Research Spotlight

Hasan, M.M., Nair, S.S., O’Leary, J.G., Thompson-Snipes, L., Nyarige, V., Wang, J., Park, W., Stegall, M., Heilman, R., Klintmalm, G.B., Joo, H. and Oh, S. (2021). “Implication of TIGIT(+) human memory B cells in immune regulation.” Nat Commun 12(1): 1534.

Full text of this article.

Regulatory B cells (Bregs) contribute to immune regulation. However, the mechanisms of action of Bregs remain elusive. Here, we report that T cell immunoreceptor with Ig and ITIM domains (TIGIT) expressed on human memory B cells especially CD19(+)CD24(hi)CD27(+)CD39(hi)IgD(-)IgM(+)CD1c(+) B cells is essential for effective immune regulation. Mechanistically, TIGIT on memory B cells controls immune response by directly acting on T cells and by arresting proinflammatory function of dendritic cells, resulting in the suppression of Th1, Th2, Th17, and CXCR5(+)ICOS(+) T cell response while promoting immune regulatory function of T cells. TIGIT(+) memory B cells are also superior to other B cells at expressing additional inhibitory molecules, including IL-10, TGFβ1, granzyme B, PD-L1, CD39/CD73, and TIM-1. Lack or decrease of TIGIT(+) memory B cells is associated with increased donor-specific antibody and TFH response, and decreased Treg response in renal and liver allograft patients. Therefore, TIGIT(+) human memory B cells play critical roles in immune regulation.

Harrison, M.R., Costello, B.A., Bhavsar, N.A., Vaishampayan, U., Pal, S.K., Zakharia, Y., Jim, H.S.L., Fishman, M.N., Molina, A.M., Kyriakopoulos, C.E., Tsao, C.K., Appleman, L.J., Gartrell, B.A., Hussain, A., Stadler, W.M., Agarwal, N., Pachynski, R.K., Hutson, T.E., Hammers, H.J., Ryan, C.W., Inman, B.A., Mardekian, J., Borham, A. and George, D.J. (2021). “Active surveillance of metastatic renal cell carcinoma: Results from a prospective observational study (MaRCC).” Cancer Mar 25. [Epub ahead of print].

Full text of this article.

BACKGROUND: Systemic therapy (ST) can be deferred in patients who have metastatic renal cell carcinoma (mRCC) and slow-growing metastases. Currently, this subset of patients managed with active surveillance (AS) is not well described in the literature. METHODS: This was a prospective observational study of patients with mRCC across 46 US community and academic centers. The objective was to describe baseline characteristics and demographics of patients with mRCC initially managed by AS, reasons for AS, and patient outcomes. Descriptive statistics were used to characterize demographics, baseline characteristics, and patient-related outcomes. Wilcoxon 2-sample rank-sum tests and χ(2) tests were used to assess differences between ST and AS cohorts in continuous and categorical variables, respectively. Kaplan-Meier survival curves were used to assess survival. RESULTS: Of 504 patients, mRCC was initially managed by AS (n = 143) or ST (n = 305); 56 patients were excluded from the analysis. Disease was present in 69% of patients who received AS, whereas the remaining 31% had no evidence of disease. At data cutoff, 72 of 143 patients (50%) in the AS cohort had not received ST. The median overall survival was not reached (95% CI, 122 months to not estimable) in patients who received AS versus 30 months (95% CI, 25-44 months) in those who received ST. Quality of life at baseline was significantly better in patients who were managed with AS versus ST. CONCLUSIONS: AS occurs frequently (32%) in real-world clinical practice and appears to be a safe and appropriate alternative to immediate ST in selected patients.

Hammond, F.M., Malec, J.F., Corrigan, J., Whitenack, G., Hart, T., Dams-O’Connor, K., Novack, T., Bogner, J.A., Dahdah, M., Eagye, C.B., Sevigny, M. and Ketchum, J. (2021). “Patterns of Functional Change 5 to 10 years Following Moderate-Severe Traumatic Brain Injury.” J Neurotrauma Mar 27. [Epub ahead of print].

Full text of this article.

This study aims to characterize the patterns of functional change experienced between 5 and 10 years following moderate-severe traumatic brain injury (TBI). The study included TBI Model Systems national database participants (N = 372) at six sites who experienced TBI, received inpatient rehabilitation, and were followed at 5 and 10 years post TBI. Outcome measures included self- or proxy-reported FIMTM structured interview at 5 and 10 years post TBI and Domain Change Indices (DCIs) at 10 years to assess subjective change over previous 5 years. When all 7 FIMTM and subjective DCI subscales were considered together, 69% reported improvement in at least one subscale and 41% reported decline in at least one subscale; 51% reported more domains improved than declined and 20% reported more domains declined than improved. Age at injury, PTA duration, FIM, and depression and anxiety at Year 5 were associated with FIM change and DCI measures. While most people with moderate-severe TBI do not experience widespread change from year 5 to 10 on individual FIMTM subscales or perceived domain-specific subscales, the vast majority do report change in one or more domains, with more improvement than decline and more change in subjective DCI than in FIMTM. Clinicians and researchers should be alert to the possibility of both positive and deleterious changes many years after TBI.

Gertz, Z.M., Herrmann, H.C., Lim, D.S., Kar, S., Kapadia, S.R., Reed, G.W., Puri, R., Krishnaswamy, A., Gersh, B.J., Weissman, N.J., Asch, F.M., Grayburn, P.A., Kosmidou, I., Redfors, B., Zhang, Z., Abraham, W.T., Lindenfeld, J., Stone, G.W. and Mack, M.J. (2021). “Implications of Atrial Fibrillation on the Mechanisms of Mitral Regurgitation and Response to MitraClip in the COAPT Trial.” Circ Cardiovasc Interv Mar 15;CIRCINTERVENTIONS120010300. [Epub ahead of print]. Circinterventions120010300.

Full text of this article.

BACKGROUND: Atrial fibrillation (AF), mitral regurgitation (MR), and left ventricular (LV) ejection fraction have a complex interplay. We evaluated the role of AF in patients with heart failure and moderate-to-severe or severe secondary MR enrolled in the randomized COAPT trial (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation) and its impact on mechanisms and outcomes with the MitraClip. METHODS: Patients in the COAPT trial were stratified by the presence (n=327) or absence (n=287) of a history of AF and by assignment to treatment group. Clinical, echocardiographic, and outcome measures were assessed. The primary outcome was the composite rate of death or heart failure hospitalization at 24 months. RESULTS: Patients with history of AF were older and more often male. They had a higher LV ejection fraction, larger left atrial volumes and mitral valve orifice areas, smaller LV volumes, and similar MR severity. Patients with AF compared with those without a history of AF had a higher unadjusted (hazard ratio [HR], 1.32 [95% CI, 1.06-1.64], P=0.01) and adjusted (HR, 1.30 [1.03-1.64], P=0.03) 2-year rate of the primary outcome. Treatment with the MitraClip compared with guideline-directed medical therapy alone reduced death or heart failure hospitalization in both those with (HR, 0.61 [0.46-0.82]) and without (HR, 0.46 [0.33-0.66]) a history of AF (P(int)=0.18). Treatment with the MitraClip was associated with a lower risk of stroke in patients with a history of AF (HR, 0.18 [0.04-0.86]) but not in those without a history of AF (HR, 1.64 [0.58-4.62]; P(int)=0.02). CONCLUSIONS: In the COAPT trial, patients with a history of AF had larger left atrial and mitral valve orifice areas with higher LV ejection fraction and smaller LV volumes, suggesting an atrial mechanism contribution to functional MR. Despite the worse prognosis of heart failure patients with a history of AF, MR reduction with the MitraClip still afforded substantial clinical benefits. Treatment with MitraClip was associated with a lower risk of stroke in patients with a history of AF. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01626079.

Ferreira, J.P., Zannad, F., Pocock, S.J., Anker, S.D., Butler, J., Filippatos, G., Brueckmann, M., Jamal, W., Steubl, D., Schueler, E. and Packer, M. (2021). “Interplay of Mineralocorticoid Receptor Antagonists and Empagliflozin in Heart Failure: EMPEROR-Reduced.” J Am Coll Cardiol 77(11): 1397-1407.

Full text of this article.

BACKGROUND: Mineralocorticoid receptor antagonists (MRAs) and sodium glucose co-transporter 2 inhibitors favorably influence the clinical course of patients with heart failure and reduced ejection fraction. OBJECTIVES: This study sought to study the mutual influence of empagliflozin and MRAs in EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction). METHODS: Secondary analysis that compared the effects of empagliflozin versus placebo in 3,730 patients with heart failure and a reduced ejection fraction, of whom 71% used MRAs at randomization. RESULTS: The effects of empagliflozin on the primary endpoint, on most efficacy endpoints, and on safety were similar in patients receiving or not receiving an MRA (interaction p > 0.20). For cardiovascular death, the hazard ratios for the effect of empagliflozin versus placebo were 0.82 (95% confidence interval [CI]: 0.65 to 1.05) in MRA users and 1.19 (95% CI: 0.82 to 1.71) in MRA nonusers (interaction p = 0.10); a similar pattern was seen for all-cause mortality (interaction p = 0.098). Among MRA nonusers at baseline, patients in the empagliflozin group were 35% less likely than those in the placebo group to initiate treatment with an MRA following randomization (hazard ratio: 0.65; 95% CI: 0.49 to 0.85). Among MRA users at baseline, patients in the empagliflozin group were 22% less likely than those in the placebo group to discontinue treatment with an MRA following randomization (hazard ratio: 0.78; 95% CI: 0.64 to 0.96). Severe hyperkalemia was less common in the empagliflozin group. CONCLUSIONS: In EMPEROR-Reduced, the use of MRAs did not influence the effect of empagliflozin to reduce adverse heart failure and renal outcomes. Treatment with empagliflozin was associated with less discontinuation of MRAs. (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction [EMPEROR-Reduced]; NCT03057977).