Radiation Dose-Dependent Changes in Lymphatic Remodeling

Kwon, Sunkuk; Janssen, Christopher F.; Velasquez, Fred Christian; Zhang, Songlin; Aldrich, Melissa B.; Shaitelman, Simona F.; DeSnyder, Sarah M.; Sevick‐Muraca, Eva M.

doi:10.1016/j.ijrobp.2019.07.054

Cited by 16 publications

(16 citation statements)

References 32 publications

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“…Evidence is accumulating that radiation itself, while efficacious for killing cancer cells and promoting up the immune system for anti-tumor immunity, may damage lymphatics. Treatment of mice with 20 Gy after popliteal lymphadenectomy showed that RT transiently disrupted lymphatic contractile activity, but when radiation was fractionated [4 × 5 Gy] or increased to 40 Gy in one fraction, persistent lymphatic dysfunction occurred, as visualized by NIRF-LI [79]. Strikingly, with increased radiation dose, there was a concomitant increase in lymphatic vessel area in the epidermis, consistent with reports of hyperplasia in the skin of patients after RT [80].…”

Section: The Role Of Lymph Node Dissection and Rt On Lymphatic Functionsupporting

confidence: 84%

“…Treatment of mice with 20 Gy after popliteal lymphadenectomy showed that RT transiently disrupted lymphatic contractile activity, but when radiation was fractionated [4 × 5 Gy] or increased to 40 Gy in one fraction, persistent lymphatic dysfunction occurred, as visualized by NIRF-LI [78]. Strikingly, with increased radiation dose, there was a concomitant increase in lymphatic vessel area in the epidermis, consistent with reports of hyperplasia in the skin of patients after RT [79]. The preclinical imaging results also confirm the hypothesis that radiation causes lymphatic vessel "leakiness," as demonstrated in rat mesenteric LECs [80] and apoptosis of LECs, with subsequent fibrosis in mouse tails [81].…”

Section: The Role Of Lymph Node Dissection and Rt On Lymphatic Functionsupporting

confidence: 84%

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The Development and Treatment of Lymphatic Dysfunction in Cancer Patients and Survivors

Aldrich

Rasmussen

Fife

et al. 2020

Cancers

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Breast-cancer-acquired lymphedema is routinely diagnosed from the appearance of irreversible swelling that occurs as a result of lymphatic dysfunction. Yet in head and neck cancer survivors, lymphatic dysfunction may not always result in clinically overt swelling, but instead contribute to debilitating functional outcomes. In this review, we describe how cancer metastasis, lymph node dissection, and radiation therapy alter lymphatic function, as visualized by near-infrared fluorescence lymphatic imaging. Using custom gallium arsenide (GaAs)-intensified systems capable of detecting trace amounts of indocyanine green administered repeatedly as lymphatic contrast for longitudinal clinical imaging, we show that lymphatic dysfunction occurs with cancer progression and treatment and is an early, sub-clinical indicator of cancer-acquired lymphedema. We show that early treatment of lymphedema can restore lymphatic function in breast cancer and head and neck cancer patients and survivors. The compilation of these studies provides insights to the critical role that the lymphatics and the immune system play in the etiology of lymphedema and associated co-morbidities.

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Section: The Role Of Lymph Node Dissection and Rt On Lymphatic Functionsupporting

confidence: 84%

Section: The Role Of Lymph Node Dissection and Rt On Lymphatic Functionsupporting

confidence: 84%

The Development and Treatment of Lymphatic Dysfunction in Cancer Patients and Survivors

Aldrich

Rasmussen

Fife

et al. 2020

Cancers

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“…Skin toxicities acutely manifest as erythema, desquamation, and alopecia or skin atrophy, while fibrosis and ulcer formation develop as late effects (7). Other late effects of RT include osteoradionecrosis, fracture, impaired wound healing and muscle atrophy, as well as lymphedema (8)(9)(10). Importantly, sarcoma is the archetypal mesenchymal cancer in which high dose RT is often used despite the high risk of toxicity.…”

Section: Introductionmentioning

confidence: 99%

FLASH Proton Radiotherapy Spares Normal Epithelial and Mesenchymal Tissues While Preserving Sarcoma Response

et al. 2021

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In studies of electron and proton radiotherapy, ultrahigh dose rates of FLASH radiation therapy appear to produce fewer toxicities than standard dose rates while maintaining local tumor control. FLASH-proton radiotherapy (F-PRT) brings the spatial advantages of PRT to FLASH dose rates (>40 Gy/sec), making it important to understand if and how F-PRT spares normal tissues while providing anti-tumor efficacy that is equivalent to standard-proton radiotherapy (S-PRT). Here we studied PRT damage to skin and mesenchymal tissues of muscle and bone and found that F-PRT of the C57BL/6 murine hind leg produced fewer severe toxicities leading to death or requiring euthanasia than S-PRT of the same dose. RNAseq analyses of murine skin and bone revealed pathways upregulated by S-PRT yet unaltered by F-PRT, such as apoptosis signaling and keratinocyte differentiation in skin, as well as osteoclast differentiation and chondrocyte development in bone. Corroborating these findings, F-PRT reduced skin injury, stem cell depletion, and inflammation, mitigated late effects including lymphedema, and decreased histopathologically detected myofiber atrophy, bone resorption, hair follicle atrophy, and epidermal hyperplasia. F-PRT was equipotent to S-PRT in control of two murine sarcoma models, including at an orthotopic intramuscular site, thereby establishing its relevance to mesenchymal cancers. Finally, S-PRT produced greater increases in TGF-β1 in murine skin and the skin of canines enrolled in a phase 1 study of F-PRT versus S-PRT. Collectively, these data provide novel insights into F-PRT-mediated tissue sparing and support its ongoing investigation in applications that would benefit from this sparing of skin and mesenchymal tissues. SignificanceThese findings will spur investigation of FLASH radiotherapy in sarcoma and additional cancers where mesenchymal tissues are at risk, including head and neck cancer, breast cancer, and pelvic malignancies.Research.

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“…Surgical models of acute and chronic phase of lymphatic edema formation of tail have been modified. In case of mouse hindlimb edema formation, radiation-induced phenotype is often described as chronic type of edema [ 55 – 57 ]. Besides hindlimbs, mouse tail has been often utilized to analyze edema by several surgical procedures.…”

Section: Discussionmentioning

confidence: 99%

Development of Surgical and Visualization Procedures to Analyze Vasculatures by Mouse Tail Edema Model

et al. 2021

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Background Because of the high frequency of chronic edema formation in the current “aged” society, analyses and detailed observation of post-surgical edema are getting more required. Post-surgical examination of the dynamic vasculature including L.V. (Lymphatic Vasculature) to monitor edema formation has not been efficiently performed. Hence, procedures for investigating such vasculature are essential. By inserting transparent sheet into the cutaneous layer of mouse tails as a novel surgery model (theTailEdema bySilicone sheet mediatedTransparency protocol; TEST), the novel procedures are introduced and analyzed by series of histological analyses including video-based L.V. observation and 3D histological reconstruction of vasculatures in mouse tails. Results The dynamic generation of post-surgical main and fine (neo) L.V. connective structure during the edematous recovery process was visualized by series of studies with a novel surgery model. Snapshot images taken from live binocular image recording for TEST samples suggested the presence of main and elongating fine (neo) L.V. structure. After the ligation of L.V., the enlargement of main L.V. was confirmed. In the case of light sheet fluorescence microscopy (LSFM) observation, such L.V. connections were also suggested by using transparent 3D samples. Finally, the generation of neo blood vessels particularly in the region adjacent to the silicone sheet and the operated boundary region was suggested in 3D reconstruction images. However, direct detection of elongating fine (neo) L.V. was not suitable for analysis by such LSFM and 3D reconstruction procedures. Thus, such methods utilizing fixed tissues are appropriate for general observation for the operated region including of L.V. Conclusions The current surgical procedures and analysis on the post-surgical status are the first case to observe vasculatures in vivo with a transparent sheet. Systematic analyses including the FITC-dextran mediated snap shot images observation suggest the elongation of fine (neo) lymphatic vasculature. Post-surgical analyses including LSFM and 3D histological structural reconstruction, are suitable to reveal the fixed structures of blood and lymphatic vessels formation.

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Radiation Dose-Dependent Changes in Lymphatic Remodeling

Cited by 16 publications

References 32 publications

The Development and Treatment of Lymphatic Dysfunction in Cancer Patients and Survivors

The Development and Treatment of Lymphatic Dysfunction in Cancer Patients and Survivors

FLASH Proton Radiotherapy Spares Normal Epithelial and Mesenchymal Tissues While Preserving Sarcoma Response

Development of Surgical and Visualization Procedures to Analyze Vasculatures by Mouse Tail Edema Model

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