Research Spotlight

Lawrence, M. C., C. M. Darden, S. Vasu, K. Kumano, J. Gu, X. Wang, J. Chan, Z. Xu, B. F. Lemoine, P. Nguyen, C. Smitherman, B. Naziruddin and G. Testa (2019). “Profiling Gene Programs in the Blood during Liver Regeneration in Living Liver Donors.” Liver Transpl Jul 24. [Epub ahead of print].

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The human liver’s capacity to rapidly regenerate to a full-sized functional organ after resection has allowed successful outcomes for living-donor liver transplantation (LDLT) procedures. However, the ability to detect and track physiological changes occurring during liver regeneration after resection and throughout the restoration process is still lacking. We performed a comprehensive whole-transcriptome RNA sequencing analysis of liver and circulating blood tissue from 12 healthy LDLT donors to define biomarker signatures for monitoring physiological activities during liver regeneration at 14 time points for up to 1 year procedural follow up. LDLT donor liver tissue differentially expressed 1238 coding and noncoding genes post resection, and an additional 1260 genes were selectively regulated post-LDLT. A total of 15,011 RNA transcript species were identified in the blood in response to liver resection. Transcripts most highly regulated were sequentially expressed within three distinct peaks that correlated with sets of functional genes involved in induction of liver resection-specific innate immune response (Peak I), activation of the complement system (Peak II), and platelet activation and erythropoiesis (Peak III). Each peak corresponded with progressive phases of extracellular matrix degradation, remodeling, and organization during liver restoration. These processes could be tracked by distinct molecular signatures of upregulated and downregulated gene profiles in the blood during phases of liver repair and regeneration. In conclusion, the results establish temporal and dynamic transcriptional patterns of gene expression following surgical liver resection that can be detected in the blood and potentially used as biomarker signatures for monitoring phases of liver regeneration.

Khwaja, R., E. Mantilla, K. Fink and E. Pan (2019). “Adult Primary Peripheral PNET/Ewing’s Sarcoma of the Cervical and Thoracic Spine.” Anticancer Res 39(8): 4463-4465.

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This case report describes a patient with a rare occurrence of primary spinal intramedullary Ewing’s sarcoma (ES) in the cervical and thoracic spine. The older age of disease occurrence, uncommon location in the cervical and thoracic spine, and EWSR1 gene fusion as the basis of diagnosis are unique features of this case. There is no clear protocol for treatment of primary extraskeletal ES of the spine, with controversy between evidence for pursuing surgery versus a combination of radiation and chemotherapy. Our patient was treated with temozolomide chemotherapy for recurrent metastatic disease of primary ES of the spine.

Kelly, R. J., A. M. Ansari, T. Miyashita, M. Zahurak, F. Lay, A. K. Ahmed, L. J. Born, M. K. Pezhouh, K. J. Salimian, C. Ng, A. E. Matsangos, A. H. Stricker-Krongrad, K. I. Mukaisho, G. P. Marti, C. H. Chung, M. I. Canto, M. A. Rudek, S. J. Meltzer and J. W. Harmon (2019). “Targeting the Hedgehog Pathway Using Itraconazole to Prevent Progression of Barrett’s Esophagus to Invasive Esophageal Adenocarcinoma.” Ann Surg Jul 8. [Epub ahead of print].

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OBJECTIVE: The aim of the study was to investigate whether inhibition of Sonic Hedgehog (SHH) pathway would prevent progression of Barrett’s Esophagus (BE) to esophageal adenocarcinoma. BACKGROUND: The hedgehog signaling pathway is a leading candidate as a molecular mediator of BE and esophageal adenocarcinoma (EAC). Repurposed use of existing off-patent, safe and tolerable drugs that can inhibit hedgehog, such as itraconazole, could prevent progression of BE to EAC. METHODS: The efficacy of itraconazole was investigated using a surgical rat reflux model of Barrett’s Metaplasia (BM). Weekly intraperitoneal injections of saline (control group) or itraconazole (treatment group; 200 mg/kg) were started at 24 weeks postsurgery. Esophageal tissue was harvested at 40 weeks. The role of the Hh pathway was also evaluated clinically. Esophageal tissue was harvested after 40 weeks for pathological examination and evaluation of the SHH pathway by immunohistochemistry. RESULTS: BM was present in control animals 29 of 31 (93%) versus itraconazole 22 of 24 (91%). EAC was significantly lower in itraconazole 2 of 24 (8%) versus control 10 of 31 (32%), respectively (P = 0.033). Esophageal SHH levels were lower in itraconazole vs control (P = 0.12). In esophageal tissue from humans with recurrent or persistent dysplastic BE within 24 months of ablative treatment, strong SHH and Indian Hedgehog expression occurred in distal BE versus proximal squamous epithelium, odds ratio = 6.1 (95% confidence interval: 1.6, 23.4) and odds ratio = 6.4 (95% confidence interval: 1.2, 32.8), respectively. CONCLUSION: Itraconazole significantly decreases EAC development and SHH expression in a preclinical animal model of BM. In humans, BE tissue expresses higher SHH, Indian Hedgehog, and bone morphogenic protein levels than normal squamous esophageal epithelium.

Johannesson, L., A. Wall, J. M. Putman, L. Zhang, G. Testa and C. Diaz-Garcia (2019). “Rethinking the time interval to embryo transfer after uterus transplantation-DUETS (Dallas UtErus Transplant Study).” BJOG Jul 8. [Epub ahead of print].

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The first successful live birth after uterus transplantation occurred in 2014. Since then, successful live births have been replicated, offering hope to women with uterine factor infertility who want to carry a pregnancy . . . Uterus transplant can allow women to carry their own pregnancy. Because of the transplant operation, infectious disease risks, and immunosuppressive medications, these pregnancies require careful planning. Conditions to achieve before ET include stable uterine graft function, absence of active rejection, stable immunosuppressive medication with agents with low teratogenic risk, and low‐risk status for harmful opportunistic infections. Our experience, the experience of other uterus transplant programmes, and results of successful pregnancies in other solid organ transplant recipients suggest ET could be considered as soon as 3 months after uterus transplantation if the above criteria are met. Given the unique characteristics of uterus transplantation and the recipient population, the transplant‐to‐ET interval should differ from recommendations in other organ and vascular allograft transplantations. The incentive of minimising the recipient‐graft time and concomitant exposure to immunosuppressants in this young, healthy patient population strongly supports shortening the transplant‐to‐ET time. (Excerpts from text, p. 1, 4; no abstract available.)

Hollander, P., J. Hill, J. Johnson, Z. Wei Jiang, G. Golm, S. Huyck, S. G. Terra, J. P. Mancuso, S. S. Engel, B. Lauring and J. Liu (2019). “Results of VERTIS SU extension study: safety and efficacy of ertugliflozin treatment over 104 weeks compared to glimepiride in patients with type 2 diabetes mellitus inadequately controlled on metformin.” Curr Med Res Opin 35(8): 1335-1343.

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Objective: To assess the safety and efficacy of ertugliflozin over 104 weeks in patients with type 2 diabetes mellitus (T2DM) inadequately controlled on metformin. Methods: In this double-blind, multicenter, randomized, phase III study (VERTIS SU; NCT01999218), adults with T2DM and glycated hemoglobin (HbA1c) 7.0-9.0% on metformin >/=1500 mg/day received ertugliflozin 5 mg or 15 mg, or glimepiride. The primary efficacy time point was Week 52; double-blinded treatment continued until Week 104. Results: Baseline characteristics of randomized, treated patients (n = 1315) were similar across groups (mean age 58.2 years, HbA1c 7.8%); 76.4% completed the study; 61.6% completed on study medication. Mean glimepiride dose at 104 weeks was 3.5 mg/day. At Week 104, least squares mean change from baseline in HbA1c (95% confidence intervals) were -0.3% (-0.4, -0.2), -0.4% (-0.5, -0.3) and -0.4% (-0.5, -0.3) for ertugliflozin 5 mg, 15 mg, and glimepiride, respectively. Ertugliflozin provided sustained reductions in body weight and systolic blood pressure (SBP) over 104 weeks. The incidence of adverse events (AEs) and serious AEs was similar across groups. The incidence of symptomatic hypoglycemia was 3.8%, 6.4% and 22.1% in the ertugliflozin 5 mg, 15 mg, and glimepiride groups, respectively. Genital mycotic infections were reported in 5.3%, 2.6% and 0% of men, respectively, and 9.2%, 12.3% and 1.4% of women, respectively. The incidence of urinary tract infection and hypovolemia AEs was similar across groups. Conclusions: Ertugliflozin was well tolerated and provided clinically meaningful glycemic control and durable reductions in body weight and SBP over 104 weeks.