Evaluation of Chelator-to-Antibody Ratio on Development of 89Zr-iPET Tracer for Imaging of PD-L1 Expression on Tumor.

89Zr-iPET has been widely used for preclinical and clinical immunotherapy studies to predict patient stratification or evaluate therapeutic efficacy. In this study, we prepared and evaluated 89Zr-DFO-anti-PD-L1-mAb tracers with varying chelator-to-antibody ratios (CARs), including 89Zr-DFO-anti-PD-L1-mAb_3X (tracer_3X), 89Zr-DFO-anti-PD-L1-mAb_10X (tracer_10X), and 89Zr-DFO-anti-PD-L1-mAb_20X (tracer_20X). The DFO-anti-PD-L1-mAb conjugates with varying CARs were prepared using a random conjugation method and then subjected to quality control. The conjugates were radiolabeled with 89Zr and evaluated in a PD-L1-expressing CT26 tumor-bearing mouse model. Next, iPET imaging, biodistribution, pharmacokinetics, and ex vivo pathological and immunohistochemical examinations were conducted. LC-MS analysis revealed that DFO-anti-PD-L1-mAb conjugates were prepared with CARs ranging from 0.4 to 2.0. Radiochemical purity for all tracer groups was >99% after purification. The specific activity levels of tracer_3X, tracer_10X, and tracer_20X were 2.2 ± 0.6, 8.2 ± 0.6, and 10.5 ± 1.6 µCi/µg, respectively. 89Zr-iPET imaging showed evident tumor uptake in all tracer groups and reached the maximum uptake value at 24 h postinjection (p.i.). Biodistribution data at 168 h p.i. revealed that the tumor-to-liver, tumor-to-muscle, and tumor-to-blood uptake ratios for tracer_3X, tracer_10X, and tracer_20X were 0.46 ± 0.14, 0.58 ± 0.33, and 1.54 ± 0.51; 4.7 ± 1.3, 7.1 ± 3.9, and 14.7 ± 1.1; and 13.1 ± 5.8, 19.4 ± 13.8, and 41.3 ± 10.6, respectively. Significant differences were observed between tracer_3X and tracer_20X in the aforementioned uptake ratios at 168 h p.i. The mean residence time and elimination half-life for tracer_3X, tracer_10X, and tracer_20X were 25.4 ± 4.9, 24.2 ± 6.1, and 25.8 ± 3.3 h and 11.8 ± 0.5, 11.1 ± 0.7, and 11.7 ± 0.6 h, respectively. No statistical differences were found between-tracer in the aforementioned pharmacokinetic parameters. In conclusion, 89Zr-DFO-anti-PD-L1-mAb tracers with a CAR of 1.4-2.0 may be better at imaging PD-L1 expression in tumors than are traditional low-CAR 89Zr-iPET tracers.

Automated Synthesis of [18F]Flumazenil Application in GABAA Receptor Neuroimaging Availability for Rat Model of Anxiety.

Clinical studies have demonstrated that the γ-aminobutyric acid type A (GABAA) receptor complex plays a central role in the modulation of anxiety. Conditioned fear and anxiety-like behaviors have many similarities at the neuroanatomical and pharmacological levels. The radioactive GABA/BZR receptor antagonist, fluorine-18-labeled flumazenil, [18F]flumazenil, behaves as a potential PET imaging agent for the evaluation of cortical damage of the brain in stroke, alcoholism, and for Alzheimer disease investigation. The main goal of our study was to investigate a fully automated nucleophilic fluorination system, with solid extraction purification, developed to replace traditional preparation methods, and to detect underlying expressions of contextual fear and characterize the distribution of GABAA receptors in fear-conditioned rats by [18F]flumazenil. A carrier-free nucleophilic fluorination method using an automatic synthesizer with direct labeling of a nitro-flumazenil precursor was implemented. The semi-preparative high-performance liquid chromatography (HPLC) purification method (RCY = 15-20%) was applied to obtain high purity [18F]flumazenil. Nano-positron emission tomography (NanoPET)/computed tomography (CT) imaging and ex vivo autoradiography were used to analyze the fear conditioning of rats trained with 1-10 tone-foot-shock pairings. The anxiety rats had a significantly lower cerebral accumulation (in the amygdala, prefrontal cortex, cortex, and hippocampus) of fear conditioning. Our rat autoradiography results also supported the findings of PET imaging. Key findings were obtained by developing straightforward labeling and purification procedures that can be easily adapted to commercially available modules for the high radiochemical purity of [18F]flumazenil. The use of an automatic synthesizer with semi-preparative HPLC purification would be a suitable reference method for new drug studies of GABAA/BZR receptors in the future.

Investigation of biodistribution and tissue penetration of PEGylated gold nanostars and their application for photothermal cancer treatment in tumor-bearing mice.

Gold nanostars (AuNSs), with unique physicochemical properties, are thought to be a promising agent for photothermal therapy (PTT). In this study, we prepared PEGylated gold nanostars (pAuNSs) using the HEPES-reduction method. The high photothermal conversion efficiency (∼80%) and photothermal stability of pAuNSs were demonstrated in vitro and in vivo. 111In-DTPA-pAuNSs were prepared as a radioactive surrogate for the biodistribution studies of pAuNSs. In both microSPECT/CT images and the biodistribution study, the tumor-to-muscle (T/M) ratio reached a maximum at 24 h post intravenous injection of 111In-DTPA-pAuNSs. The high linear correlation between the 111In radioactivity and the gold content in the tumors (R2 0.86-0.99) indicated that 111In-DTPA-pAuNSs were appropriate for noninvasively tracking pAuNSs in vivo after systemic administration. Histological examination after silver enhancement staining clearly illustrated that the accumulated pAuNSs in the tumors were mainly located on the luminal surface of vessels. The mice bearing a SKOV-3 xenograft exhibited remarkable therapeutic efficacy with negligible organ damage after receiving pAuNS-mediated photothermal therapy. Our findings suggested that pAuNSs, together with their radioactive surrogate 111In-DTPA-pAuNSs, are promising for applications in image-guided photothermal therapy.

Evaluation of the Biological Behavior of a Gold Nanocore-Encapsulated Human Serum Albumin Nanoparticle (Au@HSANP) in a CT-26 Tumor/Ascites Mouse Model after Intravenous/Intraperitoneal Administration.

Colorectal cancer is one of the major causes of cancer-related death in Taiwan and worldwide. Patients with peritoneal metastasis from colorectal cancer have reduced overall survival and poor prognosis. Hybrid protein-inorganic nanoparticle systems have displayed multifunctional applications in solid cancer theranostics. In this study, a gold nanocore-encapsulated human serum albumin nanoparticle (Au@HSANP), which is a hybrid protein-inorganic nanoparticle, and its radioactive surrogate 111In-labeled Au@HSANP (111In-Au@HSANP), were developed and their biological behaviors were investigated in a tumor/ascites mouse model. 111In-Au@HSANP was injected either intravenously (iv) or intraperitoneally (ip) in CT-26 tumor/ascites-bearing mice. After ip injection, a remarkable and sustained radioactivity retention in the abdomen was noticed, based on microSPECT images. After iv injection, however, most of the radioactivity was accumulated in the mononuclear phagocyte system. The results of biodistribution indicated that ip administration was significantly more effective in increasing intraperitoneal concentration and tumor accumulation than iv administration. The ratios of area under the curve (AUC) of the ascites and tumors in the ip-injected group to those in the iv-injected group was 93 and 20, respectively. This study demonstrated that the ip injection route would be a better approach than iv injections for applying gold-albumin nanoparticle in peritoneal metastasis treatment.

Development and validation of a reversed-phase HPLC method for analysis of radiochemical purity in [123I]IBZM.

[123I]IBZM is used widely for in vivo imaging of D2 receptors in human brain and shows relatively fast kinetics and a greater susceptibility to synaptic dopamine release than other single-photon emission computed tomography (SPECT) radioligands. A reliable and reversed-phase HPLC method using UV/VIS and radiometric detectors has been developed for qualitative analysis of BZM and IBZM and radiochemical purity in [123I]IBZM preparations. The method uses gradient elution on a Zorbax XDB C-18 column with a mobile phase that consists of 10mM 3,3-dimethylglutaric acid (DMGA), pH 7.0 and acetonitrile (ACN). The flow rate was 1.0mL/min with detection at λ=254nm. The method was validated for system suitability, precision, accuracy, specificity, linearity, robustness, limit of detection (LOD) and limit of quantification (LOQ), as described in ICH guidelines. The results are described as follows: (1) The system suitability includes the tailing factor, theoretical plate number and resolution, which are 0.962, 10656.11 and 9.367, respectively. (2) For specificity, the BZM and [123I]NH4I did not interfere with the retention time of the [123I]IBZM. (3) The percentage coefficient of variation for analysis of precision, including repeatability and intermediate precision, is less than 2.0%. (4) Accuracy of the method is within the range of 85-100%. (5) The range of linearity is from 100% to 70% radiochemical purity (%RCP) of [123I]IBZM, with the correlation coefficient (R) always being above 0.995. (6) The data of method robustness are within acceptance criteria. (7) The LOD and LOQ for impurity (BZM) are 0.145 and 0.50µg/mL, respectively. All of the analysis results demonstrate that this method is sensitive, specific and suitable for routine analysis of the radiochemical purity in [123I]IBZM preparations.

Synthesis and biological evaluation of technetium-99m labeled galactose derivatives as potential asialoglycoprotein receptor probes in a hepatic fibrosis mouse model.

Two galactose derivatives, a monovalent (99m)Tc-MAMA-MGal galactoside and a divalent (99m)Tc-MAMA-DGal galactoside, were synthesized and radiolabeled in high radiochemical purity (>98%). Dynamic microSPECT imaging and biodistribution study of two traces in normal and liver fibrosis mice showed that the (99m)Tc-MAMA-DGal revealed higher specific binding to asialoglycoprotein receptors in liver and then rapidly excreted via both hepatobiliary system and renal clearance. The results suggest that (99m)Tc-MAMA-DGal may be used as SPECT probes for noninvasive evaluation of asialoglycoprotein receptor-related liver dysfunction.

[123I]Iodooctyl fenbufen amide as a SPECT tracer for imaging tumors that over-express COX enzymes.

This study is concerned with the development of an agent for single photon emission computer tomography (SPECT) for imaging inflammation and tumor progression. [(123)I]Iodooctyl fenbufen amide ([(123)I]IOFA) was prepared from the precursor N-octyl-4-oxo-4-(4'-(trimethylstannyl)biphenyl-4-yl)butanamide with a radiochemical yield of 15%, specific activity of 37 GBq/µmol, and radiochemical purity of 95%. Analysis of the binding of [(123)I]IOFA to COX-1 and COX-2 enzymes by using HPLC and a gel filtration column showed a selectivity ratio of 1:1.3. An assay for the competitive inhibition of substrate transfer showed that IOFA exhibited a comparable IC(50) value compared to fenbufen. In the normal rat liver, a lower level and homogeneous pattern of [(123)I]IOFA radioactivity was observed by SPECT. In contrast, in the rat liver with thioacetamide-induced cholangiocarcinoma, a higher uptake and heterogeneous pattern of [(123)I]IOFA radioactivity was seen as hot spots in tumor lesions by SPECT imaging. Importantly, elevated COX-1 and COX-2 expressions from immunostaining were found in the bile ducts of tumor rats but not of normal rats. Therefore, [(123)I]IOFA was found to exhibit the potential for imaging tumors that over-express COX.

(18)F-FBHGal for asialoglycoprotein receptor imaging in a hepatic fibrosis mouse model.

Quantification of the expression of asialoglycoprotein receptor (ASGPR), which is located on the hepatocyte membrane with high-affinity for galactose residues, can help assess ASGPR-related liver diseases. A hepatic fibrosis mouse model with lower asialoglycoprotein receptor expression was established by dimethylnitrosamine (DMN) administration. This study developed and demonstrated that 4-(18)F-fluoro-N-(6-((3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)hexyl)benzamide ((18)F-FBHGal), a new (18)F-labeled monovalent galactose derivative, is an asialoglycoprotein receptor (ASGPR)-specific PET probe in a normal and a hepatic fibrosis mouse models. Immunoassay exhibited a linear correlation between the accumulation of GalH-FITC, a fluorescent surrogate of FBHGal, and the amount of ASGPR. A significant reduction in HepG2 cellular uptake (P <0.0001) was observed using confocal microscopy when co-incubated with 0.5µM of asialofetuin, a well known ASGPR blocking agent. Animal studies showed the accumulation of (18)F-FBHGal in fibrosis liver (14.84±1.10 %ID/g) was appreciably decreased compared with that in normal liver (20.50±1.51 %ID/g, P <0.01) at 30min post-injection. The receptor indexes (liver/liver-plus-heart ratio at 30min post-injection) of hepatic fibrosis mice derived from both microPET imaging and biodistribution study were significantly lower (P <0.01) than those of normal mice. The pharmacokinetic parameters (T(1/2)α, T(1/2)ß, AUC and Cl) derived from microPET images revealed prolonged systemic circulation of (18)F-FBHGal in hepatic fibrosis mice compared to that in normal mice. The findings in biological characterizations suggest that (18)F-FBHGal is a feasible agent for PET imaging of hepatic fibrosis in mice and may provide new insights into ASGPR-related liver dysfunction.

Synthesis and evaluation of [18F]Fluorobutyl ethacrynic amide: a potential PET tracer for studying glutathione transferase.

[(18)F]Flurobutyl ethacrynic amide ([(18)F]FBuEA) was prepared from the precursor tosylate N-Boc-N-[4-(toluenesulfonyloxy)butyl]ethacrynic amide with a radiochemical yield of 3%, a specific activity of 48 GBq/µmol and radiochemical purity of 98%. Chemical conjugation of [(18)F]FBuEA with glutathione (GSH) via a self-coupling reaction and enzymatic conjugation under catalysis of glutathiontransferase alpha (GST-α) and π provided about 41% yields of radiochemical conjugated product [(18)F]FBuEA-GSH, 85% and 5-16%, respectively. The catalytic selectivity of this tracer toward GST-alpha was addressed. Positron emission tomography (PET) imaging of [(18)F]FBuEA in normal rats showed that a homogeneous pattern of radioactivity was distributed in the liver, suggesting a catalytic role of GST. By contrast, PET images of [(18)F]FBuEA in rats with thioacetamide-induced cholangiocarcinoma displayed a heterogeneous pattern of radioactive accumulation with cold spots in tumor lesions. PET imaging with [(18)F]FBuEA could be used for early diagnosis of hepatic tumor with a low GST activity as well as liver function.

Study of [18F]FLT and [123I]IaraU for cellular imaging in HSV1 tk-transfected murine fibrosarcoma cells: evaluation of the tracer uptake using 5-fluoro, 5-iodo and 5-iodovinyl arabinosyl uridines as competitive probes.

As one of the most intensively studied probes for imaging of the cellular proliferation, [(18)F]FLT was investigated whether the targeting specificity of thymidine kinase 1 (TK1) dependency could be enhanced through a synergistic effect mediated by herpes simplex type 1 virus (HSV1) tk gene in terms of the TK1 or TK2 expression. 5-[(123)I]Iodo arabinosyl uridine ([(123)I]IaraU) was prepared in a radiochemical yield of 8% and specific activity of 21 GBq/µmol, respectively. Inhibition of the cellular uptake of these two tracers was compared by using the arabinosyl uridine analogs such as 5-iodo, 5-fluoro and 5-(E)-iodovinyl arabinosyl uridine along with 2'-fluoro-5-iodo arabinosyl uridine (FIAU). Due to potential instability of the iodo group, accumulation index of 1.6 for [(123)I]IaraU by HSV1-TK vs. control cells could virtually be achieved at 1.5 h, but dropped to 0.2 compared to 2.0 for [(18)F]FLT at 5 h. The results from competitive inhibition by these nucleosides against the accumulation of [(18)F]FLT implied that FLT exerted a mixed TK1- and TK2-dependent inhibition with HSV1-tk gene transfection because of the shifting of thymidine kinase status. Taken together, the combination of [(18)F]FLT and HSV1-TK provides a synergistic imaging potency.

Early detection of tumor response by FLT/microPET Imaging in a C26 murine colon carcinoma solid tumor animal model.

Fluorine-18 fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET) imaging demonstrated the change of glucose consumption of tumor cells, but problems with specificity and difficulties in early detection of tumor response to chemotherapy have led to the development of new PET tracers. Fluorine-18-fluorothymidine ((18)F-FLT) images cellular proliferation by entering the salvage pathway of DNA synthesis. In this study, we evaluate the early response of colon carcinoma to the chemotherapeutic drug, lipo-Dox, in C26 murine colorectal carcinoma-bearing mice by (18)F-FDG and (18)F-FLT. The male BALB/c mice were bilaterally inoculated with 1 × 10(5) and 1 × 10(6) C26 tumor cells per flank. Mice were intravenously treated with 10 mg/kg lipo-Dox at day 8 after (18)F-FDG and (18)F-FLT imaging. The biodistribution of (18)F-FDG and (18)F-FLT were followed by the microPET imaging at day 9. For the quantitative measurement of microPET imaging at day 9, (18)F-FLT was superior to (18)F-FDG for early detection of tumor response to Lipo-DOX at various tumor sizes (P < 0.05). The data of biodistribution showed similar results with those from the quantification of SUV (standard uptake value) by microPET imaging. The study indicates that (18)F-FLT/microPET is a useful imaging modality for early detection of chemotherapy in the colorectal mouse model.

Solution-phase parallel synthesis and screening of anti-tumor activities from fenbufen and ethacrynic acid libraries.

The derivatives with fenbufen and ethacrynic acid core compounds was synthesized through a facial preparation of 1-amino-4-azidobutane. The subsequent coupling with 102 members of carboxylic acids afforded amide products. The in situ screening using colorimetric assay with 3-(4.5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide showed that fenbufen but not ethacrynic acid butyl amide members displayed the cytotoxicities to tumor cells substantially, including two human cell lines (MCF7 and A549) and two murine cell lines (C26 and TRAMP-C1). Three fenbufen analogs were found to have a good anti-tumor activity comparable to cisplatin.

The importance of steric zipper on the aggregation of the MVGGVV peptide derived from the amyloid beta peptide.

Amyloid-like fibrils are found in many fatal diseases, such as Alzheimer's disease, Parkinson's disease, type II diabetes mellitus, and prion diseases. Recently, the structural characterization of the MVGGVV peptide from the C-terminal hydrophobic segment of the amyloid-B (AB) peptide has revealed a general feature of amyloid-like fibrils, termed as "steric zipper", which is constituted by a tight side-chain complementation of the opposing B-sheet layers. In this study, several all-atom molecular dynamics simulations with explicit water were conducted to investigate the importance of steric zipper on the aggregation of the MVGGVV peptide. Our results show that the structural stability of the MVGGVV oligomers increases with increasing the number of B-strands. We further proposed that the octameric structure (the SH2-ST4 model in this study) is the possible nucleus seed for MVGGVV protofibril formation. Our results also demonstrated that hydrophobic interaction is the principle driving force to stabilize the adjacent B-strands while the steric zipper involved M1, V2, V5 and V6 is responsible for holding the neighboring B-sheet layers together. Finally, a twisted model of the MVGGVV assembly (SH2-ST50), based on the averaged twisted angle of approximately 11.5 degrees between the adjacent B-strands of the SH2-ST4 model, was proposed. Our results gain insights into the aggregation of the MVGGVV peptide in atomic details and may provide a hint for designing new inhibitors able to prevent the fibril formation of the AB peptide.

Structural stability and aggregation behavior of the VEALYL peptide derived from human insulin: a molecular dynamics simulation study.

The VEALYL peptide from B chain (residues 12-17) of insulin has been shown to form amyloid-like fibrils. Recently, the atomic structure of the VEALYL oligomer has been determined by X-ray microcrystallography and reveals a dry, tightly self-complementing structure between the neighboring beta-sheet layers, termed as "steric zipper." In this study, several molecular dynamics simulations with all-atom explicit water were conducted to investigate the structural stability and aggregation behavior of the VEALYL peptide with various sizes and its single glycine replacement mutations. The results of our single-layer models showed that the structural stability of the VEALYL oligomers increases significantly with increasing the number of beta-strands. We further suggested that the minimal nucleus seed for VEALYL fibril formation could be as small as three or four peptides. Our results also revealed that the hydrophobic interaction between E2 and Y5 plays an important role in stabilizing the adjacent beta-strands within the same layer, whereas the hydrophobic steric zipper formed via the side chains of V1, A3, L4, Y5, and L6 locks the two neighboring beta-sheet layers together. Mutation simulations showed that the substitution of a single glycine residue directly disrupts this steric zipper, resulting in the destabilization of the VEALYL oligomers. This study provides the atomic insights into understanding the aggregation behavior of the VEALYL peptide. It may also be helpful for designing new or modified capping peptides able to break the driving force for aggregation and to prevent the fibril formation of the VEALYL peptide and the insulin protein.

Molecular dynamics simulations to investigate the structural stability and aggregation behavior of the GGVVIA oligomers derived from amyloid beta peptide.

Several neurodegenerative diseases, such as Alzheimer's, Parkinson's, and Huntington's diseases, are associated with amyloid fibrils formed by different polypeptides. Recently, the atomic structure of the amyloid-forming peptide GGVVIA from the C-terminal hydrophobic segment of amyloid-beta (Abeta) peptide has been determined and revealed a dry, tightly self-complementing structure between two beta-sheets, termed as "steric zipper". In this study, several all-atom molecular dynamics simulations with explicit water were conducted to investigate the structural stability and aggregation behavior of the GGVVIA oligomers with various sizes. The results of our single-layer models suggested that the structural stability of the GGVVIA oligomers increases remarkably with increasing the numbers of beta-strands. We further identified that SH2-ST2 may act as a stable seed in prompting amyloid fibril formations. Our results also demonstrated that hydrophobic interaction is the principle driving force to stabilize and associate the GGVVIA oligomers between beta-strands; while the hydrophobic steric zipper formed via the side chains of V3, V4, and I5 plays a critical role in holding the two neighboring beta-sheets together. Single glycine substitution at V3, V4, and I5 directly disrupted the hydrophobic steric zipper between these two beta-sheets, resulting in the destabilization of the oligomers. Our simulation results provided detailed insights into understanding the aggregation behavior of the GGVVIA oligomers in the atomic level. It may also be helpful for designing new inhibitors able to prevent the fibril formation of Abeta peptide.

18F-FDG uptake in squamous cell carcinoma of the cervix is correlated with glucose transporter 1 expression.

UNLABELLED: This prospective study investigates the relationship between glucose transporter-1 (Glut-1) expression and PET images using (18)F-FDG and its uptake and compares them with the tumor status (primary vs. recurrent or persistent), initial grade of histologic differentiation, and International Federation of Gynecologic Obstetrics (FIGO) staging for cervical cancer patients. METHODS: A dual-phase (18)F-FDG PET scan was performed on 51 participants within the 2 wk before surgery or biopsy. (18)F-FDG uptake was quantified by calculating standardized uptake values (SUVs). After (18)F-FDG PET scanning, 51 histologically proven squamous cell carcinoma specimens were examined to determine their degree of differentiation, using hematoxylin and eosin staining, and the expression of Glut-1 by an immunohistochemical stain. Twenty normal cervical and 20 cervical intraepithelial neoplasia (CIN) sets of tissue were also used to compare the results of Glut-1 expression in these tissues. The expression of Glut-1 was the product of (the intensity [with grades 0-3, defined qualitatively]) with (percentages of the lesion area that were positive). The results of Glut-1 expression were analyzed in combination with the SUVs (SUV1 was that at 40 min and SUV2 was that at 3 h), tumor status, initial cell differentiation, and FIGO staging. RESULTS: Significant overexpression of Glut-1 was noted in 48 of the 51 (94.1%) cancer specimens. None or only minimal expression of Glut-1 was observed in basal layers of normal and CIN tissues. Significant positive correlation was observed between Glut-1 expression and the SUVs in cervical cancer specimens (r = 0.74, P < 0.000 for SUV1 and r = 0.65, P < 0.000 for SUV2). In recurrent or persistent tumor, tumor size was significantly associated with both Glut-1 expression (r = 0.508, P = 0.011) and SUV1 (r = 0. 456, P = 0.025). For recurrent or persistent tumor, only SUV1 reached statistical significance when compared with lymph node metastasis (P = 0.0226). CONCLUSION: Glut-1 expression was related to (18)F-FDG uptake in cervical cancer patients. Recurrent or persistent cervical cancer tumor had significantly higher Glut-1 expression than metastatic lymph nodes. The values of SUV and the expression of Glut-1 did not correlate with the initial grade of histologic differentiation and FIGO staging.

Delayed (18)F-FDG PET for detection of paraaortic lymph node metastases in cervical cancer patients.

UNLABELLED: This prospective study investigated the usefulness of dual-phase (18)F-FDG PET scans (40 min and 3 h) in detecting paraaortic lymph node (PALN) metastasis for cervical cancer. METHODS: One hundred four consecutive cervical cancer patients (International Federation of Gynecology and Obstetrics staging Ib-IVb, recurrent or persistent tumors) were included. All patients received a whole-body (18)F-FDG PET scan at 40 min and an additional scan from the T11 level to the inguinal region at 3 h after injection of 370 MBq (18)F-FDG. The maximum standardized uptake value (SUV) and retention index (RI [%], obtained by subtracting the normalized SUV value obtained at 40 min from that at 3 h) of the lesions were determined. RESULTS: In all, 38 of the 104 patients were confirmed to have PALN metastases. For 31 patients (81.6%) with 13 upper (L1-L2 level) and 30 lower (L3-L4 level) PALNs, these metastases were detected with the 40-min scan. In addition, for 7 patients (18.4%) with 7 lower PALNs, metastases were found with the 3-h scan (RI = 12.6%). Two patients (3.0%) had 2 false-positive lesions initially (40 min) but were classified as benign with the 3-h scan. The sensitivity, specificity, and accuracy of (18)F-FDG PET scans at 40 min were 81.6%, 97.0%, and 91.3%, respectively. These quantities were all 100% when both the 40-min and 3-h scans were taken together. Eight patients (21.1%) had their treatment planning changed. We divided the 38 patients into 2 subgroups. Subgroup A included those with either only upper or only lower PALN metastases, and subgroup B included those with both upper and lower PALN metastases. In subgroup A, the SUV values were greater in the upper than in the lower PALNs in both the 40-min and 3-h images (P = 0.077). In subgroup B, there was no significant difference of SUV values between upper and lower PALNs in the 40-min (P = 0.433) and 3-h (P = 0.937) images. CONCLUSION: Our results showed that an additional 3-h scan is helpful for PALN detection of cervical cancer patients. A delayed image (3 h) is especially useful for lower PALN metastases.

Value of dual-phase 2-fluoro-2-deoxy-d-glucose positron emission tomography in cervical cancer.

PURPOSE: The role of positron emission tomography (PET) with fluorine-18-labeled fluoro-2-deoxy-d-glucose (FDG) in cervical cancer has not yet been well defined. We conducted a prospective study to investigate its efficacy in comparison with magnetic resonance imaging and/or computed tomography (MRI-CT). MATERIALS AND METHODS: Patients with untreated locally advanced (35%) or recurrent (65%) cervical cancer were enrolled onto this study. In the first part of this study, 41 patients had a conventional FDG-PET (40 minutes after injection), and in the second part, 94 patients received dual-phase PET (at both 40 minutes and 3 hours after injection). The overall results of PET scans were compared with MRI-CT, and the two protocols of PET were also compared with each other. Lesion status was determined by pathology results or clinical follow-up. The receiver operating characteristic curve method with area under the curve (AUC) calculation was used to evaluate the discriminative power. RESULTS: Overall (N = 135), FDG-PET was significantly superior to MRI-CT in identifying metastatic lesions (AUC, 0.971 v 0.879; P =.039), although the diagnostic accuracy was similar for local tumors. Dual-phase PET was also significantly better than the 40-minute PET (n = 94). The latter accurately recognized 70% of metastatic lesions and the former detected 90% (AUC, 0.943 v 0.951; P =.007). Dual-phase FDG-PET changed treatment of 29 patients (31%; upstaging 27% and downstaging 4%). CONCLUSION: This study shows that dual-phase FDG-PET is superior to conventional FDG-PET or MRI-CT in the evaluation of metastatic lesions in locally advanced or recurrent cervical cancer.