Research Spotlight

Hassan, T. M., E. Ontiveros, D. Davis and S. G. Leeds (2018). “Endoscopic Removal of Noneroded Nonadjustable Gastric Bands Using Induced Mucosal Erosion With a Stent, and Review of the Literature.” Surg Innov Dec 25. [Epub ahead of print].

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BACKGROUND: Laparoscopic removal of noneroded nonadjustable gastric bands (NAGBs) may lead to major life-threatening complications. A minimally invasive approach involving endoscopic removal by induced mucosal erosion with a stent (IMES) has been used in a few publications to remove NAGBs. OBJECTIVE: To examine a minimally invasive endoscopic approach to removal of a NAGB. SETTING: A large tertiary/quaternary referral hospital. METHODS: We report 4 patients that underwent IMES at our institution and present a literature review of published cases. The procedure includes using an endoscopically placed fully covered stent through the NAGB stricture to cause erosion of the mucosa where the stent is putting direct pressure. After a predetermined length of time, the stent is removed with the NAGB and without a laparoscopic or open procedure. Primary endpoint for our cohort was successful removal to the NAGB with IMES. Secondary endpoints included interval of time to retrieval of the stent, complications from IMES, presenting symptoms, and type of NAGB. These endpoints were then compared with previous publications indicating the use of IMES. RESULTS: Three of 4 patients were female with a mean age of 64.5 years. All patients had the NAGB successfully removed with IMES. The mean time for NAGB and stent removal after insertion was 17.5 days. No major complications were noted. Two patients had post-IMES strictures and were managed by balloon dilation. CONCLUSION: Endoscopic removal of NAGBs is a safe and feasible procedure for NAGB removal and can be used in place of laparoscopic surgery.

Hammond, F. M., J. D. Corrigan, J. M. Ketchum, J. F. Malec, K. Dams-O’Connor, T. Hart, T. A. Novack, J. Bogner, M. N. Dahdah and G. G. Whiteneck (2019). “Prevalence of Medical and Psychiatric Comorbidities Following Traumatic Brain Injury.” J Head Trauma Rehabil Jan 2. [Epub ahead of print].

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OBJECTIVE: To examine the prevalence of selected medical and psychiatric comorbidities that existed prior to or up to 10 years following traumatic brain injury (TBI) requiring acute rehabilitation. DESIGN: Retrospective cohort. SETTING: Six TBI Model Systems (TBIMS) centers. PARTICIPANTS: In total, 404 participants in the TBIMS National Database who experienced TBI 10 years prior. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Self-reported medical and psychiatric comorbidities and the onset time of each endorsed comorbidity. RESULTS: At 10 years postinjury, the most common comorbidities developing postinjury, in order, were back pain, depression, hypertension, anxiety, fractures, high blood cholesterol, sleep disorders, panic attacks, osteoarthritis, and diabetes. Comparing those 50 years and older to those younger than 50 years, diabetes (odds ratio [OR] = 3.54; P = .0016), high blood cholesterol (OR = 2.04; P = .0092), osteoarthritis (OR = 2.02; P = .0454), and hypertension (OR = 1.84; P = .0175) were significantly more prevalent in the older cohort while panic attacks (OR = 0.33; P = .0022) were significantly more prevalent in the younger cohort. No significant differences in prevalence rates between the older and younger cohorts were found for back pain, depression, anxiety, fractures, or sleep disorders. CONCLUSIONS: People with moderate-severe TBI experience other medical and mental health comorbidities during the long-term course of recovery and life after injury. The findings can inform further investigation into comorbidities associated with TBI and the role of medical care, surveillance, prevention, lifestyle, and healthy behaviors in potentially modifying their presence and/or prevalence over the life span.

Haase, V. H., G. M. Chertow, G. A. Block, P. E. Pergola, E. M. deGoma, Z. Khawaja, A. Sharma, B. J. Maroni and P. A. McCullough (2019). “Effects of vadadustat on hemoglobin concentrations in patients receiving hemodialysis previously treated with erythropoiesis-stimulating agents.” Nephrol Dial Transplant 34(1): 90-99.

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Background: Vadadustat, an inhibitor of hypoxia-inducible factor prolyl-4-hydroxylase domain dioxygenases, is an oral investigational agent in development for the treatment of anemia secondary to chronic kidney disease. Methods: In this open-label Phase 2 trial, vadadustat was evaluated in 94 subjects receiving hemodialysis, previously maintained on epoetin alfa. Subjects were sequentially assigned to one of three vadadustat dose cohorts by starting dose: 300 mg once daily (QD), 450 mg QD or 450 mg thrice weekly (TIW). The primary endpoint was mean hemoglobin (Hb) change from pre-baseline average to midtrial (Weeks 7-8) and end-of-trial (Weeks 15-16) and was analyzed using available data (no imputation). Results: Overall, 80, 73 and 68% of subjects in the 300 mg QD, 450 mg QD, and 450 mg TIW dose cohorts respectively, completed the study. For all dose cohorts no statistically significant mean change in Hb from pre-baseline average was observed, and mean Hb concentrations-analyzed using available data-remained stable at mid- and end-of-trial. There was one subject with an Hb excursion >13 g/dL. Overall, 83% of subjects experienced an adverse event (AE); the proportion of subjects who experienced at least one AE was similar among the three dose cohorts. The most frequently reported AEs were nausea (11.7%), diarrhea (10.6%) and vomiting (9.6%). No deaths occurred during the study. No serious AEs were attributed to vadadustat. Conclusions: Vadadustat maintained mean Hb concentrations in subjects on hemodialysis previously receiving epoetin. These data support further investigation of vadadustat to assess its long-term safety and efficacy in subjects on hemodialysis.

Guttman-Yassky, E., R. Bissonnette, B. Ungar, M. Suarez-Farinas, M. Ardeleanu, H. Esaki, M. Suprun, Y. Estrada, H. Xu, X. Peng, J. I. Silverberg, A. Menter, J. G. Krueger, R. Zhang, U. Chaudhry, B. Swanson, N. M. H. Graham, G. Pirozzi, G. D. Yancopoulos and D. H. JD (2019). “Dupilumab progressively improves systemic and cutaneous abnormalities in patients with atopic dermatitis.” J Allergy Clin Immunol 143(1): 155-172.

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BACKGROUND: Dupilumab is an IL-4 receptor alpha mAb inhibiting signaling of IL-4 and IL-13, key drivers of type 2-driven inflammation, as demonstrated by its efficacy in patients with atopic/allergic diseases. OBJECTIVE: This placebo-controlled, double-blind trial (NCT01979016) evaluated the efficacy, safety, and effects of dupilumab on molecular/cellular lesional and nonlesional skin phenotypes and systemic type 2 biomarkers of patients with moderate-to-severe atopic dermatitis (AD). METHODS: Skin biopsy specimens and blood were evaluated from 54 patients randomized 1:1 to weekly subcutaneous doses of 200 mg of dupilumab or placebo for 16 weeks. RESULTS: Dupilumab (vs placebo) significantly improved clinical signs and symptoms of AD, was well tolerated, and progressively shifted the lesional transcriptome toward a nonlesional phenotype (weeks 4-16). Mean improvements in a meta-analysis-derived AD transcriptome (genes differentially expressed between lesional and nonlesional skin) were 68.8% and 110.8% with dupilumab and -10.5% and 55.0% with placebo (weeks 4 and 16, respectively; P < .001). Dupilumab significantly reduced expression of genes involved in type 2 inflammation (IL13, IL31, CCL17, CCL18, and CCL26), epidermal hyperplasia (keratin 16 [K16] and MKi67), T cells, dendritic cells (ICOS, CD11c, and CTLA4), and TH17/TH22 activity (IL17A, IL-22, and S100As) and concurrently increased expression of epidermal differentiation, barrier, and lipid metabolism genes (filaggrin [FLG], loricrin [LOR], claudins, and ELOVL3). Dupilumab reduced lesional epidermal thickness versus placebo (week 4, P = .001; week 16, P = .0002). Improvements in clinical and histologic measures correlated significantly with modulation of gene expression. Dupilumab also significantly suppressed type 2 serum biomarkers, including CCL17, CCL18, periostin, and total and allergen-specific IgEs. CONCLUSION: Dupilumab-mediated inhibition of IL-4/IL-13 signaling through IL-4 receptor alpha blockade significantly and progressively improved disease activity, suppressed cellular/molecular cutaneous markers of inflammation and systemic measures of type 2 inflammation, and reversed AD-associated epidermal abnormalities.

Grayburn, P. A., A. Sannino and M. Packer (2018). “Proportionate and Disproportionate Functional Mitral Regurgitation: A New Conceptual Framework That Reconciles the Results of the MITRA-FR and COAPT Trials.” JACC Cardiovasc Imaging Dec 6. [Epub ahead of print].

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Traditional approaches to the characterization of secondary or functional mitral regurgitation (MR) have largely ignored the critical importance of the left ventricle (LV). We propose that patients with secondary MR represent a heterogenous group, which can be usefully subdivided based on understanding that the effective regurgitant orifice area (EROA) is dependent on left ventricular end-diastolic volume (LVEDV). According to the Gorlin hydraulic orifice equation, patients with heart failure, an LV ejection fraction of 30%, an LVEDV of 220 to 250 ml, and a regurgitant fraction of 50% would be expected to have an EROA of approximately 0.3 cm(2) independent of specific tethering abnormalities of the mitral valve leaflets. The MR in these patients is proportionate to the degree of LV dilatation and can respond to drugs and devices that reduce LVEDV. In contrast, patients with EROA of 0.3 to 0.4 cm(2) but with LVEDV of only 160 to 200 ml exhibit degrees of MR that are disproportionately higher than predicted by LVEDV. These patients appear to preferentially benefit from interventions directed at the mitral valve. Our proposed conceptual framework explains the apparently discordant results from 2 recent randomized controlled trials of mitral valve repair. The MITRA-FR (Percutaneous Repair with the MitraClip Device for Severe Functional/Secondary Mitral Regurgitation) trial enrolled patients who had MR that was proportionate to the degree of LV dilatation, and during long-term follow-up, the LVEDV and clinical outcomes of these patients did not differ from medically-treated control subjects. In comparison, the patients enrolled in the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation) trial had an EROA approximately 30% higher but LV volumes that were approximately 30% smaller, indicative of disproportionate MR. In these patients, transcatheter mitral valve repair reduced the risk of death and hospitalization for heart failure, and these benefits were paralleled by a meaningful decrease in LVEDV. Thus, characterization of MR as proportionate or disproportionate to LVEDV appears to be critical to the selection of an optimal treatment for patients with chronic heart failure and systolic dysfunction.