Research Spotlight

Asrani, S. K., L. W. Jennings, J. F. Trotter, J. Levitsky, M. K. Nadim, W. R. Kim, S. A. Gonzalez, B. Fischbach, R. Bahirwani, M. Emmett and G. Klintmalm (2019). “A Model for Glomerular Filtration Rate Assessment in Liver Disease (GRAIL) in the Presence of Renal Dysfunction.” Hepatology 69(3): 1219-1230.

Full text of this article.

Estimation of glomerular filtration rate (eGFR) in patients with liver disease is suboptimal in the presence of renal dysfunction. We developed a model for GFR assessment in liver disease (GRAIL) before and after liver transplantation (LT). GRAIL was derived using objective variables (creatinine, blood urea nitrogen, age, gender, race, and albumin) to estimate GFR based on timing of measurement relative to LT and degree of renal dysfunction (www.bswh.md/grail). The measured GFR (mGFR) by iothalamate clearance (n = 12,122, 1985-2015) at protocol time points before/after LT was used as reference. GRAIL was compared with the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and Modification of Diet in Renal Disease (MDRD-4, MDRD-6) equations for mGFR < 30 mL/min/1.73 m(2) . Prediction of development of chronic kidney disease (mGFR < 20 mL/min/1.73 m(2) , initiation of chronic dialysis) and listing or receipt of kidney transplantation within 5 years was examined in internal cohort (n = 785) and external validation (n = 68,217, 2001-2015). GRAIL had less bias and was more accurate and precise as compared with CKD-EPI, MDRD-4, and MDRD-6 at time points before/after LT for low GFR. For mGFR < 30 mL/min/1.73 m(2) , the median difference (eGFR-mGFR) was GRAIL: 5.24 (9.65) mL/min/1.73 m(2) as compared with CKD-EPI: 8.70 (18.24) mL/min/1.73 m(2) , MDRD-4: 8.82 (17.38) mL/min/1.73 m(2) , and MDRD-6: 6.53 (14.42) mL/min/1.73 m(2) . Before LT, GRAIL correctly classified 75% as having mGFR < 30 mL/min/1.73 m(2) versus 36.1% (CKD-EPI), 36.1% (MDRD-4), and 52.8% (MDRD-6) (P < 0.01). An eGFR < 30 mL/min/1.73 m(2) by GRAIL predicted development of CKD (26.9% versus 4.6% CKD-EPI, 5.9% MDRD-4, and 10.5% MDRD-6) in center data and needing kidney after LT (48.3% versus 22.0% CKD-EPI versus 23.1% MDRD-4 versus 48.3% MDRD-6, P < 0.01) in national data within 5 years after LT. Conclusion: GRAIL may serve as an alternative model to estimate GFR among patients with liver disease before and after LT at low GFR.

Rhodes, C. J., K. Batai, M. Bleda, M. Haimel, L. Southgate, M. Germain, M. W. Pauciulo, C. Hadinnapola, J. Aman, B. Girerd, A. Arora, J. Knight, K. B. Hanscombe, J. H. Karnes, M. Kaakinen, H. Gall, A. Ulrich, L. Harbaum, I. Cebola, J. Ferrer, K. Lutz, E. M. Swietlik, F. Ahmad, P. Amouyel, S. L. Archer, R. Argula, E. D. Austin, D. Badesch, S. Bakshi . . . and M. R. Wilkins (2019). “Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis.” Lancet Respir Med 7(3): 227-238.

Full text of this article.

BACKGROUND: Rare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes. METHODS: We did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11 744 individuals with European ancestry (including 2085 patients). One GWAS used genotypes from 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration of survival. All-cause mortality was the primary endpoint in survival analyses. FINDINGS: A locus near SOX17 (rs10103692, odds ratio 1.80 [95% CI 1.55-2.08], p=5.13 x 10(-15)) and a second locus in HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1.56 [1.42-1.71], p=7.65 x 10(-20)) within the class II MHC region were associated with pulmonary arterial hypertension. The SOX17 locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1.36 [1.25-1.48], p=1.69 x 10(-12); and rs10103692). Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reduced SOX17 expression. The HLA-DPA1/DPB1 rs2856830 genotype was strongly associated with survival. Median survival from diagnosis in patients with pulmonary arterial hypertension with the C/C homozygous genotype was double (13.50 years [95% CI 12.07 to >13.50]) that of those with the T/T genotype (6.97 years [6.02-8.05]), despite similar baseline disease severity. INTERPRETATION: This is the first study to report that common genetic variation at loci in an enhancer near SOX17 and in HLA-DPA1/DPB1 is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more common in pulmonary arterial hypertension than suggested by rare mutations in SOX17. Further studies are needed to confirm the association between HLA typing or rs2856830 genotyping and survival, and to determine whether HLA typing or rs2856830 genotyping improves risk stratification in clinical practice or trials. FUNDING: UK NIHR, BHF, UK MRC, Dinosaur Trust, NIH/NHLBI, ERS, EMBO, Wellcome Trust, EU, AHA, ACClinPharm, Netherlands CVRI, Dutch Heart Foundation, Dutch Federation of UMC, Netherlands OHRD and RNAS, German DFG, German BMBF, APH Paris, INSERM, Universite Paris-Sud, and French ANR.

Bodei, L., E. Liu, S. Paulson, A. Gulati, J. Freudman, W. Grosh, S. Kafer, P. C. Wickremesinghe and R. R. Salem (2019). “Time for a change and to adopt a novel molecular genomic approach in NETs.” Nat Rev Clin Oncol Feb 26. [Epub ahead of print].

Full text of this article.

We read with interest the News and Views article by Rindi and Wiedenmann (Neuroendocrine neoplasia goes molecular — time for a change. Nat. Rev. Clin. Oncol. 16, 149–150 (2018)), two notable and eminent authorities in the field of genomic medicine. Despite the concerns raised by these experts, the registry study discussed in their article unequivocally demonstrated the clinical utility of the NETest liquid biopsy assay in the ‘real-world’ setting. NETest scores enabled accurate prediction (100%) of disease progression and had a 98% correlation with response to therapy, reducing the requirement to perform an imaging test in 40% of patients . . . The following factual inaccuracies were stated in the News and Views by Rindi and Wiedenmann: that the Response Evaluation Criteria in Solid Tumors (RECIST) always enable an accurate assessment of NET progression; that our data should be viewed cautiously owing to tumour heterogeneity; that we provided no sensitivity data; that patient management depends on a multidisciplinary team (MDT) approach; and that the cost–benefit ratio of NETest is unfavourable. (Excerpt from correspondence.)

Forero-Torres, A., R. Ramchandren, A. Yacoub, M. S. Wertheim, W. J. Edenfield, P. Caimi, M. Gutierrez, L. Akard, C. Escobar, J. Call, D. Persky, S. Iyer, D. J. DeMarini, L. Zhou, X. Chen, F. Dawkins and T. J. Phillips (2019). “Parsaclisib, a potent and highly selective PI3Kdelta inhibitor, in patients with relapsed or refractory B-cell malignancies.” Blood Feb 25. [Epub ahead of print].

Full text of this article.

This phase 1/2 study assessed parsaclisib (INCB050465), a next-generation, potent, and highly selective phosphatidylinositol 3-kinase delta (PI3Kdelta) inhibitor, in patients with relapsed or refractory B-cell malignancies, alone or in combination with a Janus kinase 1 inhibitor (itacitinib) or chemotherapy (rituximab, ifosfamide, carboplatin, and etoposide). Seventy-two patients received parsaclisib monotherapy (5-45 mg once daily). Expansion doses were 20 and 30 mg once daily; intermittent dosing at 20 mg (once daily for 9 weeks, then once weekly) was explored. No dose-limiting toxicities were identified, and maximum tolerated dose was not reached. Most common nonhematologic treatment-emergent adverse events (TEAEs) were diarrhea/colitis (36%), nausea (36%), fatigue (31%), and rash (31%). Grade 3/4 neutropenia occurred in 19% of patients. Serious TEAEs (> 2 patients) were diarrhea/colitis (n = 9), pyrexia (n = 4), hypotension (n = 3), and sepsis (n = 3). Aspartate and alanine transaminase elevations occurring before treatment discontinuation were grade 1, except 1 grade 3 event each, secondary to sepsis. Two patients experienced 3 fatal parsaclisib-unrelated TEAEs (respiratory failure; respiratory failure and sepsis). In non-Hodgkin lymphoma (NHL), objective response rates to monotherapy were 71% in follicular lymphoma, 78% in marginal zone lymphoma, 67% in mantle cell lymphoma, and 30% in diffuse large B-cell lymphoma; 93% of responses occurred at first assessment (~9 weeks). Parsaclisib has demonstrated antitumor activity in relapsed or refractory B-cell NHL with the potential for improved long-term patient outcomes. Phase 2 studies in relapsed or refractory B-cell NHL subtypes are ongoing. This trial was registered at www.clinicaltrials.gov as #NCT02018861.

Zoghbi, W. A., F. M. Asch, C. Bruce, L. D. Gillam, P. A. Grayburn, R. T. Hahn, I. Inglessis, A. M. Islam, S. Lerakis, S. H. Little, R. J. Siegel, N. Skubas, T. C. Slesnick, W. J. Stewart, P. Thavendiranathan, N. J. Weissman, S. Yasukochi and K. G. Zimmerman (2019). “Guidelines for the Evaluation of Valvular Regurgitation After Percutaneous Valve Repair or Replacement: A Report from the American Society of Echocardiography Developed in Collaboration with the Society for Cardiovascular Angiography and Interventions, Japanese Society of Echocardiography, and Society for Cardiovascular Magnetic Resonance.” J Am Soc Echocardiogr.

Full text of this article.

Valvular disease remains a major cause of cardiovascular morbidity and mortality worldwide. Over the past decade, catheter-based interventions in valvular disease have evolved from balloon dilation of native stenotic valves to repair of paravalvular regurgitation (PVR) with vascular plugs and more recently to valve replacement and repair. Currently-approved interventions include transcatheter aortic valve replacement (TAVR), pulmonic valve replacement, and mitral valve repair, targeted to specific populations. Rapid technological advancements in device design are likely to improve acute and long-term results and expand current indications. Hemodynamics of percutaneous valves have been very favorable. However, a challenging area has been the new or residual valve regurgitation that may occur either after transcatheter valve implantation or repair of a native or prosthetic valve. This condition presents a diagnostic and therapeutic challenge to the interventional and imaging cardiology team in the catheterization laboratory and to the clinician and imager in the outpatient setting. The current document addresses the challenges of assessing residual regurgitation after percutaneous valve replacement or repair and provides a guide to the cardiac team on how best to approach this condition, based on the available data and a consensus of a panel of experts. This document supplements the previous American Society of Echocardiography (ASE) guideline on the assessment of surgically implanted prosthetic valves. It does not address flow dynamics through the percutaneous prosthetic valves since, in general, the evaluation is similar to surgically implanted valves, but focuses mostly on new or residual valvular regurgitation. In addition to the use of echocardiography and hemodynamic assessment in the acute setting, the document incorporates the role of cardiac magnetic resonance (CMR) imaging. This guideline is accompanied by a number of tutorials and illustrative case-studies on evaluation of valvular regurgitation after catheter-based interventions as well as native valve regurgitation, posted on the following website (www.asecho.org/vrcases), which will build gradually over time. (Excerpt from this article in press, p. 3.)