Research Spotlight

Sundaram, V., S. Kogachi, R. J. Wong, C. J. Karvellas, B. E. Fortune, N. Mahmud, J. Levitsky, R. S. Rahimi and R. Jalan (2019). “Effect of the clinical course of acute on chronic liver failure prior to liver transplantation on post-transplant survival.” J Hepatol Oct 25. [Epub ahead of print].

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BACKGROUND AND AIMS: We evaluated whether the clinical course of acute on chronic liver failure (ACLF) between time of listing and liver transplantation (LT) affects one-year post-transplant survival. METHODS: We identified patients from the UNOS database who were transplanted within 28 days of listing, and categorized them by ACLF grade at waitlist registration and LT, per the EASL-CLIF definition. RESULTS: 3,636 patients listed with ACLF-3 underwent LT within 28-days. Among those transplanted, 892 (24.5%) recovered to no ACLF or ACLF grade 1 or 2 (ACLF 0-2) and 2,744 (75.5%) had ACLF-3 at transplantation. One-year survival was 82.0% among those transplanted with ACLF-3 versus 88.2% among those improving to ACLF 0-2 (p<0.001). Conversely, the survival of patients listed with ACLF 0-2 who progressed to ACLF-3 at LT (n=2,265) was significantly lower than that of recipients who remained at ACLF 0-2 (n=17,631) at the time of LT (83.8% vs 90.2%, p<0.001). Cox modeling demonstrated that recovery of ACLF-3 to ACLF 0-2 at LT was associated with reduced one-year mortality after transplantation (HR=0.65, 95% CI 0.53-0.78). Improvement in circulatory (HR=0.57, 95% CI 0.43-0.75) and brain failure (HR=0.76, 95% CI 0.60-0.97) and stopping mechanical ventilation (HR=0.55, 95% CI 0.42-0.71) were also associated with reduced post-LT mortality. Age above 60 years was a risk factor for post-transplant mortality (HR=1.68, 95% CI 1.31-2.18), but one-year survival increased from 74.9% to 82.7% among those older than 60 years who improved from ACLF-3 to ACLF 0-2 (p<0.001). CONCLUSIONS: Improvement of ACLF-3 at listing to ACLF 0-2 at transplantation enhances post-LT survival, particularly in recipients who are older than age 60, who were removed from the mechanical ventilator, or who recovered from circulatory or brain failure. LAY SUMMARY: Liver transplantation (LT) for patients with acute on chronic liver failure grade 3 (ACLF-3) significantly improves survival, but 1-year survival probability after LT remains lower than the expected outcomes for transplant centers. Our study reveals that among patients transplanted within 28 days of waitlist registration, improvement of ACLF-3 at listing to a lower grade of ACLF at transplantation significantly enhances post-transplant survival, even among patients above 60 years. Subgroup analysis further demonstrates that improvement in circulatory failure, brain failure, or removal from mechanical ventilation has the strongest impact on post-transplant survival.

Silfvast-Kaiser, A., R. Youssef and S. Y. Paek (2019). “Diet in hidradenitis suppurativa: a review of published and lay literature.” Int J Dermatol 58(11): 1225-1230.

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Hidradenitis suppurativa (HS) is a chronic, recurring, inflammatory skin disorder resulting in skin abscesses and sinus tracts of the skin folds. Hidradenitis suppurativa remains a disease with limited treatment options. Management of disease activity with dietary modification has been of considerable interest to the HS patient community. Limited evidence exists to support dietary changes for treatment of HS. Strategies such as eliminating dairy products, limiting simple carbohydrate and sugar intake, and avoiding nightshades (Solanaceae) and foods containing brewer’s yeast have been reported to be helpful in some patients. Several supplements have also been touted as beneficial. Herein, we review the existing dietary recommendations in both peer-reviewed and lay literature in an attempt to consolidate and evaluate existing information, while stimulating further inquiry into the role of diet in HS. Although dietary modifications are often of considerable interest to HS patients, there is a paucity of data regarding diet as it relates to HS. It is unclear whether diet may prove to be of value in limiting the severity of HS. Further research is needed to determine the potential benefits of these dietary changes.

Shah, N. P., V. Garcia-Gutierrez, A. Jimenez-Velasco, S. Larson, S. Saussele, D. Rea, F. X. Mahon, M. Y. Levy, M. T. Gomez-Casares, F. Pane, F. E. Nicolini, M. J. Mauro, O. Sy, P. Martin-Regueira and J. H. Lipton (2019). “Dasatinib discontinuation in patients with chronic-phase chronic myeloid leukemia and stable deep molecular response: the DASFREE study.” Leuk Lymphoma Oct 24: 1-10. [Epub ahead of print].

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Treatment-free remission (TFR) in patients with chronic myeloid leukemia in chronic phase (CML-CP) is considered a feasible option, especially with the ability of second-generation tyrosine kinase inhibitors to induce higher rates of sustained deep molecular response (DMR). DASFREE is an open-label, single-arm, multicenter phase II trial assessing TFR after dasatinib discontinuation in patients with CML-CP (N = 84). At 2 years, TFR was 46% in all patients. Multivariate analyses revealed statistically significant associations between 2-year TFR and duration of prior dasatinib (>/=median; p = .0051), line of therapy (first line; p = .0138), and age (>65 years; p = .0012). No disease transformation occurred, and the most common adverse events experienced off treatment were musculoskeletal (observed in 30 patients); however, dasatinib withdrawal events were reported in nine patients (11%) by the investigator. Overall, these findings support the feasibility of discontinuing dasatinib for patients with CML-CP in sustained DMR in the first line and beyond.

Selvaraj, S., B. Claggett, A. Pozzi, J. J. V. McMurray, P. S. Jhund, M. Packer, A. S. Desai, E. F. Lewis, M. Vaduganathan, M. P. Lefkowitz, J. L. Rouleau, V. C. Shi, M. R. Zile, K. Swedberg and S. D. Solomon (2019). “Prognostic Implications of Congestion on Physical Examination Among Contemporary Patients With Heart Failure and Reduced Ejection Fraction: PARADIGM-HF.” Circulation 140(17): 1369-1379.

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BACKGROUND: The contemporary prognostic value of the physical examination- beyond traditional risk factors including natriuretic peptides, risk scores, and symptoms-in heart failure (HF) with reduced ejection fraction is unknown. We aimed to determine the association between physical signs of congestion at baseline and during study follow-up with quality of life and clinical outcomes and to assess the treatment effects of sacubitril/valsartan on congestion. METHODS: We analyzed participants from PARADIGM-HF (Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With Angiotensin Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in HF) with an available physical examination at baseline. We examined the association of the number of signs of congestion (jugular venous distention, edema, rales, and third heart sound) with the primary outcome (cardiovascular death or HF hospitalization), its individual components, and all-cause mortality using time-updated, multivariable-adjusted Cox regression. We further evaluated whether sacubitril/valsartan reduced congestion during follow-up and whether improvement in congestion is related to changes in clinical outcomes and quality of life, assessed by Kansas City Cardiomyopathy Questionnaire overall summary scores. RESULTS: Among 8380 participants, 0, 1, 2, and 3+ signs of congestion were present in 70%, 21%, 7%, and 2% of patients, respectively. Patients with baseline congestion were older, more often female, had higher MAGGIC risk scores (Meta-Analysis Global Group in Chronic Heart Failure) and lower Kansas City Cardiomyopathy Questionnaire overall summary scores (P<0.05). After adjusting for baseline natriuretic peptides, time-updated Meta-Analysis Global Group in Chronic Heart Failure score, and time-updated New York Heart Association class, increasing time-updated congestion was associated with all outcomes (P<0.001). Sacubitril/valsartan reduced the risk of the primary outcome irrespective of clinical signs of congestion at baseline (P=0.16 for interaction), and treatment with the drug improved congestion to a greater extent than did enalapril (P=0.011). Each 1-sign reduction was independently associated with a 5.1 (95% CI, 4.7-5.5) point improvement in Kansas City Cardiomyopathy Questionnaire overall summary scores. Change in congestion strongly predicted outcomes even after adjusting for baseline congestion (P<0.001). CONCLUSIONS: In HF with reduced ejection fraction, the physical exam continues to provide significant independent prognostic value even beyond symptoms, natriuretic peptides, and Meta-Analysis Global Group in Chronic Heart Failure risk score. Sacubitril/valsartan improved congestion to a greater extent than did enalapril. Reducing congestion in the outpatient setting is independently associated with improved quality of life and reduced cardiovascular events, including mortality. CLINICAL TRIAL REGISTRATION: https://www.clinicaltrials.gov. Unique identifier: NCT01035255.

Schiller, L. R. (2019). “Good News about BAD.” Clin Gastroenterol Hepatol Oct 29. [Epub ahead of print].

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The good news about bile acid diarrhea (BAD) is that research over the last 50 years has established that it is a real mechanism for chronic diarrhea, not just with ileal disease or resection, but in patients with functional diarrhea or IBS-D. It is incumbent upon physicians now to consider this diagnosis in patients with chronic diarrhea. Whether one tests, then treats or just empirically treats, we will do a great service for many of our patients with chronic diarrhea by addressing this mechanism of disease. (Excerpt from this article-in-press.)