Faculty Bibliography

Purpose: In the U.S., heart transplantation from donation after circulatory death (DCD) is increasing. We present our institutional experience of DCD transplantation by using a thoracoabdominal-normothermic regional perfusion (TA-NRP) protocol and compare the results to a cohort concomitantly transplanted, from standard brain death (

BACKGROUND:Specific aetiologies of cardiomyopathy can significantly impact treatment options as well as appropriateness and prioritisation for advanced heart failure therapies such as ventricular assist device (VAD) or orthotopic heart transplantation (OHT). We reviewed the tissue diagnoses of patients who underwent advanced therapies for heart failure (HF) to identify diagnostic discrepancies. METHODS:This study presents a retrospective cohort of the aetiology of cardiomyopathy in 118 patients receiving either durable VAD or OHT. Discrepancies between the preoperative aetiological diagnosis of cardiomyopathy with the pathological diagnosis were recorded. Echocardiographic and haemodynamic data were reviewed to examine differences in patients with differing aetiological diagnoses. RESULTS:Twelve (12) of 118 (12/118) (10.2%) had a pathological diagnosis that was discordant with pre-surgical diagnosis. The most common missed diagnoses were infiltrative cardiomyopathy (5) and hypertrophic cardiomyopathy (3). Patients with misidentified aetiology of cardiomyopathy had smaller left ventricular (LV) dimensions on echocardiography than patients with dilated cardiomyopathy (5.8±0.9 vs 6.7±1.1 respectively p=0.01). CONCLUSIONS:Most HF patients undergoing VAD and OHT had a correct diagnosis for their heart failure prior to treatment, but a missed diagnosis at time of intervention (VAD or OHT) was not uncommon. Smaller LV dimension on echocardiogram in a patient with a non-ischaemic cardiomyopathy warrants further workup for a more specific aetiology.

Unlike other checkpoint inhibitors, our targeted immunotherapeutic localizes to any solid tumor and simultaneouslyshields an agent of immuno suppression while presenting a signal for immunostimulation. Phosphatidylserine (PS)exposure on the extracellular surface of living tumor cells and their vasculatures provides one avenue by which thetumor microenvironment promotes immunosuppression. Extracellular surface PS is inherent to a tumor and itsvasculature, even for inoperable tumors, and its expression cannot be mutated nor affected by acquired drugresistance. Annexin A5 (AnxA5) is a direct, high-affinity PS-binding protein that localizes to cells with PS exposed onthe outer plasma membrane. In our studies, we conjugated a proprietary modified AnxA5, lacking cellularinternalization, to TNFalpha (AnxA5 -TNFalpha) to convert the immunosuppresive environs of a murine 4T1 triplenegative breast cancer (TNBC) into an immunostimulated one. This strategy localized the immune response to the tumor and minimized side effects, as evidenced by a lack of toxicity for up to 7 days in non-tumor bearing Balb/cfemale mice given up to 1 mg/kg. Proper assembly and functionality of AnxA5 -TNFalpha was verified simultaneouslyby ellipsometry, an optical technique similar to plasmon resonance. Fully assembled constructs were tested forbinding to PS coated slides. The degree of light polarization is proportional to the amount of PS bound by the AnxA5complex. Samples could be further incubated with TNF receptors to verify TNFalpha activity. Based on dose escalationstudies in 4T1 tumor-bearing mice where the TNBC tumors were grown in the mammary fat pads, optimal dosages were determined for AnxA5 -TNFalpha (18 mug) and AnxA5 alone as a control (180 mug). These doses were furthertested in a 4T1 growth inhibition study. Tumor size was tracked by caliper in two groups of mice (n=5/group)receiving drug treatment on days 12, 14 and 16 and a repeated measures ANOVA was conducted onmeasurements taken before, during and post-treatment. While median tumor size did not differ between control and drug treatment groups during the pre-treatment interval (p=0.84), there was a significant difference post-treatment(p<0.001) with mice receiving AnxA5 -TNFalpha having much smaller TNBC tumors. Tumors from the study were embedded in paraffin, sectioned (5 mum) and the overall immune cell content determined by H&E staining. Once it was evident there was a greater quantity of immune cells in AnxA5 -TNFalpha treated tumors vs. controls, sections were stained with validated antibodies to identify and count the immunoactivated T-cells, NK-cells and macrophages. There was a 3X greater mean percentage of CD8 and CD4 T-cells in mice receiving drug vs. control(p=0.03) along with 2.5X and 5X increases in NK-cells and M1 immunoactive macrophages, respectively.
Conclusion(s): Our AnxA5 -TNFalpha inhibits the PS inhibitor while simultaneously activating TNF activators!

OBJECTIVES/OBJECTIVE:Patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may develop end-stage lung disease requiring lung transplantation. We report the clinical course, pulmonary pathology with radiographic correlation, and outcomes after lung transplantation in three patients who developed chronic respiratory failure due to postacute sequelae of SARS-CoV-2 infection. METHODS:A retrospective histologic evaluation of explanted lungs due to coronavirus disease 2019 was performed. RESULTS:None of the patients had known prior pulmonary disease. The major pathologic findings in the lung explants were proliferative and fibrotic phases of diffuse alveolar damage, interstitial capillary neoangiogenesis, and mononuclear inflammation, specifically macrophages, with varying numbers of T and B lymphocytes. The fibrosis varied from early collagen deposition to more pronounced interstitial collagen deposition; however, pulmonary remodeling with honeycomb change was not present. Other findings included peribronchiolar metaplasia, microvascular thrombosis, recanalized thrombi in muscular arteries, and pleural adhesions. No patients had either recurrence of SARS-CoV-2 infection or allograft rejection following transplant at this time. CONCLUSIONS:The major pathologic findings in the lung explants of patients with SARS-CoV-2 infection suggest ongoing fibrosis, prominent macrophage infiltration, neoangiogenesis, and microvascular thrombosis. Characterization of pathologic findings could help develop novel management strategies.