Research Spotlight

Odiase, E., Zhang, X., Chang, Y., Nelson, M., Balaji, U., Gu, J., Zhang, Q., Pan, Z., Spechler, S.J. and Souza, R.F. (2021). “In Esophageal Squamous Cells from Eosinophilic Esophagitis Patients, Th2 Cytokines Increase Eotaxin-3 Secretion through Effects on Intracellular Calcium and a Non-Gastric Proton Pump.” Gastroenterology Feb 10;S0016-5085(21)00403-0. [Epub ahead of print].

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BACKGROUND & AIMS: In upper airway cells, Th2 cytokines that signal through IL-4 receptor alpha (IL4Rα) have been shown to stimulate eotaxin-3 secretion via a non-gastric proton pump (ngH(+),K(+)ATPase). To seek novel targets for eosinophilic esophagitis (EoE) treatments, we evaluated ngH(+),K(+)ATPase expression in EoE squamous cells, and explored molecular pathways involved in eotaxin-3 secretion by IL4Rα signaling. METHODS: ngH(+),K(+)ATPase expression in EoE cells was evaluated by qPCR and western blotting. IL-4-stimulated eotaxin-3 secretion was measured by ELISA after treatment with omeprazole, SCH 28080 (potassium-competitive acid blocker), EGTA-AM (calcium chelator), 2-APB (inhibitor of endoplasmic reticulum calcium release), verapamil and diltiazem (L-type calcium channel inhibitors). Intracellular calcium transients were measured by Fluo-4 fluorescence. Key experiments were confirmed in EoE primary cells and in RNA sequencing datasets from mucosal biopsies of EoE patients and controls. RESULTS: EoE cells expressed ngH(+),K(+)ATPase mRNA and protein. Omeprazole and SCH 28080 decreased IL-4-stimulated eotaxin-3 secretion. IL-4 increased intracellular calcium transients, and IL-4-stimulated eotaxin-3 secretion was blocked by EGTA-AM, 2-APB, verapamil, and diltiazem. The combination of omeprazole and verapamil suppressed IL-4-stimulated eotaxin-3 secretion more than either agent alone. EoE biopsies expressed higher ngH+,K+ATPase and exhibited more calcium signaling than controls. CONCLUSIONS: EoE cells express a non-gastric proton pump that mediates Th2 cytokine-stimulated eotaxin-3 secretion. IL-4 induces calcium release from the endoplasmic reticulum and calcium entry via L-type calcium channels, increasing intracellular calcium that contributes to eotaxin-3 secretion by EoE cells. L-type calcium channel inhibitors block Th2 cytokine-stimulated eotaxin-3 secretion, suggesting a potential role for these agents in EoE treatment.

Daoud, E.V., Patel, A., Gagan, J., Raisanen, J.M., Snipes, G.J., Mantilla, E., Krothapally, R., Hatanpaa, K.J. and Pan, E. (2021). “Spinal Cord Pilocytic Astrocytoma With FGFR1-TACC1 Fusion and Anaplastic Transformation.” J Neuropathol Exp Neurol 80(3): 283-285.

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Pilocytic astrocytoma (PA) is a WHO grade 1 primary neoplasm that accounts for ∼5.4% of all gliomas, occurs predominantly in childhood and adolescence, and usually arises in the cerebellum or cerebral midline structures. The treatment of choice is surgical resection and the prognosis is excellent, with survival over 95% at 10 years. If a gross total resection (GTR) is achieved, postoperative radiation therapy or chemotherapy is not warranted, with low reported recurrence rates. Development of anaplastic features is extremely uncommon, and many such tumors are associated with prior radiation therapy. However, little is known about the mechanisms and driver mutations associated with PA anaplasia. [No abstract; excerpt from article].

Fam, N.P., von Bardeleben, R.S., Hensey, M., Kodali, S.K., Smith, R.L., Hausleiter, J., Ong, G., Boone, R., Ruf, T., George, I., Szerlip, M., Näbauer, M., Ali, F.M., Moss, R., Bapat, V., Schnitzler, K., Kreidel, F., Ye, J., Deva, D.P., Mack, M.J., Grayburn, P.A., Peterson, M.D., Leon, M.B., Hahn, R.T. and Webb, J.G. (2021). “Transfemoral Transcatheter Tricuspid Valve Replacement With the EVOQUE System: A Multicenter, Observational, First-in-Human Experience.” JACC Cardiovasc Interv 14(5): 501-511.

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OBJECTIVES: The purpose of this observational first-in-human experience was to investigate the feasibility and safety of the EVOQUE tricuspid valve replacement system and its impact on short-term clinical outcomes. BACKGROUND: Transcatheter tricuspid intervention is a promising option for selected patients with severe tricuspid regurgitation (TR). Although transcatheter leaflet repair is an option for some, transcatheter tricuspid valve replacement (TTVR) may be applicable to a broader population. METHODS: Twenty-five patients with severe TR underwent EVOQUE TTVR in a compassionate-use experience. The primary outcome was technical success, with NYHA (NYHA) functional class, TR grade, and major adverse cardiac and cerebrovascular events assessed at 30-day follow-up. RESULTS: All patients (mean age 76 ± 3 years, 88% women) were at high surgical risk (mean Society of Thoracic Surgeons risk score 9.1 ± 2.3%), with 96% in NYHA functional class III or IV. TR etiology was predominantly functional, with mean tricuspid annular diameter of 44.8 ± 7.8 mm and mean tricuspid annular plane systolic excursion of 16 ± 2 mm. Technical success was 92%, with no intraprocedural mortality or conversion to surgery. At 30-day follow-up, mortality was 0%, 76% of patients were in NYHA functional class I or II, and TR grade was ≤2+ in 96%. Major bleeding occurred in 3 patients (12%), 2 patients (8%) required pacemaker implantation, and 1 patient (4%) required dialysis. CONCLUSIONS: This first-in-human experience evaluating EVOQUE TTVR demonstrated high technical success, acceptable safety, and significant clinical improvement. Larger prospective studies are needed to confirm durability and safety and the impact on long-term clinical outcomes.

Gonzalez, D., Mateo, J., Stenzinger, A., Rojo, F., Shiller, M., Wyatt, A.W., Penault-Llorca, F., Gomella, L.G., Eeles, R. and Bjartell, A. (2021). “Practical considerations for optimising homologous recombination repair mutation testing in patients with metastatic prostate cancer.” J Pathol Clin Res Feb 25. [Epub ahead of print].

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Analysis of the genomic landscape of prostate cancer has identified different molecular subgroups with relevance for novel or existing targeted therapies. The recent approvals of the poly(ADP-ribose) polymerase (PARP) inhibitors olaparib and rucaparib in the metastatic castration-resistant prostate cancer (mCRPC) setting signal the need to embed molecular diagnostics in the clinical pathway of patients with mCRPC to identify those who can benefit from targeted therapies. Best practice guidelines in overall biospecimen collection and processing for molecular analysis are widely available for several tumour types. However, there is no standard protocol for molecular diagnostic testing in prostate cancer. Here, we provide a series of recommendations on specimen handling, sample pre-analytics, laboratory workflow, and testing pathways to maximise the success rates for clinical genomic analysis in prostate cancer. Early involvement of a multidisciplinary team of pathologists, urologists, oncologists, radiologists, nurses, molecular scientists, and laboratory staff is key to enable optimal workflow for specimen selection and preservation at the time of diagnosis so that samples are available for molecular analysis when required. Given the improved outcome of patients with mCRPC and homologous recombination repair gene alterations who have been treated with PARP inhibitors, there is an urgent need to incorporate high-quality genomic testing in the routine clinical pathway of these patients.

Moreno-Martinez, D., Aguiar, P., Auray-Blais, C., Beck, M., Bichet, D.G., Burlina, A., Cole, D., Elliott, P., Feldt-Rasmussen, U., Feriozzi, S., Fletcher, J., Giugliani, R., Jovanovic, A., Kampmann, C., Langeveld, M., Lidove, O., Linhart, A., Mauer, M., Moon, J.C., Muir, A., Nowak, A., Oliveira, J.P., Ortiz, A., Pintos-Morell, G., Politei, J., Rozenfeld, P., Schiffmann, R., Svarstad, E., Talbot, A.S., Thomas, M., Tøndel, C., Warnock, D., West, M.L. and Hughes, D.A. (2021). “Standardising clinical outcomes measures for adult clinical trials in Fabry disease: A global Delphi consensus.” Mol Genet Metab Feb 20;S1096-7192(21)00035-4. [Epub ahead of print].

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BACKGROUND: Recent years have witnessed a considerable increase in clinical trials of new investigational agents for Fabry disease (FD). Several trials investigating different agents are currently in progress; however, lack of standardisation results in challenges to interpretation and comparison. To facilitate the standardisation of investigational programs, we have developed a common framework for future clinical trials in FD. METHODS AND FINDINGS: A broad consensus regarding clinical outcomes and ways to measure them was obtained via the Delphi methodology. 35 FD clinical experts from 4 continents, representing 3389 FD patients, participated in 3 rounds of Delphi procedure. The aim was to reach a consensus regarding clinical trial design, best treatment comparator, clinical outcomes, measurement of those clinical outcomes and inclusion and exclusion criteria. Consensus results of this initiative included: the selection of the adaptative clinical trial as the ideal study design and agalsidase beta as ideal comparator treatment due to its longstanding use in FD. Renal and cardiac outcomes, such as glomerular filtration rate, proteinuria and left ventricular mass index, were prioritised, whereas neurological outcomes including cerebrovascular and white matter lesions were dismissed as a primary or secondary outcome measure. Besides, there was a consensus regarding the importance of patient-related outcomes such as general quality of life, pain, and gastrointestinal symptoms. Also, unity about lysoGb3 and Gb3 tissue deposits as useful surrogate markers of the disease was obtained. The group recognised that cardiac T1 mapping still has potential but requires further development before its widespread introduction in clinical trials. Finally, patients with end-stage renal disease or renal transplant should be excluded unless a particular group for them is created inside the clinical trial. CONCLUSION: This consensus will help to shape the future of clinical trials in FD. We note that the FDA has, coincidentally, recently published draft guidelines on clinical trials in FD and welcome this contribution.