Rapid diagnosis of lymph node metastasis in breast cancer using a new fluorescent method with γ-glutamyl hydroxymethyl rhodamine green

Shinden, Yoshiaki; Ueo, Hiroki; Tobo, Taro; Gamachi, Ayako; Utou, Mitsuaki; Komatsu, Hisateru; Nambara, Sho; Saito, Tomoko; Ueda, Masami; Hirata, Hidenari; Sakimura, Shotaro; Takano, Yuki; Uchi, Ryutaro; Kurashige, Junji; Akiyoshi, Sayuri; Iguchi, Tomohiro; Eguchi, Hidetoshi; Sugimachi, Keizō; Kubota, Yōko; Kai, Yuichiro; Shibuta, Kenji; Kijima, Yuko; Yoshinaka, Heiji; Natsugoe, Shoji; Mori, Masaki; Maehara, Yoshihiko; Sakabe, Masayo; Kamiya, Mako; Kakareka, John W.; Pohida, Thomas J.; Choyke, Peter L.; Kobayashi, Hisataka; Ueo, Hiroaki; Urano, Yasuteru; Mimori, Koshi

doi:10.1038/srep27525

Cited by 24 publications

(31 citation statements)

References 20 publications

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“…γ-Glutamyl hydroxymethyl rhodamine green (gGlu-HMRG) is a nonfluorescent dye that is converted to highly fluorescent hydroxymethyl rhodamine green (HMRG) upon reaction with GGT [ 2 ]. GGT is purportedly overexpressed in several human cancers, such as breast, ovarian, brain, lung, colon, and peritoneum cancers, as well as head and neck squamous cell carcinoma, and methods exploiting gGlu-HMRG and GGT have been applied to detect such cancers [ 4 – 11 ]. When colorless gGlu-HMRG is sprayed on surgically resected breast cancer tissue, the cancer cells exhibit green fluorescence 1–2 min afterwards [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Rapid detection of papillary thyroid carcinoma by fluorescence imaging using a γ-glutamyltranspeptidase-specific probe: a pilot study

et al. 2018

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BackgroundNodular lesions of the thyroid gland, including papillary thyroid carcinoma (PTC), may be difficult to diagnose by imaging, such as in ultrasonic echo testing, or by needle biopsy. Definitive diagnosis is made by pathological examination but takes several days. A more rapid and simple method to clarify whether thyroid nodular lesions are benign or malignant is needed. Fluorescence imaging with γ-glutamyl hydroxymethyl rhodamine green (gGlu-HMRG) uses γ-glutamyltranspeptidase (GGT), a cell-surface enzyme, to hydrolyze the γ-glutamyl peptide and transfer the γ-glutamyl group. GGT is overexpressed in several cancers, such as breast, lung, and liver cancers. This imaging method is rapid and useful for detecting such cancers. In this study, we tried to develop a rapid fluorescence detection method for clinical samples of thyroid cancer, especially papillary carcinoma.MethodsFluorescence imaging with gGlu-HMRG was performed to detect PTC using 23 surgically resected clinical samples. A portable imaging device conveniently captured white-light images and fluorescence images with blue excitation light. Hematoxylin-eosin (HE) staining was used to evaluate which fluorescent regions coincided with cancer, and immunohistochemical examination was used to detect GGT expression.ResultsAll 16 PTC samples exhibited fluorescence after topical application of gGlu-HMRG, whereas the normal sections of each sample showed no fluorescence. HE staining revealed that each fluorescent region corresponded to a region with carcinoma. The PTC samples also exhibited GGT expression, as confirmed by immunohistochemistry.ConclusionsAll PTC samples were detected by fluorescence imaging with gGlu-HMRG. Thus, fluorescence imaging with gGlu-HMRG is a rapid, simple, and powerful detection tool for PTC.

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Section: Introductionmentioning

confidence: 99%

Rapid detection of papillary thyroid carcinoma by fluorescence imaging using a γ-glutamyltranspeptidase-specific probe: a pilot study

et al. 2018

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“…A variety of more recent approaches have been described that include fluorescently labeled: antibodies 7 - 10 , small-molecule receptor ligands 11 , peptides 12 , lipids 13 , and protease-activated agents 10 , 14 - 21 . Several investigational agents have entered clinical evaluation 15 , 22 - 24 .…”

Section: Introductionmentioning

confidence: 99%

Sensitive in vivo Visualization of Breast Cancer Using Ratiometric Protease-activatable Fluorescent Imaging Agent, AVB-620

Miampamba¹,

Liu²,

Harootunian³

et al. 2017

Theranostics

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With the goal of improving intraoperative cancer visualization, we have developed AVB-620, a novel intravenously administered, in vivo fluorescent peptide dye conjugate that highlights malignant tissue and is optimized for human use. Matrix metalloproteinases (MMPs) hydrolyze AVB-620 triggering tissue retention and a ratiometric fluorescence color change which is visualized using camera systems capable of imaging fluorescence and white light simultaneously. AVB-620 imaging visualizes primary tumors and demonstrated high in vivo diagnostic sensitivity and specificity (both >95%) for identifying breast cancer metastases to lymph nodes in two immunocompetent syngeneic mouse models. It is well tolerated and single-dose toxicology studies in rats determined a no-observed-adverse-effect-level (NOAEL) at >110-fold above the imaging and estimated human dose. Protease specificity and hydrolysis kinetics were characterized and compared using recombinant MMPs. To understand the human translation potential, an in vitro diagnostic study was conducted to evaluate the ability of AVB-620 to differentiate human breast cancer tumor from healthy adjacent tissue. Patient tumor tissue and healthy adjacent breast tissue were homogenized, incubated with AVB-620, and fluorogenic responses were compared. Tumor tissue had 2-3 fold faster hydrolysis than matched healthy breast tissue; generating an assay sensitivity of 96% and specificity of 88%. AVB-620 has excellent sensitivity and specificity for identifying breast cancer in mouse and human tissue. Significant changes were made in the design of AVB-620 relative to previous ratiometric protease-activated agents. AVB-620 has pharmaceutical properties, fluorescence ratio dynamic range, usable diagnostic time window, a scalable synthesis, and a safety profile that have enabled it to advance into clinical evaluation in breast cancer patients.

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“…In recent decades, a majority of studies have been devoted for developing novel, consistent SLN tracing methods, to reduce the FNR of SLNB, [ 12 ] resulting in the currently used methods of tracing SLNs: blue dye, [ 13 ] radioisotope, the combination of blue dye and isotope, [ 14 ] fluorescent dye, [ 15 , 16 ] and nanoparticles. [ 17 , 18 ] Though the novel methods of lymphoscintigraphy confer their own unique advantages in reducing the FNR of SLNB in preclinical studies, their application in practice depends upon further prospective clinical studies to identify suitable protocols, and the uptake of such advanced methods might require some time.…”

Section: Discussionmentioning

confidence: 99%

Retrospective observational study about reducing the false negative rate of the sentinel lymph node biopsy

Zhou

Du²,

Zhang³

et al. 2017

Medicine

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Reducing the false negative rate of sentinel lymph node biopsy (SLNB) for breast cancer patients has always been a focus of clinical research. We aimed to map the sentinel lymph nodes (SLNs) in detail, and analyze the factors related to SLNs located at locations that are often ignored by surgeons, to reduce the rate of false negatives from SLNB. A retrospective analysis involving 545 breast cancer patients who underwent SLNB in west China hospital between August 2010 and February 2016 was performed. Blue dye, radioisotope, or combined methods were used for tracing SLNs. Using blue dye, radioisotope, and a combination of blue dye and radioisotope successfully traced SLNs in 479, 507, and 525 patients, the detection rate was 88.2%, 93.9%, and 97.4%, respectively. Among the 1559 detected SLNs, 139 (9.6%) were located at the latissimus dorsi lateral margin, and 108 (6.9%) were located at level 2. Subcutaneous injection of radioisotope (P = .004) and intradermal injection of blue dye (P = .002) were independent factors associated with SLNs distributed at level 2 and the latissimus dorsi lateral margin, respectively. It was noteworthy that 2 of 7 patients had skipping metastasis in level 2, so subcutaneous injection of the isotope is strongly recommended for tracing SLNs distributed in level 2 because of the possibility of skipping metastasis. Though intradermal injection of blue dye was superior methods for tracing SLNs located at the latissimus dorsi lateral margin, we surprisingly found those patients with metastasis to the latissimus dorsi lateral margin nodes also could have metastasis to level 1 (expect for the latissimus dorsi lateral margin) nodes, it seemed that maybe there is no need to excise SLNs at the latissimus dorsi lateral margin in SLNB, whether such nodes should be regarded as useful for SLNB still needs to be determined by further large, multicenter clinical studies.

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Rapid diagnosis of lymph node metastasis in breast cancer using a new fluorescent method with γ-glutamyl hydroxymethyl rhodamine green

Cited by 24 publications

References 20 publications

Rapid detection of papillary thyroid carcinoma by fluorescence imaging using a γ-glutamyltranspeptidase-specific probe: a pilot study

Rapid detection of papillary thyroid carcinoma by fluorescence imaging using a γ-glutamyltranspeptidase-specific probe: a pilot study

Sensitive in vivo Visualization of Breast Cancer Using Ratiometric Protease-activatable Fluorescent Imaging Agent, AVB-620

Retrospective observational study about reducing the false negative rate of the sentinel lymph node biopsy

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