Research Spotlight

Thompson, J., N. Jones, A. Al-Khafaji, S. Malik, D. Reich, S. Munoz, R. MacNicholas, T. Hassanein, L. Teperman, L. Stein, A. Duarte-Rojo, R. Malik, T. Adhami, S. Asrani, N. Shah, P. Gaglio, A. Duddempudi, B. Borg, R. Jalan, R. Brown, H. Patton, R. Satoskar, S. Rossi, A. Parikh, A. ElSharkawy, P. Mantry, L. Sher, D. Wolf, M. Hart, C. Landis, A. Wigg, S. Habib, G. McCaughan, S. Colquhoun, A. Henry, P. Bedard, L. Landeen, M. Millis, R. Ashley, W. Frank, A. Henry, J. Stange and R. Subramanian (2018). “Extracorporeal cellular therapy (ELAD) in severe alcoholic hepatitis: A multinational, prospective, controlled, randomized trial.” Liver Transpl 24(3): 380-393.

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Severe alcoholic hepatitis (sAH) is associated with a poor prognosis. There is no proven effective treatment for sAH, which is why early transplantation has been increasingly discussed. Hepatoblastoma-derived C3A cells express anti-inflammatory proteins and growth factors and were tested in an extracorporeal cellular therapy (ELAD) study to establish their effect on survival for subjects with sAH. Adults with sAH, bilirubin >/=8 mg/dL, Maddrey’s discriminant function >/= 32, and Model for End-Stage Liver Disease (MELD) score less than or equal to 35 were randomized to receive standard of care (SOC) only or 3-5 days of continuous ELAD treatment plus SOC. After a minimum follow-up of 91 days, overall survival (OS) was assessed by using a Kaplan-Meier survival analysis. A total of 203 subjects were enrolled (96 ELAD and 107 SOC) at 40 sites worldwide. Comparison of baseline characteristics showed no significant differences between groups and within subgroups. There was no significant difference in serious adverse events between the 2 groups. In an analysis of the intent-to-treat population, there was no difference in OS (51.0% versus 49.5%). The study failed its primary and secondary end point in a population with sAH and with a MELD ranging from 18 to 35 and no upper age limit. In the prespecified analysis of subjects with MELD < 28 (n = 120), ELAD was associated with a trend toward higher OS at 91 days (68.6% versus 53.6%; P = .08). Regression analysis identified high creatinine and international normalized ratio, but not bilirubin, as the MELD components predicting negative outcomes with ELAD. A new trial investigating a potential benefit of ELAD in younger subjects with sufficient renal function and less severe coagulopathy has been initiated.

Toden, S., P. Ravindranathan, J. Gu, J. Cardenas, M. Yuchang and A. Goel (2018). “Oligomeric proanthocyanidins (OPCs) target cancer stem-like cells and suppress tumor organoid formation in colorectal cancer.” Sci Rep 8(1): 3335.

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Proanthocyanidins are a heterogeneous group of flavan-3-ol or flavan-3,4-diol oligomers present in various fruits and vegetables. In particular, the smaller oligomeric subset of proanthocyanidins, termed the oligomeric proanthocyanidins (OPCs) appear to have potent anti-tumorigenic properties, but the underlying mechanisms for their effectiveness remain unclear. Herein, we utilized a series of in vitro, in vivo and patient-derived organoid approaches to systematically investigate the chemoprotective role of OPCs in colorectal cancer. OPCs exerted anti-tumorigenic effects through inhibition of cellular proliferation, and induced apoptosis and cell cycle arrest. Intriguingly, OPCs suppressed spheroid derived cancer stem-like cell formation and decreased the expression of intestinal cancer stem cell markers including LGR5, CD44 and CD133. Mechanistically, RNA-sequencing results confirmed that OPCs prominently interfered with developmental and self-renewal pathways and identified several self-renewal associated oncogenes targeted by OPCs. Furthermore, OPCs inhibited Hippo pathway through downregulation of its key transcriptional regulators, YAP and TAZ. Finally, we confirmed anti-tumorigenic effects of OPCs using multiple xenograft experiments and recapitulated its protective effects using patient-derived colorectal tumor organoids. Collectively, we have comprehensively assessed anti-tumorigenic properties of OPCs and our data throws light on previously unrecognized chemopreventive mechanisms of OPCs highlighting its therapeutic potential.

Sorokin, I., S. L. Stevens and J. A. Cadeddu (2018). “Periarterial papaverine to treat renal artery vasospasm during robot-assisted laparoscopic partial nephrectomy.” J Robot Surg 12(1): 189-191.

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Renal artery vasospasm can be a troublesome complication during robot-assisted laparoscopic partial nephrectomy. Urologists performing this procedure, especially if utilizing selective arterial vascular microdissection, should be aware of using papaverine for both prevention and treatment of renal artery vasospasm. We present a 33-year-old male who developed severe renal artery vasospasm just with hilar dissection causing the kidney to become ischemic. Papaverine was topically applied on the renal arteries resulting in vasodilation and reperfusion of the kidney. Our objective of this report is to raise awareness of this complication as well as to review the literature on periarterial papaverine use and the dosing for topical applications.

Hamilton, R., S. Kirshblum, S. Sikka, L. Callender, M. Bennett and P. Prajapati (2018). “Sacral examination in spinal cord injury: Is it really needed?” J Spinal Cord Med: Jan 29: 1-6. [Epub ahead of print].

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OBJECTIVE: To determine if a self-report measure of S4-5 motor and sensory function in patients with chronic SCI accurately predicts sacral examination results. DESIGN: Prospective, single-blinded self-report survey compared with sacral exam. SETTING: Outpatient SCI clinic. PARTICIPANTS: 116 patients aged 18+ with chronic SCI > 6 months who have undergone sacral exam. INTERVENTIONS: The survey included demographic/clinical and sacral function information such as light tough (LT), pinprick sensation (PP), deep anal pressure (DAP) and voluntary anal contraction (VAC). Survey results and sacral exam were compared and stratified by the patient’s American Spinal Cord Injury Association Impairment Scale (AIS) category. OUTCOME MEASURES: Sacral self-report survey, AIS examination. RESULTS: Mean age was 41.3 +/- 14.4 years with majority male (69%) and Caucasian (71.6%). Overall, Positive Predictive Value (PPV) ranged between 48% (VAC) to 73% (DAP) and Negative Predictive Value (NPV) between 92% (VAC) to 100% (LT). AIS-A had NPV of 100% across all categories, and AIS-D had PPV of 100% across all categories. CONCLUSION: Patient report of sacral sparing can predict negative sensation in patients with AIS-A and predict positive sensation in persons with AIS-D. Overall, the self-report of sacral sparing of motor and sensory function is not predictive enough to rely on for accurate classification.

Tecson, K. M., D. Brown, J. W. Choi, G. Feghali, G. V. Gonzalez-Stawinski, B. L. Hamman, R. Hebeler, S. R. Lander, B. Lima, S. Potluri, J. M. Schussler, R. C. Stoler, C. Velasco and P. A. McCullough (2018). “Major Adverse Renal and Cardiac Events Following Coronary Angiography and Cardiac Surgery.” Ann Thorac Surg. Feb 2. [Epub ahead of print].

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BACKGROUND: Patients at high risk for developing post-procedural complications may receive iodixanol, an iso-osmolar contrast, during coronary angiography to minimize the risk of renal toxicity. For those who additionally require cardiac surgery, the wait-time between angiography and surgery may be a modifiable factor capable of mitigating poor surgical outcomes; however, there have been inconsistsent reports regarding the optimal wait-time. We sought to determine the effects of wait time between angiogram and cardiac surgery, as well as contrast induced acute injury (CI-AKI) on the development of major adverse renal and cardiac events (MARCE). METHODS: We merged datasets to identify adults who underwent coronary angiography with iodixanol and subsequent cardiac surgery. RESULTS: Of 965 patients, 126 (13.1%) developed CI-AKI; 133 (13.8%) experienced MARCE within 30 days and 253 (26.2%) within 1 year of surgery. After adjusting for CI-AKI, age, and Thakar acute renal failure score, the effect of wait-time lost significance for the full cohort, but remained for the 654 who had coronary artery bypass grafting. Those with coronary artery bypass grafting within 1 day of coronary angiography had an approximate 2-fold increase in risk of MARCE (30-day hazard ratio =2.13, 95% confidence interval 1.16-3.88, p=0.014; 1-year hazard ratio =2.07, 95% confidence interval 1.32, 3.23, p = 0.002) compared to those who waited 5 or more days. CONCLUSIONS: Patients who suffered CI-AKI and had cardiac surgery within 1 day of angiography had increased risk of MARCE.