The regional lymph nodes draining primary breast carcinomas are generally the first site to be invaded by disseminating tumor cells. The extent of lymph node involvement remains the most reliable indicator for staging and prognosis of breast cancer. We have investigated host-tumor interactions between breast carcinoma cells and the lymph node stroma, which may control the outcome of lymph node infiltration. In a previous study, we identified integrin-mediated cell adhesion as a correlate of the metastatic potential of human and rat carcinoma cells.

GSK2618960 was well tolerated and blocked IL-7 receptor signalling upon full target engagement. Although there was no discernible impact on peripheral T cell subsets in healthy subjects, GSK2618960 may effectively modulate the autoinflammatory activity of pathogenic T cells in diseased tissue. A relatively short half-life is likely the result of target-mediated rather than ADA-mediated clearance.

The αβ integrin is involved in the pathogenesis of cancer and fibrosis. A radiolabeled 20-amino-acid αβ-binding peptide, derived from the foot and mouth virus (NAVPNLRGDLQVLAQKVART [A20FMDV2]), has been developed to image αβ levels preclinically. This study was designed to translate these findings into a clinical PET imaging protocol to measure the expression of αβ in humans. Preclinical toxicology was undertaken, and a direct immunoassay was developed for 4-fluorobenzamide (FB)-A20FMDV2. Four healthy human subjects (2 male and 2 female)received a single microdose of F-FB-A20FMDV2 followed by a multibed PET scan of the whole body over more than 3 h. There were no findings in the preclinical toxicology assessments, and no anti-A20FMDV2 antibodies were detected before or after dosing with the PET ligand. The mean and SD of the administered mass of F-FB-A20FMDV2 was 8.7 ± 4.4 μg (range, 2.7-13.0 μg). The mean administered activity was 124 ± 20 MBq (range, 98-145 MBq). There were no adverse or clinically detectable pharmacologic effects in any of the subjects. No significant changes in vital signs, laboratory study results, or electrocardiography results were observed. Uptake of radioactivity was observed in the thyroid, salivary glands, liver, stomach wall, spleen, kidneys, ureters, and bladder. Time-activity curves indicated that the highest activity was in the bladder content, followed by the kidneys, small intestine, stomach, liver, spleen, thyroid, and gallbladder. The largest component of the residence times was the voided urine, followed by muscle, bladder, and liver. Using the mean residence time over all subjects as input to OLINDA/EXM, the effective dose was determined to be 0.0217 mSv/MBq; using residence times from single subjects gave an SD of 0.0020 mSv/MBq from the mean. The critical organ was the urinary bladder, with an absorbed dose of 0.18 mGy/MBq.F-FB-A20FMDV2 successfully passed toxicology criteria, showed no adverse effects in this first-in-humans study, and has an effective dose that enables multiple scans in a single subject.

No abstract