Citations

Background: Concerns for side-effects makes the identification of treatment targets of hypertension in the very elderly challenging. We sought to utilize natural language processing (NLP) to evaluate the prevalence of prespecified side-effects in a cohort of very elderly (≥80 years) patients. Methods and Results: We conducted a two-year, cross-sectional study involving 5169 very elderly patients with and without hypertension seen by primary or specialist providers. Hypertension patients had to have a prior hypertension ICD-9 code in the electronic medical records problem list and ≥2 office visits in 2008 and 2009. We used NLP to analyze extracted free text reports from last clinic visits between 2008 and 2009. Of the 10 prespecified side-effects, hypotension, fatigue, and dizziness were the commonest three conditions and hypotension was significantly higher in the HTN patients. Of the 2835 patients with no prior hypertension history and 2334 hypertension patients identified, the prevalence of each prespecified item in both groups were: acute renal failure (0.3% v 0.6%, p=0.13); syncope (2.8% v 2.2%, p = 0.17), dizziness (3.1% v 4.0%, p=0.09), history of fall (1.0% v 0.9%, p=0.65), fatigue (5.4% v 4.5%, p=0.19), femoral neck fracture (0.18% v 0.04%, p=0.16), palpitations (1.2% v 1.5%, p=0.35), hypotension (4.1% v 6.6%, p<0.001), hyperkalemia (1.1% v 1.7%, p=0.04), hypokalemia (0.4% v 0.9%, p=0.01). At least one presumed side-effect was present in 17.5% of all 5169 patients. Among hypertension patients, there was no significant difference in the prevalence of the side-effects among patients with BP above (578) or below 140/90 (1756) except for acute renal failure (1.21% vs 0.40%, p = 0.03). Conclusion: Analysis of free-text outpatient notes using NLP showed that hypotension and potassium abnormalities were significantly more prevalent in very elderly patients with hypertension compared to similarly aged patients with no hypertension history.

Background: Heart failure (HF) with improved ejection fraction (HFiEF) is defined as a new subset in addition to the subsets of HF with reduced EF (≤40%; HFrEF) and HF with preserved EF (>40%). The characteristics and outcomes of patients with ischemic HFiEF after coronary revascularization are unknown. Methods and Results: We identified 1,816 patients with coronary artery diseases and reduced EF (≤40%) in a large hospital in China, who underwent either coronary artery bypass graft surgery (n=1,126) or percutaneous coronary intervention with drug eluting stent (n=687) from January 2005 to December 2014. All patients had EF reassessment during follow-up. The improvement of EF peaked at 3 months and persisted for more than one year after revascularization. Thus, 589 patients who had EF reassessment between 3 to 12 months after revascularization were included in the definitions of HFiEF and HFrEF patient cohort and subsequent survival analysis. 367 (62.3%) patients had EF >40% which constituted HFiEF cohort while 222 (37.7%) patients with EF≤40% constituted HFrEF cohort. Using stepwise logistic regression, we identified preoperative EF (odds ratio [OR], 1.06; 95% confidence interval [CI], 1.02-1.11; P =0.006), left ventricular end-systolic diameter (OR, 0.93; 95% CI, 0.91-0.95; P =0.000) and history of myocardial infarction (OR, 0.61; 95% CI, 0.42-0.88; P =0.008) were associated with being in HFiEF group. Using Cox proportional hazard models, HFiEF patients had lower risk of all-cause mortality (hazard ratios [HR], 0.39; 95% CI, 0.23-0.68; P =0.001), sudden cardiac death (HR, 0.32; 95% CI, 0.14-0.75; P =0.009) and death due to HF (HR, 0.13; 95% CI, 0.03-0.52; P =0.004) compared to HFrEF patients. Nonproportional outcome of composite end points (i.e., combination of all-cause mortality, HF hospitalization and repeat revascularization) between HFiEF and HFrEF groups was detected by using the Schoenfeld residuals. By using flexible parametric model, patients with HFiEF had similar risk of composite end points in the first 5 years (HR, 0.84; 95% CI, 0.53-1.31; P =0.433), but significantly lower risk during years 6 to 11(HR, 0.12; 95% CI, 0.03-0.56; P =0.007). In the HFiEF group, the risk of death were age (HR, 1.07; 95% CI, 1.02-1.12; P =0.008), current smoking (HR, 5.62; 95% CI, 1.93-18.18; P =0.002) and history of myocardial infarction (HR, 2.89; 95% CI, 1.05-7.93; P =0.039). By contrast, in the HFrEF group, the risk factors were moderate or severe mitral regurgitation (HR, 1.81; 95% CI, 1.06-3.11; P =0.031) and estimated glomerular filtration rate (HR, 0.97; 95% CI, 0.95-0.99; P=0.014). Conclusions: Patients with ischemic HFiEF have distinct clinical characteristics and favorable outcomes. Our data support HFiEF as a distinct HF category in ischemic HF patients after revascularization therapy.

Integrins are heterodimeric (α/β) membrane proteins that play fundamental roles in many biological processes, e.g. cell adhesion and spreading, which are important for platelet function and hemostasis. Integrin function is modulated by bi-directional transmembrane signaling: inside-out and outside-in, which is mediated through the interactions between integrin cytoplasmic tails and intracellular, regulatory proteins. Here, we show that VPS33B, a member of the Sec1/Munc18 (SM) family and component of the Class C core of the CORVET/HOPS sorting complexes, binds directly to the β subunit. Overexpression of VPS33B in CHO cells potentiated α IIb β 3 outside-in signaling but not inside-out signaling. Platelets, from megakaryocyte- and platelet-specific VPS33B conditional knockout mice we generated, had normal morphology yet their spreading on fibrinogen was impaired and they failed to support clot retraction. Platelet aggregation and ATP secretion in response to low-dose thrombin were reduced in the VPS33B knockout mice. α IIb β 3 -mediated endocytosis of fibrinogen was also defective. Tail bleeding times were prolonged in the VPS33B knockout mice. Furthermore, VPS33B acted upstream of the RhoA-ROCK-MLC and Rac1 dependent pathways that leads to clot retraction and cell spreading, respectively. Our work demonstrates that vesicular trafficking complexes are a novel class of modifiers of integrin function and in hemostasis. Our data also provide insights into the molecular mechanism and treatment of ARC syndrome.

Abstract Purpose To evaluate the accuracy of the RayStation Monte Carlo dose engine (RayStation MC) in modeling small‐field block apertures in proton pencil beam scanning. Furthermore, we evaluate the suitability of MCsquare as a second check for RayStation MC. Methods We have enhanced MCsquare to model block apertures. To test the accuracy of both RayStation MC and the newly enhanced MCsquare, we compare the dose predictions of each to in‐water dose measurements obtained using diode detectors and radiochromic film. Nine brass apertures with openings of 1, 2, 3, 4, and 5 cm and either 2 cm or 4 cm thickness were used in the irradiation of a water phantom. Two measurement setups were used, one with a range shifter and 119.7 MeV proton beam energy and the other with no range shifter and 147 MeV proton beam energy. To further test the validity of RayStation MC and MCsquare in modeling block apertures and to evaluate MCsquare as a second check tool, 10 small‐field (average target volume 8.3 cm 3 ) patient treatment plans were calculated by each dose engine followed by a statistical comparison. Results Comparing to the absolute dose measurements in water, RayStation MC differed by 1.2% ± 1.0% while MCsquare differed by −1.8% ± 3.7% in the plateau region of a pristine Bragg peak. Compared to the in‐water film measurements, RayStation MC and MCsquare both performed well with an average 2D‐3D gamma passing rate of 99.4% and 99.7% (3%/3 mm), respectively. A t ‐test comparing the agreement with the film measurements between RayStation MC and MCsquare suggested that the relative spatial dose distributions calculated by MCsquare and RayStation MC were statistically indistinguishable. Directly comparing the dose calculations between MCsquare and RayStation MC over 10 patients resulted in an average 3D‐3D gamma passing rates of 98.5% (3%/3 mm) and 94.1% (2%/2 mm), respectively. Conclusion The validity of RayStation MC algorithm for use with patient‐specific apertures has been expanded to include small apertures. MCsquare has been enhanced to model apertures and was found to be an adequate second check of RayStation MC in this scenario.

Asthma is a chronic inflammatory lung disease with intermittent flares predominately mediated through memory T cells. Yet, the identity of long-term memory cells that mediate allergic recall responses is not well defined. In this report, using a mouse model of chronic allergen exposure followed by an allergen-free rest period, we characterized a subpopulation of CD4 + T cells that secreted IL-9 as an obligate effector cytokine. IL-9–secreting cells had a resident memory T cell phenotype, and blocking IL-9 during a recall challenge or deleting IL-9 from T cells significantly diminished airway inflammation and airway hyperreactivity. T cells secreted IL-9 in an allergen recall–specific manner, and secretion was amplified by IL-33. Using scRNA-seq and scATAC-seq, we defined the cellular identity of a distinct population of T cells with a proallergic cytokine pattern. Thus, in a recall model of allergic airway inflammation, IL-9 secretion from a multicytokine-producing CD4 + T cell population was required for an allergen recall response.

Background Inhaled corticosteroids (ICSs) are important in asthma management, but there are concerns regarding associated risk of pneumonia. While studies in asthmatic adults have shown inconsistent results, this risk in asthmatic children is unclear. Objective Our aim was to determine the association of ICS use with pneumonia risk in asthmatic children. Methods A nested case-control study was performed in the Mayo Clinic Birth Cohort. Asthmatic children (<18 years) with a physician diagnosis of asthma were identified from electronic medical records of children born at Mayo Clinic from 1997 to 2016 and followed until 31 December 2017. Pneumonia cases defined by Infectious Disease Society of America were 1:1 matched with controls without pneumonia by age, sex and asthma index date. Exposure was defined as ICS prescription at least 90 days prior to pneumonia. Associations of ICS use, type and dose (low, medium and high) with pneumonia risk were analysed using conditional logistic regression. Results Of the 2108 asthmatic children eligible for the study (70% mild intermittent and 30% persistent asthma), 312 children developed pneumonia during the study period. ICS use overall was not associated with risk of pneumonia (adjusted OR: 0.94, 95% CI: 0.62 to 1.41). Poorly controlled asthma was significantly associated with the risk of pneumonia (OR: 2.03, 95% CI: 1.35 to 3.05; p<0.001). No ICS type or dose was associated with risk of pneumonia. Conclusion ICS use in asthmatic children was not associated with risk of pneumonia but poorly controlled asthma was. Future asthma studies may need to include pneumonia as a potential outcome of asthma management.

Abstract Objective Accurate extraction of breast cancer patients’ phenotypes is important for clinical decision support and clinical research. This study developed and evaluated cancer domain pretrained CancerBERT models for extracting breast cancer phenotypes from clinical texts. We also investigated the effect of customized cancer-related vocabulary on the performance of CancerBERT models. Materials and Methods A cancer-related corpus of breast cancer patients was extracted from the electronic health records of a local hospital. We annotated named entities in 200 pathology reports and 50 clinical notes for 8 cancer phenotypes for fine-tuning and evaluation. We kept pretraining the BlueBERT model on the cancer corpus with expanded vocabularies (using both term frequency-based and manually reviewed methods) to obtain CancerBERT models. The CancerBERT models were evaluated and compared with other baseline models on the cancer phenotype extraction task. Results All CancerBERT models outperformed all other models on the cancer phenotyping NER task. Both CancerBERT models with customized vocabularies outperformed the CancerBERT with the original BERT vocabulary. The CancerBERT model with manually reviewed customized vocabulary achieved the best performance with macro F1 scores equal to 0.876 (95% CI, 0.873–0.879) and 0.904 (95% CI, 0.902–0.906) for exact match and lenient match, respectively. Conclusions The CancerBERT models were developed to extract the cancer phenotypes in clinical notes and pathology reports. The results validated that using customized vocabulary may further improve the performances of domain specific BERT models in clinical NLP tasks. The CancerBERT models developed in the study would further help clinical decision support.

AbstractPurposeRural populations are disproportionately affected by the COVID‐19 pandemic. We characterized urban‐rural disparities in patient portal messaging utilization for COVID‐19, and, of those who used the portal during its early stage in the Midwest.MethodsWe collected over 1 million portal messages generated by midwestern Mayo Clinic patients from February to August 2020. We analyzed patient‐generated messages (PGMs) on COVID‐19 by urban‐rural locality and incorporated patients’ sociodemographic factors into the analysis.FindingsThe urban‐rural ratio of portal users, message senders, and COVID‐19 message senders was 1.18, 1.31, and 1.79, indicating greater use among urban patients. The urban‐rural ratio (1.69) of PGMs on COVID‐19 was higher than that (1.43) of general PGMs. The urban‐rural ratios of messaging were 1.72‐1.85 for COVID‐19‐related care and 1.43‐1.66 for other health care issues on COVID‐19. Compared with urban patients, rural patients sent fewer messages for COVID‐19 diagnosis and treatment but more messages for other reasons related to COVID‐19‐related health care (eg, isolation and anxiety). The frequent senders of COVID‐19‐related messages among rural patients were 40+ years old, women, married, and White.ConclusionsIn this Midwest health system, rural patients were less likely to use patient online services during a pandemic and their reasons for its use differ from urban patients. Results suggest opportunities for increasing equity in rural patient engagement in patient portals (in particular, minority populations) for COVID‐19. Public health intervention strategies could target reasons why rural patients might seek health care in a pandemic, such as social isolation and anxiety.

Abstract Background: Partial breast irradiation (PBI) is an established option for selected patients with early stage breast cancer. The optimal technique, target volume and dose/fractionation for PBI has yet to be defined. The most studied regimen in North America (38.5 Gy in 10 fractions twice daily) has been associated with cosmetic deterioration. We hypothesized that condensing treatment and reducing the total administered dose could improve the therapeutic ratio in luminal breast cancer and DCIS based on emerging evidence that breast cancer is more sensitive than surrounding normal tissues to high dose fractions. Herein, we report cosmetic, tolerability, disease control, and patient reported outcomes of a novel ultra-accelerated PBI regimen. Methods: We conducted a single arm, three cohort trial of photon, proton, and brachytherapy PBI. Technique was selected at physician and patient discretion. Eligible women were age ≥ 50 years with estrogen receptor positive (ER+), sentinel lymph node negative invasive or in-situ breast cancer measuring ≤ 2.5 cm. The regimen was designed to have comparable biologically equivalent effect as 40 Gy in 15 fractions, assuming an α/β ratio of 3.5. Intracavitary brachytherapy target volume was lumpectomy cavity plus 1 cm and prescribed 21 Gy in 3 fractions. Photon and proton target volumes were post-operative tumor bed plus 1 cm and a 3 mm setup uncertainty margin, prescribed 21.9 Gy (RBE) in 3 fractions, and delivered with image guidance. The primary outcome was the percentage difference in patients with adverse cosmesis (defined as fair or poor cosmesis) at 3 years compared to baseline pre-PBI, as assessed by trained nurses using the 4-point Harvard breast cosmesis scale. Patients also completed quality of life surveys and self-reported cosmesis using the 4-point scale. Locoregional and distant recurrence-free survival was determined using the Kaplan-Meier method. Adverse events were assessed using CTCAE, v 4.0. Results: Between 2015 and 2017, 163 patients were treated: photons in 58, protons in 48, and brachytherapy in 57. Median patient age was 66 years. 129 (79%) patients had invasive breast cancer (all ER+) and 34 (21%) had DCIS (83% ER+). Median tumor size was 1.1 cm. Grade was 2-3 in 102 (63%). The median mean heart/ipsilateral lung doses were photons 0.1/1.6 Gy, protons &lt;0.001/0.1 Gy, and brachytherapy 0.5/0.9 Gy. Median follow-up was 4.1 years (IQR 3.9-5.0). The proportion of patients with adverse cosmesis (by RN assessment) was 14.3% at baseline and 3.8% at 3 years, with four patients (1 photon, 1 proton, 2 brachytherapy) experiencing cosmetic deterioration at 3 years from baseline. The proportion with adverse cosmesis by self-report at 3 years was 2.4%, with three patients (1 photon, 1 proton, 1 brachytherapy) reporting cosmetic deterioration. Four patients developed locoregional recurrence (1 photons, 2 protons, 1 brachytherapy); three were local only and one was local and distant. 4-year locoregional recurrence and distant metastasis-free survival were 97.9% and 97.4%, respectively. There were 2 treatment related ≥ grade 2 late events (grade 2 fibrosis and grade 2 seroma, both brachytherapy associated), and no evidence of deterioration in patient-reported pain, fatigue, breast related or overall quality of life, as assessed by the patient reported outcomes version of the CTCAE, 10-point linear analog scales, and the breast cancer treatment outcomes scale. Conclusions: Ultra-accelerated 3-fraction PBI exquisitely spared normal tissues and was associated with favorable cosmetic outcomes, disease control, and excellent long-term tolerability. This ‘precision-radiotherapy’ approach may optimize the therapeutic ratio over more aggressive radiotherapy options as well as radiotherapy omission, particularly in patients with long life expectancies. Citation Format: Robert Mutter, Tina Hieken, Todd DeWees, Arslan Afzal, Stephanie Kenison, Laura Vallow, Christopher Deufel, Nicholas Remmes, Kathryn Ruddy, Judy Boughey, Keith Furutani, Amy Degnim, James Jakub, Tamara Vern-Gross, Dean Shumway, William Wong, Samir Patel, Lisa McGee, Minetta Liu, Carlos Vargas, Daniel Visscher, Bradley Stish, Deanna Pafundi, Mark Waddle, Michael Golafshar, Michele Halyard, Kimberly Corbin, Sean Park. Ultra-accelerated photon, proton, and brachytherapy partial breast irradiation: Primary results of the Mayo 3-fraction trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD7-03.

Abstract Background: Survival advantages with neoadjuvant chemotherapy (NACT) have been observed in patients (pts) with locally advanced breast cancer (BC) who achieve pathological complete response (pCR). Predicting risk of early recurrence in pts without pCR remains difficult. Circulating tumor DNA (ctDNA) may be a biomarker of neoadjuvant therapy response and recurrence. This study applied tumor genotyping of peripheral blood in pts with HER2− tumor BRCA-mutated (tBRCAm) BC treated with neoadjuvant niraparib. The relationship between ctDNA and tumor response was also characterized, with a focus on circulating TP53 mutant allelic frequency (MAF). Methods: Blood was collected from 21 pts enrolled in the study (NCT03329937) evaluating neoadjuvant niraparib in pts with localized HER2− tBRCAm BC. Pts received niraparib 200 mg once daily for two 28-day cycles. After 2 cycles, pts underwent surgery or received up to 6 cycles of niraparib and/or NACT prior to surgery. Blood samples were collected at screening, Cycle 1 Day 28 (C1D28), Cycle 2 Day 28 (C2D28), and pre-surgery. Ultrasound (USG) was done after each cycle and MRI after Cycle 2. Next-generation sequencing of cell-free plasma DNA was carried out using a proprietary target capture and analysis (Paweletz, Clin Cancer Res 2016). Results: ctDNA and TP53 mutations (TP53m) were detected at screening in 10/21 pts (47.6%). Across all 21 pts there was a correlation between TP53 MAF and baseline tumor stage (T) (mean [standard deviation], T1 0 [0], T2 0.05 [0.09], and T3 0.21 [0.12]; P=0.005). Linear regression modelling showed a positive correlation between tumor volume and baseline TP53 MAF (R2=0.206, P=0.0386). Baseline TP53 MAF also appeared to be associated with advanced disease stage (Table 1). Depletion of detectable TP53m from baseline was evident by C1D28 and persisted to pre-surgery (Table 2). This corresponded with decreases in tumor volume at C1D28 and further decreases at C2D28. Of 11 pts analyzed, 6 pts with &gt;90% tumor volume decreases by MRI or USG at C2D28 had sustained TP53m depletion. Three pts had pCR; of these, 2 had sustained TP53m depletion (data unavailable for third pCR pt). Two pts with less robust tumor responses had increased pre-surgery TP53 MAF. Conclusions: We report the potential utility of ctDNA as a predictive biomarker for neoadjuvant niraparib response in pts with HER2− tBRCAm BC. Although sample size limited analysis of genes other than TP53, baseline ctDNA strongly correlated with tumor volume, and TP53 MAF was associated with tumor volume and trended towards association with disease stage. Longitudinal analysis of TP53 MAF suggested a correlation with niraparib response. Further study of ctDNA dynamics during NACT and correlation with pCR and long-term clinical outcomes is warranted. Funding: GlaxoSmithKline (GSK) study 213355; NCT03329937. Medical writing support was provided by Fishawack Indicia, part of Fishawack Health, funded by GSK. Table 1.Baseline TP53 MAF association with disease stage and subtypeTP53 MAFDisease Stage (I–III)Disease SubtypeStage IStage IIStage IIIHR+TNBC(n=8)(n=10)(n=3)(n=6)(n=15)Mean (SD)0.01 (0.02)0.07 (0.12)0.10 (0.05)0.02 (0.02)0.06 (0.10)HR, hormone receptor; MAF, mutant allelic frequency; SD, standard deviation; TNBC, triple-negative breast cancer. Table 2.TP53 MAF correlation with tumor volume decrease by ultrasound and MRIOutcomeScreeningCycle 1 Day 28 Cycle 2 Day 28 Pre-Surgeryn11997TP53 MAF, mean, (SD)0.09 (0.11)000.01 (0.02)n11112Percent change in tumor volume from baseline by MRI, mean (SD)-N/A*−72.6 (22.5)N/A*Percent change in tumor volume from baseline by ultrasound, mean (SD)-−60.8 (24.0)−80.6 (21.8)−95.9 (4.3)*MRI was only performed at Cycle 2 Day 28. MAF, mutant allelic frequency; MRI, magnetic resonance imaging; N/A, not applicable; SD, standard deviation. Citation Format: Ming Shan, Laura Spring, Minetta C Liu, Erika Hamilton, Hanna Irie, Cesar A Santa-Maria, Steven J Isakoff, James Reeves, Leif W Ellisen, Lee P Lim, Kavita Garg, Caterina Bertucci, Bin Feng, Hailei Zhang, Kaiming Sun, Julie R Graham, Erin Hofstatter, Hyo Han. Relationship between circulating tumor DNA and response to neoadjuvant niraparib in HER2-negative, BRCA-mutated breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-13-21.