Citations

AbstractHow to deliver best care in various clinical settings remains a vexing problem. All pertinent healthcare-related questions have not, cannot, and will not be addressable with costly time- and resource-consuming controlled clinical trials. At present, evidence-based guidelines can address only a small fraction of the types of care that clinicians deliver. Furthermore, underserved areas rarely can access state-of-the-art evidence-based guidelines in real-time, and often lack the wherewithal to implement advanced guidelines. Care providers in such settings frequently do not have sufficient training to undertake advanced guideline implementation. Nevertheless, in advanced modern healthcare delivery environments, use of eActions (validated clinical decision support systems) could help overcome the cognitive limitations of overburdened clinicians. Widespread use of eActions will require surmounting current healthcare technical and cultural barriers and installing clinical evidence/data curation systems. The authors expect that increased numbers of evidence-based guidelines will result from future comparative effectiveness clinical research carried out during routine healthcare delivery within learning healthcare systems.

Abstract Background The development of novel glioma therapies necessitates rapid, longitudinal, and individualized feedback from each patient's tumor. Due in part to the relative inaccessibility of dynamic gliomas, little information is available regarding mechanisms of in situ therapeutic response and resistance which may be needed to iteratively develop candidate therapies and combinations thereof. To address this challenge, we are performing glioma biomarker discovery by serial cerebrospinal fluid (CSF) sampling from Ommaya reservoirs to determine how the CSF proteome can reveal early longitudinal intelligence regarding glioma status, biology, and therapeutic response. Material and Methods Global proteomic analysis of CSF was performed on the Somalogic platform -- an aptamer-based technology for highly sensitive and specific analyses of over 7,000 proteins. Discovery analysis comprised of the top-500 ranked proteins in CSF from seven patients with high-grade gliomas (HGG) versus non-glioma controls. The top-500 HGG proteins were then preliminarily filtered to include only proteins that met two additional criteria: 1) decrease with lower tumor burden as defined by tumor resection, and 2) increase with greater tumor burden as defined by recurrence in individual paired patient samples. Results Proteomic enrichment analysis revealed a conserved HGG CSF proteomic signature defined by 79 proteins, including ones known to be over-expressed in solid tumor malignancies, such as retinoblastoma binding protein 4, heat shock protein 90, and sorcin. When queried in an independent validation cohort, the HGG proteomic signature was consistently enriched across 13 gliomas diverse in primary versus recurrent status, subtype, and grade, when compared to control CSF samples. In two patients for whom CSF was available prior to and immediately after resections, proteins in the HGG signature decreased as indicated by a lower tumor burden. Interestingly, the glioma CSF proteomic signature was highly enriched for blood-associated proteins (as defined by two paired sets of CSF samples with low vs. high hemoglobin), despite these patients' samples containing little-to-no hemoglobin proteins. Conclusion Global CSF proteomics acquired from longitudinal neurosurgical access to unique gliomas has the promise to yield biomarkers which may be used to gain insights regarding glioma biology, tumor burden, and evolution throughout a patient's disease and treatment course.

AbstractNon‐Hodgkin lymphoma (NHL) is composed of a heterogeneous collection of subtypes with considerable differences in genetics, biology and aetiology. Studies to date on physical activity and NHL risk have not had sufficient sample size to evaluate whether associations differ by subtype. We pooled data from nine case‐control studies to examine the association between moderate‐to‐vigorous intensity physical activity (MVPA) and risk of NHL overall and by subtype (diffuse large B‐cell lymphoma, follicular lymphoma, chronic lymphocytic leukaemia/small lymphocytic lymphoma, marginal zone lymphoma and mature T‐cell lymphoma). A total of 5653 cases and 9115 controls were included in the pooled analysis. Physical activity was harmonised across nine studies and modelled as study‐specific tertiles. Multinomial logistic regression was used to estimate the association between physical activity and NHL, adjusting for confounders. The overall odds of NHL was 13% lower among participants in the most active tertile of MVPA compared to the least active tertile (adjusted odds ratio = 0.87, 95% CI = 0.80, 0.95). Similar decreases were observed across NHL subtypes. In summary, in this pooled analysis of case‐control studies, physical activity was associated with a modest risk reduction for each NHL subtype examined and with overall NHL.

Background and aims: The American Gastroenterological Association (AGA) recently launched the Clinical Care Pathway for the Risk Stratification and Management of Patients with NAFLD to identify adults with significant fibrosis. We aimed to examine this pathway’s performance in the US population. Approach and Results: Using the 2017–2018 National Health and Nutrition Examination Survey data, we identified participants aged ≥18 with available Fibrosis‐4 (FIB‐4) score and liver stiffness measurement (LSM) in the absence of other liver diseases. Based on the AGA clinical pathway, FIB‐4 < 1.3 and LSM < 8 kilopascals (kPa) by vibration‐controlled transient elastography (VCTE) are associated with low risk of significant fibrosis. Using these cutoffs, we examined the pathway performance using negative predictive value (NPV) and positive predictive value (PPV) and explored alternative risk‐stratification strategies. There were 2322 participants with available data (projected to 94.2 million US adults). The NPV of LSM ≥ 8 kPa among those with FIB‐4 < 1.3 was 90%, whereas the PPV among those with FIB‐4 1.3–2.67 was 13%. As diabetes was a strong predictor of fibrosis, we propose a simple, alternative strategy to eliminate the indeterminate FIB‐4 range and perform VCTE in those with FIB‐4 ≥ 1.3 and diabetes. This strategy would decrease the number of VCTEs from 14.5 to 4.9 million and increase PPV from 13% to 33% without compromising the NPV among those who did not undergo VCTE. Conclusion: The implementation of the current AGA clinical pathway would lead to overutilization of VCTE. An alternative strategy using FIB‐4 ≥ 1.3 and diabetes to select adults undergoing second‐line testing will improve this pathway’s performance and minimize unnecessary VCTEs.

Abstract Gliomas may leverage alternate metabolic pathways in response to metabolism-targeted therapeutic intervention, all of which remain unexplored in the live human glioma, in situ. Defining emergent mechanisms of metabolic resistance in response to therapeutic challenge can help guide rational combinatorial therapies. To date, the metabolic response of gliomas in response to therapeutic intervention has remained poorly understood due to the relative inaccessibility of the live human tumor, in situ. Microdialysis is an underutilized tool that could be leveraged to overcome this longstanding challenge. Data from our ongoing intraoperative microdialysis trial have revealed an upregulation of polyamine metabolism and a novel glioma-associated metabolite, guanidinoacetate (GAA) -- a metabolite co-produced with ornithine, which is required for polyamine synthesis. In a Phase 0 trial, we will evaluate in situ glioma responses to polyamine depletion (difluoromethylornithine, DFMO) with or without blockade of polyamine uptake (AMXT 1501) to identify candidate extracellular biomarkers of target engagement and cytotoxicity in fifteen post-operative patients who have undergone a standard-of-care planned subtotal resection for high-grade glioma. Intraoperatively, high-molecular-weight catheters will be implanted into the residual tumor and brain adjacent to the resection cavity for post-operative longitudinal monitoring of extracellular metabolites via microdialysis. Polyamines and guanidinoacetate, a candidate biomarker of glioma-upregulated polyamine synthesis, will be monitored throughout therapeutic intervention from post-operative day (POD) 1 to POD5 via longitudinal microdialysis to determine live in situ glioma pharmacodynamic responses to polyamine depletion. Catheters will be removed on post-operative day five prior to discharge. We hypothesize that GAA will reflect local tumor production of polyamine metabolism. Additionally, in situ microdialysis in Phase 0 trials will allow for pharmacodynamic and pharmacokinetic, in addition to metabolic, monitoring, an opportunity which is rarely afforded in most clinical trials due to lack of access to the CNS.

Abstract INTRODUCTION Rapid, detailed feedback is needed to understand the individualized biological impacts of novel glioma therapies. We are performing glioma biomarker discovery by serial cerebrospinal fluid (CSF) sampling from Ommaya reservoirs to determine how the CSF proteome can reveal early longitudinal intelligence regarding glioma status, biology, and therapeutic response. METHODS Global proteomic analysis of CSF was performed on the Somalogic platform − an aptamer-based technology for highly sensitive and specific analysis of over 7,000 proteins. Discovery analysis comprised of the top-500 ranked proteins in CSF from seven patients with high-grade gliomas (HGG) versus non-glioma controls. The top-500 HGG proteins were then preliminarily filtered to include only proteins that met two additional criteria of decrease with resection and increase with recurrence in individual paired patient samples. RESULTS Proteomic enrichment analysis revealed a conserved HGG CSF proteomic signature defined by 79 proteins, including ones known to be over-expressed in solid tumor malignancies, such as retinoblastoma binding protein 4, heat shock protein 90, and sorcin. The HGG proteomic signature was consistently enriched in an independent validation cohort consisting of 13 gliomas diverse in primary versus recurrent status, subtype, and grade, when compared to control CSF samples. Encouragingly, proteins in the HGG signature decreased in the two patients for whom CSF was collected prior to and after resection (both at POD16 and POD18) with decreased tumor burden. CONCLUSION Our preliminary data demonstrate the ability to gain detailed, individualized insights regarding glioma biology, tumor burden, and evolution through global CSF proteomics acquired from longitudinal neurosurgical access to unique gliomas.

Abstract Introduction: There is growing evidence to support a modest inverse association between daily aspirin use and ovarian cancer risk. We previously hypothesized that this association may differ by immune cell infiltration. In our prior study evaluating heterogeneity by tumor-associated macrophage (TAM) infiltration, aspirin use was associated with lower risk of ovarian cancer with high protumorigenic M2-type TAM infiltration, but not low M2-type TAM infiltration. The goal of the present study was to evaluate the hypothesis that the association between aspirin use and ovarian cancer risk also differs by infiltration with tumor-infiltrating lymphocytes (TILs). Methods: We included cases and matched controls from the Nurses’ Health Study (NHS), NHSII, and New England Case Control Study. Study participants self-reported aspirin use including regular use (≥1 x per week), duration of use, and number of tablets. A gynecologic pathologist (JLH), who was blinded to exposure status, reviewed hematoxylin and eosin stained tumor slides to quantify TILs for all cases (n=547). We used polytomous logistic regression, adjusted for ovarian cancer risk factors, to estimate odds ratios (OR) for aspirin use and ovarian cancer risk by TIL infiltration. Results: Overall, recent aspirin use was associated with lower risk of ovarian cancer compared with no regular aspirin use (OR=0.65, 95%CI=0.47-0.89). Recent aspirin use was associated with a lower risk of ovarian cancer exhibiting TIL infiltration (OR=0.38, 95%CI=0.26-0.56) but not with TIL-negative cancers (OR=1.00, 95%CI=0.71-1.41; p-heterogeneity &lt;0.001). We observed similar results for aspirin duration and tablets. For duration, comparing ≥10 years of aspirin use to &lt;1 year we observed a significantly lower risk of ovarian cancer with TILs (OR=0.47, 95%CI=0.41-0.71; p-trend=0.004), but a nonsignificant reduction for ovarian cancer without TILs (OR=0.86, 95%CI=0.59-1.26; p-trend=0.72; p-heterogeneity=0.03). Comparing ≥6 tablets to &lt;1 tablet per week, there was evidence of a lower risk of ovarian cancer with TILs (OR=0.47, 95%CI=0.30-0.75; p-trend=0.001) but not without TILs (OR=1.02, 95%CI=0.70-1.48; p-trend=0.84; p-heterogeneity=0.003). Conclusions: Our results suggest that prediagnosis aspirin use may be an important modulator of immune cell infiltration in ovarian tumors, supporting an immunogenic mechanism for aspirin in ovarian carcinogenesis. Further work is under way to evaluate nonaspirin nonsteroidal anti-inflammatory drugs, and to consider which subsets of TAMs and TILs may be driving heterogeneity in the associations between anti-inflammatory drugs and ovarian cancer risk. Citation Format: Mollie E. Barnard, Britton Trabert, Jonathan L. Hecht, Ellen L. Goode, Naoko Sasamoto, Kathryn L. Terry, Shelley S. Tworoger. Aspirin use and ovarian cancer risk by lymphocyte infiltration [abstract]. In: Proceedings of the AACR Special Conference on Modernizing Population Sciences in the Digital Age; 2019 Feb 19-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(9 Suppl):Abstract nr A19.

ObjectivePatients with myelin oligodendrocyte glycoprotein antibody (MOG‐IgG)‐associated disease (MOGAD) suffer from severe optic neuritis (ON) leading to retinal neuro‐axonal loss, which can be quantified by optical coherence tomography (OCT). We assessed whether ON‐independent retinal atrophy can be detected in MOGAD.MethodsEighty patients with MOGAD and 139 healthy controls (HCs) were included. OCT data was acquired with (1) Spectralis spectral domain OCT (MOGAD: N = 66 and HCs: N = 103) and (2) Cirrus high‐definition OCT (MOGAD: N = 14 and HCs: N = 36). Macular combined ganglion cell and inner plexiform layer (GCIPL) and peripapillary retinal nerve fiber layer (pRNFL) were quantified.ResultsAt baseline, GCIPL and pRNFL were lower in MOGAD eyes with a history of ON (MOGAD‐ON) compared with MOGAD eyes without a history of ON (MOGAD‐NON) and HCs (p < 0.001). MOGAD‐NON eyes had lower GCIPL volume compared to HCs (p < 0.001) in the Spectralis, but not in the Cirrus cohort. Longitudinally (follow‐up up to 3 years), MOGAD‐ON with ON within the last 6–12 months before baseline exhibited greater pRNFL thinning than MOGAD‐ON with an ON greater than 12 months ago (p < 0.001). The overall MOGAD cohort did not exhibit faster GCIPL thinning compared with the HC cohort.InterpretationOur study suggests the absence of attack‐independent retinal damage in patients with MOGAD. Yet, ongoing neuroaxonal damage or edema resolution seems to occur for up to 12 months after ON, which is longer than what has been reported with other ON forms. These findings support that the pathomechanisms underlying optic nerve involvement and the evolution of OCT retinal changes after ON is distinct in patients with MOGAD. ANN NEUROL 2022;92:476–485

Abstract Background: Ovarian cancer is the deadliest gynecologic cancer. Standard treatments for advanced stage high-grade serous ovarian cancer, the most common type, include (1) primary cytoreductive surgery (PCS) followed by adjuvant chemotherapy or (2) neoadjuvant chemotherapy (NACT) with interval debulking surgery. Patients in whom PCS is unlikely to yield optimal cytoreduction to no visible residual disease (R0) or who have medical contraindications to PCS are recommended to undergo NACT. Previous studies on associations between environmental factors and risk of any macroscopic residual disease have yielded inconsistent results. We aimed to (1) comprehensively examine the associations between demographic, lifestyle and reproductive factors and risk of residual disease after PCS; and (2) develop and internally validate a risk prediction model based on these factors. Methods: We used pooled data on 3,492 women who had PCS following a diagnosis with advanced stage high-grade serous ovarian, fallopian tube or primary peritoneal cancers from the Ovarian Cancer Association Consortium. Fifteen exposures of interest included age at diagnosis, menopausal status, race/ethnicity, education level, first-degree family history of ovarian cancer, endometriosis, smoking, body mass index, parity, incomplete pregnancy, tubal ligation, use of combined oral contraceptives, depot-medroxyprogesterone acetate, estrogen (ET), and combined estrogen-progestin therapy. We fit logistic regression models to examine each exposure-residual disease association in 80% of the data (n=2,794; random selection of participants). We developed a risk prediction model including the factors with p-values ≤0.2. Area under the receiver operating characteristic curve (AUC) was used to assess the model’s discrimination in the remaining 20% of the data (n=698). Results: Of the 3,492 participants, 2,003 (57%) had residual disease following PCS. Older age at diagnosis was associated with an increased risk of residual disease (OR=1.07 per five years, 95% CI 1.03-1.11). In contrast, a family history of ovarian cancer (OR=0.63, 95% CI 0.42-0.95) or ET use for 5+ years (OR=0.61, 95% CI 0.39-0.96) were associated with achieving R0. These above factors were included in the risk prediction model as were race/ethnicity, personal history of endometriosis, and smoking, whose p-values ≤0.2. The model showed modest performance in the validation set (AUC=0.64). Conclusions: Younger age at diagnosis, family history of ovarian cancer, and long-term ET use were associated with achieving R0 following PCS. Future studies incorporating genetic and clinical factors to improve the risk prediction for residual disease following PCS are warranted. Citation Format: Minh Tung Phung, Andrew Berchuck, Ellen L. Goode, Marc T. Goodman, Gillian E. Hanley, Jean Richardson, Bronwyn Grout, Anne Chase, Cindy McKinnon Deurloo, Beth Y. Karlan, Toon Van Gorp, Keitaro Matsuo, Karen McLean, Malcolm C. Pike, Joellen M. Schildkraut, Kathryn L. Terry, Anna DeFazio, Penelope M. Webb, Paul D. P. Pharoah, Susan J. Ramus, Celeste Leigh Pearce. Environmental factors associated with residual disease after ovarian cancer primary cytoreduction surgery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2248.