Positron emission tomography imaging of tumor angiogenesis with a (61/64)Cu-labeled F(ab')(2) antibody fragment.

The objective of this study was to characterize the in vitro and in vivo properties of the F(ab')(2) fragment of TRC105, a human/murine chimeric IgG1 monoclonal antibody that binds with high avidity to human and murine CD105 (i.e., endoglin), and investigate its potential for positron emission tomography (PET) imaging of tumor angiogenesis after (61/64)Cu-labeling. TRC105-F(ab')(2) of high purity was produced by pepsin digestion of TRC105, which was confirmed by SDS-PAGE, HPLC analysis, and mass spectrometry. (61/64)Cu-labeling of NOTA-TRC105-F(ab')(2) (NOTA denotes 1,4,7-triazacyclononane-1,4,7-triacetic acid) was achieved with yields of >75% (specific activity: ∼115 GBq/µmol). PET imaging revealed rapid tumor uptake of (64)Cu-NOTA-TRC105-F(ab')(2) in the 4T1 murine breast cancer model (5.8 ± 0.8, 7.6 ± 0.6, 5.6 ± 0.4, 5.0 ± 0.6, and 3.8 ± 0.7% ID/g at 0.5, 3, 16, 24, and 48 h postinjection respectively; n = 4). Since tumor uptake peaked at 3 h postinjection, (61)Cu-NOTA-TRC105-F(ab')(2) also gave good tumor contrast at 3 and 8 h postinjection. CD105 specificity of the tracers was confirmed by blocking studies and histopathology. In conclusion, the use of a F(ab')(2) fragment led to more rapid tumor uptake (which peaked at 3 h postinjection) than radiolabeled intact antibody (which often peaked after 24 h postinjection), which may allow for same day immunoPET imaging in future clinical studies.

Barriers and facilitators to influenza-like illness absenteeism among healthcare workers in a tertiary-care healthcare system, 2017-2018 influenza season.

OBJECTIVE: Influenza can be introduced and propagated in healthcare settings by healthcare workers (HCWs) working while ill with influenza. However, reasons driving this behavior are unclear. In this study, we examined barriers to and facilitators of absenteeism during the influenza season. DESIGN: Cross-sectional mixed methods study. SETTING: Ambulatory and inpatient settings in a large, tertiary-care healthcare system. METHODS: An anonymous electronic survey was sent to HCWs between June 11 and July 13, 2018, asking participants to self-report influenza-like illness (ie, ILI symptoms of fever, chills, cough, or sore throat) during the 2017-2018 influenza season. We conducted a logistical regression analysis to identify factors associated with absenteeism. RESULTS: Of 14,250 HCWs, 17% responded to the survey. Although 1,180 respondents (51%) reported symptoms of ILI, 575 (43%) did not stay home while ill. The most commonly perceived barriers to ILI absenteeism included being understaffed (odds ratio [OR], 1.78; P = .04), unable to find a replacement for work (OR, 2.26; P = .03), desiring not to use time off (OR, 2.25; P = .003), and paid by the hour or unable to afford being absent (OR, 2.05; P = .02). Common perceived facilitators of absenteeism included support from coworkers and management, clearer policy, better sick days availability, and lower perceived threat of disciplinary action. CONCLUSIONS: Reporting to work with ILI symptoms is common among HCWs. Most barriers and facilitators are related to systems. Addressing system factors, such as policies regarding sick days and sick leave and ensuring adequate backup staffing, is likely to facilitate absenteeism among ill HCWs.

Intraoperative targeted optical imaging: a guide towards tumor-free margins in cancer surgery.

Over the last several decades, development of various imaging techniques such as computed tomography, magnetic resonance imaging, and positron emission tomography greatly facilitated the early detection of cancer. Another important aspect that is closely related to the survival of cancer patients is complete tumor removal during surgical resection. The major obstacle in achieving this goal is to distinguish between tumor tissue and normal tissue during surgery. Currently, tumor margins are typically assessed by visual assessment and palpation of the tumor intraoperatively. However, the possibility of microinvasion to the surrounding tissues makes it difficult to determine an adequate tumor-free excision margin, often forcing the surgeons to perform wide excisions including the healthy tissue that may contain vital structures. It would be ideal to remove the tumor completely, with minimal safety margins, if surgeons could see precise tumor margins during the operation. Molecular imaging with optical techniques can visualize the tumors via fluorophore conjugated probes targeting tumor markers such as proteins and enzymes that are upregulated during malignant transformation. Intraoperative use of this technique may facilitate complete excision of the tumor and tumor micromasses located beyond the visual capacity of the naked eye, ultimately improving the clinical outcome and survival rates of cancer patients.

In vivo targeting and imaging of tumor vasculature with radiolabeled, antibody-conjugated nanographene.

Herein we demonstrate that nanographene can be specifically directed to the tumor neovasculature in vivo through targeting of CD105 (i.e., endoglin), a vascular marker for tumor angiogenesis. The covalently functionalized nanographene oxide (GO) exhibited excellent stability and target specificity. Pharmacokinetics and tumor targeting efficacy of the GO conjugates were investigated with serial noninvasive positron emission tomography imaging and biodistribution studies, which were validated by in vitro, in vivo, and ex vivo experiments. The incorporation of an active targeting ligand (TRC105, a monoclonal antibody that binds to CD105) led to significantly improved tumor uptake of functionalized GO, which was specific for the neovasculature with little extravasation, warranting future investigation of these GO conjugates for cancer-targeted drug delivery and/or photothermal therapy to enhance therapeutic efficacy. Since poor extravasation is a major hurdle for nanomaterial-based tumor targeting in vivo, this study also establishes CD105 as a promising vascular target for future cancer nanomedicine.

Positron emission tomography imaging of CD105 expression with a 64Cu-labeled monoclonal antibody: NOTA is superior to DOTA.

Optimizing the in vivo stability of positron emission tomography (PET) tracers is of critical importance to cancer diagnosis. In the case of (64)Cu-labeled monoclonal antibodies (mAb), in vivo behavior and biodistribution is critically dependent on the performance of the bifunctional chelator used to conjugate the mAb to the radiolabel. This study compared the in vivo characteristics of (64)Cu-labeled TRC105 (a chimeric mAb that binds to both human and murine CD105), through two commonly used chelators: 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). Flow cytometry analysis confirmed that chelator conjugation of TRC105 did not affect its CD105 binding affinity or specificity. PET imaging and biodistribution studies in 4T1 murine breast tumor-bearing mice revealed that (64)Cu-NOTA-TRC105 exhibited better stability than (64)Cu-DOTA-TRC105 in vivo, which resulted in significantly lower liver uptake without compromising the tumor targeting efficiency. In conclusion, this study confirmed that NOTA is a superior chelator to DOTA for PET imaging with (64)Cu-labeled TRC105.