Search

Background Hepatic epithelioid hemangioendothelioma (HEH) is rare; it is reported in Case presentation The present report describes the histologically proven three HEH cases evaluated using Sonazoid® CEUS. Case 1 was a 33-year-old female patient with no relevant past medical history, who experienced right upper quadrant pain. Conventional abdominal US revealed multiple low echoic liver nodules with vague borderlines. In CEUS, the vascularity of the nodules was similar to that seen in the neighboring normal liver. Later in the portal venous and late phases (PVLP) and post vascular phase, washout of Sonazoid® was detected in the nodules. Case 2 was a 93-year-old female patient with a previous medical history including operations for breast cancer and ovary cancer in her 50’s. Conventional abdominal US revealed multiple low echoic nodules, some of which contained cystic lesions. In the early vascular phase of CEUS, nodules excluding the central anechoic regions were enhanced from peripheral sites. Although the enhancement inside the nodules persisted in both the PVLP and post vascular phase, anechoic areas in the center of some nodules were not enhanced at all. Case 3 was a 39-year-old male patient presented with right upper-quadrant pain, without any relevant past medical history. Conventional abdominal US revealed multiple low echoic liver nodules. In the early vascular phase of CEUS, nodules were gradually enhanced from the peripheral sites as ringed enhancement. Sonazoid®was washed out from the nodules in the PVLP and post vascular phase. Conclusions The most important feature was peripheral enhancement in the early vascular phase. In case 2, the enhancement of the parenchyma of liver nodules persisted even in the PVLP; indicating the lower degree of malignant potential than others. Actually, the tumors did not extend without any treatment in case 2. Since case 2 is the first case report of HEH with cystic lesions, in patients with liver nodules including cystic lesions, HEH is a potential diagnosis.

Interferon-alpha (IFN-α) has strong antitumor effects, and IFN-α gene therapy has been used clinically against some cancers. In this study, we evaluated the efficacy of the combination of IFN-α-transduced tumor cell vaccines and programmed cell death 1 (PD-1) blockade, and investigated the mechanisms of the antitumor effects of the combined therapy. A poorly immunogenic murine colorectal cancer cell line, MC38, was transduced to overexpress IFN-α. In a therapeutic model, parental tumor-bearing mice were inoculated with MC38-IFNα cells and an anti-PD-1 antagonistic antibody. Analyses of immunohistochemistry and tumor-specific lysis were performed. The outgrowth of the established tumors was significantly reduced in mice treated with the combination of IFN-α and anti-PD-1. Immunohistochemical analyses of the therapeutic model showed marked infiltration of CD4(+) cells and CD8(+) cells in the established MC38 tumors of mice treated with both IFN-α and anti-PD-1. Significant tumor-specific cytolysis was detected when splenocytes of mice that were treated with both IFN-α and anti-PD-1 were used as effector cells. These results suggest that blockade of the PD-1 PD-ligand enhanced the Th1-type antitumor immune responses induced by IFN-α. The combination of IFN-α gene-transduced tumor cell vaccines and PD-1 blockade may be a possible candidate for a cancer vaccine for clinical trials.

Both dendritic cell (DC)-based immunotherapy and interferon (IFN)-alpha therapy have been proved to have potent long-lasting antitumor effects. In anticipation of synergistic antitumor effects, we performed combination therapy with DCs and IFN-alpha gene-transduced murine colorectal cancer MC38 cells (MC38-IFN-alpha). DCs incubated with MC38-IFN-alpha, but not neomycin-resistance gene-transduced MC38 cells (MC38-Neo), effectively enhanced proliferation of allogeneic splenocytes in vitro. In 12 of 17 mice, DCs in combination with MC38-IFN-alpha prevented the development of a parental tumor, while DCs and MC38-Neo did in only three of 17 mice (P=0.008). In a therapeutic model of an established parental tumor, inoculation of DCs and MC38-IFN-alpha suppressed the growth of the established parental tumors significantly compared with the administration of DCs with MC38-Neo or naive splenocytes with MC38-IFN-alpha (P=0.016 and 0.024, respectively). Analyses of immunohistochemistry and tumor-infiltrating mononuclear cells showed that CD8(+), CD11c(+), and NK1.1(+) cells markedly infiltrated the established tumors of mice treated with DCs and MC38-IFN-alpha. From the results of observation of parental tumor outgrowth in immune cell-depleted mice, CD8(+) cells, and asialo-GM-1(+) cells were thought to contribute to the antitumor effects induced by the combination therapy. Furthermore, MC38-specific cytolysis was detected when splenocytes of mice inoculated with DCs and MC38-IFN-alpha cells were stimulated with MC38-IFN-alpha cells in vitro. Since DC-based immunotherapy in combination with IFN-alpha-expressing tumor cells induces potent antitumor cellular immune responses, it should be considered for clinical application.

Cytokine gene therapy is applied in clinical studies of tumors, and IFN-alpha and IL-12 are widely used for cancer immunotherapy. Using a poorly immunogenic murine colorectal cancer cell line, MC38, we compared antitumor effects of IFN-alpha and IL-12. Transduced MC38 cell lines expressing IFN-alpha or IL-12 (MC38-IFNalpha or MC38-IL12, respectively) were established using retroviral vectors. Transduction of IFN-alpha or IL-12 gene to MC38 cells significantly reduced tumorigenicity in immunocompetent mice. When tumor-free mice initially injected with MC38-IFNalpha or MC38-IL12 cells were reinjected contralaterally with wild-type MC38 cells (MC38-WT) after 35 days, 7 of 12 or 2 of 12 mice rejected MC38-WT cells, respectively. In therapy-model mice with established tumor derived from MC38-WT cells, inoculation of gene-transduced cells significantly suppressed growth of the tumor in MC38-IFNalpha-inoculated groups, but not in the IL-12-inoculated group. Immunohistologic and flow cytometric analyses showed marked infiltration of CD8(+) cells in wild-type tumors of mice inoculated with IFN-alpha-expressing cells. Leukocyte-depletion experiments implicated CD8(+) T cells in tumor rejection induced by IFN-alpha-transduction; both CD8(+) T cells and natural killer cells were implicated in the more modest antitumor effect from IL-12 expression. To investigate induction of tumor-specific immune responses, we stimulated splenocytes from tumor-free mice twice in vitro with genetically modified MC38 cells. In vitro stimulations with MC38-IFNalpha cells induced definite MC38-specific lysis, but not stimulations with MC38-IL-12 cells. Injecting combination of MC38-IFNalpha and MC38-IL-12 cells caused an additive antitumor effect in the therapy model. These data suggested that IFN-alpha induces cytotoxic T lymphocytes and elicits long-lasting tumor-specific immunity, whereas IL-12 seems to stimulate non-specific killing. With additional refinements, combined IFN-alpha and IL-12 gene therapy might warrant clinical trials.

BackgroundToll-like receptor (TLR)3 ligands serve as natural inducers of pro-inflammatory cytokines capable of promoting Type-1 adaptive immunity, and TLR3 is abundantly expressed by cells within the central nervous system (CNS). To improve the efficacy of vaccine strategies directed against CNS tumors, we evaluated whether administration of a TLR3 ligand, polyinosinic-polycytidylic (poly-IC) stabilized with poly-lysine and carboxymethylcellulose (poly-ICLC) would enhance the anti-CNS tumor effectiveness of tumor peptide-based vaccinations.MethodsC57BL/6 mice bearing syngeneic CNS GL261 glioma or M05 melanoma received subcutaneous (s.c.) vaccinations with synthetic peptides encoding CTL epitopes- mEphA2 (671–679), hgp100 (25–33) and mTRP-2 (180–188) for GL261, or ovalbumin (OVA: 257–264) for M05. The mice also received intramuscular (i.m.) injections with poly-ICLC.ResultsThe combination of subcutaneous (s.c.) peptide-based vaccination and i.m. poly-ICLC administration promoted systemic induction of antigen (Ag)-specific Type-1 CTLs expressing very late activation antigen (VLA)-4, which confers efficient CNS-tumor homing of vaccine-induced CTLs based on experiments with monoclonal antibody (mAb)-mediated blockade of VLA-4. In addition, the combination treatment allowed expression of IFN-γ by CNS tumor-infiltrating CTLs, and improved the survival of tumor bearing mice in the absence of detectable autoimmunity.ConclusionThese data suggest that poly-ICLC, which has been previously evaluated in clinical trials, can be effectively combined with tumor Ag-specific vaccine strategies, thereby providing a greater index of therapeutic efficacy.