Chi-Wei Chang

Fluorine-18 fluoromisonidazole tumour to muscle retention ratio for the detection of hypoxia in nasopharyngeal carcinoma

In vivo demonstration of hypoxia is of significance for tumour patient management. Fluorine-18 fluoromisonidazole ([18F]FMISO) is a proven hypoxie imaging agent. We developed an [18F]FMISO tumour to muscle retention ratio (TMRR) for the detection of tumour hypoxia in nasopharyngeal carcinoma (NPC). Data were acquired by positron emission tomography (PET) of the nasopharynx and neck after intravenous injection of 370 MBq of [18F]FMISO. Two imaging protocols were adopted: a long protocol for comprehensive dynamic information and a short protocol for a simple, clinically convenient imaging procedure. Tomograms were reconstructed and evaluated visually. ROI analysis on the basis of time-activity curve evaluation was performed to calculate the TMRR of NPC or cervical nodal metastases (CNMs) in relation to the suboccipital muscles at 2 h. The calculation of the TMRR was exactly the same for both the long and the short protocol as two 30-min composite frames had been created immediately after intravenous injection and 2 h after injection of [18F]FMISO in the long protocol. The normal tissue to muscle retention ratio (NTMRR) was derived similarly from the normal nasopharynx. The data of 12 controls and 24 patients with NPC were analysed. The long protocol was used in 15 patients, and the short protocol in nine. In controls, the mean NTMRR±1 SD was 0.96±0.14. The mean TMRRs for NPC and CNMs were 2.56±1.50 and 1.35±0.51, respectively; these values were significantly higher than the mean NTMRR for normal controls (P<0.005 in each case). At the retention threshold value of 1.24, tumour hypoxia occurred in 100% of the primary lesions of NPC and 58% of CNMs. The TMRR for undifferentiated carcinoma was significantly lower than that for non-keratinized carcinoma (P<0.05). The [18F]FMISO TMRR is a simple and clinically useful index for detecting tumour hypoxia in NPC.

Detection of anaerobic odontogenic infections by fluorine-18 fluoromisonidazole.

Odontogenic infections are a potential risk for patients who receive cervicofacial radiotherapy and should be treated before irradiation. Anaerobic microbial infections are the most common causes. This study assessed the value of the hypoxic imaging agent fluorine-18 fluoromisonidazole (FMISO) in detecting anaerobic odontogenic infections. Positron emission tomography (PET) imaging was performed at 2 h after injection of 370 MBq (10 mCi) of FMISO in 26 nasopharyngeal carcinoma patients and six controls with healthy teeth. Tomograms were interpreted visually to identify hypoxic foci in the jaw. All patients received thorough dental examinations as a pre-radiotherapy work-up. Fifty-one sites of periodontitis, 15 periodontal abscesses, 14 sites of dental caries with root canal infection, 23 sites of dental caries without root canal infection, and seven necrotic pulps were found by dental examination. Anaerobic pathogens were isolated from 12 patients. Increased uptake of FMISO was found at 45 out of 51 sites of periodontitis, all 15 sites of periodontal abscess, all 14 sites of dental caries with root canal infection, all seven sites of necrotic pulp and 15 sites of dental caries without obvious evidence of active root canal infection. No abnormal uptake was seen in the healthy teeth of patients or in the six controls. The diagnostic sensitivity, specificity, positive and negative predictive values, and accuracy of FMISO PET scan in detecting odontogenic infections were 93%, 97%, 84%, 99% and 96%, respectively.18F-fluoride ion bone scan done in three patients showed that18F-fluoride ion plays no role in the demonstration of anaerobic odontogenic infection. FMISO PET scan is a sensitive method for the detection of anaerobic odontogenic infections, and may play a complementary role in the evaluation of the dental condition of patients with head and neck tumours prior to radiation therapy.

BNCT for locally recurrent head and neck cancer: preliminary clinical experience from a phase I/II trial at Tsing Hua Open-Pool Reactor.

To introduce our preliminary experience of treating locally and regionally recurrent Head and Neck cancer patients at Tsing Hua Open-Pool Reactor in Taiwan, four patients (M/F=3/1, median age 68 Y/O) were enrolled. BNCT with BPA (400 mg/kg) injected in 2 phases and prescription dose of 12-35 Gy (Eq.)/fraction for 2 fractions at 30 day interval can be given with sustained blood boron concentration and tolerable early toxicities for recurrent H & N cancer.

1-11C-Acetate Versus 18F-FDG PET in Detection of Meningioma and Monitoring the Effect of γ-Knife Radiosurgery

This study aimed to define the potential of 1-11C-acetate PET, compared with 18F-FDG, in detecting meningiomas and monitoring the effect of γ-knife radiosurgery. Methods: Twenty-two patients with the neuroradiologic diagnosis of meningioma were examined by 1-11C-acetate and 18F-FDG PET on the same day. There were 12 cases of histopathologically proven meningioma (8 grade I, 2 grade II, and 2 grade III), 1 of tuberculous granuloma, and 1 of degenerative tissue. 1-11C-acetate PET scans of fasting patients were obtained 10 min after intravenous administration of 740 MBq of 1-11C-acetate. 18F-FDG PET was performed at 2 h after 1-11C-acetate scanning. The PET images were evaluated by a qualitative method and semiquantitative analysis using standardized uptake value and tumor-to-cortex ratio. Results: The 18F-FDG PET study revealed a hypometabolic focus in 17 meningiomas (8 grade I, 1 grade II, and 8 unknown grade) and hypermetabolism in 1 grade II and 2 grade III meningiomas. High uptake of 1-11C-acetate was observed in all 20 meningiomas, in contrast to the low uptake in surrounding normal brain tissue, allowing a clearer demarcation of the tumor boundary than that provided by 18F-FDG. Dissociation of regional accumulation of 1-11C-acetate and 18F-FDG within the tumor was also noted on the coregistered images. The standardized uptake value for 1-11C-acetate was not different from that for 18F-FDG (mean ± SD, 3.16 ± 1.75 vs. 3.22 ± 1.50, P = 0.601), but the tumor-to-cortex ratio for 1-11C-acetate was higher than that for 18F-FDG (3.46 ± 1.38 vs. 0.93 ± 1.08, P < 0.005). 18F-FDG was able to differentiate grade I from grade II–III meningiomas, whereas 1-11C-acetate was unable to do so. Tuberculous granuloma had a high 1-11C-acetate and 18F-FDG uptake similar to that of grade II/III meningioma. Five patients received 1-11C-acetate and 18F-FDG PET before and after γ-knife surgery. 1-11C-acetate performed better than did 18F-FDG in monitoring the response of tumor metabolism to radiosurgery. Conclusion: 1-11C-acetate was found to be useful for detecting meningiomas and evaluating the extent of meningiomas and potentially useful for monitoring tumor response to radiosurgery. However, 1-11C-acetate was not useful for evaluating the tumor grade. 18F-FDG was found to be less useful than 1-11C-acetate for evaluating the extent of meningiomas and the response to radiosurgical treatment but may be useful for differentiating benign from malignant meningiomas. 18F-FDG and 1-11C-acetate are complementary for assessing diverse cell metabolism of meningioma.

PET imaging of brain astrocytoma with 1-11C-acetate

PurposeThe purpose of this study was to assess the use of 1-11C-acetate (ACE) as a metabolic tracer for the detection and characterisation of astrocytomas.MethodsPositron emission tomography (PET) studies with ACE and 2-18F-fluoro-2-deoxy-D-glucose (FDG) were performed sequentially in 26 patients with primary astrocytomas. Images were analysed by visual interpretation and determination of the tumour to cortex ratio (T/C ratio) and standardised uptake value (SUV). The tumour uptake was visually scored into three grades as compared with the contralateral cortex: clearly lower (–), almost equal (+) and clearly higher (++).ResultsThere were 85% of astrocytomas with ++ ACE uptake, 15% with + ACE uptake and none with – ACE uptake. Only 19% of astrocytomas had ++ FDG uptake. Thirty-seven percent of high-grade astrocytomas had + FDG uptake and 37% had – FDG uptake. The sensitivity and specificity of the FDG T/C ratio in discriminating high-grade from low-grade astrocytomas were 79% and 100%, respectively, at the cutoff value of 0.75. Using 2.33 as the cutoff value of the ACE T/C ratio, the sensitivity and specificity were 42% and 86%, respectively. FDG was better than ACE in discriminating high-grade from low-grade astrocytomas. T/C ratios and SUVs of FDG uptake of tumours correlated with the histological grades, but those of ACE uptake did not.ConclusionACE appears to be a promising tracer for use in the detection of primary astrocytomas, but is of limited value in the differentiation of high- and low-grade astrocytomas. ACE is complementary to FDG for the diagnosis and characterisation of astrocytoma.

Fractionated BNCT for locally recurrent head and neck cancer: experience from a phase I/II clinical trial at Tsing Hua Open-Pool Reactor.

To introduce our experience of treating locally and regionally recurrent head and neck cancer patients with BNCT at Tsing Hua Open-Pool Reactor in Taiwan, 12 patients (M/F=10/2, median age 55.5 Y/O) were enrolled and 11 received two fractions of treatment. Fractionated BNCT at 30-day interval with adaptive planning according to changed T/N ratios was feasible, effective and safe for selected recurrent head and neck cancer in this trial.

Pharmacokinetic Analysis and Uptake of 18F-FBPA-Fr After Ultrasound-Induced Blood–Brain Barrier Disruption for Potential Enhancement of Boron Delivery for Neutron Capture Therapy

Boronophenylalanine has been applied in clinical boron neutron capture therapy for the treatment of high-grade gliomas. The purpose of this study was to evaluate the pharmacokinetics of 4-borono-2-18F-fluoro-l-phenylalanine-fructose (18F-FBPA-Fr) in F98 glioma–bearing Fischer 344 rats by means of intravenous injection of 18F-FBPA-Fr both with and without blood–brain barrier disruption (BBB-D) induced by focused ultrasound (FUS). Methods: Dynamic PET imaging of 18F-FBPA-Fr was performed on the ninth day after tumor implantation. Blood samples were collected to obtain an arterial input function for tracer kinetic modeling. Ten animals were scanned for approximately 3 h to estimate the uptake of 18F radioactivity with respect to time for the pharmacokinetic analysis. Rate constants were calculated by use of a 3-compartment model. Results: The accumulation of 18F-FBPA-Fr in brain tumors and the tumor-to-contralateral brain ratio were significantly elevated after intravenous injection of 18F-FBPA-Fr with BBB-D. 18F-FBPA-Fr administration after sonication showed that the tumor-to-contralateral brain ratio for the sonicated tumors (3.5) was approximately 1.75-fold higher than that for the control tumors (2.0). Furthermore, the K1/k2 pharmacokinetic ratio after intravenous injection of 18F-FBPA-Fr with BBB-D was significantly higher than that after intravenous injection without BBB-D. Conclusion: This study demonstrated that radioactivity in tumors and the tumor-to-normal brain ratio after intravenous injection of 18F-FBPA-Fr with sonication were significantly higher than those in tumors without sonication. The K1/k2 ratio may be useful for indicating the degree of BBB-D induced by FUS. Further studies are needed to determine whether FUS may be useful for enhancing the delivery of boronophenylalanine in patients with high-grade gliomas.

Biodistribution of phenylboric acid derivative entrapped lipiodol and 4-borono-2-18F-fluoro-l-phenylalanine-fructose in GP7TB liver tumor bearing rats for BNCT

A new phenylboric acid derivative entrapped lipiodol (PBAD-lipiodol) was developed as a boron carrier for the boron neutron capture therapy (BNCT) of hepatoma in Taiwan. The biodistribution of both PBAD-lipiodol and BPA-fructose was assayed in GP7TB hepatoma-bearing rat model. The highest uptake of PBAD-lipiodol was found at 2h post injection. The application of BNCT for the hepatoma treatment in tumor-bearing rats is suggested to be 2-4h post PBAD-lipiodol injection.

Fractionated Boron Neutron Capture Therapy in Locally Recurrent Head and Neck Cancer: A Prospective Phase I/II Trial

PURPOSE To investigate the efficacy and safety of fractionated boron neutron capture therapy (BNCT) for recurrent head and neck (H&N) cancer after photon radiation therapy. METHODS AND MATERIALS In this prospective phase 1/2 trial, 2-fraction BNCT with intravenous L-boronophenylalanine (L-BPA, 400 mg/kg) was administered at a 28-day interval. Before each fraction, fluorine-18-labeled-BPA-positron emission tomography was conducted to determine the tumor/normal tissue ratio of an individual tumor. The prescription dose (D80) of 20 Gy-Eq per fraction was selected to cover 80% of the gross tumor volume by using a dose volume histogram, while minimizing the volume of oral mucosa receiving >10 Gy-Eq. Tumor responses and adverse effects were assessed using the Response Evaluation Criteria in Solid Tumors v1.1 and the Common Terminology Criteria for Adverse Events v3.0, respectively. RESULTS Seventeen patients with a previous cumulative radiation dose of 63-165 Gy were enrolled. All but 2 participants received 2 fractions of BNCT. The median tumor/normal tissue ratio was 3.4 for the first fraction and 2.5 for the second, whereas the median D80 for the first and second fraction was 19.8 and 14.6 Gy-Eq, respectively. After a median follow-up period of 19.7 months (range, 5.2-52 mo), 6 participants exhibited a complete response and 6 exhibited a partial response. Regarding acute toxicity, 5 participants showed grade 3 mucositis and 1 participant showed grade 4 laryngeal edema and carotid hemorrhage. Regarding late toxicity, 2 participants exhibited grade 3 cranial neuropathy. Four of six participants (67%) receiving total D80 > 40 Gy-Eq had a complete response. Two-year overall survival was 47%. Two-year locoregional control was 28%. CONCLUSIONS Our results suggested that 2-fraction BNCT with adaptive dose prescription was effective and safe in locally recurrent H&N cancer. Modifications to our protocol may yield more satisfactory results in the future.

Intranasal Administration of a Polyethylenimine-Conjugated Scavenger Peptide Reduces Amyloid-β Accumulation in a Mouse Model of Alzheimer’s Disease

Amyloid-β (Aβ) aggregation in the brain plays a central and initiatory role in pathogenesis and/or progression of Alzheimers disease (AD). Inhibiting Aβ aggregation is a potential strategy in the prevention of AD. A scavenger peptide, V24P(10-40), designed to decrease Aβ accumulation in the brain, was conjugated to polyethylenimine (PEI) and tested as a preventive/therapeutic strategy for AD in this study. This PEI-conjugated V24P(10-40) peptide was delivered intranasally, as nasal drops, to four-month-old APP/PS1 double transgenic mice for four or eight months. Compared with control values, peptide treatment for four months significantly reduced the amount of GdnHCl-extracted Aβ40 and Aβ42 in the mices hippocampus and cortex. After treatment for eight months, amyloid load, as quantified by Pittsburgh compound B microPET imaging, was significantly decreased in the mices hippocampus, cortex, amygdala, and olfactory bulb. Our data suggest that this intranasally delivered scavenger peptide is effective in decreasing Aβ accumulation in the brain of AD transgenic mice. Nasal application of peptide drops is easy to use and could be further developed to prevent and treat AD.