Research Spotlight

Still, S., M. Mencio, E. Ontiveros, J. Burdick and S. G. Leeds (2018). “Primary and Rescue Endoluminal Vacuum Therapy in the Management of Esophageal Perforations and Leaks.” Ann Thorac Cardiovasc Surg Jun 7. [Epub ahead of print].

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BACKGROUND: To investigate the efficacy of primary and rescue endoluminal vacuum (EVAC) therapy in the treatment of esophageal perforations and leaks. METHODS: We conducted a retrospective review of a prospectively gathered, Institutional Review Board (IRB) approved database of EVAC therapy patients at our center from July 2013 to September 2016. RESULTS: In all, 13 patients were treated for esophageal perforations or leaks. Etiologies included iatrogenic injury (n = 8), anastomotic leak (n = 2), Boerhaave syndrome (n = 1), and bronchoesophageal fistula (n = 2). In total, 10 patients underwent primary treatment and three were treated with rescue therapy. Mean Perforation Severity Scores (PSSs) in the primary and rescue treatment groups were 7 and 10, respectively. Average defect size was 2.4 (range: 0.5-6) cm. The rescue group had a shorter mean time to defect closure (25 vs. 33 days). In all, 12 of 13 defects healed. One death occurred following the implementation of comfort care. One therapy-specific complication occurred. Hospital length of stay (LOS) was longer in the rescue group (72 vs. 53 days); however, the intensive care unit (ICU) duration was similar between groups. Totally, 10 patients (83%) resumed an oral diet after successful defect closure. CONCLUSION: Utilized as either a primary or rescue therapy, EVAC therapy appears to be beneficial in the management of esophageal perforations or leaks.

Shigeyasu, K., Y. Okugawa, S. Toden, J. Miyoshi, Y. Toiyama, T. Nagasaka, N. Takahashi, M. Kusunoki, T. Takayama, Y. Yamada, T. Fujiwara, L. Chen and A. Goel (2018). “AZIN1 RNA editing confers cancer stemness and enhances oncogenic potential in colorectal cancer.” JCI Insight 3(12) Jun 21. [Epub ahead of print].

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Adenosine-to-inosine (A-to-I) RNA editing, a process mediated by adenosine deaminases that act on the RNA (ADAR) gene family, is a recently discovered epigenetic modification dysregulated in human cancers. However, the clinical significance and the functional role of RNA editing in colorectal cancer (CRC) remain unclear. We have systematically and comprehensively investigated the significance of the expression status of ADAR1 and of the RNA editing levels of antizyme inhibitor 1 (AZIN1), one of the most frequently edited genes in cancers, in 392 colorectal tissues from multiple independent CRC patient cohorts. Both ADAR1 expression and AZIN1 RNA editing levels were significantly elevated in CRC tissues when compared with corresponding normal mucosa. High levels of AZIN1 RNA editing emerged as a prognostic factor for overall survival and disease-free survival and were an independent risk factor for lymph node and distant metastasis. Furthermore, elevated AZIN1 editing identified high-risk stage II CRC patients. Mechanistically, edited AZIN1 enhances stemness and appears to drive the metastatic processes. We have demonstrated that edited AZIN1 functions as an oncogene and a potential therapeutic target in CRC. Moreover, AZIN1 RNA editing status could be used as a clinically relevant prognostic indicator in CRC patients.

Sathananthan, J., D. J. Murdoch, B. R. Lindman, A. Zajarias, W. A. Jaber, P. Cremer, D. Wood, R. Moss, A. Cheung, J. Ye, R. T. Hahn, A. Crowley, M. B. Leon, M. J. Mack and J. G. Webb (2018). “Implications of Concomitant Tricuspid Regurgitation in Patients Undergoing Transcatheter Aortic Valve Replacement for Degenerated Surgical Aortic Bioprosthesis: Insights From the PARTNER 2 Aortic Valve-in-Valve Registry.” JACC Cardiovasc Interv 11(12): 1154-1160.

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OBJECTIVES: The aim of this study was to assess the implications of concomitant tricuspid regurgitation (TR) in patients undergoing valve-in-valve (VIV) transcatheter aortic valve replacement. BACKGROUND: Patients undergoing VIV transcatheter aortic valve replacement with concomitant TR may have worse outcomes, and optimal management remains undetermined. METHODS: The multicenter PARTNER 2 (Placement of Aortic Transcatheter Valves) VIV trial enrolled patients with symptomatic degenerated surgical aortic bioprostheses who were at high risk for reoperation. Outcomes were assessed between patients with mild or no TR versus moderate or severe TR. RESULTS: A total of 237 patients underwent VIV procedures (mean age 78.7 +/- 10.8 years, mean Society of Thoracic Surgeons score 9.1 +/- 4.8%). In this cohort, 162 patients (68.4%) had mild or no TR, and 75 patients (31.6%) had moderate or severe TR. Although there was no difference in New York Heart Association functional class III or IV symptomatic status (89.3% vs. 91.4%; p = 0.62) or moderate or severe right ventricular dysfunction (9.4% vs. 16.9%; p = 0.11), patients with moderate or severe TR were more likely to be at high surgical risk, with a Society of Thoracic Surgeons score of >8 (62.7% vs 46.9%; p = 0.02). There was no difference in a composite endpoint of death and rehospitalization between moderate or severe TR and mild or no TR, either at 30 days (10.7% vs. 9.9%; p = 0.85) or at 1-year follow-up (24.1% vs. 23.2%; p = 0.80). There was a significant reduction in overall moderate or severe TR from baseline at 30 days (31.1% vs. 21.1%; p = 0.002), which was sustained at 1-year follow-up (38.0% vs. 22.8%; p = 0.004). CONCLUSIONS: Despite higher predicted surgical risk, the presence of TR was not a predictor of long-term outcomes. Importantly, there was significant reduction in TR severity at both short- and long-term follow-up. In selected patients undergoing VIV transcatheter aortic valve replacement, it may be appropriate to conservatively manage concomitant TR.

Sanchez, K., M. O. Killian, T. L. Mayes, T. L. Greer, J. M. Trombello, R. Lindblad, B. D. Grannemann, T. J. Carmody, A. J. Rush, R. Walker and M. H. Trivedi (2018). “A psychometric evaluation of the Concise Health Risk Tracking Self-Report (CHRT-SR)- a measure of suicidality-in patients with stimulant use disorder.” J Psychiatr Res 102: 65-71.

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Stimulant use disorders are both common and associated with suicidal ideation and attempts. The psychometric properties of the 12-item Concise Health Risk Tracking Scale Self-Report (CHRT-SR), a measure that was created to assess suicidal thinking and several factors associated with a propensity to act, has been established in persons with mood disorders. This is a secondary analysis to assess the CHRT-SR in 302 stimulant abusing patients that had participated in a clinical trial. A confirmatory factor analysis (CFA) was conducted to assess the factor validity of the 12-item CHRT-SR model with a second-order Propensity factor. The CHRT-SR total score and 2 factor scores (Propensity and Suicidal Thoughts) demonstrated acceptable internal consistency and test-retest reliabilities. These two subscales and the total score were modestly but significantly associated with measures of depression and life satisfaction, demonstrating construct validity. Two additional items assessing Impulsivity were also analyzed, and demonstrated acceptable internal consistency, test-retest reliability, and construct validity. The CHRT-SR appears to be a reliable and valid tool to assess suicidality in persons with stimulant use disorder.

Rodon, J., A. Perez-Fidalgo, I. E. Krop, H. Burris, A. Guerrero-Zotano, C. D. Britten, C. Becerra, J. Schellens, D. A. Richards, M. Schuler, M. Abu-Khalaf, F. M. Johnson, M. Ranson, J. Edenfield, A. P. Silva, W. Hackl, C. Quadt, D. Demanse, V. Duval and J. Baselga (2018). “Phase 1/1b dose escalation and expansion study of BEZ235, a dual PI3K/mTOR inhibitor, in patients with advanced solid tumors including patients with advanced breast cancer.” Cancer Chemother Pharmacol Jun 7. [Epub ahead of print].

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PURPOSE: To determine the maximum tolerated dose (MTD) of BEZ235, an oral inhibitor of class I PI3K and mTOR complexes 1 and 2. METHODS: We performed a phase I/Ib, multicenter, open-label study of oral BEZ235 administered in a continuous daily schedule. The study consisted of two parts: dose-escalation part and safety-expansion part. BEZ235 was administered as a single agent to patients with solid tumors or in combination with trastuzumab for HER2+ advanced breast cancer (aBC). Primary end points were MTD, safety, and tolerability. The secondary end point was pharmacokinetics. Other formulations of BEZ235, solid dispersion system (SDS) sachet, and SDS capsules were also assessed. RESULTS: One hundred and eighty-three patients were enrolled; single-agent BEZ235 was administered as hard gelatin capsule (n = 59), SDS capsules A and B (n = 33), and SDS sachet (n = 61), amongst which SDS sachet was chosen as the preferred formulation. The monotherapy MTD for capsule A and SDS sachet was determined to be 1000 and 1200 mg/day, respectively. Thirty patients with HER2+ aBC received BEZ235 in combination with trastuzumab. The MTD of BEZ235 in combination with trastuzumab was 600 mg/day. A total of four patients (13.3%) achieved partial response across the different groups. Most frequent AEs in single agent and combination cohorts included nausea (80.3 and 93.3%), diarrhea (75.4 and 80.0%), and vomiting (63.9 and 63.3%). CONCLUSIONS: The MTD of BEZ235 as single agent was 1200 and 600 mg/day with trastuzumab. Pharmacokinetic profiles showed low-to-moderate variability at low dose (10 mg) and high variability at high doses (100 mg and above). Gastrointestinal AEs were frequent at high doses.