Research Spotlight

Baylor Health Sciences Library brings to you each month the latest published research from the Baylor Scott & White community. Each newly published article features the researcher, the abstract, and link to the full text. For information on including your own research, please contact John Fullinwider, john.fullinwider@baylorhealth.edu. 214-828-8989.


Posted May 15th 2019

Aberrant p53 Immunostaining in Barrett’s Esophagus Predicts Neoplastic Progression: Systematic Review and Meta-Analyses.

Vani J.A. Konda M.D.

Vani J.A. Konda M.D.

Snyder, P., K. Dunbar, D. J. Cipher, R. F. Souza, S. J. Spechler and V. J. A. Konda (2019). “Aberrant p53 Immunostaining in Barrett’s Esophagus Predicts Neoplastic Progression: Systematic Review and Meta-Analyses.” Dig Dis Sci 64(5): 1089-1097.

Full text of this article.

Risk stratification of patients with Barrett’s esophagus (BE) presently relies on the histopathologic grade of dysplasia found in esophageal biopsies, which is limited by sampling error and inter-pathologist variability. p53 immunostaining of BE biopsies has shown promise as an adjunct tool but is not recommended by American gastroenterology societies, who cite insufficient evidence of its prognostic value. We have conducted a systematic review and meta-analyses to clarify this value. We searched for studies that: (1) used immunohistochemistry to assess p53 expression in esophageal biopsies of BE patients and (2) reported subsequent neoplastic progression. We performed separate meta-analyses of case-control studies and cohort studies. We identified 14 relevant reports describing 8 case-control studies comprising 1435 patients and 7 cohort studies comprising 582 patients. In the case-control study meta-analysis of the risk of neoplasia with aberrant p53 expression, the fixed- and random-effect estimates of average effect size with aberrant p53 expression were OR 3.84, p < .001 (95% CI 2.79-5.27) and OR 5.95, p < .001 (95% CI 2.68-13.22), respectively. In the cohort study meta-analysis, the fixed- and random-effect estimates of average effect size were RR = 17.31, p < .001 (95% CI 9.35-32.08) and RR = 14.25, p < .001 (95% CI 6.76-30.02), respectively. Separate meta-analyses of case-control and cohort studies of BE patients who had baseline biopsies with p53 immunostaining revealed consistent, strong, and significant associations between aberrant p53 immunostaining and progression to high-grade dysplasia or esophageal adenocarcinoma. These findings support the use of p53 immunostaining as an adjunct to routine clinical diagnosis for dysplasia in BE patients.


Posted May 15th 2019

Disproportionate functional mitral regurgitation: a new therapeutic target in patients with heart failure and a reduced ejection fraction.

Milton Packer M.D.

Milton Packer M.D.

Packer, M. (2019). “Disproportionate functional mitral regurgitation: a new therapeutic target in patients with heart failure and a reduced ejection fraction.” Eur J Heart Fail Apr 24. Epub ahead of print].

Full text of this article.

Patients with chronic heart failure and a reduced ejection fraction who have severe and disproportionate mitral regurgitation (MR) are likely to experience important clinical consequences resulting from the haemodynamic stresses imposed by the regurgitant lesion, and the severity of MR is not likely to be reduced by conventional therapy with neurohormonal antagonists, even when administered in maximally tolerated doses. Such patients should first be treated with cardiac resynchronization (if they qualify for the procedure), and non‐candidates and non‐responders should be seriously considered for transcatheter mitral valve repair. Therefore, when treating heart failure with a reduced ejection fraction, it is now time for physicians to identify patients who also have severe and disproportionate MR, because they require specialized procedures beyond optimal pharmacological therapy. (Excerpt from text, p. 2-3; no abstract available.)


Posted May 15th 2019

Transcatheter Aortic-Valve Replacement with a Balloon-Expandable Valve in Low-Risk Patients.

Michael J. Mack M.D.

Michael J. Mack M.D.

Mack, M. J., M. B. Leon, V. H. Thourani, R. Makkar, S. K. Kodali, M. Russo, S. R. Kapadia, S. C. Malaisrie, D. J. Cohen, P. Pibarot, J. Leipsic, R. T. Hahn, P. Blanke, M. R. Williams, J. M. McCabe, D. L. Brown, V. Babaliaros, S. Goldman, W. Y. Szeto, P. Genereux, A. Pershad, S. J. Pocock, M. C. Alu, J. G. Webb and C. R. Smith (2019). “Transcatheter Aortic-Valve Replacement with a Balloon-Expandable Valve in Low-Risk Patients.” New England Journal of Medicine 380(18): 1695-1705.

Full text of this article.

BACKGROUND: Among patients with aortic stenosis who are at intermediate or high risk for death with surgery, major outcomes are similar with transcatheter aortic-valve replacement (TAVR) and surgical aortic-valve replacement. There is insufficient evidence regarding the comparison of the two procedures in patients who are at low risk. METHODS: We randomly assigned patients with severe aortic stenosis and low surgical risk to undergo either TAVR with transfemoral placement of a balloon-expandable valve or surgery. The primary end point was a composite of death, stroke, or rehospitalization at 1 year. Both noninferiority testing (with a prespecified margin of 6 percentage points) and superiority testing were performed in the as-treated population. RESULTS: At 71 centers, 1000 patients underwent randomization. The mean age of the patients was 73 years, and the mean Society of Thoracic Surgeons risk score was 1.9% (with scores ranging from 0 to 100% and higher scores indicating a greater risk of death within 30 days after the procedure). The Kaplan-Meier estimate of the rate of the primary composite end point at 1 year was significantly lower in the TAVR group than in the surgery group (8.5% vs. 15.1%; absolute difference, -6.6 percentage points; 95% confidence interval [CI], -10.8 to -2.5; P<0.001 for noninferiority; hazard ratio, 0.54; 95% CI, 0.37 to 0.79; P = 0.001 for superiority). At 30 days, TAVR resulted in a lower rate of stroke than surgery (P = 0.02) and in lower rates of death or stroke (P = 0.01) and new-onset atrial fibrillation (P<0.001). TAVR also resulted in a shorter index hospitalization than surgery (P<0.001) and in a lower risk of a poor treatment outcome (death or a low Kansas City Cardiomyopathy Questionnaire score) at 30 days (P<0.001). There were no significant between-group differences in major vascular complications, new permanent pacemaker insertions, or moderate or severe paravalvular regurgitation. CONCLUSIONS: Among patients with severe aortic stenosis who were at low surgical risk, the rate of the composite of death, stroke, or rehospitalization at 1 year was significantly lower with TAVR than with surgery. (Funded by Edwards Lifesciences; PARTNER 3 ClinicalTrials.gov number, NCT02675114.).


Posted May 15th 2019

Veverimer versus placebo in patients with metabolic acidosis associated with chronic kidney disease: a multicentre, randomised, double-blind, controlled, phase 3 trial.

Donald E. Wesson M.D.

Donald E. Wesson M.D.

Wesson, D. E., V. Mathur, N. Tangri, Y. Stasiv, D. Parsell, E. Li, G. Klaerner and D. A. Bushinsky (2019). “Veverimer versus placebo in patients with metabolic acidosis associated with chronic kidney disease: a multicentre, randomised, double-blind, controlled, phase 3 trial.” Lancet 393(10179): 1417-1427.

Full text of this article.

BACKGROUND: Patients with advanced chronic kidney disease lose the capacity to fully excrete endogenous acid, resulting in chronic metabolic acidosis that increases the risk of disease progression and causes muscle catabolism and bone resorption. Veverimer, a non-absorbed, counterion-free, polymeric drug, selectively binds and removes hydrochloric acid from the gastrointestinal lumen, unlike current oral sodium bicarbonate therapy for metabolic acidosis that only neutralises accumulated acid. We assessed the efficacy and safety of veverimer as a treatment for metabolic acidosis in patients with chronic kidney disease. METHODS: We did a multicentre, parallel, randomised, double-blind, placebo-controlled study at 37 sites (hospitals and specialty clinics) in Bulgaria, Croatia, Georgia, Hungary, Serbia, Slovenia, Ukraine, and the USA. Eligible participants were patients aged 18-85 years with non-dialysis-dependent chronic kidney disease (estimated glomerular filtration rate of 20-40 mL/min per 1.73 m(2)) and metabolic acidosis (serum bicarbonate concentration of 12-20 mmol/L). Patients were randomly assigned (4:3) to veverimer 6 g/day or placebo for 12 weeks while they consumed their typical diet. Both drugs were taken as oral suspensions in water with lunch. Randomisation was done by study site personnel with a computer-generated randomisation code with balanced permuted blocks (block size of seven) and stratified by baseline bicarbonate (18 mmol/L). Patients and investigators were masked to treatment allocation; however, because the appearance of placebo differed from veverimer, a non-masked site staff member who had no other role in the study dispensed, prepared, and supervised dosing of the study drugs. The composite primary efficacy endpoint was the difference (veverimer-placebo) in the proportion of patients achieving at week 12 either an increase of 4 mmol/L or more from baseline in serum bicarbonate concentration or serum bicarbonate in the normal range of 22-29 mmol/L, assessed in the modified intention-to-treat population (all patients with a baseline and at least one post-baseline serum bicarbonate value). Patients fasted for at least 4 h (consuming only water) before measurements of bicarbonate. Safety was assessed in all patients who received any amount of study drug. This trial is registered with ClinicalTrials.gov, number NCT03317444. FINDINGS: Between Sept 26, 2017, and Feb 9, 2018, we randomly assigned 124 participants to veverimer and 93 to placebo. The composite primary endpoint was met by 71 (59%) of 120 patients in the veverimer group versus 20 (22%) of 89 patients in the placebo group (a difference of 37%, 95% CI 23-49; p<0.0001). The most common body system in which adverse events in the veverimer group occurred was gastrointestinal; of these, non-treatment limiting diarrhoea was the most common event (11 [9%] vs three [3%] in the veverimer and placebo groups, respectively). The most common treatment-related adverse events were gastrointestinal (diarrhoea, flatulence, nausea, and constipation) occurring in 16 (13%) patients with veverimer and five (5%) patients with placebo. Two deaths occurred during the study, both in the placebo group (unstable angina and pneumonia). INTERPRETATION: Veverimer effectively and safely corrected metabolic acidosis. Longer-term studies are warranted to assess the effects of veverimer on physical functioning and to assess other deleterious consequences of metabolic acidosis including progression of chronic kidney disease and bone health. FUNDING: Tricida.


Posted May 15th 2019

Targeting LIF-mediated paracrine interaction for pancreatic cancer therapy and monitoring.

Carlos Becerra M.D.

Carlos Becerra M.D.

Shi, Y., W. Gao, N. K. Lytle, P. Huang, X. Yuan, A. M. Dann, M. Ridinger-Saison, K. E. DelGiorno, C. E. Antal, G. Liang, A. R. Atkins, G. Erikson, H. Sun, J. Meisenhelder, E. Terenziani, G. Woo, L. Fang, T. P. Santisakultarm, U. Manor, R. Xu, C. R. Becerra, E. Borazanci, D. D. Von Hoff, P. M. Grandgenett, M. A. Hollingsworth, M. Leblanc, S. E. Umetsu, E. A. Collisson, M. Scadeng, A. M. Lowy, T. R. Donahue, T. Reya, M. Downes, R. M. Evans, G. M. Wahl, T. Pawson, R. Tian and T. Hunter (2019). “Targeting LIF-mediated paracrine interaction for pancreatic cancer therapy and monitoring.” Nature 569(7754): 131-135.

Full text of this article.

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis largely owing to inefficient diagnosis and tenacious drug resistance. Activation of pancreatic stellate cells (PSCs) and consequent development of dense stroma are prominent features accounting for this aggressive biology(1,2). The reciprocal interplay between PSCs and pancreatic cancer cells (PCCs) not only enhances tumour progression and metastasis but also sustains their own activation, facilitating a vicious cycle to exacerbate tumorigenesis and drug resistance(3-7). Furthermore, PSC activation occurs very early during PDAC tumorigenesis(8-10), and activated PSCs comprise a substantial fraction of the tumour mass, providing a rich source of readily detectable factors. Therefore, we hypothesized that the communication between PSCs and PCCs could be an exploitable target to develop effective strategies for PDAC therapy and diagnosis. Here, starting with a systematic proteomic investigation of secreted disease mediators and underlying molecular mechanisms, we reveal that leukaemia inhibitory factor (LIF) is a key paracrine factor from activated PSCs acting on cancer cells. Both pharmacologic LIF blockade and genetic Lifr deletion markedly slow tumour progression and augment the efficacy of chemotherapy to prolong survival of PDAC mouse models, mainly by modulating cancer cell differentiation and epithelial-mesenchymal transition status. Moreover, in both mouse models and human PDAC, aberrant production of LIF in the pancreas is restricted to pathological conditions and correlates with PDAC pathogenesis, and changes in the levels of circulating LIF correlate well with tumour response to therapy. Collectively, these findings reveal a function of LIF in PDAC tumorigenesis, and suggest its translational potential as an attractive therapeutic target and circulating marker. Our studies underscore how a better understanding of cell-cell communication within the tumour microenvironment can suggest novel strategies for cancer therapy.