Research Spotlight

Adelmann, D., K. Kronish and M. A. Ramsay (2017). “Anesthesia for liver transplantation.” Anesthesiol Clin 35(3): 491-508.

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The provision of anesthesia for a liver transplant program requires a dedicated team of anesthesiologists. Liver transplant anesthesiologists must have an understanding of liver physiology and anatomy; the spectrum of clinical disease associated with liver dysfunction; the impact of warm and cold ischemia times, surgical techniques in liver transplantation, and the impact of ischemia-reperfusion syndrome; and optimal practices to protect the liver. The team must provide a 24-hour service, be actively involved in the selection committee process, and stay current with advances in the subspecialty.

Agopian, V. G., M. P. Harlander-Locke, R. M. Ruiz, G. B. Klintmalm, S. Senguttuvan, S. S. Florman, B. Haydel, M. Hoteit, M. H. Levine, D. D. Lee, C. B. Taner, E. C. Verna, K. J. Halazun, R. Abdelmessih, A. D. Tevar, A. Humar, F. Aucejo, W. C. Chapman, N. Vachharajani, M. H. Nguyen, M. L. Melcher, T. L. Nydam, C. Mobley, R. M. Ghobrial, B. Amundsen, J. F. Markmann, A. N. Langnas, C. A. Carney, J. Berumen, A. W. Hemming, D. L. Sudan, J. C. Hong, J. Kim, M. A. Zimmerman, A. Rana, M. L. Kueht, C. M. Jones, T. M. Fishbein and R. W. Busuttil (2017). “Impact of pretransplant bridging locoregional therapy for patients with hepatocellular carcinoma within milan criteria undergoing liver transplantation: Analysis of 3601 patients from the us multicenter hcc transplant consortium.” Ann Surg 266(3): 525-535.

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OBJECTIVE: To evaluate the effect of pretransplant bridging locoregional therapy (LRT) on hepatocellular carcinoma (HCC) recurrence and survival after liver transplantation (LT) in patients meeting Milan criteria (MC). SUMMARY BACKGROUND DATA: Pre-LT LRT mitigates tumor progression and waitlist dropout in HCC patients within MC, but data on its impact on post-LT recurrence and survival remain limited. METHODS: Recurrence-free survival and post-LT recurrence were compared among 3601 MC patients with and without bridging LRT utilizing competing risk Cox regression in consecutive patients from 20 US centers (2002-2013). RESULTS: Compared with 747 LT recipients not receiving LRT, 2854 receiving LRT had similar 1, 3, and 5-year recurrence-free survival (89%, 77%, 68% vs 85%, 75%, 68%; P = 0.490) and 5-year post-LT recurrence (11.2% vs 10.1%; P = 0.474). Increasing LRT number [3 LRTs: hazard ratio (HR) 2.1, P < 0.001; 4+ LRTs: HR 2.5, P < 0.001), and unfavorable waitlist alphafetoprotein trend significantly predicted post-LT recurrence, whereas LRT modality did not. Treated patients achieving complete pathologic response (cPR) had superior 5-year RFS (72%) and lower post-LT recurrence (HR 0.52, P < 0.001) compared with both untreated patients (69%; P = 0.010; HR 1.0) and treated patients not achieving cPR (67%; P = 0.010; HR 1.31, P = 0.039), who demonstrated increased recurrence compared with untreated patients in multivariate analysis controlling for pretransplant and pathologic factors (HR 1.32, P = 0.044). CONCLUSIONS: Bridging LRT in HCC patients within MC does not improve post-LT survival or HCC recurrence in the majority of patients who fail to achieve cPR. The need for increasing LRT treatments and lack of alphafetoprotein response to LRT independently predict post-LT recurrence, serving as a surrogate for underlying tumor biology which can be utilized for prioritization of HCC LT candidates.

Blum, J. L., P. J. Flynn, G. Yothers, L. Asmar, C. E. Geyer, Jr., S. A. Jacobs, N. J. Robert, J. O. Hopkins, J. A. O’Shaughnessy, C. T. Dang, H. L. Gomez, L. Fehrenbacher, S. J. Vukelja, A. P. Lyss, D. Paul, A. M. Brufsky, J. H. Jeong, L. H. Colangelo, S. M. Swain, E. P. Mamounas, S. E. Jones and N. Wolmark (2017). “Anthracyclines in early breast cancer: The abc trials-usor 06-090, nsabp b-46-i/usor 07132, and nsabp b-49 (nrg oncology).” J Clin Oncol 35(23): 2647-2655.

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Purpose Docetaxel and cyclophosphamide (TC) was superior to doxorubicin and cyclophosphamide (AC) in a trial in early breast cancer. However, activity of TC relative to AC regimens with a taxane (TaxAC) is unknown. Methods In a series of three adjuvant trials, women were randomly assigned to TC for six cycles (TC6) or to a standard TaxAC regimen. US Oncology Research (USOR) 06-090 compared TC6 with docetaxel, doxorubicin, and cyclophosphamide (TAC6). National Surgical Adjuvant Breast and Bowel Project (NSABP) B-46-I/USOR 07132 compared TC6, TAC6, or TC6 plus bevacizumab. NSABP B-49 compared TC6 with several standard AC and taxane combination regimens. Before any analysis of individual trials, a joint efficacy analysis of TC versus the TaxAC regimens was planned, with invasive disease-free survival (IDFS) as the primary end point. Patients who received TC6 plus bevacizumab on NSABP B-46-I/USOR 07132 were not included. A hazard ratio (HR) from a stratified Cox model that exceeded 1.18 for TC6 versus TaxAC was predefined as inferiority for TC6. The prespecified interim monitoring plan was to report for futility if the HR was > 1.18 when 334 IDFS events were observed (50% of 668 events required for definitive analysis). Results A total of 2,125 patients were randomly assigned to receive TC6 regimens and 2,117 patients were randomly assigned to receive TaxAC regimens. The median follow-up time was 3.3 years. There were 334 IDFS events, and the HR for TC6 versus TaxAC was 1.202 (95% CI, 0.97 to 1.49), which triggered early reporting for futility. The 4-year IDFS was 88.2% for TC6 and was 90.7% for TaxAC ( P = .04). Tests for treatment interaction by protocol, hormone receptor status, and nodal status were negative. Conclusion The TaxAC regimens improved IDFS in patients with high-risk human epidermal growth factor receptor 2-negative breast cancer compared with the TC6 regimen.

Krop, I., N. Ismaila, F. Andre, R. C. Bast, W. Barlow, D. E. Collyar, M. E. Hammond, N. M. Kuderer, M. C. Liu, R. G. Mennel, C. Van Poznak, A. C. Wolff and V. Stearns (2017). “Use of biomarkers to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer: American society of clinical oncology clinical practice guideline focused update.” J Clin Oncol 35(24): 2838-2847.

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Purpose This focused update addresses the use of MammaPrint (Agendia, Irvine, CA) to guide decisions on the use of adjuvant systemic therapy. Methods ASCO uses a signals approach to facilitate guideline updates. For this focused update, the publication of the phase III randomized MINDACT (Microarray in Node-Negative and 1 to 3 Positive Lymph Node Disease May Avoid Chemotherapy) study to evaluate the MammaPrint assay in 6,693 women with early-stage breast cancer provided a signal. An expert panel reviewed the results of the MINDACT study along with other published literature on the MammaPrint assay to assess for evidence of clinical utility. Recommendations If a patient has hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative, node-negative breast cancer, the MammaPrint assay may be used in those with high clinical risk to inform decisions on withholding adjuvant systemic chemotherapy due to its ability to identify a good-prognosis population with potentially limited chemotherapy benefit. Women in the low clinical risk category did not benefit from chemotherapy regardless of genomic MammaPrint risk group. Therefore, the MammaPrint assay does not have clinical utility in such patients. If a patient has hormone receptor-positive, HER2-negative, node-positive breast cancer, the MammaPrint assay may be used in patients with one to three positive nodes and a high clinical risk to inform decisions on withholding adjuvant systemic chemotherapy. However, such patients should be informed that a benefit from chemotherapy cannot be excluded, particularly in patients with greater than one involved lymph node. The clinician should not use the MammaPrint assay to guide decisions on adjuvant systemic therapy in patients with hormone receptor-positive, HER2-negative, node-positive breast cancer at low clinical risk, nor any patient with HER2-positive or triple-negative breast cancer, because of the lack of definitive data in these populations.

Mack, M. J. and R. Stoler (2017). “Intervention for aortic stenosis: The measurement of frailty matters.” J Am Coll Cardiol 70(6): 701-703.

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Frailty is a relatively common condition in patients with cardiovascular disease. This condition, which includes impairment of multiple physiological systems, occurs more frequently with advancing age and is particularly relevant when these patients undergo cardiovascular interventions or surgery. As a general rule of thumb, the more invasive the procedure and the older the patient, the more that frailty matters in terms of influencing procedure outcomes, recovery, and benefit. There are multiple risk models that have accuracy in predicting early, 30-day outcomes after surgical aortic valve replacement (SAVR) and transcatheter aortic valve replacement (TAVR) (1 2) . Although a wide spectrum of patient factors and comorbid disease conditions are used as covariates in constructing these predictive algorithms, measures of frailty have not been routinely included. The reasons for lack of inclusion include the wide variety of tools available to measure frailty, a lack of a consensus on which tools to use, and the burden and time required to perform the tests, leading to variability and incompleteness of collection. In addition, routine use has been hampered by the lack of a solid evidence base for the measurement of frailty really having value in determining the ability of a patient to undergo a procedure successfully and withstand the associated systemic and physiological insults that may preclude full recovery. However, with the advent of less-invasive procedures, which offer treatment options to patients previously not considered candidates, measurement of frailty in the elderly population has assumed greater import. The 2014 American Heart Association/American College of Cardiology Guideline for the Management of Patients with Valvular Heart Disease (3) included frailty, major organ system dysfunction, and procedure-specific impediments as adjunctive to the Society of Thoracic Surgeons Predicted Risk of Mortality (STS PROM) in risk assessment in patients under consideration for treatment (4) . The tools most commonly used in current clinical evaluation of patients with aortic stenosis are the measurement of gait speed using the 5-m walk test and the Fried Criteria, which measure 4 domains of frailty, including mobility, strength, nutritional status, and habitual activity.