Research Spotlight

Posted December 15th 2018

Outcomes of immunosuppression minimization and withdrawal early after liver transplantation.

Göran Klintmalm M.D.

Göran Klintmalm M.D.

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.


Posted December 15th 2018

Intermediate Susceptibility Dose-Dependent Breakpoints For High-Dose Rifampin, Isoniazid, and Pyrazinamide Treatment in Multidrug-Resistant Tuberculosis Programs.

Tawanda Gumbo M.D.

Tawanda Gumbo M.D.

Zuur, M. A., J. G. Pasipanodya, D. van Soolingen, T. S. van der Werf, T. Gumbo and J. C. Alffenaar (2018). “Intermediate Susceptibility Dose-Dependent Breakpoints For High-Dose Rifampin, Isoniazid, and Pyrazinamide Treatment in Multidrug-Resistant Tuberculosis Programs.” Clin Infect Dis 67(11): 1743-1749.

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Background: Bacterial susceptibility is categorized as susceptible, intermediate-susceptible dose-dependent (ISDD), and resistant. The strategy is to use higher doses of first-line agents in the ISDD category, thereby preserving the use of these drugs. This system has not been applied to antituberculosis drugs. Pharmacokinetic/pharmacodynamic (PK/PD) target exposures, in tandem with Monte Carlo experiments, recently identified susceptibility breakpoints of 0.0312 mg/L for isoniazid, 0.0625 mg/L for rifampin, and 50 mg/L for pyrazinamide. These have been confirmed in clinical studies. Methods: Target attainment studies were carried out using Monte Carlo experiments to investigate whether rifampin, isoniazid, and pyrazinamide dose increases would achieve the PK/PD target in >90% of 10000 patients with tuberculosis caused by bacteria, revealing minimum inhibitory concentrations (MICs) between the proposed and the traditional breakpoints. Results: We found that an isoniazid dose of 900 mg/day identified a new ISDD MIC range of 0.0312-0.25 mg/L and resistance at MIC >/=0.5 mg/L. Rifampin 1800 mg/day would result in an ISDD of 0.0625-0.25 mg/L and resistance at MIC >/=0.5 mg/L. At a dose of pyrazinamide 4 g/day, the ISDD MIC range was 37.5-50 mg/L and resistance at MIC >/=100 mg/L. Based on MIC distributions, 93% (isoniazid), 78% (rifampin), and 27% (pyrazinamide) of isolates would be within the ISDD range. Conclusions: Drug susceptibility testing at 2 concentrations delineating the ISDD range, and subsequently using higher doses, could prevent switching to a more toxic second-line treatment. Confirmatory clinical studies would provide evidence to change treatment guidelines.


Posted December 15th 2018

Racial/Ethnic Disparities in Longer-term Outcomes Among Emergency General Surgery Patients: The Unique Experience of Universally Insured Older Adults.

Shahid Shafi M.D.

Shahid Shafi M.D.

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.


Posted December 15th 2018

Integrative network biology analysis identifies miR-508-3p as the determinant for the mesenchymal identity and a strong prognostic biomarker of ovarian cancer.

Ajay Goel Ph.D.

Ajay Goel Ph.D.

Zhao, L., W. Wang, L. Xu, T. Yi, X. Zhao, Y. Wei, L. Vermeulen, A. Goel, S. Zhou and X. Wang (2018). “Integrative network biology analysis identifies miR-508-3p as the determinant for the mesenchymal identity and a strong prognostic biomarker of ovarian cancer.” Oncogene Nov 26. [Epub ahead of print].

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Ovarian cancer is a heterogeneous malignancy that poses tremendous clinical challenge. Based on unsupervised classification of whole-genome gene expression profiles, four molecular subtypes of ovarian cancer were recently identified. However, single-driver molecular events specific to these subtypes have not been clearly elucidated. We aim to characterize the regulatory mechanisms underlying the poor prognosis mesenchymal subtype of ovarian cancer using a systems biology approach, involving a variety of molecular modalities including gene and microRNA expression profiles. miR-508-3p emerged as the most powerful determinant that regulates a cascade of dysregulated genes in the mesenchymal subtype, including core genes involved in epithelial-mesenchymal transition (EMT) program. Moreover, miR-508-3p down-regulation, due to promoter hypermethylation, was directly correlated with metastatic behaviors in vitro and in vivo. Taken together, our multidimensional network analysis identified miR-508-3p as a master regulator that defines the mesenchymal subtype and provides a novel prognostic biomarker to improve management of this disease.


Posted December 15th 2018

CBX2 identified as driver of anoikis escape and dissemination in high grade serous ovarian cancer.

Monique A. Spillman M.D.

Monique A. Spillman M.D.

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.