Citations

Abstract Purpose: Colorectal cancers with deficient DNA mismatch repair (dMMR) are presumed to uniformly have dense lymphocytic infiltration that underlies their favorable prognosis and is critical to their responsiveness to immunotherapy, as compared with MMR-proficient (pMMR) tumors. We examined T-cell densities and their potential heterogeneity in a large cohort of dMMR tumors. Experimental Design: CD3+ and CD8+ T-cell densities were quantified at the invasive margin (IM) and tumor core (CT) in 561 stage III colon cancers (dMMR, n = 278; pMMR, n = 283) from a phase III adjuvant trial (N0147). Their association with overall survival (OS) was determined using multivariable Cox analysis. Results: Although CD3+ and CD8+ T-cell densities in the tumor microenvironment were higher in dMMR versus pMMR tumors overall, intertumoral heterogeneity in densities between tumors was significantly higher by 30% to 88% among dMMR versus pMMR cancers (P < 0.0001 for all four T-cell subtypes [CD3+IM, CD3+CT, CD8+IM, CD8+CT]). A substantial proportion of dMMR tumors (26% to 35% depending on the T-cell subtype) exhibited T-cell densities as low as that in the bottom half of pMMR tumors. All four T-cell subtypes were prognostic in dMMR with CD3+IM being the most strongly prognostic. Low (vs. high) CD3+IM was independently associated with poorer OS among dMMR (HR, 4.76; 95% confidence interval, 1.43–15.87; P = 0.0019) and pMMR tumors (P = 0.0103). Conclusions: Tumor-infiltrating T-cell densities exhibited greater intertumoral heterogeneity among dMMR than pMMR colon cancers, with CD3+IM providing robust stratification of both dMMR and pMMR tumors for prognosis. Potentially, lower T-cell densities among dMMR tumors may contribute to immunotherapy resistance.

Background: Increasing evidence points to intracranial atherosclerosis as a risk factor not only for stroke but also for dementia, but whether it is linked to Alzheimer’s disease-specific pathology itself is less understood. In the community-based Atherosclerosis Risk in Communities (ARIC) study, we evaluated the cross-sectional association between intracranial atherosclerosis and cerebral amyloid deposition, in nondemented participants. Methods: In 2011-2014, a subset of participants from the ARIC Neurocognitive Study underwent both a brain MRI, including high-resolution vessel wall imaging, and florbetapir PET, as a marker of amyloid deposition. We analyzed the association between elevated amyloid (defined as a global cortical florbetapir standardized uptake value ratio (SUVR)>1.2) and intracranial arterial plaque presence, frequency, and extent of stenosis, with adjustment for demographic and vascular risk factors. We tested effect modification by APOE ε4 genotype. Results: In 300 participants (mean age of 76y, 44% African-American, 56% female, 31% carriers of at least one APOE ε4 allele), intracranial plaque was found in 105 (35%) participants. Mean SUVR was higher in individuals with vs without plaque (1.34 ± 0.29 vs 1.27 ± 0.23, p=0.03). In adjusted models, plaque presence was not associated significantly with elevated SUVR in the total sample, nor was number of plaques. Associations between plaque presence and extent were generally stronger in APOE ε4 carriers than noncarriers (p<0.05 for interaction for some plaque features; see Table). Conclusions: Although intracranial arterial plaque or stenosis was not definitively associated with brain amyloid in this sample of nondemented older adults, associations with brain amyloid appeared stronger in carriers of an APOE ε4 allele, consistent with studies demonstrating a similar relationship as that seen with other more traditionally measured vascular risk factors.

Key PointsDUSP22-rearranged ALCLs belong to a distinct subset of ALCLs lacking activated STAT3. DUSP22-rearranged ALCLs have a unique molecular signature characterized by DNA hypomethylation and an immunogenic phenotype.

Objectives To examine the association between hospitalization, critical illness, and infection occurring during middle‐ and late‐life and structural brain abnormalities in older adults. Design Prospective cohort study. Setting Atherosclerosis Risk in Communities (ARIC) Study. Participants A community sample of adults who were 44 to 66 years of age at study baseline. Measurements Active surveillance of local hospitals and annual participant contact were used to gather hospitalization information (including International Classification of Diseases, Ninth Revision , codes) on all participants over a 24‐year surveillance period. Subsequently, a subset of participants underwent 3‐Tesla brain magnetic resonance imaging (MRI) to quantify total and regional brain volumes, white matter hyperintensity (WMH) volume, and white matter microstructural integrity (fractional anisotropy (FA) and mean diffusivity (MD) as measured using diffusion tensor imaging (DTI)). Results Of the 1,689 participants included (mean age at MRI 76±5), 72% were hospitalized, 14% had a major infection, and 4% had a critical illness during the surveillance period. Using covariate‐adjusted regression, hospitalization was associated with 0.12–standard deviation (SD) greater WMH volume (95% confidence interval (CI)=0.00–0.24) and poorer white matter microstructural integrity (0.17‐SD lower FA, 95% CI=–0.27 to –0.06; 0.16‐SD greater MD, 95% CI=0.07–0.25) than no hospitalization. There was a dose‐dependent relationship between number of hospitalizations, smaller brain volumes, and lower white matter integrity ( p ‐trends ≤.048). In hospitalized participants, critical illness was associated with smaller Alzheimer's disease (AD) signature region (–1.64 cm 3 , 95% CI=–3.16 to –0.12); major infection was associated with smaller AD signature region (–1.28 cm 3 , 95% CI=–2.21 to –0.35) and larger ventricular volume (3.79 cm 3 , 95% CI= 0.81–6.77). Conclusions Whereas all‐cause hospitalization was primarily associated with lower white matter integrity, critical illness and major infection were associated with smaller brain volume, particularly within regions implicated in AD.

BACKGROUND Expanding quantities of mesenchymal stem cells (MSCs) sufficient to treat large numbers of patients in cellular therapy and regenerative medicine clinical trials is an ongoing challenge for cell manufacturing facilities. STUDY DESIGN AND METHODS We evaluated options for scaling up large quantities of bone marrow–derived MSCs (BM‐MSCs) using methods that can be performed in compliance with Good Manufacturing Practices (GMP). We expanded BM‐MSCs from fresh marrow aspirate in αMEM supplemented with 5% human platelet lysate using both an automated cell expansion system (Quantum, Terumo BCT) and a manual flask‐based method using multilayer flasks. We compared MSCs expanded using both methods and assessed their differentiation to adipogenic and osteogenic tissue, capacity to suppress T‐cell proliferation, cytokines, and growth factor secretion profile and cost‐effectiveness of manufacturing enough BM‐MSCs to administer a single dose of 100 × 10 6 cells per subject in a clinical trial of 100 subjects. RESULTS We have established that large quantities of clinical‐grade BM‐MSCs manufactured with an automated hollow‐fiber bioreactor were phenotypically (CD73, CD90, CD105) and functionally (adipogenic and osteogenic differentiation and cytokine and growth factor secretion) similar to manually expanded BM‐MSCs. In addition, MSC manufacturing costs significantly less and required less time and effort when using the Quantum automated cell expansion system over the manual multilayer flasks method. CONCLUSION MSCs manufactured by an automated bioreactor are physically and functionally equivalent to the MSCs manufactured by the manual flask method and have met the standards required for clinical application.

7547 Background: E1412 statistical design is based on results of lenalidomide/RCHOP (R2CHOP) vs RCHOP in ABC-DLBCL as determined by NanoString gene expression profiling (GEP). Central pathology review (CPR) was conducted to confirm diagnosis and to ensure adequate tissue for GEP. Initially, CPR occurred after randomization and treatment initiation. Due to high ineligibility rate (IR), the protocol was amended to include real-time CPR to determine patient eligibility prior to study enrollment. We describe the revision and how it affected the IR. Methods: Pre-amendment, CPR was done retrospectively. Post-amendment, CPR was done prior to enrollment, in real time, on a submitted tissue block, H&E, and CD20 slides. Based on CPR, if a diagnosis of DLBCL was confirmed, and sufficient tissue remained for GEP, a patient was deemed eligible and the submitter was notified by fax. Protocol goal was notification within 2 working days (WD) of receipt of materials at the CPR site. Results: Pre-amendment, 219 patients were enrolled. Material was typically received at the CPR site 6-9 months after patient registration. The IR with CPR was 36% for all those enrolled, and 26% for patients with adequate tissue for GEP. Post-amendment, 218 patients were submitted for CPR: 145 (67%) were eligible; 73 (33%) were ineligible. Reasons for ineligibility included insufficient tissue (n=27) or a diagnosis other than de novo DLBCL (n=46). Notification of eligibility occurred in a median of 2 WD (Mean 2 WD; Range 1-5 WD). 90% were notified within the protocol goal of 2 WD. GEP for all enrolled was completed within 6 weeks of CPR. Conclusions: The success of this novel, real-time CPR serves as a model for the future of NCTN DLBCL trials. When CPR is performed rapidly prior to enrollment, study slots may more accurately reflect the target population and eliminate excess costs. In the precision medicine era, rapid collection of relevant pathology and biomarker data is essential to trial success. Study Coordinated by ECOG-ACRIN Cancer Research Group (Robert L. Comis, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs), supported by NCI grant # CA180820, CA180794, CA180790, CA180799, CA180833.