Antitumoral effect of local injection of TLR-9 agonist emulsified in Lipiodol with systemic anti-PD-1 in a murine model of colorectal carcinoma.

Introduction: Local treatments of cancer, including transarterial chemoembolization, could enhance responses to systemic immune checkpoint inhibitors such as anti-PD-1 antibodies. Lipiodol, a radiopaque oil, is widely used for transarterial chemoembolization as a tumor-targeting drug carrier and could be used in emulsion with immunomodulators. This study aimed at evaluating the antitumoral effect of intra-tumoral injection of Lipiodol-immunomodulator emulsions combined with systemic anti-PD-1 therapy in a murine model of colorectal carcinoma. Method: Mice (male BALB/c) with anti-PD-1-resistant subcutaneous CT26 tumors were injected with immunomodulators, emulsified or not with Lipiodol (N=10-12/group). Results: The TLR-9 agonist CpG displayed antitumor effects, while Poly I:C and QS21 did not. The Lipiodol-CpG emulsion appeared to be stable and maintained CpG within tumors for a longer time. Repeated intra-tumoral injections, combined with anti-PD-1, induced responses towards the tumor as well as to a distant metastatic-like nodule. This treatment was associated with an increase in proliferative CD8+ T cells and of IFN-γ expression, a decrease in proliferative regulatory T cells but also, surprisingly, an increase in myeloid derived suppressor cells. Conclusions: Local administration of CpG emulsified with Lipiodol led to an effective antitumoral effect when combined to systemic anti-PD-1 therapy. Lipiodol, apart from its radiopaque properties, is an efficient drug-delivery system. The formulated oil-in-water emulsion allows efficient loading and control release of CpG, which induces favorable immune modifications in this murine tumor model.

Evaluation of intratumoral hemodynamics with color Doppler imaging in patients with colorectal carcinoma: comparison between waveform analysis and histopathologic characteristics.

PURPOSE: We studied the relation between intratumoral hemodynamics and histopathologic characteristics in patients with colorectal carcinoma. METHODS: A series of 82 patients with 28 well-differentiated adenocarcinomas, 40 moderately differentiated adenocarcinomas, 10 poorly differentiated adenocarcinomas, and 4 mucinous adenocarcinomas underwent color Doppler examination and surgical treatment. The waveform of blood flow in the thickened wall of the colon was analyzed by determining the maximum velocity (Vmax) and resistance index (RI). These parameters were compared with histopathologic findings of the resected specimens: gross form, tumor size, depth of invasion, histologic stage, and histopathologic classification. RESULTS: Both Vmax and RI were higher in the invasive tumors rather than the expansive ones. Vmax and tumor size were not correlated; however, the RI increased proportionately with tumor size in tumors larger than 4 cm in diameter. Both parameters increased with depth of invasion and histologic stage through stage IIIb. Both were markedly higher in mucinous adenocarcinomas than in the other histopathologic types. Furthermore, Vmax in well, moderately, and poorly differentiated adenocarcinomas did not differ significantly, although RI was negatively associated with the degree of differentiation. CONCLUSIONS: We concluded that blood-flow analysis is closely associated with histopathologic findings of colorectal carcinomas and that it provides information useful in the clinical management of these patients.