The fate of circulating tumor cells (CTC) is an important determinant of metastasis and recurrence, which leads to most deaths in hepatocellular carcinoma (HCC). Therefore, quantification of CTCs proves to be an emerging tool for diagnosing, stratifying, and monitoring patients with metastatic diseases. In vivo flow cytometry has the capability to monitor the dynamics of fluorescently labeled CTCs continuously and noninvasively. Here, we combine in vivo flow cytometry technique and a GFP-transfected HCC orthotopic metastatic tumor model to monitor CTC dynamics. Our in vivo flow cytometry has approximately 1.8-fold higher sensitivity than whole blood analysis by conventional flow cytometry. We found a significant difference in CTC dynamics between orthotopic and subcutaneous tumor models. We also investigated whether liver resection promotes or restricts hematogenous metastasis in advanced HCC. Our results show that the number of CTCs and early metastases decreases significantly after the resection. The resection prominently restricts hematogenous metastasis and distant metastases. CTC dynamics is correlated with tumor growth in our orthotopic tumor model. The number and size of distant metastases correspond to CTC dynamics. The novel in vivo flow cytometry technique combined with orthotopic tumor models might provide insights to tumor hematogenous metastasis and guidance to cancer therapy. Cancer Res; 72(10); 2683-91. Ó2012 AACR.
ObjectiveTo assess long‐term efficacy and safety of canakinumab and the response to vaccination in children ages ≤5 years with cryopyrin‐associated periodic syndrome (CAPS).Methods CAPS patients (ages ≤5 years) received 2 mg/kg canakinumab subcutaneously every 8 weeks; patients with neonatal‐onset multisystem inflammatory disease (NOMID) received a starting dose of 4 mg/kg in this open‐label trial. Efficacy was evaluated using physician global assessment of disease activity and serum levels of C‐reactive protein (CRP) and amyloid A (SAA). Adverse events (AEs) were recorded. Vaccination response was evaluated using postvaccination antibody titers at 4 and 8 weeks after immunization.ResultsOf the 17 patients enrolled, 12 (71%) had Muckle‐Wells syndrome, 4 (24%) had NOMID, and 1 (6%) had familial cold autoinflammatory syndrome. All 17 patients had a complete response to canakinumab. Disease activity improved according to the physician global assessment, and for 65% of the patients autoinflammatory disease was characterized as “absent” at the end of the study. Median CRP levels decreased over time. No such change was evident in SAA levels. During the extension study, postvaccination antibody titers increased above protective levels in 16 (94%) of 17 assessable vaccinations. Ten of the patients (59%) had AEs suspected to be related to canakinumab; 8 (47%) experienced at least 1 serious AE (SAE). None of the AEs or SAEs required interruption of canakinumab therapy.ConclusionOur findings indicate that canakinumab effectively maintains efficacy through 152 weeks and appears to have no effect on the ability to produce antibodies against standard childhood non‐live vaccines. The safety profile of canakinumab was consistent with previous studies, supporting long‐term use of canakinumab for CAPS in children ≤5 years of age.
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