Ernest K. Amankwah

Global ovarian cancer health disparities

OBJECTIVE The objective of this article is to broadly review the scientific literature and summarize the most up-to-date findings on ovarian cancer health disparities worldwide and in the United States (U.S.). METHODS The present literature on disparities in ovarian cancer was reviewed. Original research and relevant review articles were included. RESULTS Ovarian cancer health disparities exist worldwide and in the U.S. Ovarian cancer disproportionately affect African American women at all stages of the disease, from presentation through treatment, and ultimately increased mortality and decreased survival, compared to non-Hispanic White women. Increased mortality is likely to be explained by unequal access to care and non-standard treatment regimens frequently administered to African American women, but may also be attributed to genetic susceptibility, acquired co-morbid conditions and increased frequency of modifiable risk factors, albeit to substantially lesser extent. Unequal access to care is, in turn, largely a consequence of lower socioeconomic status and lack of private health insurance coverage among the African American population. CONCLUSIONS Our findings suggest the need for policy changes aimed at facilitating equal access to quality medical care. At the same time, further research is necessary to fully resolve racial disparities in ovarian cancer.

Epidemiology and therapies for metastatic sarcoma.

Sarcomas are cancers arising from the mesenchymal layer that affect children, adolescents, young adults, and adults. Although most sarcomas are localized, many display a remarkable predilection for metastasis to the lungs, liver, bones, subcutaneous tissue, and lymph nodes. Additionally, many sarcoma patients presenting initially with localized disease may relapse at metastatic sites. While localized sarcomas can often be cured through surgery and often radiation, controversies exist over optimal management of patients with metastatic sarcoma. Combinations of chemotherapy are the most effective in many settings, and many promising new agents are under active investigation or are being explored in preclinical models. Metastatic sarcomas are excellent candidates for novel approaches with additional agents as they have demonstrated chemosensitivity and affect a portion of the population that is motivated toward curative therapy. In this paper, we provide an overview on the common sarcomas of childhood (rhabdomyosarcoma), adolescence, and young adults (osteosarcoma, Ewing sarcoma, synovial sarcoma, and malignant peripheral nerve sheath tumor) and older adults (leiomyosarcoma, liposarcoma, and undifferentiated high grade sarcoma) in terms of the epidemiology, current therapy, promising therapeutic directions and outcome with a focus on metastatic disease. Potential advances in terms of promising therapy and biologic insights may lead to more effective and safer therapies; however, more clinical trials and research are needed for patients with metastatic sarcoma.

Hospital-associated venous thromboembolism in pediatrics: a systematic review and meta-analysis of risk factors and risk assessment models

Hospital-associated venous thromboembolism, including deep vein thrombosis and pulmonary embolism, is increasing in pediatric centers. The objective of this work was to systematically review literature on pediatric hospital-acquired venous thromboembolism risk factors and risk-assessment models, to inform future prevention research. We conducted a literature search on pediatric venous thromboembolism risk via PubMed (1946–2014) and Embase (1980–2014). Data on risk factors and risk-assessment models were extracted from case-control studies, while prevalence data on clinical characteristics were obtained from registries, large (n>40) retrospective case series, and cohort studies. Meta-analyses were conducted for risk factors or clinical characteristics reported in at least three studies. Heterogeneity among studies was assessed with the Cochran Q test and quantified by the I2 statistic. From 394 initial articles, 60 met the final inclusion criteria (20 case-control studies and 40 registries/large case series/cohort studies). Significant risk factors among case-control studies were: intensive care unit stay (OR: 2.14, 95% CI: 1.97–2.32); central venous catheter (OR: 2.12, 95% CI: 2.00–2.25); mechanical ventilation (OR: 1.56, 95%CI: 1.42–1.72); and length of stay in hospital (per each additional day, OR: 1.03, 95% CI: 1.03–1.03). Three studies developed/applied risk-assessment models from a combination of these risk factors. Fourteen significant clinical characteristics were identified through non-case-control studies. This meta-analysis confirms central venous catheter, intensive care unit stay, mechanical ventilation, and length of stay as risk factors. A few pediatric hospital-acquired venous thromboembolism risk scores have emerged employing these factors. Prospective validation is necessary to inform risk-stratified prevention trials.

Characteristics of hypertensive Canadians not receiving drug therapy

BACKGROUND Many Canadians known to have hypertension remain untreated. To aid in the development of specific programs to improve hypertension management, the present report characterizes Canadians who indicated that they had hypertension but were not taking antihypertensive drug therapy. METHODS The 2005 Canadian Community Health Survey (cycle 3.1) was used to estimate the proportion of Canadians 20 years of age and older who reported having high blood pressure or ever being diagnosed with high blood pressure. Sociodemographic characteristics, reported health, lifestyle factors and health care resource use of those who reported taking or not taking high blood pressure medication in the previous month were described and compared. RESULTS Over one-half of hypertensive respondents 20 to 39 years of age reported no antihypertensive treatment compared with 17% and 5% among those 40 to 59 years and 60 years of age and older, respectively. In most age groups, several factors were associated with the absence of pharmacotherapy (eg, male sex, fewer health care professional consultations, perceived excellent health status and most markers of lower cardiovascular risk, with the exception of daily smoking). The proportion of young hypertensive Canadians not receiving pharmacotherapy remained consistent, regardless of the presence of cardiovascular risk factors. CONCLUSIONS Many hypertensive Canadians, particularly those who are younger than 60 years of age, are not taking antihypertensive drug therapy despite having one or more cardiovascular risks. The increased risk of no drug therapy among smokers warrants special attention.

SNP-SNP Interaction Network in Angiogenesis Genes Associated with Prostate Cancer Aggressiveness

Angiogenesis has been shown to be associated with prostate cancer development. The majority of prostate cancer studies focused on individual single nucleotide polymorphisms (SNPs) while SNP-SNP interactions are suggested having a great impact on unveiling the underlying mechanism of complex disease. Using 1,151 prostate cancer patients in the Cancer Genetic Markers of Susceptibility (CGEMS) dataset, 2,651 SNPs in the angiogenesis genes associated with prostate cancer aggressiveness were evaluated. SNP-SNP interactions were primarily assessed using the two-stage Random Forests plus Multivariate Adaptive Regression Splines (TRM) approach in the CGEMS group, and were then re-evaluated in the Moffitt group with 1,040 patients. For the identified gene pairs, cross-evaluation was applied to evaluate SNP interactions in both study groups. Five SNP-SNP interactions in three gene pairs (MMP16+ ROBO1, MMP16+ CSF1, and MMP16+ EGFR) were identified to be associated with aggressive prostate cancer in both groups. Three pairs of SNPs (rs1477908+ rs1387665, rs1467251+ rs7625555, and rs1824717+ rs7625555) were in MMP16 and ROBO1, one pair (rs2176771+ rs333970) in MMP16 and CSF1, and one pair (rs1401862+ rs6964705) in MMP16 and EGFR. The results suggest that MMP16 may play an important role in prostate cancer aggressiveness. By integrating our novel findings and available biomedical literature, a hypothetical gene interaction network was proposed. This network demonstrates that our identified SNP-SNP interactions are biologically relevant and shows that EGFR may be the hub for the interactions. The findings provide valuable information to identify genotype combinations at risk of developing aggressive prostate cancer and improve understanding on the genetic etiology of angiogenesis associated with prostate cancer aggressiveness.

Outcomes in highly sensitized pediatric heart transplant patients using current management strategies

BACKGROUND Previous studies have suggested that children with pre-formed anti-HLA antibodies (PRA) undergoing orthotopic heart transplantation (OHT) have increased risk for rejection, coronary artery vasculopathy (CAV) and death. In 2005, our program started utilizing aggressive desensitization (including plasmapheresis, IVIg, pulse cytoxan and rituximab) with the goal of improving outcomes for these patients. The purpose of this study was to compare outcomes with this new strategy in recipients with pre-OHT high PRA (>10%) vs low PRA ≤10%). METHODS A retrospective study of 70 consecutive pediatric OHT patients was undertaken between January 2005 and July 2013 to identify patients with pre-OHT PRA >10% (high PRA), or PRA ≤10% (low PRA). Demographic/data information and detailed post-OHT outcomes, including rejection, 30-day and overall mortality, freedom from significant rejection, and CAV, were analyzed. RESULTS Fourteen (20%) patients had high PRA and 56 (80%) did not. There was a significant decrease in PRA values before and after desensitization. Thirty-day and overall mortality and the proportion of patients with rejections or CAV were lower in the high PRA group, although the difference was not statistically significant. Kaplan-Meier survival analysis revealed no significant difference in survival between the two groups. There was a significant difference in survival in our sensitized patients before 2005 vs after 2005. CONCLUSIONS We identified no significant differences in outcomes between high or low PRA patients. These preliminary findings may suggest improvement in OHT outcomes for high PRA patients as a result of aggressive desensitization. A larger study is warranted to confirm these findings.

miR-21, miR-221 and miR-222 expression and prostate cancer recurrence among obese and non-obese cases.

Recent evidence shows that certain microRNAs (miRNAs) play a role in both obesity and prostate cancer recurrence, but the association between the expression of these miRNAs and obesity in prostate cancer recurrence is unknown. In this study, we examined the effect of the interaction between obesity and miR-21, miR-221 or miR-222 expression on prostate cancer recurrence among 28 recurrent and 37 non-recurrent prostate cancer cases. miRNA expression was determined using quantitative real-time polymerase chain reaction. Cox proportional hazard models adjusting for age at diagnosis, clinical stage and Gleason score were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) for recurrence free survival. A significantly (P=0.014) higher proportion of recurrent cases (78.6%) than non-recurrent cases (48.6%) had a low expression of miR-21 and the difference was more prominent in obese than non-obese patients. Multivariate analysis showed that the expression of miR-21 was an independent risk factor for recurrence in obese (HR=6.15, 95% CI=1.04-36.48, P=0.045), but not in non-obese (HR=1.28, 95% CI=0.30-5.49, P=0.74) cases. A significant association with recurrence was not observed for the expression of miR-221 and miR-222. In summary, our findings show that miR-21 is associated with prostate cancer recurrence after radical prostatectomy and suggest that the differential expression of miR-21 is more prominent in obese than in non-obese cases. Future larger studies are warranted to confirm these initial findings and to elucidate the mechanisms involved.

Risk factors for hospital-sssociated venous thromboembolism in the neonatal intensive care unit

OBJECTIVE To determine hospital-associated venous thromboembolism (HA-VTE) risk factors in critically ill neonates. METHODS We conducted a case-control study in the neonatal intensive care unit (NICU) of All Childrens Hospital Johns Hopkins Medicine (St. Petersburg, FL), from January 1, 2006 - April 10, 2013. We identified HA-VTE cases using electronic health record. Four NICU controls were randomly selected for each HA-VTE case. Associations between putative risk factors and HA-VTE were estimated using odds ratios (ORs) and ninety-five percent confidence intervals (95%CIs) from univariate and multivariate regression analyses. RESULTS Twenty-three HA-VTE cases and 92 controls were included. The annual HA-VTE incidence was approximately 1.4 HA-VTE cases per 1,000 NICU admissions. In univariate analyses, mechanical ventilation (OR=7.27, 95%CI=2.02-26.17, P=0.002), central venous catheter (CVC; OR=52.95, 95%CI=6.80-412.71, P<0.001), infection (OR=7.24, 95%CI=2.66-19.72, P<0.001), major surgery (OR=5.60, 95%CI=1.82-17.22, P=0.003) and length of stay ≥15days (OR=6.67, 95%CI=1.85-23.99, P=0.004) were associated with HA-VTE. Only CVC (OR=29.04, 95%CI=3.18-265.26, P=0.003) remained an independent risk factor in the multivariate analysis. Based on this result, the estimated risk of HA-VTE in NICU patients with a CVC was 0.9%. CONCLUSION This study identifies CVC as an independent risk factor for HA-VTE in critically ill neonates. However, the level of risk associated with CVC is below the conventional threshold for primary anticoagulation thromboprophylaxis. Larger studies are needed to substantiate these findings and identify novel putative risk factors to further distinguish NICU patients at highest HA-VTE risk.

Gene variants in the angiogenesis pathway and prostate cancer.

Although the causes of prostate cancer are still unknown, numerous studies support the role of genetic factors in the development and progression of this disease. Single nucleotide polymorphisms (SNPs) in key angiogenesis genes have been studied in prostate cancer. In this review, we provide an overview of the current knowledge of the role of genetic variants in the angiogenesis pathway in prostate cancer risk and progression. Of the 17 prostate cancer genome-wide association studies (GWAS) conducted to date, only one identified disease-associated SNPs in a region of an angiogenesis pathway gene. An association was observed between aggressive disease and three intergenic SNPs (rs11199874, rs10749408 and rs10788165) in a region on chromosome 10q26 that encompasses FGFR2. The majority (27/32, 84.4%) of primary candidate gene studies reviewed had a small (n < 800, 20/32, 62.5%) to medium sample size (n = 800-2000, 7/32, 21.9%), whereas only five (15.6%) had a large sample size (n ≥ 2000). Results from the large studies revealed associations with risk and aggressive disease for SNPs in NOS2A, NOS3 and MMP-2 and risk for HIF1-α. Meta-analyses have so far been conducted on FGFR2, TGF-β, TNF-α, HIF1-α and IL10 and the results reveal an association with risk for SNPs in FGFR2 and TGF-β and aggressive disease for SNPs in IL-10. Thus, existing evidence from GWAS and large candidate gene studies indicates that SNPs from a limited number of angiogenesis pathway genes are associated with prostate cancer risk and progression.

Development of a new risk score for hospital-associated venous thromboembolism in critically-ill children not undergoing cardiothoracic surgery

BACKGROUND Although risk of hospital-associated venous thromboembolism (HA-VTE) differs between critically and non-critically ill children, studies to date have not led to distinct, pragmatic risk scores. OBJECTIVE To determine risk factors for HA-VTE in critically ill children not undergoing cardiothoracic surgery, in order to derive a novel HA-VTE risk score for this population. METHODS We conducted a retrospective analysis from January 2006 through April 2013 at All Childrens Hospital Johns Hopkins Medicine. HA-VTE cases were identified using ICD-9 discharge diagnosis codes, with subsequent validation via radiologic record review. Cases were restricted to Pediatric Intensive Care Unit (PICU) admissions. Patients who underwent cardiothoracic surgery were excluded; cardiac catheterization per se was not exclusionary. For each case, three non-HA-VTE PICU controls were randomly selected. Data were abstracted on putative risk factors, and associations between risk factors and HA-VTE were estimated using odds ratios (ORs) and 95% confidence intervals (95%CIs). RESULTS There were 57 HA-VTE cases and 171 controls. HA-VTE occurrence was 3 per 1000 PICU admissions (0.3%). Central venous catheter (CVC) (OR:26.64; 95%CI:7.46-95.13), length of stay (LOS) ≥4days (OR:20.22; 95%CI:2.27-180.07), and significant infection (OR:3.41; 95%CI:1.13-10.29) were independent, statistically-significant risk factors for HA-VTE in a multivariate model. A risk score was derived in which HA-VTE risk exceeded 2% (threshold for anticoagulant thromboprophylaxis in hospitalized adults) with a score of 15, and was >1% but <2% (risk zone for mechanical thromboprophylaxis in hospitalized adults) with scores of 7-14. CONCLUSION The presence of a CVC, LOS≥4days and infection are significant risk factors for HA-VTE in critically ill children not undergoing cardiothoracic surgery, forming the basis for a new risk score that warrants prospective validation.