Transfection of hypoxia-inducible factor-1α mRNA upregulates the expression of genes encoding angiogenic growth factors.

Hypoxia-Inducible Factor-1α (HIF-1α) has presented a new direction for ischemic preconditioning of surgical flaps to promote their survival. In a previous study, we demonstrated the effectiveness of HIF-1a DNA plasmids in this application. In this study, to avoid complications associated with plasmid use, we sought to express HIF-1α through mRNA transfection and determine its biological activity by measuring the upregulation of downstream angiogenic genes. We transfected six different HIF-1a mRNAs-one predominant, three variant, and two novel mutant isoforms-into primary human dermal fibroblasts using Lipofectamine, and assessed mRNA levels using RT-qPCR. At all time points examined after transfection (3, 6, and 10 h), the levels of HIF-1α transcript were significantly higher in all HIF-1α transfected cells relative to the control (all p < 0.05, unpaired Student's T-test). Importantly, the expression of HIF-1α transcription response genes (VEGF, ANG-1, PGF, FLT1, and EDN1) was significantly higher in the cells transfected with all isoforms than with the control at six and/or ten hours post-transfection. All isoforms were transfected successfully into human fibroblast cells, resulting in the rapid upregulation of all five downstream angiogenic targets tested. These findings support the potential use of HIF-1α mRNA for protecting ischemic dermal flaps.

Neoadjuvant nivolumab or nivolumab plus LAG-3 inhibitor relatlimab in resectable esophageal/gastroesophageal junction cancer: a phase Ib trial and ctDNA analyses.

Gastroesophageal cancer dynamics and drivers of clinical responses with immune checkpoint inhibitors (ICI) remain poorly understood. Potential synergistic activity of dual programmed cell death protein 1 (PD-1) and lymphocyte-activation gene 3 (LAG-3) inhibition may help improve immunotherapy responses for these tumors. We report a phase Ib trial that evaluated neoadjuvant nivolumab (Arm A, n = 16) or nivolumab-relatlimab (Arm B, n = 16) in combination with chemoradiotherapy in 32 patients with resectable stage II/stage III gastroesophageal cancer together with an in-depth evaluation of pathological, molecular and functional immune responses. Primary endpoint was safety; the secondary endpoint was feasibility; exploratory endpoints included pathological complete (pCR) and major pathological response (MPR), recurrence-free survival (RFS) and overall survival (OS). The study met its primary safety endpoint in Arm A, although Arm B required modification to mitigate toxicity. pCR and MPR rates were 40% and 53.5% for Arm A and 21.4% and 57.1% for Arm B. Most common adverse events were fatigue, nausea, thrombocytopenia and dermatitis. Overall, 2-year RFS and OS rates were 72.5% and 82.6%, respectively. Higher baseline programmed cell death ligand 1 (PD-L1) and LAG-3 expression were associated with deeper pathological responses. Exploratory analyses of circulating tumor DNA (ctDNA) showed that patients with undetectable ctDNA post-ICI induction, preoperatively and postoperatively had a significantly longer RFS and OS; ctDNA clearance was reflective of neoantigen-specific T cell responses. Our findings provide insights into the safety profile of combined PD-1 and LAG-3 blockade in gastroesophageal cancer and highlight the potential of ctDNA analysis to dynamically assess systemic tumor burden during neoadjuvant ICI that may open a therapeutic window for future intervention. ClinicalTrials.gov registration: NCT03044613 .

Racial disparities among patients on venovenous extracorporeal membrane oxygenation in the pre-Coronavirus Disease 2019 and Coronavirus Disease 2019 eras: A retrospective registry review.

Objectives: Although many studies have addressed such disparities caused by COVID-19, to our knowledge, no study has focused on the association of race on outcomes for patients with COVID-19 requiring venovenous extracorporeal membrane oxygenation support. The goal of this study was to assess association of race on death and duration on venovenous extracorporeal membrane oxygenation in both the pre-COVID-19 and COVID-19 eras. Methods: We retrospectively reviewed the Extracorporeal Life Support Organization registry and included adults (≥18 years) who required venovenous extracorporeal membrane oxygenation between January 2019 and April 2021. We performed descriptive statistics and multivariable logistic regression. Our primary outcomes were death and extracorporeal membrane oxygenation duration. Results: A total of 7477 patients were included after excluding 340 patients (4.3%) who were missing race data. In the COVID-19 era, 1474 of 2777 COVID-19-positive patients (53.1%) died. Our regression model suggested somewhat of a protective effect on death for Black and multiple race patients. Additionally, a diagnosis of COVID-19 and patients in the COVID-19 era in general, irrespective of COVID-19 diagnosis, had higher odds of death. Hispanic patients had the longest average venovenous extracorporeal membrane oxygenation run times. Conclusions: Our study using data from the international Extracorporeal Life Support Organization Registry provides updated data on patients supported with venovenous extracorporeal membrane oxygenation in the pre-COVID-19 and COVID-19 eras between 2019 and 2021 with a focus on race. Patients in the COVID-19 era group also had higher mortality compared with those in the pre-COVID-19 era even after being adjusted for COVID-19 diagnosis. Black and multiple races appeared somewhat protective in terms of death. Hispanic race was associated with longer venovenous extracorporeal membrane oxygenation duration.

Uptake and 1-year outcomes of lung transplantation for COVID-19.

OBJECTIVE: End-stage lung disease from severe COVID-19 infection is an increasingly common indication for lung transplantation (LT), but there are limited data on outcomes. We evaluated 1-year COVID-19 LT outcomes. METHODS: We identified all adult US LT recipients January 2020 to October 2022 in the Scientific Registry for Transplant Recipients, using diagnosis codes to identify recipients transplanted for COVID-19. We used multivariable regression to compare in-hospital acute rejection, prolonged ventilator support, tracheostomy, dialysis, and 1-year mortality between COVID-19 and non-COVID-19 recipients, adjusting for donor, recipient, and transplant characteristics. RESULTS: LT for COVID-19 increased from 0.8% to 10.7% of total LT volume during 2020 to 2021. The number of centers performing LT for COVID-19 increased from 12 to 50. Recipients transplanted for COVID-19 were younger; were more likely to be male and Hispanic; were more likely to be on a ventilator, extracorporeal membrane oxygenation support, and dialysis pre-LT; were more likely to receive bilateral LT; and had higher lung allocation score and shorter waitlist time than other recipients (all P values < .001). COVID-19 LT had higher risk of prolonged ventilator support (adjusted odds ratio, 2.28; P < .001), tracheostomy (adjusted odds ratio 5.3; P < .001), and longer length of stay (median, 27 vs 19 days; P < .001). Risk of in-hospital acute rejection (adjusted odds ratio, 0.99; P = .95) and 1-year mortality (adjusted hazard ratio, 0.73; P = .12) were similar for COVID-19 LTs and LTs for other indications, even accounting for center-level differences. CONCLUSIONS: COVID-19 LT is associated with higher risk of immediate postoperative complications but similar risk of 1-year mortality despite more severe pre-LT illness. These encouraging results support the ongoing use of LT for COVID-19-related lung disease.

The effect of allograft ischemic time on outcomes following bilateral, single, and reoperative lung transplantation.

OBJECTIVE: To determine whether allograft ischemic times affect outcomes following bilateral, single, and redo lung transplantation. METHODS: A nationwide cohort of lung transplant recipients from 2005 through 2020 was examined using the Organ Procurement and Transplantation Network registry. The effects of standard (<6 hours) and extended (≥6 hours) ischemic times on outcomes following primary bilateral (n = 19,624), primary single (n = 688), redo bilateral (n = 8461), and redo single (n = 449) lung transplantation were analyzed. A priori subgroup analysis was performed in the primary and redo bilateral-lung transplant cohorts by further stratifying the extended ischemic time group into mild (≥6 and <8 hours), moderate (≥8 and <10 hours), and long (≥10 hours) subgroups. Primary outcomes included 30-day mortality, 1-year mortality, intubation at 72 hours' posttransplant, extracorporeal membrane oxygenation (ECMO) support at 72 hours' posttransplant, and a composite variable of intubation or ECMO at 72 hours' posttransplant. Secondary outcomes included acute rejection, postoperative dialysis, and hospital length of stay. RESULTS: Recipients of allografts with ischemic times ≥6 hours experienced increased 30-day and 1-year mortality following primary bilateral-lung transplantation, but increased mortality was not observed following primary single, redo bilateral, or redo single-lung transplants. Extended ischemic times correlated with prolonged intubation or increased postoperative ECMO support in the primary bilateral, primary single, and redo bilateral-lung transplant cohorts but did not affect these outcomes following redo single-lung transplantation. CONCLUSIONS: Since prolonged allograft ischemia correlates with worse transplant outcomes, the decision to use donor lungs with extended ischemic times must consider the specific benefits and risks associated with individual recipient factors and institutional expertise.

Outcomes of Recipients Aged 65 Years and Older Bridged to Lung Transplant With Extracorporeal Membrane Oxygenation.

Extracorporeal membrane oxygenation (ECMO) as a bridge to lung transplant (BTT) has been used for critically ill candidates with excellent outcomes, but data on this strategy in older recipients remain limited. We compared outcomes of no BTT, mechanical ventilation (MV)-only BTT, and ECMO BTT in recipients of greater than or equal to 65 years. Lung-only recipients of greater than or equal to 65 years in the United Network for Organ Sharing database between 2008 and 2022 were included and stratified by bridging strategy. Of the 9,936 transplants included, 226 (2.3%) were MV-only BTT and 159 (1.6%) were ECMO BTT. Extracorporeal membrane oxygenation BTT recipients were more likely to have restrictive disease pathology, had higher median lung allocation score, and spent fewer days on the waitlist (all p < 0.001). Compared to no-BTT recipients, ECMO BTT recipients were more likely to be intubated or on ECMO at 72 hours posttransplant and had longer hospital lengths of stay (all p < 0.001). Extracorporeal membrane oxygenation BTT recipients had increased risk of 3 years mortality compared to both no-BTT (adjusted hazard ratio [aHR] = 1.48 [95% confidence interval {CI}: 1.14-1.91], p = 0.003) and MV-only recipients (aHR = 1.50 [95% CI: 1.08-2.07], p = 0.02). Overall, we found that ECMO BTT in older recipients is associated with inferior posttransplant outcomes compared to MV-only or no BTT, but over half of recipients remained alive at 3 years posttransplant.

Anxiety and dysautonomia symptoms in patients with a NaV1.7 mutation and the potential benefits of low-dose short-acting guanfacine.

PURPOSE: Guanfacine is an α2A-adrenergic receptor agonist, FDA-approved to treat attention-deficit hyperactivity disorder and high blood pressure, typically as an extended-release formulation up to 7 mg/day. In our dysautonomia clinic, we observed that off-label use of short-acting guanfacine at 1 mg/day facilitated symptom relief in two families with multiple members presenting with severe generalized anxiety. We also noted anecdotal improvements in associated dysautonomia symptoms such as hyperhidrosis, cognitive impairment, and palpitations. We postulated that a genetic deficit existed in these patients that might augment guanfacine susceptibility. METHODS: We used whole-exome sequencing to identify mutations in patients with shared generalized anxiety and dysautonomia symptoms. Guanfacine-induced changes in the function of voltage-gated Na+ channels were investigated using voltage-clamp electrophysiology. RESULTS: Whole-exome sequencing uncovered the p.I739V mutation in SCN9A in the proband of two nonrelated families. Moreover, guanfacine inhibited ionic currents evoked by wild-type and mutant NaV1.7 encoded by SCN9A, as well as other NaV channel subtypes to a varying degree. CONCLUSION: Our study provides further evidence for a possible pathophysiological role of NaV1.7 in anxiety and dysautonomia. Combined with off-target effects on NaV channel function, daily administration of 1 mg short-acting guanfacine may be sufficient to normalize NaV channel mutation-induced changes in sympathetic activity, perhaps aided by partial inhibition of NaV1.7 or other channel subtypes. In a broader context, expanding genetic and functional data about ion channel aberrations may enable the prospect of stratifying patients in which mutation-induced increased sympathetic tone normalization by guanfacine can support treatment strategies for anxiety and dysautonomia symptoms.

National utilization, trends, and lung transplant outcomes of static versus portable ex vivo lung perfusion platforms.

BACKGROUND: This study compared utilization and outcomes of the 2 widely utilized ex vivo lung perfusion (EVLP) platforms in the United States: a static platform and a portable platform. METHODS: Adult (age 18 years or older) bilateral lung-only transplants utilizing EVLP between February 28, 2018, and December 31, 2022, in the United Network for Organ Sharing database were included. Predischarge acute rejection, intubation at 72 hours posttransplant, extracorporeal membrane oxygenation at 72 hours posttransplant, primary graft dysfunction grade 3 at 72 hours posttransplant, 30-day mortality, and 1-year mortality were evaluated using multivariable regressions. RESULTS: Overall, 607 (6.3%) lung transplants during the study period used EVLP (51.2% static, 48.8% portable). Static EVLP was primarily utilized in the eastern United States, whereas portable EVLP was primarily utilized in the western United States. Static EVLP donors were more likely to be donation after circulatory death (33.4% vs 26.0%; P = .005), have a >20 pack-year smoking history (13.5% vs 6.5%; P = .005), and be extended criteria donors (92.3% vs 85.0%; P = .013), whereas portable EVLP donors were more likely to be older than age 55 years (14.2% vs 8.0%; P = .02). Transplants utilizing the static and portable platforms had similar risk of acute rejection, intubation at 72 hours, extracorporeal membrane oxygenation at 72 hours, primary graft dysfunction grade 3 at 72 hours, and posttransplant mortality at 30 days and 1 year (all P values > .05). CONCLUSIONS: The static and portable platforms had significant differences in donor characteristics and geographic distributions of utilization. Despite this, posttransplant survival was similar between the 2 EVLP platforms.

Outcomes Comparison of Robot-Assisted and Video-Assisted Thoracoscopic Cardiac Sympathetic Denervation.

OBJECTIVE: Cardiac sympathetic denervation (CSD) is a surgical antiadrenergic procedure that can reduce sustained ventricular tachyarrhythmia (VT). Video-assisted thoracoscopic surgery (VATS) is currently the standard approach used in CSD, and the practicality for robot-assisted thoracoscopic surgery (RATS) has yet to be investigated. METHODS: We conducted a single-center retrospective study of all adult patients (N = 67) who underwent CSD from 2015 to 2021. We compared short-term outcomes of those treated with RATS versus VATS thoracic sympathectomy. For patients with VT, we examined the effectiveness of a RATS approach in reducing implantable cardioverter defibrillator (ICD) shock burden. RESULTS: A total of 34 patients underwent RATS cardiac denervation, and 33 underwent VATS cardiac denervation. Those undergoing RATS denervation had a significantly shorter procedure duration with a median of 129 min (P = 0.008). Patients receiving the VATS approach were significantly more complicated by pneumothorax (P = 0.004) and overall complications (P = 0.01) when compared with the RATS approach. At 1 year after surgery, both groups had significant reductions in ICD shocks compared with before surgery, both decreasing from a median of 4 to 0 shocks (P < 0.001). In addition, at 1 year after surgery, the percentage of patients with persistent ICD shocks and the median of ICD shocks were similar between the groups. CONCLUSIONS: The RATS approach to cardiac denervation has similar 1-year follow-up outcomes in reducing recurrent VT as the VATS approach. However, patients undergoing RATS denervation experienced better perioperative outcomes. This shows promise for robotic CSD to be an effective and safe therapeutic option for patients with malignant arrhythmias.

To decline or not to decline: Consequences of decision-making regarding lung offers from donors with hepatitis C.

OBJECTIVE: Lung transplants from donors with hepatitis C (HCV D+) have excellent outcomes, but these organs continue to be declined. We evaluated whether (1) being listed to consider and (2) accepting versus declining HCV D+ offers provided a survival benefit to lung transplant candidates. METHODS: Using the Scientific Registry of Transplant Recipients, we identified all adult (≥18 years) lung transplant candidates 2016-2021 and compared waitlist mortality between those willing versus not willing to consider HCV D+ offers using competing risk regression. We identified all candidates offered an HCV D+ lung that was later accepted and followed them from offer decision until death or end-of-study. We estimated adjusted mortality risk of accepting versus declining an HCV D+ lung offer using propensity-weighted Cox regression. RESULTS: From 2016 to 2021, we identified 21,007 lung transplant candidates, 33.8% of whom were willing to consider HCV D+ offers. Candidates willing to consider HCV D+ offers had a 17% lower risk of waitlist mortality (subhazard ratio, 0.83; 95% confidence interval, 0.75-0.91, P < .001). Over the same period, 665 HCV D+ lung offers were accepted after being declined a total of 2562 times. HCV D+ offer acceptance versus decline was associated with a 20% lower risk of mortality (adjusted hazard ratio, 0.80; 95% confidence interval, 0.66-0.96, P = .02). CONCLUSIONS: Considering HCV D+ lung offers was associated with a 17% lower risk of waitlist mortality, whereas accepting versus declining an HCV D+ lung offer was associated with a 20% lower risk of mortality. Centers and candidates should consider accepting suitable HCV D+ lung offers to optimize outcomes.

Current status and future potential of ex vivo lung perfusion in clinical lung transplantation.

Lung transplantation is accepted as a well-established and effective treatment for patients with end-stage lung disease. While the number of candidates added to the waitlist continues to rise, the number of transplants performed remains limited by the number of suitable organ donors. Ex vivo lung perfusion (EVLP) emerged as a method of addressing the organ shortage by allowing the evaluation and potential reconditioning of marginal donor lungs or minimizing risks of prolonged ischemic time due to logistical challenges. The currently available FDA-approved EVLP systems have demonstrated excellent outcomes in clinical trials, and retrospective studies have demonstrated similar post-transplant survival between recipients who received marginal donor lungs perfused using EVLP and recipients who received standard criteria lungs stored using conventional methods. Despite this, widespread utilization has plateaued in the last few years, likely due to the significant costs associated with initiating EVLP programs. Centralized, dedicated EVLP perfusion centers are currently being investigated as a potential method of further expanding utilization of this technology. In the preclinical setting, potential applications of EVLP that are currently being studied include prolongation of organ preservation, reconditioning of unsuitable lungs, and further enhancement of already suitable lungs. As adoption of EVLP technology becomes more widespread, we may begin to see future implementation of these potential applications into the clinical setting.

Outcomes of Lung Transplant Candidates Aged ≥70 Years During the Lung Allocation Score Era.

BACKGROUND: With the increasing age of lung transplant candidates, we studied waitlist and posttransplantation outcomes of candidates ≥70 years during the Lung Allocation Score era. METHODS: Adult lung transplant candidates from 2005 to 2020 in the United Network for Organ Sharing database were included and stratified on the basis of age at listing into 18 to 59 years old, 60 to 69 years old, and ≥70 years old. Baseline characteristics, waitlist outcomes, and posttransplantation outcomes were assessed. RESULTS: A total of 37,623 candidates were included (52.3% aged 18-59 years, 40.6% aged 60-69 years, 7.1% aged ≥70 years). Candidates ≥70 years were more likely than younger candidates to receive a transplant (81.9% vs 72.7% [aged 60-69 years] vs 61.6% [aged 18-59 years]) and less likely to die or to deteriorate on the waitlist within 1 year (9.1% vs 10.1% [aged 60-69 years] vs 12.2% [aged 18-59 years]; P < .001). Donors for older recipients were more likely to be extended criteria (75.7% vs 70.1% [aged 60-69 years] vs 65.7% [aged 18-59 years]; P < .001). Recipients ≥70 years were found to have lower rates of acute rejection (6.7% vs 7.4% [aged 60-69 years] vs 9.2% [aged 18-59 years]; P < .001) and prolonged intubation (21.7% vs 27.4% [aged 60-69 years] vs 34.5% [aged 18-59 years]; P < .001). Recipients aged ≥70 years had increased 1-year (adjusted hazard ratio [aHR], 1.19 [95% CI, 1.06-1.33]; P < .001), 3-year (aHR, 1.28 [95% CI, 1.18-1.39]; P < .001), and 5-year mortality (aHR, 1.29 [95% CI, 1.21-1.38]; P < .001) compared with recipients aged 60 to 69 years. CONCLUSIONS: Candidates ≥70 years had favorable waitlist and perioperative outcomes despite increased use of extended criteria donors. Careful selection of candidates and postoperative surveillance may improve posttransplantation survival in this population.

Early United States experience with lung donation after circulatory death using thoracoabdominal normothermic regional perfusion.

Thoracoabdominal normothermic regional perfusion (TA-NRP) has recently begun being utilized in the United States for recovery of cardiothoracic allografts from some donors after circulatory death (DCD), but data on lungs recovered in this method is limited to case reports. We conducted a national retrospective review of lung transplants from DCD donors recovered using TA-NRP. Of the 434 total DCD lung transplants performed between January 2020 and March 2022, 17 were recovered using TA-NRP. Compared to direct recovery DCD transplants, recipients of TA-NRP DCD transplants had lower likelihood of ventilation >48 hours (23.5% vs 51.3%, p = 0.027) and similar likelihood of predischarge acute rejection, requirement for extracorporeal membrane oxygenation at 72 hours, hospital lengths of stay, and survival at 30, 60, and 90 days post-transplant. These early data suggest that DCD lung recovery using TA-NRP might be a safe way to further expand the donor pool and warrant further study.

The COVID-19 Era Is Associated With Delays in Esophageal Cancer Diagnosis and Treatment.

INTRODUCTION: The coronavirus disease-2019 (COVID-19) pandemic has substantially affected the delivery of healthcare globally. The purpose of this study was to evaluate the association of this era with the timeline of care in esophageal cancer patients. METHODS: We performed a retrospective chart-review of patients presenting to a single high-volume tertiary care center with the diagnosis of esophageal cancer. COVID era was defined as March 2020-December 2020 and compared with the year before (3/2019-12/2019). RESULTS: In total, 117 patients presented in the COVID-era versus 190 in pre-COVID. Stage 3 + 4 disease was found in 77.8% of the patients in the COVID-era compared to 68.9% in the pre-COVID era (P = 0.34). Diagnoses through emergency department admission were 35.5% in the COVID versus 26.7% in the pre-COVID group (P = 0.15). In the COVID era it took a median of 78 d to visit primary care provider (versus 52 d, P = 0.12 in pre-COVID), 45 d to endoscopy (versus 18 d, P = 0.004) and 38 d to treatment initiation (versus 36 d, P = 0.48). Thirty-five percent of the patients underwent esophagectomy compared to 26% in the pre-COVID-era. Median days of intensive-care-unit (ICU) (2 versus 3, P = 0.16) and hospital stay (14 versus 15, P = 0.28) were similar in both groups as well as postoperative 30-day morbidities (63 versus 63%, P = 0.48). One-year follow-up showed 83.7% (95% confidence interval [CI]: 73.8%-90.1%) survival in the COVID-group compared to 76.4% (95% CI: 66.9%-83.5%) in the pre-COVID-group (P = 0.58). Only three patients had a positive COVID result. CONCLUSIONS: Our institution treated fewer esophageal cancer patients during COVID-19 accompanied by a delay in endoscopic diagnosis. Postoperative outcomes and 1-year survival remained similar.

How to Do It: A Safe Bedside Protocol for Dual-Lumen Right Internal Jugular Cannulation for Venovenous Extracorporeal Membrane Oxygenation in COVID-19 Patients With Severe Acute Respiratory Distress Syndrome.

In appropriately selected patients with COVID-19 acute respiratory distress syndrome, venovenous extracorporeal membrane oxygenation (VV ECMO) may offer a promising bridge to lung recovery or lung transplantation if lung recovery fails. Although the cannulation technique for VV ECMO via a right internal jugular (RIJ) dual-lumen catheter (DLC) requires expertise and guidance by either fluoroscopy or transesophageal echocardiography (TEE), it offers theoretical circulatory support advantages by using bicaval venous drainage to deliver oxygenated blood systemically with minimal recirculation as compared with the femoral vein and RIJ dual-site cannula configuration. In addition, patients are often too unstable to transport safely to an operating room or catheterization laboratory, and fluoroscopy is not always readily available to guide RIJ DLC placement. Here, we provide a comprehensive description of a safe, bedside protocol for VV ECMO cannulation via a RIJ DLC under TEE guidance. We will report our center's experience (March 30, 2020 to November 21, 2021) and discuss important hemodynamic, safety, and infection control considerations.

Trends in use and three-year outcomes of hepatitis C virus-viremic donor lung transplants for hepatitis C virus-seronegative recipients.

OBJECTIVE: The feasibility and 6-month outcome safety of lung transplants (LTs) from hepatitis C virus (HCV)-viremic donors for HCV-seronegative recipients (R-) were established in 2019, but longer-term safety and uptake of this practice nationally remain unknown. METHODS: We identified HCV-seronegative LT recipients (R-) 2015-2020 using the Scientific Registry of Transplant Recipients. We classified donors as seronegative (D-) or viremic (D+). We used χ2 testing, rank-sum testing, and Cox regression to compare posttransplant outcomes between HCV D+/R- and D-/R- LT recipients. RESULTS: HCV D+/R- LT increased from 2 to 97/year; centers performing HCV D+/R- LT increased from 1 to 25. HCV D+/R- versus HCV D-/R- LT recipients had more obstructive disease (35.7% vs 23.3%, P < .001), lower lung allocation score (36.5 vs 41.1, P < .001), and longer waitlist time (P = .002). HCV D+/R- LT had similar risk of acute rejection (adjusted odds ratio [aOR], 0.87; P = .58), extracorporeal membranous oxygenation (aOR, 1.94; P = .10), and tracheostomy (aOR, 0.42; P = .16); similar median hospital stay (P = .07); and lower risk of ventilator > 48 hours (aOR, 0.68; P = .006). Adjusting for donor, recipient, and transplant characteristics, risk of all-cause graft failure and mortality were similar at 30 days, 1 year, and 3 years for HCV D+/R- versus HCV D-/R- LT (all P > .1), as well as for high- (≥20/year) versus low-volume LT centers and high- (≥5/year) versus low-volume HCV D+/R- LT centers (all P > .5). CONCLUSIONS: HCV D+/R- and HCV D-/R- LT have similar outcomes at 3 years posttransplant. These results underscore the safety of HCV D+/R- LT and the potential benefit of expanding this practice further.

A dedicated robotic bedside physician assistant significantly enhances trainee console operating time in general thoracic surgery.

Objective: As trainees rotate through thoracic subspecialties within their curricula, a crucial portion of their robotic training consists of actual console operating time. The more time spent on the surgeon console, the greater the development will be through the course of their training. Implementing a physician assistant at the bedside may increase the operative console time for the trainee and develop robotic skills in a more expeditious rate. The objective was to evaluate the impact a designated robotic physician assistant can have on trainee console learning opportunity. Methods: Operating room data collected consisted of all robotic general thoracic surgical cases that trainees participated in with and without a physician assistant present. Metrics regarding case efficiency included anesthesia ready-to-incision, incision-to-console, and raw resident console times. By using PRISM software, a nonparametric t test was used to analyze each averaged data group compared between when a physician assistant was present and not present. Results: The mean resident console time without and with a physician assistant assist was 45.8 minutes and 80.9 minutes, respectively (P < .0001). The average portion of a case performed by a trainee similarly without and with a physician assistant present was 28.0% and 77.1%, respectively (P < .0001). Case efficiency metrics between physician assistant presence cohorts showed no difference. Conclusions: Thoracic surgical trainees have increased opportunity for robotic skill development within a fellowship or resident program curriculum when a designated robotic physician assistant is present in the operating room. These findings are significant for the improvement of residency and fellowship robotic training models moving forward by incorporating robotic-specialized physician assistants in academic institutions.

Potential Role of Silencing Ribonucleic Acid for Esophageal Cancer Treatment.

INTRODUCTION: Esophageal cancer is an aggressive malignancy with high mortality. Optimal treatment of esophageal cancer remains an elusive goal. Ribonucleic acid (RNA) interference is a novel potential targeted approach to treat esophageal cancer. Targeting oncogenes that can alter critical cellular functions with silencing RNA molecules is a promising approach. The silencing of specific oncogenes in esophageal cancer cells in the experimental setting has been shown to decrease the expression of oncogenic proteins. This has resulted in cell apoptosis, reduction in cell proliferation, reduced invasion, migration, epithelial-mesenchymal transition, decrease in tumor angiogenesis and metastasis, and overcoming drug resistance. The Hedgehog (Hh) signaling pathway has been shown to be involved in esophageal adenocarcinoma formation in a reflux animal model. In addition to Hh, we will focus on other targets with clinical potential in the treatment of esophageal cancer. MATERIALS AND METHODS: We searched for articles published from 2005 to August 2020 that studied the siRNA effects on inhibiting esophageal cancer formation in experimental settings. We used combinations of the following terms for searching: "esophageal cancer," "RNA interference," "small interfering RNA," "siRNA," "silencing RNA," "Smoothened (Smo)," "Gli," "Bcl-2," "Bcl-XL," "Bcl-W,″ "Mcl-1," "Bfl-1," "STAT3,"and "Hypoxia inducible factor (HIF)". A total of 21 relevant articles were found. RESULTS AND CONCLUSIONS: Several proto-oncogenes/oncogenes including Hh pathway mediators, glioma-associated oncogene homolog 1 (Gli-1), Smoothened (Smo), and antiapoptotic Bcl-2 have potential as targets for silencing RNA in the treatment of esophageal cancer.