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Cancer metastasis to lymph nodes (LNs) almost certainly contributes to distant metastasis. Elevation of LN internal pressure (intranodal pressure, INP) during tumor proliferation is associated with a poor prognosis for patients. We have previously reported that a lymphatic drug delivery system (LDDS) allows the direct delivery of anticancer drugs into the lymphatic system and is a promising treatment strategy for early‐stage LN metastasis. However, methods for evaluating the treatment effects have not been established. Here, we used a mouse model of MXH10/Mo‐lpr/lpr, which develops a systemic swelling of LNs, and murine malignant fibrous histiocytoma‐like (KM‐Luc/GFP) cells or murine breast cancer (FM3A‐Luc) cells inoculated into the subiliac LN of mice to produce a tumor‐bearing LN model. The changes in INP during intranodal tumor progression and after treatment with cis‐dichlorodiammineplatinum(II) (CDDP) using an LDDS were measured. We found that tumor progression was associated with an increase in INP that occurred independently of LN volume changes. The elevation in INP was suppressed by CDDP treatment with the LDDS when intranodal tumor progression was significantly inhibited. These findings indicate that INP is a useful parameter for monitoring the therapeutic effect in patients with LN metastasis who have been given drugs using an LDDS, which will serve to manage cancer metastasis treatment and contribute to an improved quality of life for cancer patients., Direct delivery of an anticancer drugs into the lymphatic system using a novel lymphatic drug delivery system (LDDS) was an effective treatment for early‐stage lymph node (LN) metastasis in a mouse model. Intranodal pressure (INP) reflects tumor activity in tumor‐bearing LN. Therefore, measurement of INP could be a useful method to evaluate the therapeutic effects of cancer treatment given using an LDDS.

Nanocomposite catalysts consisting of metallic cobalt and tantalum carbide were synthesized and they efficiently promoted an uphill conversion of greenhouse gases including CO2 and CH4 into CO and H2 under visible light. Electromagnetic simulations demonstrated that the efficient energy transformation by Co@TaC was attributed to the enhanced surface-located plasmon resonance.

Cancer cells metastasize to lymph nodes, with distant metastasis resulting in poor prognosis. The role of lymph node metastasis (LNM) in the spread of cancer to distant organs remain incompletely characterized. The visualization of flow dynamics in the lymphatic and blood vessels of MXH10/Mo-lpr/lpr mice, which develop systemic swelling of lymph nodes up to 10mm in diameter, has revealed that lymph nodes have the potential to be a direct source of systemic metastasis. However, it is not known whether these fluid dynamics characteristics are universal phenomena present in other strains of laboratory mice. Here we show that the fluid dynamics observed in MXH10/Mo-lpr/lpr mice are the same as those observed in C57BL/6J, BALB/cAJcl and NOD/ShiJic-scidJcl mice. Furthermore, when fluorescent solution was injected into a tumor-bearing lymph node, the flow dynamics observed in the efferent lymphatic vessels and thoracoepigastric vein depended on the type of tumor cell. Our results indicate that fluid dynamics in the lymphatic and blood vessels of MXH10/Mo-lpr/lpr mice are generalized phenomena seen in conventional laboratory mice. We anticipate our results can facilitate studies of the progression of lymphatic metastasis to hematogenous metastasis via lymph nodes and the early diagnosis and treatment of LNM.

Dry reforming of methane (DRM) is one of the most attractive chemical reactions, since it converts global‐warming gases into valuable syngas including hydrogen and carbon monoxide. Numerous previous studies used metal oxides catalysis supports, such as Al2O3, but their operating temperature was very high and severe coking occurred and deteriorated their catalytic activities. The present study reports that a metal carbide like tantalum carbide (TaC) acts as a multifunctional catalyst support for the DRM reaction, including light‐harvesting properties for saving energy operation as well as an anticoking property for long‐term stability. Nickel nanoparticles loaded on tantalum carbide (Ni/TaC) are prepared by impregnation and reductive hydrogen treatment. TaC particles act as a light‐harvesting support to promote the DRM reaction by photon irradiation through plasmonic photothermal energy conversion in TaC. Furthermore, Ni/TaC exhibits an excellent long‐term anticoking property, as compared to Ni loaded on conventional metal oxide supports such as Al2O3 or Ta2O5. According to the sole gas condition's experiment, and secondary ion mass spectroscopy, the oxy‐carbide layer near the interface between TaC and Ni plays an essential role in imparting the efficient anticoking property of Ni/TaC., Tantalum carbide functions as a light‐harvesting and anticoking catalysis support for dry reforming of methane.

[Background]McH-lpr/lpr-RA1 mice are a new strain of mice which spontaneously develop arthritis in the ankle, leading finally to ankylosis. There is no published data that drug treatment has been trialed on these mice.[Objectives]This study examined the effect of the mouse anti-IL-6 receptor antibody, MR16-1, for the treatment of ankylosis in McH-lpr/lpr-RA1 mice.[Methods]Male McH-lpr/lpr-RA1 mice were randomly divided into control and treatment groups. MR16-1 was administered from 10 weeks of age for the treatment group. Saline was applied for the control group. The drug was administered once a week, at an initial dose of 2 mg, then maintained at 0.5 mg once per week thereafter. The effects were evaluated by the histopathological synovitis score, in vivo imaging using indocyanine green liposomes, and analysis of the gene expression of inflammatory cytokines.[Results]Tissue analyses were carried out at 14, 17 and 20 weeks of age. The synovitis scores of treated groups were significantly lower compared with those of the control group at every age. The kappa coefficient was 0.77. However, progression of ankylosis persisted in the MR16-1 treated group. In vivo imaging using indocyanine green liposomes showed significant decreases in signal intensities of treated groups at week 14, but no significant differences were observed at week 18. Blood serum amyloid A levels in treated groups were significantly lower at 17 weeks of age. The gene expression levels of Tnf and Il17 were also significantly lower in MR16-1 treated groups.[Conclusions]Administration of the anti-IL-6 receptor antibody is effective for the treatment of synovitis and bone destruction of McH-lpr/lpr-RA1 mice. McH-lpr/lpr-RA1 mice may be a suitable experimental model for the development of new treatments for spondyloarthritis. IL6 signal blockade could contribute to the treatment of spondyloarthritis, and further studies should be carried out to confirm its potential in the prevention of deformity associated with ankylosis.

The lymphatic drug delivery system (LDDS) is a new technique that permits the injection of drugs into a sentinel lymph node (SLN) at an early stage of tumor metastasis, thereby treating metastasis in the SLN and its secondary lymph nodes (LNs). The quantity of drug required for a LDDS is much smaller than that needed for systemic chemotherapy. However, the relationship between the rate of drug injection into a SLN and the amount of drug reaching the secondary LNs has not been investigated. In this study, we used an MXH10/Mo-lpr/lpr mouse model to show that the optimal rate for the injection of a fluorescent dye by a LDDS was 10 to 80 μL/min. An injection rate of 10 to 80 μL/min was able to fill the downstream LN. However, an injection rate of 100 μL/min drove the fluorescent dye into the efferent lymphatic vessels and thoracoepigastric vein, decreasing the amount of dye retained in the downstream LN. Bolus injection (defined as an injection rate of 2400 μL/min) was unable to deliver fluorescent dye into the downstream LN. These results agree with the impulse values calculated from the injection pressures in the upstream LN. We anticipate that our findings will facilitate the development of a LDDS for use in the clinic.

Regional lymph node status is an important prognostic indicator of tumor aggressiveness. However, early diagnosis of metastasis using intranodal pressure, at a stage when lymph node size has not changed significantly, has not been investigated. Here, we use an MXH10/Mo-lpr/lpr mouse model of lymph node metastasis to show that intranodal pressure increases in both the subiliac lymph node and proper axillary lymph node, which are connected by lymphatic vessels, when tumor cells are injected into the subiliac lymph node to induce metastasis to the proper axillary lymph node. We found that intranodal pressure in the subiliac lymph node increased at the stage when metastasis was detected by in vivo bioluminescence, but when proper axillary lymph node volume (measured by high-frequency ultrasound imaging) had not increased significantly. Intravenously injected liposomes, encapsulating indocyanine green, were detected in solid tumors by in vivo bioluminescence, but not in the proper axillary lymph node. Basic blood vessel and lymphatic channel structures were maintained in the proper axillary lymph node, although sinus histiocytosis was detected. These results show that intranodal pressure in the proper axillary lymph node increases at early stages when metastatic tumor cells have not fully proliferated. Intranodal pressure may be a useful parameter for facilitating early diagnosis of lymph node metastasis.

The lymphatic system in mice consists of lymphatic vessels and 22 types of lymph nodes. Metastatic tumor cells in the lymphatic system spread to distant organs through the venous system. However, the communication routes between the lymphatic and venous systems have not been fully elucidated. Here, we identify the communication routes between the lymphatic and venous systems in the axillary and subiliac regions of MXH10/Mo-lpr/lpr inbred mice, which develop systemic swelling of lymph nodes up to 10mm in diameter, allowing investigation of the topography of the lymph nodes and lymphatic vessels. Using a gross anatomy dissection approach, the efferent lymphatic vessels of the proper axillary lymph node were shown to communicate with the subclavian vein. Furthermore, we found that the thoracoepigastric vein, which connects the subclavian vein and inferior vena cava, runs adjacent to the subiliac and proper axillary lymph nodes, and receives venous blood from these lymph nodes routed through small branches. The direction of blood flow in the thoracoepigastric vein occurred in two directions in the intermediate region between the proper axillary lymph node and subiliac lymph node; one to the subclavian vein, the other to the inferior vena cava. This paper reveals the anatomy of the communication between the lymphatic and venous systems in the axillary and subiliac regions of the mouse, and provides new insights relevant to the investigation of the mechanisms of lymph node metastasis and cancer immunology, and the development of diagnostic and treatment methods for lymph node metastasis, including drug delivery systems.

Intravenous chemotherapy has poor access to metastatic lymph nodes (LNs) and is limited by short-lived drug concentrations. Here, we describe the administration of chemotherapy via the lymphatic network as a new concept for the prevention and treatment of metastatic LNs. A metastatic LN can be treated by the injection of drugs into an upstream LN, either the sentinel LN (SLN) or another upstream LN. In a mouse model, tumor cells were inoculated into the subiliac LN (SiLN) to induce metastasis to the proper axillary LN (PALN). Two routes were used for drug delivery to the PALN, namely from the SiLN and from the accessory axillary LN (AALN). We found that tumor masses were formed in lymphatic vessels between the SiLN and PALN. The flow of fluorescent solution injected into the SiLN towards the PALN decreased with tumor mass formation. Delivery from the AALN (free of metastatic tumor cells) to the PALN was identified as an alternative route. Intranodal injection can deliver high concentrations of drugs to secondary metastatic LNs. The study advocates a new concept for the prevention and treatment of metastatic lymph nodes whereby drugs injected into upstream lymph nodes can reach metastatic lymph nodes via the lymphatic network.

Cancer metastasis is a major cause of death in cancer patients and metastatic lymph nodes (MLN) are associated with poor prognosis. In the field of breast cancer research, the role of MLN has been discussed for nearly a hundred years. Halsted formulated “Halsted theory”, whereby breast cancer spread through the lymphatic system first to nearby lymph nodes and subsequently to other organs in the body. An alternative hypothesis, “Systemic theory” was put forward by Fisher who believed that breast cancer was a systemic disease, with tumors having the ability to spread to distant sites from the primary locus. Thu, MLN can hardly be the source of systemic metastasis. However, the actual role of MLN in routing cancer cells to distant organs remains incompletely characterized because of inadequate investigations in animal experiments. In the present study, we show that MLN can be the source of systemic metastasis using MXH10/Mo-lpr/lpr (MXH10/Mo/lpr) mice, which develop systemic swelling of lymph nodes up to 10 mm in diameter. Previously we developed a MLN model using MXH10/Mo/lpr by injection of tumor cells into its LN directory. In the present study, we first investigated the venous/lymphatic system around the subiliac LN (SiLN) where SiLN is one of the superficial LNs in the MXH10/Mo/lpr and the proper axially LN is the downstream LN of SiLN. The thoracoepigastric vein (TEV) runs along the lymphatic vessels between the SiLN and the PALN and connects to the inferior vena cava and subclavian vein via the SiLN and PALN. After intravenous injection of fluorescence liposomes, we demonstrated that intranodal venulas perforated the capsule of the SiLNs and anastomosed with the TEV. Next, we investigated the flow dynamics of a fluorescent solution that was injected into the SiLNs. We found that the fluorescent solution flowed into the efferent lymphatic vessels as well as the TEV. Moreover, the MLN model showed different flow dynamics compared to the control LN. Fluorescent solution tended to flow into the blood circulation more than the efferent lymphatic vessel. This finding suggested that the vasculature and lymphatic systems have a connection with the LN under specific mechanistic conditions, such as elevation of intranodal pressure by injection. This mechanical force could have facilitated the fluorescent solution to flow into the efferent lymphatic vessel along with the development of a connection between the two circulation systems in the LN. We previously reported that intranodal pressure increases in MLN during tumor cell proliferation and circulatory connection can be developed in the MLN. Therefore, tumor cells metastasized into the LN can route their metastatic pathways to the hematogenous system. Thus, the MLN has the potential to be a direct source of systemic metastasis. We anticipate that our results will facilitate the study of the progression of systemic metastasis via the MLN. Citation Format: Kazu Takeda, Shiro Mori, Tetsuya Kodama. Metastatic lymph nodes can serve as a source of systemic metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 88.