UCSF Multidisciplinary Resident Research Symposium Sponsored by CTSI Resident Research Training Program, Global Health Sciences and the Molecular Medicine Pathway

s: Oral Presentations UCSF Multidisciplinary Resident Research Symposium Wednesday, May 25, 2016 Mission Bay, Mission Hall, MH-1400 Abstract title: Secondary Malignancy in Neuroblastoma After 131I-metaiodobenzylguanidine Treatmenttitle: Secondary Malignancy in Neuroblastoma After 131I-metaiodobenzylguanidine Treatment Resident’s name: Kelly E. Huibregtse, MD, MS Name of program: Pediatrics Purpose: 131I-MIBG is a highly active form of tumor-targeted radiotherapy in patients with relapsed neuroblastoma, with response rates of 30% to 40%. Several reports of second malignant neoplasm (SMN) in patients after treatment with 131I-MIBG suggest the possibility of increased risk, particularly myelodysplasia and leukemia. Incidence of and risk factors for SMN after 131I-MIBG have not been defined. Methods: This is a multi-institutional retrospective review of patients with neuroblastoma treated with 131I-MIBG therapy at four institutions. A competing risks approach was used to calculate the cumulative incidence of SMN from time of first exposure to 131I-MIBG. Competing risks regression using the Fine-Gray method was used to identify potential risk factors for secondary malignancy. Results: The analytical cohort included 644 patients treated with 131I-MIBG. The cumulative incidence of SMN was 7.6% (90% CI 4.8-11.9%) and 14.3% (90% CI 9.1-22.1%) at five and ten years from first 131I-MIBG, respectively. No increase in SMN risk was found with increased number of 131IMIBG treatments or higher cumulative activity per kilogram of 131I-MIBG received (p=0.72 and p=0.84, respectively). An increased risk of SMN was found in patients who had bone disease at the time of first 131I-MIBG therapy. In a multivariate analysis controlling for variables with p<0.1 (stage, age at first 131I-MIBG, bone disease, disease status at time of first 131I-MIBG), patients with relapsed/progressive disease had significantly lower risk of SMN (Subdistribution Hazard Ratio 0.3, 95% CI, 0.1-0.8, p=0.023) compared to patients with persistent/refractory neuroblastoma. Conclusions: The cumulative risk of SMN after 131I-MIBG therapy for patients with relapsed or refractory neuroblastoma is similar to the published incidence for high-risk neuroblastoma overall. We found no dose-dependent increase in SMN risk. As the number of patients treated with 131I-MIBG earlier after diagnosis and length of follow up time from 131I-MIBG therapy increases, it will be important to reassess this risk. Abstract title: Cost-Effectiveness of a Fixed-Dose Combination Pill for Secondary Prevention of Cardiovascular Disease in India, Mexico, Ghana, and South Africatitle: Cost-Effectiveness of a Fixed-Dose Combination Pill for Secondary Prevention of Cardiovascular Disease in India, Mexico, Ghana, and South Africa Resident’s name: John K. Lin, MD Name of Program: Categorical Internal Medicine Purpose: Cardiovascular disease (CVD) is the leading cause of death worldwide, with lowand middleincome countries (LMIC) facing more than 75% of the global burden. Although evidencebased medications for secondary prevention of CVD are effective and relatively inexpensive, less than a quarter of eligible patients in LMICs receive these drugs. The fixed-dose combination pill (“polypill”) improves patient adherence to evidence-based medications and costs less than the individual components separately. The polypill is currently being evaluated for inclusion in the WHO’s essential medicines list for its potential impact in LMICs. We aim to assess whether the polypill is cost-effective in four LMICs with a large burden of CVD: India, Mexico, South Africa, and Ghana. Methods: We developed a microsimulation model of 100,000 adults aged 30 to 80 years with prevalent CVD (prior myocardial infarction or stroke) in each of India, Mexico, Ghana, and South Africa. In each setting, we evaluated two treatment strategies: (1) Usual care: monocomponents (ACE inhibitor, aspirin, beta-blocker, and statin) at real-world levels of prescription and adherence (2) Polypill containing aspirin 75 mg, simvastatin 40 mg, lisinopril 10 mg, and atenolol 50 mg at real-world levels of prescription. We assumed the polypill would be as efficacious as its individual components, but would be associated with increased adherence as observed in randomized controlled trials. We derived country-level demographics from UN Population data and ageand gender-specific estimates of prevalent CVD from nationally representative surveys. We used an ingredients approach to costing acute and chronic CVD care, using data from WHO CHOICE 2013 and the International Drug Price Indicator Guide 2014. We assumed the cost of the polypill was 80% of the sum of its individual components (e.g., $I 21.16 in India). We derived effectiveness estimates from GBD 2010. We adopted a health system perspective and a 10-year analytic horizon. Our main outcomes are healthcare costs in international dollars ($I), disability-adjusted life years (DALY), and incremental cost-effectiveness ratio (ICER) of the polypill compared with usual care. We defined an ICER < GDP per capita as very cost-effective. We performed two sensitivity analyses: (1) Increasing the polypill prescription rate to 80% of all eligible patients (per WHO 25x25 target); and (2) Increasing the cost of the polypill to twice as much as the individual components. Results: At real-world levels of adoption of evidence-based medications, the use of the polypill instead of monocomponents would avert 710-2685 deaths per 100,000 people with CVD in the countries studied. The polypill strategy was very cost-effective among patients with preexisting CVD in India, South Africa, and Ghana (ICER ranging $I 23.04-$I 77.05 per DALY averted). In Mexico, the polypill strategy was dominant, i.e., the polypill strategy cost less than usual care and produced better outcomes. If 80% of eligible patients were to receive the polypill, it would save substantially more lives relative to usual care (6500-10,500 deaths averted per 100,000 people with CVD), and the polypill would become even more cost-effectiveness (ICER = $I 40.31 per DALY averted in India, $I 50.31 per DALY averted in Ghana, and dominant in Mexico and South Africa). Even if the polypill were to cost twice as much as the individual components, it would remain very cost-effective in all countries (ICER ranging $I 136.75-$I 273.20 per DALY averted). A limitation of the analysis was that we did not capture programmatic costs that may be incurred in increasing levels of prescription. Conclusions: In our microsimulation-based analysis, the polypill is a highly cost-effective approach compared with usual care in India, South Africa, and Ghana, and is cost-saving in Mexico. Addition of an appropriately priced polypill to the WHO essential medications list has the potential to avert a large number of deaths from CVD in LMICs. Abstract title: Morbid Obesity and Diabetes (DM) are Associated with Increased Risk of Death on the Liver Transplant (LT) Waiting Listtitle: Morbid Obesity and Diabetes (DM) are Associated with Increased Risk of Death on the Liver Transplant (LT) Waiting List Resident’s name: Ani Kardashian, MD Name of program: Categorical Internal Medicine Purpose: Obesity is a growing problem in LT candidates, paralleling the US obesity epidemic and the increase in LT for nonalcoholic steatohepatitis (NASH). While post-LT survival appears to be similar in obese and non-obese patients, data is scarce regarding risk of waitlist dropout in morbidly obese patients. We aimed to determine the impact of obesity on waitlist outcomes and evaluate predictors of dropout in those with morbid obesity or NASH. Methods: We retrospectively evaluated LT candidates listed between 3/02-12/13. We performed a competing risk analysis to evaluate predictors of removal or death on the waitlist. Variables with pvalue. Results: 84,511 patients (34% female, median age 55, 15% Hispanic) were included. 10,001 (12%) had NASH and 3,159 (4%) had BMI>40. Compared with BMI 25-29.9, patients with BMI≥40 were more likely to be female (46% vs 28%), diabetic (25% vs 18%), have NASH (35% vs 13%), and have shorter median waitlist times (161 vs 208 days); all p40, DM was associated with higher dropout risk but was not significant (HR=1.12, CI 1.0-1.26). Conclusions: Patients with morbid obesity or DM are less likely to undergo LT due to death or removal from the waitlist. Interventions to improve waitlist outcomes and access to LT in this growing patient group should be explored. Abstract title: Identifying Prefrontal Cortex Microcircuit Disruptions Underlying Depression Resident’s name: Scott A. Wilke, MD, PhD Name of program: Psychiatry Purpose: The prefrontal cortex (PFC) and the neurotransmitter dopamine have been centrally implicated in depression. In animal models, prefrontal neurons expressing dopamine D2 receptors (D2Rs) project subcortically to regulate depression related behaviors. However, it is not known how manipulations that either contribute to or treat depression affect the responses of local prefrontal microcircuits to dopaminergic input.title: Identifying Prefrontal Cortex Microcircuit Disruptions Underlying Depression Resident’s name: Scott A. Wilke, MD, PhD Name of program: Psychiatry Purpose: The prefrontal cortex (PFC) and the neurotransmitter dopamine have been centrally implicated in depression. In animal models, prefrontal neurons expressing dopamine D2 receptors (D2Rs) project subcortically to regulate depression related behaviors. However, it is not known how manipulations that either contribute to or treat depression affect the responses of local prefrontal microcircuits to dopaminergic input. Methods: Our lab has recently developed a novel assay, using live brain slices to image patterns of neural activity in isolated prefrontal microcircuits. A fluorescent reporter of neural activity, GCaMP6 is stereotactically targeted to medial PFC (mPFC) in mice. Subsequently, live slices are cut and activity is imaged simultaneously from 70-100 prefrontal neurons during a baseline period and after exposure to a D2R agonist (quinpirole, 10 μM). Results: I have imaged the response of prefrontal microcircuits to D2R stimulation in two manipulations related to depression. First, using an established mouse model of genetic risk for depression, a Disc1 mutant mouse and second looking at mice treated with the rapid acting antidepressant ketamine. In control slices, mean network activity increases nearly 2-fold in response to D2R stimulation. This response is significantly blunted in slices from Disc1 mutant mice and is preserved or possibly enhanced in mice treated with ketamine. During the baseline period, Disc1 mutants exhibit an altered organization of network activity, shifted towards more negative pairwise correlations. Intriguingly, mice treated with an antidepressant dose of ketamine show an opposing effect on the organization of network activity. Conclusions: This novel assay allows an unbiased approach to discovering prefrontal microcircuit endophenotypes in psychiatric disorders. I have used this technique to identify altered activity in local networks which may be important in depression. Abstract title: Predictors of undergoing cell-free DNA simultaneously with multiple marker screening or after negative multiple marker screen resultstitle: Predictors of undergoing cell-free DNA simultaneously with multiple marker screening or after negative multiple marker screen results Resident’s name: Adam K. Lewkowitz, MD Name of program: Obstetrics, Gynecology and RS Purpose: The American Board of Internal Medicine has partnered with the Society of Maternal Fetal Medicine to create a Choosing Wisely campaign to encourage high-value care in obstetrics. One of the ten proposed clinical guidelines is to avoid simultaneous testing with cell-free DNA (cfDNA) and multiple marker screening (MMS) due to the limited clinical value of dual screening. Despite these recommendations, many women are obtaining dual screening. Our objective is to identify predictors of simultaneous MMS and cfDNA screening or cfDNA screening after negative MMS results among women seeking testing who will be at least 35 years old at the time of delivery. Methods: Women of advanced maternal age carrying a singleton pregnancy were recruited at the University of California, San Francisco, Prenatal Diagnosis Center. Participants completed a sociodemographic and attitudinal questionnaire, which included items related to knowledge about testing, pregnancy worry, and, attitudes toward potential testing outcomes. Data on prenatal test use was obtained via medical record review. Multivariate analysis with logistic regression using backward elimination was used to identify factors associated with dual screening. Results: Of the 164 participants, 47 underwent MMS alone, 15 had cfDNA alone, 80 had both MMS and cfDNA, and 22 had invasive testing with or without MMS. Compared to the 46 MMS-negative women who did not undergo further testing, those who underwent cfDNA simultaneously with MMS (n=15) or after negative MMS results (n=57) were more likely to feel that having a miscarriage would be worse than having a child with an intellectual disability (adjusted odds ratio (aOR) 4.59 for every 1point increase on a 4-point scale, 95% confidence interval (CI) 1.11-19.10; p 0.04); to desire comprehensive testing for intellectual disability (aOR 6.06 for every 1-point increase on a 4-point scale, 95% CI 1.84-19.97; p 0.003); and to have greater pregnancy worry (aOR 3.16 for every 1-point increase on a 4-point scale, 95% CI 1.17-8.51; p 0.02, respectively). They were also more likely to be nulliparous (aOR 2.91, 95% CI 0.99-8.58; p 0.05) and older (aOR 1.29 for every one-year increment in age, 95% CI 1.00-1.66; p 0.05). Conclusions: Most women who initially opted for screening rather than diagnostic testing underwent cfDNA simultaneously with MMS or after negative MMS results. These women were more likely to, have higher scores on the pregnancy worry scale, view miscarriage as a worse outcome than having a child with an intellectual disability, and to more highly desire comprehensive testing for intellectual disability. These findings suggest that women who are particularly concerned about intellectual disability but are not willing to incur miscarriage may be more likely to undergo dual screening. .Patients should be counseled more effectively regarding the appropriate sequencing of these tests to avoid unnecessary tests and reduce costs. Resident Research Training Program CTSI Resident Research Funding Award 2015 Recipients