Prognostic significance of volume-based 18F-FDG PET/CT parameters and correlation with PD-L1 expression in patients with surgically resected lung adenocarcinoma.

ABSTRACT: The aim of this study was to retrospectively analyze 18F-FDG positron emission tomography/computed tomography (18F-FDG PET/CT) metabolic variables, programmed death-ligand 1 (PD-L1) and phosphorylated signal transducer and activator of transcription 3 (p-STAT3) tumor expression, and other factors as predictors of disease-free survival (DFS) in patients with lung adenocarcinoma (LUAD) (stage IA-IIIA) who underwent surgical resection. We still lack predictor of immune checkpoint (programmed cell death-1 [PD-1]/PD-L1) inhibitors. Herein, we investigated the correlation between metabolic parameters from 18F-FDG PET/CT and PD-L1 expression in patients with surgically resected LUAD.Seventy-four patients who underwent 18F-FDG PET/CT prior to treatment were consecutively enrolled. The main 18F-FDG PET/CT-derived variables were primary tumor maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG). Surgical tumor specimens were analyzed for PD-L1 and p-STAT3 expression using immunohistochemistry. Correlations between immunohistochemistry results and 18F-FDG PET/CT-derived variables were compared. Associations of PD-L1 and p-STAT3 tumor expression, 18F-FDG PET/CT-derived variables, and other factors with DFS in resected LUAD were evaluated.All tumors were FDG-avid. The cutoff values of low and high SUVmax, MTV, and TLG were 12.60, 14.87, and 90.85, respectively. The results indicated that TNM stage, PD-L1 positivity, and high 18F-FDG PET/CT metabolic volume parameters (TLG ≥90.85 or MTV ≥14.87) were independent predictors of worse DFS in resected LUAD. No 18F-FDG metabolic parameters associated with PD-L1 expression were observed (chi-square test), but we found that patients with positive PD-L1 expression have significantly higher SUVmax (P = .01), MTV (P = .00), and TLG (P = .00) than patients with negative PD-L1 expression.18F-FDG PET/CT metabolic volume parameters (TLG ≥90.85 or MTV ≥14.87) were more helpful in prognostication than the conventional parameter (SUVmax), PD-L1 expression was an independent predictor of DFS in patients with resected LUAD. Metabolic parameters on 18F-FDG PET/CT have a potential role for 18F-FDG PET/CT in selecting candidate LUAD for treatment with checkpoint inhibitors.

Predictive value of 3'-deoxy-3'-18F-fluorothymidine PET in the early response to anti-programmed death-1 therapy in patients with advanced non-small cell lung cancer.

BACKGROUND: Anti-programmed death-1 (anti-PD-1) therapy has shown clinical success in patients with advanced non-small cell lung cancer (NSCLC). However, it is difficult to evaluate the early response to anti-PD-1 therapy. We determined whether changes in 3'-deoxy-3'-[18F]-fluorothymidine (18F-FLT) PET parameters before and soon after treatment initiation predicted the therapeutic effect of anti-PD-1 antibody. METHODS: Twenty-six patients with advanced NSCLC treated with anti-PD-1 antibody were enrolled prospectively and underwent 18F-FLT PET before and at 2 and 6 weeks after treatment initiation. Changes in maximal standardized uptake value (ΔSUVmax), proliferative tumor volume (ΔPTV) and total lesion proliferation (ΔTLP) of the lesions were calculated and evaluated for their associations with the clinical response to therapy. RESULTS: The disease control rate was 64%. Patients with non-progressive disease (non-PD) had significantly decreased TLP at 2 weeks, and decreased SUVmax, PTV, and TLP at 6 weeks, compared with those with PD, while three of eight (37.5%) patients who responded had increased TLP from baseline at 2 weeks (ie, pseudoprogression). Among the parameters that changed between baseline and 2 weeks, ΔPTV0-2 and ΔTLP0-2 had the highest accuracy (76.0%) to predict PD. Among the parameters that changed between baseline and 6 weeks, ΔSUVmax0-6, ΔPTV0-6 and ΔTLP0-6 had the highest accuracy (90.9%) to predict PD. ΔTLP0-2 (≥60%, HR 3.41, 95% CI 1.34-8.65, p=0.010) and ΔTLP0-6 (≥50%, HR 31.4, 95% CI 3.55 to 276.7, p=0.0019) were indicators of shorter progression-free survival. CONCLUSIONS: Changes in 18F-FLT PET parameters may have value as an early predictive biomarker for the response to anti-PD-1 therapy in patients with NSCLC. However, it should be noted that pseudoprogression was observed in 18F-FLT PET imaging at 2 weeks after treatment initiation. TRIAL REGISTRATION NUMBER: jRCTs051180147.

The prostate-specific membrane antigen (PSMA)-targeted radiotracer 18F-DCFPyL detects tumor neovasculature in metastatic, advanced, radioiodine-refractory, differentiated thyroid cancer.

Prostate-specific membrane antigen (PSMA; also termed glutamate carboxypeptidase II (GCP II)) is abundantly expressed in prostate cancer. It has been shown recently that PSMA is expressed in neovasculature of differentiated thyroid cancer. In this study, we show that 18F-DCFPyl might detect neovasculature in advanced, metastatic differentiated thyroid cancer (DTC). We first stained the preserved lymph node samples of three patients with DTC who had undergone total thyroidectomy and neck dissection for cervical lymph node metastatic disease to identify PSMA expression, with the PSMA antibody (DAKO Monoclonal). Then, we performed 18F-DCFPyl imaging in two other advanced DTC patients with elevated serum thyroglobulin (Tg), indicative of residual disease. We compared the findings with contemporaneous FDG PET/CT scan, conventional Imaging (CT,MRI) and whole-body scan performed with I123/I131. All the three lymph node samples stained positive for PSMA expression in the neovasculature. In the first imaged patient, 18F-DCFPyl detected activity within the retropharyngeal CT contrast-enhancing lymph node. Compared to FDG PET/CT, the 18F-DCFPyl scan showed a greater SUV (3.1 vs 1.8). In the second imaged patient, 18F-DCFPyl showed intense uptake in the L3 vertebra (not seen on the post treatment 131I scan or the 18F-FDG PET/CT). MRI of the lumbar spine confirmed the presence of sclerotic-lytic lesion at the location, consistent with metastatic disease. Our exploratory study is proof of principle, that the prostate cancer imaging agent 18F-DCFPyl may prove useful for the localization of metastases, in patients with metastatic RAI-refractory DTC by detecting neoangiogenesis within the tumor.

In†Vivo Imaging of the Tumor-Associated Enzyme NCEH1 with a Covalent PET Probe.

Herein, we report the development of an 18 F-labeled, activity-based small-molecule probe targeting the cancer-associated serine hydrolase NCEH1. We undertook a focused medicinal chemistry campaign to simultaneously preserve potent and specific NCEH1 labeling in live cells and animals, while permitting facile 18 F radionuclide incorporation required for PET imaging. The resulting molecule, [18 F]JW199, labels active NCEH1 in live cells at nanomolar concentrations and greater than 1000-fold selectivity relative to other serine hydrolases. [18 F]JW199 displays rapid, NCEH1-dependent accumulation in mouse tissues. Finally, we demonstrate that [18 F]JW199 labels aggressive cancer tumor cells in vivo, which uncovered localized NCEH1 activity at the leading edge of triple-negative breast cancer tumors, suggesting roles for NCEH1 in tumor aggressiveness and metastasis.

Fluorine-18 (18F)-labeled retinoid x receptor (RXR) partial agonist whose tissue transferability is affected by other RXR ligands.

Bexarotene (1), a retinoid X receptor (RXR) agonist approved for the treatment of cutaneous T cell lymphoma (CTCL), was reported to migrate into baboon brain based on findings obtained by positron emission tomography (PET) with a 11C-labeled tracer. However, co-administration of non-radioactive 1 had no effect on the distribution of [11C]1, probably due to non-specific binding of 1 as a result of its high lipophilicity. Here, we report a fluorine-18 (18F)-labeled PET tracer [18F]6 derived from RXR partial agonist CBt-PMN (2), which has lower lipophilicity and weaker RXR-binding ability than [11C]1. The concomitant administration of 1 or 2 with [18F]6 with resulted in decreased accumulation of [18F]6 in liver, together with increased brain uptake and increased accumulation in kidney and muscle, as visualized by PET. A plausible explanation of these findings is the inhibition of [18F]6 uptake into the liver by concomitantly administered 1 or 2, leading to an increase in blood concentration of [18F]6 followed by increased accumulation in other tissues.

Monitoring of intracerebellarly-administered natural killer cells with fluorine-19 MRI.

PURPOSE: Medulloblastoma (MB) is the most common malignant brain tumor in children. Recent studies have shown the ability of natural killer (NK) cells to lyse MB cell lines in vitro, but in vivo successes remain elusive and the efficacy and fate of NK cells in vivo remain unknown. METHODS: To address these questions, we injected MB cells into the cerebellum of immunodeficient mice and examined tumor growth at various days after tumor establishment via bioluminescence imaging. NK cells were labeled with a fluorine-19 (19F) MRI probe and subsequently injected either intratumorally or contralaterally to the tumor in the cerebellum and effect on tumor growth was monitored. RESULTS: The 19F probe efficiently labeled the NK cells and exhibited little cytotoxicity. Fluorine-19 MRI confirmed the successful and accurate delivery of the labeled NK cells to the cerebellum of the mice. Administration of 19F-labeled NK cells suppressed MB growth, with the same efficacy as unlabeled cells. Immunohistochemistry confirmed the presence of NK cells within the tumor, which was associated with induction of apoptosis in tumor cells. NK cell migration to the tumor from a distal location as well as activation of apoptosis was also demonstrated by immunohstochemistry. CONCLUSIONS: Our results show that NK cells present a novel opportunity for new strategies in MB treatment. Further, 19F-labeled NK cells can suppress MB growth while enabling 19F MRI to provide imaging feedback that can facilitate study and optimization of therapeutic paradigms.

Comparison of 18F-FES, 18F-FDG, and 18F-FMISO PET Imaging Probes for Early Prediction and Monitoring of Response to Endocrine Therapy in a Mouse Xenograft Model of ER-Positive Breast Cancer.

BACKGROUND: There is an increasing need to characterize biological processes for early prediction and monitoring of response to endocrine therapy in breast cancer using multiple positron emission tomography (PET) imaging probes. However, use of more than two PET tracers in a single clinical trial is quite challenging. In this study we carried out a longitudinal investigation of 18F-FES, 18F-FDG, and 18F-FMISO PET imaging probes for early prediction and monitoring of response to endocrine therapy in a mouse xenograft model of estrogen receptor (ER)-positive breast cancer. METHOD: ER+ human breast cancer ZR-75-1 models were established in female mice that were then randomly assigned to a treatment (fulvestrant, 5.0 mg/week for 21 days) or vehicle group. Micro-PET/CT imaging with 18F-FES, 18F-FDG, and 18F-FMISO was performed on days 0, 3, 14, and 21 after treatment. The uptake value (percentage injected dose per gram, %ID/g) for each probe in tumor (T) tissue and contralateral muscle (M) was measured for quantitative analysis and T/M calculation. Tumor volume was measured to record tumor growth at each time point. Tumor tissues were sampled for immunohistochemical staining of ER expression. Correlations for tumor volume and ERα levels with uptake data for the probe were tested. RESULTS: Uptake data for 18F-FES in ZR-75-1 tumor tissues corresponded well with tumor response to endocrine therapy, but not for 18F-FDG and 18F-FMISO, according to longitudinal micro-PET/CT imaging and quantitative correlation analysis. There was a significant positive correlation between 18F-FES uptake and ER levels (%ID/gmax r2 = 0.76, P< 0.05; T/M r2 = 0.82, P<0.05). Notably, 18F-FES uptake on day 3 was significantly correlated with the day 21/baseline tumor volume ratio (%ID/gmax r2 = 0.74, P < 0.05; T/M r2 = 0.78, P < 0.05). CONCLUSIONS: Comparison of 18F-FES, 18F-FDG, and 18F-FMISO probes revealed that 18F-FES PET/CT molecular imaging can provide a precise early prediction of tumor response to endocrine therapy in ER+ breast cancer in a ZR-75-1 xenograft model. This molecular imaging strategy with 18F-FES PET/CT will be useful in evaluating the efficacy of endocrine therapies and in developing new endocrine drugs.

ASSESSMENT OF THE LOCAL EXPOSURE OF SKIN ON HANDS OF NUCLEAR MEDICINE WORKERS HANDLING 18F-LABELLED RADIOPHARMACEUTICALS: PRELIMINARY CZECH STUDY.

The article summarises some preliminary results of the assessment of the exposure of hands of workers manipulating 18F-labelled radiopharmaceuticals based on personal monitoring at two nuclear medicine clinics in the Czech Republic. The measurements were carried out using special thermoluminescence dosemeters the readings of which could be interpreted in terms of the personal dose equivalent Hp(0.07) approximating the equivalent dose to the skin at various locations on the surface of both hands. The results have shown that out of 21 workers monitored, ∼43 % (preparation and applications of radiopharmaceuticals) may reach an exposure equal to three-tenth of the annual dose limit to the skin. At the same time, it can also be concluded that in ∼10 % cases of workers, the relevant dose limit may be exceeded.

Potential applications for sigma receptor ligands in cancer diagnosis and therapy.

Sigma receptors (sigma-1 and sigma-2) represent two independent classes of proteins. Their endogenous ligands may include the hallucinogen N,N-dimethyltryptamine (DMT) and sphingolipid-derived amines which interact with sigma-1 receptors, besides steroid hormones (e.g., progesterone) which bind to both sigma receptor subpopulations. The sigma-1 receptor is a ligand-regulated molecular chaperone with various ion channels and G-protein-coupled membrane receptors as clients. The sigma-2 receptor was identified as the progesterone receptor membrane component 1 (PGRMC1). Although sigma receptors are over-expressed in tumors and up-regulated in rapidly dividing normal tissue, their ligands induce significant cell death only in tumor tissue. Sigma ligands may therefore be used to selectively eradicate tumors. Multiple mechanisms appear to underlie cell killing after administration of sigma ligands, and the signaling pathways are dependent both on the type of ligand and the type of tumor cell. Recent evidence suggests that the sigma-2 receptor is a potential tumor and serum biomarker for human lung cancer and an important target for inhibiting tumor invasion and cancer progression. Current radiochemical efforts are focused on the development of subtype-selective radioligands for positron emission tomography (PET) imaging. Right now, the mostpromising tracers are [18F]fluspidine and [18F]FTC-146 for sigma-1 receptors and [11C]RHM-1 and [18F]ISO-1 for the sigma-2 subtype. Nanoparticles coupled to sigma ligands have shown considerable potential for targeted delivery of antitumor drugs in animal models of cancer, but clinical studies exploring this strategy in cancer patients have not yet been reported. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers.

Application of a whole-body pharmacokinetic model for targeted radionuclide therapy to NM404 and FLT.

We have previously developed a model that provides relative dosimetry estimates for targeted radionuclide therapy (TRT) agents. The whole-body and tumor pharmacokinetic (PK) parameters of this model can be noninvasively measured with molecular imaging, providing a means of comparing potential TRT agents. Parameter sensitivities and noise will affect the accuracy and precision of the estimated PK values and hence dosimetry estimates. The aim of this work is to apply a PK model for TRT to two agents with different magnitudes of clearance rates, NM404 and FLT, explore parameter sensitivity with respect to time and investigate the effect of noise on parameter precision and accuracy. Twenty-three tumor bearing mice were injected with a 'slow-clearing' agent, (124)I-NM404 (n = 10), or a 'fast-clearing' agent, (18)F-FLT (3'-deoxy-3'-fluorothymidine) (n = 13) and imaged via micro-PET/CT pseudo-dynamically or dynamically, respectively. Regions of interest were drawn within the heart and tumor to create time-concentration curves for blood pool and tumor. PK analysis was performed to estimate the mean and standard error of the central compartment efflux-to-influx ratio (k(12)/k(21)), central elimination rate constant (k(el)), and tumor influx-to-efflux ratio (k(34)/k(43)), as well as the mean and standard deviation of the dosimetry estimates. NM404 and FLT parameter estimation results were used to analyze model accuracy and parameter sensitivity. The accuracy of the experimental sampling schedule was compared to that of an optimal sampling schedule found using Cramer-Rao lower bounds theory. Accuracy was assessed using correlation coefficient, bias and standard error of the estimate normalized to the mean (SEE/mean). The PK parameter estimation of NM404 yielded a central clearance, k(el) (0.009 ± 0.003 h(-1)), normal body retention, k(12)/k(21) (0.69 ± 0.16), tumor retention, k(34)/k(43) (1.44 ± 0.46) and predicted dosimetry, D(tumor) (3.47 ± 1.24 Gy). The PK parameter estimation of FLT yielded a central elimination rate constant, k(el) (0.050 ± 0.025 min(-1)), normal body retention, k(12)/k(21) (2.21 ± 0.62) and tumor retention, k(34)/k(43) (0.65 ± 0.17), and predicted dosimetry, D(tumor) (0.61 ± 0.20 Gy). Compared to experimental sampling, optimal sampling decreases the dosimetry bias and SEE/mean for NM404; however, it increases bias and decreases SEE/mean for FLT. For both NM404 and FLT, central compartment efflux rate constant, k(12), and central compartment influx rate constant, k(21), possess mirroring sensitivities at relatively early time points. The instantaneous concentration in the blood, C(0), was most sensitive at early time points; central elimination, k(el), and tumor efflux, k(43), are most sensitive at later time points. A PK model for TRT was applied to both a slow-clearing, NM404, and a fast-clearing, FLT, agents in a xenograft murine model. NM404 possesses more favorable PK values according to the PK TRT model. The precise and accurate measurement of k(12), k(21), k(el), k(34) and k(43) will translate into improved and precise dosimetry estimations. This work will guide the future use of this PK model for assessing the relative effectiveness of potential TRT agents.

Single photon emission computed tomography/positron emission tomography imaging and targeted radionuclide therapy of melanoma: new multimodal fluorinated and iodinated radiotracers.

This study reports a series of 14 new iodinated and fluorinated compounds offering both early imaging ((123)I, (124)I, (18)F) and systemic treatment ((131)I) of melanoma potentialities. The biodistribution of each (125)I-labeled tracer was evaluated in a model of melanoma B16F0-bearing mice, using in vivo serial γ scintigraphic imaging. Among this series, [(125)I]56 emerged as the most promising compound in terms of specific tumoral uptake and in vivo kinetic profile. To validate our multimodality concept, the radiosynthesis of [(18)F]56 was then optimized and this radiotracer has been successfully investigated for in vivo PET imaging of melanoma in B16F0- and B16F10-bearing mouse model. The therapeutic efficacy of [(131)I]56 was then evaluated in mice bearing subcutaneous B16F0 melanoma, and a significant slow down in tumoral growth was demonstrated. These data support further development of 56 for PET imaging ((18)F, (124)I) and targeted radionuclide therapy ((131)I) of melanoma using a single chemical structure.

Evaluation of response to fractionated radioimmunotherapy with 90Y-epratuzumab in non-Hodgkin's lymphoma by 18F-fluorodeoxyglucose positron emission tomography.

BACKGROUND: The study aimed to evaluate FDG-PET imaging for early prediction of response to radioimmunotherapy in patients with non-Hodgkin's lymphoma. DESIGN AND METHODS: Twenty-seven patients from a large ongoing, multicenter, phase I/II trial of fractionated radioimmunotherapy using anti-CD22 (90)Y-epratuzumab underwent FDG-PET imaging. They also underwent assessment by conventional diagnostic methods that included chemotherapy at baseline and six weeks post-radioimmunotherapy, and every three months until progression. Responses evaluated from conventional methods were classified using International Workshop Response Criteria as complete response, unconfirmed CR, partial response, stable disease, or progression of disease. FDG-PET images were evaluated visually and were classified as complete response, partial response or progression of disease. The gold standard was histology and follow-up. RESULTS: A total of 81 paired imaging studies were obtained post-radioimmunotherapy (including 3 patients after retreatment) and evaluated as complete response (n=34), partial response (n=24) or progression of disease (n=23) by FDG-PET, and complete response (n=12), unconfirmed complete response (n=31), partial response (n=15), stable disease (n=8) or progression of disease (n=15) by conventional methods. Of the 31 responses evaluated as unconfirmed complete response by conventional methods, 20 (65%) were classified as negative for disease (complete response) by PET while the other 11 (35%) were positive for disease (7 partial response and 4 progression of disease). Among 22 assessable PET images acquired at six weeks post-radioimmunotherapy, the mean time-to-progression was 15.6 months when PET was negative for disease (complete response), compared with 5.4 months when PET was positive (partial response or progression of disease) (p=0.008). Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of PET six weeks after radioimmunotherapy were 86%, 63%, 80%, 71% and 77% respectively, compared with 36%, 87%, 83%, 44% and 55% respectively using conventional methods. CONCLUSIONS: A positive assessment of disease by PET acquired six weeks after radioimmunotherapy corresponded with a shorter time to progression.

[Clinical use of nuclear medicine in the management of thyroid diseases].

Radionuclides are widely used for the diagnosis and therapy of many diseases. Among them, 131I has the longest history of more than 60 years of clinical use, and has been still used for the therapy of Graves' disease, Plummer disease (hyperfunctional adenoma) and thyroid cancer. Radiodine is specifically taken into thyroid cells and organized. Recently PET using 18F-FDG(glucose analogue) is applied to know the extent of thyroid cancer. New tumor specific drugs, such as 131I- or 90Y labeled antibodies, have been discovered and succeeded in the therapy of lymphoma.

Boron neutron capture therapy in the treatment of locally recurred head and neck cancer.

PURPOSE: Head and neck carcinomas that recur locally after conventional irradiation pose a difficult therapeutic problem. We evaluated safety and efficacy of boron neutron capture therapy (BNCT) in the treatment of such cancers. METHODS AND MATERIALS: Twelve patients with inoperable, recurred, locally advanced (rT3, rT4, or rN2) head and neck cancer were treated with BNCT in a prospective, single-center Phase I-II study. Prior treatments consisted of surgery and conventionally fractionated photon irradiation to a cumulative dose of 56-74 Gy administered with or without concomitant chemotherapy. Tumor responses were assessed using the RECIST (Response Evaluation Criteria in Solid Tumors) criteria and adverse effects using the National Cancer Institute common toxicity grading v3.0. Intravenously administered boronophenylalanine-fructose (BPA-F, 400 mg/kg) was used as the boron carrier. Each patient was scheduled to be treated twice with BNCT. RESULTS: Ten patients received BNCT twice; 2 were treated once. Ten (83%) patients responded to BNCT, and 2 (17%) had tumor growth stabilization for 5.5 and 7.6 months. The median duration of response was 12.1 months; six responses were ongoing at the time of analysis or death (range, 4.9-19.2 months). Four (33%) patients were alive without recurrence with a median follow-up of 14.0 months (range, 12.8-19.2 months). The most common acute adverse effects were mucositis, fatigue, and local pain; 2 patients had a severe (Grade 3) late adverse effect (xerostomia, 1; dysphagia, 1). CONCLUSIONS: Boron neutron capture therapy is effective and safe in the treatment of inoperable, locally advanced head and neck carcinomas that recur at previously irradiated sites.

The positron emission tomography with F18 17beta-estradiol has the potential to benefit diagnosis and treatment of endometrial cancer.

BACKGROUND: The positron emission tomography (PET) with F18 17beta-estradiol (FES) has good imaging for assessment of estrogen receptor in breast cancer. CASE: We report on a 30-year-old woman who desired to preserve her fertility with well-differentiated endometrial adenocarcinoma. Before hormone treatment was started, FES-PET showed increased uptake of endometrium, magnetic resonance imaging (MRI) showed thickness and F-18 fluorodeoxyglucose (FDG)-PET showed increased uptake. FES-PET after 3 months showed remaining FES uptake, but there were no abnormal findings on MRI and FDG-PET. Hysteroscopy showed remaining adenocarcinoma. After additional treatment, FES-PET showed a therapeutic response, and hysteroscopy showed no abnormal finding. CONCLUSIONS: To our knowledge, this is the first report that FES-PET has the potential to provide more useful information than did FDG-PET about the hormone therapy.

Carbogen breathing differentially enhances blood plasma volume and 5-fluorouracil uptake in two murine colon tumor models with a distinct vascular structure.

For the systemic treatment of colorectal cancer, 5-fluorouracil (FU)-based chemotherapy is the standard. However, only a subset of patients responds to chemotherapy. Breathing of carbogen (95% O2 and 5% CO2) may increase the uptake of FU through changes in tumor physiology. This study aims to monitor in animal models in vivo the effects of carbogen breathing on tumor blood plasma volume, pH, and energy status, and on FU uptake and metabolism in two colon tumor models C38 and C26a, which differ in their vascular structure and hypoxic status. Phosphorus-31 magnetic resonance spectroscopy (MRS) was used to assess tumor pH and energy status, and fluorine-19 MRS was used to follow FU uptake and metabolism. Advanced magnetic resonance imaging methods using ultrasmall particles of iron oxide were performed to assess blood plasma volume. The results showed that carbogen breathing significantly decreased extracellular pH and increased tumor blood plasma volume and FU uptake in tumors. These effects were most significant in the C38 tumor line, which has the largest relative vascular area. In the C26a tumor line, carbogen breathing increased tumor growth delay by FU. In this study, carbogen breathing also enhanced systemic toxicity by FU.

MicroPET-based pharmacokinetic analysis of the radiolabeled boron compound [18F]FBPA-F in rats with F98 glioma.

Boron neutron capture therapy (BNCT) is one of the effective methods of radiation therapy for the treatment of tumors such as malignant glioma. Boronophenylalanine ((10)B-BPA) solution has been used as a potential boron carrier for such a treatment. The aim of this study is to investigate 4-borono-2-[(18)F]-fluoro-l-phenylalanine-fructose ([(18)F]FBPA-F) in rats injected in the brain with glioma using in vivo small animal positron emission tomography (PET) imaging (microPET). Male Fischer 344 rats with F98 glioma in the left brain were used for these studies. Dynamic PET imaging of [(18)F]FBPA-F was performed on the 13th day after tumor inoculation. Arterial blood sampling was performed to obtain an input function for tracer kinetic modeling. The accumulation ratios of [(18)F]FBPA-F for the glioma-to-normal brain approached 3. The uptake characteristics of BPA-F and [(18)F]FBPA-F were similar. The results indicate that 4h after BPA-F injection would be the optimal irradiation time for BNCT. Rate constants were estimated using a three-compartment model. This study provides useful information for the clinical application of BNCT in patients with brain tumors.

Update of the FDG PET search strategy.

The comprehensive search strategy for identification of FDG PET literature in the electronic databases MEDLINE and EMBASE, published in 2000, has been updated for PubMed. The new search strategy presented here is freely available at the VU website and can be easily copied from there and pasted into the PubMed search window. In addition, the strategy can be stored using the 'Cubby' feature on the PubMed interface and run whenever needed in a minimum of time. It can therefore be used for quick searches during clinical practice as well as extensive searches for systematic reviews. To increase sensitivity, new search terms and term combinations for 'PET' and 'FDG' were added. The existing truncations and field qualifications had to be changed for PubMed. The new strategy is even more sensitive than the previous and therefore identifies more articles without affecting precision (proportion of the retrieved articles that are relevant). Since 2000, MeSH indexing of FDG and PET has hardly improved. Our proposal to introduce the MeSH 'positron emission tomography' as a narrower term of the current 'Tomography, emission-computed' and to replace the current MeSH 'Fludeoxyglucose F-18' by '18F-Fluorodeoxyglucose' has been accepted by the National Library of Medicine. The new MeSH terms will be included in the MeSH edition for 2004-2005.

Prognostic and therapeutic indicator of fluoroboronophenylalanine positron emission tomography in patients with gliomas.

PURPOSE: Boron neutron capture therapy (BNCT) for the treatment of brain tumors has attracted attention recently, and its clinical application has been progressing. We have focused on the use of BNCT with 10B-boronophenylalanine, which preferentially delivers boron-10 atoms to malignant cells through the amino acid transport system. In the present study, we evaluated the long-term outcomes of treatments using 18F-10B-fluoroboronophenylalanine (FBPA), which is an analogue of 10B-boronophenylalanine, by investigating the prognostic significance of the metabolic values and ratios of FBPA as determined by positron emission tomography (PET) in patients with gliomas. EXPERIMENTAL DESIGN: Our subjects were 22 patients who underwent an FBPA-PET study and were followed for at least 4 months thereafter. PET parameters, such as the rate constants K1, k2, k3, and k4, were measured before treatment. Data regarding the tumors, the contralateral normal region, and the uptake ratio of FBPA between the tumor and normal tissue 40 min after injection of the tracer were compared with survival rates after the PET treatment. The survival time and the prognostic factors were tested using a Kaplan-Meier survival curve and Cox regression analysis, respectively. RESULTS: Among the clinical parameters, the histological grade of a tumor influences survival significantly. When the survival of patients with PET parameters or ratios above the median was compared with that of patients with parameters or ratios below the median, the most significant PET parameter was the K1 value of the tumor. Median survival in patients with a tumor K1 value of 0.033 ml/min (median value) or higher was 11 months, which was significantly shorter than the 77 months in patients with a K1 value below the median (P=0.0006 by generalized Wilcoxon test). CONCLUSIONS: The kinetic constants of FBPA metabolism as determined by PET can be of ancillary significance in predicting the prognosis and indicating the feasibility of BNCT in patients with gliomas. The mean survival time was significantly shorter in patients with high uptakes of FBPA. A contributing factor is the K1 value, which reflects amino acid transport activity. FBPA-PET images can allow clinicians to develop treatment plans that are better tailored to the clinical features of their patients.