Research Spotlight

O’Leary, J.G., Philippe, A., Freeman, R., Heidecke, H., Jennings, L.W., Catar, R., Klintmalm, G.B. and Dragun, D. (2021). “Non-HLA Autoantibodies at 1 Year Negatively Affect 5-Year Native Renal Function in Liver Transplant Recipients.” Transplant Proc Feb 9;S0041-1345(21)00017-8. [Epub ahead of print].

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BACKGROUND: Angiotensin II type-1 receptor (AT(1)R) and endothelin-1 type A receptor (ET(A)R) autoantibodies, in addition to allograft injury, can bind native endothelial cells and cause vascular vasoconstriction and fibrosis progression in nontransplanted organs. Therefore, we investigated long-term native renal function in liver transplant (LT) recipients with and without anti-AT(1)R-Abs and/or anti-ET(A)R-Abs present in serum. METHODS: Primary LT recipients at our single center from January 2000 to April 2009 had their prospectively collected pre-LT (1269 patients) and year 1 post-LT (795 patients) serum tested retrospectively for anti-AT(1)R-Abs and/or anti-ET(A)R-Abs. Anti-AT(1)R-Abs and anti-ET(A)R-Abs testing was accomplished with a standardized solid phase assay in which >10 U was considered positive. RESULTS: Pretransplant anti-AT(1)R-Abs and/or anti-ET(A)R-Abs did not change the median delta creatinine from pretransplant to 1 year post-transplant. In multivariable analysis controlling for diabetes (DM) and calcineurin inhibitor (CNI) use, anti-AT(1)R-Abs and/or anti-ET(A)R-Abs at 1-year remained statistically significantly associated with a decline in GFR (measured by Modification of Diet in Renal Disease-6) from years 1-5 post-LT (P = .04). In diabetic patients the association with a decline in renal function was more pronounced with (-9.29 mL/min) vs without (-2.28 mL/min) anti-AT(1)R-Abs and/or anti-ET(A)R-Abs at year 1, respectively (P = .004). CONCLUSION: At 1-year post-LT, the autoantibodies anti-AT(1)R-Abs and/or anti-ET(A)R-Abs are associated in multivariable analysis with an increased risk of native renal function decline especially in diabetic patients.

Zaidi, A.H., Kelly, R.J., Gorbunova, A., Omstead, A.N., Salvitti, M.S., Zheng, P., Kosovec, J.E., Lee, S., Ayazi, S., Babar, L., Finley, G.G., Goel, A. and Jobe, B.A. (2021). “Intratumoral immunotherapy with STING agonist, ADU-S100, induces CD8+ T-cell mediated anti-tumor immunity in an esophageal adenocarcinoma model.” Oncotarget 12(4): 292-303.

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BACKGROUND: Esophageal adenocarcinoma (EAC) is a deadly disease with limited treatment options. STING is a transmembrane protein that activates transcription of interferon genes, resulting in stimulation of APCs and enhanced CD8+ T-cell infiltration. The present study evaluates STING agonists, alone and in combination with radiation to determine durable anticancer activity in solid tumors. MATERIALS AND METHODS: Esophagojejunostomy was performed on rats to induce reflux leading to the development of EAC. At 32 weeks post operatively, rats received intratumorally either 50 μg STING (ADU-S100) or placebo (PBS), +/- 16Gy radiation. Drug activity was evaluated by pre- and post- treatment MRI, histology, immunofluorescence and RT-PCR. RESULTS: Mean MRI tumor volume decreased by 30.1% and 50.8% in ADU-S100 and ADU-S100 + radiation animals and increased by 76.7% and 152.4% in placebo and placebo + radiation animals, respectively (P < 0.0001). Downstream gene expression, pre- to on- and post- treatment, demonstrated significant upregulation of IFNβ, TNFα, IL-6, and CCL-2 in the treatment groups vs. placebo. On- or post- treatment, radiation alone, ADU-S100 alone, and ADU-S100 + radiation groups demonstrated enhanced PD-LI expression, induced by upregulation of CD8+ T-cells (p < 0.01). CONCLUSIONS: ADU-S100 +/- radiation exhibits potent antitumor activity and a promising immunomodulatory profile in a de novo EAC.

Johannesson, L., Wall, A., Warren, A.M., Gregg, A.R. and Testa, G. (2021). “Decisions on second pregnancy after uterus transplantation and timing for removal of the uterus-DUETS (Dallas UtErus Transplant Study).” Bjog Mar 4. [Epub ahead of print].

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Since the first live birth to a woman after uterus transplantation (UTx) was reported in 2014,(1) the number of UTx procedures has increased and births have occurred in multiple centers worldwide.(2) Despite the growth of UTx, it is a novel procedure, with most cases having been done under experimental protocols, and there remains much debate about the ethics of UTx. Centers have allowed recipients one or two pregnancies, limiting recipient-graft time (RGT), the time from UTx to hysterectomy, to 5 years. Few UTx recipients have delivered more than one baby to date.

Jensen, G.L., Axelrud, G., Fink, D., Hammonds, K., Walker, K., Volz, M., Gowan, A., Rao, A., Deb, N. and Jhavar, S.G. (2021). “Improved local control in p16 negative oropharyngeal cancers with hypermethylated MGMT.” Radiother Oncol Feb 10;157:234-240. [Epub ahead of print]. 234-240.

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INTRODUCTION: Patients with oropharyngeal cancers that are p16 negative (p16-) have worse outcomes than those who are p16 positive (p16+) and there is an unmet need for prognostic markers in this population. O6-Methylguanine (O6-MG)-DNA-methyltransferase (MGMT) gene methylation has been associated with response to chemoradiotherapy (CRT) in glioblastoma. We sought to find if MGMT promoter methylation was associated with outcomes of locally advanced oropharyngeal and oral cavity squamous cell carcinoma (OOSCC) in patients treated with definitive concurrent CRT. METHODS: Patients were identified with primary OOSCC, known p16 status, retrievable pre-treatment biopsies, and at least 6 months of follow-up who received definitive concurrent CRT from 2004 to 2015. Biopsies were tested for MGMT hypermethylation (MGMT+) using a Qiagen pyrosequencing kit (Catalog number 970061). Outcomes were subsequently recorded and analyzed. RESULTS: Fifty-eight patients were included with a median follow up of 78 (range 6-196) months. Fourteen patients (24.1%) had oral cavity cancer and 44 (75.9%) had oropharyngeal cancer. A significant difference was found for local recurrence free survival (LRFS) by combined MGMT and p16 status (p = 0.0004). Frequency of LR in MGMT+/p16+, MGMT+/p16-, MGMT-/p16+, and MGMT-p16- patients was 14.3%, 14.3%, 13.0%, and 69.2%, respectively (p = 0.0019). A significant difference was not found for distant recurrence free survival (p = 0.6165) or overall survival (p = 0.1615). LRFS remained significant on analysis restricted to oropharyngeal cancer patients (p-value = 0.0038). CONCLUSION: Patients who are p16- and MGMT+ with oropharyngeal and oral cavity squamous cell carcinoma have significantly better LC with definitive CRT than those who are p16- and MGMT-. Prospective studies are needed to verify these findings.

Huebinger, R.M., Stilgenbauer, H., Jarvis, J.L., Ostermayer, D.G., Schulz, K. and Wang, H.E. (2021). “Video laryngoscopy for out of hospital cardiac arrest.” Resuscitation Feb 25;162:143-148. [Epub ahead of print].

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INTRODUCTION: Endotracheal intubation is an import component of out-of-hospital cardiac arrest (OHCA) resuscitation. In this analysis, we evaluate the association of video laryngoscopy (VL) with first pass success and return of spontaneous circulation (ROSC) using a national OHCA cohort. METHODS: We analyzed 2018 data from ESO Inc. (Austin, TX), a national prehospital electronic health record. We included all adult, non-traumatic cardiac arrests undergoing endotracheal intubation. We defined VL and direct laryngoscopy (DL) based on paramedic recorded intubation device. The primary outcomes were first pass success, ROSC, and sustained ROSC. Using multivariable, mixed models, we determined the association between VL and first pass success rate, ROSC, and sustained ROSC (survival to ED or ROSC in the field for greater than 20 min), fitting agency as a random intercept and adjusting for confounders. RESULTS: We included 22,132 patients cared for by 914 EMS agencies, including 5702 (25.7%) VL and 16,430 (74.2%) DL. Compared to DL, VL had a lower rate of bystander CPR, but other characteristics were similar between the groups. VL exhibited higher first pass success than DL (75.1% v 69.5%, p < .001). On mixed model analysis, VL was associated with a higher first pass success (OR 1.5, CI 1.3-1.6) but not ROSC (OR 1.1, CI 0.97-1.2) or sustained ROSC (OR 1.1, CI 0.9-1.2). CONCLUSION: While associated with higher FPS, VL was not associated with increased rate of ROSC. The role of VL in OHCA remains unclear.