Cardiovascular profiles associated with white matter hyperintensities in healthy young women.

Women who experience hypertension in pregnancy have increased risk of both chronic hypertension and dementia. High blood pressure is associated with increased evidence of white matter hyperintensities (WMH) in brain imaging. WMH are disruptions of the white matter of the brain that occur with demyelination and axonal degeneration, are associated with vascular disease, occur more frequently in people with hypertension, and are associated with cognitive impairment. We evaluated the relationship between WMH and subclinical cardiovascular function in healthy young nulliparous women and women with a history of early-onset preeclampsia. Sixty-two reproductive-aged women were assessed during the follicular phase of the menstrual cycle after a 3-day sodium/potassium-controlled diet. Half of participants had a history of early-onset preeclampsia, and half were nulliparous. Blood was drawn to assess inflammatory markers. Cardiovascular assessments included tonometric blood pressure monitoring, volume loading to assess vascular compliance, echocardiography to assess cardiac ejection time, brachial pulse wave velocity of the brachial artery, assessing cardiovascular stiffness, and brachial artery flow mediated vasodilation to assess endothelial mediated dilatory response. T2 fluid-attenuated inversion recovery (FLAIR) MRI imaging was obtained. Two raters, blinded to cardiovascular assessments and pregnancy history, reviewed MRI scans for evidence of WMH using the Fazekas rating scale. WMHs were detected in 17 women; 45 had normal white matter structure. Participants with Fazekas score>0 had exaggerated response to volume loading compared to women with a Fazekas score of 0 and longer cardiac ejection times. Fazekas scores >0 had lower brachial flow-mediated vasodilation and increased white blood count compared to those with no evidence of WMH. Women with WMH had reduced cardiovascular compliance, and a trend towards decreased endothelial responsiveness compared to those without WMH. These data demonstrated that the relationship between cardiovascular and brain health was detectable in young, healthy, reproductive-aged women, and may play a role in later development of clinical disease. These findings may help identify women who are at risk for cognitive decline and pathological aging.

Molecular Profiling Practices in Pancreatic Adenocarcinoma: Academic vs Community Physicians.

Background: Pancreatic adenocarcinoma (PDAC) is relatively rare but highly aggressive, with most patients diagnosed once they have metastatic or locally invasive disease. Molecular profiling is being explored as a tool for selecting patients for targeted therapy clinical trials and for assessing whether targeted therapies may be effective in PDAC. Whether molecular profiling is being performed at both academic and community oncology clinics has yet to be examined. Here, we characterized the molecular profiling practice patterns in patients with PDAC in academic versus community practices in Denver, Colorado. Methods: We retrospectively reviewed records of all patients with refractory, metastatic PDAC who were referred to a tertiary clinical trials drug development unit in Denver between 2014 and 2019. Results: Of 77 patients, 41 (55%) were men with a mean age of 65 years (SD, 9.3). Fifty-three patients (69%) were referred from the community and 20 (26%) from academic centers; 4 (5%) were self-referred. A total of 51% received profiling prior to referral; 29 of 50 (58%) were from the community and 10 of 21 (47%) from academic settings. Guardant was the most commonly ordered test (47 of 77; 61%); FoundationOne was the second most common (40 of 77; 52%). Twenty-three of 77 patients (30%) received both Guardant and FoundationOne testing, and 3 of 77 (4%) received Caris MI Profile. One patient received a Mocha assay and another received Ascend/Clarient fluorescence in situ hybridization (FISH). Four patients were self-referred, 2 of whom underwent both Guardant and FoundationOne, 1 who underwent Guardant testing only, and 1 who did not receive any molecular profiling testing. Conclusions: This study characterizes molecular profiling practice patterns in individuals with advanced PDAC who were referred to a tertiary clinical trials drug development unit. Both academic and community physicians were found to order profiling about 50% of the time. Further research is needed to determine impact on clinical trial enrollment and detection of PDAC.

Characterization of Blood-Based Molecular Profiling in Pancreatic Adenocarcinoma.

Background: Molecular profiling is being explored in pancreatic adenocarcinoma (PDAC) as a tool to assist with early detection, prognosis, and patient selection in targeted therapy clinical trials. Due to the challenges and risks of traditional tissue biopsies in pancreatic adenocarcinoma, the utility of blood-based molecular profiling is now being explored more broadly. However, given its novelty, what value blood-based molecular profiling may provide to oncologists caring for individuals with PDAC remains unknown. Herein, we characterize the mutational landscape of metastatic PDAC using blood-based circulating tumor DNA (ctDNA) collected in patients with refractory, metastatic PDAC who were referred to an oncology drug development unit in Denver, Colorado, between August 2014 and May 2019. Methods: We retrospectively analyzed results of blood-based molecular profiling that was performed on 77 consecutive patients with metastatic PDAC who underwent Guardant-360 testing for whom results were available. Results: In our data set, 55% of patients (41/77) were men, median (SD) age was 66 (9.3) years (range, 44-83). Of 77 patients, 34 (44%) had 1 or more somatic alterations. Variants reported as being of unknown significance were not included in the analyses. The total number of alterations were 119 (nonunique) and 96 (unique). The median number of alterations per patient was 3 and the median mutant allele frequency was 0.5%. TP53 was the most commonly altered gene (29 unique alterations), followed by KRAS (27 unique alterations). Of the patients with any alteration, 34% had 1 or more actionable alterations that could be potentially targeted in a clinical trial. Conclusions: Detection of genomic alterations in ctDNA from patients with metastatic PDAC is feasible and reveals a wide range of genomic alterations, the actionability of which is being explored in clinical trials. Further investigation is needed to determine the extent to which blood-based molecular profiling can provide clinical utility in helping to select patients into clinical trials and determine its impact on survival.

Barriers to Clinical Trial Enrollment in Patients With Pancreatic Adenocarcinoma Eligible for Early-Phase Clinical Trials.

BACKGROUND: Early-phase clinical trials are critical to the advancement of cancer care, especially in patients with pancreatic ductal adenocarcinoma, given its aggressive nature and limited available therapeutic options. METHODS: A retrospective chart review of all patients with refractory or metastatic pancreatic ductal adenocarcinoma, referred to the Sarah Cannon Research Institute at HealthONE between 2014 and 2019, were reviewed. Patients who completed genomic profiling and qualified for a phase 1 trial (primarily 1a but some 1b) were identified to assess barriers to trial enrollment. RESULTS: Of 74 identified patients, 54 patients (73%) qualified for at least 1 clinical trial based on eligibility criteria and alterations detected via molecular profiling. Up to 40 industry-sponsored clinical trials were available during this time for consideration. Of the 54, 28 patients (52%) enrolled in a clinical trial, while 26 (48%) did not enroll. The most frequently cited barriers to enrollment were concerns regarding time commitment (12%), prolonged wait time for enrollment (12%), and fear of adverse events (8%). Seven of the 26 patients (27%) were lost to follow-up or had no stated reason for declining enrollment; others did not go on trial due to death/transition to hospice (n=5; 19%) or progression of disease/declining functional status (n=4; 15%). There were few statistically significant differences between patients who chose to go on trial and those who declined. CONCLUSIONS: An understanding of why eligible patients elect not to participate in early-phase clinical trials provides insight into the patient experience and can help identify misperceptions and areas for improvement in education and the clinical trial enrollment process.

Drug Development in Soft Tissue Sarcomas: Novel Targets and Recent Early Phase Trial Results.

Soft tissue sarcomas are a heterogeneous group of rare malignancies with few effective standard therapies. Our understanding of the underlying biology driving tumorigenesis in these mesenchymal tumors have led to a growth in drug development for soft tissue sarcomas. This review focuses on novel targets in soft tissue sarcomas, describes early clinical trial results of drugs directed at these targets, and discusses the data surrounding the use of these compounds in clinical practice and rationale for possible future US Food and Drug Administration approvals.