Comparing Functional Frailty and Radiographic Sarcopenia as Predictors of Outcomes After Liver Transplant.

INTRODUCTION: Frailty and sarcopenia are associated with an increased risk of hospitalization and mortality in patients with end-stage liver disease. The ability to identify frail patients at risk of adverse outcomes could help optimize liver transplant (LT) evaluations and pre-transplant care. This study compared sarcopenia, via L3-psoas muscle index (L3-PMI), to frailty, via liver frailty index (LFI) and analyzed associated outcomes after liver transplantation (LT). METHODS: A retrospective review of consecutive LT-recipients with cross-sectional abdominal/pelvic imaging were reviewed over 5 years at a single transplant center. RESULTS: Four hundred and twenty-six patients underwent transplant during this study interval; 31% of patients were sarcopenic. Two hundred eight patients underwent LFI evaluation: 25% were frail, 59% were prefrail, and 16% were robust. Sarcopenic patients had higher LFI scores indicating greater frailty (p = 0.02). Both sarcopenia and LFI-frailty were associated with significantly higher MELD-Na scores. Length of post-LT hospital stay was increased in sarcopenic (mean 14 vs. nonsarcopenic 11 days, p = 0.02) and LFI-frail patients (mean 13 vs. 10 prefrail, 8 robust, p = 0.04). As a categorical variable, neither LFI-frailty nor sarcopenia were significantly associated with reduced survival at 1-year (robust 100%, prefrail 93.5%, frail 91.1%, p = 0.31) (nonsarcopenic 94.4%, sarcopenic 91.4%, p = 0.30). However, LFI score was significantly associated with mortality at 1-year (OR 2.133, p = 0.047). CONCLUSIONS: Radiographic sarcopenia is a suitable proxy for in-person frailty assessment as both L3-PMI and LFI capture frail patients' pre-LT. However, physical assessment with frailty better predicts 1-year mortality post-LT than the measurement of muscle mass.

Multicenter CT Image-Based Anatomic Assessment of Patients with Aortoiliac Aneurysm Undergoing Endovascular Repair with Iliac Branch Devices.

BACKGROUND: The Global Iliac Branch Study (NCT05607277) is an international, multicenter, retrospective cohort study of anatomic predictors of adverse iliac events (AIEs) in aortoiliac aneurysms treated with iliac branch devices (IBDs). METHODS: Patients with pre-IBD and post-IBD computed tomography imaging were included. We measured arterial diameters, stenosis, calcification, bifurcation angles, and tortuosity indices using a standardized, validated protocol. A composite of ipsilateral AIE was defined, a priori, as occlusion, type I or III endoleak, device constriction, or clinical event requiring reintervention. Paired t-test compared tortuosity indices and splay angles pretreatment and post-treatment for all IBDs and by device material (stainless steel and nitinol). Two-sample t-test compared anatomical changes from pretreatment to post-treatment by device material. Logistic regression assessed associations between AIE and anatomic measurements. Analysis was performed by IBD. RESULTS: We analyzed 297 patients (286 males, 11 females) with 331 IBDs (227 stainless steel, 104 nitinol). Median clinical follow-up was 3.8 years. Iliac anatomy was significantly straightened with all IBD treatment, though stainless steel IBDs had a greater reduction in total iliac artery tortuosity index and aortic splay angle compared to nitinol IBDs (absolute reduction -0.20 [-0.22 to -0.18] vs. -0.09 [-0.12 to -0.06], P < 0.0001 and -19.6° [-22.4° to -16.9°] vs. -11.2° [-15.3° to -7.0°], P = 0.001, respectively). There were 54 AIEs in 44 IBDs in 42 patients (AIE in 13.3% of IBD systems), requiring 35 reinterventions (median time to event 41 days; median time to reintervention 153 days). There were 18 endoleaks, 29 occlusions, and 5 device constrictions. There were no strong associations between anatomic measurements and AIE overall, though internal iliac diameter was inversely associated with AIE in nitinol devices (nAIE, nitinol = 8). CONCLUSIONS: Purpose-built IBDs effectively treat aortoiliac disease, including that with tortuous anatomy, with a high patency rate (91.5%) and low reintervention rate (9.1%) at 4 years. Anatomic predictors of AIE are limited.

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.

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.

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.

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 .

Rapid progression of adult T-cell leukemia/lymphoma as tumor-infiltrating Tregs after PD-1 blockade.

Immune checkpoint inhibitors are a powerful new tool in the treatment of cancer, with prolonged responses in multiple diseases, including hematologic malignancies, such as Hodgkin lymphoma. However, in a recent report, we demonstrated that the PD-1 inhibitor nivolumab led to rapid progression in patients with adult T-cell leukemia/lymphoma (ATLL) (NCT02631746). We obtained primary cells from these patients to determine the cause of this hyperprogression. Analyses of clonality, somatic mutations, and gene expression in the malignant cells confirmed the report of rapid clonal expansion after PD-1 blockade in these patients, revealed a previously unappreciated origin of these malignant cells, identified a novel connection between ATLL cells and tumor-resident regulatory T cells (Tregs), and exposed a tumor-suppressive role for PD-1 in ATLL. Identifying the mechanisms driving this alarming outcome in nivolumab-treated ATLL may be broadly informative for the growing problem of rapid progression with immune checkpoint therapies.

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.

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.

An activating mutation of interferon regulatory factor 4 (IRF4) in adult T-cell leukemia.

The human T-cell leukemia virus-1 (HTLV-1) oncoprotein Tax drives cell proliferation and resistance to apoptosis early in the pathogenesis of adult T-cell leukemia (ATL). Subsequently, probably as a result of specific immunoediting, Tax expression is down-regulated and functionally replaced by somatic driver mutations of the host genome. Both amplification and point mutations of interferon regulatory factor 4 (IRF4) have been previously detected in ATL., K59R is the most common single-nucleotide variation of IRF4 and is found exclusively in ATL. High-throughput whole-exome sequencing revealed recurrent activating genetic alterations in the T-cell receptor, CD28, and NF-κB pathways. We found that IRF4, which is transcriptionally activated downstream of these pathways, is frequently mutated in ATL. IRF4 RNA, protein, and IRF4 transcriptional targets are uniformly elevated in HTLV-1-transformed cells and ATL cell lines, and IRF4 was bound to genomic regulatory DNA of many of these transcriptional targets in HTLV-1-transformed cell lines. We further noted that the K59R IRF4 mutant is expressed at higher levels in the nucleus than WT IRF4 and is transcriptionally more active. Expression of both WT and the K59R mutant of IRF4 from a constitutive promoter in retrovirally transduced murine bone marrow cells increased the abundance of T lymphocytes but not myeloid cells or B lymphocytes in mice. IRF4 may represent a therapeutic target in ATL because ATL cells select for a mutant of IRF4 with higher nuclear expression and transcriptional activity, and overexpression of IRF4 induces the expansion of T lymphocytes in vivo.

Derivation and validation of thoracic sarcopenia assessment in patients undergoing thoracic endovascular aortic repair.

OBJECTIVE: Sarcopenia, as assessed by computed tomography (CT)-based measurements of muscle mass, is an objective and patient-specific indicator of frailty, which is an important predictor of operative morbidity and mortality. Studies to date have primarily focused on psoas-defined sarcopenia, which may not be valid among patients with thoracic aortic disease. Using psoas sarcopenia as the reference for sarcopenia, the purpose of this study was to create and to validate a new thoracic-level method of measuring sarcopenia as a novel method to assess frailty among patients undergoing thoracic endovascular aortic repair. METHODS: Prospectively collected data of patients undergoing thoracic endovascular aortic repair for thoracic aortic dissection, aneurysm, or injury using a conformable thoracic graft were reviewed. Patients with preoperative abdominal and thoracic CT imaging were included. Thoracic muscle mass was measured on axial images at the T12 level using our newly established standardized computer-assisted protocol. Psoas sarcopenia was measured at the L3 level using standard methods. Optimal sex-specific diagnostic T12 measurements were determined by receiver operating characteristic (ROC) curve analysis. A subset of scans were reviewed in duplicate by two trained observers and intraobserver and interobserver reliability tested by intraclass correlation coefficient. Agreement between T12 and L3 sarcopenia was tested by Cohen κ (scale, 0-1). RESULTS: There were 147 patients included for analysis, including 34 dissection, 80 trauma, and 33 aneurysm patients. ROC curve analysis yielded sarcopenic cutoff values of 106.00 cm2/m2 for women and 110.00 cm2/m2 for men at the T12 level. Based on ROC curve analysis, overall accuracy of T12 measurements was high (area under ROC curve, 0.91 for men and 0.90 for women). Quantitative interobserver and intraobserver reliability yielded excellent intraclass correlation coefficient values (>0.95). Qualitative interobserver reliability yielded nearly perfect Cohen κ values (>0.85). Qualitative intraobserver reliability of calculating sarcopenia at both the T12 and L3 levels was fair for both readers (0.361 and 0.288). There was additionally a general correlation between changes in muscle area at L3 with changes at T12 during 48 months. CONCLUSIONS: Thoracic sarcopenia can be readily and reliably reproduced from CT-derived measurement of T12-level muscle area. This approach may be used as an alternative method to objectively define sarcopenia in patients without abdominal CT imaging. Future studies to assess the predictability of thoracic vs abdominal sarcopenia on postoperative outcomes will enhance the utility of these tools.

Segmental arterial mediolysis (SAM): Systematic review and analysis of 143 cases.

Segmental arterial mediolysis (SAM) is a rare but serious nonatherosclerotic, noninflammatory vasculopathy of unknown etiology that often results in dissection, aneurysm, occlusion, or stenosis of, primarily, the abdominal arteries. Current literature lacks consensus on diagnostic criteria and management options for SAM. This review summarizes 143 cases and aims to advance appropriate recognition and management of SAM. Literature review of all relevant SAM case studies from 2005 to 2018 yielded 126 individual SAM cases from 66 reports. We identified 17 additional SAM cases from our center, bringing our analysis to 143 patients. Patients with SAM were most commonly men (68%) in their 60s. Hypertension (43%), tobacco use (12%), and hyperlipidemia (12%) were common comorbidities. Abdominal pain (80%) and intraabdominal bleeding (50%) were the most common presenting symptoms. Computed tomography was the most frequently used imaging method (78%), and histology was available in 44% of cases. The most commonly affected vessels were the superior mesenteric (53%), hepatic (45%), celiac (36%), renal (26%), and splenic (25%) arteries with aneurysm (76%), dissection (61%), and arterial rupture (46%). Treatments included coil embolization (28%), abdominal organ surgery (24%), open arterial repair (21%), and medical management (20%). Case-specific treatment modalities yielded symptom relief in the vast majority (91%) of patients, with a mortality rate of 7%.

A Novel Frameshift COL3A1 Variant in Vascular Ehlers-Danlos Syndrome.

Ehlers-Danlos syndromes (EDSs) are a group of heritable connective tissue disorders with distinct genetic etiologies. Of the 13 currently recognized types of EDS, the vascular type EDS (vEDS) is generally considered the most severe and is associated with a decreased life expectancy due to spontaneous arterial, intestinal, and or uterine rupture. Diagnosis of vEDS is supported by genetic testing confirming the presence of pathogenic variations in COL3A1, a type III procollagen gene. Management of vEDS is usually conservative with control of hemodynamic stress, frequent cardiovascular imaging, and, if indicated, a thoughtful endovascular intervention or surgical repair. We present a novel frameshift variant in COL3A1 leading to vEDS with multiple vascular involvements. Based on our literature review, this variant has not been reported and may result in a less severe form of vEDS. Our case report provides insight into genetic variants and clinical expression of vEDS.

Nonatherosclerotic Abdominal Vasculopathies.

BACKGROUND: Nonatherosclerotic abdominal arterial vasculopathies (NAVs), including mesenteric or renal artery dissection, aneurysm, stenosis, and vasculitis, are rare but have great clinical significance. Patients may present emergently with life-threatening complications such as arterial rupture and hemorrhagic shock. Herein, we present our center's experience with NAVs and provide extensive literature review to close the gap in the scarce, related literature. METHODS: From a single-center retrospective data analysis, we identified and characterized subjects (aged 18-60 years) who presented with NAV between January 2000 and December 2015. Of the 1416 charts reviewed, 118 met inclusion criteria. RESULTS: The average age of patients with NAV was 47.0 ± 9.9 years, mostly affecting women (64%). Primary diagnoses included fibromuscular dysplasia (FMD) (25.4%), isolated aneurysms (24.6%), and median arcuate ligament syndrome (MALS) (15.3%). Less common diagnoses were localized vasculitis of the gastrointestinal tract (LVGT) (7.6%), isolated dissection (5.1%), microscopic polyangiitis and granulomatosis with polyangiitis (5.1%), trauma (4.2%), segmental arterial mediolysis (4.2%), Ehlers-Danlos syndrome (2.5%), Takayasu's arteritis (2.5%), polyarteritis nodosa (1.7%), idiopathic abdominal aortitis (0.8%), and Loeys-Dietz syndrome (0.8%). Females constituted 90% of patients with FMD, 77.8% with MALS, 77.8% with isolated aneurysms, 66.7% with Takayasu arteritis, and 55.6% with LVGT. Prevalent comorbidities included tobacco use (43.6%) and hypertension (52.1%). Coil embolization was used in 14.4%, anticoagulation in 11.9%, angioplasty/stenting in 11.9%, open resection/surgical revascularization in 10.2%, and prednisone in 10.2% of the cases. Conservative management was pursued in 33.1% of the patients. A high degree of symptom relief was shown in 91.7%. CONCLUSIONS: NAV are rare and can be caused by different etiologies that primarily affect females. Hypertension and tobacco use were prevalent. Various imaging strategies revealed aneurysms, stenosis, dissection, and/or thrombosis affecting renal and celiac arteries. Most patients improved with conservative, medical, endovascular, or surgical approach. More research is needed to standardize management approach to patients with NAV.

Hypoxia in uterine fibroids: role in pathobiology and therapeutic opportunities.

Uterine fibroids are the most common tumors in females affecting up to 70% of women world-wide, yet targeted therapeutic options are limited. Oxidative stress has recently surfaced as a key driver of fibroid pathogenesis and provides insights into hypoxia-induced cell transformation, extracellular matrix pathophysiology, hypoxic cell signaling cascades, and uterine biology. Hypoxia drives fibroid tumorigenesis through (1) promoting myometrial stem cell proliferation, (2) causing DNA damage propelling transformation of stem cells to tumor initiating cells, and (3) driving excess extracellular matrix (ECM) production. Common fibroid-associated DNA mutations include MED12 mutations, HMGA2 overexpression, and Fumarate hydratase loss of function. Evidence suggests an interaction between hypoxia signaling and these mutations. Fibroid development and growth are promoted by hypoxia-triggered cell signaling via various pathways including HIF-1, TGFß, and Wnt/ß-catenin. Fibroid-associated hypoxia persists due to antioxidant imbalance, ECM accumulation, and growth beyond adequate vascular supply. Current clinically available fibroid treatments do not take advantage of hypoxia-targeting therapies. Growing pre-clinical and clinical studies identify ROS inhibitors, anti-HIF-1 agents, Wnt/ß-catenin inhibition, and TGFß cascade inhibitors as agents that may reduce fibroid development and growth through targeting hypoxia.

Common Beverage Consumption and Benign Gynecological Conditions.

The purpose of this article is to review the effects of four commonly consumed beverage types-sugar-sweetened beverages (SSBs), caffeinated beverages, green tea, and alcohol-on five common benign gynecological conditions: uterine fibroids, endometriosis, polycystic ovary syndrome (PCOS), anovulatory infertility, and primary dysmenorrhea (PD). Here we outline a plethora of research, highlighting studies that demonstrate possible associations between beverage intake and increased risk of certain gynecological conditions-such as SSBs and dysmenorrhea-as well as studies that demonstrate a possible protective effect of beverage against risk of gynecological condition-such as green tea and uterine fibroids. This review aims to help inform the diet choices of those with the aforementioned conditions and give those with uteruses autonomy over their lifestyle decisions.

Cell-intrinsic platinum response and associated genetic and gene expression signatures in ovarian cancer cell lines and isogenic models.

Ovarian cancers are still largely treated with platinum-based chemotherapy as the standard of care, yet few biomarkers of clinical response have had an impact on clinical decision making as of yet. Two particular challenges faced in mechanistically deciphering platinum responsiveness in ovarian cancer have been the suitability of cell line models for ovarian cancer subtypes and the availability of information on comparatively how sensitive ovarian cancer cell lines are to platinum. We performed one of the most comprehensive profiles to date on 36 ovarian cancer cell lines across over seven subtypes and integrated drug response and multiomic data to improve on our understanding of the best cell line models for platinum responsiveness in ovarian cancer. RNA-seq analysis of the 36 cell lines in a single batch experiment largely conforms with the currently accepted subtyping of ovarian cancers, further supporting other studies that have reclassified cell lines and demonstrate that commonly used cell lines are poor models of high-grade serous ovarian carcinoma. We performed drug dose response assays in the 32 of these cell lines for cisplatin and carboplatin, providing a quantitative database of IC50s for these drugs. Our results demonstrate that cell lines largely fall either well above or below the equivalent dose of the clinical maximally achievable dose (Cmax) of each compound, allowing designation of cell lines as sensitive or resistant. We performed differential expression analysis for high-grade serous ovarian carcinoma cell lines to identify gene expression correlating with platinum-response. Further, we generated two platinum-resistant derivatives each for OVCAR3 and OVCAR4, as well as leveraged clinically-resistant PEO1/PEO4/PEO6 and PEA1/PEA2 isogenic models to perform differential expression analysis for seven total isogenic pairs of platinum resistant cell lines. While gene expression changes overall were heterogeneous and vast, common themes were innate immunity/STAT activation, epithelial to mesenchymal transition and stemness, and platinum influx/efflux regulators. In addition to gene expression analyses, we performed copy number signature analysis and orthogonal measures of homologous recombination deficiency (HRD) scar scores and copy number burden, which is the first report to our knowledge applying field-standard copy number signatures to ovarian cancer cell lines. We also examined markers and functional readouts of stemness that revealed that cell lines are poor models for examination of stemness contributions to platinum resistance, likely pointing to the fact that this is a transient state. Overall this study serves as a resource to determine the best cell lines to utilize for ovarian cancer research on certain subtypes and platinum response studies, as well as sparks new hypotheses for future study in ovarian cancer.