, surgical, and cost outcomes in patients undergoing head and neck free-flap reconstructive surgery in the setting of postoperative intensive care unit (ICU) against general floor management. MethodsRetrospective analysis of head and neck free-flap reconstructive surgery patients at a single tertiary academic medical center. Clinical data was obtained from medical records. Cost data was obtained via the Mayo Clinic Rochester Cost Data Warehouse, which assigns Medicare reimbursement rates to all professional billed services. ResultsA total of 502 patients were included, with 82 managed postoperatively in the ICU and 420 on the general floor. Major postoperative outcomes did not differ significantly between groups (Odds Ratio[OR] 1.54; p = 0.41). After covariate adjustments, patients managed in the ICU had a 3.29 day increased average length of hospital stay (Standard Error 0.71; p < 0.0001) and increased need for take-back surgery (OR 2.35; p = 0.02) when compared to the general floor. No significant differences were noted between groups in terms of early free-flap complications (OR 1.38;p = 0.35) or late free-flap complications (Hazard Ratio 0.81; p = 0.61). Short-term cost was $8772 higher in the ICU (range = $5640–$11,903; p < 0.01). Long-term cost did not differ significantly. ConclusionPostoperative management of head and neck oncologic free-flap patients in the ICU does not significantly improve major postoperative outcomes or free-flap complications when compared to general floor care, but does increase short-term costs. General floor management may be appropriate when cardiopulmonary compromise is not present.

The Clinical Impact of Proteomics in Amyloid Typing

The Clinical Impact of Proteomics in Amyloid Typing

The "Quiet TED"-A Special Subgroup of Thyroid Eye Disease.

Thyroid eye disease (TED) or Graves' orbitopathy starts with an active inflammatory stage (active disease) followed by resolution of inflammation and progression to a fibrotic, inactive stage. In our practice, we have encountered cases that have not had active disease despite presence of fibrotic sequelae and disease progression. We aim to delineate the clinical characteristic of this unique group of patients. We conducted a single-center (Mayo Clinic Rochester) retrospective chart review of TED patients who throughout the course of their disease had only evidence for inactive TED, defined as clinical activity score <3. Median age in the cohort (n = 19) was 54 years (IQR 47-61). 58% had a prior diagnosis of Graves' disease (GD) before referral. 80% (n = 15) were euthyroid at the time of TED onset (median thyroid-stimulating hormone 1.7 mIU/L). The most common finding was diplopia (100%, n = 19) followed by proptosis (63%, n = 12). Interestingly the disease was asymmetric in 42% of cases. Overall median clinical activity score on presentation was 1 (IQR 0-1). Severity wise, 85% (n = 16) of patients were classified as moderate-to-severe during follow up. Orbital decompression was performed in only 1 case, while extraocular muscle surgery was performed in 13 cases. Quiet TED is a subgroup of TED patients that defies the classic disease paradigm. It presents primarily with diplopia and proptosis. Further evaluation of this group might identify useful insights in TED pathophysiology and help optimize therapeutic choices.

54443 Pharmacogenomic Profiling of East and West African Populations

ABSTRACT IMPACT: Genomic variation likely plays a role in differences in rates of adverse reactions and efficacy for African populations, and this research will add to the understudied field of pharmacogenomics in African populations. OBJECTIVES/GOALS: We aim to characterize the frequency of variants in clinically relevant genes in East and West African populations to assess the prevalence of potential drug-gene interactions. METHODS/STUDY POPULATION: Our pilot study will consist of 100 Somali patients enrolled at Mayo Clinic Rochester and 100 Ghanaian patients recruited at Teaching Hospitals in Ghana. Germline DNA will be extracted from pre-existing blood samples. Sequencing will be performed using Admera Health’s PGxOne Plus test, interrogating a panel of 62 genes. Variants will be reported along with the predicted response for a list of drugs. Differences between frequencies of variants in East and West African populations will be analyzed. We will look for correlations with reported adverse reaction rates. We will then compare our findings with allele frequency data from publicly available data bases. Additionally, we will analyze the flanking regions of the panel for novel variants, using machine learning to predict gene-drug interactions. RESULTS/ANTICIPATED RESULTS: African populations are known to have more genetic diversity than any other population. Additionally, only African-Americans, African-Caribbeans from Barbados, Esan and Yoruba Nigerians, Gambians, Kenyans, and Sierra Leoneans are accounted for within the publicly available data bases most often used for variant studies. Thus, it is anticipated that we will find differences in the variant allele frequencies of our populations compared to European allele frequencies, and differences in frequencies between the East and West African populations. In the 200 base pair flanking regions that are sequenced in the assay along with the known variant regions, we may find novel previously unreported variants. DISCUSSION/SIGNIFICANCE OF FINDINGS: The lack of knowledge of pharmacogenomic variation in African populations contributes to ethnic disparities in patient outcomes. This study addresses this gap by adding to our comprehension of variants in clinically relevant genes, giving insight into underlying mechanisms of ethnicity-based drug responses.

Abstract MP7: Multicenter Study of Intracranial Hemorrhage and Death Risk and Predictors in the Untreated Course of Brain Arteriovenous Malformation Patients

Background: Accurate and reliable models of intracranial hemorrhage (ICH) risk in the untreated course of brain arteriovenous malformation (BAVM) patients are needed to help weigh the risk-benefit of treatment. We present preliminary estimates of rates and risk factors for ICH or death in the Multicenter AVM Research Study (MARS), which is the largest individual patient data meta-analysis (IPDMA) of cohort studies of unruptured BAVM. Methods: Longitudinal data from 9 cohorts comprising 2,839 unruptured BAVM at time of diagnosis were included: UCSF (n=557), Macquarie (n=462), Kaiser Permanente Northern California (n=354), Columbia (n=335), Barrow Neurological Institute (n=324), Tiantan Hospital (n=303), Mayo Clinic-Rochester (n=244), Scottish Intracranial Vascular Malformation Study (n=194), and Toronto Western Hospital (n=66). Clinical and angiographic data were collected using standardized definitions across cohorts. Cox proportional hazards analysis of time-to-event (ICH or death) in the untreated course after diagnosis was performed, censoring at first treatment or last visit. Baseline hazard rates were stratified by cohort to account for different rates and follow-up times. Results: The combined cohort was 49% female, 72% white race, and 17% Hispanic ethnicity; mean age at diagnosis was 37±17 years and mean follow-up was 3.4±7.0 years. The most common presenting symptom was seizures (43%). Mean AVM size was 3.5±1.9 cm and 46% were Spetzler-Martin grade I-II. Overall, 123 ICH and 131 deaths occurred over 9,608 person-years (PY) for an event rate of 2.64 per 100 PY [95% CI: 2.34-2.99]. Cox regression analyses adjusting for age at diagnosis (HR=1.67 [1.54, 1.82], P&lt;0.001) identified cerebellar location (HR=1.73 [1.03-2.93], P=0.040) and exclusively deep venous drainage (HR=1.83 [1.09-3.09], P=0.022) as predictors. Conclusion: Our current model identified increasing age, exclusively deep venous drainage, and cerebellar location as risk factors for ICH or death in the untreated course of unruptured bAVM patients. Review of imaging data, multiple imputation of missing angioarchitectural data, and additional data from pending cohorts will provide greater power to search for additional risk factors in this ongoing IPDMA.

Abstract PS8-02: Influence of a breast cancer polygenic risk score on adherence to preventive endocrine therapy in high risk women at 1 and 2 year follow-up: The genetic risk estimate (GENRE) trial

Abstract Background: Preventive endocrine therapy (ET) has been proven extensively to decrease breast cancer (BC) risk by 50-65%. Despite this significant reduction, a small proportion of high risk women take ET, due to attitudes toward medications, inaccurate risk perception and drug side-effects. The addition of a polygenic risk score (PRS), comprised of 77 BC genetic susceptibility loci (Single Nucleotide Polymorphisms (SNP)), to the standard risk calculator estimates, can be used to improve BC risk estimation. We previously reported on the influence of the PRS-adjusted BC risk estimates on the intent to use ET (Abstract, SABCS, 2019). Here we report on the influence of PRS-adjusted BC risk estimates on ET adherence at 1 and 2 year follow –up. We also report on ET side effects over this same time period. Methods: Women older than age 35 were eligible if they were deemed at high risk for BC by either a 5 year Gail Model risk of ≥3% or 10 year Tyrer-Cuzick risk (IBIS) of ≥5%. We excluded women with a personal history of BC or hereditary BC syndromes. At baseline, participants were counseled on their BC risk using standard risk calculators: Gail and IBIS risk scores (5 yr, 10 yr, &amp; lifetime) and ET options were discussed, including benefits and risks. Blood samples were obtained and genotyped for 77 SNPs, and an updated BC -PRS risk report was shared with study participants that reflected the IBIS and Gail risk predictions for 5 yr, 10 yr, &amp; lifetime BC risk with and without the PRS. A baseline self-reported questionnaire assessed understanding of BC risk and decision to take ET. Follow-up questionnaires at 1 and 2 years assessed self-reported ET adherence and ET side effects (vasomotor symptoms, vaginal symptoms, sexual dysfunction, weight gain, GI symptoms, headaches, breast sensitivity, mood changes, and joint pain). Adherence to ET at 1 and 2 year follow-up was stratified by three categories of lifetime PRS-BC risk: 0-20%; 20-40%; 40-100%. Results: 151 women at Mayo Clinic Rochester and CancerCare Manitoba were enrolled in the study from 2016 to 2017. Of the 149 participants with evaluable data at 1 and 2 year follow-up, 57 (38%) started on ET therapy, all within 1 year of the baseline visit; 43 (29%) were taking ET at 1 year and 33 (22%) were taking ET at 2 year follow-up, representing a discontinuation rate of 26% at 1 year and 42% at 2 year follow-up. Adherence to ET use at 1 year and 2 year follow-ups correlated significantly with the category of PRS-BC risk estimation: at 1 year follow up, 17% of those in the lowest PRS-IBIS risk category, 23% in the middle risk category and 50% of those in the highest risk category were taking ET (p=0.001). At 2 year follow up, 12% of those in the lowest PRS-IBIS risk category, 18% in the middle risk category and 38% of those in the highest risk category were taking ET (p=0.008). At 1 year follow up, participants taking ET reported significantly more bothersome symptoms of vaginal itching (p=0.010), weight gain (p=0.015) and joint pain (p=0.044), compared with those not on ET. There was a trend towards increased irritability and mood swings on those taking ET (p=0.059). At year 2 there was no significant difference in side effects between those taking and not taking ET. Conclusion: Adherence to ET in a population of women at high risk for BC decreased overtime and strongly correlated with the level of risk, with 38% of those at highest risk of breast cancer taking ET at 2 year follow up. Side effects of vaginal itching, weight gain and body aches were more common on those taking ET versus not taking ET at the 1 year follow-up, but did not differ at 2 year follow-up, possibly due to the fact that those with the most bothersome symptoms have discontinued ET by the 2 year follow up. Citation Format: Daniela Stan, Julian Kim, Daniel Schaid, Erin Carlson, Andrew Cooke, Christina A. Kim, Benjamin Goldenberg, Jason Sinnwell, Debjani Grenier, Amy Degnim, Fergus Couch, Celine Vachon, Sandhya Pruthi. Influence of a breast cancer polygenic risk score on adherence to preventive endocrine therapy in high risk women at 1 and 2 year follow-up: The genetic risk estimate (GENRE) trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS8-02.

Discordance Between Measured vs Calculated Oxygen Consumption in Adults With Congenital Heart Disease: Limitations and Clinical Implications.

Oxygen consumption (VO2) is frequently estimated using derived formulas for ease of use. We performed a prospective study to assess the correlation and limits of agreement between measured and assumed VO2 (mL/min) in adults with congenital heart disease (CHD). Consecutive adults with CHD who have undergone cardiac catheterization at Mayo Clinic Rochester from January 2018 to December 2019 were retrospectively enrolled in the study. Expired gas analysis was performed to measure VO2. We estimated VO2 using LaFarge (VO2L), Dehmer (VO2D), and Bergstra (VO2B) formulas. Bland-Altman and linear-regression analyses were used to assess the correlation between measured and calculated VO2. We enrolled 84 patients with a mean age of 43 ± 12 years; 66% were men. Linear correlation analysis showed a moderate correlation of VO2L and VO2B with VO2M (r = 0.58; P<.001 and r = 0.44; P<.01, respectively) and good correlation of VO2D with VO2M (r = 0.79; P<.001). The large spread of limits of agreement assessed using Bland-Altman analysis demonstrates poor agreement of VO2L and VO2B with VO2M (bias, -58; 95% confidence interval [CI], -258 to 48) and bias, 38; 95% CI, -91 to 167, respectively). The limits of agreement for VO2D have a large spread, demonstrating a low degree of agreement with VO2M (bias, 13; 95% CI, -64 to 89). VO2L predominantly misclassified patients as low cardiac index and VO2D and VO2B misclassified patients as normal/ high cardiac index. In adults with CHD, assumed VO2 will lead to a significant error while assessing invasive intracardiac hemodynamics.

Family History Extraction From Synthetic Clinical Narratives Using Natural Language Processing: Overview and Evaluation of a Challenge Data Set and Solutions for the 2019 National NLP Clinical Challenges (n2c2)/Open Health Natural Language Processing (OHNLP) Competition.

BackgroundAs a risk factor for many diseases, family history (FH) captures both shared genetic variations and living environments among family members. Though there are several systems focusing on FH extraction using natural language processing (NLP) techniques, the evaluation protocol of such systems has not been standardized.ObjectiveThe n2c2/OHNLP (National NLP Clinical Challenges/Open Health Natural Language Processing) 2019 FH extraction task aims to encourage the community efforts on a standard evaluation and system development on FH extraction from synthetic clinical narratives.MethodsWe organized the first BioCreative/OHNLP FH extraction shared task in 2018. We continued the shared task in 2019 in collaboration with the n2c2 and OHNLP consortium, and organized the 2019 n2c2/OHNLP FH extraction track. The shared task comprises 2 subtasks. Subtask 1 focuses on identifying family member entities and clinical observations (diseases), and subtask 2 expects the association of the living status, side of the family, and clinical observations with family members to be extracted. Subtask 2 is an end-to-end task which is based on the result of subtask 1. We manually curated the first deidentified clinical narrative from FH sections of clinical notes at Mayo Clinic Rochester, the content of which is highly relevant to patients’ FH.ResultsA total of 17 teams from all over the world participated in the n2c2/OHNLP FH extraction shared task, where 38 runs were submitted for subtask 1 and 21 runs were submitted for subtask 2. For subtask 1, the top 3 runs were generated by Harbin Institute of Technology, ezDI, Inc., and The Medical University of South Carolina with F1 scores of 0.8745, 0.8225, and 0.8130, respectively. For subtask 2, the top 3 runs were from Harbin Institute of Technology, ezDI, Inc., and University of Florida with F1 scores of 0.681, 0.6586, and 0.6544, respectively. The workshop was held in conjunction with the AMIA 2019 Fall Symposium.ConclusionsA wide variety of methods were used by different teams in both tasks, such as Bidirectional Encoder Representations from Transformers, convolutional neural network, bidirectional long short-term memory, conditional random field, support vector machine, and rule-based strategies. System performances show that relation extraction from FH is a more challenging task when compared to entity identification task.

Overwhelmed Hospitals May Soon Lead to Overwhelmed Rehabilitation Facilities Unless Post-Acute Care Infrastructure Is Strengthened.

Overwhelmed Hospitals May Soon Lead to Overwhelmed Rehabilitation Facilities Unless Post-Acute Care Infrastructure Is Strengthened.

Faculty Disclosure of Personal Mental Health History and Resident Physician Perceptions of Stigma Surrounding Mental Illness.

Distress, depression, and burnout are common during medical training. Stigma surrounding seeking help for mental illness during medical training may involve fear of negative peer perceptions, academic jeopardy, and adverse future career consequences. Faculty disclosure of personal mental health illness may reduce stigma surrounding mental health disorders and reassure and encourage trainees to seek help when needed. The authors aimed to assess the impact of faculty disclosure of mental health issues on stigma toward help-seeking during training, self-reflection about mental health, and resident physician awareness of mental health resources. Three self-selected faculty members shared their personal experiences with depression and mental health during a confidential noon conference intended for internal medicine residents at Mayo Clinic Rochester as part of their core curriculum in December 2016. Institutional and community mental health resources were provided. After the conference, attendees completed an anonymous survey assessing self-reported knowledge, attitudes, and behaviors surrounding mental health during medical training. One hundred percent of residents (39/39) agreed that they enjoyed the conference. Thirty-five of 39 (89.7%) respondents agreed that their knowledge of available mental health resources increased and 33/39 (84.6%) agreed they were more likely to pursue mental health resources after attending the conference. Thirty-eight of 39 (97.4%) residents agreed that faculty sharing their personal struggles destigmatizes mental health issues during training, and the same percentage reported engaging in postconference self-reflection regarding their own mental health and well-being. Resident conference sessions during which faculty self-disclose personal mental health experiences may help decrease the stigma of mental health issues during medical training and increase the likelihood residents will seek assistance when needed. The authors encourage further study of longer-term outcomes and actual help-seeking behaviors across learner levels and training environments.