Faculty Bibliography

BACKGROUND:The optimal management of patients with intermediate-risk pulmonary embolism (PE), who have right heart dysfunction (determined by a combination of imaging and cardiac biomarkers) but a normal blood pressure, is uncertain. These patients suffer from reduced functional capacity and a lower quality of life over the long-term, despite use of anticoagulant therapy. Catheter-directed therapy (CDT) is a promising treatment for acute PE that rapidly removes thrombus and potentially improves cardiac dysfunction. However, CDT has risk and is costly, and it is not known whether it improves long-term cardiorespiratory fitness and/or quality of life compared with anticoagulation alone. METHODS:) with cardiopulmonary exercise testing at 3 months and reduce New York Heart Association (NYHA) Class at 12 months compared with No-CDT. These 2 primary efficacy outcomes will be analyzed sequentially using a "gatekeeping" procedure; for NYHA class to be compared, peak oxygen consumption must first be shown to be significantly increased by CDT. Safety and cost-effectiveness will also be assessed. CONCLUSION/CONCLUSIONS:When completed, PE-TRACT will provide important evidence regarding the benefits and risks of CDT to treat intermediate-risk PE compared with anticoagulation alone. TRIAL REGISTRATION/BACKGROUND:clinicaltrials.gov: NCT05591118.

AIM/OBJECTIVE:Chemoradiation therapy (CRT) is considered as the first line of treatment for patients with squamous cell carcinoma of the anal canal. Following initial CRT, patients who present with either persistent or locally recurrent disease are treated by surgical intervention. The aim of our study is to determine the prognostic factors associated with failure of CRT and overall mortality in patients with anal squamous cell carcinoma (SCC). METHODS:We performed a 14-year analysis (2004-2017) of the National Cancer Database and included patients diagnosed with non-metastatic SCC of the anal canal who underwent CRT. Baseline patient characteristics including demographics, comorbidities and tumour characteristics were analysed. Outcome measures were needed for operative intervention after 4 months of initiation of CRT (failure of CRT) and 5-year overall mortality. Multivariate logistic regression analysis identified prognostic factors independently associated with failure of CRT. RESULTS:We included a total of 37 615 patients with anal SCC who received CRT. Predictors of operative intervention included male sex, higher Deyo-Charlson Comorbidity Index (DCCI) and higher primary tumour stage. The 5-year overall survival rate was 77.6%, and 2.4% of patients failed CRT, defined as requiring and undergoing surgical intervention within 4 months post-initiation of CRT. Median follow-up time was 47 (95% CI 24-84) months. Independent predictors of overall mortality within the first 5 years of diagnosis were increased age, male sex, Black race, non-insured status, higher DCCI, higher primary tumour grade, and higher primary tumour and lymph node stage. The 5-year survival rate was significantly lower in patients who underwent operative intervention compared to those who received CRT alone (57.4% vs. 78.1%; P < 0.01). CONCLUSION/CONCLUSIONS:Our study showed that male sex, younger age, DCCI of 1 and 3, and increased tumour size were predictive of CRT failure among patients with anal SCC. Increased age, male sex, Black race, non-insured status, increased DCCI, and more aggressive tumour characteristics were associated with increased 5-year overall mortality. More importantly, patients who failed CRT had worse 5-year overall survival. Our findings support increased emphasis on intensive surveillance for these high-risk patient cohorts.

Central body fat distribution affects kidney function. Abdominal fat measurements using computed tomography (CT) may prove superior in assessing body composition-related kidney risk in living kidney donors. This retrospective cohort study including 550 kidney donors aimed to determine the association between CT-measured abdominal fat areas and kidney function before and after donor nephrectomy. Donors underwent glomerular filtration rate measurements (¹²⁵I-Iothalamate, mGFR) before and 3 months after donation. Linear regression analyses with body surface area (BSA)-standardized and crude mGFR were performed to assess the association of height-indexed tomographic fat measurements with kidney function. In age-, and sex-adjusted analyses higher levels of total abdominal, visceral, subcutaneous, and intramuscular adipose tissue index were significantly associated with lower mGFR levels before donation (BSA-standardized mGFR: visceral adipose tissue index: Βeta=-0.11, p < 0.001, subcutaneous: Βeta=-0.10, p < 0.001, intramuscular: Βeta=-1.18, p < 0.001, total abdominal: Βeta=-0.07, p < 0.001). Higher tomographic abdominal fat is associated with lower BSA-standardized mGFR after donation and a greater decrease in mGFR between screening and 3 months post-donation. This study shows that CT-measured abdominal fat area is associated with kidney function before and after living kidney donation.

INTRODUCTION/UNASSIGNED:This study examined the potential interplay between motor development and intervention in support of action understanding. METHODS/UNASSIGNED:Eighty nine-month-old infants completed a tool-use training session and goal imitation paradigm that assessed action understanding in counterbalanced order. A metric of motor development was obtained using the Early Motor Questionnaire. RESULTS/UNASSIGNED:Results indicated that training improved action understanding, particularly for those infants who started out with lower means-end skills. Results further indicated that infants who did not receive any training experience in the lab beforehand, drew on their existing means-end skills. DISCUSSION/UNASSIGNED:These results emphasize independent contributions of training and motor development on action understanding and shed light on the interaction between training and individual motor readiness in facilitating action understanding in infancy.

BACKGROUND:Hypertrophic cardiomyopathy is a genetic, life-threatening cardiovascular disease that often goes unidentified in pediatric patients. Patients are often asymptomatic and neither history or physical examination are reliable to detect the disease. The only reliable method to diagnose hypertrophic cardiomyopathy is with echocardiography to look at interventricular septal thickness. Emerging literature has shown that cardiac point-of-care ultrasound (POCUS) performed by pediatric emergency medicine (PEM) physicians is as effective and accurate compared with cardiac echocardiography performed by pediatric cardiologists. OBJECTIVE:The objective of the study was to determine the diagnostic accuracy of POCUS performed by ultrasound-trained PEM physicians in measuring the interventricular septum end diastole (IVSd) thickness in the pediatric emergency department. METHODS:We conducted a prospective, single-center, observational, diagnostic accuracy study to examine the diagnostic accuracy of POCUS in measuring IVSd thickness in pediatric patients who presented to the pediatric emergency department with symptoms that prompted a cardiac POCUS. Cardiac POCUS findings were interpreted by a PEM physician at the bedside and retrospectively by a pediatric cardiologist. Diagnostic concordance of the measurements obtained by the PEM physician and cardiologist was assessed. RESULTS:Forty-eight patients were enrolled. Median patient age was 13.4 years. There was excellent diagnostic agreement on the measurement of the IVSd thickness between PEM physicians and the pediatric cardiologist (81.25% of cases; 39/48). Disagreement was seen in 18.75% of the cases (9/48). The mean error of disagreement was -0.32, with a 95% confidence interval of -0.37 to -0.28. Overall, the mean error of both agreement and disagreement was -0.046, with 95% confidence interval of -0.08 to -0.01 and P value of 0.008. CONCLUSIONS:Point-of-care ultrasound performed by ultrasound-trained PEM physicians to measure pediatric IVSd thickness has a high diagnostic accuracy with excellent agreement with a pediatric cardiologist.

Broad-spectrum RAS inhibition has the potential to benefit roughly a quarter of human patients with cancer whose tumours are driven by RAS mutations^1,2. RMC-7977 is a highly selective inhibitor of the active GTP-bound forms of KRAS, HRAS and NRAS, with affinity for both mutant and wild-type variants³. More than 90% of cases of human pancreatic ductal adenocarcinoma (PDAC) are driven by activating mutations in KRAS⁴. Here we assessed the therapeutic potential of RMC-7977 in a comprehensive range of PDAC models. We observed broad and pronounced anti-tumour activity across models following direct RAS inhibition at exposures that were well-tolerated in vivo. Pharmacological analyses revealed divergent responses to RMC-7977 in tumour versus normal tissues. Treated tumours exhibited waves of apoptosis along with sustained proliferative arrest, whereas normal tissues underwent only transient decreases in proliferation, with no evidence of apoptosis. In the autochthonous KPC mouse model, RMC-7977 treatment resulted in a profound extension of survival followed by on-treatment relapse. Analysis of relapsed tumours identified Myc copy number gain as a prevalent candidate resistance mechanism, which could be overcome by combinatorial TEAD inhibition in vitro. Together, these data establish a strong preclinical rationale for the use of broad-spectrum RAS-GTP inhibition in the setting of PDAC and identify a promising candidate combination therapeutic regimen to overcome monotherapy resistance.