Research Spotlight

Wang, W., R. Kandimalla, H. Huang, L. Zhu, Y. Li, F. Gao, A. Goel and X. Wang (2018). “Molecular subtyping of colorectal cancer: Recent progress, new challenges and emerging opportunities.” Semin Cancer Biol. May 17. [Epub ahead of print].

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Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. Similar to many other malignancies, CRC is a heterogeneous disease, making it a clinical challenge for optimization of treatment modalities in reducing the morbidity and mortality associated with this disease. A more precise understanding of the biological properties that distinguish patients with colorectal tumors, especially in terms of their clinical features, is a key requirement towards a more robust, targeted-drug design, and implementation of individualized therapies. In the recent decades, extensive studies have reported distinct CRC subtypes, with a mutation-centered view of tumor heterogeneity. However, more recently, the paradigm has shifted towards transcriptome-based classifications, represented by six independent CRC taxonomies. In 2015, the colorectal cancer subtyping consortium reported the identification of four consensus molecular subtypes (CMSs), providing thus far the most robust classification system for CRC. In this review, we summarize the historical timeline of CRC classification approaches; discuss their salient features and potential limitations that may require further refinement in near future. In other words, in spite of the recent encouraging progress, several major challenges prevent translation of molecular knowledge gleaned from CMSs into the clinic. Herein, we summarize some of these potential challenges and discuss exciting new opportunities currently emerging in related fields. We believe, close collaborations between basic researchers, bioinformaticians and clinicians are imperative for addressing these challenges, and eventually paving the path for CRC subtyping into routine clinical practice as we usher into the era of personalized medicine.

Tumlin, J. A., R. Murugan, A. M. Deane, M. Ostermann, L. W. Busse, K. R. Ham, K. Kashani, H. M. Szerlip, J. R. Prowle, A. Bihorac, K. W. Finkel, A. Zarbock, L. G. Forni, S. J. Lynch, J. Jensen, S. Kroll, L. S. Chawla, G. F. Tidmarsh and R. Bellomo (2018). “Outcomes in Patients with Vasodilatory Shock and Renal Replacement Therapy Treated with Intravenous Angiotensin II.” Crit Care Med 46(6): 949-957.

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OBJECTIVE: Acute kidney injury requiring renal replacement therapy in severe vasodilatory shock is associated with an unfavorable prognosis. Angiotensin II treatment may help these patients by potentially restoring renal function without decreasing intrarenal oxygenation. We analyzed the impact of angiotensin II on the outcomes of acute kidney injury requiring renal replacement therapy. DESIGN: Post hoc analysis of the Angiotensin II for the Treatment of High-Output Shock 3 trial. SETTING: ICUs. PATIENTS: Patients with acute kidney injury treated with renal replacement therapy at initiation of angiotensin II or placebo (n = 45 and n = 60, respectively). INTERVENTIONS: IV angiotensin II or placebo. MEASUREMENTS AND MAIN RESULTS: Primary end point: survival through day 28; secondary outcomes included renal recovery through day 7 and increase in mean arterial pressure from baseline of >/= 10 mm Hg or increase to >/= 75 mm Hg at hour 3. Survival rates through day 28 were 53% (95% CI, 38%-67%) and 30% (95% CI, 19%-41%) in patients treated with angiotensin II and placebo (p = 0.012), respectively. By day 7, 38% (95% CI, 25%-54%) of angiotensin II patients discontinued RRT versus 15% (95% CI, 8%-27%) placebo (p = 0.007). Mean arterial pressure response was achieved in 53% (95% CI, 38%-68%) and 22% (95% CI, 12%-34%) of patients treated with angiotensin II and placebo (p = 0.001), respectively. CONCLUSIONS: In patients with acute kidney injury requiring renal replacement therapy at study drug initiation, 28-day survival and mean arterial pressure response were higher, and rate of renal replacement therapy liberation was greater in the angiotensin II group versus the placebo group. These findings suggest that patients with vasodilatory shock and acute kidney injury requiring renal replacement therapy may preferentially benefit from angiotensin II.

Titan, A., L. Graham, A. Rosen, K. Itani, L. A. Copeland, H. J. Mull, E. Burns, J. Richman, S. Kertesz, T. Wahl, M. Morris, J. Whittle, G. Telford, M. Wilson and M. Hawn (2018). “Homeless Status, Postdischarge Health Care Utilization, and Readmission After Surgery.” Med Care 56(6): 460-469.

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INTRODUCTION: Homeless Veterans are vulnerable to poor care transitions, yet little research has examined their risk of readmission following inpatient surgery. This study investigates the predictors of surgical readmission among homeless relative to housed Veteran patients. METHODS: Inpatient general, vascular, and orthopedic surgeries occurring in the Veterans Health Administration from 2008 to 2014 were identified. Administrative International Classification of Diseases, Ninth Revision, Clinical Modification codes and Veterans Health Administration clinic stops were used to identify homeless patients. Bivariate analyses examined characteristics and predictors of readmission among homeless patients. Multivariate logistic models were used to estimate the association between homeless experience and housed patients with readmission following surgery. RESULTS: Our study included 232,373 surgeries: 43% orthopedic, 39% general, and 18% vascular with 5068 performed on homeless patients. Homeless individuals were younger (56 vs. 64 y, P<0.01), more likely to have a psychiatric comorbidities (51.3% vs. 19.4%, P<0.01) and less likely to have other medical comorbidities such as hypertension (57.1% vs. 70.8%, P<0.01). Homeless individuals were more likely to be readmitted [odds ratio (OR), 1.43; confidence interval (CI), 1.30-1.56; P<0.001]. Discharge destination other than community (OR, 0.57; CI, 0.44-0.74; P<0.001), recent alcohol abuse (OR, 1.45; CI, 1.15-1.84; P<0.01), and elevated American Society Anesthesiologists classification (OR, 1.86; CI, 1.30-2.68; P<0.01) were significant risk factors associated with readmissions within the homeless cohort. CONCLUSIONS: Readmissions are higher in homeless individuals discharged to the community after surgery. Judicious use of postoperative nursing or residential rehabilitation programs may be effective in reducing readmission and improving care transitions among these vulnerable Veterans. Relative costs and benefits of alternatives to community discharge merit investigation.

Tecson, K. M., B. Lima, A. Y. Lee, F. S. Raza, G. Ching, C. H. Lee, J. Felius, R. D. Baxter, S. Still, J. D. G. Collier, S. A. Hall and S. M. Joseph (2018). “Determinants and Outcomes of Vasoplegia Following Left Ventricular Assist Device Implantation.” J Am Heart Assoc 7(11).

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BACKGROUND: Vasoplegia is associated with adverse outcomes following cardiac surgery; however, its impact following left ventricular assist device implantation is largely unexplored. METHODS AND RESULTS: In 252 consecutive patients receiving a left ventricular assist device, vasoplegia was defined as the occurrence of normal cardiac function and index but with the need for intravenous vasopressors within 48 hours following surgery for >24 hours to maintain a mean arterial pressure >70 mm Hg. We further categorized vasoplegia as none; mild, requiring 1 vasopressor (vasopressin, norepinephrine, or high-dose epinephrine [>5 mug/min]); or moderate to severe, requiring >/=2 vasopressors. Predictors of vasoplegia severity were determined using a cumulative logit (ordinal logistic regression) model, and 1-year mortality was evaluated using competing-risks survival analysis. In total, 67 (26.6%) patients developed mild vasoplegia and 57 (22.6%) developed moderate to severe vasoplegia. The multivariable model for vasoplegia severity utilized preoperative Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile, central venous pressure, systolic blood pressure, and intraoperative cardiopulmonary bypass time, which yielded an area under the curve of 0.76. Although no significant differences were noted in stroke or pump thrombosis rates (P=0.87 and P=0.66, respectively), respiratory failure and major bleeding increased with vasoplegia severity (P<0.01). Those with moderate to severe vasoplegia had a significantly higher risk of mortality than those without vasoplegia (adjusted hazard ratio: 2.12; 95% confidence interval, 1.08-4.18; P=0.03). CONCLUSIONS: Vasoplegia is predictive of unfavorable outcomes, including mortality. Risk factors for future research include preoperative INTERMACS profile, central venous pressure, systolic blood pressure, and intraoperative cardiopulmonary bypass time.

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 After Coronary Angiography and Cardiac Surgery.” Ann Thorac Surg 105(6): 1724-1730.

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BACKGROUND: Patients at high risk for having postprocedural complications may receive iodixanol, an iso-osmolar contrast, during coronary angiography to minimize the risk of renal toxicity. For those who also 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 inconsistent reports regarding the optimal wait time. We sought to determine the effects of wait time between angiography and cardiac surgery, as well as contrast-induced acute kidney injury 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%) had contrast-induced acute kidney injury; 133 (13.8%) had MARCE within 30 days and 253 (26.2%) within 1 year of surgery. After adjusting for contrast-induced acute kidney injury, age, and Thakar acute renal failure score, the effect of wait time lost significance for the full cohort, but remained for the subgroup of 654 who had coronary artery bypass graft surgery. Patients undergoing coronary artery bypass graft surgery within 1 day of coronary angiography had an approximate twofold increase in risk of MARCE (30-day hazard ratio 2.13, 95% confidence interval: 1.16 to 3.88, p = 0.014; 1-year hazard ratio 2.07, 95% confidence interval: 1.32 to 3.23, p = 0.002) compared with patients who waited 5 or more days. CONCLUSIONS: Patients who had contrast-induced acute kidney injury and had cardiac surgery within 1 day of angiography had an increased risk of MARCE.