UCSD Research Articles

Polygenic hazard scores in superagers: Supergenes or superresilience?

AbstractBackgroundUnusually successful cognitive aging (e.g. SuperAging) may reflect underlying resistance to age‐associated cognitive decline and the neuropathologic markers of Alzheimer’s disease (AD). However, it is unknown whether these individuals vary in their genetic protection from AD relative to other clinically normal elderly individuals.MethodThe Northwestern SuperAgers cohort (n=41) was limited to clinically normal individuals who were at least 80 years old but performed at or above normative values for average 50 to 65‐year‐olds on delayed recall of the Rey Auditory Verbal Learning Test and within one standard deviation of the average normative range for their age, or better, on non‐episodic memory tests including the 30‐item Boston Naming Test, Trail Making Test Part‐B and Category Fluency Test (Animals). The UC San Diego (UCSD) Shiley Marcos Alzheimer’s Disease Research Center and Alzheimer’s Disease Neuroimaging Initiative (ADNI) comparison cohorts (n=17 and 46, respectively) included all clinically normal individuals with available genetic data who were at least 80 years old but did not meet the criteria for SuperAgers outlined above. Polygenic hazard scores (PHS) were downloaded from ADNI and calculated for each participant as described (Desikan et al., 2017) for the Northwestern and UCSD cohorts. Briefly, the PHS combines an individual’s genotype for 31 AD‐associated SNPs in addition to APOE.ResultAll three cohorts were similar in age (range: 80‐101) and years of education (range: 12‐20). However, there were significantly more women in the Northwestern SuperAgers cohort (p < 0.001). The mean PHS in each cohort was negative, indicating that these individuals had less than average population risk for AD. However, there were no significant differences in PHS between cohorts.ConclusionAs a group, SuperAgers did not have lower polygenic risk for AD than clinically normal elderly individuals, suggesting determinants of superior memory performance in older age cannot be solely explained by having unusually low risk for AD as assessed by common genetic variants. Given the sex differences in these cohorts, future work should consider whether sex‐specific polygenic risk for AD contributes to the superior memory performance of SuperAgers.

A comparison of homemade vascular access ultrasound phantom models for peripheral intravenous catheter insertion.

Ultrasound (U/S) guided peripheral IV catheter (PIV) placement is often needed after unsuccessful traditional IV attempts. Commercial U/S PIV training phantoms are expensive and difficult to alter. Non-commercial phantoms have been described; however, there has been no comparison of these models. The primary objectives of this study were to compare the echogenic and haptic properties of various non-commercial phantoms. Secondary objectives were to characterize the cost and ease of making the phantoms. This prospective observational study trialed six unique phantom models: Amini Ballistics; Morrow Ballistics; University of California San Diego (UCSD) gelatin; Rippey Chicken; Nolting Spam; and Johnson Tofu. Total cost and creation time were noted. Emergency Ultrasound Fellowship trained physicians performed U/S guided PIV placement on each model to evaluate their resemblance to human tissue haptic and echogenicity properties, utility for training, and comparability to commercial phantoms (Likert scale 1-5; higher performance = 5). The Rippey model scored highest for each primary objective with an aggregate score of 4.8/5. UCSD ranked second and Nolting last for all primary objectives, with aggregate scores 3.7/5 and 1.3/5 respectively. Cost of production ranged from $4.39 (Johnson) to $29.76 (UCSD). Creation times ranged from 10 min (Johnson) to 120 min (UCSD). In our study the Rippey model performed best and offered a mid-level cost and creation time. Non-commercial U/S phantoms may represent cost-effective and useful PIV practice tools. Future studies should investigate the utility of these phantoms in teaching U/S guided PIV to novices and compare non-commercial to commercial phantoms.

Flossie Wong-Staal (1946–2020)

Trailblazing HIV researcher

133P HER2 transcription status of diverse solid tumours with clinical implications

Utility of HER2 mRNA expression as a potential therapeutic biomarker is unclear. We previously reported the discordant HER2 status between copy number variation (CNV), mRNA and immunohistochemistry (IHC) from a large multi-institute dataset. Herein, we investigated comprehensive HER2 status by cancer (CA) type with clinical outcome among HER2 positive patients (pts) at University of California San Diego (UCSD). By Paradigm Diagnostics (CLIA-certified laboratory), HER2 status was evaluated using IHC, qRT-PCR and NGS between 2015-2019. We evaluated pts who had all three HER2 testing available by tumor type, with UCSD outcomes included. Of 5,305 pts, 723 had CNV, mRNA and IHC evaluated (Table). Among diverse solid tumors, HER2 positivity in at least one test were seen in 76.6% (49/64) of NSCLC and 58.8% (20/34) of pancreas CA. Sole mRNA positivity (CNV-/IHC-) were found ≥35% in NSCLC, pancreatic and colorectal cancers. Among 53 UCSD pts who had all three HER2 testing, 22 pts had ≥ 1 positive HER2 test (including 24.5% [13/53] pts with mRNA+ only). We identified 7 pts that were given Anti-HER2 therapy (Tx). One pt with CNV+/mRNA+/IHC+ metastatic esophageal CA achieved complete response with chemotherapy plus trastuzumab followed by trastuzumab maintenance (progression-free survival [PFS]: 48 + months). One pt with metastatic cholangiocarcinoma mRNA+ (CNV and IHC unable to perform) achieved durable partial response with dual-anti-Her2 Tx (trastuzumab and lapatinib) (PFS: 24+ months). In contrast, 5 pts had poor outcomes despite anti-HER2 Tx, given after 3-5 previous Tx lines.Table 133PHER2 status per cancer typeCancer Type (N>10)TotalCNV + mRNA + IHC +CNV+ mRNA + IHC -CNV+ mRNA- IHC+CNV- mRNA+ IHC+CNV+ mRNA- IHC-CNV- mRNA+ IHC-CNV- mRNA- IHC+Any +NN%N%N%N%N%N%N%N%Multi-institutionBreast2603513.5––124.6–4416.983.19938.1Colon8844.5––22.3–3236.422.34045.5NSCLC6411.6––1625–3046.923.14976.6Pancreas34–––38.8–1647.112.92058.8Ovary3013.3––26.7–62013.31033.3Sarcoma27–CUP2528––141414416936Prostate21–––––14.814.829.5Hepatobiliary20210––––1515420Bladder19421.1––421.1–15.315.31052.6Gastroesophageal16212.5–16.3––16.316.3531.3H&N14–Rectal14214.317.1–––535.7–857.1Appendix11–UCSD5323.8––47.5–1324.535.72241.5 Open table in a new tab We found diverse HER2 expression patterns among solid tumors, including difficult to treat cancer of unknown primary, pancreatic CA, and hepatobiliary CA. Although it is a small cohort, patients with HER2 mRNA overexpression could respond to anti-HER2 regimen. Further clinical investigation is warranted.

Eleanor Margaret Burbidge

Eleanor Margaret Burbidge

The University of California San Diego performance-based skills assessment: a useful tool to detect mild everyday functioning difficulties in HIV-infected patients with very good immunological condition

Everyday functioning (EF) impairment is frequent in people living with HIV (PLWH). Our aim was to better explore EF and its association with PLWH cognition, by administering both the IADL scale, the most common functional scale, and a new and ecologic multi-domain (communication and financial skills) tool to measure EF as the University of California San Diego (UCSD) Performance-Based Skills Assessment-Brief Version (UPSA-B). Eighty-five PLWH on cART with very good immunological condition and 23 age- and education-matched healthy controls (HC) were enrolled. PLWH underwent a standardized neuropsychological battery plus IADL, and cognitive impairment was defined according to Frascati criteria. Both groups underwent the UPSA-B. Only 6 subjects (7%) were affected by cognitive impairment (asymptomatic profile). While IADL score was at ceiling for all patients, the UPSA-B total score was significantly worse in PLWH when compared with HC [mean 82.1 (SD 9.3) vs 89.2 (SD 6.2); p < 0.001]. At communication subtest, PLWH group and HC were significantly different (p = 0.002), while no difference emerged at financial skills (p = 0.096). Higher score at UPSA-B was independently associated with better global cognitive performance (composite Z-score) (β 7.79; p < 0.001). Also considering each single cognitive domain, UPSA-B performance (both total and at subtests) confirmed the association with neurocognitive performance. In conclusion, UPSA-B seems to better discriminate EF impairment than IADL in PLWH, and it was associated with cognitive functions, also in the absence of symptomatic cognitive impairment. Thus, it appears a promising tool in the context of HIV infection to avoid misdiagnosis and to better detect also mild EF.

Psychological Stress May Not Be Only Route Of COVID-19’s Psychiatric Burden

Psychological Stress May Not Be Only Route Of COVID-19’s Psychiatric Burden

Elevated Intraocular Pressure in Burn Patients Undergoing Fluid Resuscitation: An Opportunity to Avoid Orbital Compartment Syndrome

Abstract Objective This study aims to discuss clinical characteristics of burn patients who developed elevated intraocular pressure (IOP). We propose management strategies to prevent orbital compartment syndrome before invasive treatment is required. Methods A retrospective review of 47 burn patients at the University of California San Diego (UCSD), Burn Intensive Care Unit (ICU; major regional burn center for San Diego county), was analyzed for demographics, fluid resuscitation volumes, and physical exam findings. Patients requiring topical treatment for high-IOP, defined as ≥30 mm Hg in either or both eyes, were compared with those who did not require treatment, using the t-test and Fisher's exact test. Linear regression tested for an association between peak IOP and fluid volume. Logistic regression evaluated the association between total fluid and treatment of high IOP, while adjusting for other characteristics. Results Six of 47 patients required IOP-lowering treatment. Of the patients requiring treatment, one drop of dorzolamide/timolol in both eyes twice daily was the most common treatment recommendation. Presence of periocular burns was a significant risk factor in patients who required treatment for high IOP. No patients developed orbital compartment syndrome or required surgical intervention to lower IOP. The mean total fluid volume delivered in the first 24 hours was 0.8 times the level prescribed by fluid resuscitation guidelines. Conclusion By treating early clinical signs and properly managing fluid resuscitation, development of orbital compartment syndrome in burn patients can be avoided.

Por uma retórica do extraordinário: loucura, cultura e experiência

“Extraordinary conditions: Culture and Experience in Mental Illness” é um livro dedicado a reflexão sobre cultura e experiência da doença. O livro é composto por um conjunto de artigos da antropóloga Janis H. Jenkins, professora na Universidade da Califórnia, San Diego (UCSD), que resultam de uma longa trajetória dedicada a pesquisa sobre saúde mental a partir da antropologia. O livro é dividido em duas partes, “Psychosis, psychopharmacology, and families” e “Violence, trauma, and depression”, cada uma contendo três artigos, escritos em diferentes momentos da trajetória da autora.

Abstract D005: Outcomes of a cancer research fellowship program for underrepresented high school students

Abstract Introduction: Minority populations and individuals from socioeconomically disadvantaged backgrounds suffer from high rates of cancer, yet these at-risk communities are underrepresented in the biomedical research and clinical workforce. Disparities start from an early age and stem from multiple factors, though gaps in education play a role. In the summer of 2018, University of California San Diego (UCSD) created a cancer research fellowship program for minority high school students called Outreach Program to Inspire Minority and Underrepresented Students (OPTIMUS). This report presents early outcomes of the inaugural cohort of OPTIMUS scholars. Methods: The OPTIMUS program recruits students from four underserved public high schools in southeast San Diego. Selected students (OPTIMUS scholars) are provided transportation to Moores Cancer Center at UCSD daily for a 6-week paid summer internship. Each OPTIMUS scholar is paired with a supportive cancer research lab for a mentored-lab experience. In parallel to the lab experience, scholars participate in a cancer research education curriculum, clinical shadowing, and other endeavors including college preparatory activities and social networking events. Under UCSD faculty oversight, the program is run by medical students, residents, and fellows. We surveyed students about their perceptions of different curricular elements during the program, and again 9-months after completion of the program. Results: OPTIMUS launched in July 2018, and received 132 complete applications, with applicants self-identifying as African American (28%), Hispanic (17%), Pacific Islander (32%), multiracial (10%), and other (13%). The majority of students came from socioeconomic disadvantaged households (61%) and had parents who did not attend college (66%). Ten OPTIMUS scholars were selected for the initial program, and completed all 6-weeks of the summer fellowship. Survey results indicated that students were “very satisfied” to “mostly satisfied” with the majority of the components of the program (scoring 3 or 4 on a 4 point satisfaction scale). The 5 high school seniors in our initial OPTIMUS cohort have each received acceptance letters from 4-year universities, and each plans to major in a biology-based or health science related field. Conclusions: The OPTIMUS cancer research fellowship has generated interest among local underrepresented students, and early outcomes show promising results with students successfully transitioning into university. Long term follow up of students will help to fully understand the impact of this program, though success with OPTIMUS and other programs focusing on strengthening the educational pipeline stand to help improve diversity in the oncology workforce. Citation Format: Ekenechukwu A Akabike, Alexa Azuara, Elena S Heide, Cristal Vieyra, Nicolas Villanueva, Daniel M Seible, James D Murphy. Outcomes of a cancer research fellowship program for underrepresented high school students [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr D005.

Abstract A042: Increasing the participation of minorities in research in a biorepository in UC San Diego, California

Abstract Background: The UC San Diego (UCSD) Moores Cancer Center Biorepository (BR) is a College of American Pathologists (CAP)-accredited core. The BR provides a full array of services including tissue biobanking following informed consent, under an IRB-approved protocol. However, internal review demonstrated low enrollment of minority populations. Methods: In January 2018, the BR launched the MORE (Minorities Outreach Repository Effort) Initiative to: 1) increase research participation by minorities, 2) evaluate the perceptions of research participation by minority groups, 3) evaluate the disease group distributions of minorities at our institution, and 4) increase the participation of minorities in clinical research. Oncology clinic schedules were prescreened, and patients were identified for potential enrollment. Eligible patients were interviewed and informed consent was obtained in collaboration with the treatment teams. The research consent form was translated from English into Spanish, Russian, Vietnamese, Farsi, Tagalog, Simplified Chinese, and Arabic to enable the participation of non-English speaking patients. Race and ethnicity data were obtained from the Epic electronic medical record. Perception of minorities towards tissue collection was evaluated as the percentage of patients who declined consent. Disease distribution was obtained from the California Cancer Registry (data specific for the MCC). Results: Since MORE began, we increased minority participation in our study by 213%. The percentage of declines was similar between Hispanics and non-Hispanics in general, although there was a significantly higher number of declines among Asians and non-Hispanic African Americans, 8% vs. 19% (p =0.01). Disparities were observed in disease distribution with Hispanics having lower incidences of skin cancers, soft tissues/bone sarcomas (12.94% vs. 86.57%; p =0.066), and the highest for liver diseases (41.76% vs. 57.14%; p=0.00001), as compared with all other populations. Surprisingly, the number of patients consulting for genitourinary (GU) and breast diseases is significantly lower in Hispanics, as compared with all other ethnic groups (16.08% as compared with 83.45% for GU, and 20.41% as compared with 79.14 % for breast). In addition, from 420 who self-identified as belonging to a minority group, only 37.5% needed translation. Conclusions: The MORE initiative has been demonstrated to be an efficient way of increasing the participation of minorities, and has allowed us to better understand research participation perceptions and disease distribution in this group. We are now moving to follow up these preliminary results with a full research trial, to start early next year. Citation Format: Sharmeela Kaushal, Jim Salinas, Katherine Crouthamel, Jason K. Sicklick, Alfredo A. Molinolo. Increasing the participation of minorities in research in a biorepository in UC San Diego, California [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr A042.

Abstract D037: Training the next generation of undergraduate URM cancer scientists: Results and lessons learned from a cancer research Partnership Scholar Program

Abstract Background: To improve cancer disparities among underrepresented minority (URM) populations, better representation of URM individuals in cancer research is needed. The San Diego State University (SDSU) and University of California San Diego (UCSD) Moores Cancer Center Partnership is addressing cancer disparities through an educational program targeting undergraduate URM students. Aims: To increase the proportion of URM individuals participating in cancer research by providing a range of research education opportunities supported by the Partnership Scholar Program Methods: The Partnership provides a paid intensive summer research internship enriched with year-round activities that include educational sessions, a journal club, mentorship, social activities, and poster sessions and presentations. Program evaluation through follow-up surveys, focus groups and other formal and informal feedback, including advisory and program steering committees are used to improve the program. Long-term follow-up among scholars (minimum of 10 years) provides data to evaluate the program’s long-term impact on scholars’ education and career path. Results: Since 2016, 63 URM undergraduate students participated in the scholar program. At the Year 2 follow-up (2016 cohort; n=12), 50% had completed their GRE and/or applied to graduate school or medical school. Lessons learned during the course of the program led to changes that were implemented to provide a better learning experience and increase overall program satisfaction, which include: 1) Lengthening the recruitment timeline to improve reach of eligible students and to provide more time for scholar selection and onboarding. 2) Improving the recruitment processes by collaborating with organizations serving URM students. 3) Refining the program contracts and onboarding meetings to help clarify expectations for scholars and faculty mentors. 4) Program coordinator skills and responsibilities (e.g., communication with scholars and mentors) are key to scholar satisfaction and retention. The coordinator organizes and communicates program activities, holds one-on-one in-person meetings, and provides ongoing mentorship to increase retention and scholar success in their ongoing academic development. 5) Adjustments to program components, such as scheduling and curricula of the summer education sessions, pairing scholars with clinicians, and the addition of social events were implemented to improve scholars’ learning experience. 6) Efficient tracking of the multitude of evaluation metrics requires a well-mapped and scheduled evaluation plan that includes automated publication notification systems and LinkedIn groups to evaluate scholars’ satisfaction and achievements post-program completion. Conclusions: The Partnership identified best practices and lessons learned for implementing lab-based internship scholar programs in biomedical and public health fields that could be considered in other programs. (U54CA132384 &amp; U54CA132379) Citation Format: Elinor Gaida, Elva M Arredondo, Anthony J Barrios, Sanford I Bernstein, Richard M Cripps, Sheila E Crowe, Jill Dumbauld Nery, Maria Elena Martinez, Bilge Pakiz, Mercedes A Quintana Serrano, Roland Wolkowicz, Hala Madanat. Training the next generation of undergraduate URM cancer scientists: Results and lessons learned from a cancer research Partnership Scholar Program [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr D037.

2019 DAC Roundtable

As demands for computing have been continuously increasing, various solutions have been proposed. Some approaches deal with improving algorithms and software programs, mainly through the tuning of advanced heuristics and learning methods. Some other tackle the problem by providing specialized hardware to enhance computation. Other revolutionary approaches, such as memcomputing and quantum computing, explore new paradigms in computation to beat the barrier of computational complexity. A highly attended plenary panel at the 2019 Design Automation Conference (DAC) in Las Vegas, NV, USA, with the provocative title “Evolutionary Computing or Heuristic Forever?” spurred a lively discussion that is reported in this Roundtable. It is moderated by the panel organizer and moderator Giovanni De Micheli, EPFL, Switzerland. Panelists include Antun Domic, former CTO and senior VP at Synopsys; Jason Cong, University of California Los Angeles (UCLA); Massimiliano Di Ventra, University of California San Diego (UCSD); and Martin Roettler, Microsoft Research.

Special issue in honour of Prof. Reto J. Strasser - Foreword

This Special issue of Photosynthetica has been compiled to honour Professor Reto Jorg Strasser’s 75th birthday which was on 28 December, 2018. Reto has been a famous scientist in the field of photosynthesis and chlorophyll a fluorescence since the beginning of his PhD studies in 1968 at University of Bern. In 1976, he got a habilitation degree in photobiology at the same university and within the next year (1977) he moved to the USA to work as Principal Acting Investigator (PAI) at University of California, San Diego (UCSD).

A Stroke Care Model at an Academic, Comprehensive Stroke Center During the 2020 COVID-19 Pandemic

Background and purposeThe COVID-19 pandemic has required the adaptation of hyperacute stroke care (including stroke code pathways) and hospital stroke management. There remains a need to provide rapid and comprehensive assessment to acute stroke patients while reducing the risk of COVID-19 exposure, protecting healthcare providers, and preserving personal protective equipment (PPE) supplies. While the COVID infection is typically not a primary cerebrovascular condition, the downstream effects of this pandemic force adjustments to stroke care pathways to maintain optimal stroke patient outcomes. MethodsThe University of California San Diego (UCSD) Health System encompasses two academic, Comprehensive Stroke Centers (CSCs). The UCSD Stroke Center reviewed the national COVID-19 crisis and implications on stroke care. All current resources for stroke care were identified and adapted to include COVID-19 screening. The adjusted model focused on comprehensive and rapid acute stroke treatment, reduction of exposure to the healthcare team, and preservation of PPE. AimsThe adjusted pathways implement telestroke assessments as a specific option for all inpatient and outpatient encounters and accounts for when telemedicine systems are not available or functional. COVID screening is done on all stroke patients. We outline a model of hyperacute stroke evaluation in an adapted stroke code protocol and novel methods of stroke patient management. ConclusionsThe overall goal of the model is to preserve patient access and outcomes while decreasing potential COVID-19 exposure to patients and healthcare providers. This model also serves to reduce the use of vital PPE. It is critical that stroke providers share best practices via academic and vetted social media platforms for rapid dissemination of tools and care models during the COVID-19 crisis.

Inferior rectus displacement in heavy eye syndrome and sagging eye syndrome.

To evaluate if there is a nasal displacement of the vertical rectus muscles in heavy eye syndrome (HES) and/or sagging eye syndrome (SES) compared with age-matched controls. We reviewed the charts of all patients with the diagnosis of HES or SES who were seen at the University of California San Diego (UCSD) between the years 2008-2016 who underwent magnetic resonance imaging (MRI) of the brain and orbits. The control group included patients who had brain and orbital MRIs at UCSD in the absence of known pathology in the orbits or globes. Measurements were taken by 3 separate examiners for all groups. Twenty-four patients (16 with SES and 8 with HES) and 24 age-matched controls were retrospectively reviewed. The superior rectus (SR) of patients with HES and SES was more nasally displaced from the midline compared with that of age-matched controls (p = 0.04, p = 0.03, respectively). The inferior rectus (IR) of patients with HES but not with SES was more nasally displaced from the midline compared with that of age-matched controls (p = 0.04, p = 0.62, respectively). In all groups, the IR nasal displacement from the midline was approximately double compared with the SR. There is a significant nasal displacement of the SR in HES and SES and IR in HES. The observed IR nasal displacement in HES is a new finding and may explain the residual hypotropia and/or esotropia following surgical interventions for HES not involving the IR.

Correlation of serum protein biomarkers with disease activity in psoriatic arthritis

ABSTRACTObjective: To assess the correlation of serum protein biomarkers with disease activity across different domains of psoriatic arthritis (PsA).Material and methods: A cross-sectional cohort of 45 adult patients with PsA fulfilling the classification for psoriatic arthritis (CASPAR) criteria was recruited from University of California San Diego (UCSD) Arthritis Clinics. Clinical data and serum samples were collected and serum was analyzed for protein biomarkers hypothesized to be relevant to disease activity in PsA. Correlations were evaluated for clinical disease activity measures across disease domains.Results: Biomarkers with the highest correlation to the composite indices and disease domains were SAA, IL-6, YKL-40, and ICAM-1. In addition, several biomarkers were moderately correlated with individual composite indices and/or disease domains. Low or no correlation was observed with some biomarkers, e.g. MMP-3, MMP-1, EGF, VEGF, and IL-6R. In contrast, the correlation of all biomarkers with certain disease domains was low; specifically, pain, percent body surface area of psoriasis, and patient global assessment. The multi-biomarker disease activity score (MBDA) developed for rheumatoid arthritis (RA) showed high correlations with most composite indices and some disease domains in PsA.Conclusions: These data suggest biomarker analysis can reflect disease activity across disease domains in PsA. Certain domains would likely benefit from the evaluation of additional biomarkers.

PREVALENCE OF MISMATCH REPAIR GENE MUTATIONS IN UVEAL MELANOMA.

Uveal melanomas are associated with characteristic genetic changes. Germline mutations in mismatch repair (MMR) genes and microsatellite instability have been implicated in the development of numerous malignant neoplasms such as colon and ovarian cancers. The frequency of MMR defects in uveal melanomas has yet to be determined. Here, we analyzed the frequency of MMR gene mutations in uveal melanoma specimens from the University of California, San Diego (UCSD), The Cancer Genome Atlas (TGCA), and the Catalogue of Somatic Mutations in Cancer (COSMIC). We identified only two mutations in a MMR gene: one premature stop codon in the PMS gene within the UCSD cohort (0.5% frequency) and one in-frame deletion in MSH3 within the COSMIC database (0.8% frequency). We report copy number variation of MLH1 in monosomy 3 and show decreased mRNA expression of MLH1 in uveal melanoma specimens with monosomy 3. Expression levels of MLH1 were not found to correlate with the observed number of total mutations. Overall, we show that mutations in MMR genes in uveal melanoma specimens are exceedingly rare, and although one copy of MLH1 is lost in monosomy 3, it does not seem to have pathologic consequences in uveal melanoma pathogenesis.

Abstract TP323: The Role of Ejection Fraction in 90 Day Functional Outcome in Acute Ischemic Infarction Patients Receiving Acute Stroke Therapy

Background: Cardiovascular disease is associated with unfavorable outcomes following acute ischemic stroke (AIS). Left ventricularejection fraction (LVEF) alone has not been reported as a significant predictor of unfavorable outcomes in observational studies of AIS.The purpose of this study was to evaluate the relationship between LVEF and 90 day functional outcome in AIS patients who received acute stroke therapy with IV recombinant tissue plasminogen activator (rt-PA), endovascular therapy (EVT), or combination IV rt-PA+EVT. Methods: This was a retrospective review of prospectively collected data from the University of California San Diego (UCSD) Stroke registry from October 2014-June 2019. Analysis included all patients for whom a stroke code was activated and who had a transthoracic echocardiogram (TTE) during stroke admission or within the previous 30 days prior to AIS. Acute stroke therapy was defined as 1) IV tPA only; 2) EVT only; or 3) IV tPA + EVT. LVEF function was defined as: low &lt;35%, moderately low 36 -49% and normal &gt;50% on TTE. Primary outcome was modified ranking scale(mRS) at 90 days post stroke. Data was examined for frequencies and distribution. Continuous variables were assessed by Pearson correlation and t test. Kruskal-Wallis or ANOVA were used to evaluate group differences. ANCOVA was used for adjusted analysis. Results: In the 227 patients identified, low EF patients were more likely to have atrial fibrillation (61.9%, p=.004) and lower mean admission systolic blood pressure (132.6, p=0.009). LVEF was not significantly associated with 90 day outcome in all treated patients in both unadjusted (p=0.992) and adjusted (p=0.62). LVEF was not significantly associated with 90 day outcome for individual acute stroke therapy groups both unadjusted and adjusted. mRS at 90 days was significantly associated with baseline NIHSS (p&lt;0.001), age (p=0.002), and treatment with IV tPA (p=0.01). Conclusion: In this study, LVEF was not independently associated with 90 day functional outcome in AIS patients who received acute stroke therapy. Further studies in more heterogenous samples are warranted to assess the relationship between LVEF and outcome in all stroke populations.

Abstract WP122: Refusal of Intravenous Thrombolysis for Acute Ischemic Stroke in San Diego

Purpose: To assess the demographic and clinical characteristics of patients who refuse intravenous thrombolysis (IV tPA) for acute ischemic stroke from the Stroke Registry population collected by the University of California San Diego (UCSD) Stroke Team and to compare outcomes between those who were treated with IV tPA and those who refused. Methods: We evaluated patients between July 2004 and July 2019 from the prospective Institutional Review Board (IRB) approved Stroke Registry project. Patients who either received IV tPA or refused IV tPA were included. Baseline demographics, NIHSS, treatment times and 90 day mRS were collected. Results: A total of 1056 patients were included in the analysis. Forty-seven patients (4.5%) refused IV tPA. There were no differences in demographics between patients who were treated with IV tPA and those who refused. Patients who refused IV tPA had a significantly lower baseline NIHSS (4 vs 9, p=&lt;0.0001) and higher baseline mRS (1.3 vs 0.6, p=0.00043) compared to patients who received IV tPA. The time from arrival to treatment decision was significantly longer in patients who refused IV tPA (group mean 57.9 min vs 48.8 min, p=0.03). There was no difference in 90 day mRS between groups. Conclusions: There is a low rate of IV tPA refusal in our registry population which is similar to what previous studies have shown 1,2 . We found that patients who refuse IV tPA have milder deficits and worse pre-morbid disability. We suspect that the longer “arrival to treatment decision” time in the refuse IV tPA group is due to longer informed consent discussions. This study demonstrates the utility of informed consent in clinical practice and highlights the importance of respecting patient autonomy.