Citations

Abstract In vivo positron emission tomography (PET) imaging is a key modality to evaluate disease status of brain tumors. In recent years, tremendous efforts have been made in developing PET imaging methods for pediatric brain tumors. Carbon-11 labelled tryptophan derivatives are feasible as PET imaging probes in brain tumor patients with activation of the kynurenine pathway, but the short half-life of carbon-11 limits its application. Using a transgenic mouse model for the sonic hedgehog (Shh) subgroup of medulloblastoma, here we evaluated the potential of the newly developed 1-(2-[18F]fluoroethyl)-L-tryptophan (1-L-[18F]FETrp) as a PET imaging probe for this common malignant pediatric brain tumor. 1-L-[18F]FETrp was synthesized on a PETCHEM automatic synthesizer with good chemical and radiochemical purities and enantiomeric excess values. Imaging was performed in tumor-bearing Smo/Smo medulloblastoma mice using a Perkin-Elmer G4 PET-X-Ray scanner. Medulloblastoma tumors showed significant and specific accumulation of 1-L-[18F]FETrp. 1-L-[18F]FETrp also showed significantly higher tumor uptake than its D-enantiomer 1-D-[18F]FETrp. The uptake of 1-L-[18F]FETrp in normal brain tissue was low, suggesting that 1-L-[18F]FETrp may prove a valuable PET imaging probe for the Shh subgroup of medulloblastoma and possibly other pediatric and adult brain tumors. Citation Format: Xuyi Yue, Yangchun Xin, Hua Li, Zhiqin Li, Hancheng Cai, Sigrid A. Langhans. Tumor-specific PET imaging with an 18F-labeled tryptophan analogue in a transgenic medulloblastoma mouse model [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1652.

G 4 C 2 repeat–derived poly(GR) plays a key role in mediating TDP-43 mislocalization and aggregation in vitro and in vivo.

Glial fibrillary acidic protein (GFAP) is cleared by the Food and Drug Administration (FDA) to determine need for head computed tomography (CT) within 12 h after mild traumatic brain injury (TBI) (Glasgow Coma Score [GCS] 13–15); S100 calcium-binding protein B (S100B) serves this function in Europe. This phase 1 biomarker cohort analysis of the multi-center, observational Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study compares GFAP's diagnostic performance, measured on a rapid point-of-care platform, against protein S100B to predict intracranial abnormalities on CT within 24 h post-injury across the spectrum of TBI (GCS 3–15). Head CT scan performed in TBI subjects and blood was collected for all consenting subjects presenting to 18 United States level 1 trauma centers. Plasma was analyzed on a point-of-care device prototype assay for GFAP and serum was analyzed for S100B. In 1359 patients with TBI (GCS 3–15), mean (standard deviation [SD]) age = 40.1 (17.0) years; 68% were male. Plasma GFAP levels were significantly higher in CT+ TBI subjects (median = 1358 pg/mL, interquartile range [IQR]: 472–3803) than in CT- TBI subjects (median = 116 pg/mL, IQR: 26–397) or orthopedic trauma controls ( n = 122; median = 13 pg/mL, IQR: 7–20), p < 0.001. Serum S100B levels were likewise higher in CT+ TBI subjects (median = 0.17 μg/L, IQR: 0.09–0.38) than in CT- TBI subjects (median = 0.10 μg/L, IQR: 0.06–0.18), p < 0.001. Receiver operating characteristic curves were generated for prediction of intracranial injury on admission CT scan; area under the curve (AUC) for GFAP was significantly higher than for S100B in the same cohort (GFAP AUC – 0.85, 95% confidence interval [CI] 0.83–0.87; S100B AUC – 0.67, 95% CI 0.64-0.70; p < 0.001). GFAP, measured on a point-of-care platform prototype assay, has high discriminative ability to predict intracranial abnormalities on CT scan in patients with TBI across the full injury spectrum of GCS 3–15 through 24 h post-injury. GFAP substantially outperforms S100B.

BackgroundStudies have reported racial disparities in access to and use of multiple myeloma (MM) treatments between African American (AA) and White patients. Although AA patients demonstrate longer disease‐specific survival, this has not uniformly translated into improved survival over time. The association between race and treatment patterns and survival outcomes was analyzed using data from the Connect MM Registry.MethodsThe Connect MM Registry is a large US, multicenter, prospective observational cohort study of patients with newly diagnosed MM. Patients who received first‐line (1L) stem cell transplantation (SCT) or who did not receive SCT (non‐SCT or non–stem cell transplantation [NSCT]) were grouped by raceEffects of race and transplantation status on the use of triplet treatment were estimated using logistic regression.ResultsTreatment patterns in 1L (types and duration of induction, posttransplantation maintenance) were similar between AA and White patients. SCT rates in 1L (32% vs 36%) and triplet treatment use (AA: 44% for NSCT patients and 72% for SCT patients; and White: 48% for NSCT patients and 72% for SCT patients) during first induction were similar. No significant effect of race or transplantation status on 1L triplet treatment use was observed. Race was not found to be associated with survival outcomes among patients who underwent NSCT; however, AA patients who received SCT had significantly longer overall survival compared with White patients who underwent SCT (not reached vs 88.2 months; hazard ratio, 0.56; 95% CI, 0.35‐0.89 [P = .0141]).ConclusionsAA and White patients were found to have similar treatment patterns in the Connect MM Registry, suggesting that both groups had equal access to health care. In this real‐world setting, AA patients received standard‐of‐care treatment, which might have contributed to better MM‐specific survival compared with White patients.

Abstract Asparagine‐linked glycosylation 13 homolog ( ALG13 ) encodes a nonredundant, highly conserved, X‐linked uridine diphosphate (UDP)‐ N ‐acetylglucosaminyltransferase required for the synthesis of lipid linked oligosaccharide precursor and proper N‐linked glycosylation. De novo variants in ALG13 underlie a form of early infantile epileptic encephalopathy known as EIEE36, but given its essential role in glycosylation, it is also considered a congenital disorder of glycosylation (CDG), ALG13‐CDG. Twenty‐four previously reported ALG13‐CDG cases had de novo variants, but surprisingly, unlike most forms of CDG, ALG13‐CDG did not show the anticipated glycosylation defects, typically detected by altered transferrin glycosylation. Structural homology modeling of two recurrent de novo variants, p.A81T and p.N107S, suggests both are likely to impact the function of ALG13. Using a corresponding ALG13‐deficient yeast strain, we show that expressing yeast ALG13 with either of the highly conserved hotspot variants rescues the observed growth defect, but not its glycosylation abnormality. We present molecular and clinical data on 29 previously unreported individuals with de novo variants in ALG13 . This more than doubles the number of known cases. A key finding is that a vast majority of the individuals presents with West syndrome, a feature shared with other CDG types. Among these, the initial epileptic spasms best responded to adrenocorticotropic hormone or prednisolone, while clobazam and felbamate showed promise for continued epilepsy treatment. A ketogenic diet seems to play an important role in the treatment of these individuals.

Abstract Background Although diagnostic error (DE) is a significant problem, it remains challenging for clinicians to identify it reliably and to recognize its contribution to the clinical trajectory of their patients. The purpose of this work was to evaluate the reliability of real-time electronic health record (EHR) reviews using a search strategy for the identification of DE as a contributor to the rapid response team (RRT) activation. Objectives Early and accurate recognition of critical illness is of paramount importance. The objective of this study was to test the feasibility and reliability of prospective, real-time EHR reviews as a means of identification of DE. Methods We conducted this prospective observational study in June 2019 and included consecutive adult patients experiencing their first RRT activation. An EHR search strategy and a standard operating procedure were refined based on the literature and expert clinician inputs. Two physician-investigators independently reviewed eligible patient EHRs for the evidence of DE within 24 hours after RRT activation. In cases of disagreement, a secondary review of the EHR using a taxonomy approach was applied. The reviewers categorized patient experience of DE as Yes/No/Uncertain. Results We reviewed 112 patient records. DE was identified in 15% of cases by both reviewers. Kappa agreement with the initial review was 0.23 and with the secondary review 0.65. No evidence of DE was detected in 60% of patients. In 25% of cases, the reviewers could not determine whether DE was present or absent. Conclusion EHR review is of limited value in the real-time identification of DE in hospitalized patients. Alternative approaches are needed for research and quality improvement efforts in this field.

ABSTRACT Background Implementation of checklists has been shown to be effective in improving patient safety. This study aims to evaluate the effectiveness of implementation of a checklist for daily care processes into clinical practice of pediatric intensive care units (PICUs) with limited resources. Methods Prospective before–after study in eight PICUs from China, Congo, Croatia, Fiji, and India after implementation of a daily checklist into the ICU rounds. Results Seven hundred and thirty-five patients from eight centers were enrolled between 2015 and 2017. Baseline stage had 292 patients and post-implementation 443. The ICU length of stay post-implementation decreased significantly [9.4 (4–15.5) vs. 7.3 (3.4–13.4) days, p = 0.01], with a nominal improvement in the hospital length of stay [15.4 (8.4–25) vs. 12.6 (7.5–24.4) days, p = 0.055]. The hospital mortality and ICU mortality between baseline group and post-implementation group did not show a significant difference, 14.4% vs. 11.3%; p = 0.22 for each. There was a variable impact of checklist implementation on adherence to various processes of care recommendations. A decreased exposure in days was noticed for; mechanical ventilation from 42.6% to 33.8%, p &lt; 0.01; central line from 31.3% to 25.3%, p &lt; 0.01; and urinary catheter from 30.6% to 24.4%, p &lt; 0.01. Although there was an increased utilization of antimicrobials (89.9–93.2%, p &lt; 0.01). Conclusions Checklists for the treatment of acute illness and injury in the PICU setting marginally impacted the outcome and processes of care. The intervention led to increasing adherence with guidelines in multiple ICU processes and led to decreased length of stay.

ObjectivesCrohn disease (CD) is a chronic inflammation in the digestive tract that affects millions of Americans. Bowel vascularity has important diagnostic information because inflammation is associated with blood flow changes. We recently developed an ultrasensitive ultrasound microvessel imaging (UMI) technique with high vessel sensitivity. This study aimed to evaluate the feasibility of UMI to assist CD detection and staging.MethodsUltrasound microvessel imaging was performed on 76 bowel wall segments from 48 symptomatic patients with CD. Clinically indicated computed tomographic/magnetic resonance enterography was used as the reference standard. The vessel‐length ratio (VLR, the number of vessel pixels in the bowel wall segment normalized to the segment length) was derived in both conventional color flow imaging (CFI) and UMI to quantitatively stage disease activity. Receiver operating characteristic curves were then analyzed between different disease groups.ResultsThe VLR‐CFI and VLR‐UMI detected similar correlations between vascularization and disease activity: severe inflammation had a higher VLR than normal/mildly inflamed bowels (P < .05). No significant difference was found between quiescent and mild CD due to the small sample size. The VLR‐CFI had more difficulties in distinguishing quiescent versus mild CD compared to the VLR‐UMI. After combining the VLR‐UMI with thickness, in the receiver operating characteristic curve analysis, the areas under the curves (AUCs) improved to AUC1 = 0.996 for active versus quiescent CD, AUC2 = 0.978 for quiescent versus mild CD, and AUC3 = 0.931 for mild versus severe CD, respectively, compared to those using thickness alone (AUC1 = 0.968; P = .04; AUC2 = 0.919; P = .16; AUC3 = 0.857; P = .01).ConclusionsUltrasound microvessel imaging offers a safe and cost‐effective tool for CD diagnosis and staging, which may potentially assist disease activity classification and therapy efficacy evaluation.

Abstract Purpose: NOTCH signaling is associated with tumorigenesis, mutagenesis, and immune tolerance in non–small cell lung cancer (NSCLC), indicating its association with the clinical benefit of immune checkpoint inhibitors (ICI). We hypothesized that NOTCH mutation in NSCLC might be a robust predictor of immunotherapeutic efficacy. Experimental Design: Multiple-dimensional data including genomic, transcriptomic, and clinical data from cohorts of NSCLC internal and public cohorts involving immunotherapeutic patients were analyzed. Polymorphism Phenotyping v2 (PolyPhen-2) system was performed to determine deleterious NOTCH mutation (del-NOTCHmut). Further investigation on molecular mechanism was performed in The Cancer Genome Atlas (TCGA) data via CIBERSORT and gene set enrichment analysis. Results: Our 3DMed cohort (n = 58) and other four cohorts (Rizvi, POPLAR/OAK, Van Allen, and MSKCC; n = 1,499) uncovered marked correlation between NOTCH1/2/3 mutation and better ICI outcomes in EGFR/ALKWT population, including objective response rate (2.20-fold, P = 0.001), progression-free survival [HR, 0.61; 95% confidence interval (CI), 0.46–0.81; P = 0.001], and overall survival (HR, 0.56; 95% CI, 0.32–0.96; P = 0.035). Del-NOTCHmut exhibited better predictive function than non-deleterious NOTCH mutation, potentially via greater transcription of genes related to DNA damage response and immune activation. Del-NOTCHmut was not linked with prognosis in TCGA cohorts and chemotherapeutic response, but was independently associated with immunotherapeutic benefit, delineating the predictive, but not prognostic, utility of del-NOTCHmut. Conclusions: This work distinguishes del-NOTCHmut as a potential predictor to favorable ICI response in NSCLC, highlighting the importance of genomic profiling in immunotherapy. More importantly, our results unravel a possibility of personalized combination immunotherapy as adding NOTCH inhibitor to ICI regimen in NSCLC, for the optimization of ICI treatment in clinical practice.

Abstract BACKGROUND Fertility can be diminished by adjuvant chemotherapy or by age-related decline in ovarian reserve in young women with breast cancer (BC). We sought to better understand the burden of concern about fertility, utilization of fertility preservation strategies, and the impact of fertility concerns on treatment decision-making among young women newly diagnosed with BC enrolled in a large multi-site study. METHODS The Young and Strong study was a cluster-randomized study that tested the effect of an educational and supportive care intervention for young women with BC (≤45) and their oncologists, at community and academic sites across the US. Patients were surveyed following diagnosis at enrollment (within 3 months of diagnosis), and at 3, 6 and 12 months thereafter. The surveys included sociodemographic and psychosocial measures (HADS anxiety and depression; Perceived Stress Scale), as well as a modified Fertility Issues Survey, which assessed fertility concerns and preservation. Treatment and tumor pathology data were abstracted from the medical record. Logistic regression was used to identify sociodemographic, clinical, and psychosocial factors that were associated with fertility concern. Variables with p ≤ 0.20 in univariable analyses were evaluated in the multivariable model using stepwise selection; variables achieving significance at p &lt; 0.05 were included in the final model. RESULTS Of 467 women enrolled from 54 sites (14 academic, 40 community), 419 had evaluable data regarding treatment decision-making. Median age of participants at diagnosis was 40 yrs (range 22-45), 11% were African American, 80% were married/lived with a partner, and 75% had children. 35% of tumors were stage I, 51% stage II, and 14% stage III; 82% of women were treated with chemotherapy. At the time of treatment decision-making, 133 (32%) were concerned about fertility, varying by age, with fertility concern reported by 73%, 28% and 13% of those age ≤35, 36-40 and &gt;40 (p&lt;.01), respectively. 67 (16%) said their treatment decisions had been affected by fertility concerns, including 62 of the 133 (47%) with fertility concern. 12/419 (3%) chose one chemotherapy regimen over another, 4 (1%) chose not to take hormonal medication, and 32 (8%) chose or may choose to take it for less than 5 years. 251 (60%) reported having discussed fertility issues with their physician before starting therapy, including 117/133 (88%) of women with fertility concern. 29 (7%), including 27/133 (20%) of the concerned, took special steps to lessen the chance of infertility: 14 underwent cryopreservation of embryos, 14 cryopreservation of eggs and 12 took GnRH agonist or pursued other strategies. In the multivariable model, history of difficulty becoming pregnant (versus none, OR=3.86, 95%CI: 1.84-8.1) was associated with greater concern about fertility. Older age (OR=.75 per 1-year increase, 95%CI: 0.69-0.81) and having more than one child at diagnosis (versus never delivered, OR=0.14, 95%CI: 0.05-0.40) were associated with less concern about fertility. Race, being partnered, high-education, income, symptoms of depression, stress or anxiety at diagnosis, tumor stage, hormone receptor status and receipt of chemotherapy were not independently associated with concern about fertility in the multivariable model. CONCLUSION In a geographically and ethnically diverse study of young women with newly diagnosed BC in the U.S., many were concerned about fertility, with potential impact on their treatment decisions. For the majority of women, these concerns were discussed with their providers, though only a minority underwent fertility preservation strategies prior to treatment. Citation Format: Elisabeth Etaix, Yue Zheng, Shoshana Rosenberg, Kathryn J Ruddy, J Russel Hoverman, Karen M Emmons, Ann H Partridge. Fertility concerns and treatment decision-making among young women with breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-13-17.