Citations

Alzheimer’s disease (AD) is characterized by the deposition of extracellular amyloid plaques and intracellular accumulation of neurofibrillary tangles (NFT). Amyloid beta (Aβ) and tau imaging are widely used for diagnosing and monitoring AD in clinical settings. We evaluated the pathology of a recently developed 6 × Tg − AD (6 × Tg) mouse model by crossbreeding 5 × FAD mice with mice expressing mutant (P301L) tau protein using micro-positron emission tomography (PET) image analysis. PET studies were performed in these 6 × Tg mice using [18F]Flutemetamol, which is an amyloid PET radiotracer; [18F]THK5351 and [18F]MK6240, which are tau PET radiotracers; moreover, [18F]DPA714, which is a translocator protein (TSPO) radiotracer, and comparisons were made with age-matched mice of their respective parental strains. We compared group differences in standardized uptake value ratio (SUVR), kinetic parameters, biodistribution, and histopathology. [18F]Flutemetamol images showed prominent cortical uptake and matched well with 6E10 staining images from 2-month-old 6 × Tg mice. [18F]Flutemetamol images showed a significant correlation with [18F]DPA714 in the cortex and hippocampus. [18F]THK5351 images revealed prominent hippocampal uptake and matched well with AT8 immunostaining images in 4-month-old 6 × Tg mice. Moreover, [18F]THK5351 images were confirmed using [18F]MK6240, which revealed significant correlations in the cortex and hippocampus. Uptake of [18F]THK5351 or [18F]MK6240 was highly correlated with [18F]Flutemetamol in 4-month-old 6 × Tg mice. In conclusion, PET imaging revealed significant age-related uptake of Aβ, tau, and TSPO in 6 × Tg mice, which was highly correlated with age-dependent pathology.

Abstract This study aimed to explore the prognostic impact of spatial distribution of tumor‐infiltrating lymphocytes (TILs) quantified by deep learning (DL) approaches based on digitalized whole‐slide images stained with hematoxylin and eosin in patients with colorectal cancer (CRC). The prognostic impact of spatial distributions of TILs in patients with CRC was explored in the Yonsei cohort ( n = 180) and validated in The Cancer Genome Atlas (TCGA) cohort ( n = 268). Two experienced pathologists manually measured TILs at the most invasive margin (IM) as 0–3 by the Klintrup–Mäkinen (KM) grading method and this was compared to DL approaches. Inter‐rater agreement for TILs was measured using Cohen's kappa coefficient. On multivariate analysis of spatial TIL features derived by DL approaches and clinicopathological variables including tumor stage, microsatellite instability, and KRAS mutation, TIL densities within 200 μm of the IM (f_im200) remained the most significant prognostic factor for progression‐free survival (PFS) (hazard ratio [HR] 0.004 [95% confidence interval, CI, 0.0001–0.15], p = 0.0028) in the Yonsei cohort. On multivariate analysis using the TCGA dataset, f_im200 retained prognostic significance for PFS (HR 0.031 [95% CI 0.001–0.645], p = 0.024). Inter‐rater agreement of manual KM grading was insignificant in the Yonsei ( κ = 0.109) and the TCGA ( κ = 0.121) cohorts. The survival analysis based on KM grading showed statistically significant different PFS in the TCGA cohort, but not the Yonsei cohort. Automatic quantification of TILs at the IM based on DL approaches shows prognostic utility to predict PFS, and could provide robust and reproducible TIL density measurement in patients with CRC.

Abstract Background and Aims Although many studies revealed transcriptomic subtypes of HCC, concordance of the subtypes are not fully examined. We aim to examine a consensus of transcriptomic subtypes and correlate them with clinical outcomes. Approach and Results By integrating 16 previously established genomic signatures for HCC subtypes, we identified five clinically and molecularly distinct consensus subtypes. STM (STeM) is characterized by high stem cell features, vascular invasion, and poor prognosis. CIN (Chromosomal INstability) has moderate stem cell features, but high genomic instability and low immune activity. IMH (IMmune High) is characterized by high immune activity. BCM (Beta‐Catenin with high Male predominance) is characterized by prominent β‐catenin activation, low miRNA expression, hypomethylation, and high sensitivity to sorafenib. DLP (Differentiated and Low Proliferation) is differentiated with high hepatocyte nuclear factor 4A activity. We also developed and validated a robust predictor of consensus subtype with 100 genes and demonstrated that five subtypes were well conserved in patient‐derived xenograft models and cell lines. By analyzing serum proteomic data from the same patients, we further identified potential serum biomarkers that can stratify patients into subtypes. Conclusions Five HCC subtypes are correlated with genomic phenotypes and clinical outcomes and highly conserved in preclinical models, providing a framework for selecting the most appropriate models for preclinical studies.

Abstract Background Facial regions with a high risk for causing injection-related visual comprise are dual-supply vascular areas such as the nose, glabella, and forehead. These regions have in common that they receive arterial blood supply both by branches of the internal (ICA) and the external carotid artery (ECA). Objective The authors sought to investigate the anastomotic pathways between ICA and ECA branches in the upper face. Methods Postmortem computed tomographic angiographic scans of n = 38 Chinese non-embalmed hemifaces (25 males, 13 females; mean age, 37.79 [11.8] years; mean BMI, 21.90 [2.3] kg/m2) were conducted. Data analysis relied on the calculation of depth, distances, and pathways of forehead and temporal arteries to investigate the number of anastomotic connections, the connecting branches, and the layer of connection between ICA and ECA territories. Results Between ICA and ECA territories, only 1 connection in 57.9%, 2 connections in 31.6%, 3 connections in 5.3%, and 4 and 5 connections in 2.6% each were identified. A superficial connection was observed in 15.8% whereas in 84.2% the anastomotic connection was identified to be both superficial and deep. Conclusions Adverse events following facial minimally invasive soft-tissue filler injections for aesthetic purposes are not frequent but devastating if they occur. Anatomic knowledge as presented in this study can help to increase awareness of 3-dimensional vascular anastomotic pathways and identify safer injection zones and safer fascial planes. Evidence-based injection techniques should be followed, and safety aspects should be placed over the aesthetic outcome.

Abstract Introduction: Advances in technology and internet capability have provided an opportunity for efficient collection of Patient Reported Outcomes (PRO) during medical treatment. Here we describe the development and implementation of a system for monitoring patient reported adverse events (AEs) and quality of life (QoL) using electronic PRO (ePRO) instruments for patients enrolled on the Investigation of Serial studies to Predict Your Therapeutic Response with Imaging And moLecular analysis (I-SPY 2 TRIAL), a phase II adaptive platform clinical trial for locally advanced breast cancer. Methods: We designed an ePRO system to increase the accuracy of patient-reported QoL and AE data collection with the intent to act on symptoms in real time. Using the OpenClinica electronic data capture system, we developed rules-based logic to build automated ePRO surveys, customized to the I-SPY 2 treatment schedule. Weekly surveys contained a maximum of 126 validated, branching logic questions from the Patient Reported Outcomes Measurement Information System (PROMIS®) Health Measures and the National Cancer Institute’s Patient Reported Outcomes - Common Terminology Criteria for Adverse Events (PRO-CTCAE™) instruments. We piloted ePROs at the University of California, San Francisco (UCSF) to evaluate compatibility with a variety of I-SPY 2 patient scenarios (e.g., dose delays). We then staggered rollout of the ePRO system to 22 I-SPY 2 sites to ensure technological feasibility. In order to improve accuracy of data collection, we utilized real-time tracking and developed a Clinical Research Coordinator (CRC) training manual, which integrated workflow diagrams with technical solutions. CRCs were trained using remote video sessions. Results: The UCSF ePRO pilot began in September of 2020. Over 9-months, we accrued 43 I-SPY 2 patients (average age of 43.8 years), whose interactions with the ePRO system informed design improvements. Of the patients who received a baseline ePRO survey, the completion rate was 75.9% (average age of 44.2 years). This represents an increase from the 15-20% baseline completion rate for the 360 UCSF I-SPY 2 patients who received paper-based PRO surveys between May 2012 - January 2019. As of June 2021, the ePRO system was operational at all 22 I-SPY 2 sites. The UCSF pilot revealed that engagement with patients at critical timepoints improved survey completion. CRCs facilitated patient participation by sending instructional emails and communicating with patients weekly. We tracked data completeness using a Patient Tracking report, which displayed each patient’s survey completion history. This real-time tool enabled CRCs to identify patients who had not completed ePRO surveys prior to their visit, so they could be provided a tablet computer to complete the survey in the clinic. After introducing tablets into the workflow at UCSF, patient completion of the baseline survey increased from 75.9% to 80%. Conclusion: The transition from paper to electronic QOL and AE data collection improves the ability of patients to complete PRO surveys, but the process must also be optimized and integrated into clinical workflow and trial conduct. In the future, we will present additional results highlighting the feasibility of multilingual ePRO integration into I-SPY 2. ePRO also provides a new opportunity for data analysis, as well as the potential to reduce high grade toxicity through early intervention. It will allow us to assess QoL and AE data by drug regimen, site, provider, and study treatment. The creation of clinician-facing reports also enables access to patient responses in real-time. By implementing ePRO within I-SPY 2, we not only increase efficiency and accuracy of patient-reported data collection, but also improve quality of care and patient safety. Citation Format: Anna Northrop, Anika Christofferson, Michelle Melisko, Laura Sit, Ebunoluwa Olunuga, Ananya Mittal, Adi Goldman, Thelma Brown, Diane Heditsian, Bev Parker, Susie Brain, Carol Simmons, Alessandra Taboada, Kathryn J Ruddy, Tina Hieken, Mara Piltin, Kiri Cook, Carolina Salvador, Candace Mainor, Anosheh Afghahi, Sarah Tevis, Anne Blaes, Irene Kang, Susan Melin, Laura Esserman, Adam Asare, Dawn L Hershman, Amrita Basu. Improving patient-reported outcome data capture for clinical research: ePRO in ISPY 2, a phase 2 breast cancer study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-12-02.

Study Design. Delphi expert panel consensus. Objective. To obtain expert consensus on best practices for appropriate telemedicine utilization in spine surgery. Summary of Background Data. Several studies have shown high patient satisfaction associated with telemedicine during the COVID-19 peak pandemic period as well as after easing of restrictions. As this technology will most likely continue to be employed, there is a need to define appropriate utilization. Methods. An expert panel consisting of 27 spine surgeons from various countries was assembled in February 2021. A two-round consensus-based Delphi method was used to generate consensus statements on various aspects of telemedicine (separated as video visits or audio visits) including themes, such as patient location and impact of patient diagnosis, on assessment of new patients. Topics with ≥75% agreement were categorized as having achieved a consensus. Results. The expert panel reviewed a total of 59 statements. Of these, 32 achieved consensus. The panel had consensus that video visits could be utilized regardless of patient location and that video visits are appropriate for evaluating as well as indicating for surgery multiple common spine pathologies, such as lumbar stenosis, lumbar radiculopathy, and cervical radiculopathy. Finally, the panel had consensus that video visits could be appropriate for a variety of visit types including early, midterm, longer term postoperative follow-up, follow-up for imaging review, and follow-up after an intervention (i.e., physical therapy, injection). Conclusion. Although telemedicine was initially introduced out of necessity, this technology most likely will remain due to evidence of high patient satisfaction and significant cost savings. This study was able to provide a framework for appropriate telemedicine utilization in spine surgery from a panel of experts. However, several questions remain for future research, such as whether or not an in-person consultation is necessary prior to surgery and which physical exam maneuvers are appropriate for telemedicine. Level of Evidence: 4

The NCCN Guidelines for Multiple Myeloma provide recommendations for diagnosis, initial workup, treatment, follow-up, and supportive care for patients with various plasma cell neoplasms, including multiple myeloma. These NCCN Guidelines Insights highlight some of the important updates/changes specific to the treatment of patients with multiple myeloma in the 2022 version of the guidelines.

359881 Background: Sunitinib is approved for advanced gastrointestinal stromal tumor (GIST) after imatinib failure. Ripretinib, a broad-spectrum KIT and PDGFRA switch-control tyrosine kinase inhibitor (TKI), is indicated for the treatment of adult patients (pts) with GIST who received prior treatment with 3 or more TKIs, including imatinib. We compared the efficacy and safety of ripretinib vs sunitinib in pts with advanced GIST who progressed on or were intolerant to imatinib. Methods: This multicenter, global, randomized, open-label phase 3 study (NCT03673501) enrolled adult pts with GIST who progressed on or had intolerance to imatinib. Pts were randomized 1:1 to ripretinib 150 mg once daily (QD) or sunitinib 50 mg QD (4 wks on/2 wks off). Randomization was stratified by KIT mutational status and imatinib intolerance. The primary endpoint was progression-free survival (PFS) by independent radiologic review (IRR) using modified RECIST version 1.1. Key secondary endpoints were objective response rate (ORR) by IRR and overall survival (OS). Hierarchical testing was performed for primary and key secondary endpoints in a prespecified sequence; testing pts with a KIT exon 11 primary mutation (Ex11 intention-to-treat [ITT] population) preceded the all-patient (AP) ITT population. Data cutoff was 1 Sep 2021; final analyses of PFS and ORR and the first interim analysis of OS were conducted. Results: A total of 453 pts were randomized to ripretinib (n = 226; Ex11 ITT, n = 163) or sunitinib (n = 227; Ex11 ITT, n = 164). Median age was 60 yrs (range 18–88) and most pts were white (66.2%) males (62.0%). PFS was not statistically different between ripretinib and sunitinib in the Ex11 ITT (hazard ratio [HR] 0.88, 95% CI 0.66, 1.16; P = 0.36; median 8.3 vs 7.0 mos) or in the AP populations (HR 1.05, 95% CI 0.82, 1.33; P = 0.72; median 8.0 vs 8.3 mos). ORR was numerically higher for ripretinib vs sunitinib in the Ex11 ITT (23.9% vs 14.6%; difference 9.3%, 95% CI 0.7, 17.8; nominal P = 0.03) and AP ITT populations (21.7% vs 17.6%; difference 4.2%, 95% CI −3.2, 11.5; nominal P = 0.27). OS data was highly immature; median OS was not reached in either arm. Fewer pts in the ripretinib arm experienced Grade 3-4 (G3-4) treatment-emergent adverse events (TEAEs) vs sunitinib (41.3% vs 65.6%). Among G3-4 TEAEs with a difference ≥5% between arms, ripretinib had fewer events vs sunitinib (hypertension [8.5% vs 26.7%], palmar-plantar erythrodysesthesia [1.3% vs 10.0%], neutropenia [0% vs 6.3%], and neutrophil count decreased [0% vs 7.2%]). Conclusions: The PFS in both arms was longer than PFS achieved by sunitinib in its pivotal phase 3 trial. While the PFS for ripretinib did not meet the primary endpoint of superiority vs sunitinib, meaningful clinical activity and fewer G3-4 TEAEs were observed in pts with advanced GIST treated with ripretinib after imatinib failure. Clinical trial information: NCT03673501.