Long-term engraftment and maturation of autologous iPSC-derived cardiomyocytes in two rhesus macaques.

Cellular therapies with cardiomyocytes produced from induced pluripotent stem cells (iPSC-CMs) offer a potential route to cardiac regeneration as a treatment for chronic ischemic heart disease. Here, we report successful long-term engraftment and in vivo maturation of autologous iPSC-CMs in two rhesus macaques with small, subclinical chronic myocardial infarctions, all without immunosuppression. Longitudinal positron emission tomography imaging using the sodium/iodide symporter (NIS) reporter gene revealed stable grafts for over 6 and 12 months, with no teratoma formation. Histological analyses suggested capability of the transplanted iPSC-CMs to mature and integrate with endogenous myocardium, with no sign of immune cell infiltration or rejection. By contrast, allogeneic iPSC-CMs were rejected within 8 weeks of transplantation. This study provides the longest-term safety and maturation data to date in any large animal model, addresses concerns regarding neoantigen immunoreactivity of autologous iPSC therapies, and suggests that autologous iPSC-CMs would similarly engraft and mature in human hearts.

Dark continuous noise from mutant G90D-rhodopsin predominantly underlies congenital stationary night blindness.

Congenital stationary night blindness (CSNB) is an inherited retinal disease that causes a profound loss of rod sensitivity without severe retinal degeneration. One well-studied rhodopsin point mutant, G90D-Rho, is thought to cause CSNB because of its constitutive activity in darkness causing rod desensitization. However, the nature of this constitutive activity and its precise molecular source have not been resolved for almost 30 y. In this study, we made a knock-in (KI) mouse line with a very low expression of G90D-Rho (equal in amount to ~0.1% of normal rhodopsin, WT-Rho, in WT rods), with the remaining WT-Rho replaced by REY-Rho, a mutant with a very low efficiency of activating transducin due to a charge reversal of the highly conserved ERY motif to REY. We observed two kinds of constitutive noise: one being spontaneous isomerization (R*) of G90D-Rho at a molecular rate (R* s-1) 175-fold higher than WT-Rho and the other being G90D-Rho-generated dark continuous noise comprising low-amplitude unitary events occurring at a very high molecular rate equivalent in effect to ~40,000-fold of R* s-1 from WT-Rho. Neither noise type originated from G90D-Opsin because exogenous 11-cis-retinal had no effect. Extrapolating the above observations at low (0.1%) expression of G90D-Rho to normal disease exhibited by a KI mouse model with RhoG90D/WTand RhoG90D/G90D genotypes predicts the disease condition very well quantitatively. Overall, the continuous noise from G90D-Rho therefore predominates, constituting the major equivalent background light causing rod desensitization in CSNB.

Clinical features and outcomes of young patients with low-grade non-rhabdomyosarcoma soft tissue sarcomas treated with a risk-based strategy: A report from Children's Oncology Group study ARST0332.

BACKGROUND: In retrospective analyses, the Pediatric Oncology Group [POG) and the Federation National des Centres de Lutte Contre le Cancer (FNCLCC) histologic grade predict outcome in pediatric non-rhabdomyosarcoma soft tissue sarcoma (NRSTS), but prospective data on grading, clinical features, and outcomes of low-grade NRSTS are limited. METHODS: We analyzed patients less than 30 years of age enrolled on Children's Oncology Group (COG) study ARST0332 (NCT00346164) with POG grade 1 or 2 NRSTS. Low-risk patients were treated with surgery alone. Intermediate-/high-risk patients received ifosfamide/doxorubicin and radiotherapy, with definitive resection either before or after 12 weeks of chemoradiotherapy. RESULTS: Estimated 5-year event-free and overall survival were 90% and 100% low risk (n = 80), 55% and 78% intermediate risk (n = 15), and 25% and 25% high risk (n = 4). In low-risk patients, only local recurrence was seen in 10%; none with margins greater than 1 mm recurred locally. Sixteen of 17 intermediate-/high-risk patients who completed neoadjuvant chemoradiotherapy underwent gross total tumor resection, 80% with negative margins. Intermediate-/high-risk group events included one local and seven metastatic recurrences. Had the FNCLCC grading system been used to direct treatment, 29% of low-risk (surgery alone) patients would have received radiotherapy ± chemotherapy. CONCLUSIONS: Most low-risk patients with completely resected POG low-grade NRSTS are successfully treated with surgery alone, and surgical margins greater than 1 mm may be sufficient to prevent local recurrence. Patients with intermediate- and high-risk low-grade NRSTS have outcomes similar to patients with high-grade histology, and require more effective therapies. Use of the current FNCLCC grading system may result in overtreatment of low-risk NRSTS curable with surgery alone.

Trends in hospitalization of patients undergoing endovascular treatment of thoracoabdominal aortic aneurysms based on cerebrospinal fluid drainage strategy.

OBJECTIVE: The aim of this study was to identify trends in hospital (HLOS) and ICU (ICULOS) lengths of stay, and the relationship with cerebrospinal fluid drainage (CSFD) protocols in patients undergoing fenestrated-branched endovascular aortic repair (FB-EVAR) of thoracoabdominal aortic aneurysms (TAAAs). METHODS: A retrospective review of patients who underwent elective FB-EVAR for extent I-IV TAAAs between 2008-2023 at a single aortic center of excellence was conducted. Patient demographics, cardiovascular comorbidities, surgical risk, technical details, CSFD strategy (prophylactic or therapeutic), procedural success, and perioperative outcomes were collected. Patients were divided into two groups based on CSFD protocol. Group 1 included patients treated before 2020 when prophylactic CSFD was performed widely, and Group 2 consisted of patients treated since 2020 with therapeutic CSFD. Primary endpoints were HLOS, ICULOS, major adverse events (MAE), and perioperative mortality. RESULTS: FB-EVAR was performed in 702 patients; 412 underwent elective TAAA repair and were included in the analysis. Mean age was 73 years (SD±8) and 68% were males. Patient-specific manufactured devices were used in 252 patients (61%), physician-modified endografts in 110 (27%), and 50 patients (12%) were treated with off-the-shelf devices. Demographics, aneurysm extent, MAE (including spinal cord ischemia), and mortality were similar in both groups. A significant reduction in mean HLOS between the groups (9±9. vs 6±5 days, p = .02) coincided with decreased use of prophylactic CSFD (70% vs 1.2%, p < .001), with similar rates of SCI (7.6% vs 4.9%, p = .627) and ICULOS (3±3 vs 2.5±3, p = .19). Patients in the therapeutic drainage cohort (group 2) had a higher incidence of congestive heart failure (24% vs 11%, p = .003), hypercholesterolemia (91% vs 80%, p = .015), COPD (55% vs 37%, p = .004), and peripheral artery disease (39% vs 19%, p < .001) compared to group 1, suggesting treatment of a more complex patient cohort. On adjusted multivariable analysis accounting for ASA score, comorbidities, and device type, the difference in HLOS remained statistically significant (p = .01). CONCLUSION: HLOS decreased over time in patients undergoing FB-EVAR for TAAA following transition from prophylactic to therapeutic CSFD protocol. This transition was the only modifiable, independent risk factor for shorter HLOS, without an increase in SCI, albeit with similar ICULOS.

Genetic and Epigenetic Characterization of Sarcoma Stem Cells Across Subtypes Identifies EZH2 as a Therapeutic Target.

High-grade complex karyotype soft tissue sarcomas (STS) are a heterogeneous and aggressive set of cancers that share a common treatment strategy. Disease progression and failure to respond to anthracycline based chemotherapy, standard first-line treatment, is associated with poor patient outcomes. To address this, we investigated the contribution of STS cancer stem cells (STS-CSCs) to doxorubicin resistance. We identified a positive correlation between CSC abundance and doxorubicin IC 50 in resistant cell lines. We investigated if a common genetic signature across STS-CSCs could be targeted. Utilizing patient derived samples from five sarcoma subtypes we identified Enhancer of Zeste homolog 2 (EZH2), a member of the polycomb repressive complex 2 (PRC2) responsible for H3K27 methylation as being enriched in the CSC population. EZH2 activity and a shared epigenetic profile was observed across subtypes. Targeting of EZH2 using Tazemetostat, an FDA approved inhibitor specifically ablated the STS-CSC population. Treatment of doxorubicin resistant cell lines with tazemetostat resulted in a decrease in the STS-CSC population. Further, co-treatment was not only synergistic in the parent cell lines, but restored chemosensitivity in doxorubicin resistant lines. These data confirm the presence of shared genetic programs across distinct subtypes of CSC-STS that can be therapeutically targeted.

Carotid artery replacement with superficial femoral artery in a patient with recurrent radiation-induced carotid artery stenosis.

A 58-year-old man presented with a right hemispheric transient ischemic attack from recurrent common carotid artery (CCA) in-stent restenosis. He had undergone prior neck radiation for carcinoma of the right tonsil and subsequent right carotid endarterectomy (10 years prior) and right CCA stenting (5 years prior), all for symptomatic radiation-induced stenosis. We performed CCA reconstruction using a transposed superficial femoral artery and pectoralis major myocutaneous flap coverage. Early stenosis of the proximal graft required angioplasty and stent grafting. However, at 1.5 years postoperatively, he has no further issues and a patent graft. This case highlights the options available for complex radiation-induced lesions of the carotid vessels.

Executive Summary: Fostering Collaborative Teamwork-A Comprehensive Approach to Vascular Graft Infection Following Arterial Reconstructive Surgery.

Vascular graft infection (VGI) is one of the most serious complications following arterial reconstructive surgery. VGI has received increasing attention over the past decade, but many questions remain regarding its diagnosis and management. In this review, we describe our approach to VGI through multidisciplinary collaboration and discuss decision-making for challenging presentations. This document will concentrate on VGI that impacts both aneurysms and pseudoaneurysms excluding the ascending thoracic aorta.

Fostering Collaborative Teamwork-A Comprehensive Approach to Vascular Graft Infection Following Arterial Reconstructive Surgery.

Vascular graft infection (VGI) is one of the most serious complications following arterial reconstructive surgery. VGI has received increasing attention over the past decade, but many questions remain regarding its diagnosis and management. In this review, we describe our approach to VGI through multidisciplinary collaboration and discuss decision making for challenging presentations. This review will concentrate on VGI that impacts both aneurysms and pseudoaneurysms excluding the ascending thoracic aorta.

Implications and late outcomes of type II endoleaks after endovascular aneurysm repair.

OBJECTIVE: Type II endoleaks (T2ELs) are the most common cause of reintervention after endovascular aneurysm repair (EVAR). Although most resolve spontaneously, the long-term implications of T2ELs remain elusive. We aim to evaluate the impact of persistent and late T2ELs on clinical outcomes after EVAR. METHODS: This was a single-institution retrospective review of patients who underwent EVAR for degenerative infrarenal abdominal aortic aneurysm between January 2010 and June 2022 with no type I (T1EL) or III (T3EL) endoleak seen at EVAR completion. Patients were categorized based on T2EL status. Group 1 included patients with never detected or transient T2ELs (detected at EVAR completion but not after). Group 2 encompassed persistent T2ELs (seen at EVAR completion and again during follow-up) and late T2ELs (detected for the first time at any point during follow-up). Time-to-event analysis was conducted using a time-dependent approach to T2EL status. Primary outcomes included freedom from sac enlargement (SE), aneurysm-related reinterventions, and overall survival. RESULTS: A total of 803 patients met inclusion criteria. Group 1 included 418 patients (52%), of which 85% had no T2ELs and 15% had transient T2ELs. Group 2 had 385 patients; 23% had persistent T2ELs, and 77% developed a new T2EL. Patients in group 1 had a higher prevalence of smoking (88% vs 83%; P < .001), chronic obstructive pulmonary disease (33% vs 25%; P = .008), chronic kidney disease (13% vs 8%; P = .021), and a higher mean Society for Vascular Surgery score (7 vs 6 points; P = .049). No differences were found in aneurysm diameter or morphology. Mean follow-up was 5 years for the entire cohort. In Group 2, 58 patients (15%) underwent T2EL treatment, most commonly transarterial embolization. At 10 years after EVAR, Group 2 was associated with lower freedom from SE (P < .001) and abdominal aortic aneurysm-related reinterventions (P < .001) and comparable overall survival (P = .42). More T1ELs were detected during follow-up in Group 2 (6 [1%] vs 20 [5%]; P = .004), with 15 (75%) of these detected at a median of 3 years after the T2EL. No difference between groups was observed in explant (0.7% vs 2.1%; P = .130) or aneurysm rupture (0.5% vs 1.3%; P = .269) rates. CONCLUSIONS: One-half of patients treated with infrarenal EVAR developed persistent/late T2ELs, which are associated with a higher risk of SE and reinterventions. No difference in overall survival or aneurysm rupture risk was seen at 10 years, based on T2EL status or T2EL intervention. A conservative approach to T2ELs may be appropriate for most patients with absent T1ELs or T3ELs.

Changing trends of suicidal ideation, and impact of social trust and social communication during transition from quarantine to non-quarantine in the COVID-19 epidemic in China.

BACKGROUND: In order to curb the rapid spread of COVID-19, many countries have implemented lockdown or quarantine requirements, but little is known about how this impacts suicide ideation. The purpose of this study is to examine changing trends of suicidal ideation, social trust, and social communication from the quarantine to non-quarantine period during the COVID-19 epidemic in China and the effects of quarantine on suicidal ideation. METHODS: A prospective longitudinal observation design was utilized. There were six waves of interviews from the quarantine to the non-quarantine period. Two hundred and twenty-one participants completed all observation points and were included in the study. For the continuing variables, the Mann-Kendall test was used to assess changing trends across the six observation points. For categorical variables, the Cochran-Armitage test was used to examine their changing trends. A generalized estimating equation was used to examine the association between several independent variables and suicide ideation. RESULTS: The prevalence of suicide ideation was 16.7, 14.5 %, and 14.5 %, respectively, in the quarantine period, and 13.8, 10.9 %, and 10.0 %, respectively in the non-quarantine period, which there was a significant downward trend (T: -4.06, p < 0.01) across the total observation period. Negative behavioral belief, negative social trust, and low levels of social communications were positively associated with suicide ideation, with a ß of 0.0310 (P < 0.01), 0.0541 (P < 0.01), and 0.0245 (P < 0.05) respectively. The positive attitude toward lockdown was negatively associated with suicide ideation, with a ß of -0.0137 (P < 0.01) among guaranteed classmates and it was -0.0121 (P < 0.01) among unguaranteed classmates. CONCLUSIONS: This study yielded new information and may have important policy implications to design effective intervention strategies to reduce future new infectious diseases while maintaining positive mental health and reducing suicide ideation.

The Benefit of an Umbrella Protocol: Reducing Challenges in Orthopedic Oncology Research.

Background: Orthopedic oncology research is hindered by the scarcity of musculoskeletal tumors and research administrative inefficiencies. This paper introduces observational research through an innovative institution-specific methodology-termed an umbrella protocol. This protocol outlines a comprehensive standard procedure to expedite ethical approval for future aligned studies, reducing administrative barriers to research. Methods: We developed an umbrella protocol at an academic center, involving meticulous methodological identification and coordination with the institutional review board (IRB) to adhere to local guidelines. The protocol encompasses identifying investigators, research objectives, study goals, and data and safety monitoring frameworks necessary for typical standards. Results: Implementation of the umbrella protocol took 110 days to achieve exemption status, following multiple discussions with the IRB and extensive revisions. At the authors institution, this protocol significantly reduces protocol review times from an average of six-to-eight weeks to nearly instantaneous, facilitating a streamlined research process. Additionally, we established a dedicated orthopedic oncology patient registry to enhance future research endeavors. Conclusions: The adoption of umbrella protocols represents a pioneering strategy in orthopedic oncology. This approach mitigates research administrative burdens and broadens research scope in the field. It underscores the necessity of IRB collaboration, methodological precision, and stringent data management. The article also reflects on the ethical implications and potential biases introduced by emerging technologies like artificial intelligence, advocating for diligent ethical oversight. The establishment of an umbrella protocol marks a significant step towards more efficient research methodologies, ultimately aiming to improve patient care and outcomes for individuals with rare musculoskeletal conditions.

National trends in utilization of surgeon-modified grafts for complex and thoracoabdominal aortic aneurysms.

INTRODUCTION: Custom-branched/fenestrated grafts are widely available in other countries, but in the United States, they are limited to a handful of centers, with the exception of a 3-vessel juxtarenal device (ZFEN). Consequently, many surgeons have turned to alternative strategies such as physician-modified endografts (PMEGs). We therefore sought to determine how widespread the use of these grafts is. METHODS: We studied all complex endovascular repairs of complex and thoracoabdominal aortic aneurysms in the Vascular Quality Initiative from 2014 to 2022 to examine temporal trends. RESULTS: A total of 5826 repairs were performed during the study period: 1895 ZFEN, 3241 PMEG, 595 parallel grafting, and 95 where parallel grafting was used in addition to ZFEN, with a mean of 2.7 ± 0.98 vessels incorporated. Over time, the number of PMEGs steadily increased, both overall and for juxtarenal aneurysms, whereas the number of ZFENs essentially leveled off by 2017 and has remained steady ever since. In the most recent complete year (2021), PMEGs outnumbered ZFENs by over 2:1 overall (567 to 256) and nearly twofold for juxtarenal repairs. In three-vessel cases involving juxtarenal aneurysms, PMEGs were used as frequently as ZFENs (43% vs 43%), whereas the proportion of juxtarenal aneurysms repaired using a four-vessel graft configuration increased from 20% in 2014 to 29% in 2021 (P < .001). The differences in PMEG use were more pronounced as surgeon volume increased. Surgeons in the lowest quartile of volume performed <2 complex repairs annually, evenly split between PMEGs and ZFENs. However, surgeons in the highest quartile of volume performed a median of 18 (interquartile range: 10-21) PMEGs/y, but only 1.6 (interquartile range: 0.8-3.4) ZFENs/y. The number of physician-sponsored investigational device exemption trials of PMEGs has expanded from 1 in 2012 to 8 currently enrolling. As those data are not included in the Vascular Quality Initiative, the true number of PMEGs is likely substantially higher. CONCLUSIONS: PMEGs have become the dominant endovascular repair modality of complex abdominal and thoracoabdominal aortic aneurysms outside of investigational device exemptions. The field of endovascular aortic surgery and patients with complex aneurysms would benefit from broader publication of PMEG techniques, outcomes, and comparisons to custom-manufactured grafts.

Effect of ALDH1A1 and CD44 on Survival and Disease Recurrence in Patients With Osteosarcoma.

PURPOSE: Emerging evidence suggests that osteosarcoma stem cells (OSCs) may be responsible for tumor initiation propagation, recurrence, and resistance to therapy. We set out to evaluate the relationship between the abundance of ALDH1A1 and CD44-positive cells in biopsy and resection samples on disease recurrence and overall survival. METHODS: A retrospective review of 20 patients, including biopsy and resection samples, was performed at a comprehensive cancer center. Additionally, we queried the publicly available TARGET dataset of osteosarcoma patients. RESULTS: Neither the percentages of ALDH1A1-positive cells nor CD44-positive cells were significantly associated with overall mortality or disease recurrence in either biopsy or resection samples. Unlike our institutional data, overall survival was significantly correlated to higher ALDH1A1 expression in the TARGET dataset both in univariate and age-adjusted analyses. CONCLUSIONS: ADLH1 and CD44, potential markers of OSCs, were not found to be reliable clinical immunohistochemical prognostic markers for osteosarcoma patient survival, specifically disease-free survival. Osteosarcoma patients with high ALDH1A1 RNA expression showed improved overall survival in examining a national genomic database of osteosarcoma patients but again no association with disease-free survival. The potential of CD44 and ALDH1A1 as cellular-specific prognostic markers of survival, and as possible molecular targets, may be limited in osteosarcoma.

Receipt of Guideline-Concordant Care Is Associated With Improved Survival in Patients With Osteosarcoma in California: A Population-Based Analysis.

PURPOSE: To examine the relationship between guideline-concordant care (GCC) on the basis of national clinical practice guidelines and survival in children (0-14 years), adolescents and young adults (AYAs, 15-39 years), and adults (40 years and older) with osteosarcoma, and to identify sociodemographic and clinical factors associated with receipt of GCC and survival. METHODS: We used data from the California Cancer Registry (CCR) on patients diagnosed with osteosarcoma during 2004-2019, with detailed treatment information extracted from the CCR text fields, including chemotherapy regimens. Multivariable logistic and Cox proportional hazard regression were used for statistical analyses. RESULTS: Of 1,716 patients, only 47% received GCC, with variation by age at diagnosis: 67% of children, 43% of AYAs, and 30% of adults. In multivariable models, patients who received part or all care (v none) at specialized cancer centers were more likely to receive GCC. AYAs and adults were less likely to receive GCC than children (odds ratio [OR], 0.38 [95% CI, 0.30 to 0.50] and OR, 0.40 [95% CI, 0.28 to 0.56], respectively). In a model excluding adults, patients treated by pediatric (v medical) oncologists were more likely to receive GCC (OR, 3.44 [95% CI, 2.40 to 4.94]). Patients with metastatic osteosarcoma at diagnosis who did not receive GCC had a greater hazard of death (hazard ratio [HR], 2.02 [95% CI, 1.55 to 2.63]) but no statistical differences were found in those diagnosed at earlier stages (HR, 1.15 [95% CI, 0.92 to 1.43]). CONCLUSION: GCC was associated with improved survival in patients with metastatic osteosarcoma in California. However, we found disparities in the delivery of GCC, highlighting the need for target interventions to improve delivery of GCC in this patient population.

Outcomes of Arterial Bypass With the Human Acellular Vessel for Chronic Limb-Threatening Ischemia Performed Under the FDA Expanded Access Program.

OBJECTIVE: To report outcomes of the human acellular vessel (HAV) implanted for limb salvage through the Food and Drug Administration (FDA) Expanded Access Program for patients with chronic limb-threatening ischemia with no autologous conduit. METHODS: The HAV is a bioengineered vascular conduit designed with human vascular smooth muscle cells. The product is under regulatory study. From April 2019 to November 2021, the HAV was implanted in 14 patients (12 men; mean age, 62±14 years) at 3 US centers. Each case was performed with a single-use investigational new drug Expanded Access Program issued by the FDA. Institutional review board approval was obtained; technical and clinical outcomes were analyzed. RESULTS: A single 6-mm-diameter (40-cm-long) HAV was implanted in 9 patients; 5 patients required 2 HAVs sewn together as a composite. Technical success was 100%. Median follow-up was 12 (range, 1 to 41) months. Primary and secondary patency rates were 72% and 81% at 12 months; assisted primary patency was attained in 4 patients. Amputation-free survival was 93% at 6 months and 77% at 12 months. All patients with a patent HAV experienced clinical improvement with no HAV-related infections or adverse events. There were 4 deaths in the cohort, late mortality unrelated to the HAV. CONCLUSION: The HAV is a safe and effective "off-the-shelf" biologic conduit. This experience from the FDA Expanded Access Program in this population with few alternative limb salvage options will help guide regulatory deliberations for patients with lower extremity ischemia and no autologous bypass conduit options.

The MOTION study: a randomized, phase III study of vimseltinib for the treatment of tenosynovial giant cell tumor.

Tenosynovial giant cell tumor (TGCT) is a rare, locally aggressive neoplasm that occurs in the synovium of joints, bursae, or tendon sheaths and is caused by upregulation of the CSF1 gene. Vimseltinib is an oral switch-control tyrosine kinase inhibitor specifically designed to selectively and potently inhibit the CSF1 receptor. Here, we describe the rationale and design for the phase III MOTION trial (NCT05059262), which aims to evaluate the efficacy and safety of vimseltinib in participants with TGCT not amenable to surgical resection. In part 1, participants are randomized to receive vimseltinib 30 mg twice weekly or matching placebo for ≤24 weeks. Part 2 is a long-term treatment phase in which participants will receive open-label vimseltinib.

Tenosynovial giant cell tumor (or TGCT) is a rare, noncancerous tumor that grows in the soft tissue lining the spaces of joints and bursae (fluid-filled sacs that work to reduce friction in the joints). These tumors are linked to increased levels of a protein called CSF1. While this condition is typically treated with surgery, some patients may not be candidates for surgical removal of the tumor due to factors such as location or complexity of the tumor; therefore, drug treatments are needed to help these patients. Vimseltinib is an investigational oral drug specifically designed to inhibit the receptor to which the CSF1 protein binds. In this article, we describe the rationale and design for a phase III clinical trial that will test how well vimseltinib works in participants with TGCT who are not candidates for surgery. In the first part of the study, participants are randomly assigned to receive vimseltinib 30 mg twice weekly or a matching placebo (inactive substance) for up to 24 weeks. This first part is blinded, so participants will not know if they are receiving vimseltinib or the placebo. The second part of the study is a long-term treatment phase in which all participants will receive vimseltinib (unblinded). Clinical Trial Registration: NCT05059262 (ClinicalTrials.gov).

Preoperative predictors of nonhome discharge after fenestrated-branched endovascular repair of complex abdominal and thoracoabdominal aortic aneurysms.

BACKGROUND: Nonhome discharge (NHD) has significant implications for patient counseling and discharge planning and is frequently required following fenestrated-branched endovascular aortic repair (FB-EVAR) of complex abdominal aortic aneurysms (CAAA) and thoracoabdominal aortic aneurysms (TAAA). We aimed to identify preoperative predictors of NHD after elective FB-EVAR for CAAA and TAAA and develop a risk calculator able to predict NHD. METHODS: A retrospective review of prospectively collected data on all patients undergoing FB-EVAR between January 2007 and December 2021 at a single institution was performed. Exclusion criteria were admission from a nonhome setting, emergency and repeat FB-EVAR, and discharge to an unknown destination. The cohort was randomly split into separate development (70% of patients) and validation (30%) cohorts to develop a predictive calculator for NHD. Independent variables associated with NHD were assessed in a series of logistic regression analyses from 100 bootstrapped samples of the development set, and a model was developed using the most predictive variables. Resulting parameter estimates were applied to data in the validation set to assess model discrimination and calibration. RESULTS: From the initial cohort of 712 FB-EVAR patients, 644 were included in the study (74% male; mean age, 75.4 ± 7.6 years), including 452 with CAAA (70%) and 192 with TAAA (30%). Early mortality occurred in eight patients (1.2%; 5 in CAAA and 3 in TAAA) and the median hospital stay was 5 days (4 for CAAA and 7 for TAAA). Ninety-seven patients (15%) had a NHD. On multivariable analysis, older age (per year, odds ratio [OR], 1.08; P < .001), female gender (OR, 3.03; P < .001), smoking (OR, 2.86; P = .01), congestive heart failure (OR, 3.05; P = .004), peripheral artery disease (OR, 1.81; P = .07), and extent I (OR, 3.17), II (OR, 2.84), and III (OR, 2.52; all P = .08) TAAAs were associated with an increased likelihood of NHD in the development set. Based on these factors, the risk calculator was developed which accurately predicts NHD in the validation set with an area under the curve of 0.7. CONCLUSIONS: Older, female smokers with congestive heart failure and peripheral artery disease and more extensive aneurysms are at highest risk of NHD after FB-EVAR. Using only preoperative factors, our risk calculator can predict accurately who will have a NHD, allowing enhanced preoperative patient counselling and accelerated hospital discharge.

Outcomes of lower extremity arterial bypass using the Human Acellular Vessel in patients with chronic limb-threatening ischemia.

OBJECTIVE: Patients with chronic limb-threatening ischemia (CLTI) and no great saphenous vein to use as a conduit for arterial bypass have a high risk for amputation despite advances in medical and endovascular therapies. This report presents findings from a U.S. Food and Drug Administration (FDA) supported study of the Human Acellular Vessel (HAV) (Humacyte Inc.) used as a conduit for arterial bypass in patients with CLTI and inadequate or absent autologous conduit. METHODS: The HAV is a 6-mm, 40-cm vessel created from human vascular smooth muscle cells seeded onto a polyglycolic acid scaffold pulsed in a bioreactor for 8 weeks as cells proliferate and the scaffold dissolves. The resultant vessel is decellularized, creating a nonimmunogenic conduit composed of collagen, elastin, and extracellular matrix. The FDA issued an Investigational New Drug for an intermediate-sized, single-center study of the HAV under the agency's Expanded Access Program in patients with advanced CLTI and inadequate or absent autologous conduit. Technical results and clinical outcomes were analyzed and reported. RESULTS: Between March 2021 and July 2023, 29 patients (20 males; mean age, 71 ± 11 years) underwent limb salvage operation using the HAV as a bypass conduit. Most patients had advanced CLTI (Rutherford class 5/6 in 72%; wound, ischemia, and foot infection stage 3/4 in 83%), and 97% had previously failed revascularization(s) of the extremity. Two HAVs were sewn together to attain the needed bypass length in 24 patients (83%). Bypasses were to tibial arteries in 23 patients (79%) and to the popliteal artery in 6 (21%). Technical success was 100%, and the 30-day mortality rate was 7% (2 patients). With 100% follow-up (median, 9.3 months), the limb salvage rate was 86% (25/29 patients). There were 16 reinterventions to restore secondary patency, of which 15 (94%) were successful. Primary and secondary patency of the HAV at 9 months were 59% and 71%, respectively. CONCLUSIONS: The HAV has demonstrated short- to intermediate-term safety and efficacy as an arterial bypass conduit in a complex cohort of patients with limb-threatening ischemia and no autologous options. This experience using the FDA's Expanded Access Program provides real-world data to inform regulatory deliberations and future trials of the HAV, including the study of the vessel as a first-line bypass conduit in less severe cases of chronic limb ischemia.

Emerging innovations and advancements in the treatment of extremity and truncal soft tissue sarcomas.

In this special edition update on soft tissue sarcomas (STS), we cover classifications, emerging technologies, prognostic tools, radiation schemas, and treatment disparities in extremity and truncal STS. We discuss the importance of enhancing local control and reducing complications, including the role of innovative imaging, surgical guidance, and hypofractionated radiation. We review advancements in systemic and immunotherapeutic treatments and introduce disparities seen in this vulnerable population that must be considered to improve overall patient care.