Research Spotlight

Posted January 19th 2016

Circulating microRNA-203 predicts prognosis and metastasis in human colorectal cancer.

Keun Hur Ph.D.

Keun Hur, Ph.D.

Hur, K., Y. Toiyama, Y. Okugawa, S. Ide, H. Imaoka, C. R. Boland and A. Goel (2015). “Circulating microRNA-203 predicts prognosis and metastasis in human colorectal cancer.” Gut. 2015 Dec 23. pii: gutjnl-2014-308737. doi: 10.1136/gutjnl-2014-308737. [Epub ahead of print].

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BACKGROUND AND AIMS: Distant metastasis is a major cause of deaths in patients with colorectal cancer (CRC), which is partly due to lack of robust metastasis-predictive biomarkers. In spite of the important function of microRNA (miR)-203 in cancer metastasis, its clinical significance in CRC metastasis remains unknown. Here, we evaluated the potential role of serum miR-203 as a non-invasive biomarker for CRC metastasis. METHODS: MiR-203 expression was quantified by quantitative reverse-transcription PCR in 58 pairs of primary CRC (pCRC) and corresponding matched liver metastasis (LM), as well as 186 serum and 154 matched tissue specimens from patients with CRC in cohort 1. Next, we performed validation of miR-203 levels in serum from 144 patients with CRC in an independent cohort (cohort 2). Mouse models of CRC-associated metastases were established to identify the source of circulating miR-203. Expression patterns of miR-203 in tissues were determined by in situ hybridisation. RESULTS: MiR-203 expression was significantly upregulated in LM compared with matched pCRC tissues. Serum miR-203 levels were significantly upregulated in a stage-dependent manner, and high miR-203 expression was associated with poor survival in patients with CRC in both patient cohorts. Increased miR-203 levels in serum indicated high risk for poor prognosis (HR=2.1), as well as metastasis to lymph nodes (OR=2.5), liver (OR=6.2), peritoneum (OR=7.2) and distant organs (OR=4.4). Serum miR-203 levels were significantly higher in animals with liver or systemic metastasis compared with controls. CONCLUSIONS: High levels of serum miR-203 associate with poor survival and metastasis, suggesting it to be a promising non-invasive prognostic and metastasis-predictive biomarker in patients with CRC.


Posted January 19th 2016

Cuddling Nightmare Bacteria: Amikacin Pharmacokinetics / Pharmacodynamics in a Novel Hollow Fiber Mycobacterium abscessus Disease Model.

Shashikant Srivastava M.D.

Shashikant Srivastava, M.D.

Ferro, B. E., S. Srivastava, D. Deshpande, C. M. Sherman, J. G. Pasipanodya, D. van Soolingen, J. W. Mouton, J. van Ingen and T. Gumbo (2015). “Cuddling Nightmare Bacteria: Amikacin Pharmacokinetics / Pharmacodynamics in a Novel Hollow Fiber Mycobacterium abscessus Disease Model.” Antimicrobial Agents and Chemotherapy.

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The treatment of pulmonary Mycobacterium abscessus disease treatment is associated with very high failure rates and ease of acquired drug resistance. Amikacin is the key drug in treatment regimens, but optimal doses are unknown. No good pre-clinical model exists to perform formal pharmacokinetics/pharmacodynamics experiments for this. We developed a hollow fiber system model of M. abscessus disease and studied amikacin exposure-effect and dose-scheduling. We mimicked amikacin human pulmonary pharmacokinetics. Both amikacin microbial kill and acquired drug resistance were linked to the peak to minimum inhibitory concentration (MIC) ratios; the peak/MIC associated with 80% of maximal kill (EC80) was 3.20. However, on day of the most extensive microbial kill, the bacillary burden did not fall below starting inoculum. We performed Monte Carlo simulations of 10,000 patients with pulmonary M. abscessus and examined the probability that patients treated with one of 6 doses from 750 mg to 4,000 mg would achieve or exceed the EC80. We also examined these doses for the ability of achieve a cumulative area under the concentration time curve of 82,232 mg*h/L x days that is associated with ototoxicity. The standard amikacin doses of 750-1,500 mg a day achieved EC80 in </=21%, while 4 grams/day achieved this in 70%, but at the cost of high rates of ototoxicity within a month or two. The susceptibility breakpoint was an MIC of 8-16 mg/L. Thus, amikacin, as currently dosed, has limited efficacy against M. abscessus. Different antibiotics should be urgently tested in our pre-clinical model and new regimens developed.


Posted January 19th 2016

Stomatitis Associated With Use of mTOR Inhibitors: Implications for Patients With Invasive Breast Cancer.

Josephine Divers R.N.

Josephine Divers, R.N.

Divers, J. and J. O’Shaughnessy (2015). “Stomatitis Associated With Use of mTOR Inhibitors: Implications for Patients With Invasive Breast Cancer.” Clinical Journal of Oncology Nursing 19(4): 468-474.

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Background: The mammalian target of rapamycin (mTOR) inhibitor everolimus is approved (in combination with exemestane) for the treatment of postmenopausal women with advanced hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer resistant to endocrine therapy. Stomatitis is among the most frequently reported dose-limiting adverse events associated with everolimus use, often requiring treatment interruption or dose reduction. Objectives: This article aims to educate nurses on the identification and management of stomatitis associated with mTOR inhibitors in hormone receptor-positive advanced breast cancer and to assist nurses with additional management techniques to improve patient outcomes. Methods: An evaluation of the literature highlighting the incidence, identification, and management of stomatitis in cancer was performed with a particular focus on breast cancer. In addition, the experiences of the authors’ cancer center on managing stomatitis are described. Findings: A growing body of clinical evidence shows the benefits of adding steroid-based mouth rinses to the treatment plan. Clinical experience provides additional insight into stomatitis preventive and management strategies for patients with breast cancer receiving treatment with everolimus.


Posted January 19th 2016

Preimplantation valvuloplasty in transcatheter aortic valve replacement: To BAV or not to BAV

Mani Arsalan M.D.

Mani Arsalan, M.D.

Arsalan, M., J. J. Squiers and T. Walther (2015). “Preimplantation valvuloplasty in transcatheter aortic valve replacement: To BAV or not to BAV?” Journal of Thoracic and Cardiovascular Surgery 150(5): 1118-1119.

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Balloon aortic valvuloplasty can be omitted when using balloon-expandable transcatheter aortic valve prostheses. The existing literature confirms both the feasibility and safety of transapical (TA) transcatheter aortic valve replacement (TAVR) without preimplantation BAV. Whether omitting BAV truly reduces cerebrovascular events, however, remains unknown. Thus the question remains: To BAV or not to BAV? On the basis of current clinical experience, omitting BAV is feasible during the implantation of balloon-expandable valves through the retrograde TF approach or the antegrade TA approach. Improved patient screening (with perfect computed tomographically based sizing), large operator experience, and technically well-developed systems, including specific nose cones, together allow safe and routine procedures without preimplantation BAV. In rare cases, secondary BAV can be performed as a bailout if required. Simplification of the TAVR procedure is an obvious advantage of omitting BAV. Further advantages, such as reduced hemodynamic compromise, lower stroke risk, and the potential for better valve sealing (and thus less PVL), will have to be proved by larger studies, ideally prospective, randomized trials.


Posted January 15th 2016

Hypothermic Circulatory Arrest in Cardiac Transplantation.

Brian Lima M.D.

Brian Lima, M.D.

Lima, B., T. Chamogeorgakis, J. C. MacHannaford and G. V. Gonzalez-Stawinski (2015). “Hypothermic Circulatory Arrest in Cardiac Transplantation.” Transplantation Proceedings 47(9): 2719-2721.

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PURPOSE: Infrequently, hypothermic circulatory arrest (HCA) must be used during cardiac transplantation. Such cases may include concomitant aortic arch surgery, explantation of ventricular assist devices with outflow grafts or pseudoaneurysms closely abutting the sternum, and other scenarios for which dense mediastinal adhesions preclude exposure and anatomic dissection by conventional methods of adhesiolysis. Outcomes of heart transplantations performed with HCA have not been previously catalogued in the literature and are presented in the current case series. METHODS: Between November 2012 and December 2014, 193 patients underwent heart transplantation at a single institution. Of these, 7 cases (3.6%) required implementation of HCA. Postoperative outcomes in these patients were analyzed using a prospectively maintained clinical database. RESULTS: The HCA patients included 28% females, with mean age of 46 years, and 71% had nonischemic cardiomyopathies. The majority (N = 5, 71%) had prior ventricular assist device implantation, including 1 patient with a paracorporeal biventricular assist device. One of the remaining 2 patients had three previous surgeries for repair of tetralogy of Fallot, with a completely calcified right ventricular outflow tract and pulmonary arterial system. Mean HCA and cold ischemic times were 25 minutes (range, 9-34 minutes) and 285 minutes (range, 181-425 minutes), respectively. Mean postoperative length of stay was 31 days, and six of seven patients (86%) survived to hospital discharge. One patient expired as an outpatient 2 months following transplant. Rates of postoperative renal failure, respiratory failure, and stroke were 43%, 43%, and 29%, respectively. CONCLUSION: On rare occasions, HCA must be instituted to safely conduct a complex heart transplantation procedure. Based on this small case series, these patients can be salvaged and discharged from the hospital, but may experience prolonged lengths of stay with moderate rates of other end-organ complications.