Characterizing perfusion defects in metastatic lymph nodes at an early stage using high-frequency ultrasound and micro-CT imaging

Yamaki, Teppei; Sukhbaatar, Ariunbuyan; Mishra, Radhika; Kikuchi, Ryoichi; Sakamoto, Maya; Mori, Shiro; Kodama, Tetsuya

doi:10.1007/s10585-021-10127-6

Cited by 9 publications

(7 citation statements)

References 45 publications

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“…LNs are organs rich in vascular networks; 17 , 18 , 19 therefore, tumor cells that have metastasized to LN can proliferate by replacing parenchyma with tumor cells but without inducing tumor neovascularization at an early stage (i.e., formation of a perfusion defect). 20 , 21 , 22 , 23 Thus, the effect cannot be relied upon to deliver macromolecular drugs during the early stage of LN metastasis. 22 Therefore, there is an urgent need to develop new ways to treat tumor cells in LN independent of hematogenous delivery.…”

Section: Introductionmentioning

confidence: 99%

Intranodal delivery of modified docetaxel: Innovative therapeutic method to inhibit tumor cell growth in lymph nodes

2022

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Lymph node (LN) metastasis is one of the most salient prognostic factors for many types of cancer. Despite recent advances in the treatment of metastasis, the 5-year survival rate of patients remains poor, particularly for head and neck cancer, with average 5-year survival rates of approximately 77%, 52%, and 35% for patients with local, regional LN, and distant sites exhibiting metastases, respectively. Thus, the prognosis is worse for patients with LN metastases than for those patients with only localized tumors. 1,2 Survival rates depend on the stage of the cancer metastasis and are mostly correlated with the numbers of LN containing metastases. Therefore, controlling the regional LN is extremely important. Intravenous (i.v.) administration of chemotherapeutic agents is widely used for the treatment of metastatic LN. Most small molecule drugs (<10 nm) have poor aqueous solubility, low bioavailability, and little tissue selectivity. 3 In addition,

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Section: Introductionmentioning

confidence: 99%

Intranodal delivery of modified docetaxel: Innovative therapeutic method to inhibit tumor cell growth in lymph nodes

2022

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“…Alternative therapeutic interventions, such as chemotherapy, are routinely used in the clinic for the treatment of MLNs. However, due to the unique architecture and biologics of early‐stage MLNs, 13 , 14 , 15 systemic chemotherapy fails to maintain sufficient concentration of drugs in the targeted LN. 16 …”

Section: Introductionmentioning

confidence: 99%

Drug formulation augments the therapeutic response of carboplatin administered through a lymphatic drug delivery system

et al. 2022

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Treatment of metastatic lymph nodes (LNs) is challenging due to their unique architecture and biophysical traits. Systemic chemotherapy fails to impede tumor progression in LNs due to poor drug uptake and retention by LNs, resulting in fatal systemic metastasis. To effectively treat LN metastasis, achieving specific and prolonged retention of chemotherapy drugs in the tumor‐draining LNs is essential. The lymphatic drug‐delivery system (LDDS) is an ultrasound‐guided drug‐delivery methodology for administration of drugs to LNs that addresses these requirements. However, early‐stage metastatic LNs have an additional set of drug transport barriers, such as elevated intranodal pressure and viscosity, that negatively impact drug diffusion. In the present study, using formulations of elevated osmotic pressure and viscosity relative to saline, we sought to favorably alter the LN's physical environment and study its impact on pharmacokinetics and consequently the therapeutic efficacy of carboplatin delivered using the LDDS. Our study confirmed the capability of a drug formulation with elevated osmotic pressure and viscosity to alter the architecture of LNs, as it caused notable expansion of the lymphatic sinus. Additionally, the study delineated an optimal range of osmotic pressure and viscosity, centered around 1897 kPa and 11.5 mPa·s, above and below which therapeutic efficacy was found to decline markedly. These findings suggest that formulation osmotic pressure and viscosity are parameters that require critical consideration as they can both hinder and promote tumorigenesis. The facile formulation reported here has wide‐ranging applicability across cancer spectrums and is thus anticipated to be of great clinical benefit.

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“…For systemic chemotherapy with hematogenous anticancer drugs, therapeutic effects on metastatic LNs are limited 8 , 9 because of the lack of blood vessels and lymphatic vessels (perfusion defect formation), 10 , 11 , 12 non‐angiogenesis, 3 , 13 and increase in intranodal pressure in early metastatic LNs.…”

Section: Introductionmentioning

confidence: 99%

“…4 LN dissection is often undertaken on LNs that are metastatic and resectable (clinical N1 or greater), with the disadvantage that it is highly invasive, and there are multiple reports of surgical stress affecting postoperative tumor recurrence and immunosuppression. [5][6][7] For systemic chemotherapy with hematogenous anticancer drugs, therapeutic effects on metastatic LNs are limited 8,9 because of the lack of blood vessels and lymphatic vessels (perfusion defect formation), [10][11][12] non-angiogenesis, 3,13 and increase in intranodal pressure in early metastatic LNs.…”

Section: Introductionmentioning

confidence: 99%

Combination therapy of lymphatic drug delivery and total body irradiation in a metastatic lymph node and lung mouse model

et al. 2022

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Chemotherapy using a lymphatic drug delivery system (LDDS) targeting lymph nodes (LNs) in the early stage of metastasis has a superior antitumor effect to systemic chemotherapy. An LDDS produces a higher drug retention rate and tissue selectivity in LNs. To expand the therapeutic coverage of LDDS from local treatment of metastatic LNs to prevention of distant metastases, the combination of treatment with therapies that enhance systemic tumor immune effects is an important therapeutic strategy. Recently, total body irradiation (TBI) has been shown to activate immune responses and alter the tumor microenvironment. Here we show that combination therapy with TBI and LDDS improves the antitumor effect of metastatic LNs and lung metastasis. Tumor cells were inoculated into the subiliac LN (SiLN) to induce metastasis into the proper axillary LN (PALN) and lung in a mouse model. TBI was carried out on day 4 after inoculation using a gamma irradiator. Lymphatic drug delivery into the accessory axillary LN was used to treat PALN. In vivo bioluminescence imaging, high‐frequency ultrasound, and histology showed that combination therapy using TBI (total dose 1.0 Gy once) and the LDDS suppressed tumor growth in LNs and lung metastases and was more effective than using LDDS or TBI alone. Quantitative RT‐PCR of spleens after combination therapy revealed increased expression of CD4 , CD8 , and IL‐12b , indicating an activated immune response. The results show that combination therapy with TBI and LDDS is a method to improve the efficacy of LN metastases and distant metastases therapy and is a promising novel approach to treat cancer patients.

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Characterizing perfusion defects in metastatic lymph nodes at an early stage using high-frequency ultrasound and micro-CT imaging

Cited by 9 publications

References 45 publications

Intranodal delivery of modified docetaxel: Innovative therapeutic method to inhibit tumor cell growth in lymph nodes

Intranodal delivery of modified docetaxel: Innovative therapeutic method to inhibit tumor cell growth in lymph nodes

Drug formulation augments the therapeutic response of carboplatin administered through a lymphatic drug delivery system

Combination therapy of lymphatic drug delivery and total body irradiation in a metastatic lymph node and lung mouse model

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