Research Spotlight

Eustace, A. J., N. T. Conlon, M. S. J. McDermott, B. C. Browne, P. O’Leary, F. A. Holmes, V. Espina, L. A. Liotta, J. O’Shaughnessy, C. Gallagher, L. O’Driscoll, S. Rani, S. F. Madden, N. A. O’Brien, C. Ginther, D. Slamon, N. Walsh, W. M. Gallagher, R. Zagozdzon, W. R. Watson, N. O’Donovan and J. Crown (2018). “Development of acquired resistance to lapatinib may sensitise HER2-positive breast cancer cells to apoptosis induction by obatoclax and TRAIL.” BMC Cancer 18(1): 965.

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BACKGROUND: Lapatinib has clinical efficacy in the treatment of trastuzumab-refractory HER2-positive breast cancer. However, a significant proportion of patients develop progressive disease due to acquired resistance to the drug. Induction of apoptotic cell death is a key mechanism of action of lapatinib in HER2-positive breast cancer cells. METHODS: We examined alterations in regulation of the intrinsic and extrinsic apoptosis pathways in cell line models of acquired lapatinib resistance both in vitro and in patient samples from the NCT01485926 clinical trial, and investigated potential strategies to exploit alterations in apoptosis signalling to overcome lapatinib resistance in HER2-positive breast cancer. RESULTS: In this study, we examined two cell lines models of acquired lapatinib resistance (SKBR3-L and HCC1954-L) and showed that lapatinib does not induce apoptosis in these cells. We identified alterations in members of the BCL-2 family of proteins, in particular MCL-1 and BAX, which may play a role in resistance to lapatinib. We tested the therapeutic inhibitor obatoclax, which targets MCL-1. Both SKBR3-L and HCC1954-L cells showed greater sensitivity to obatoclax-induced apoptosis than parental cells. Interestingly, we also found that the development of acquired resistance to lapatinib resulted in acquired sensitivity to TRAIL in SKBR3-L cells. Sensitivity to TRAIL in the SKBR3-L cells was associated with reduced phosphorylation of AKT, increased expression of FOXO3a and decreased expression of c-FLIP. In SKBR3-L cells, TRAIL treatment caused activation of caspase 8, caspase 9 and caspase 3/7. In a second resistant model, HCC1954-L cells, p-AKT levels were not decreased and these cells did not show enhanced sensitivity to TRAIL. Furthermore, combining obatoclax with TRAIL improved response in SKBR3-L cells but not in HCC1954-L cells. CONCLUSIONS: Our findings highlight the possibility of targeting altered apoptotic signalling to overcome acquired lapatinib resistance, and identify potential novel treatment strategies, with potential biomarkers, for HER2-positive breast cancer that is resistant to HER2 targeted therapies.

Lee, A. Y., K. M. Tecson, B. Lima, A. F. Shaikh, J. Collier, S. Still, R. Baxter, J. M. DiMaio, J. Felius, S. A. Carey, G. V. Gonzalez-Stawinski, R. Nauret, M. Wong, S. A. Hall and S. M. Joseph (2018). “Durable Left Ventricular Assist Device Implantation in Extremely Obese Heart Failure Patients.” Artif Organs Oct 25. [Epub ahead of print].

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BACKGROUND: Left ventricular assist devices (LVADs) have improved clinical outcomes and quality of life for those with end-stage heart failure. However, the costs and risks associated with these devices necessitate appropriate patient selection. LVAD candidates are becoming increasingly more obese and there are conflicting reports regarding obesity’s effect on outcomes. Hence, we sought to evaluate the impact of extreme obesity on clinical outcomes after LVAD placement. METHODS: Consecutive LVAD implantation patients at our center from June 2008- May 2016 were studied retrospectively. We compared patients with a body mass index (BMI) >/=40 kg/m(2) (extremely obese) to those with BMI <40 kg/m(2) with respect to patient characteristics and surgical outcomes, including survival. RESULTS: 252 patients were included in this analysis, 30 (11.9%) of whom met the definition of extreme obesity. We found that patients with extreme obesity were significantly younger (47[33, 57] v. 60[52, 67] years, p<0.001) with fewer prior sternotomies (16.7% v. 36.0%, p=0.04). They had higher rates of pump thrombosis (30% vs 9.0%, p=0.003) and stage 2/3 acute kidney injury (46.7% vs 27.0%, p=0.003), but there were no differences in 30-day or 1-year survival, even after adjusting for age and clinical factors. CONCLUSION: Extreme obesity does not appear to place LVAD implantation patients at a higher risk for mortality compared to those who are not extremely obese; however, extreme obesity was associated with an increased risk of pump thrombosis, suggesting that these patients may require additional care to reduce the need for urgent device exchange. This article is protected by copyright. All rights reserved.

Durko, A. P., M. J. Reardon, N. S. Kleiman, J. J. Popma, N. M. Van Mieghem, T. G. Gleason, T. Bajwa, D. O’Hair, D. L. Brown, W. H. Ryan, Y. Chang, S. D. De Leon and A. P. Kappetein (2018). “Neurological Complications After Transcatheter Versus Surgical Aortic Valve Replacement in Intermediate-Risk Patients.” J Am Coll Cardiol 72(18): 2109-2119.

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BACKGROUND: Neurological events after aortic valve interventions are associated with increased mortality and morbidity. Transcatheter aortic valve replacement (TAVR) is increasingly offered for lower-risk patients with severe aortic stenosis, previously considered candidates for surgical aortic valve replacement (SAVR). Differences in post-procedural neurological events have important implications in treatment allocation. OBJECTIVES: The authors sought to analyze the neurological events in the randomized SURTAVI (Surgical Replacement and Transcatheter Aortic Valve Implantation) trial. METHODS: Patients with severe, symptomatic aortic stenosis at intermediate surgical risk were randomized 1:1 to TAVR or SAVR. The rates of neurological events and quality of life were analyzed at 30 days, and 6 and 12 months post-procedure in a modified intention-to-treat population (mean age 79.8 +/- 6.2 years; N = 1,660). RESULTS: The rates of early (30-day) stroke and post-procedural encephalopathy were higher after SAVR versus TAVR (5.4% vs. 3.3%; p = 0.031; and 7.8% vs. 1.6%; p < 0.001, respectively). At 12 months, the rate of stroke was not different between SAVR and TAVR (6.9% vs. 5.2%; p = 0.136). Early stroke and early encephalopathy resulted in an elevated mortality at 12 months in both treatment groups. Quality of life after an early stroke was significantly lower in SAVR versus TAVR patients at 30 days and was similar at 6 and 12 months. CONCLUSIONS: The early stroke rate was lower after TAVR than SAVR. In patients with early strokes, QOL improved earlier after TAVR. At 12-month follow-up, stroke rates and QOL were not different between TAVR and SAVR patients. (Surgical Replacement and Transcatheter Aortic Valve Implantation [SURTAVI]; NCT01586910).

Driver, S., M. Reynolds, A. Woolsey, L. Callender, P. K. Prajapati, M. Bennett and K. Kramer (2018). “Impact of a Community-Based Healthy Lifestyle Program on Individuals With Traumatic Brain Injury.” J Head Trauma Rehabil 33(6): E49-e58.

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OBJECTIVES: To examine adherence with and effect of an evidence-based healthy lifestyle intervention modified for individuals with traumatic brain injury (TBI). DESIGN: Pre-/postintervention without control. SETTING: Community. PARTICIPANTS: Eighteen individuals with TBI: primarily male (61%), white (67%), with private insurance (50%). Mean age was 45.6 +/- 12.3 years, weight 210 +/- 42.6 lb, and body mass index 31.8 +/- 4.6 (obese category) at baseline. INTERVENTIONS: The primary goal of the Diabetes Prevention Program Group Lifestyle Balance program is 5% to 7% weight loss through increased physical activity and improved dietary behaviors. MAIN OUTCOME MEASURE(S): Adherence (ie, session attendance and self-monitoring of dietary behaviors), physiologic changes (ie, weight loss, blood pressure; waist and arm circumference; and lipid profile), and quality of life (ie, self-reported health, quality of life, and step count). RESULTS: Average participant attendance (85% over 12 months) and self-monitoring (90% over 6 months) were high. Significant decreases were observed in diastolic blood pressure and waist and arm circumference from baseline through 12 months and from baseline to 3 months only for weight and total cholesterol. No significant changes were observed in self-reported health, quality of life, or step count. CONCLUSIONS: Participants demonstrated high adherence with the program, suggesting that individuals with TBI are able to successfully engage in the program and achieve significant weight loss and changes in key physiologic outcomes.

Culp, B. L., J. W. Roden-Foreman, E. V. Thomas, E. E. McShan, M. M. Bennett, K. R. Martin, M. B. Powers, M. L. Foreman, L. B. Petrey and A. M. Warren (2018). “Better with age? A comparison of geriatric and non-geriatric trauma patients’ psychological outcomes 6 months post-injury.” Cogn Behav Ther Nov 5: 1-13. [Epub ahead of print].

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This is the first study to compare both physical and psychological outcomes in geriatric and non-geriatric patients (n = 268) at baseline and 6 months post-trauma. Demographic, clinical, and psychological data, including screens for alcohol use, depressive symptoms, and post-traumatic stress symptoms (PTSS) were collected from 67 geriatric patients (70.7 +/- 8.0 years) and 201 non-geriatric patients (40.2 +/- 12.8 years) admitted to a Level I trauma center for >/= 24 h. Geriatric patients were significantly less likely to screen positive for alcohol use at baseline, and depression, PTSS, and alcohol use at follow-up. When not controlling for discharge to rehabilitation or nursing facility, geriatric patients had significantly lower odds of alcohol use at follow-up. There was no significant difference in injury severity, resilience, or pre-trauma psychological status between the two groups. Results indicate that geriatric trauma patients fare better than their younger counterparts at 6 months post-trauma on measures of alcohol use, depression, and PTSS. Screenings and interventions for both age groups could improve psychological health post-trauma, but younger patients may require additional attention.