Highlights d Proteomic profiles of extracellular vesicles and particles (EVPs) from 426 human samples d Identification of pan-EVP markers d Characterization of tumor-derived EVP markers in human tissues and plasma d EVP proteins can be useful for cancer detection and determining cancer type

AUTHOR CONTRIBUTIONS G.R. designed the experimental approach, performed the experimental work, analyzed the data, coordinated the project and wrote the manuscript. A.H. performed primary tumour growth and exosome education in vivo studies, cancer cell proliferation in vitro studies, cancer cell culture and exosome isolation, coordinated the project and wrote the manuscript. C.M.K. generated CEMIP overexpression, performed molecular cloning work and genetic manipulation of cancer cells, cancer cell culture and exosome isolation, coordinated the project and wrote the manuscript. I.R.M. performed brain slice ex vivo FACS analysis and exosome education in vivo studies, cancer cell culture and exosome isolation, coordinated the project, wrote and reviewed the manuscript. L.S. performed brain slice ex vivo experimental work, tissue processing and immunostaining, ex vivo and in vivo ImageJ data analysis and quantification, cancer cell invasion in vitro studies, western blot analysis, cancer cell culture and exosome isolation, and contributed to figure panel assembly. D.F. performed density gradient exosome isolation, characterization and analysis, western blot analysis, and cancer cell culture. H.S.K. and P.R.O. performed RNA sequencing data analysis. I.S. performed tissue processing and immunostaining, ex vivo and in vivo ImageJ data analysis and quantification, cancer cell culture and exosome isolation. I.C.S. performed western blot analysis and assisted in analysis of human data.

Only a few studies in children have evaluated the efficacy of prophylactic regimens using tacrolimus on acute graft-versus-host disease (aGVHD). As a result, optimal tacrolimus levels in children after matched sibling donor allogeneic hematopoietic cell transplantation (alloHCT) are not well defined. We measured the association between subtherapeutic levels (<10 ng/mL) during weeks 1 to 4 after alloHCT and the cumulative incidence of grades II to IV aGVHD in children. Additionally, we identified optimal lower cutoff levels for tacrolimus. Sixty patients (median age, 8 years) received tacrolimus/mycophenolate mofetil between March 2003 and September 2012. Twenty-three had a malignant disease and 37 nonmalignant disorders. The stem cell source included peripheral blood stem cells (n = 12) and bone marrow or cord blood (n = 48). Conditioning regimen varied. Specifically, 38.3% received a myeloablative regimen, 36.7% receiving a reduced-toxicity regimen, and 25% receiving a reduced-intensity regimen. Tacrolimus was initiated at .03 mg/kg/day via continuous i.v. infusion or .12 mg/kg/day orally. The dose was adjusted to maintain daily steady state concentrations within a range of 10 to 20 ng/mL. The overall incidence of grades II to IV aGVHD was 33.3%. On multivariate analysis, a mean tacrolimus level < 10 ng/mL during week 3 (P = .042; 95% confidence interval, 1.051 to 14.28) was significantly associated with increased incidence of grades II to IV aGVHD. Using weekly receiver operator curves, the optimal lower cutoff for tacrolimus levels was 10 to 11.2 ng/mL. Further prospective studies are warranted to study the incidence of aGVHD comparing the conventional tacrolimus levels of 5 to 15 versus 10 to 15 ng/mL.

Tacrolimus (FK506) is a calcineurin inhibitor and is an essential component of many immunosuppressive regimens. The oral bioavailability of tacrolimus may be affected by many factors, including patient age and gender, as well as by drug-drug interactions or genetic polymorphisms in drug metabolism. The dosing recommendations for pediatric allogeneic hematopoietic cell transplantation (alloHCT) recipients have been derived from tacrolimus use in adult solid-organ transplantation patients. Data describing the impact of conversion of i.v. tacrolimus to oral on the incidence of acute graft-versus-host disease (aGVHD) are limited in children after alloHCT. In this study, we describe the incidence of grades II to IV aGVHD after conversion from i.v. tacrolimus to oral tacrolimus and study the clinical factors associated with delayed achievement of therapeutic blood levels. In this retrospective analysis, 68 pediatric patients (median age, 6.7 years; range, .25 to 22 years), underwent alloHCT for malignant and nonmalignant diseases and received tacrolimus and mycophenolate mofetil for aGVHD prophylaxis. Among all patients, the median number of days to achieve therapeutic tacrolimus trough concentration (10 ng/mL to 20 ng/mL) was 7 days (range, 0 to 37 days). Twenty-two patients developed grades II to IV aGVHD and the cumulative incidence of grades II to IV aGVHD in all patients was 32.4% (standard error, .06). On multivariate analysis ethnicity (white versus others: odds ratio [OR], −4.5; 95% confidence interval [95% CI], 1.091 to 18.91; P = .038) and ≥ 10 days of subtherapeutic tacrolimus levels in first 30 days on i.v. (OR, −3.8; 95% CI, 1.276 to 11.43; P =.017) were significantly associated with delay in achieving therapeutic tacrolimus trough concentration. The impact of race/ethnicity on therapeutic tacrolimus trough concentration in pediatric alloHCT recipients should be further studied prospectively so that individualized dosing plans can be developed.