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 (

Spread through air spaces (STAS) is reportedly associated with worse prognosis in sublobar resections of lung adenocarcinoma. Recently, it was proposed that STAS detected on frozen sections can be an indication for lobectomy instead of sublobar resection. We undertook this study to evaluate the reliability of STAS assessment on frozen sections compared to permanent sections, as well as the associations among STAS, tumor grade, and recurrence-free survival (RFS) after sublobar resection. A total of 163 stage I lung adenocarcinoma resections with frozen sections were identified retrospectively. For each case, and for frozen and permanent sections separately, the presence or absence of STAS, as well as the tumor grade, were recorded. Compared to permanent sections, STAS detection on frozen sections had low sensitivity (55%), low positive predictive value (48%), and fair agreement (K = 0.34), whereas there was higher specificity (80%) and negative predictive value (85%). Accuracy was 74%. Tumor grade assessment on frozen sections showed higher sensitivity (77%), positive predictive value (90%), agreement (K = 0.72), specificity (94%), and accuracy (87%), and the same negative predictive value (85%). High-grade histology on frozen sections was associated with shorter RFS (p = 0.02), whereas STAS on frozen sections was not (p = 0.47). Our results suggest that the intraoperative detection of STAS has low sensitivity and positive predictive value. False-positive results may lead to overtreatment of patients with lung cancer. The determination of tumor grade on frozen sections offers better sensitivity and specificity, plus it is associated with RFS, whereas STAS on frozen sections is not. Further study is needed to explore the utility of assessing tumor grade on frozen sections.

BACKGROUND:Histological analyses of deep vein thrombi (DVT) are based on autopsy samples and animal models. No prior study has reported on thrombus composition following percutaneous mechanical extraction. As elements of chronicity and organization render thrombus resistant to anticoagulation and thrombolysis, a better understanding of clot evolution may inform therapies. METHODS:We performed histologic evaluation of DVTs from consecutive patients undergoing mechanical thrombectomy for extensive iliofemoral DVTs using the Clottriever/ Flowtriever device (Inari Medical, Irvine, CA). Thrombi were scored in a semi-quantitative manner based on the degree of fibrosis (collagen deposition on trichrome stain), and organization (endothelial growth with capillaries and fibroblastic penetration). RESULTS:Twenty-three specimens were available for analysis with 20 presenting with acute DVT (≤14 days from symptom onset). Eleven of 23 patients (48%) had >5% fibrosis (collagen deposition) and 14/23 patients (61%) had >5% organization (endothelial growth, capillaries, fibroblasts). Four patients with acute DVT had ≥25% organized thrombus and 2 had ≥ 25% collagen deposition. Among the 20 patients with acute DVT, 40% had >5% fibrosis and 55% had > 5% organization. Acuity of DVT did not correlate with the fibrosis or organizing scores. CONCLUSIONS:A large proportion of patients with acute DVT have histologic elements of chronicity and fibrosis. A better understanding of the relationship between such elements and response to anticoagulants and fibrinolytics may inform our approach to therapeutics.

OBJECTIVES/OBJECTIVE:F-FDG uptake is associated with hypertension, and if it correlates to elevated pulmonary pressures. BACKGROUND: METHODS:F-FDG uptake in the PA was quantified according to maximum standardized uptake value (SUVmax) and target-to-background ratio (TBR) and compared with available results from right heart catheterization (RHC) or transthoracic echocardiography (TTE). RESULTS:F-FDG uptake in the PA wall showed a sensitivity of 33% and specificity of 96% for separating patients with PH based on RHC-derived PA pressures. SUVmax and TBR in the PA wall correlated with PA pressure derived from RHC and/or TTE. CONCLUSIONS:F-FDG uptake by PET/CMR in the PA is associated with PH and that its intensity correlates with PA pressure.

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!