Research Spotlight

Ghisoli, M., M. Barve, R. Mennel, C. Lenarsky, S. Horvath, G. Wallraven, B. O. Pappen, S. Whiting, D. Rao, N. Senzer and J. Nemunaitis (2016). “Three-year follow up of gmcsf/bi-shrnafurin DNA-transfected autologous tumor immunotherapy (vigil) in metastatic advanced ewing’s sarcoma.” Mol Ther: 2016 Jul [Epub ahead of print].

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Ewing’s sarcoma is a devastating rare pediatric cancer of the bone. Intense chemotherapy temporarily controls disease in most patients at presentation but has limited effect in patients with progressive or recurrent disease. We previously described preliminary results of a novel immunotherapy, FANG (Vigil) vaccine, in which 12 advanced stage Ewing’s patients were safely treated and went on to achieve a predicted immune response (IFNgamma ELISPOT). We describe follow-up through year 3 of a prospective, nonrandomized study comparing an expanded group of Vigil-treated advanced disease Ewing’s sarcoma patients (n = 16) with a contemporaneous group of Ewing’s sarcoma patients (n = 14) not treated with Vigil. Long-term follow-up results show a survival benefit without evidence of significant toxicity (no >/= grade 3) to Vigil when administered once monthly by intradermal injection (1 x 10e6 cells/injection to 1 x 10e7 cells/injection). Specifically, we report a 1-year actual survival of 73% for Vigil-treated patients compared to 23% in those not treated with Vigil. In addition, there was a 17.2-month difference in overall survival (OS; Kaplan-Meier) between the Vigil (median OS 731 days) and no Vigil patient groups (median OS 207 days). In conclusion, these results supply the rational for further testing of Vigil in advanced stage Ewing’s sarcoma.

Grodzinsky, A., A. Goyal, K. Gosch, P. A. McCullough, G. C. Fonarow, A. Mebazaa, F. A. Masoudi, J. A. Spertus, B. F. Palmer and M. Kosiborod (2016). “Prevalence and prognosis of hyperkalemia in patients with acute myocardial infarction.” Am J Med 129(8): 858-865.

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BACKGROUND: Hyperkalemia is common and potentially dangerous in hospitalized patients; its contemporary prevalence and prognostic importance after acute myocardial infarction are not well described. METHODS: In 38,689 consecutive patients with acute myocardial infarction from the Cerner Health Facts database, we evaluated the association between maximum in-hospital potassium levels and in-hospital mortality. Patients were stratified by dialysis status and grouped by maximum potassium as follows: <5 mEq/L, 5 to <5.5 mEq/L, 5.5 to <6.0 mEq/L, 6.0 to <6.5 mEq/L, and >/=6.5 mEq/L. Multivariable logistic regression was used to adjust for multiple patient and site characteristics. The relationship between the number of hyperkalemic values and the in-hospital mortality was evaluated. RESULTS: Of 38,689 patients with acute myocardial infarction, 886 were on dialysis. The rate of hyperkalemia (maximum potassium >/=5.0 mEq/L) was 22.6% in patients on dialysis and 66.8% in patients not on dialysis. Moderate to severe hyperkalemia (maximum potassium >/=5.5 mEq/L) occurred in 9.8% of patients. There was a steep increase in mortality with higher maximum potassium levels. In-hospital mortality exceeded 15% once maximum potassium was >/=5.5 mEq/L regardless of dialysis status. The relationship between higher maximum potassium and increased mortality risk persisted after multivariable adjustment. In addition, patients with a greater number of hyperkalemic values (vs a single value) experienced higher in-hospital mortality. CONCLUSIONS: Hyperkalemia is common in patients who are hospitalized with acute myocardial infarction. Higher maximum potassium levels and number of hyperkalemic events are associated with a steep mortality increase, with higher risks for adverse outcomes observed even at mild levels of hyperkalemia. Whether more intensive management of hyperkalemia may improve outcomes in patients with acute myocardial infarction merits further study.

Huffman, L. E., D. K. Wilson, H. Kitzman-Ulrich, J. E. Lyerly, H. M. Gause and K. Resnicow (2016). “Associations between culturally relevant recruitment strategies and participant interest, enrollment and generalizability in a weight-loss intervention for african american families.” Ethn Dis 26(3): 295-304.

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OBJECTIVE: Culturally relevant recruitment strategies may be an important approach for recruiting ethnic minorities for interventions. Previous research has examined associations between recruitment strategies and enrollment of African Americans (AA), but has not explored more deeply the role of incorporating sociocultural values into recruitment strategies. Our current study explores whether sociocultural recruitment mediums were associated with demographics, interest and enrollment in a weight-loss intervention. METHOD: Sociocultural mediums included community partnerships, culturally relevant ads, sociocultural events, or word-of-mouth. Non-sociocultural mediums included community/school events that did not specifically target AAs. Analyses examined whether demographics of enrolled families differed by recruitment strategy and if recruitment strategy predicted scheduling a baseline visit, enrolling in a run-in phase, and enrolling in the intervention program. RESULTS: Families recruited from culturally relevant ads, sociocultural events, or word-of-mouth were 1.96 times more likely to schedule a baseline visit (OR=1.96, 95% CI=1.05, 3.68) than families recruited from non-sociocultural mediums. No differences were found for sociocultural mediums on enrolling in the run-in phase or the intervention. However, among enrolled families, those recruited from sociocultural mediums were less likely to be employed (X(2) [1, N=142] =5.53, P<.05) and more likely to have lower income (X(2) [1, N=142] =13.57, P<.05). CONCLUSION: Sociocultural mediums were associated with scheduling a baseline visit, but not enrollment. They were, however, effective in recruiting a more generalizable sample among enrolled participants based on demographic characteristics. Integrating sociocultural values into recruitment methods may be a valuable strategy for increasing interest in participation among underrepresented AA families.

Kanak, M. A., R. Shahbazov, G. Yoshimatsu, M. F. Levy, M. C. Lawrence and B. Naziruddin (2016). “A small molecule inhibitor of nfkappab blocks er stress and the nlrp3 inflammasome and prevents progression of pancreatitis.” J Gastroenterol: 2016 Jul [Epub ahead of print].

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BACKGROUND: The underlying molecular mechanism that leads to development of chronic pancreatitis remains elusive. The aim of this study is to understand the downstream inflammatory signaling involved in progression of chronic pancreatitis, and to use withaferin A (WA), a small molecule inhibitor of nuclear factor kappaB (NFkappaB), to prevent progression of chronic pancreatitis. METHODS: Two different protocols were used to induce pancreatitis in mice: standard and stringent administration of cerulein. The severity of pancreatitis was assessed by means of pancreatic histology and serum amylase levels. Immunohistochemistry and flow-cytometric analysis was performed to visualize immune cell infiltration into the pancreas. Real-time PCR and Western blot were used to analyze the downstream signaling mechanism involved in the development of chronic pancreatitis. RESULTS: The severity of cerulein-induced pancreatitis was reduced significantly by WA, used as either preventive or curative treatment. Immune cell infiltration into the pancreas and acinar cell death were efficiently reduced by WA treatment. Expression of proinflammatory and proapoptotic genes regulated by NFkappaB activation was increased by cerulein treatment, and WA suppressed these genes significantly. Sustained endoplasmic reticulum stress activation by cerulein administration was reduced. NLRP3 inflammasome activation in cerulein-induced pancreatitis was identified, and this was also potently blocked by WA. The human pancreatitis tissue gene signature correlated with the mouse model. CONCLUSIONS: Our data provide evidence for the role of NFkappaB in the pathogenesis of chronic pancreatitis, and strongly suggest that WA could be used as a potential therapeutic drug to alleviate some forms of chronic pancreatitis.

Kane, E. P., A. W. Collinsworth, K. L. Schmidt, R. M. Brown, C. A. Snead, S. A. Barnes, N. S. Fleming and J. W. Walton (2016). “Improving diabetes care and outcomes with community health workers.” Fam Pract: 2016 Jul [Epub ahead of print].

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BACKGROUND: Type II diabetes continues to be a major health problem in USA, particularly in minority populations. The Diabetes Equity Project (DEP), a clinic-based diabetes self-management and education program led by community health workers (CHWs), was designed to reduce observed disparities in diabetes care and outcomes in medically underserved, predominantly Hispanic communities. OBJECTIVE: The purpose of this study was to evaluate the impact of the DEP on patients’ clinical outcomes, diabetes knowledge, self-management skills, and quality of life. METHODS: The DEP was implemented in five community clinics from 2009 to 2013 and 885 patients completed at least two visits with the CHW. Student’s paired t-tests were used to compare baseline clinical indicators with indicators obtained from patients’ last recorded visit with the CHW and to assess differences in diabetes knowledge, perceived competence in managing diabetes, and quality of life. A mixed-effects model for repeated measures was used to examine the effect of DEP visits on blood glucose (HbA1c), controlling for patient demographics, clinic and enrolment date. RESULTS: DEP patients experienced significant (P < 0.0001) improvements in HbA1c control, blood pressure, diabetes knowledge, perceived competence in managing diabetes, and quality of life. Mean HbA1c for all DEP patients decreased from 8.3% to 7.4%. CONCLUSION: Given the increasing prevalence of diabetes in USA and documented disparities in diabetes care and outcomes for minorities, particularly Hispanic patients, new models of care such as the DEP are needed to expand access to and improve the delivery of diabetes care and help patients achieve improved outcomes.