Research Spotlight

Jones, B. P., S. Saso, A. L’Heveder, T. Bracewell-Milnes, M. Y. Thum, C. Diaz-Garcia, D. A. MacIntyre, I. Quiroga, S. Ghaem-Maghami, G. Testa, L. Johannesson, P. R. Bennett, J. Yazbek and J. R. Smith (2020). “The vaginal microbiome in uterine transplantation.” BJOG 127(2): 230-238.

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Women with congenital absolute uterine factor infertility (AUFI) often need vaginal restoration to optimise sexual function. Given their lack of procreative ability, little consideration has previously been given to the resultant vaginal microbiome (VM). Uterine transplantation (UTx) now offers the opportunity to restore these women’s reproductive potential. The structure of the VM is associated with clinical and reproductive implications that are intricately intertwined with the process of UTx. Consideration of how vaginal restoration methods impact VM is now warranted and assessment of the VM in future UTx procedures is essential to understand the interrelation of the VM and clinical and reproductive outcomes. TWEETABLE ABSTRACT: The vaginal microbiome has numerous implications for clinical and reproductive outcomes in the context of uterine transplantation.

Sukumar, J. S., S. Sukumar, D. Purohit, B. J. Welch, J. Balani, S. Yan and S. S. Hathiramani (2019). “Activating BRAF mutation in sclerosing mucoepidermoid carcinoma with eosinophilia of the thyroid gland: two case reports and review of the literature.” J Med Case Rep 13(1): 385.

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BACKGROUND: Sclerosing mucoepidermoid carcinoma with eosinophilia is a rare form of thyroid carcinoma. The underlying molecular mechanisms of sclerosing mucoepidermoid carcinoma with eosinophilia tumorigenesis remain unknown. CASE PRESENTATION: We present two cases of sclerosing mucoepidermoid carcinoma with eosinophilia, both with a concurrent papillary thyroid carcinoma. Patient 1, a 70-year-old Caucasian woman, presented with sclerosing mucoepidermoid carcinoma with eosinophilia with distant renal metastasis and coexisting papillary thyroid carcinoma. Patient 2, a 74-year-old Caucasian woman with a remote history of thyroid cancer treated with thyroidectomy, presented with locoregionally invasive sclerosing mucoepidermoid carcinoma with eosinophilia and recurrent papillary thyroid carcinoma in the thyroid bed. BRAF mutation studies were performed on the sclerosing mucoepidermoid carcinoma with eosinophilia tumors. In both cases, sclerosing mucoepidermoid carcinoma with eosinophilia was positive for the BRAF V600E mutation by polymerase chain reaction. Patient 1 is the first reported case of sclerosing mucoepidermoid carcinoma with eosinophilia with renal metastasis, to the best of our knowledge. CONCLUSIONS: Our findings suggest, for the first time, to our knowledge, involvement of the RAS-RAF-MEK-ERK signaling pathway in the pathogenesis of sclerosing mucoepidermoid carcinoma with eosinophilia. Thus, BRAF inhibitors may prove to be a useful targeted medical therapy in the treatment of a subset of patients with aggressive sclerosing mucoepidermoid carcinoma with eosinophilia tumors who exhibit BRAF activating mutation.

Rini, B. I., D. Battle, R. A. Figlin, D. J. George, H. Hammers, T. Hutson, E. Jonasch, R. W. Joseph, D. F. McDermott, R. J. Motzer, S. K. Pal, A. J. Pantuck, D. I. Quinn, V. Seery, M. H. Voss, C. G. Wood, L. S. Wood and M. B. Atkins (2019). “The society for immunotherapy of cancer consensus statement on immunotherapy for the treatment of advanced renal cell carcinoma (RCC).” J Immunother Cancer 7(1): 354.

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The approval of immunotherapeutic agents and immunotherapy-based combination strategies in recent years has revolutionized the treatment of patients with advanced renal cell carcinoma (aRCC). Nivolumab, a programmed death 1 (PD-1) immune checkpoint inhibitor monoclonal antibody, was approved as monotherapy in 2015 for aRCC after treatment with a VEGF-targeting agent. In April 2018, the combination of nivolumab and ipilimumab, a CTLA-4 inhibitor, was approved for intermediate- and poor-risk, previously untreated patients with aRCC. Then, in 2019, combinations therapies consisting of pembrolizumab (anti-PD-1) or avelumab (anti-PD-ligand (L) 1) with axitinib (a VEGF receptor tyrosine kinase inhibitor) were also approved to treat aRCC and are likely to produce dramatic shifts in the therapeutic landscape. To address the rapid advances in immunotherapy options for patients with aRCC, the Society for Immunotherapy of Cancer (SITC) reconvened its Cancer Immunotherapy Guidelines (CIG) Renal Cell Carcinoma Subcommittee and tasked it with generating updated consensus recommendations for the treatment of patients with this disease.

Raphael, K. L., T. Isakova, J. H. Ix, D. S. Raj, M. Wolf, L. F. Fried, J. J. Gassman, C. Kendrick, B. Larive, M. F. Flessner, S. R. Mendley, T. H. Hostetter, G. A. Block, P. Li, J. P. Middleton, S. M. Sprague, D. E. Wesson and A. K. Cheung (2020). “A Randomized Trial Comparing the Safety, Adherence, and Pharmacodynamics Profiles of Two Doses of Sodium Bicarbonate in CKD: the BASE Pilot Trial.” J Am Soc Nephrol 31(1): 161-174.

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BACKGROUND: Oral sodium bicarbonate (NaHCO3) may preserve kidney function in CKD, even if initiated when serum bicarbonate concentration is normal. Adequately powered trials testing this hypothesis have not been conducted, partly because the best dose for testing is unknown. METHODS: This multicenter pilot trial assessed the safety, tolerability, adherence, and pharmacodynamics of two doses of NaHCO3 over 28 weeks in adults with eGFR 20-44 or 45-59 ml/min per 1.73 m(2) with urinary albumin/creatinine (ACR) >/=50 mg/g and serum bicarbonate 20-28 meq/L. We randomly assigned 194 participants from ten clinical sites to receive higher-dose (HD-NaHCO3; 0.8 meq/kg of lean body wt per day; n=90) or lower-dose (LD-NaHCO3; 0.5 meq/kg of lean body wt per day; n=52) NaHCO3 or matching placebo (n=52). The dose was adjusted depending on side effects. The prescribed dose at week 28 was the primary outcome; a dose was considered acceptable for a full-scale trial if >/=67% of participants were on full-dose and >/=80% were on >/=25% of the per-protocol dose. RESULTS: Mean+/-SD baseline eGFR was 36+/-9 ml/min per 1.73 m(2), serum bicarbonate was 24+/-2 meq/L, and median (IQR) ACR was 181 (25-745) mg/g. Both doses were well tolerated without significant changes in BP, weight, or serum potassium. The proportions of adverse events and hospitalizations were similar across the groups. Consequently, 87% in HD-NaHCO3, 96% in LD-NaHCO3, and 87% in placebo were on full dose at week 28; and 91% in HD-NaHCO3, 98% in LD-NaHCO3, and 92% in placebo were on >/=25% of the per-protocol dose. Mean urinary ammonium excretion was 25% lower and serum bicarbonate concentration was 1.3 meq/L higher in HD-NaHCO3 compared with LD-NaHCO3 at week 28. However, mean ACR increased by 12% in the lower-dose group and 30% in the higher-dose group. CONCLUSIONS: Both NaHCO3 doses were well tolerated over 28 weeks with no significant difference in adverse events or hospitalization compared with placebo. The higher dose lowered urinary ammonium excretion and increased serum bicarbonate more than the lower dose but was associated with a greater increase in ACR. The higher 0.8 meq/kg of lean body wt per day dose of NaHCO3 may be a reasonable choice for future trials.

Plenter, R. J., M. G. Coulombe, H. M. Roybal, C. M. Lin, R. G. Gill, M. R. Zamora and T. J. Grazia (2020). “C-kit-derived CD11b(+) cells are critical for cardiac allograft prolongation by autologous C-kit(+) progenitor cells.” Cell Immunol 347: 104023.

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Autologous C-kit(+) cells robustly prolong cardiac allografts. As C-kit(+) cells can transdifferentiate to hematopoietic cells as well as non-hematopoietic cells, we aimed to clarify the class(es) of C-kit-derived cell(s) required for cardiac allograft prolongation. Autologous C-kit(+) cells were administered post-cardiac transplantation and allografts were evaluated for C-kit(+) inoculum-derived cells. Results suggested that alloimmunity was a major signal for trafficking of C-kit-derived cells to the allograft and demonstrated that C-kit(+) inoculum-derived cells expressed CD11b early after transfer. Allograft survival studies with CD11b-DTR C-kit(+) cells demonstrated a requirement for C-kit(+)-derived CD11b(+) cells. Co-therapy studies demonstrated near complete abrogation of acute rejection with concomitant CTLA4-Ig therapy and no loss of prolongation in combination with Cyclosporine A. These results strongly implicate a C-kit-derived myeloid population as critical for allograft preservation and demonstrate the potential therapeutic application of autologous C-kit(+) progenitor cells as calcineurin inhibitor-sparing agents and possibly as co-therapeutics for durable graft survival.