Research Spotlight

Zeidner, J. F., M. C. Foster, A. L. Blackford, M. R. Litzow, L. E. Morris, S. A. Strickland, J. E. Lancet, P. Bose, M. Y. Levy, R. Tibes, I. Gojo, C. D. Gocke, G. L. Rosner, R. F. Little, J. J. Wright, L. A. Doyle, B. D. Smith and J. E. Karp (2015). “Randomized multicenter phase II study of flavopiridol (alvocidib), cytarabine, and mitoxantrone (FLAM) versus cytarabine/daunorubicin (7+3) in newly diagnosed acute myeloid leukemia.” Haematologica 100(9): 1172-1179.

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Serial studies have demonstrated that induction therapy with FLAM [flavopiridol 50 mg/m(2) days 1-3, cytarabine 667 mg/m(2)/day continuous infusion days 6-8, and mitoxantrone 40 mg/m(2) day 9] yields complete remission rates of nearly 70% in newly diagnosed poor-risk acute myeloid leukemia. Between May 2011-July 2013, 165 newly diagnosed acute myeloid leukemia patients (18-70 years) with intermediate/adverse-risk cytogenetics were randomized 2:1 to receive FLAM or 7+3 (cytarabine 100 mg/m(2)/day continuous infusion days 1-7 and daunorubicin 90 mg/m(2) days 1-3), across 10 institutions. Some patients on 7+3 with residual leukemia on day 14 received 5+2 (cytarabine 100 mg/m(2)/day continuous infusion days 1-5 and daunorubicin 45 mg/m(2) days 1-2), whereas patients on FLAM were not retreated based on day 14 bone marrow findings. The primary objective was to compare complete remission rates between 1 cycle of FLAM and 1 cycle of 7+3. Secondary endpoints included safety, overall survival and event-free survival. FLAM led to higher complete remission rates than 7+3 alone (70% vs. 46%, p=0.003) without an increase in toxicity, and this improvement persisted after 7+3+/-5+2 (70% vs. 57%, p=0.08). There were no significant differences in overall survival and event-free survival in both arms but post-induction strategies were not standardized. These results substantiate the efficacy of FLAM induction in newly diagnosed AML. A phase 3 study is currently in development.

Thijs, V. N., J. Brachmann, C. A. Morillo, R. S. Passman, T. Sanna, R. A. Bernstein, H. C. Diener, V. Di Lazzaro, M. M. Rymer, L. Hogge, T. B. Rogers, P. D. Ziegler and M. D. Assar (2015). “Predictors for atrial fibrillation detection after cryptogenic stroke: Results from CRYSTAL AF.” Neurology.

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OBJECTIVE: We assessed predictors of atrial fibrillation (AF) in cryptogenic stroke (CS) or transient ischemic attack (TIA) patients who received an insertable cardiac monitor (ICM). METHODS: We studied patients with CS/TIA who were randomized to ICM within the CRYSTAL AF study. We assessed whether age, sex, race, body mass index, type and severity of index ischemic event, CHADS2 score, PR interval, and presence of diabetes, hypertension, congestive heart failure, or patent foramen ovale and premature atrial contractions predicted AF development within the initial 12 and 36 months of follow-up using Cox proportional hazards models. RESULTS: Among 221 patients randomized to ICM (age 61.6 +/- 11.4 years, 64% male), AF episodes were detected in 29 patients within 12 months and 42 patients at 36 months. Significant univariate predictors of AF at 12 months included age (hazard ratio [HR] per decade 2.0 [95% confidence interval 1.4-2.8], p = 0.002), CHADS2 score (HR 1.9 per one point [1.3-2.8], p = 0.008), PR interval (HR 1.3 per 10 milliseconds [1.2-1.4], p < 0.0001), premature atrial contractions (HR 3.9 for >123 vs 0 [1.3-12.0], p = 0.009 across quartiles), and diabetes (HR 2.3 [1.0-5.2], p < 0.05). In multivariate analysis, age (HR per decade 1.9 [1.3-2.8], p = 0.0009) and PR interval (HR 1.3 [1.2-1.4], p < 0.0001) remained significant and together yielded an area under the receiver operating characteristic curve of 0.78 (0.70-0.85). The same predictors were found at 36 months. CONCLUSION: Increasing age and a prolonged PR interval at enrollment were independently associated with an increased AF incidence in CS patients. However, they offered only moderate predictive ability in determining which CS patients had AF detected by the ICM.

Squiers, J. J., K. B. Harrington, M. Arsalan and J. M. DiMaio (2016). “Preventative medicine: The next revolution in the treatment of aortic stenosis.” Journal of Thoracic and Cardiovascular Surgery 151(1): 263-264.

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Calcific aortic stenosis (AS) has been the most common indication for surgical valve replacement in the developed world for decades. The pathophysiology of aortic valve (AV) calcification is driven by 3 interrelated mechanisms: (1) classical cardiovascular risk factors, (2) genetic factors, and (3) valve cellular biology. Although AV calcification was long believed to be a passive process (“degenerative” valve disease), a growing body of literature has demonstrated that the progression of calcification on the AV is actively regulated. The natural progression of calcific AV disease was first described by Otto and colleagues. The initial stage of AV calcification, called valve sclerosis, is associated with focal leaflet thickening that leads to calcification without hemodynamic consequences. Eventually leaflet thickening and calcification obstruct the left ventricular outflow tract, causing hemodynamic changes and a resulting diagnosis of AS. Notably, aortic sclerosis is slow to progress to AS, which is the primary reason AS is typically considered a disease of the elderly. AS ultimately leads to heart failure, and the major predictor of mortality for this pathology is the onset of associated symptoms, left ventricular dysfunction, or both. Despite the rapid growth in our understanding of the etiology of AV calcification, no preventive strategy for AS is currently available. Currently, there are an estimated 500,000 elderly people (age ≥75 years) with severe symptomatic AS living in the United States, a number that is expected to triple by 2050.

Sorrentino, D., M. Marino, T. Dassopoulos, D. Zarifi and T. Del Bianco (2015). “Low Dose Infliximab for Prevention of Postoperative Recurrence of Crohn’s Disease: Long Term Follow-Up and Impact of Infliximab Trough Levels and Antibodies to Infliximab.” PloS One 10(12): e0144900.

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OBJECTIVE: In patients with postoperative recurrence of Crohn’s disease endoscopic and clinical remission can be maintained for up to 1 year with low infliximab doses (3 mg/Kg). However, in theory low-dose infliximab treated patients could develop subtherapeutic trough levels, infiximab antibodies, and might loose response to therapy. To verify this hypothesis infliximab pharmacokinetics and clinical/endoscopic response were checked in a group of patients treated in the long term with low infliximab doses. DESIGN: Infliximab antibodies, infliximab levels, highly-sensitive CRP and fecal calprotectin were measured during the 8-week interval in 5 consecutive patients in clinical (Crohn’s Disease Activity Index < 150) and endoscopic (Rutgeerts scores 0-1) remission after one year of therapy with infliximab 3 mg/Kg. For comparison with reported standards, infliximab pharmacokinetics and inflammatory parameters were also tested in 6 Crohn's disease patients who did not undergo surgery and who were in clinical remission while on infliximab 5 mg/Kg. Patients on low infliximab dose also underwent colonoscopy after 18 additional months of therapy. RESULTS: Highly sensitive CRP and fecal calprotectin increased in all patients during the 8-week interval. Infliximab trough levels were lower in patients treated with the low dose compared to controls (mean+/-SE: 2.0+/-0.3 vs 4.75+/-0.83 mug/mL respectively p<0.05). Infliximab antibodies were present in two of the subjects treated with low infliximab dose and in none of the controls. However, in low dose-treated patients after 18 additional months of therapy endoscopy continued to show mucosal remission and none of them developed clinical recurrence or side effects. CONCLUSIONS: Patients treated with low infliximab doses had lower trough levels compared to patients treated with 5 mg/Kg and some developed antibodies to infliximab. However, low infliximab doses sustained clinical and endoscopic remission for a total of 30 months of treatment.

Singhal, N. K., S. Li, E. Arning, K. Alkhayer, R. Clements, Z. Sarcyk, R. S. Dassanayake, N. E. Brasch, E. J. Freeman, T. Bottiglieri and J. McDonough (2015). “Changes in Methionine Metabolism and Histone H3 Trimethylation Are Linked to Mitochondrial Defects in Multiple Sclerosis.” Journal of Neuroscience 35(44): 15170-15186.

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Mitochondrial changes, including decreased expression of electron transport chain subunit genes and impaired energetic, have been reported in multiple sclerosis (MS), but the mechanisms involved in these changes are not clear. To determine whether epigenetic mechanisms are involved, we measured the concentrations of methionine metabolites by liquid chromatography tandem mass spectrometry, histone H3 methylation patterns, and markers of mitochondrial respiration in gray matter from postmortem MS and control cortical samples. We found decreases in respiratory markers as well as decreased concentrations of the methionine metabolites S-adenosylmethionine, betaine, and cystathionine in MS gray matter. We also found expression of the enzyme betaine homocysteine methyltransferase in cortical neurons. This enzyme catalyzes the remethylation of homocysteine to methionine, with betaine as the methyl donor, and has previously been thought to be restricted to liver and kidney in the adult human. Decreases in the concentration of the methyl donor betaine were correlated with decreases in histone H3 trimethylation (H3K4me3) in NeuN+ neuronal nuclei in MS cortex compared with controls. Mechanistic studies demonstrated that H3K4me3 levels and mitochondrial respiration were reduced in SH-SY5Y cells after exposure to the nitric oxide donor sodium nitroprusside, and betaine was able to rescue H3K4me3 levels and respiratory capacity in these cells. Chromatin immunoprecipitation experiments showed that betaine regulates metabolic genes in human SH-SY5Y neuroblastoma cells. These data suggest that changes to methionine metabolism may be mechanistically linked to changes in neuronal energetics in MS cortex.