Invasive Assessment of Coronary Artery Disease in Clonal Hematopoiesis of Indeterminate Potential.

BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP) occurs due to acquired mutations in bone marrow progenitor cells. CHIP confers a 2-fold risk of atherosclerotic cardiovascular disease. However, there are limited data regarding specific cardiovascular phenotypes. The purpose of this study was to define the coronary artery disease phenotype of the CHIP population-based on coronary angiography. METHODS: We recruited 1142 patients from the Vanderbilt University Medical Center cardiac catheterization laboratory and performed DNA sequencing to determine CHIP status. Multivariable logistic regression models and proportional odds models were used to assess the association between CHIP status and angiography phenotypes. RESULTS: We found that 18.4% of patients undergoing coronary angiography had a CHIP mutation. Those with CHIP had a higher risk of having obstructive left main (odds ratio, 2.44 [95% CI, 1.40-4.27]; P=0.0018) and left anterior descending (odds ratio, 1.59 [1.12-2.24]; P=0.0092) coronary artery disease compared with non-CHIP carriers. We additionally found that a specific CHIP mutation, ten eleven translocase 2 (TET2), has a larger effect size on left main stenosis compared with other CHIP mutations. CONCLUSIONS: This is the first invasive assessment of coronary artery disease in CHIP and offers a description of a specific atherosclerotic phenotype in CHIP wherein there is an increased risk of obstructive left main and left anterior descending artery stenosis, especially among TET2 mutation carriers. This serves as a basis for understanding enhanced morbidity and mortality in CHIP.

Clonal hematopoiesis and inflammation in the vasculature: CHIVE, a prospective, longitudinal clonal hematopoiesis cohort and biorepository.

ABSTRACT: Clonal hematopoiesis (CH) is an age-associated phenomenon leading to an increased risk of both hematologic malignancy and nonmalignant organ dysfunction. Increasingly available genetic testing has made the incidental discovery of CH clinically common yet evidence-based guidelines and effective management strategies to prevent adverse CH health outcomes are lacking. To address this gap, the prospective CHIVE (clonal hematopoiesis and inflammation in the vasculature) registry and biorepository was created to identify and monitor individuals at risk, support multidisciplinary CH clinics, and refine taxonomy and standards of practice for CH risk mitigation. Data from the first 181 patients enrolled in this prospective registry recapitulate the molecular epidemiology of CH from biobank-scale retrospective studies, with DNMT3A, TET2, ASXL1, and TP53 as the most commonly mutated genes. Blood counts across all hematopoietic lineages trended lower in patients with CH. In addition, patients with CH had higher rates of end organ dysfunction, in particular chronic kidney disease. Among patients with CH, variant allele frequency was independently associated with the presence of cytopenias and progression to hematologic malignancy, whereas other common high-risk CH clone features were not clear. Notably, accumulation of multiple distinct high-risk clone features was also associated with cytopenias and hematologic malignancy progression, supporting a recently published CH risk score. Surprisingly, ∼30% of patients enrolled in CHIVE from CH clinics were adjudicated as not having clonal hematopoiesis of indeterminate potential, highlighting the need for molecular standards and purpose-built assays in this field. Maintenance of this well-annotated cohort and continued expansion of CHIVE to multiple institutions are underway and will be critical to understanding how to thoughtfully care for this patient population.

Image-based assessment of aortoiliac aneurysm anatomical characteristics in patients from the global iliac branch study.

OBJECTIVE: Endovascular repair is the preferred treatment for aortoiliac aneurysm, with preservation of at least one internal iliac artery recommended. This study aimed to assess pre-endovascular repair anatomical characteristics of aortoiliac aneurysm in patients from the Global Iliac Branch Study (GIBS, NCT05607277) to enhance selection criteria for iliac branch devices (IBD) and improve long-term outcomes. METHODS: Pre-treatment CT scans of 297 GIBS patients undergoing endovascular aneurysm repair were analyzed. Measurements included total iliac artery length, common iliac artery length, tortuosity index, common iliac artery splay angle, internal iliac artery stenosis, calcification score, and diameters in the device's landing zone. Statistical tests assessed differences in anatomical measurements and IBD-mediated internal iliac artery preservation. RESULTS: Left total iliac artery length was shorter than right (6.7 mm, P = .0019); right common iliac artery less tortuous (P = .0145). Males exhibited greater tortuosity in the left total iliac artery (P = .0475) and larger diameter in left internal iliac artery's landing zone (P = .0453). Preservation was more common on right (158 unilateral, 34 bilateral) than left (105 unilateral, 34 bilateral). There were 192 right-sided and 139 left-sided IBDs, with 318 IBDs in males and 13 in females. CONCLUSION: This study provides comprehensive pre-treatment iliac anatomy analysis in patients undergoing endovascular repair with IBDs, highlighting differences between sides and sexes. These findings could refine patient selection for IBD placement, potentially enhancing outcomes in aortoiliac aneurysm treatment. However, the limited number of females in the study underscores the need for further research to generalize findings across genders.

Multiomic Profiling of Human Clonal Hematopoiesis Reveals Genotype and Cell-Specific Inflammatory Pathway Activation.

Clonal hematopoiesis (CH) is an age-associated phenomenon that increases risk for hematologic malignancy and cardiovascular disease. CH is thought to enhance disease risk through inflammation in the peripheral blood1. Here, we profile peripheral blood gene expression in 66,968 single cells from a cohort of 17 CH patients and 7 controls. Using a novel mitochondrial DNA barcoding approach, we were able to identify and separately compare mutant TET2 and DNMT3A cells to non-mutant counterparts. We discovered the vast majority of mutated cells were in the myeloid compartment. Additionally, patients harboring DNMT3A and TET2 CH mutations possessed a pro-inflammatory profile in CD14+ monocytes through previously unrecognized pathways such as galectin and macrophage Inhibitory Factor (MIF). We also found that T cells from CH patients, though mostly un-mutated, had decreased expression of GTPase of the immunity associated protein (GIMAP) genes, which are critical to T cell development, suggesting that CH impairs T cell function.

Effect of Two Years of Doxycycline Treatment on Infrarenal Aortic Neck Diameter.

Objective: Endovascular aneurysm repair (EVAR) is a widely used option for patients with suitable vascular anatomy who have a large infrarenal abdominal aortic aneurysm (AAA). Neck diameter is the primary anatomical determinant of EVAR eligibility and device durability. Doxycycline has been proposed to stabilise the proximal neck after EVAR. This study explored doxycycline mediated aortic neck stabilisation in patients with small AAA, monitored by computed tomography over two years. Methods: This was a multicentre prospective randomised clinical trial. Subjects from the Non-Invasive Treatment of Abdominal Aortic Aneurysm Clinical Trial (N-TA3CT, NCT01756833) were included in this secondary a priori analysis. Female baseline AAA maximum transverse diameter was between 3.5 and 4.5 cm, and male was between 3.5 and 5.0 cm. Subjects were included if they completed pre-enrolment and two year follow up computed tomography (CT) imaging. Proximal aortic neck diameter was measured at the lowest renal artery, and 5, 10, and 15 mm caudal to this point; mean neck diameter was calculated from these values. Unpaired, two tailed parametric t test analysis with post hoc Bonferroni correction was used to detect differences between neck diameters in subjects treated with placebo vs. doxycycline at baseline and two years. Results: One hundred and ninety-seven subjects (171 male, 26 female) were included in the analysis. All patients, regardless of treatment arm, demonstrated larger neck diameter caudally, a slight increase in diameter at all anatomical levels over time, and greater growth caudally. There was no statistically significant difference in infrarenal neck diameter between treatment arms at any anatomical level at any time point, nor mean change in neck diameter over two years. Conclusion: Doxycycline does not demonstrate infrarenal aortic neck growth stabilisation in small AAA followed for two years by thin cut CT imaging using a standardised acquisition protocol and cannot be recommended for mitigation of growth of the aortic neck in patients with untreated small abdominal aortic aneurysms.

Effect of Doxycycline on Progression of Arterial Calcification in the Noninvasive Treatment of Abdominal Aortic Aneurysm Clinical Trial (N-TA(3)CT).

BACKGROUND: Doxycycline has been shown to prevent arterial calcification via attenuation of matrix metalloproteinases (MMP) in preclinical models. We assessed the effects of doxycycline on progression of arterial calcification in patients enrolled in the Non-Invasive Treatment of Abdominal Aortic Aneurysm Clinical Trial (N-TA3CT). METHODS: Two hundred and sixty-one patients were randomized to 100 mg doxycycline twice daily or placebo. Arterial calcification was measured in abdominal vessels on noncontrast computed tomography scans. Patients with baseline computed tomography scan and 1 or more follow-up scans within the 2-year study were included for analysis. For individual arteries, mean change in iliofemoral artery calcification over time was calculated via linear regression. Serum MMP-3 and MMP-9 levels were measured at baseline and 6 months. RESULTS: Sixty-five patients in the doxycycline and 66 in the placebo arm were included in this analysis. Baseline characteristics between the groups were similar. The unadjusted mean change in iliofemoral calcium score per year trended toward higher values in patients treated with doxycycline compared with placebo (322 ± 399 units/year vs. 217 ± 307 units/year, P = 0.09). After 6 months, changes in serum MMP-3 and MMP-9 levels were not significantly different between study arms. CONCLUSIONS: In patients with small aortic aneurysm, treatment with doxycycline 100 mg twice daily did not decrease circulating levels of the matrix degrading enzymes MMP-3 and 9 or alter the progression of arterial calcification.

Disparities in surgical health service delivery and outcomes for indigenous children.

BACKGROUND: Evidence of health disparities for Indigenous children requiring surgical care is lacking. We present a systematic review of the literature examining possible disparities in surgical care and outcomes for pediatric patients of Indigenous ethnicity. DATA SOURCES: PubMed, Cochrane, MEDLINE, gray literature. METHODS: Literature review, using PubMed, Cochrane, MEDLINE, and gray literature was conducted to identify articles published more than 2010-2020 examining children's surgical health service delivery (epidemiology, access, operations provided) and outcomes for pediatric patients of Indigenous ethnicity compared with others. Extracted data included study design, setting, participant race/ethnicity, operations examined, and surgical outcomes. Article quality was assessed using the Newcastle-Ottawa Scales. RESULTS: From 411 abstracts, 125 articles were reviewed and 33 included for data abstraction. These were cohort and cross-sectional studies investigating a wide range of patient populations and procedures across the United States, Canada, Australia, and New Zealand. Articles were organized naturally by theme into birth malformations (15 articles), trauma (6 articles), pediatric general surgery/appendicitis (5 articles), pediatric otolaryngology (6 articles), and renal transplant (1 article) surgery. Four articles also described access and resource utilization related to inpatient care. Notable disparities observed included apparent increased prevalence of gastroschisis, rates of traumatic fatality, non accidental injury, and self harm among North American Indigenous children. CONCLUSIONS: Indigenous children appear to be vulnerable to a number of health and treatment outcome disparities related to conditions treated by surgeons. Surgeons are thus uniquely poised to act in identifying and eliminating Indigenous ethnicity-based pediatric health disparities.

Mesenteric Artery Dissection and Wall-Thickening, Case Study and General Review.

Mesenteric artery dissection (D) and wall-thickening (WT) are rare vasculopathies that can lead to serious complications. This is a single center analysis of all patients evaluated for mesenteric arterial (celiac, superior (SMA) and/or inferior mesenteric (IMA)) D and/or WT from January 1, 2000, to January 31, 2020 at our hospital. Among the 101 included patients, the average age was 55.6 ± 13.6 years, mostly affecting men (62%). There were 20 celiac artery D, 8 WT, 15 D with WT, 15 SMA D, 7 WT, 8 D with WT, one IMA D, two WT, and 25 with multiple arterial involvement. Primary etiologies included segmental arterial mediolysis (SAM) (n = 17), isolated D (n = 17), localized vasculitis of the gastrointestinal tract (LVGT) (n = 16), fibromuscular dysplasia (FMD) (n = 13), extension of thoracoabdominal aortic D (n = 12), and trauma (n = 12). Most (71%) patients presented with abdominal pain. Hypertension (55%), hyperlipidemia (33%) and tobacco use (31%) were prevalent. Management included conservative (22%), medical (47%), endovascular (19%), and/or open repair (12%) with high in-hospital survival (98%) and symptom relief (73%). Our paper complements the scarce literature addressing the diagnosis and management of rare mesenteric vasculopathies. Most patients improved with conservative management, reserving endovascular or surgical interventions for symptomatic patients with more complicated presentations.

Surgeon perceptions of volume threshold and essential practices for pediatric thyroidectomy✰.

INTRODUCTION: The topics of sub-specialization and regionalization of care have garnered increased attention among pediatric surgeons. Thyroid surgeries are one such sub-specialty and are commonly concentrated within practices. A national survey was conducted examining current surgeon practices and beliefs surrounding pediatric thyroid surgery. METHODS: Non-resident members of the American Pediatric Surgical Association (APSA) were surveyed in October 2020. Respondents were stratified based on self-reported thyroid surgical experience. Those who performed thyroid surgery were asked about surgical technique and operative practices; those who did not were asked about referral patterns. All respondents were asked about perceptions surrounding the volume-outcome relationship for pediatric thyroid surgery. RESULTS: Among 1015 APSA members, 405 (40%) responded, with 79% (317/400) practicing at academic hospitals, 58% (232/401) practicing in major metropolitan area, and 41% (161/392) with over 10 years of attending pediatric surgery experience. Most respondents (88%, n = 356) agreed that thyroid surgery volume affects outcome, though wide variation was reported in the annual case threshold for "high volume" surgery. Eighty-four respondents (21%) reported performing ≥ 1 pediatric thyroid surgery in the past year. Of these, 82% routinely use recurrent laryngeal nerve monitoring, 32% routinely send hemithyroidectomy patients home the same day, and there was little consensus surrounding postoperative hypocalcemia management. The majority of respondents endorse performing thyroid procedures with a colleague. CONCLUSIONS: Pediatric thyroid surgery appears to be performed by a subset of active pediatric surgeons, most of whom endorse the use of a dual operating team. More evidence is needed to build consensus around additional perioperative practices.

Effect of surgeon volume on pediatric thyroid surgery outcomes: A systematic review.

BACKGROUND: Pediatric thyroidectomy has been identified as a surgical procedure that may benefit from concentrating cases to high-volume surgeons. This systematic review aimed to address the definition of "high-volume surgeon" for pediatric thyroidectomy and to examine the relationship between surgeon volume and outcomes. METHODS: PubMed, Embase, Cochrane Library, Scopus, Web of Science, ClinicalTrials.gov, and OpenGrey databases were searched for through February 2020 for studies which reported on pediatric thyroidectomy and specified surgeon volume and surgical outcomes. RESULTS: Ten studies, encompassing 6430 patients, were included in the review. Five single-center retrospective studies reported only on high-volume surgeons, one single center retrospective study reported on only low-volume surgeons, and four national database studies (2 cross sectional, 2 retrospective reviews) reported outcomes for both high-volume and low-volume surgeons. Majority of patients underwent total thyroidectomy (54.9%); common indications for surgery were malignancy (41.7%) and hyperthyroidism/thyroiditis (40.5%). Rates of transient hypocalcemia (11.4% - 74.2%), transient recurrent laryngeal nerve injury (0% - 9.7%), and bleeding (0.5% - 4.3%) varied across studies. Definitions for high-volume pediatric thyroid surgeons ranged from ≥9 annual pediatric thyroid operations to >200 annual thyroid operations (with >30 pediatric cases). Four studies reported significantly better outcomes, including lower post-operative complications and shorter length of hospital stay, for patients treated by high-volume surgeons. CONCLUSIONS: Despite significant variation in caseloads to define volume, pediatric thyroid patients have generally better outcomes when operated on by higher volume surgeons. Concentration thyroidectomy cases to a smaller cohort of surgeons within pediatric practices may confer improved outcomes. LEVEL OF EVIDENCE: Systematic Reviews and Meta-Analyses; Level IV.

Role of volume in small abdominal aortic aneurysm surveillance.

OBJECTIVE: Current management of small abdominal aortic aneurysms (AAAs) primarily involves serial imaging surveillance of maximum transverse diameter (MTD) to estimate rupture risk. Other measurements, such as volume and tortuosity, are less well-studied and may help characterize and predict AAA progression. This study evaluated predictors of AAA volume growth and discusses the role of volume in clinical practice. METHODS: Subjects from the Non-invasive Treatment of Abdominal Aortic Aneurysm Clinical Trial (baseline AAA MTD, 3.5-5.0 cm) with ≥2 computed tomography scans were included in this study (n = 250). Computed tomography scans were conducted approximately every 6 months over 2 years. MTD, volume, and tortuosity were used to model growth. Univariable and multivariable backwards elimination least squares regressions assessed associations with volume growth. RESULTS: Baseline MTD accounted for 43% of baseline volume variance (P < .0001). Mean volume growth rate was 10.4 cm3/year (standard deviation, 8.8 cm3/year) (mean volume change +10.4%). Baseline volume accounted for 30% of volume growth variance; MTD accounted for 13% of volume growth variance. More tortuous aneurysms at baseline had significantly larger volume growth rates (difference, 32.8 cm3/year; P < .0001). Univariable analysis identified angiotensin II receptor blocker use (difference, -3.4 cm3/year; P = .02) and history of diabetes mellitus (difference, -2.8 cm3/year; P = .04) to be associated with lower rates of volume growth. Baseline volume, tortuosity index, current tobacco use, and absence of diabetes mellitus remained significantly associated with volume growth in multivariable analysis. AAAs that reached the MTD threshold for repair had a wide range of volumes: 102 cm3 to 142 cm3 in female patients (n = 5) and 105 cm3 to 229 cm3 in male patients (n = 20). CONCLUSIONS: Baseline AAA volume and MTD were found to be moderately correlated. On average, AAA volume grows about 10% annually. Baseline volume, tortuosity, MTD, current tobacco use, angiotensin II receptor blocker use, and history of diabetes mellitus were predictive of volume growth over time.

Surgeon Learning Curve and Clinical Outcomes of Minimally Invasive Anterior Lumbar Interbody Fusion With Posterior Percutaneous Instrumentation.

OBJECTIVES: This study reports the learning phase of the minimally invasive anterior lumbar interbody fusion (mini-ALIF) approach with a vascular and orthopaedic spine surgeon team. METHODS: Adult patients who underwent primary mini-ALIF at the lowest two segments of the lumbar spine (i.e., L4/5, L5/S1) between January 2010 and December 2018 were analyzed. RESULTS: One hundred twenty-seven patients were included. There was no notable change in total surgical time over the study period. Estimated blood loss markedly decreased until stabilizing at case 30 and slowly declined thereafter. The mean estimated blood loss was 184 mL for L5/S1, 232 mL for L4/L5, and 458 mL for two-level mini-ALIF. There were 20 vascular issues requiring primary repair or packing. Vascular issues declined over time, with a rate of 32% in the first 25 cases and 0% in the last 25. The postoperative complication rate was highest in the first 25 cases (7 of 21 total complications). The odds ratio of vascular injury with body mass index (BMI) > 35 was 4.09 (1.4 to 11.7 confidence interval, P ≤ 0.008). Total surgical time and postoperative complications increased with increasing BMI. CONCLUSION: Performance of the mini-ALIF approach is associated with a learning curve of 25 to 30 cases before complications begin to decline. BMI > 35 is associated with increased surgical time and complications.

Conformability of the GORE EXCLUDER iliac branch endoprosthesis is associated with freedom from adverse iliac events.

OBJECTIVE: The GORE EXCLUDER iliac branch endoprosthesis (IBE; W.L. Gore & Associates, Flagstaff, Ariz) is designed to preserve internal iliac artery (IIA) patency during endovascular treatment of aneurysms involving the common iliac artery. The device is intended to conform to iliac tortuosity, which may decrease adverse iliac events (AIE). The objective of this study was to evaluate risk factors for AIE after IBE implantation. METHODS: This was a post hoc analysis of the prospective, multicenter GORE 12-04 IBE pivotal trial. Patients with preoperative and postoperative axial imaging were included, with analysis based on each treated iliac system. An independent core laboratory performed all scan measurements, including iliac diameters, lengths, and tortuosity. Conformability was analyzed by the changes in tortuosity after IBE deployment, with less change indicating greater conformation. The end point was AIE, defined as ipsilateral radiographic or clinical complications. Critical nonconformation was defined as a threshold change in tortuosity associated with a significant increase in AIE. RESULTS: We included 98 patients with 101 treated iliac systems. There were eight AIE (8%; six IIA component occlusions, one iliac branch component occlusion, and one EIA dissection requiring reintervention). Patients with AIE had smaller IIA diameters and less IBE conformability. After multivariable logistic regression analysis, an IIA diameter of less than 10 mm and a change in total iliac tortuosity beyond -15% were independently associated with AIE (odds ratio, 12 [interquartile range, 1.4-110] and odds ratio, 8.2 [interquartile range, 1.5-46], respectively), and the latter was used to define critical nonconformation. Critical nonconformation occurred in 11% of treated systems, and was associated with a high rate of AIE (36% vs 4%; P = .004). CONCLUSIONS: Endograft conformation is a novel device property and technical outcome that, along with a larger IIA diameter, is associated with freedom from AIE after IBE deployment. An evaluation of these risk factors may better inform the management of patients with iliac aneurysmal disease. Further research on endograft conformation and patient outcomes is warranted, particularly for those with challenging anatomy undergoing complex procedures.

Anatomic eligibility for endovascular aneurysm repair preserved over 2 years of surveillance.

OBJECTIVE: Endovascular aneurysm repair (EVAR) is a widely used option for patients with suitable vascular anatomy who have a large infrarenal abdominal aortic aneurysm (AAA). Patients with small AAAs are managed with careful surveillance and it is a common concern that their anatomy may change with AAA growth, and their option for EVAR may become limited. Device innovation has resulted in expanded ranges of anatomy that may be eligible for EVAR. This study sought to identify changes in anatomic eligibility for repair with contemporary endovascular devices in AAA patients, monitored by computed tomography scan over the course of 2 years. METHODS: Patients from the Non-Invasive Treatment of Abdominal Aortic Aneurysm Clinical Trial (N-TA3CT, NCT01756833) were included in this analysis. Females had baseline AAA maximum transverse diameter between 3.5 and 4.5 cm, and males had baseline maximum transverse diameter between 3.5 and 5.0 cm. Patients were included in this analysis if they completed pre-enrollment and 2-year follow-up computed tomography imaging. Pertinent anatomic measurements were performed on a postprocessing workstation in a centralized imaging core laboratory. EVAR candidacy was determined by measuring proximal aortic neck diameter, AAA length, and infrarenal neck angulation. Patients were considered to be eligible for EVAR if they qualified for at least one of the seven studied devices' instructions for use at baseline and at 2 years. A paired t test analysis was used to detect differences in aortic measurements over 2 years, and the McNemar test was used to compare eligibility over 2 years. RESULTS: We included 192 patients in this analysis-168 male and 24 female. Of these patients, 85% were eligible for EVAR at baseline and 85% after 2 years of follow-up (P = 1.00; 95% confidence interval -0.034 to 0.034). Of the 164 EVAR candidates at baseline, 160 (98%) remained eligible over 2 years of surveillance. Insufficient neck length was the most common reason for both ineligibility at baseline (18 of 28 patients) as well as loss of candidacy over 2 years (3 of 4 patients). CONCLUSIONS: The majority of patients eligible for EVAR when entering a surveillance program for small AAA remain eligible after 2 years. Substantial changes in AAA neck anatomy resulting in loss of EVAR treatment options are infrequent. Patients with anatomic AAA progression beyond EVAR eligibility remain candidates for complex EVAR and open repair.

Segmentor: a tool for manual refinement of 3D microscopy annotations.

BACKGROUND: Recent advances in tissue clearing techniques, combined with high-speed image acquisition through light sheet microscopy, enable rapid three-dimensional (3D) imaging of biological specimens, such as whole mouse brains, in a matter of hours. Quantitative analysis of such 3D images can help us understand how changes in brain structure lead to differences in behavior or cognition, but distinguishing densely packed features of interest, such as nuclei, from background can be challenging. Recent deep learning-based nuclear segmentation algorithms show great promise for automated segmentation, but require large numbers of accurate manually labeled nuclei as training data. RESULTS: We present Segmentor, an open-source tool for reliable, efficient, and user-friendly manual annotation and refinement of objects (e.g., nuclei) within 3D light sheet microscopy images. Segmentor employs a hybrid 2D-3D approach for visualizing and segmenting objects and contains features for automatic region splitting, designed specifically for streamlining the process of 3D segmentation of nuclei. We show that editing simultaneously in 2D and 3D using Segmentor significantly decreases time spent on manual annotations without affecting accuracy as compared to editing the same set of images with only 2D capabilities. CONCLUSIONS: Segmentor is a tool for increased efficiency of manual annotation and refinement of 3D objects that can be used to train deep learning segmentation algorithms, and is available at https://www.nucleininja.org/ and https://github.com/RENCI/Segmentor .

CXCR4 allows T cell acute lymphoblastic leukemia to escape from JAK1/2 and BCL2 inhibition through CNS infiltration.

Targeting the JAK/STAT and BCL2 pathways in patients with relapsed/refractory T cell acute lymphoblastic leukemia (T-ALL) may provide an alternative approach to achieve clinical remissions. Ruxolitinib and venetoclax show a dose-dependent effect on T-ALL individually, but combination treatment reduces survival and proliferation of T-ALL in vitro. Using a xenograft model, the combination treatment fails to improve survival, with death from hind limb paralysis. Despite on-target inhibition by the drugs, histopathology demonstrates increased leukemic infiltration into the central nervous system (CNS) as compared to liver or bone marrow. Liquid chromatography-tandem mass spectroscopy shows that ruxolitinib and venetoclax insufficiently cross into the CNS. The addition of the CXCR4 inhibitor plerixafor with ruxolitinib and venetoclax reduces clinical scores and enhances survival. While combination therapy with ruxolitinib and venetoclax shows promise for treating T-ALL, additional inhibition of the CXCR4-CXCL12 axis may be needed to maximize the possibility of complete remission.

Evaluating Growth Patterns of Abdominal Aortic Aneurysm Diameter With Serial Computed Tomography Surveillance.

Importance: Small abdominal aortic aneurysms (AAAs) are common in the elderly population. Their growth rates and patterns, which drive clinical surveillance, are widely disputed. Objective: To assess the growth patterns and rates of AAAs as documented on serial computed tomography (CT) scans. Design, Setting, and Participants: Cohort study and secondary analysis of the Non-Invasive Treatment of Abdominal Aortic Aneurysm Clinical Trial (N-TA3CT), a randomized, double-blind placebo-controlled clinical trial conducted from 2013 to 2018, with CT imaging every 6 months for 2 years. The trial was a multicenter, observational secondary analysis, not related to treatment hypotheses of data collected in the N-TA3CT. Participants included 254 patients with baseline AAA diameter between 3.5 and 5.0 cm. Exposures: Patients received serial CT scan measurements, analyzed for maximum transverse diameter, at 6-month intervals. Main Outcomes and Measures: The primary study outcome was AAA annual growth rate. Secondary analyses included characterizing AAA growth patterns, assessing likelihood of AAA diameter to exceed sex-specific intervention thresholds over 2 years. Results: A total of 254 patients, 35 women with baseline AAA diameter 3.5 to 4.5 cm and 219 men with baseline diameter 3.5 to 5.0 cm, were included. Yearly growth rates of AAA diameters were a median of 0.17 cm/y (interquartile range [IQR], 0.16) and a mean (SD), 0.19 (0.14) cm/y. Ten percent of AAAs displayed minimal to no growth (<0.05 cm/y), 62% displayed low growth (0.05-0.25 cm/y), and 28% displayed high growth (>0.25 cm/y). Baseline AAA diameter accounted for 5.4% of variance of growth rate (P < .001; R2, 0.054). Most AAAs displayed linear growth (70%); large variations in interval growth rates occurred infrequently (3% staccato growth and 4% exponential growth); and some patients' growth patterns were not clearly classifiable (23% indeterminate). No patients with a maximum transverse diameter less than 4.25 cm exceeded sex-specific repair thresholds at 2 years (men, 0 of 92; 95% CI, 0.00-0.055; women, 0 of 25 ; 95% CI, 0.00-0.247). Twenty-six percent of patients with a maximum transverse diameter of at least 4.25 cm exceeded sex-specific repair thresholds at 2 years (n = 12 of 83 men with diameter ranging from 4.25 to <4.75 cm; 95% CI, 0.091-0.264; n = 21 of 44 men with diameter ranging from 4.75-5.0 cm; 95% CI, 0.362-0.669; n = 3 of 10 women with diameter ≥4.25 cm; 95% CI, 0.093-0.726). Conclusions and Relevance: Most small AAAs showed linear growth; large intrapatient variations in interval growth rates were infrequently observed over 2 years. Linear growth modeling of AAAs in individual patients suggests smaller AAAs (<4.25 cm) can be followed up with a CT scan in at least 2 years with little chance of exceeding interventional thresholds. Trial Registration: ClinicalTrials.gov Identifier: NCT01756833.

Interferon regulatory factor 4 as a therapeutic target in adult T-cell leukemia lymphoma.

BACKGROUND: Adult T-cell leukemia lymphoma (ATLL) is a chemotherapy-resistant malignancy with a median survival of less than one year that will afflict between one hundred thousand and one million individuals worldwide who are currently infected with human T-cell leukemia virus type 1. Recurrent somatic mutations in host genes have exposed the T-cell receptor pathway through nuclear factor κB to interferon regulatory factor 4 (IRF4) as an essential driver for this malignancy. We sought to determine if IRF4 represents a therapeutic target for ATLL and to identify downstream effectors and biomarkers of IRF4 signaling in vivo. RESULTS: ATLL cell lines, particularly Tax viral oncoprotein-negative cell lines, that most closely resemble ATLL in humans, were sensitive to dose- and time-dependent inhibition by a next-generation class of IRF4 antisense oligonucleotides (ASOs) that employ constrained ethyl residues that mediate RNase H-dependent RNA degradation. ATLL cell lines were also sensitive to lenalidomide, which repressed IRF4 expression. Both ASOs and lenalidomide inhibited ATLL proliferation in vitro and in vivo. To identify biomarkers of IRF4-mediated CD4 + T-cell expansion in vivo, transcriptomic analysis identified several genes that encode key regulators of ATLL, including interleukin 2 receptor subunits α and ß, KIT ligand, cytotoxic T-lymphocyte-associated protein 4, and thymocyte selection-associated high mobility group protein TOX 2. CONCLUSIONS: These data support the pursuit of IRF4 as a therapeutic target in ATLL with the use of either ASOs or lenalidomide.

A Frailty-Based Risk Score Predicts Morbidity and Mortality After Elective Endovascular Repair of Descending Thoracic Aortic Aneurysms.

BACKGROUND: Thoracic endovascular aortic repair (TEVAR) has expanded access to descending thoracic aortic aneurysm (DTAA) repair particularly for elderly and frail patients. This high-risk population has limited long-term overall survival, such that appropriate patient selection is required to optimize patient benefit and resource utilization. Our objective is to develop and validate a frailty-based, procedure-specific risk score for patients undergoing elective TEVAR for DTAA. METHODS: Patients undergoing nonemergent TEVAR for DTAA during 2005-2016 were identified in the National Surgical Quality Improvement Program database. Those with concurrent cardiac or open aortic surgery, abdominal visceral intervention, or Zone 0 deployment were excluded. Patients were randomly divided between derivation and validation samples. The primary outcome was 30-day major adverse events (MAE), including mortality and major systemic complications. Using the derivation cohort, variables associated with MAE were identified by univariable analyses. Those with P < 0.05 were included in multivariable logistic regression analysis. Independent procedure-specific and frailty-related risk factors for MAE were used to develop a pragmatic score to assess risk for TEVAR. RESULTS: Overall, 1,784 patients were included. 14% of the derivation patients had MAE (14% major complications, 4% mortality). Independent risk factors for MAE were primarily associated with markers of frailty and TEVAR extent and complexity and included functional dependence (OR 2.9, 95% CI 1.6-5.4), pulmonary disease (1.6, 1.1-2.4), thoracoabdominal extent (2.2 (1.4-3.4), need for iliac access (2.1, 1.1-3.8), and Zone I or II deployment (OR 1.7, 1.1-2.5). According to their respective beta coefficients, each variable was assigned a single point. Based on total points, patients were stratified as low- (0 points), intermediate- (1 point), or high-risk (≥2 points), with stepwise increases in mortality (0%, 4%, and 9%) and major complications (7%, 11%, and 23%) between strata. Validation patients had similar characteristics, risk strata distribution, and outcomes as the derivation patients, and the risk model had similar performance in both groups. CONCLUSIONS: Markers of frailty and procedure complexity strongly predict MAE after TEVAR for DTAA and can improve patient selection by enabling patient and procedure-specific risk stratification. While TEVAR is safe in low-risk patients, intermediate-risk patients warrant careful discussion of the risks and benefits of aortic intervention; under certain circumstances, high-risk patients may not benefit. Further study is required to define the association between frailty and long-term outcomes.

CT-Derived Pretreatment Thoracic Sarcopenia Is Associated with Late Mortality after Thoracic Endovascular Aortic Repair.

BACKGROUND: Frailty, characterized by physiologic depletion, predicts postoperative morbidity and mortality in vascular surgery patients. CT-derived sarcopenia is a valuable method for objectively staging frailty preoperatively. PURPOSE: With prior analyses primarily measuring psoas cross-sectional area on CT, we compared a method of measuring thoracic sarcopenia to existing techniques of lumbar sarcopenia and assessed the association with long-term survival and outcomes post-Thoracic Endovascular Aortic Repair (TEVAR). METHODS: Prospectively collected data of 217 patients undergoing TEVAR from 2009 to 2012 were reviewed. Thoracic sarcopenia was quantified by measuring total area of the rectus abdominis, latissimus dorsi, intercostal, erector spinae, and external and internal oblique muscles at the T12 vertebral level. Total psoas area at the L3 was used to measure lumbar sarcopenia. RESULTS: 200 patients had preoperative imaging enabling measurements of thoracic sarcopenia, 186 of these patients were also assessed for lumbar sarcopenia. Thoracic sarcopenic patients were older, had lower body mass indices, were more commonly female, and most commonly being treated for aneurysms. Thoracic sarcopenic patients had significantly higher rates of congestive heart failure, hypertension, prior vascular intervention, and TEVAR-related adverse events. Thoracic sarcopenia was associated with significantly higher mortality at 2 and 5 years post-TEVAR (2-year mortality: 19% vs 8%, P = 0.02; 5-year mortality: 31% vs 18%, P = 0.03). Lumbar sarcopenia was not associated with increased mortality at any time point. Patients whose muscle mass degraded over 48-month follow-up did not experience significantly higher rates of adverse events. CONCLUSIONS: CT-derived thoracic sarcopenia, but not lumbar sarcopenia, is significantly associated with 5-year mortality post-TEVAR.