Citations

ABSTRACTThis study was to test our hypothesis that flexor tendon reconstruction with an allograft revitalized with bone marrow stromal cells (BMSCs) and synovialized with carbodiimide derivatized autologous synovial fluid (cd‐SYN) would result in better digit functional restoration than the conventional allograft tendon. A total of 32 flexor digital profundus tendons from the second and fifth digit of 16 dogs were created a repair failure model first. Then, failed‐repaired tendons were reconstructed with either a revitalized‐synovialized allograft tendon or a clinical standard autograft tendon (control group). The allograft tendon was seeded with autologous BMSCs in multiple slits and the graft surface was coated with cd‐SYN. A 6 weeks after tendon reconstruction, the digits were harvested and evaluated for digit function, adhesion status, tendon gliding resistance, attachment strength, cell viability, and histologic factors. The allograft group had significantly improved digit function compared with the control group through decreased work of flexion, increased digit range of motion under 2‐Newton force, and less adhesion score (p < .05). However, the distal attachment‐site strength and stiffness in the allograft tendon were significantly weaker than the autografts (p < .05). No significant difference was found for gliding resistance. Histologically, allograft tendons coated with allograft had smoother surfaces and showed tendon‐to‐bone and tendon‐to‐tendon incorporation. Viable BMSCs were found in the tendon slits 6 weeks after the graft. In conclusion, cellular lubricant‐based modification of allograft tendons improved digit function and reduced the adhesions compared with autograft for flexor tendon reconstruction. However, improvement of graft‐to‐host tendon healing is still challenging. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2218–2227, 2018.

Abstract CCGA [NCT02889978] is the largest study of cfDNA-based early cancer detection; the first CCGA learnings from multiple cfDNA assays are reported here. This prospective, multi-center, observational study has enrolled 10,012 of 15,000 demographically-balanced participants at 141 sites. Blood was collected from participants with newly diagnosed therapy-naive cancer (C, case) and participants without a diagnosis of cancer (noncancer [NC], control) as defined at enrollment. This preplanned substudy included 878 cases, 580 controls, and 169 assay controls (n=1627) across 20 tumor types and all clinical stages. All samples were analyzed by: 1) Paired cfDNA and white blood cell (WBC)-targeted sequencing (60,000X, 507 gene panel); a joint caller removed WBC-derived somatic variants and residual technical noise; 2) Paired cfDNA and WBC whole-genome sequencing (WGS; 35X); a novel machine learning algorithm generated cancer-related signal scores; joint analysis identified shared events; and 3) cfDNA whole-genome bisulfite sequencing (WGBS; 34X); normalized scores were generated using abnormally methylated fragments. In the targeted assay, non-tumor WBC-matched cfDNA somatic variants (SNVs/indels) accounted for 76% of all variants in NC and 65% in C. Consistent with somatic mosaicism (i.e., clonal hematopoiesis), WBC-matched variants increased with age; several were non-canonical loss-of-function mutations not previously reported. After WBC variant removal, canonical driver somatic variants were highly specific to C (e.g., in EGFR and PIK3CA, 0 NC had variants vs 11 and 30, respectively, of C). Similarly, of 8 NC with somatic copy number alterations (SCNAs) detected with WGS, 4 were derived from WBCs. WGBS data revealed informative hyper- and hypo-fragment level CpGs (1:2 ratio); a subset was used to calculate methylation scores. A consistent “cancer-like” signal was observed in &lt;1% of NC participants across all assays (representing potential undiagnosed cancers). An increasing trend was observed in NC vs stages I-III vs stage IV (nonsyn. SNVs/indels per Mb [Mean±SD] NC: 1.01±0.86, stages I-III: 2.43±3.98; stage IV: 6.45±6.79; WGS score NC: 0.00±0.08, I-III: 0.27±0.98; IV: 1.95± 2.33; methylation score NC: 0±0.50; I-III: 1.02±1.77; IV: 3.94±1.70). These data demonstrate the feasibility of achieving &gt;99% specificity for invasive cancer, and support the promise of cfDNA assay for early cancer detection. Additional data will be presented on detected plasma:tissue variant concordance and on multi-assay modeling. Citation Format: Alexander A. Aravanis, Geoffrey R. Oxnard, Tara Maddala, Earl Hubbell, Oliver Venn, Arash Jamshidi, Ling Shen, Hamed Amini, John A. Beausang, Craig Betts, Daniel Civello, Konstantin Davydov, Saniya Fazullina, Darya Filippova, Sante Gnerre, Samuel Gross, Chenlu Hou, Roger Jiang, Byoungsok Jung, Kathryn Kurtzman, Collin Melton, Shivani Nautiyal, Jonathan Newman, Joshua Newman, Cosmos Nicolaou, Richard Rava, Onur Sakarya, Ravi Vijaya Satya, Seyedmehdi Shojaee, Kristan Steffen, Anton Valouev, Hui Xu, Jeanne Yue, Nan Zhang, Jose Baselga, Rosanna Lapham, Daron G. Davis, David Smith, Donald Richards, Michael V. Seiden, Charles Swanton, Timothy J. Yeatman, Robert Tibshirani, Christina Curtis, Sylvia K. Plevritis, Richard Williams, Eric Klein, Anne-Renee Hartman, Minetta C. Liu. Development of plasma cell-free DNA (cfDNA) assays for early cancer detection: first insights from the Circulating Cell-Free Genome Atlas Study (CCGA) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-343.

Abstract Biodistribution detection methods currently hold a central role in evaluating clinical potential of new drugs and nanomedicine in vivo, either through therapeutic efficacy or toxicity assays. However, the explorative nature of these methods makes it practically difficult to validate them for clinical studies to comply with regulations as determined by the Food and Drug Administration. This work proposes a new systematic comparison of biodistribution methods to facilitate clinical validation and employment in pre-clinical and early stage clinical studies. Several optical methods (detection through IVIS, confocal microscopy, fluorescence emission), direct detection methods (detection through ICP-OES), and radiation-based methods (detection through gamma counter) are systematically tested and validated on cGMP grade microparticles. The classification here proposed quantitatively highlights the advantages and disadvantages of each method, expressing them in terms of: limit of detection, recovery rate, reproducibility, and sensitivity. As a result, this quantitative evaluation of several preclinical biodistribution detection methods leads to a new rational and objective classification of biodistribution methods based on quantitative characteristics, which is essential to facilitate clinical translation of pre-clinical data collection. Their different characteristics and application-specific advantages are also discussed based in light of the results presented. Overall, this work proposes a new and rational quantitative comparison of biodistribution detection methods with the goal to provide a guide to facilitate clinical translation of on-going and future pre-clinical and early-stage clinical studies. Citation Format: Sara Nizzero, Feng Li, Alessandro Venuta, Guodong Zhang, Carlotta Borsoi, Joy Wolfram, Junhua Mai, Haifa Shen, Zheng Li, Elvin Blanco, Mauro Ferrari. Empowering preclinical studies: A systematic and quantitative analysis of biodistribution methods to facilitate clinical translation of new drugs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-019.