[18F]FES PET Resolves the Diagnostic Dilemma of COVID-19-Vaccine-Associated Hypermetabolic Lymphadenopathy in ER-Positive Breast Cancer.

Coronavirus disease (COVID-19) vaccination is known to cause a diagnostic dilemma due to false-positive findings on [18F]FDG PET in vaccine-associated hypermetabolic lymphadenopathy. We present two case reports of women with estrogen-receptor (ER)-positive cancer of the breast who were vaccinated for COVID-19 in the deltoid muscle. [18F]FDG positron emission tomography (PET) demonstrated primary breast cancer and multiple axillary lymph nodes with increased [18F]FDG uptake, diagnosed as vaccine-associated [18F]FDG-avid lymph nodes. Subsequent [18F]FES PET revealed single axillary lymph node metastasis in the vaccine-associated [18F]FDG-avid lymph nodes. To the best of our knowledge, this is the first study showing the usefulness of [18F]FES PET in diagnosing axillary lymph node metastasis in COVID-19-vaccinated patients harboring ER-positive breast cancer. Thus, [18F]FES PET has potential applications in the detection of true-positive metastatic lymph nodes in patients with ER-positive breast cancer regardless of the ipsilateral or contralateral side, who have received COVID-19 vaccination.

COVID-19 pneumonia detected by [18F]FDG PET/MRI: a case with negative antigen test and chest X-ray results.

Since the outbreak of pneumonia caused by a novel coronavirus (SARS-CoV-2) named Coronavirus disease 2019 (COVID-19) in China, researchers have reported the fluorodeoxyglucose positron emission tomography/CT (FDG PET/CT) manifestations of COVID-19 infection. We present a 37-year-old female with early-stage cervical cancer and fever without a focus who had negative SARS-CoV-2 antigen test and chest X-ray results. FDG PET/MRI performed for preoperative evaluation incidentally detected pneumonia showing high FDG uptake and diffusion-weighted imaging signals in right lung base. She retested positive for SARS-CoV-2 and was diagnosed as having COVID-19 pneumonia. Whole-body PET/MRI can provide multi functional images and could be useful for evaluating the pathophysiology of COVID-19.

Pearls and pitfalls of imaging features of pancreatic cystic lesions: a case-based approach with imaging-pathologic correlation.

A variety of neoplastic and non-neoplastic lesions of the pancreas can present with a predominantly cystic architecture. These lesions are increasingly being detected as incidental findings on routine cross-sectional imaging following technological advances in these techniques and their widespread use. The different histopathological behaviors show various common and uncommon imaging findings, and some cases show similar appearance in spite of different histopathology. Each lesion requires specific management because of the differing risk of progression to malignancy, and an accurate imaging diagnosis is crucial. The typical imaging characteristics that differentiate pancreatic cystic lesions have been well described and fully summarized. However, in addition to a small percentage of cases that shows uncommon imaging findings, a substantial percentage of cystic lesions shows overlapping imaging findings that can lead to radiological misdiagnosis. For appropriate diagnosis and optimal treatment strategy, it is important to know the uncommon and overlapping imaging findings of these lesions, in addition to familiarity with the typical aspects. In this article, we reconfirm the well-known characteristic imaging features of pancreatic cystic lesions and present several diagnostically challenging cases, focusing on the uncommon and overlapping imaging findings.

Primary hepatic diffuse large B-cell lymphoma presenting unusual imaging features.

Primary hepatic lymphomas are frequently misdiagnosed, due to their rarity and non-specific clinical manifestations. As these tumors can be successfully treated with chemotherapy and/or radiotherapy, early recognition on imaging is essential to avoid unnecessary surgery. We report a case of primary hepatic lymphoma in a 73-year-old woman presenting with a 1-week history of persistent fever and elevated hepatobiliary enzymes. Ultrasound showed a hypoechoic hepatic mass in the anterior segment. Dynamic contrast-enhanced computed tomography (CT) revealed an ill-defined solitary mass showing peripherally dominant slight-to-moderate enhancement contrasting with a hypovascular central area. On magnetic resonance imaging, the mass showed moderate hyperintensity on T2-weighted imaging, hypointensity on T1-weighted imaging, doughnut-like hyperintensity on diffusion-weighted imaging, and an obviously low apparent diffusion coefficient (ADC). The pattern of enhancement resembled that of CT. Neither calcification nor any fat component was observed. Doughnut-like accumulation was seen on 18F-fluorodeoxyglucose (FDG)-positron emission tomography/CT without other FDG-avid lesions. Imaging findings suggested the possibility of cholangiocellular carcinoma, but the low ADC and extremely high FDG accumulation were suggestive of malignant lymphoma, and diffuse large B-cell lymphoma was pathologically confirmed from percutaneous biopsy. The mass disappeared after radiochemotherapy, and no recurrence has been observed for 3 years.

FDG-PET/CT imaging findings of hepatic tumors and tumor-like lesions based on molecular background.

The usefulness of whole-body 18-fluoro-2-deoxyglucose (FDG)-fluorodeoxyglucose positron emission (PET)/computed tomography (CT) is established for assessment of disease staging, detection of early disease recurrence, therapeutic evaluation, and predicting prognosis in various malignancies; and for evaluating the spread of inflammation. However, the role of FDG-PET/CT for the liver is limited because CT and magnetic resonance imaging (MRI) can provide an accurate diagnosis of most tumors. In addition, in other potentially useful roles there are several pitfalls in the interpretation of FDG uptake in PET/CT imaging. Accurate evaluation demands knowledge of the FDG uptake of each lesion, including potential negative and positive uptakes, and requires an understanding of the underlying background of the molecular mechanisms. The degree of FDG uptake is dependent on cellular metabolic rate and the expression of glucose transporter, hexokinase, and glucose-6-phosphatase, which in turn are closely affected by biological characteristics such as pathological category (e.g., adenocarcinoma, squamous cell carcinoma, small cell cancer, transitional cell cancer, neuroendocrine tumor, sarcoma, lymphoma), tumor differentiation, histological behavior (e.g., solid, cystic, mucinous), and intratumoral alterations (e.g., necrosis, degeneration, hemorrhage). Correlation with the CT and MRI findings, which also precisely depict the pathological findings, is important to avoid misdiagnosis.

Evaluation of retained products of conception using pulsed continuous arterial spin-labeling MRI: clinical feasibility and initial results.

OBJECTIVES: We evaluated the vascularity of retained products of conception (RPOC) using arterial spin-labeling magnetic resonance imaging (ASL-MRI) to clarify the clinical feasibility of this approach. MATERIALS AND METHODS: A pulsed-continuous ASL sequence with echo-planar imaging (EPI) acquisitions was used. Ten consecutive patients with RPOC were enrolled. All ASL images were evaluated visually and semiquantitatively and compared with the findings of Doppler ultrasound (US) and dynamic contrast-enhanced MRI (DCE-MRI). RESULTS: The technical success rate was 93.7% (15/16 scans). One failed case was excluded from the analysis. Six patients showed quite high signals over RPOC, while three patients showed no abnormal signals. Doppler US alone failed to detect the hypervascular area in two cases, and ASL-MRI alone failed in three. A significant linear correlation was found between semiquantitative values of ASL-MRI and DCE-MRI. All six patients showing high signals on ASL-MRI underwent follow-up MRI after therapy. High signals in five patients decreased visually and semiquantitatively, while one patient showed signal increases. CONCLUSION: Evaluation of RPOC using ASL-MRI was clinically feasible and response to therapy could be evaluated. However, the clinical advantages over conventional imaging remain unclear and need to be evaluated.

Evaluation of obliteration of arteriovenous malformations after stereotactic radiosurgery with arterial spin labeling MR imaging.

PURPOSE: Complete obliteration of treated arteriovenous malformations (AVMs) can be diagnosed only by confirming the disappearance of arterio-venous (A-V) shunts with invasive catheter angiography. The authors evaluated whether non-invasive arterial spin labeling (ASL) magnetic resonance (MR) imaging can be used to diagnose the obliteration of AVMs facilitate the diagnosis of AVM obliteration after treatment with stereotactic radiosurgery (SRS). MATERIAL AND METHODS: Seven patients with a cerebral AVM treated by SRS were followed up with ASL images taken with a 3T-MR unit, and received digital subtraction angiography (DSA) after the AVM had disappeared on ASL images. Three patients among the seven received DSA also after the postradiosurgical AVM had disappeared on conventional MR images but A-V shunt was residual on ASL images. Four patients among the seven received contrast-enhanced (CE) MR imaging around the same period as DSA. RESULTS: ASL images could visualize postradiosurgical residual A-V shunts clearly. In all seven patients, DSA after the disappearance of A-V shunts on ASL images demonstrated no evidence of A-V shunts. In all three patients, DSA after the AVM had disappeared on conventional MR images but not on ASL images demonstrated residual A-V shunt. CE MR findings of AVMs treated by SRS did not correspond with DSA findings in three out of four patients. CONCLUSIONS: Findings of radiosurgically treated AVMs on ASL images corresponded with those on DSA. The results of this study suggest that ASL imaging can be utilized to follow up AVMs after SRS and to decide their obliteration facilitate to decide the precise timing of catheter angiography for the final diagnosis of AVM obliteration after SRS.

Simultaneous acquisition of high-contrast and quantitative liver T1 images using 3D phase-sensitive inversion recovery: a feasibility study.

Background Tumor-to-liver contrast is low in images of chronically diseased livers because gadolinium-based hepatocyte-specific contrast agents (Gd-EOB-DTPA) accumulate less to hepatocytes. Purpose To determine whether phase-sensitive inversion recovery (PSIR) could improve the T1 contrasts of Gd-based contrast agents and liver parenchyma and simultaneously provide accurate T1 values for abdominal organs. Material and Methods The image contrasts of phantoms with different Gd concentrations that were obtained using PSIR were compared to conventional turbo field echo (TFE) results. T1 value was estimated using PSIR by performing iterations to investigate the two IR magnetization evolutions. The estimated T1 values were validated using IR-spin echo (IR-SE) and Look-Locker (L-L) sequences. In an in vivo study, the liver-to-spleen and liver-to-muscle contrasts of the PSIR and TFE images of seven volunteers were compared, as were the T1 values of liver parenchyma, spleen, and muscle obtained using PSIR and L-L sequences. Results The PSIR images showed T1 contrasts higher than those in the TFE results. The PSIR and IR-SE T1 values were linearly correlated. Additionally, the R1 estimated using PSIR were correlated with those measured using IR-SE and L-L. In the in vivo study, the liver-to-spleen and liver-to-muscle contrasts of PSIR were significantly higher than those obtained using TFE. T1 values of abdominal organs obtained using PSIR and L-L were clearly correlated. Conclusion PSIR may be capable of improving liver image T1 contrasts when Gd-based contrast agents are employed and simultaneously yielding accurate T1 values of abdominal organs.

Sensitive ß-galactosidase-targeting fluorescence probe for visualizing small peritoneal metastatic tumours in vivo.

Fluorescence-guided diagnostics is one of the most promising approaches for facile detection of cancer in situ. Here we focus on ß-galactosidase, which is overexpressed in primary ovarian cancers, as a molecular target for visualizing peritoneal metastases from ovarian cancers. As existing fluorescence probes are unsuitable, we have designed membrane-permeable HMRef-ßGal, in which the optimized intramolecular spirocyclic function affords >1,400-fold fluorescence enhancement on activation. We confirm that HMRef-ßGal sensitively detects intracellular ß-galactosidase activity in several ovarian cancer lines. In vivo, this probe visualizes metastases as small as <1 mm in diameter in seven mouse models of disseminated human peritoneal ovarian cancer (SHIN3, SKOV3, OVK18, OVCAR3, OVCAR4, OVCAR5 and OVCAR8). Because of its high brightness, real-time detection of metastases with the naked eye is possible. Endoscopic fluorescence detection of metastases is also demonstrated. The results clearly indicate preclinical potential value of the probe for fluorescence-guided diagnosis of peritoneal metastases from ovarian cancers.

Serial changes of (18)F-FDG PET/CT findings in ischiopubic synchondrosis: comparison with contrast-enhanced MRI.

UNLABELLED: A 3 years old female patient underwent resection and chemotherapy for a yolk sac tumor of the retroperitoneum. Two years later, fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) showed high uptake in the right ischiopubic synchondrosis (IPS), which had a radiolucent structure on CT. The structure showed contrast enhancement on magnetic resonance imaging (MRI), which was a non-specific finding. Six weeks later, a follow-up (18)F-FDG PET/CT scan was performed which showed no abnormal uptake in the IPS. The disappearance of (18)F-FDG uptake preceded that of contrast enhancement on MRI, which was seen 7 months after the initial (18)F-FDG PET/CT scan. CONCLUSION: This is the first report showing serial changes of (18)F-FDG uptake in IPS, in comparison to MRI findings.

Standardized uptake value differences between primary and metastatic lesions in ¹8F-FDG PET/CT of patients with lung cancer.

BACKGROUND: FDG-PET/CT is a robust tool for staging of lung cancer, but the differences in FDG uptake between primary and metastatic lesions have not yet been well described. PURPOSE: To define the potential range of standardized uptake value (SUV) differences between primary and metastatic lesions in lung cancer patients and to identify the factors responsible for these differences. MATERIAL AND METHODS: FDG-PET/CT images of 75 lung cancers with 296 metastases were analyzed retrospectively. Histological types, primary locations, and metastatic sites were recorded. The average and maximum SUV (SUVavg, SUVmax) of each primary tumor and metastasis were measured, and the ratio of metastatic SUVs to primary SUVs (M/Pavg, M/Pmax), its difference from 100% (diff-M/Pavg, diff-M/Pmax), the ratio of ROI area of metastatic to primary lesions (ROI-M/P), and its difference from 100% (diff-ROI-M/P) were calculated. RESULTS: M/Pavg was in the range of 35.9-224.6% (mean ± SD: 97.9% ± 35.9%), while M/Pmax was in the range of 24.8-286.7% (98.1% ± 45.3%). Furthermore, values were in the range of 50-200% for M/Pavg in 280/296 lesions (94.6%) and for M/Pmax in 255/296 lesions (86.1%). M/Pavg and M/Pmax showed significant linear correlations with ROI-M/P (r = 0.62, 0.64, respectively). Multivariate analysis showed that diff-ROI-M/P had the greatest effect on diff-M/Pavg and diff-M/Pmax. CONCLUSION: The SUVs of most metastatic lesions ranged from half to double those of primaries in lung cancer patients. When the SUV of a suspected metastasis is beyond the range of half to double that of the primary lung cancer, other non-metastatic lesions should be considered, while taking ROI size into account.

Arterial spin labeling perfusion-weighted MRI for long-term follow-up of a cerebral arteriovenous malformation after stereotactic radiosurgery.

We present a longitudinal series of arterial spin-labeling magnetic resonance imaging (ASL-MRI) in a patient with cerebral arteriovenous malformations (AVMs) treated by stereotactic radiosurgery (SRS). Pretreatment ASL-MRI showed high signal intensity in both the nidus and draining veins, and the latter signal abnormality gradually moved proximally by 14 months after SRS. At 24 months, the signal abnormalities finally disappeared, indicating complete obliteration of the nidus. The hemodynamic changes in the AVM were clearly visualized in the longitudinal ASL-MRI series, thus this non-invasive MR method may be useful not only for detecting AVMs but also for assessment of their response after SRS.

Assessment of tumor blood flow and its correlation with histopathologic features in skull base meningiomas and schwannomas by using pseudo-continuous arterial spin labeling images.

OBJECTIVE: We aimed to investigate whether pseudo-continuous arterial spin labeling (pcASL)-MRI can adequately evaluate tumor perfusion even if the tumors are located in the skull base region and evaluate the correlation between tumor blood flow (TBF) and the histopathologic features of skull base meningiomas and schwannomas. MATERIALS AND METHODS: We enrolled 31 patients with skull base meningioma (n=14) and schwannoma (n=17) who underwent surgical resection. TBF was calculated from pcASL. Tissue sections were stained with CD34 to evaluate microvessel area (MVA). TBF and MVA ratio were compared between meningiomas and schwannomas using Mann-Whitney U-test. The correlations between MVA ratio and TBF were evaluated in each tumor by using single linear regression analysis and Spearman's rank correlation coefficients (rs). RESULTS: MVA ratio and TBF were significantly higher in meningioma than in schwannoma (both p<0.01). Correlation analyses revealed significant positive correlations between MVA ratio and both mean and max TBF for meningiomas (rs=0.89, 0.81, both p<0.01). There was a weak positive correlation between MVA ratio and mean TBF for schwannomas (rs=0.43, p=0.04). However, no significant correlation was found between MVA ratio and max TBF for schwannoma. CONCLUSIONS: pcASL-MRI is useful for evaluating tumor perfusion even if the tumors are located in the skull base region. Moreover, pcASL-TBF was significantly higher in most meningiomas compared to schwannomas, which can help in the differential diagnosis of the 2 tumor types even without the use of contrast material.

Monitoring of extra-axial brain tumor response to radiotherapy using pseudo-continuous arterial spin labeling images: preliminary results.

INTRODUCTION: Technological developments have increased the ease of performing perfusion MRI by arterial spin labeling (ASL) in clinical settings. The objective of this study was to evaluate the effects of radiotherapy on extra-axial brain tumors by using MR perfusion images obtained using the pseudo-continuous arterial spin labeling (pcASL) method. MATERIALS AND METHODS: Six consecutive patients (nine lesions) with extra-axial brain tumors treated only with radiotherapy were enrolled in this study. MR examinations, including pcASL imaging, were performed before and after radiotherapy. Cerebral blood flow, maximum tumor blood flow (mTBF), tumor volume and the ratio of signal enhancement by contrast material (enhancement ratio) were evaluated in serial examinations during the course of radiotherapy. Both the percentage change in mTBF (mTBF ratio) and the percentage change in volume (volume ratio) were calculated using values obtained before and after radiotherapy. The correlation between the volume ratio and the mTBF ratio was assessed using linear regression analysis and Spearman's rank correlation coefficient (rs). RESULTS: A strong correlation was demonstrated between the tumor volume ratio and the mTBF ratio before and after radiotherapy (rs=0.93, P<.01). However, no significant correlation was identified between changes in enhancement and volume ratio (rs=0.20) or between changes in enhancement and mTBF ratio (rs=0.30) before and after radiotherapy. CONCLUSION: The mTBF measured using pcASL may serve as an additive index for tumor volume when determining tumor response to radiotherapy even in the absence of contrast material.

Fluorescence endoscopic detection of murine colitis-associated colon cancer by topically applied enzymatically rapid-activatable probe.

OBJECTIVES: Screening colonoscopy to monitor for early colitis-associated colon cancer (CAC) is difficult due to the aberrant mucosal patterns associated with long-standing colitis. The aim of this study was to develop a rapid fluorescent detection method for use during colonoscopy for improving the detection of CAC utilising a topically applied enzymatically activatable probe (gGlu-HMRG) which fluoresces in the presence of γ-glutamyltranspeptidase (GGT), an enzyme associated with cancer. METHODS: Expression of GGT in colon cell lines was examined with fluorescence microscopy and flow cytometry. A mouse model (azoxymethane/dextran sulphate sodium) of CAC was used and mice were examined with white light and fluorescence colonoscopy before and after topical gGlu-HMRG administration. RESULTS: Expression of GGT, although variable, was higher in human colon cancer cells than normal human colon cells. Using fluorescence colonoscopy in mice, gGlu-HMRG fluorescent lesions were detected 5 min after topical administration and fluorescence persisted for at least 30 min. Fluorescence guided biopsy revealed all fluorescent lesions that contained cancer or dysplasia (n=16), whereas three out of 12 non-fluorescent lesions contained low grade dysplasia and others did not contain neoplastic histology. Microscopic inflammatory infiltration also had variable fluorescence but in general was much lower (∼10-fold) in signal than cancer. Repeat fluorescence endoscopy allowed individual tumours to be monitored. CONCLUSION: These results suggest that gGlu-HMRG can improve endoscopic detection of CAC with a higher target to background ratio than conventional white light colonoscopy. This could be of benefit to patients with long-standing colitis who must undergo repeated screening colonoscopies.

A rare congenital anomaly, bridge-like appendiceal fistula to the terminal ileum, demonstrated by MDCT.

Although appendiceal anatomical anomalies are very rare, understanding of the anatomical details of these anomalies is important for surgery. In this case report, we present images from multi-detector row computed tomography (MDCT) and histological findings of a rare anatomical appendiceal anomaly originating from the cecum and opening into the terminal ileum like a bridge. These anatomical details were clearly depicted on MDCT with multi-planar reconstruction. MDCT demonstrated a communication between the appendix and terminal ileum. Histological analysis revealed that a normal mucosal layer was maintained from the appendix to the connected ileum, without any evidence of inflammatory or neoplastic changes, and only thickening of the muscular layer of the appendix was identified. Based on these histological findings, the appendix was considered to represent an anatomical anomaly rather than secondary fistula caused by inflammation or neoplasm, which has not yet been reported.

The use of fluorescent proteins for developing cancer-specific target imaging probes.

Target-specific imaging probes represent a promising tool in the molecular imaging of human cancer. Fluorescently-labeled target-specific probes are useful in imaging cancers because of their ability to bind a target receptor with high sensitivity and specificity. The development of probes relies upon preclinical testing to validate the sensitivity and specificity of these agents in animal models. However, this process involves both conventional histology and immunohistochemistry, which require large numbers of animals and samples with costly handling. In this chapter, we describe a novel validation tool that takes advantage of genetic engineering technology, whereby cell lines are transfected with genes that induce the target cell to produce fluorescent proteins with characteristic emission spectra, thus enabling their easy identification as cancer cells in vivo. Combined with multicolor fluorescence imaging, this can provide rapid validation of newly-developed exogenous probes that fluoresce at different wavelengths. For example, the plasmid containing the gene encoding red fluorescent protein (RFP) was transfected into cell lines previously developed to either express or not express specific cell surface receptors. Various antibody-based or ligand-based optical-contrast agents, with green fluorophores were developed to concurrently target cancer cells and validate their positive and negative controls, such as the ß-D: -galactose receptor, HER1, and HER2 in a single animal/organ. Spectrally-resolved multicolor fluorescence imaging was used to detect separate fluorescence emission spectra from the exogenous green fluorophore and RFP. Here, we describe the use of "co-staining" (matching the exogenous fluorophore and the endogenous fluorescent protein to the positive control cell line) and "counter-staining" (matching the exogenous fluorophore to the positive control and the endogenous fluorescent protein to the negative control cell line) to validate the sensitivity and specificity of target-specific probes. Using these in vivo imaging techniques, we are able to determine the sensitivity and specificity of target-specific optical contrast agents in several distinct animal models of cancer in vivo, thus exemplifying the versatility of our technique, while reducing the number of animals needed to conduct these experiments.

MR and optical imaging of early micrometastases in lymph nodes: triple labeling with nano-sized agents yielding distinct signals.

Few imaging methods are available for depicting in vivo cancer cell migration within the lymphatic system. Detection of such early micrometastases requires extremely high target to background. In this study, we dual-labeled human breast cancer cells (MDA-MB468) with a small particle of iron oxide (SPIO) and a quantum dot (QD), and tracked these cells in the lymphatic system in mice using in vivo MRI and optical imaging. A generation-6 gadolinium-dendrimer-based MRI contrast agent (Gd-G6) was employed for visualizing regional lymphatic channels and nodes. Since Gd-G6 shortened T(1) leading to high signal, whereas SPIO-labeled cancer cells greatly lowered signal, a small number of cells were simultaneously visualized within the draining lymphatic basins. One million dual-labeled cancer cells were subcutaneously injected into the paws of mice 24 h prior to imaging. Then whole body images were acquired pre- and post-intracutaneous injection of Gd-G6 with 3D-T(1) w-FFE and balanced-FFE sequences for cancer cell tracking and MR lymphangiography. In vivo MRI clearly visualized labeled cancer cells migrating from the paw to the axillary lymph nodes using draining lymphatics. In vivo optical imaging using a fluorescence surgical microscope demonstrated tiny cancer cell clusters in the axillary lymph node with high spatial resolution. Thus, using a combination of MRI and optical imaging, it is possible to depict macro- and early micrometastases within the lymphatic system. This platform offers a versatile research tool for investigating and treating lymphatic metastases in animal models.

Activatable optical imaging with a silica-rhodamine based near infrared (SiR700) fluorophore: a comparison with cyanine based dyes.

Optical imaging is emerging as an important tool to visualize tumors. However, there are many potential choices among the available fluorophores. Optical imaging probes that emit in the visible range can image superficial tumors with high quantum yields; however, if deeper imaging is needed then near-infrared (NIR) fluorophores are necessary. Most commercially available NIR fluorophores are cyanine based and are prone to nonspecific binding and relatively limited photostability. Silica-containing rhodamine (SiR) fluorophores represent a new class of NIR fluorophores, which permit photoactivation via H-dimer formation as well as demonstrate improved photostability. This permits higher tumor-to-background ratios (TBRs) to be achieved over longer periods of time. Here, we compared an avidin conjugated with SiR700 (Av-SiR700) to similar compounds based on cyanine dyes (Av-Cy5.5 and Av-Alexa Fluor 680) in a mouse tumor model of ovarian cancer metastasis. We found that the Av-SiR700 probe demonstrated superior quenching, enabling activation after binding-internalization to the target cell. As a result, Av-SiR700 had higher TBRs compared to Av-Cy5.5 and better biostability compared to Av-Alexa Fluor 680.

Rapid cancer detection by topically spraying a γ-glutamyltranspeptidase-activated fluorescent probe.

The ability of the unaided human eye to detect small cancer foci or accurate borders between cancer and normal tissue during surgery or endoscopy is limited. Fluorescent probes are useful for enhancing visualization of small tumors but are typically limited by either high background signal or the requirement for administration hours to days before use. We synthesized a rapidly activatable, cancer-selective fluorescence imaging probe, γ-glutamyl hydroxymethyl rhodamine green (gGlu-HMRG), with intramolecular spirocyclic caging for complete quenching. Activation occurs by rapid one-step cleavage of glutamate with γ-glutamyltranspeptidase (GGT), which is not expressed in normal tissue, but is overexpressed on the cell membrane of various cancer cells, thus leading to complete uncaging and dequenching of the fluorescence probe. In vitro activation of gGlu-HMRG was evident in 11 human ovarian cancer cell lines tested. In vivo in mouse models of disseminated human peritoneal ovarian cancer, activation of gGlu-HMRG occurred within 1 min of topically spraying the tumor, creating high signal contrast between the tumor and the background. The gGlu-HMRG probe is practical for clinical application during surgical or endoscopic procedures because of its rapid and strong activation upon contact with GGT on the surface of cancer cells.