Research Spotlight

Kandimalla, R., F. Gao, Y. Li, H. Huang, J. Ke, X. Deng, L. Zhao, S. Zhou, A. Goel and X. Wang (2019). “RNAMethyPro: a biologically conserved signature of N6-methyladenosine regulators for predicting survival at pan-cancer level.” NPJ Precis Oncol 3: 13.

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Accumulating evidence indicates the role of N (6)-methyladenosine (m(6)A) regulator-mediated RNA methylation in cancer progression and metastasis; yet its potential clinical significance, if any, remains unclear. In this first-of-its-kind study, we systematically evaluated the role of m(6)A regulators as potential disease biomarkers based on comprehensive analysis of gene expression profiles of 9770 cancer cell lines and clinical specimens from 25 publicly available datasets, encompassing 13 human cancers. We developed and established RNAMethyPro-a gene expression signature of seven m(6)A regulators, which robustly predicted patient survival in multiple human cancers. Pan-cancer analysis identified activated epithelial-mesenchymal transition (EMT), as a highly conserved pathway in high-risk patients predicted by RNAMethyPro in 10 of the 13 cancer types. A network-based analysis revealed an intimate functional interplay between m(6)A regulators and EMT-associated factors via druggable targets such as XPO1 and NTRK1. Finally, the clinical significance of RNAMethyPro was further exemplified in colorectal cancer, where high-risk patients demonstrated strong associations with a mesenchymal subtype, activated stromal infiltration, and poor therapeutic response to targeted anti-EGFR therapy. In summary, RNAMethyPro is a novel, EMT-associated prognostic gene-expression signature in multiple human cancers and may offer an important clinical decision-making tool in the future.

Juengst, S. B., V. Silva, Y. Goldin, K. Cicerone, J. Lengenfelder, N. Chiaravalloti, S. Driver, D. Mellick, G. Dart, C. L. Kew, A. Nabasny and K. R. Bell (2019). “Care partner problem solving training (CP-PST) for care partners of adults with traumatic brain injury during inpatient rehabilitation: Study protocol for a multisite, randomized, single-blind clinical feasibility trial.” Contemp Clin Trials 80: 9-15.

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Traumatic brain injury (TBI) often leads to immediate and chronic functional impairments that affect care partners, or those providing physical and/or emotional support to individuals with TBI. The many challenges associated with being a care partner often lead to caregiver burden and can compromise the well-being and quality of life of care partners and individuals with TBI under their care. Equipping care partners with problem-solving skills could facilitate and sustain their transition into this supportive role. Problem-solving training (PST) has demonstrated efficacy for providing such skills to care partners of individuals with TBI after discharge from inpatient rehabilitation. We propose that PST delivered to care partners during inpatient rehabilitation of individuals with TBI will provide care partners with the skills to manage their caregiving roles across the transition from hospital to home. Herein, we describe the methodology of a current randomized controlled trial that examines the feasibility and efficacy of PST plus TBI education compared to TBI education alone to improve care partner burden, emotional distress, and adaptive coping when delivered during the inpatient rehabilitation stay of individuals with moderate-severe TBI.

Jacob, S., B. Lima, G. V. Gonzalez-Stawinski, M. M. El-Sayed Ahmed, P. C. Patel, E. V. Belli, I. A. Makey, M. Thomas, K. Landolfo, C. Landolfo, J. C. Leoni Moreno, D. S. Yip and S. M. Pham (2019). “Extracorporeal membrane oxygenation as a salvage therapy for patients with severe primary graft dysfunction after heart transplant.” Clin Transplant 33(5): e13538.

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BACKGROUND: Severe primary graft dysfunction (PGD) is the leading cause of early death after heart transplant. AIM: To examine the outcomes of heart transplant recipients who received venoarterial extracorporeal membrane oxygenation (VA-ECMO) for severe PGD. METHODS: We reviewed electronic health records of adult patients who underwent heart transplant from November 2005 through June 2015. We defined severe PGD according to International Society for Heart and Lung Transplantation consensus statements. RESULTS: Of 1030 heart transplant patients, 31 (3%) had severe PGD and required VA-ECMO. The mean (range) age was 59 (43-69) years. Fifteen patients (48%) underwent prior sternotomy and 10 (32%) received a left ventricular assist device as a bridge to transplant. Severe PGD manifested as failure to wean from cardiopulmonary bypass in 20 patients (65%) and as severe hemodynamic instability in the immediate postoperative period in 10 (32%), including cardiac arrest in 3 (10%). Twenty-five patients (81%) were successfully weaned from VA-ECMO, and 19 (61%) were discharged; the other 12 (39%) died. CONCLUSIONS: Although VA-ECMO is a common method for providing mechanical circulatory support to patients with PGD, multicenter studies are needed to assess factors associated with successful outcomes and improved survival of these patients.

Hurvitz, S. A., J. O’Shaughnessy, G. Mason, D. A. Yardley, M. Jahanzeb, A. Brufsky, H. S. Rugo, S. M. Swain, P. A. Kaufman, D. Tripathy, L. Chu, H. Li, V. Antao and M. Cobleigh (2019). “Central Nervous System Metastasis in Patients with HER2-Positive Metastatic Breast Cancer: Patient Characteristics, Treatment, and Survival from SystHERs.” Clin Cancer Res 25(8): 2433-2441.

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PURPOSE: Patients with HER2-positive metastatic breast cancer (MBC) with central nervous system (CNS) metastasis have a poor prognosis. We report treatments and outcomes in patients with HER2-positive MBC and CNS metastasis from the Systemic Therapies for HER2-positive Metastatic Breast Cancer Study (SystHERs). EXPERIMENTAL DESIGN: SystHERs (NCT01615068) was a prospective, U.S.-based, observational registry of patients with newly diagnosed HER2-positive MBC. Study endpoints included treatment patterns, clinical outcomes, and patient-reported outcomes (PRO). RESULTS: Among 977 eligible patients enrolled (2012-2016), CNS metastasis was observed in 87 (8.9%) at initial MBC diagnosis and 212 (21.7%) after diagnosis, and was not observed in 678 (69.4%) patients. White and younger patients, and those with recurrent MBC and hormone receptor-negative disease, had higher risk of CNS metastasis. Patients with CNS metastasis at diagnosis received first-line lapatinib more commonly (23.0% vs. 2.5%), and trastuzumab less commonly (70.1% vs. 92.8%), than patients without CNS metastasis at diagnosis. Risk of death was higher with CNS metastasis observed at or after diagnosis [median overall survival (OS) 30.2 and 38.3 months from MBC diagnosis, respectively] versus no CNS metastasis [median OS not estimable: HR 2.86; 95% confidence interval (CI), 2.05-4.00 and HR 1.94; 95% CI, 1.52-2.49]. Patients with versus without CNS metastasis at diagnosis had lower quality of life at enrollment. CONCLUSIONS: Despite advances in HER2-targeted treatments, patients with CNS metastasis continue to have a poor prognosis and impaired quality of life. Observation of CNS metastasis appears to influence HER2-targeted treatment choice.

Huang, J., R. Chaudhary, A. L. Cohen, K. Fink, S. Goldlust, J. Boockvar, P. Chinnaiyan, L. Wan, S. Marcus and J. L. Campian (2019). “A multicenter phase II study of temozolomide plus disulfiram and copper for recurrent temozolomide-resistant glioblastoma.” J Neurooncol 142(3): 537-544.

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PURPOSE: Preclinical studies have suggested promising activity for the combination of disulfiram and copper (DSF/Cu) against glioblastoma (GBM) including re-sensitization to temozolomide (TMZ). A previous phase I study demonstrated the safety of combining DSF/Cu with adjuvant TMZ for newly diagnosed GBM. This phase II study aimed to estimate the potential effectiveness of DSF/Cu to re-sensitize recurrent GBM to TMZ. METHODS: This open-label, single-arm phase II study treated recurrent TMZ-resistant GBM patients with standard monthly TMZ plus concurrent daily DSF 80 mg PO TID and Cu 1.5 mg PO TID. Eligible patients must have progressed after standard chemoradiotherapy and within 3 months of the last dose of TMZ. Known isocitrate dehydrogenase (IDH) mutant or secondary GBMs were excluded. The primary endpoint was objective response rate (ORR), and the secondary endpoints included progression-free survival (PFS), overall survival (OS), clinical benefit (response or stable disease for at least 6 months), and safety. RESULTS: From March 2017 to January 2018, 23 recurrent TMZ-resistant GBM patients were enrolled across seven centers, and 21 patients were evaluable for response. The median duration of DSF/Cu was 1.6 cycles (range: 0.1-12.0). The ORR was 0%, but 14% had clinical benefit. Median PFS was 1.7 months, and median OS was 7.1 months. Only one patient (4%) had dose-limiting toxicity (grade three elevated alanine transaminase). CONCLUSIONS: Addition of DSF/Cu to TMZ for TMZ-resistant IDH-wild type GBM appears well tolerated but has limited activity for unselected population.