Recent Research Publications- February 2024
Rimel BJ, Enserro D, Bender DP, Jackson CG, Tan A, Alluri N, Borowsky M, Moroney J, Hendrickson AW, Backes F, Swisher E, Powell M, MacKay H.
Cancer. 2023 Dec 21. doi: 10.1002/cncr.35151. Epub ahead of print. PMID: 38127487.
- This paper reports the efficacy of the poly (ADP-ribose) polymerase inhibitor olaparib alone and in combination with the antiangiogenesis agent cediranib compared with cediranib alone in patients with advanced endometrial cancer.
- This was open-label, randomized, phase 2 trial (NCT03660826). Eligible patients had recurrent endometrial cancer, received at least one (<3) prior lines of chemotherapy, and were Eastern Cooperative Oncology Group performance status 0 to 2. Patients were randomly assigned (1:1:1), stratified by histology (serous vs. other) to receive cediranib alone (reference arm), olaparib, or olaparib and cediranib for 28-day cycles until progression or unacceptable toxicity. The primary end point was progression-free survival in the intention-to-treat population. Homologous repair deficiency was explored using the BROCA-GO sequencing panel.
- A total of 120 patients were enrolled and all were included in the intention-to-treat analysis. Median age was 66 (range, 41-86) years and 47 (39.2%) had serous histology. Median progression-free survival for cediranib was 3.8 months compared with 2.0 months for olaparib (hazard ratio, 1.45 [95% CI, 0.91-2.3] p = .935) and 5.5 months for olaparib/cediranib (hazard ratio, 0.7 [95% CI, 0.43-1.14] p = .064). Four patients receiving the combination had a durable response lasting more than 20 months. The most common grade 3/4 toxicities were hypertension in the cediranib (36%) and olaparib/cediranib (33%) arms, fatigue (20.5% olaparib/cediranib), and diarrhea (17.9% cediranib). The BROCA-GO panel results were not associated with response.
Conclusion: The combination of cediranib and olaparib demonstrated modest clinical efficacy; however, the primary end point of the study was not met. The combination was safe without unexpected toxicity.
Erickson BA, Griffith JW, Wensheng G, Mengying Y, Herman T, Bradley CS, Quentin Clemens J, Farrar JT, Gupta P, Kreder KJ, Henry Lai H, Naliboff BD, Newman DK, Rodriguez LV, Spitznagle T, Sutcliffe S, Sutherland SE, Taple BJ, Richard Landis J.
Neurourol Urodyn. 2024 Jan 22. doi: 10.1002/nau.25363. Epub ahead of print. PMID: 38247366.
Purpose: This study tested the hypothesis that ecological momentary assessment (EMA) of pelvic pain (PP) and urinary urgency (UU) would reveal unique Urologic Chronic Pelvic Pain Syndrome (UCPPS) phenotypes that would be associated with disease specific quality of life (QOL) and illness impact metrics (IIM).
Materials and methods: A previously validated smart phone app (M-app) was provided to willing Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) participants. M-app notifications were sent 4-times daily for 14 days inquiring about PP and UU severity. A clustering algorithm that accounted for variance placed participants into PP and UU variability? clusters. Associations between clusters and QOL and IIM were then determined.
- A total of 204 participants enrolled in the M-app study (64% female). M-app compliance was high (median 63% of surveys). Cluster analysis revealed k = 3 (high, low, none) PP clusters and k = 2 (high, low) UU clusters. When adjusting for baseline pain severity, high PP variability, but not UU variability, was strongly associated with QOL and IIM; specifically worse mood, worse sleep and higher anxiety. UU and PP clusters were associated with each other (p < 0.0001), but a large percentage (33%) of patients with high PP variability had low UU variability.
- PP variability is an independent predictor of worse QOL and more severe IIM in UCPPS participants after controlling for baseline pain severity and UU. These findings suggest alternative pain indices, such as pain variability and unpredictability, may be useful adjuncts to traditional measures of worst and average pain when assessing UCPPS treatment responses.
Weber MA, Kerr G, Thangavel R, Conlon MM, Gumusoglu SB, Gupta K, Abdelmotilib HA, Halhouli O, Zhang Q, Geerling JC, Narayanan NS, Aldridge GM.
J Parkinsons Dis. 2023 Dec 30. doi: 10.3233/JPD-230129. Epub ahead of print. PMID: 38189765.
- Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB) are characterized by diffuse spread of alpha-synuclein (α-syn) throughout the brain. Patients with PDD and DLB have a neuropsychological pattern of deficits that include executive dysfunction, such as abnormalities in planning, timing, working memory, and behavioral flexibility. The prefrontal cortex (PFC) plays a major role in normal executive function and often develops α-syn aggregates in DLB and PDD.
- : To investigate the long-term behavioral and cognitive consequences of α-syn pathology in the cortex and characterize pathological spread of α-syn.
Methods: We injected human α-syn pre-formed fibrils into the PFC of wild-type male mice. We then assessed the behavioral and cognitive effects between 12- and 21-months post-injection and characterized the spread of pathological α-syn in cortical, subcortical, and brainstem regions.
Results: We report that PFC PFFs: 1) induced α-syn aggregation in multiple cortical and subcortical regions with sparse aggregation in midbrain and brainstem nuclei; 2) did not affect interval timing or spatial learning acquisition but did mildly alter behavioral flexibility as measured by intraday reversal learning; and 3) increased open field exploration.
- This model of cortical-dominant pathology aids in our understanding of how local α-syn aggregation might impact some symptoms in PDD and DLB.
Hereditary Breast Cancer, Genetics, and Fertility Preservation.
Huber-Keener KJ
Curr Breast Cancer Rep. 2023 Dec 20;15(4):329–336. doi: 10.1007/s12609-023-00515-0
Purpose of Review Fertility preservation is an important consideration in patients with hereditary breast cancer. Breast cancer mutation carriers may present with their cancers at younger ages and require more gonadotoxic treatments. The intent of this review is to discuss the data and research behind the particular fertility challenges mutation carriers may encounter.
Recent Findings Limited data exist for the impact of hereditary breast cancer genes on fertility in breast cancer patients. Data is conflicting on baseline fertility of BRCA1/2 carriers, but breast cancer patients with these mutations become pregnant more often than noncarrier patients. Artificial reproductive technologies (ART) appear to be safe in this patient population, and these patients may benefit from preimplantation genetic testing.
- Discussion of future fertility is important at time of diagnosis of a cancer mutation and breast cancer. Additional research is needed on mutation carriers to determine how their pathogenic variants affect fertility and risks of fertility preservation options.
For a full text of the article, go here: S:\Applications\Departmental Publications, 2024\Hereditary Breast Cancer, Genetics, and Fertility Preservation. Curr Breast Cancer Rep 2023
Boulet SL, Stanhope KK, Platner M, Costley LK, Jamieson DJ.
Am J Obstet Gynecol MFM. 2024 Jan;6(1):101225. doi: 10.1016/j.ajogmf.2023.101225. Epub 2023 Nov 14. PMID: 37972925.
- Although severe maternal morbidity is associated with adverse health outcomes in the year after delivery, patterns of healthcare use beyond the 6-week postpartum period have not been well documented.
Objective: This study aimed to estimate healthcare utilization and expenditures for deliveries with and without severe maternal morbidity in the 12 months following delivery among commercially insured patients.
Study design: Using data from the 2016 to 2018 IBM Marketscan Commercial Claims and Encounters Research Databases, we identified deliveries to individuals 15 to 49 years of age who were continuously enrolled in noncapitated health plans for 12 months after delivery discharge. We used multivariable generalized linear models to estimate adjusted mean 12-month medical expenditures and 95% confidence intervals for deliveries with and without severe maternal morbidity, accounting for region, health plan type, delivery method, and obstetrical comorbidities. We estimated expenditures associated with inpatient admissions, nonemergency outpatient visits, outpatient emergency department visits, and outpatient pharmaceutical claims.
- We identified 366,282 deliveries without severe maternal morbidity and 3976 deliveries (10.7 per 1000) with severe maternal morbidity. Adjusted mean total medical expenditures for deliveries with severe maternal morbidity were 43% higher in the 12 months after discharge than deliveries without severe maternal morbidity ($5320 vs $3041; difference $2278; 95% confidence interval, $1591-$2965). Adjusted mean expenditures for readmissions and nonemergency outpatient visits during the 12-month postpartum period were 61% and 39% higher, respectively, for deliveries with severe maternal morbidity compared with deliveries without severe maternal morbidity. Among deliveries with severe maternal morbidity, adjusted mean total costs were highest for patients living in the western region ($7831; 95% confidence interval, $5518-$10,144) and those having a primary cesarean ($7647; 95% confidence interval, $6323-$8970).
Conclusion: Severe maternal morbidity at delivery is associated with increased healthcare use and expenditures in the year after delivery. These estimates can inform planning of severe maternal morbidity prevention efforts.
Bujimalla PV, Kenne KA, Steffen HA, Swartz SR, Wendt LH, Skibbe AM, Jackson JB, Rysavy MB.
J Rural Health. 2023 Dec 27. doi: 10.1111/jrh.12820. Epub ahead of print. PMID: 38151483.
Purpose: Our aim was to investigate the roles of rurality and distance to care on adverse perinatal outcomes and COVID-19 seroprevalence at the time of delivery over a 1-year period.
Methods: Data were collected from the electronic medical record on all pregnant patients who delivered at a single, large, Midwest academic medical center over 1 year. Rurality was classified using standard Rural-Urban Commuting Area codes. Geographic Information System tools were used to map outcomes. Data were analyzed with univariate and multivariate models, controlling for Body Mass Index (BMI), insurance status, and parity.
- A total of 2,497 patients delivered during the study period; 20% of patients were rural (n = 499), 18.6% were micropolitan (n = 466), and 61.4% were metropolitan (n = 1,532). 10.4% of patients (n = 259) were COVID-19 seropositive. Rural patients did not experience higher rates of any measured adverse outcomes than metropolitan patients; micropolitan patients had increased odds of preterm labor (OR = 1.41, P = .022) and pre-eclampsia (OR = 1.78, P<.001). Patients living 30+ miles away from the medical center had increased odds of preterm labor (OR = 1.94, P<.001), pre-eclampsia (OR = 1.73, P = .002), and infant admission to the neonatal intensive care unit (OR = 2.12, P<.001), as well as lower gestational age at delivery (β = -9.2 days, P<.001) and birth weight (β = -206 grams, P<.001).
Conclusion: Distance to care, rather than rurality, was the key predictor of multiple adverse perinatal outcomes in this cohort of deliveries over a 1-year period. Our study suggests that rurality should not be used as a standalone indicator of access to care without further knowledge of the specific barriers affecting a given population.
Meredith ME, Steimle LN, Radke SM.
medRxiv [Preprint]. 2023 Nov 1:2023.10.31.23297779. doi: 10.1101/2023.10.31.23297779. PMID: 37961292; PMCID: PMC10635247.
- Among the factors contributing to the maternal mortality crisis in the United States is a lack of risk-appropriate access to obstetric care. There are several existing measures of access to obstetric care in the literature and popular media. In this study, we explored how current measures of obstetric access inform the number and location of additional obstetric care facilities required to improve access.
- We formulated two facility location optimization models to determine the number of new facilities required to minimize the number of reproductive-aged women living in obstetric care deserts. We define deserts as either "maternity care deserts", designated by the March of Dimes to be counties with no obstetric care hospital or obstetric providers, or regions further than 50 miles from critical care obstetric (CCO) services. We gathered information on hospitals with obstetric services from Georgia Department of Public Health public reports and estimated the female reproductive-age population by census block group using the American Community Survey.
Results: Out of the 1,910,308 reproductive-aged women who live in Georgia, 104,158 (5.5%) live in maternity care deserts, 150,563 (7.9%) reproductive-aged women live further than 50 miles from CCO services, and 38,202 (2.0%) live in both "maternity care desert" and further than 50 miles from CCO services. Our optimization analysis suggests that 16 new obstetric facilities (a 19% increase from the current 83 facilities) are required to reduce the number of reproductive-aged women living in "maternity care deserts" by 50% (from 104,158 to 51,477). At least 56 new obstetric care facilities (a 67% increase) would be required to eliminate maternity care deserts in Georgia. Meanwhile, expansion of 2 obstetric care facilities to offer CCO services would reduce the number of reproductive-aged women living further than 50 miles from CCO services by 50% (from 150,563 to 57,338), and 8 facilities would ensure all women in Georgia live within 50 miles of CCO services.
- Current measures of access to obstetric care may not be sufficient for evaluating access and tracking progress toward improvements. In a state like Georgia with a large number of small counties, eliminating maternity care deserts would require a prohibitively large number of new obstetric care facilities. This work suggests that additional measures and tools are needed to estimate the number and type of obstetric care facilities that best match practical resources to obstetric care needs.
Multiplexed Live-Cell Imaging for Drug Responses in Patient-Derived Organoid Models of Cancer.
Colling KE, Symons EL, Buroni L, Sumanasiri HK, Andrew-Udoh J, Witt E, Losh HA, Morrison AM, Leslie KK, Dunnill CJ, de Bono JS, Thiel KW.
J Vis Exp. 2024 Jan 5;(203). doi: 10.3791/66072. PMID: 38251777.
Patient-derived organoid (PDO) models of cancer are a multifunctional research system that better recapitulates human disease as compared to cancer cell lines. PDO models can be generated by culturing patient tumor cells in extracellular basement membrane extracts (BME) and plating them as three-dimensional domes. However, commercially available reagents that have been optimized for phenotypic assays in monolayer cultures often are not compatible with BME. Herein, we describe a method to plate PDO models and assess drug effects using an automated live-cell imaging system. In addition, we apply fluorescent dyes that are compatible with kinetic measurements to quantify cell health and apoptosis simultaneously. Image capture can be customized to occur at regular time intervals over several days. Users can analyze drug effects in individual Z-plane images or a Z Projection of serial images from multiple focal planes. Using masking, specific parameters of interest are calculated, such as PDO number, area, and fluorescence intensity. We provide proof-of-concept data demonstrating the effect of cytotoxic agents on cell health, apoptosis, and viability. This automated kinetic imaging platform can be expanded to other phenotypic readouts to understand diverse therapeutic effects in PDO models of cancer.
Cervical Cancer: Preventable Deaths Among American Indian/Alaska Native Communities
Buck DiSilvestro J, Ulmer KK, Hedges M, Kardonsky K, Bruegl AS.
Obstet Gynecol Clin N Am. 2024 Mar;51(1):125–141. doi: 10.1016/j.ogc.2023.11.009.
American Indian/Alaska Native (AI/AN) individuals have twice the mortality rate of cervical cancer than the general US population. Participation in prevention programs such as cervical cancer screening and human papillomavirus (HPV) vaccination are under-utilized in this population. There are high rates of established cervical cancer risk factors among this community, with AI/AN people having a higher likelihood of infection with high-risk HPV strains not included in the 9-valent vaccine. There is a need for more robust and urgent prevention and treatment efforts in regard to cervical cancer in the AI/AN community.