Citations

Abstract Endocrine therapies (ET) with cyclin-dependent kinase 4/6 (CDK4/6) inhibition are the standard treatment for estrogen receptor-α-positive (ER+) breast cancer, however drug resistance is common. In this study, proteogenomic analyses of patient-derived xenografts (PDXs) from patients with 22 ER+ breast cancer demonstrated that protein kinase, membrane-associated tyrosine/threonine one (PKMYT1), a WEE1 homolog, is estradiol (E2) regulated in E2-dependent PDXs and constitutively expressed when growth is E2-independent. In clinical samples, high PKMYT1 mRNA levels associated with resistance to both ET and CDK4/6 inhibition. The PKMYT1 inhibitor lunresertib (RP-6306) with gemcitabine selectively and synergistically reduced the viability of ET and palbociclib-resistant ER+ breast cancer cells without functional p53. In vitro the combination increased DNA damage and apoptosis. In palbociclib-resistant, TP53 mutant PDX-derived organoids and PDXs, RP-6306 with low-dose gemcitabine induced greater tumor volume reduction compared to treatment with either single agent. Our study demonstrates the clinical potential of RP-6306 in combination with gemcitabine for ET and CDK4/6 inhibitor resistant TP53 mutant ER+ breast cancer.

Objectives: Upregulation of endothelin-1 (ET-1) and its receptors have been linked to increases in hypoxic sensitivity of the carotid chemoreceptors and the development of hypertension. As such, chemoreflex sensitization has been shown in pre-clinical models to be attenuated by ET-1 receptor blockade. Herein, we sought to assess a role for ET-1 in the maintenance of resting blood pressure (BP) in healthy young men and determine whether chemoreflex control of BP could be altered by ET-1 blockade. We hypothesized endothelin receptor antagonism with oral bosentan would lower resting BP in healthy young men as well as the acute BP response to hypoxia. Methods: Twenty-four healthy young men (31±5 yrs, 26±3 kg/m2) completed two study visits (control, bosentan) separated by a minimum of 1 week. The nonspecific endothelin receptor antagonist bosentan (62.5 mg) was taken by mouth twice daily for 3 days prior to the second study visit. On each visit, beat-by-beat BP was assessed under 3 inspiratory air conditions: 1) steady-state normoxia (FiO2 0.21), 2) chemoreflex excitation produced by acute, graded hypoxia (FiO2 0.05 – 0.21), 3) chemoreflex inhibition elicited by transient hyperoxia (FiO2 1.00). Results: Oral bosentan treatment resulted in an increase in plasma ET-1 (0.9±0.9 to 1.3±0.6 pg/mL, p=0.004), supporting receptor blockade. Resting diastolic and mean BP were reduced following 3 days of bosentan treatment compared to control (diastolic: 73±5 to 69±7 mmHg, p=0.007; mean: 93±7 to 88±7 mmHg, p=0.005) with no change in systolic BP (p=0.507). Notably, the BP response to both acute hypoxia (-0.48±0.38 to -0.25±0.31 mmHg/%, p=0.004) and hyperoxia (main effect of bosentan, p=0.025) were attenuated following bosentan. Conclusions: Acute oral bosentan treatment resulted in a reduction in resting BP in healthy young men. The effect of endothelin receptor inhibition with bosentan further attenuated the rise in BP during chemoreflex excitation via acute, graded hypoxia as well as the fall in BP during chemoreflex inhibition (transient hyperoxia). Together these data support a role for ET-1 in control of resting BP in healthy young men, possibly through a chemoreceptor-mediated mechanism. NIH HL130339 (JL), Mayo Clinic Center for Biomedical Discovery (JL, SB). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Purpose To (1) analyze trends in the publishing of statistical fragility index (FI)–based systematic reviews in the orthopaedic literature, including the prevalence of misleading or inaccurate statements related to the statistical fragility of randomized controlled trials (RCTs) and patients lost to follow‐up (LTF), and (2) determine whether RCTs with relatively “low” FIs are truly as sensitive to patients LTF as previously portrayed in the literature. Methods All FI‐based studies published in the orthopaedic literature were identified using the Cochrane Database of Systematic Reviews, Web of Science Core Collection, PubMed, and MEDLINE databases. All articles involving application of the FI or reverse FI to study the statistical fragility of studies in orthopaedics were eligible for inclusion in the study. Study characteristics, median FIs and sample sizes, and misleading or inaccurate statements related to the FI and patients LTF were recorded. Misleading or inaccurate statements—defined as those basing conclusions of trial fragility on the false assumption that adding patients LTF back to a trial has the same statistical effect as existing patients in a trial experiencing the opposite outcome—were determined by 2 authors. A theoretical RCT with a sample size of 100, P = .006, and FI of 4 was used to evaluate the difference in effect on statistical significance between flipping outcome events of patients already included in the trial (FI) and adding patients LTF back to the trial to show the true sensitivity of RCTs to patients LTF. Results Of the 39 FI‐based studies, 37 (95%) directly compared the FI with the number of patients LTF. Of these 37 studies, 22 (59%) included a statement regarding the FI and patients LTF that was determined to be inaccurate or misleading. In the theoretical RCT, a reversal of significance was not observed until 7 patients LTF (nearly twice the FI) were added to the trial in the distribution of maximal significance reversal. Conclusions The claim that any RCT in which the number of patients LTF exceeds the FI could potentially have its significance reversed simply by maintaining study follow‐ups is commonly inaccurate and prevalent in orthopaedic studies applying the FI. Patients LTF and the FI are not equivalent. The minimum number of patients LTF required to flip the significance of a typical RCT was shown to be greater than the FI, suggesting that RCTs with relatively low FIs may not be as sensitive to patients LTF as previously portrayed in the literature; however, only a holistic approach that considers the context in which the trial was conducted, potential biases, and study results can determine the merits of any particular RCT. Clinical Relevance Surgeons may benefit from re‐examining their interpretation of prior FI reviews that have made claims of substantial RCT fragility based on comparisons between the FI and patients LTF; it is possible the results are more robust than previously believed.

Abstract Background and Aims Non-invasive cross-sectional imaging via magnetic resonance enterography [MRE] offers excellent accuracy for the diagnosis of stricturing complications in Crohn’s disease [CD] but is limited in determining the degrees of fibrosis and inflammation within a stricture. We developed and validated a radiomics-based machine-learning model for separately characterizing the degree of histopathological inflammation and fibrosis in CD strictures and compared it to centrally read visual radiologist scoring of MRE. Methods This single-centre, cross-sectional study included 51 CD patients [n = 34 for discovery; n = 17 for validation] with terminal ileal strictures confirmed on diagnostic MRE within 15 weeks of resection. Histopathological specimens were scored for inflammation and fibrosis and spatially linked with corresponding pre-surgical MRE sequences. Annotated stricture regions on MRE were scored visually by radiologists as well as underwent 3D radiomics-based machine learning analysis; both were evaluated against histopathology. Results Two distinct sets of radiomic features capturing textural heterogeneity within strictures were linked with each of severe inflammation or severe fibrosis across both the discovery (area under the curve [AUC = 0.69, 0.83] and validation [AUC = 0.67, 0.78] cohorts. Radiologist visual scoring had an AUC = 0.67 for identifying severe inflammation and AUC = 0.35 for severe fibrosis. Use of combined radiomics and radiologist scoring robustly augmented identification of severe inflammation [AUC = 0.79] and modestly improved assessment of severe fibrosis [AUC = 0.79 for severe fibrosis] over individual approaches. Conclusions Radiomic features of CD strictures on MRE can accurately identify severe histopathological inflammation and severe histopathological fibrosis, as well as augment performance of the radiologist visual scoring in stricture characterization.

Abstract Funding Acknowledgements None. Background Hyperoxemia (a high PaO2, i.e. >200-300 mmHg) has been associated with adverse outcomes in general critical care settings as well as in acute cardiovascular care conditions. The association between hyperoxemia and mortality has not been characterized in the heterogeneous population admitted to the cardiac intensive care unit (CICU). We aimed to examine the association between hyperoxemia on CICU admission with in-hospital mortality. Methods We retrospectively analyzed Mayo Clinic CICU patients from January 2007 to April 2018. PaO2 closest on admission was analyzed as a continuous variable (per 100 mmHg) and categorized as: 60-100 mmHg (51.9%), 101-150 mmHg (28.6%), 151-200 mmHg (10.6%), 201-300 mmHg (6.4%), and >300 mmHg (2.5%). Those without PaO2 on admission and those with hypoxemia were excluded. The primary outcome was all-cause in-hospital mortality evaluated using logistic regression, after adjusting for age, Charlson Comorbidity Index, M-CARS, and use of IMV and NIPPV. Results A total of 3,368 patients were included (median 70.3 years, 39.4% women). Admission diagnoses included ACS (37.0%, with 19.8% STEMI), HF (67.8%), shock (33.0%) and cardiac arrest (25.3%). Median admission PaO2 was 99 (IQR 78, 136) mmHg, with no difference in median PaO2 between hospital survivors and inpatient deaths (99 versus 98, p = 0.38). A J-shaped relationship was observed between admission PaO2 and in-hospital mortality (Figure A), with slightly higher mortality below 100 mmHg and incrementally higher mortality above this threshold (esp. at >200 mmHg). The incremental association between higher PaO2 and mortality (adjusted OR 1.17 per 100 mmHg higher, 95% CI 1.01-1.34, P = 0.03) was focused in the highest PaO2 group (i.e., >300 mmHg; Figure B). Conclusion Hyperoxia (esp. PaO2 >300 mmHg) on CICU admission is associated with increased in-hospital mortality, demonstrating a J-shaped association with an inflection point of lowest mortality around 100 mmHg. Further studies are warranted to assess if specific oxygen targets influence outcomes in critically ill cardiac patients.

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Aarhus University Dagmar Marshalls Fond. Background The assessment of left ventricular (LV) function through transthoracic echocardiography (TTE) is essential for guiding diagnosis and treatment in cases of cardiogenic shock (CS). Myocardial global longitudinal strain (GLS) provides an objective and reproducible measure of systolic function, independently predicting outcomes in acute heart failure, regardless of left ventricular ejection fraction (LVEF). However, whether assessment of GLS can predict mortality in patients with CS remains unknown. Purpose In this study, we aimed to evaluate the prognostic significance of GLS in patients with CS. Methods Data from cardiac intensive care unit (CICU) patients admitted between 2007 and 2018 with CS who received vasoactive agents and/or mechanical circulatory support were analysed. GLS (as absolute values) and biplane LVEF were measured via TTE performed within 24 hours of CICU admission. Patients with CS were categorised based on the GLS quartile: mild (GLS >9.7%), moderate (7.0% < GLS <9.6%), severe (5.0% < GLS < 6.9%), and very severe (GLS ≤ 4.9%). CICU and in-hospital mortality were compared across GLS categories, and the relationship between GLS and mortality was assessed using multivariable logistic regression. Results The study included 626 patients with a median age of 68.6 years, a median LVEF of 31% (IQR 24 to 40%), and a median GLS of 7.0% (IQR 5.0 to 9.7%). In-hospital mortality was 29.1%. As GLS deteriorated, there was an increasing need for vasopressors (P<0.001). Patients with progressively lower GLS exhibited significantly higher CICU and in-hospital mortality across the GLS quartiles (Figure A; P<0.001). Patients in the severe (adjusted OR 2.67; p<0.001) and very severe category (adjusted OR 3.54; P<0.001) had significantly increased risk of in-hospital death compared with mild category. In multivariable analysis, every 1% decrease in GLS corresponded to a 14% higher risk of in-hospital mortality (P<0.001). Finally, GLS outperformed LVEF for discrimination of in-hospital mortality (P=0.002), and when both measurements were included in the same multivariable model, only GLS remained significant. When patients were divided according to whether they had GLS and/or LVEF below the median value, patients with low GLS had higher mortality irrespective of the LVEF (Figure B). Conclusion In patients with CS, GLS assessment surpasses LVEF in its prognostic value and improves risk stratification. Routine evaluation of GLS should be considered for patients with CS.Figure AFigure B

Abstract Background The presence of a chimeric gracilis and profunda artery perforator (PAP) flap with a common arterial pedicle has been demonstrated on computed tomography angiography in up to 59% of patients and confirmed in a cadaveric model. Already utilized for head and neck reconstruction by Heredero et al, this novel flap could provide more volume than either flap alone which is advantageous, particularly in patients with sizable defects. The purpose of this study was to determine the average tissue volume that can be utilized from this chimeric flap. Methods CT Angiogram imaging studies exhibiting chimeric flap anatomy were reviewed over a 7-year period at a single institution utilizing Visage Version 7.1, a radiology picture archiving and communication system. This software was used to trace the flap pedicles and to capture estimated soft tissue volumes of each respective flap. Results A total of 31 patients, consisting of 52 lower extremity gracilis and PAP chimeric flaps, underwent tissue volume analysis. The average total volume of soft tissue supplied by the gracilis flap was found to be 70.21 cm3 (standard deviation [SD] = 26.99). The average volume of the PAP flap was 31.73 cm3 (SD = 26.12). The average total volume captured by the chimeric gracilis and PAP flap was 101.94 cm3 (SD = 62.40). Conclusion The potential soft tissue volume that can be harvested from a chimeric gracilis and PAP flap is significantly greater than solitary gracilis or PAP flaps. This chimeric flap may serve as a viable and advantageous reconstructive option for patients requiring large volume soft tissue coverage, particularly if other sizable options are not available.