Research Spotlight

Shaked, A., M. R. DesMarais, H. Kopetskie, S. Feng, J. D. Punch, J. Levitsky, J. Reyes, G. B. Klintmalm, A. J. Demetris, B. E. Burrell, A. Priore, N. D. Bridges and P. H. Sayre (2018). “Outcomes of immunosuppression minimization and withdrawal early after liver transplantation.” Am J Transplant Dec 1. [Epub ahead of print].

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ITN030ST A-WISH assessed immunosuppression withdrawal in liver transplant recipients with hepatitis C or nonimmune nonviral liver disease. Of 275 recipients enrolled before transplantation, 95 were randomly assigned 4:1 to withdrawal (n=77) or maintenance (n=18) 1-to-2 years post-transplant. Randomization eligibility criteria included stable immunosuppression monotherapy; adequate liver and kidney function; /= 8 weeks per level. Fifty-two of 77 subjects (67.5%) reduced to /= 1 year. Acute rejection and/or abnormal liver tests were treated with increased immunosuppression; 5 of 32 rejection episodes required a methylprednisolone bolus. The composite endpoint (death or graft loss; grade 4 secondary malignancy or opportunistic infection; Ishak stage >/=3; or > 25% decrease in glomerular filtration rate: within 24 months of randomization) occurred in 12 of 66 (18%) and 4 of 13 (31%) subjects in the withdrawal and maintenance groups. Early immunosuppression minimization is feasible in selected liver recipients, while complete withdrawal is successful in only a small proportion. The composite endpoint comparison was inconclusive for non-inferiority of the withdrawal to the maintenance group.

Zogg, C. K., W. Jiang, T. D. Ottesen, S. Shafi, K. Schuster, R. Becher, K. A. Davis and A. H. Haider (2018). “Racial/Ethnic Disparities in Longer-term Outcomes Among Emergency General Surgery Patients: The Unique Experience of Universally Insured Older Adults.” Ann Surg 268(6): 968-979.

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OBJECTIVES: To determine whether racial/ethnic disparities in 30/90/180-day mortality, major morbidity, and unplanned readmissions exist among universally insured older adult (>/=65 years) emergency general surgery patients; vary by diagnostic category; and can be explained by variations in geography, teaching status, age-cohort, and a hospital’s percentage of minority patients. SUMMARY OF BACKGROUND DATA: As the US population ages and discussions surrounding the optimal method of insurance provision increasingly enter into national debate, longer-term outcomes are of paramount concern. It remains unclear the extent to which insurance changes disparities throughout patients’ postacute recovery period among older adults. METHODS: Survival analysis of 2008 to 2014 Medicare data using risk-adjusted Cox proportional-hazards models. RESULTS: A total of 6,779,649 older adults were included, of whom 82.8% identified as non-Hispanic white (NHW), 9.2% non-Hispanic black (NHB), 5.6% Hispanic, and 1.5% non-Hispanic Asian (NHA). Relative to NHW patients, each group of minority patients was significantly less likely to die [30-day NHB vs NHW hazard ratio (95% confidence interval): 0.88 (0.86-0.89)]. Differences became less apparent as outcomes approached 180 days [180-day NHB vs NHW: 1.00 (0.98-1.02)]. For major morbidity and unplanned readmission, differences among NHW, Hispanic, and NHA patients were comparable. NHB patients did consistently worse. Efforts to explain the occurrence found similar trends across diagnostic categories, but significant differences in disparities attributable to geography and the other included factors that combined accounted for up to 50% of readmission differences between racial/ethnic groups. CONCLUSION: The study found an inversion of racial/ethnic mortality differences and mitigation of non-NHB morbidity/readmission differences among universally insured older adults that decreased with time. Persistent disparities among nonagenarian patients and hospitals managing a regionally large share of minority patients warrant particular concern.

Wheeler, L. J., Z. L. Watson, L. Qamar, T. M. Yamamoto, M. D. Post, A. A. Berning, M. A. Spillman, K. Behbakht and B. G. Bitler (2018). “CBX2 identified as driver of anoikis escape and dissemination in high grade serous ovarian cancer.” Oncogenesis 7(11): 92.

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High grade serous ovarian carcinoma (HGSOC) is often diagnosed at an advanced stage. Chromobox 2 (CBX2), a polycomb repressor complex subunit, plays an oncogenic role in other cancers, but little is known about its role in HGSOC. We hypothesize that CBX2 upregulation promotes HGSOC via induction of a stem-like transcriptional profile and inhibition of anoikis. Examination of Gene Expression Omnibus (GEO) datasets and The Cancer Genome Atlas (TCGA) established that increased CBX2 expression conveyed chemoresistance and worse disease-free and overall survival. In primary HGSOC tumors, we observed CBX2 expression was significantly elevated compared to benign counterparts. In HGSOC cell lines, forced suspension promoted CBX2 expression. Subsequently, CBX2 knockdown inhibited anchorage-independent proliferation and potentiated anoikis-dependent apoptosis. Furthermore, CBX2 knockdown re-sensitized cells to platinum-based chemotherapy. Forced suspension promoted increased ALDH activity and ALDH3A1 expression and CBX2 knockdown led to a decrease in both ALDH activity and ALDH3A1 expression. Investigation of CBX2 expression on a HGSOC tissue microarray revealed CBX2 expression was apparent in both primary and metastatic tissues. CBX2 is an important regulator of stem-ness, anoikis escape, HGSOC dissemination, and chemoresistance and potentially serves as a novel therapeutic target.

Tolia, V. N., K. Murthy, M. M. Bennett, R. G. Greenberg, D. K. Benjamin, P. B. Smith and R. H. Clark (2018). “Morphine vs Methadone Treatment for Infants with Neonatal Abstinence Syndrome.” J Pediatr 203: 185-189.

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OBJECTIVE: To estimate the relationship of initial pharmacotherapy with methadone or morphine and length of stay (LOS) in infants with neonatal abstinence syndrome (NAS) admitted to the neonatal intensive care unit (NICU). STUDY DESIGN: From the Pediatrix Clinical Data Warehouse database, we identified all infants born at >/=36 weeks of gestation between 2011 and 2015 who were diagnosed with NAS (International Classification of Diseases, Ninth Revision code 779.5) and treated with methadone or morphine in the first 7 days of life. We used multivariable Cox proportional hazards regression analysis to quantify the association between initial treatment and LOS after adjusting for maternal age, maternal race/ethnicity, maternal drug use, maternal smoking, gestational age, small for gestational age status, inborn status, and discharge year. RESULTS: We identified a total of 7667 eligible infants, including 1187 treated with methadone (15%) and 6480 treated with morphine (85%). Birth weight, gestational age, and sex were similar in the 2 groups. Methadone treatment was associated with a 22% shorter median LOS (18 days [IQR, 11-30 days] vs 23 days [IQR, 16-33]; P < .001) and a 19% shorter median NICU stay (17 days [IQR, 10-29 days] vs 21 days [IQR, 14-36 days]; P < .001). After adjustment, methadone was associated with a shorter LOS (hazard ratio for discharge, 1.24; 95% CI, 1.11-1.37; P < .001) CONCLUSION: Among infants born at >/=36 weeks of gestation with NAS, initial methadone treatment was associated with a shorter LOS compared with morphine treatment. Future prospective comparative effectiveness trials to treat infants with NAS are needed to verify this observation.

Tisminetzky, M., H. L. Nguyen, J. H. Gurwitz, D. McManus, J. Gore, S. Singh, J. Yarzebski and R. J. Goldberg (2018). “Magnitude and impact of multiple chronic conditions with advancing age in older adults hospitalized with acute myocardial infarction.” Int J Cardiol 272: 341-345.

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BACKGROUND: To examine age-specific differences in the frequency and impact of cardiac and non-cardiac conditions among patients aged 65years and older hospitalized with acute myocardial infarction (AMI). METHODS: Study population consisted of 3863 adults hospitalized with AMI at 11 medical centers in central Massachusetts on a biennial basis between 2001 and 2011. The presence of 11 chronic conditions (five cardiac and six non-cardiac) was based on the review of hospital medical records. RESULTS: Participants’ median age was 79years, 49% were men, and had an average of three chronic conditions (average of cardiac conditions: 2.6 and average of non-cardiac conditions: 1.0). Approximately one in every two patients presented with two or more cardiac related conditions whereas one in every three patients presented with two or more non-cardiac related conditions. The most prevalent chronic conditions in our study population were hypertension, diabetes, heart failure, chronic kidney disease, and peripheral vascular disease. Patients across all age groups with a greater number of previously diagnosed cardiac or non-cardiac conditions were at higher risk for developing important clinical complications or dying during hospitalization as compared to those with 0-1 condition. CONCLUSIONS: The prevalence of multimorbidity among older adults hospitalized with AMI is high and associated with worse outcomes that should be considered in the management of this vulnerable population.