Tumor-Targeted Nonablative Radiation Promotes Solid Tumor CAR T-cell Therapy Efficacy.

Infiltration of tumor by T cells is a prerequisite for successful immunotherapy of solid tumors. In this study, we investigate the influence of tumor-targeted radiation on chimeric antigen receptor (CAR) T-cell therapy tumor infiltration, accumulation, and efficacy in clinically relevant models of pleural mesothelioma and non-small cell lung cancers. We use a nonablative dose of tumor-targeted radiation prior to systemic administration of mesothelin-targeted CAR T cells to assess infiltration, proliferation, antitumor efficacy, and functional persistence of CAR T cells at primary and distant sites of tumor. A tumor-targeted, nonablative dose of radiation promotes early and high infiltration, proliferation, and functional persistence of CAR T cells. Tumor-targeted radiation promotes tumor-chemokine expression and chemokine-receptor expression in infiltrating T cells and results in a subpopulation of higher-intensity CAR-expressing T cells with high coexpression of chemokine receptors that further infiltrate distant sites of disease, enhancing CAR T-cell antitumor efficacy. Enhanced CAR T-cell efficacy is evident in models of both high-mesothelin-expressing mesothelioma and mixed-mesothelin-expressing lung cancer-two thoracic cancers for which radiotherapy is part of the standard of care. Our results strongly suggest that the use of tumor-targeted radiation prior to systemic administration of CAR T cells may substantially improve CAR T-cell therapy efficacy for solid tumors. Building on our observations, we describe a translational strategy of "sandwich" cell therapy for solid tumors that combines sequential metastatic site-targeted radiation and CAR T cells-a regional solution to overcome barriers to systemic delivery of CAR T cells.

Aortic arch replacement and autologous pericardial tracheal patch for an aorto-tracheal fistula.

Aorto-tracheal fistulas are rare and highly lethal, with few reports of successful surgical intervention. We present a 48-year-old man with an aorto-tracheal fistula induced by radiation therapy for tracheal squamous cell carcinoma. He presented with hemoptysis and chest pain and workup revealed the aorta-tracheal fistula between the posterior aortic arch and anterior distal trachea. He was emergently taken to surgery. To our knowledge, this is the first report of an aorto-tracheal fistula successfully treated with a transverse aortic arch replacement and complex tracheal repair using autologous pericardium with an omental buttress.

Type A Aortic Dissection With Concurrent Aortic Valve Endocarditis, Subarachnoid Hemorrhage, and Disseminated Intravascular Coagulation.

We describe surgical repair of a Stanford Type A aortic dissection with concurrent aortic valve Streptococcus equi endocarditis in the setting of subarachnoid hemorrhage and disseminated intravascular coagulation. Multidisciplinary collaboration among specialists from a variety of disciplines is essential when treating acutely ill cardiovascular patients with multisystem involvement. (Level of Difficulty: Beginner.).

Direct innominate artery access for transcatheter aortic valve replacement.

Hostile vascular disease can pose a challenge for transcatheter aortic valve replacement, for which the preferred access is via a common femoral artery. However, extensive peripheral arterial disease may also preclude traditional points of alternative access in some patients. Herein, we describe two patients in whom successful transcatheter aortic valve replacement was performed via direct innominate artery access.

The great vessel freeze-out: A meta-analysis of conventional versus frozen elephant trunks in aortic arch surgery.

BACKGROUND: The optimal treatment strategy for complex aortic arch and proximal descending aortic pathologies remains controversial. Despite the frozen elephant trunk (FET) technique's increasing popularity, its use over the conventional elephant trunk (CET) remains a matter of physician preference and outcomes are varied. METHODS: This meta-analysis of available comparative studies of FET versus CET sought to examine differences in survival, reintervention, and adverse events. The following databases were searched from inception-May 2020: Ovid MEDLINE, Ovid EMBASE, and The Cochrane Library. Studies retrieved were then screened for eligibility against predefined inclusion/exclusion criteria with a protocol registered on Open Science Framework at https://osf.io/hrfze/. RESULTS: The search identified 1911 citations, with five studies included. The resultant meta-analysis included 313 CET and 292 FET cases. FET had lower perioperative mortality (risk ratio [RR]: 0.50, 95% confidence interval [CI]: [0.42; 0.60], p < .001) and improved 1-year survival compared to CET (hazard ratio: 0.63, 95% CI: [0.42; 0.95], p = .03). There were no significant differences in rates of overall or open reinterventions following FET versus CET, but FET did yield a significantly higher rate of endovascular reintervention (RR: 2.32, 95% CI: [1.17; 4.61], p = .03). No significant differences were observed in the incidences of postoperative stroke, spinal cord injury, or renal failure between groups. CONCLUSIONS: The FET technique yields superior rates of perioperative and medium-term survival with no significant increase in overall reinterventions. There was no significant difference in the rate of spinal cord injury between groups, providing further large-scale evidence that the FET is an acceptable, safe alternative to the CET.

Successful beating-heart repair of pulmonary artery dissection using a composite valve-tube graft.

Pulmonary artery dissection is rare but highly lethal. Recent reports suggest that surgical repair of pulmonary artery dissection may yield good outcomes in selected patients, although postoperative right ventricular failure and death have been described. Currently, only one patient over age 60 years old has been reported to survive open surgical repair of pulmonary artery dissection. Here, we present the case of a sexagenarian with pulmonary artery hypertension complicated by a dissected pulmonary artery aneurysm which was successfully repaired using a composite valve-tube graft under a beating-heart strategy.

Morbidity and mortality after general surgery in heart and lung transplant patients.

BACKGROUND: Heart and lung transplant patients can develop conditions necessitating general surgery procedures. Their postoperative morbidity and mortality remain poorly characterized and limited to case series from select centers. METHODS: The National Inpatient Sample (1998-2015) was used to identify 6433 heart and 3015 lung transplant patient admissions for general surgery procedures. For a comparator group, we identified 23,764,164 nontransplant patient admissions for the same procedures. Patient morbidity and mortality after general surgery were compared between transplant patients and nontransplant patients. Data were analyzed with frequency tables, χ 2 analysis, and a mixed-effects multivariate regression. RESULTS: Overall mortality was higher and length of stay longer in the transplant group compared to the nontransplant group. Analysis revealed that hospital size and comorbidities were predictors of mortality for patients undergoing certain general surgery procedures. Transplant status alone did not predict mortality. CONCLUSION: Our findings demonstrate that heart and lung transplant patients, compared to nontransplant patients, have more complications and a higher length of stay after certain general surgery procedures.

Distal Perfusion Cannulation and Limb Complications in Venoarterial Extracorporeal Membrane Oxygenation.

The utility of distal perfusion cannula (DPC) placement for the prevention of limb complications in patients undergoing femoral venoarterial (VA) extracorporeal membrane oxygenation (ECMO) is poorly characterized. Patients undergoing femoral VA ECMO cannulation at two institutions were retrospectively assessed. Patients were grouped into those who did and those who did not receive a DPC at the time of primary cannulation. The primary outcome was any limb complication. Secondary outcomes included successfully weaning ECMO and in-hospital mortality. A total of 75 patients underwent femoral cannulation between December 2010 and December 2017. Of those, 65 patients (86.7%) had a DPC placed during primary cannulation and 10 patients (13.3%) did not. Baseline demographics, indications for ECMO, and hemodynamic perturbations were well matched between groups. The rate of limb complications was 14.7% (11/75) for the overall cohort and did not differ between groups (p = .6). Three patients (4%) required a four-compartment fasciotomy for compartment syndrome in the DPC group; no patients without a DPC required fasciotomy. Of the three patients who required a thrombectomy for distal ischemia, two were in the DPC group and one was in the no-DPC group (p = .3). Two patients (2.7%) underwent delayed DPC placement for limb ischemia with resolution of symptoms. The in-hospital morality rate was 59.5% and did not differ between groups (p = .5). Patients in the present study, undergoing femoral VA ECMO without preemptive DPC placement did not experience a higher rate of limb complications. However, the two patients who underwent delayed DPC placement for post-cannulation ischemia experienced resolution of symptoms, suggesting that a DPC may be used as an effective limb salvage intervention.

Aortic Angulation Does Not Impact Outcomes in Self-Expandable or Balloon-Expandable Transcatheter Aortic Valve Replacement.

OBJECTIVES: The role of aortic angulation in attenuating procedural success in balloon-expandable (BE) and self-expandable (SE) transcatheter aortic valve replacement (TAVR) has been controversial. METHODS: We retrospectively assessed patients undergoing SE and BE TAVR who had an aortic angle measured on multidetector computed tomography at a single tertiary referral center. The primary outcome was device success, measured per the Valve Academic Research Consortium-2 criteria. Clinical outcomes at 30 days (including mortality) were also assessed. RESULTS: A total of 251 patients were identified; 182 patients received a BE valve and 69 patients an SE valve. The median aortic angle was 46.8° (range 24.4-70°) in the BE group and 43.3° (range 20-71°) in the SE group. In multivariate logistic regression analysis, aortic angulation did not affect device success. Mortality at 30 days and 12 months and postprocedural clinical outcomes were similarly not associated with aortic angulation. CONCLUSION: In this cohort of patients undergoing BE and SE TAVR over a wide range of aortic angles, we found no associations between angle and device success or any other clinical metrics. Increased aortic angulation does not adversely affect outcomes in BE or SE TAVR.

Systemic blood pressure trends and antihypertensive utilization following continuous-flow left ventricular assist device implantation: an analysis of the interagency registry for mechanically assisted circulatory support.

BACKGROUND: Elevated systemic blood pressure (SBP) has been linked to complications in Continuous-flow left ventricular assist devices (CF-LVADs), including stroke and pump thrombosis. We queried Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) to describe the response of SBP to CF-LVAD implantation and to delineate contemporary trends in antihypertensive (AH) utilization for patients with these pumps. METHODS: We identified all CF-LVAD implantations in patients older than 18 years from 2006-2014, excluding those whose durations were less than 30 days. Pre-implant patient demographics and characteristics were obtained for each record. SBPs [i.e., mean arterial pressures (MAPs)], AH-use data, and vital status were tabulated, extending up to 5 years following implantation. RESULTS: A total of 10,329 CF-LVAD implantations were included for study. Post-implant, SBPs increased rapidly during the first 3 months but plateaued thereafter; AH utilization mirrored this trend. By 6 months, mean MAPs climbed 12.2% from 77.6 mmHg (95% CI: 77.4-77.8) pre-implantation to 87.1 mmHg (95% CI: 86.7-87.4) and patients required a mean of 1.8 AH medications (95% CI: 1.75-1.78) -a 125% increase from AH use at 1-week post-implantation (0.8 AHs/patient, 95% CI: 0.81-0.83) but a 5.3% decrease from pre-implant utilization (1.9 AHs/patient, 95% CI: 1.90-1.92). Once medication changes stabilized, the most common AH regimens were lone beta blockade (15%, n=720) and a beta blocker plus an ACE inhibitor (14%, n=672). CONCLUSIONS: SBP rises rapidly after CF-LVAD implantation, stabilizing after 3 months, and is matched by concomitant changes in AH utilization; this AH use has increased over consecutive implant years.

Does a balanced transfusion ratio of plasma to packed red blood cells improve outcomes in both trauma and surgical patients? A meta-analysis of randomized controlled trials and observational studies.

BACKGROUND: The effect of high transfusion ratios of fresh frozen plasma (FFP): packed red blood cell (RBC) on mortality is still controversial. Observational evidence contradicts a recent randomized controlled trial regarding mortality benefit. This is an updated meta-analysis, including a non-trauma cohort. METHODS: Patients were grouped into high vs. low based on FFP:RBC ratio. Primary outcomes were 24-h and 30-day/in-hospital mortality. Secondary outcomes were acute respiratory distress syndrome and acute lung injury rates. Random model and leave-one-out-analyses were used. RESULTS: In 36 studies, lower ratio showed poorer 24-h and 30-day survival (p < 0.001). In trauma and non-trauma settings, a lower ratio was associated with worse 24-h and 30-day mortality (P < 0.001). A ratio of 1:1.5 provided the largest 24-h and 30-day survival benefit (p < 0.001). The ratio was not associated with ARDS or ALI. CONCLUSIONS: High FFP:RBC ratio confers survival benefits in trauma and non-trauma settings, with the highest survival benefit at 1:1.5.

Short- and mid-term results after transapical transcatheter aortic valve replacement in nonagenarians.

BACKGROUND: Recent reports have suggested that advanced age may preclude favorable outcomes in transcatheter aortic valve replacement (TAVR), particularly when performed via transapical (TA) access. However, detailed examinations of TA-TAVR in nonagenarian patients are lacking in the contemporary literature. We therefore describe our experience with 25 consecutive nonagenarians who underwent TA-TAVR and report their short- and mid-term outcomes. METHODS: We identified all patients 90 years old or greater who underwent TA-TAVR between 2009-2014 at our institution. Demographic, comorbidity and echocardiographic data were obtained for all patients as were their in-hospital, 30-day, and 1-year outcomes. Overall survival was calculated using the Kaplan-Meier method. RESULTS: The mean Society of Thoracic Surgeons' predicted risk of mortality was 10.2% (SD±3.4). Twenty-four nonagenarians received TA-TAVR secondary to severe aortic stenosis while 1 had a valve-in-valve procedure for a regurgitant bioprosthetic valve. There were no conversions to open surgery, no aborted procedures, and no in-hospital deaths or strokes; 44% of patients (N.=11) were discharged to home. Five patients required cardiac rehospitalization within the first 30 days and 2 experienced strokes during the first year. Overall 30-day and 1-year survival were 100% and 83%, respectively. CONCLUSIONS: TA-TAVR can safely be performed on nonagenarians subjected to otherwise standard selection criteria. Chronology should not stand as a routine contraindication to this procedure; rather, comorbidities and functional status should define patient eligibility for TA-TAVR.

Electrocardiographic Correlates of Myocardial Injury After Transcatheter Aortic Valve Replacement.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) is associated with several conduction abnormalities and a need for pacemaker placement. The study aim was to describe all electrocardiographic (ECG) changes seen after TAVR, to compare such changes between transapical (TA) and transfemoral (TF) patient cohorts, and to assess their impact on postoperative outcomes. METHODS: Between March 2009 and July 2014, a total of 286 consecutive patients underwent TAVR at the present authors' institution. Perioperative data were collected prospectively, while preoperative and predischarge electrocardiograms were reviewed retrospectively by an independent cardiologist. RESULTS: A greater proportion of TA patients experienced ECG changes than TF patients at the time of discharge (78% versus 42%; p <0.0001), with more intraventricular conduction abnormalities (29% versus 15%; p = 0.006), and a trend towards more frequent atrioventricular block and pacemaker placement. Troponin levels were higher in patients with new ECG changes (4.61ng/ml versus 2.12 ng/ml; p = 0.0009). New intraventricular conduction abnormalities were associated with increased one-year mortality only in the TF subgroup (65% versus 84%; p = 0.028). Six TA patients demonstrated new ECG findings of myocardial infarction, and this was associated with greater 30-day mortality (67% versus 98%; p = 0.012), although none met the clinical criteria for myocardial infarction. CONCLUSIONS: New ECG changes after TAVR, including new conduction abnormalities, were seen more frequently in TA patients. When seen in TF patients, they were associated with decreased survival. ECG findings of new myocardial infarction, seen only in TA patients, were also associated with decreased survival.

Transapical transcatheter aortic valve replacement in patients with or without prior coronary artery bypass graft operation.

BACKGROUND: Transapical approach (TA) is an established access alternative to the transfemoral technique in patients undergoing transcatheter aortic valve replacement (TAVR) for treatment of symptomatic aortic valve stenosis. The impact of prior coronary artery bypass grafting (CABG) on clinical outcomes in patients undergoing TA-TAVR is not well defined. METHODS: A single center retrospective cohort analysis of 126 patients (male 41%, mean age 85.8 ± 6.1 years) who underwent TA balloon expandable TAVR (Edwards SAPIEN, SAPIEN XT or SAPIEN 3) was performed. Patients were classified as having prior CABG (n = 45) or no prior CABG (n = 81). Baseline clinical characteristics, in-hospital, 30-day, 6 months and one-year clinical outcomes were compared. RESULTS: Compared to patients without prior CABG, CABG patients were more likely to be male (62.2 vs. 29.6%, p < 0.001) with a higher STS score (11.66 ± 5.47 vs. 8.99 ± 4.19, p = 0.003), history of myocardial infarction (55 vs. 21.1%, p < 0.001), implantable cardioverter defibrillator (17.8 vs. 3.7%, p = 0.017), left main coronary artery disease (42.2 vs. 4.9%, p < 0.001), and proximal left anterior descending coronary artery stenosis (57.8 vs. 16%, p < 0.001). They also presented with a lower left ventricular ejection fraction (%) (42.3 ± 15.3 vs. 54.3 ± 11.6, p < 0.01) and a larger effective valve orifice area (0.75 ± 0.20 cm2 vs. 0.67 ± 0.14 cm2, p = 0.025). There were no intra-procedural deaths, no differences in stroke (0 vs. 1.2%, p = 1.0), procedure time in hours (3.50 ± 0.80 vs. 3.26 ± 0.86, p = 0.127), re-intubation rate (8.9 vs. 8.6% p = 1.0), and renal function (highest creatinine value 1.73 ± 0.71 mg/ml vs.1.88 ± 1.15 mg/ml, p = 0.43). All-cause mortality at 6 months was similar in both groups (11.4, vs. 17.3% p = 0.44), and one-year survival was 81.8 and 77.8% respectively (p = 0.51). On multivariate analysis, the only factor significantly associated with one-year mortality was prior history of stroke (HR, 2.76; 95% CI, 1.06-7.17, p = 0.037). CONCLUSION: Despite the higher baseline clinical risk profile, patients with history of prior CABG undergoing TA-TAVR had comparable in-hospital, 6 months and one-year clinical outcomes to those without prior CABG.

National Analysis of Short-Term Outcomes and Volume-Outcome Relationships for Transcatheter Aortic Valve Replacement in the Era of Commercialization.

OBJECTIVES: We queried the 2012 National Inpatient Sample in order to (1) further describe the short-term outcomes for transcatheter aortic valve replacement (TAVR) and (2) characterize possible volume-outcome relationships and other prognostic factors for this procedure. METHODS: Demographics and inhospital outcomes were tabulated for all patients, as were hospital characteristics and procedural-volume data for all centers at which patients underwent TAVR. Logistic regression analyses were performed to identify independent risk factors for mortality or morbidity. RESULTS: 7,635 patients aged ≥ 18 years received TAVR during the study period; 84.5% (n = 6,450) underwent transfemoral TAVR and the rest were treated transapically. The median age was 83 years (IQR 77-88 years) and cardiovascular comorbidities were widespread. Overall inhospital mortality was 5.0% (n = 380), and 1.4% (n = 105) of the patients experienced a stroke. All-cause procedure-related morbidity was 24.7% (n = 1,885). Annual hospital TAVR volume did not predict inhospital mortality or morbidity (OR 1.00, 95% CI 0.99-1.00, p = 0.111 and OR 1.00, 95% CI 0.99-1.00, p = 0.947, respectively). CONCLUSIONS: Our analysis helps to confirm the short-term safety profile of TAVR and further demonstrates that inhospital outcomes have remained acceptable as this procedure has become commercialized.

Variability in End-Organ Perfusion with Femoral-Femoral Venoarterial Extracorporeal Membrane Oxygenation: Aortographic Evidence.

In femoral-femoral venoarterial extracorporeal membrane oxygenation (VA-ECMO), the outflow of oxygenated blood from the circuit enters the aorta in retrograde fashion. As a result, variability in end-organ oxygenation (e.g., cerebral vs. splanchnic) may arise-particularly, when the heart is unable to contribute forward flow. We present the case of a 74-year-old man supported by femoral-femoral VA-ECMO in whom aortography was used to visualize the retrograde distribution of arterial ECMO flow that can produce such differences in end-organ perfusion. We do this by describing a series of still images captured during the aortography; we then discuss the importance of monitoring end-organ oxygenation in this setting and outline several interventions that can ameliorate this flow phenomenon.