Primecuts – This Week in the Journals

March 1, 2017

Primecuts 3.1.17By Bradley Lankowsky, MD

Peer Reviewed

NASA scientists announced the discovery of a solar system of 7 Earth-sized planets surrounding a nearby dwarf star about 40 light years away. [1] Their findings published in Nature report that 3 of the planets are located within the habitable zone, the area around a star where liquid water may exist. However, NASA scientists believe all 7 may contain liquid water. [2] The planetary system, named TRAPPIST-1 after the telescope used to discover it, raises the question of whether life exists outside of our solar system.

In this week’s Primecuts, we explore scientific discoveries on planet Earth, including a new therapy for lung cancer, a new diagnostic tool for coronary artery disease, diets that may reduce liver fat in type 2 diabetics, and the effect of Medicaid expansion on ED visits.

Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer. [3] 

First line treatment for patients with advanced non-small-lung caner with a mutant epidermal growth factor receptor (EGFR) is an EGFR tyrosine kinase inhibitor (TKI). The treatment initially shows a good response, but patients begin to show disease progression at 9 to 13 months. Approximately 60% of patient with disease progression have a point mutation, T790M, in the gene encoding EGFR. This confers resistance to first and second generation EFGR-TKI [4] Osimertinib is an oral, irreversible EGFR-TKI that binds to mutant EGFR of non-small-cell lung cancer and those with the T790M point mutation with activity in the CNS.  [5]

The AURA3 investigator group used a randomized, open label, international phase 3 trial to randomly assign 419 patients to treatment with osimertinib or a platinum-pemetrexed control. Patients with histological or cytological evidence of locally advanced or metastatic non-small cell lung cancer and disease progression after first-line EGFR-TKI therapy who had a T790M EGFR mutation were enrolled. . Progression of disease occurred in 50% of the osimertinib group and in 79% of the platinum-pemetrexed group. Duration of progression free survival was significantly longer in the osimertinib group at median of 10.1 months over the platinum-pemetrexed group at median of 4.4 months (hazard ratio after adjustment for Asian or non-Asian race, 0.30; 95% confidence interval [CI], 0.23 to 0.41; P<0.001). In those with CNS manifestations, progression free survival was also significantly longer in the osimertinib group.(8.5 months vs. 4.2 months; hazard ratio, 0.32; 95% CI, 0.21 to 0.49) Response rate for all individuals was significantly better in the osimertinib group (71% vs. 31% ; OR 5.39; 95% CI, 3.47 to 8.48; P<0.001). This study concludes that osimertinib is more effective than combined platinum based chemotherapy in treatment of T790M non-small cell lung cancer including CNS metastases after progression with first line EGFR-TKI therapy. 

Cardiodynamicsgram as a New Diagnostic Tool in Coronary Artery Disease in Patients With Nondiagnostic Electrocardiograms [6]

Cardiodynamicsgram (CDG) is a novel complimentary diagnostic tool to ECG that extracts cardiac dynamics information from 12-lead ECG and plots the information into 3-dimentional graphics. [7] The twelve dimensions of the ST segment is reduced to 3-dimension vectorcardiography signals. CDG represents the rate of change of the vectorcardiography. In healthy individuals, repolarization of myocardium is homogenous leading to a regular “annular” shape of the CDG graph. Whereas, repolarization in those with coronary artery disease (CAD) is heterogeneous. This results in an irregular shape in CDG. [8]

This study looked to establish whether CDG could be used to diagnose CAD in patients with non-diagnostic ECGs. A total of 412 patients with suspected CAD based on clinical assessment including symptoms, risk factors, physical exam, blood analysis, and stress test underwent, simultaneous 12-lead ECG and CDG prior to diagnostic coronary angiography. The dispersion index (DI), a marker for morphology of the CDG graph, was used to determine the presence or absence of CAD. A DI>0 was considered positive for CAD and DI<0 was considered negative for CAD. [8] After CDG assessment, all patients underwent coronary angiography, where CAD was defined as having a stenosis of 50% or more in at least 1 of the 3 main epicardial coronary arteries. By angiography, a total of 347 patients had CAD and 74 did not have obstructive lesions. CDG correctly identified 294 of 347 patients with CAD (sensitivity of 84.7%). CDG incorrectly identified 11patients without CAD on angiography as positive for CAD by DI.  Patients with a positive CDG with a negative catheterization were all found to have higher coronary artery atherosclerosis rate than those with negative CDG. CDG had a sensitivity of 84.7%, and specificity of 85.1%. The study was limited as a single center study and may lack generalizability.  However, the utilization of CDG shows promise in detecting early CAD without invasive measures.

Isocaloric Diets High in Animal or Plant Protein Reduce Liver Fat and Inflammation in Individuals With Type 2 Diabetes [9]

The incidence of nonalcoholic fatty liver disease is rapidly increasing in industrialized countries. High protein diets are shown to reduce the accumulation intrahepatic lipids (IHLs) induced by fructose [10] and high-fat diets in healthy individuals [11]; however, studies of the metabolic effect of high protein interventions in patients with NAFLD are lacking. This week in Gastroenterology, results from a study of a high protein diet on patients with both NAFLD and type two diabetes were examined. Levels of liver fat, markers of insulin resistance, and markers of hepatic inflammation were collected for 37 participants randomized to receive a diet high in animal protein (AP) or plant protein (PP). The diets were isocaloric and contained the same amount of macronutrients. Intrahepatic fat (IHL) was determined at baseline and at 6 weeks by MRI. There was a significant reduction in IHL in both groups (48% in the AP group and by 35.7% in the PP group), a significant drop in body mass index, and visceral and nonvisceral adipose tissue.  As branched chain amino acids and methionine in high protein diets may induce insulin resistance, insulin sensitivity was measure as a countermeasure to the improvement in IHL. Unexpectedly, researchers found an improvement in insulin sensitivity that correlated with reduction in intrahepatic fat.

This study concludes that high protein diets, regardless of the origin of the protein, reduce intrahepatic fat and may actually increase in insulin sensitivity in patients with NAFLD and type two diabetes. Longer studies with more participants are needed to ascertain the extent of this metabolic response and potential adverse effects of the diets.

Insurance Expansion and Hospital Emergency Department Access: Evidence From the Affordable Care Act (ACA) [12]

The ACA expanded Medicaid to households making less than 138% of the federal poverty level. An estimated 8.8 million uninsured Americans obtained health insurance from 2013-2014; however, some states refused to comply with this regulation. In 2015, 7.5% of 18-64 year olds in Medicaid expansion states were uninsured vs 14.4% in those whose states refused Medicaid expansion.

In this article, differences in ED resource utilization were examined for uninsured and Medicaid insured populations in Medicaid expansion versus Medicaid non-expansion states. Data was collected about patient visits for uninsured and Medicaid insured adults aged 18-64 from 2 large, multi-state, for-profit hospital chains from January 2012 to December 2014. A total of almost 9 million ED visits were examined from 17 expansion and 19 non-expansion states. The type of service provided before and after Medicaid expansion as well as the location of service provision was collected.

In expansion states, there was in increase in ED visits among Medicaid patients from the end of 2013 to end of 2014 of 125.7% (CI, 89.2% to 162.6) and in non-expansion states the increase was 11.4% (CI, -43.6% to 51.3%). The increase in expansion states started immediately in January 2014 when Medicaid expansion occurred. In non-expansion states the increase was more gradual. For all types of visits (emergent vs. non-emergent) to the ED after Medicaid expansion regardless of the states participation in expansion, there was a decrease in uninsured visits and an increase in Medicaid visits. In Medicaid expansion states, emergent visits for the uninsured dropped 41.9% (CI, -53.1% to -30.8%) and Medicaid visits increased 212.9% (CI, 164.9% to 261.6%). The average travel time from the patients’ home to the EDs decreased by 6.2% (CI, -8.9% to -3.5%) among Medicaid patients in expansion states. There was no decrease in travel time in non-expansion states.

In Medicaid expansion states, utilization of emergency services for those with Medicaid insurance increased at a higher rate than the decrease in utilization by uninsured patients in for-profit hospital settings. There were shorter travel times to the facilities among Medicaid patients in Medicaid expansion states, implying that with insurance granted by the ACA, patients were able to choose where they sought care in emergent situations and that they were more likely to choose care closer to their home.  This study does not take into account how public or nonprofit hospitals were affected by Medicaid expansion, therefore it is an incomplete characterization of the far-reaching effects of providing insurance to millions of low-income Americans.

Mini-cuts

Testing the Efficacy of Contrast-Enhanced Ultrasound in Detecting Transplant Rejection Using a Murine Model of Heart Transplantation [13]

Contrast-enhance ultrasound is being used to identify decrease in micro-vascular perfusion in heart transplants in mice models. This noninvasive modality may be the future of detecting graft rejection.

Integrating APOL1 Gene Variants Into Renal Transplantation: Considerations Arising From the American Society of Transplantation Expert Conference [14]

A variant of the APOL1 gene which disproportionately affects individuals of African ancestry is associated with an increased risk of end-stage renal disease and decreased transplant survival.  Transplantation experts discuss whether the APOL1 variant should be integrated into clinical practice. 

Relation of ST-Segment Elevation Myocardial Infarction to Daily Ambient Temperature and Air Pollutant Levels in a Japanese Nationwide Percutaneous Coronary Intervention Registry [15]

Using data from the Japanese Nationwide Percutaneous Coronary Intervention Registry, researchers determined that STEMI occurrence was independently associated with lower average temperature and an increase in maximum temperature from the day before while the association with air pollutants was ill defined after adjusting for these temperature findings.

Dr.  Bradley Lankowsky is a 1st year resident at NYU Langone Medical Center

Peer reviewed by Kerrilynn Carney, MD, 4th year resident at NYU Langone Medical Center

Image courtesy of NASA/JPL-Caltech

References 

[1] NASA,. NASA Telescope Reveals Largest Batch Of Earth-Size, Habitable-Zone Planets Around Single Star. 2017. Web. 24 Feb. 2017. https://www.nasa.gov/press-release/nasa-telescope-reveals-largest-batch-of-earth-size-habitable-zone-planets-around

[2] Gillon, Michaël et al. “Seven Temperate Terrestrial Planets Around The Nearby Ultracool Dwarf Star TRAPPIST-1”. Nature 542.7642 (2017): 456-460. http://www.nature.com.ezproxy.med.nyu.edu/nature/journal/v542/n7642/full/nature21360.html 

[3] Mok, Tony S. et al. “Osimertinib Or Platinum–Pemetrexed In EGFR T790M–Positive Lung Cancer”. New England Journal of Medicine 376.7 (2017): 629-640. http://www.nejm.org.ezproxy.med.nyu.edu/doi/full/10.1056/NEJMoa1612674#t=article

[4] Oxnard, G. R. et al. “Acquired Resistance To EGFR Tyrosine Kinase Inhibitors In EGFR-Mutant Lung Cancer: Distinct Natural History Of Patients With Tumors Harboring The T790M Mutation”. Clinical Cancer Research 17.6 (2010): 1616-1622. https://www-ncbi-nlm-nih-gov.ezproxy.med.nyu.edu/pubmed/21135146?dopt=Abstract

[5] Cross, D. A. E. et al. “AZD9291, An Irreversible EGFR TKI, Overcomes T790M-Mediated Resistance To EGFR Inhibitors In Lung Cancer”. Cancer Discovery 4.9 (2014): 1046-1061. https://www-ncbi-nlm-nih-gov.ezproxy.med.nyu.edu/pubmed/24893891?dopt=Abstract 

[6] Deng, Muqing et al. “Cardiodynamicsgram As A New Diagnostic Tool In Coronary Artery Disease Patients With Nondiagnostic Electrocardiograms”. The American Journal of Cardiology 119.5 (2017): 698-704. http://www.sciencedirect.com.ezproxy.med.nyu.edu/science/article/pii/S0002914916318975

[7] Wang, Cong et al. “A New Method For Early Detection Of Myocardial Ischemia: Cardiodynamicsgram (CDG)”. Science China Information Sciences 59.1 (2015): 1-11. http://www.sciencedirect.com.ezproxy.med.nyu.edu/science/article/pii/S0002914916318975 

[8]Dong X, Wang C, Hu J, Ou S. “Electrocardiogram (ECG) pattern modeling and recognition via deterministic learning”. Control Theor Technol 2014;12:333e344. http://link.springer.com/article/10.1007%2Fs11768-014-4056-4

[9] Markova, Mariya et al. “Isocaloric Diets High In Animal Or Plant Protein Reduce Liver Fat And Inflammation In Individuals With Type 2 Diabetes”. Gastroenterology 152.3 (2017): 571-585.e8. http://www.sciencedirect.com.ezproxy.med.nyu.edu/science/article/pii/S0016508516352295 

[10]Theytaz, F. et al. “Effects Of Supplementation With Essential Amino Acids On Intrahepatic Lipid Concentrations During Fructose Overfeeding In Humans”. American Journal of Clinical Nutrition 96.5 (2012): 1008-1016. http://ajcn.nutrition.org.ezproxy.med.nyu.edu/content/96/5/1008 

[11] Bortolotti, M. et al. “High Protein Intake Reduces Intrahepatocellular Lipid Deposition In Humans”. American Journal of Clinical Nutrition 90.4 (2009): 1002-1010. http://ajcn.nutrition.org.ezproxy.med.nyu.edu/content/90/4/1002 

[12] Garthwaite, Craig et al. “Insurance Expansion And Hospital Emergency Department Access: Evidence From The Affordable Care Act”. Annals of Internal Medicine 166.3 (2016): 172. http://annals.org.ezproxy.med.nyu.edu/aim/article/2593599/insurance-expansion-hospital-emergency-department-access-evidence-from-affordable-care

[13] Fischer, K. et al. “Testing The Efficacy Of Contrast-Enhanced Ultrasound In Detecting Transplant Rejection Using A Murine Model Of Heart Transplantation”. American Journal of Transplantation (2017): n. pag. http://onlinelibrary.wiley.com.ezproxy.med.nyu.edu/doi/10.1111/ajt.14180/full

[14] Newell, K. A. et al. “Integrating APOL1 Gene Variants Into Renal Transplantation: Considerations Arising From The American Society Of Transplantation Expert Conference”. American Journal of Transplantation (2017): n. pag. http://onlinelibrary.wiley.com.ezproxy.med.nyu.edu/doi/10.1111/ajt.14173/full

[15] Yamaji, Kyohei et al. “Relation Of ST-Segment Elevation Myocardial Infarction To Daily Ambient Temperature And Air Pollutant Levels In A Japanese Nationwide Percutaneous Coronary Intervention Registry”. The American Journal of Cardiology 119.6 (2017): 872-880. http://www.sciencedirect.com.ezproxy.med.nyu.edu/science/article/pii/S0002914916319415

 

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