Research & Publications
My areas of interest include Sickle cell disease and Solid Tumors especially germ cell tumors and rare cancers. In sickle cell disease, my research has focused on a variety of areas including identifying the prevalence and risk factors of various complications, management of these complications and quality improvement projects to decrease the burden of disease and improve quality of life.
In oncology, my research activities have focused on collaborative studies through the Children's Oncology Group ( COG) in germ cell tumors and rare tumors. I serve on the steering committees for Germ Gell Tumors and Rare Tumors at COG. I am a member of the Malignant Germ Cell Tumor International Collaborative. Through this collaborative, we have merged 25 years of clinical trial data from US and UK pediatric and adult germ cell clinical trials. This has helped us redefine risk stratification and conduct several analyses. I took leadership of analyzing the data on ovarian immature teratomas. Ovarian immature teratomas are a rare malignancy. There is significant difference in treatment approach between the adult and pediatric groups. In pediatrics, patients are primarily treated with surgery alone, whereas adults receive chemotherapy for all ovarian IT, except Stage I, grade 1 patientsI analyzed the pediatric and adult clinical trial data, and found that grade was the most important risk factor for relapse. More importantly, I found that despite a wide difference in treatment approaches, between adults and pediatrics, the outcomes were similar, bringing up the question of the necessity of adjuvant chemotherapy for ovarian IT.
Specialized Terms: Clinical trials in Pediatric Oncology; Sickle cell anemia
Extensive Research Description
1. Sickle Cell Disease
My research has focused on a variety of areas including identifying the prevalence and risk factors of various complications, management of these complications and quality improvement projects to decrease the burden of disease and improve quality of life.
In the 1990’s, a landmark study from the NIH reported that pulmonary hypertension occurred in a third of adults and was associated with increased mortality. There was limited data in children. I thus designed the first prospective screening study and identified that elevated pulmonary artery pressures (PAP) occur in 30% of children, and is associated with hypoxia, hemolysis and a high platelet count. This was published in Pediatrics and has been widely quoted. Although elevated PAP occurred in children, there was no data on the long-term outcome and possible reversibility of this complication. I conducted a single institution pilot study to determine if treatment with Hydroxyurea, an antihemolytic agent could reverse elevated PAP in children. This study showed that elevated PAP was reversible with hydroxyurea and was published in British Journal of Hematology. Due to the exciting results from our single center pilot, we secured CTSA funding and conducted a multicenter study. This study showed that hydroxyurea improved oxygenation in SCD and had a trend in decreasing PAP.
Working with a medical student, we studied the association of PAP with other complications and found that elevated PAP was associated with early signs of nephropathy. This was the first study describing this association.
Over the years I have collaborated with colleagues at Yale and through the New York Connecticut Consortium and New England Pediatric Sickle Cell consortium to study other complications such as retinopathy, AVN, obesity and determine genetic determinants of hydroxyurea response and look at barriers to hydroxyurea use.
Recently I have focused on quality improvement projects to improve pain management at home and decrease ED visits and hospitalizations. This has been very successful in reducing hospitalizations and improving the quality of life for these families. This work was published and has been adopted by many institutions.
Current Studies and Future Direction:
1. Understanding and Addressing the Social Determinants of Health for Families of Children with Sickle Cell Anemia within Pediatric Hematology
2. Rare Tumors
I was the chair of the Infrequent Tumor Subcommittee at COG till 2020. We developed and published guidelines for several rare tumors and have recently completed two international clinical trials, on adrenocortical carcinoma and nasoparyngeal carcinoma.
3. Germ Cell Tumors
In germ cell tumors, my research has focused on redefining management of immature teratomas (IT) and clinical trial development. The management of ovarian IT is controversial. In children, ovarian IT is treated with surgery alone, whereas adults treat all patients with chemotherapy except those with Stage I, grade 1 tumors. I analyzed pediatric and adult clinical trial data from the MaGIC database and found that grade was the most important risk factor for relapse. In patients with grade 3 tumors, the outcome was similar between the pediatric and adult cohort despite a marked difference in treatment, questioning the role of chemotherapy. Since that initial analyses, I have published other reports showing chemo unresponsiveness of ovarian IT. We have also diligently worked with the adult gynecologic oncology community to move away from using chemotherapy postoperatively in ovarian IT.
Our efforts have been somewhat successful and while designing the current open trial AGCT1531 in conjunction with Gynecology Oncology Group, they agreed to observation alone not only for stage I, grade 1 tumors but also for Stage I, grade 2 and 3 tumors. This is a major change and has the potential to spare chemotherapy to many adult women if the trial proves our hypothesis. We are currently working on an amendment to expand surveillance alone to all patients with ovarian IT, irrespective of stage and I am also organizing a pathology consensus conference to standardize grading of IT.
Another area that I have been actively involved in is clinical trial development at Children’s Oncology Group (COG). Currently we have two clinical trials open – I am the Vice Chair on an international trial for low and intermediate risk germ cell tumors and am the Chair for all US sites for an international trial for poor risk germ cell tumors run by Australia New Zealand Urogenital group, that is open in the US through National Clinical Trials Network.
At Yale, I direct the solid tumor program, and have been actively working to bring innovative industry sponsored trials in addition to trial through COG to broaden our trial portfolio.
Anemia, Sickle Cell; Echocardiography; Hematology; Hypertension, Pulmonary; Medical Oncology; Pediatrics