Research Spotlight

Posted September 15th 2017

Proceedings of the Editorial Board Meeting of The American Journal of Cardiology on March 17, 2017.

William C. Roberts M.D.

William C. Roberts M.D.

Roberts, W. C. (2017). “Proceedings of the editorial board meeting of the american journal of cardiology on march 17, 2017.” Am J Cardiol 120(4): 718-719.

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The annual editorial board meeting of The American Journal of Cardiology ( AJC ) was held on March 17, 2017, at the time of the Annual Scientific Sessions of the American College of Cardiology. The major purpose of the meeting was to thank the editorial board members for their considerable help during the previous year in reviewing manuscripts and to seek their suggestions for improving the journal. Several changes occurred during 2016: there was a publisher change from Ms. Joan Anuels to Ms. Heather Luciano, and the Managing Editor in the Dallas office changed from Ms. Lynn Guillen to Ms. Jill Rutherford. In early 2017, the Journal Manager in St. Louis changed from Ms. Ashley Rodenberry to Mr. John Beckemeier. I think these changes will be advantageous for the journal.


Posted September 15th 2017

FOXD3 Regulates CSC Marker, DCLK1-S, and Invasive Potential: Prognostic Implications in Colon Cancer.

Ajay Goel Ph.D.

Ajay Goel Ph.D.

Sarkar, S., M. R. O’Connell, Y. Okugawa, B. S. Lee, Y. Toiyama, M. Kusunoki, R. D. Daboval, A. Goel and P. Singh (2017). “Foxd3 regulates csc marker, dclk1-s, and invasive potential: Prognostic implications in colon cancer.” Mol Cancer Res: 2017 Aug [Epub ahead of print].

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The 5′ (alpha)-promoter of the human doublecortin-like kinase 1 (DCLK1) gene becomes epigenetically silenced during colon carcinogenesis, resulting in loss of expression of the canonical long(L)-isoform1 (DCLK1-L) in human colon adenocarcinomas (hCRCs). Instead, hCRCs express a short(S)-isoform2 (DCLK1-S) from an alternate (beta)-promoter of DCLK1. The current study, examined if the transcriptional activity of the (beta)-promoter is suppressed in normal-vs-cancerous cells. Based on in silico and molecular approaches it was discovered that FOXD3 potently inhibits the transcriptional activity of the (beta)-promoter. FOXD3 becomes methylated in human colon cancer cells (hCCCs), with loss of FOXD3 expression, allowing expression of the DCLK1(S) variant in hCCCs/hCRCs. Relative levels of FOXD3/DCLK1(S/L) were measured in a cohort of CRC patient specimens (n=92), in relation to overall survival (OS). Patients expressing high DCLK1(S), with or without low FOXD3, had significantly worse OS compared to patients expressing low DCLK1(S). The relative levels of DCLK1-L did not correlate with OS. In a pilot retrospective study, colon adenomas from high-risk patients (who developed CRCs in <15 years) demonstrated significantly higher staining for DCLK1(S) + significantly lower staining for FOXD3, compared to adenomas from low-risk patients (who remained free of CRCs). Latter results strongly suggest a prognostic value of measuring DCLK1(S)/FOXD3 in adenomas. Overexpression of DCLK1(S), but not DCLK1(L), caused a significant increase in the invasive potential of hCCCs, which may explain worse outcomes for patients with high DCLK1-S expressing tumors. Based on these data, FOXD3 is a potent repressor of DCLK1-S expression in normal cells; loss of FOXD3 in hCCCs/hCRCs allows up-regulation of DCLK1-S, imparting a potent invasive potential to the cells. IMPLICATIONS: This study indicates that loss of DCLK1(L)/FOXD3 expression, associated with increased expression of DCLK1-S, represents a potential diagnostic/prognostic paradigm for early-stage, epigenetic-changes associated with colon carcinogenesis.


Posted September 15th 2017

Impact of Delayed Chest Closure on Surgical Site Infection After Lung Transplantation.

Patrick R. Aguilar M.D.

Patrick R. Aguilar M.D.

Aguilar, P. R., B. C. Bemiss, C. Witt, D. E. Byers, D. Kreisel, V. Puri, B. Meyers, G. A. Patterson, A. S. Krupnick, R. D. Yusen, E. P. Trulock and R. R. Hachem (2017). “Impact of delayed chest closure on surgical site infection after lung transplantation.” Ann Thorac Surg: 2017 Aug [Epub ahead of print].

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BACKGROUND: Delayed chest closure is an increasingly used approach in the management of bleeding and hemodynamic instability after lung transplantation. We sought to evaluate the impact of delayed chest closure on surgical site infection. METHODS: We performed a single-center retrospective cohort study and included adult patients who received a lung transplant at our center between January 1, 2010, and July 31, 2014. We defined surgical site infection as a thoracotomy incision wound or pleural space infection. Follow-up was complete through 6 months after transplantation. We used logistic regression models to examine the impact of delayed chest closure on surgical site infection and to identify other potential risk factors. RESULTS: During the study period, 67 of the 232 transplant procedures (29%) required delayed chest closure, and surgical site infection developed in 22 recipients (9%). Among the patients with surgical site infection, 18 experienced a wound infection, and 8 experienced a pleural space infection; 4 experienced concomitant wound and pleural space infection. Among the 67 who underwent delayed chest closure, 13 patients (19%) experienced a surgical site infection compared with 9 of the 165 patients (5%) who underwent primary closure (p = 0.001). In multivariate analysis, delayed chest closure was an independent risk factor for surgical site infection. CONCLUSIONS: Although delayed chest closure may have an important role in the immediate management of recipients of a lung transplant, it is an independent risk factor for surgical site infection, and this is associated with increased morbidity.


Posted September 15th 2017

The potential role and rationale for treatment of heart failure with sodium-glucose co-transporter 2 inhibitors.

Peter McCullough M.D.

Peter McCullough M.D.

Butler, J., C. E. Hamo, G. Filippatos, S. J. Pocock, R. A. Bernstein, M. Brueckmann, A. K. Cheung, J. T. George, J. B. Green, J. L. Januzzi, S. Kaul, C. S. P. Lam, G. Y. H. Lip, N. Marx, P. A. McCullough, C. R. Mehta, P. Ponikowski, J. Rosenstock, N. Sattar, A. Salsali, B. M. Scirica, S. J. Shah, H. Tsutsui, S. Verma, C. Wanner, H. J. Woerle, F. Zannad and S. D. Anker (2017). “The potential role and rationale for treatment of heart failure with sodium-glucose co-transporter 2 inhibitors.” Eur J Heart Fail: 2017 Aug [Epub ahead of print].

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Heart failure (HF) and type 2 diabetes mellitus (T2DM) are both growing public health concerns contributing to major medical and economic burdens to society. T2DM increases the risk of HF, frequently occurs concomitantly with HF, and worsens the prognosis of HF. Several anti-hyperglycaemic medications have been associated with a concern for worse HF outcomes. More recently, the results of the EMPA-REG OUTCOME trial showed that the sodium-glucose co-transporter 2 (SGLT2) inhibitor empagliflozin was associated with a pronounced and precocious 32% reduction in cardiovascular mortality in subjects with T2DM and established cardiovascular disease. These benefits were more related to a reduction in incident HF events rather than to ischaemic vascular endpoints. Several mechanisms have been put forward to explain these benefits, which also raise the possibility of using these drugs as therapies not only in the prevention of HF, but also for the treatment of patients with established HF regardless of the presence or absence of diabetes. Several large trials are currently exploring this postulate.


Posted September 15th 2017

Prolonged survival in patients with breast cancer and a history of brain metastases: results of a preplanned subgroup analysis from the randomized phase III BEACON trial.

Joyce O'Shaughnessy M.D.

Joyce O’Shaughnessy M.D.

Cortes, J., H. S. Rugo, A. Awada, C. Twelves, E. A. Perez, S. A. Im, P. Gomez-Pardo, L. S. Schwartzberg, V. Dieras, D. A. Yardley, D. A. Potter, A. Mailliez, A. Moreno-Aspitia, J. S. Ahn, C. Zhao, U. Hoch, M. Tagliaferri, A. L. Hannah and J. O’Shaughnessy (2017). “Prolonged survival in patients with breast cancer and a history of brain metastases: Results of a preplanned subgroup analysis from the randomized phase iii beacon trial.” Breast Cancer Res Treat 165(2): 329-341.

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PURPOSE: Conventional chemotherapy has limited activity in patients with breast cancer and brain metastases (BCBM). Etirinotecan pegol (EP), a novel long-acting topoisomerase-1 inhibitor, was designed using advanced polymer technology to preferentially accumulate in tumor tissue including brain metastases, providing sustained cytotoxic SN38 levels. METHODS: The phase 3 BEACON trial enrolled 852 women with heavily pretreated locally recurrent or metastatic breast cancer between 2011 and 2013. BEACON compared EP with treatment of physician’s choice (TPC; eribulin, vinorelbine, gemcitabine, nab-paclitaxel, paclitaxel, ixabepilone, or docetaxel) in patients previously treated with anthracycline, taxane, and capecitabine, including those with treated, stable brain metastases. The primary endpoint, overall survival (OS), was assessed in a pre-defined subgroup of BCBM patients; an exploratory post hoc analysis adjusting for the diagnosis-specific graded prognostic assessment (GPA) index was also conducted. RESULTS: In the trial, 67 BCBM patients were randomized (EP, n = 36; TPC, n = 31). Treatment subgroups were balanced for baseline characteristics and GPA indices. EP was associated with a significant reduction in the risk of death (HR 0.51; P < 0.01) versus TPC; median OS was 10.0 and 4.8 months, respectively. Improvement in OS was observed in both poorer and better GPA prognostic groups. Survival rates at 12 months were 44.4% for EP versus 19.4% for TPC. Consistent with the overall BEACON population, fewer patients on EP experienced grade >/=3 toxicity (50 vs. 70%). CONCLUSIONS: The significant improvement in survival in BCBM patients provides encouraging data for EP in this difficult-to-treat subgroup of patients. A phase three trial of EP in BCBM patients is underway.