Shozo Okamoto

High Reproducibility of Tumor Hypoxia Evaluated by 18F-Fluoromisonidazole PET for Head and Neck Cancer

Tumor hypoxia is well known to be radiation resistant. 18F-fluoromisonidazole (18F-FMISO) PET has been used for noninvasive evaluation of hypoxia. Quantitative evaluation of 18F-FMISO uptake is thus expected to play an important role in the planning of dose escalation radiotherapy. However, the reproducibility of 18F-FMISO uptake has remained unclarified. We therefore investigated the reproducibility of tumor hypoxia by using quantitative analysis of 18F-FMISO uptake. Methods: Eleven patients with untreated head and neck cancer underwent 2 18F-FMISO PET/CT scans (18F-FMISO1 and 18F-FMISO2) with a 48-h interval prospectively. All images were acquired at 4 h after 18F-FMISO injection for 10 min. The maximum standardized uptake (SUVmax), tumor-to-blood ratio (TBR), and tumor-to-muscle ratio (TMR) of 18F-FMISO uptake were statistically compared between the 2 18F-FMISO scans by use of intraclass correlation coefficients (ICCs). The hypoxic volume was calculated as the area with a TBR of greater than or equal to 1.5 or the area with a TMR of greater than or equal to 1.25 to assess differences in hypoxic volume between the 2 18F-FMISO scans. The distances from the maximum uptake locations of the 18F-FMISO1 images to those of the 18F-FMISO2 images were measured to evaluate the locations of 18F-FMISO uptake. Results: The SUVmax (mean ± SD) for 18F-FMISO1 and 18F-FMISO2 was 3.16 ± 1.29 and 3.02 ± 1.12, respectively, with the difference between the 2 scans being 7.0% ± 4.6%. The TBRs for 18F-FMISO1 and 18F-FMISO2 were 2.98 ± 0.83 and 2.97 ± 0.64, respectively, with a difference of 9.9% ± 3.3%. The TMRs for 18F-FMISO1 and 18F-FMISO2 were 2.25 ± 0.71 and 2.19 ± 0.67, respectively, with a difference of 7.1% ± 5.3%. The ICCs for SUVmax, TBR, and TMR were 0.959, 0.913, and 0.965, respectively. The difference in hypoxic volume based on TBR was 1.8 ± 1.8 mL, and the difference in hypoxic volume based on TMR was 0.9 ± 1.3 mL, with ICCs of 0.986 and 0.996, respectively. The maximum uptake locations of the 18F-FMISO1 images were different from those of the 18F-FMISO2 images and were within the full width at half maximum of the PET/CT scanner, except in 1 case. Conclusion: The values for 18F-FMISO PET uptake and hypoxic volume in head and neck tumors between the 2 18F-FMISO scans were highly reproducible. Such high reproducibility of tumor hypoxia is promising for accurate radiation planning.

18F-Fluoromisonidazole PET Uptake Is Correlated with Hypoxia-Inducible Factor-1α Expression in Oral Squamous Cell Carcinoma

Hypoxia is a common feature of cancer and a prognostic factor for many types of cancer. 18F-fluoromisonidazole (18F-FMISO) PET can detect tumor hypoxia noninvasively. Hypoxia-inducible factor-1 (HIF-1) is a key player in the transcriptional response to low oxygen tension in many types of cancer. Its activity is mainly dependent on the stability and modification of HIF-1α, which is a composition of HIF-1. However, it is unclear whether 18F-FMISO PET can identify HIF-1α expression in oral squamous cell carcinoma (OSCC). The present study was performed to elucidate the correlation between 18F-FMISO PET findings and HIF-1α expression in OSCC. Methods: Twenty-three patients (age range, 42–84 y; 15 men, 8 women) with OSCC were enrolled in this study. The T-stages of cancer were T1 in 1 patient, T2 in 9, T3 in 2, and T4a in 11. The N-stages were N0 in 13 patients, N1 in 5, and N2 in 5. Each patient underwent 18F-FMISO and 18F-FDG PET before surgery, and the maximum standardized uptake value (SUVmax) of both PET studies was measured. HIF-1α expression in the operation materials was evaluated by immunohistochemical staining. The SUVmax of both PET studies and HIF-1α findings were compared statistically. Results: 18F-FMISO PET detected uptake in the primary site in 14 of the 23 patients (61%). The median SUVmax of 18F-FMISO and 18F-FDG PET in the primary site was 1.83 (range, 0.8–2.7) and 16.5 (range, 1.0–32.3), respectively. There was a weak significant correlation between 18F-FMISO and 18F-FDG PET SUVmax (P = 0.02, r = 0.48). HIF-1α expression was clearly detected in 11 of the 23 patients (48%). The 18F-FMISO PET SUVmax was significantly higher in the HIF-1α–positive cases than in the HIF-1α–negative cases (median, 2.1; range, 1.5–2.4, vs. median, 1.6; range, 0.8–2.0, respectively) (P = 0.002). However, there were no significant correlations between 18F-FDG PET SUVmax and HIF-1α expression (median, 21.8; range, 7.7–29.1 vs. 1.0–32.2) (P = 0.06). Conclusion: 18F-FMISO uptake in the primary site of OSCC indicates a hypoxic environment with HIF-1α expression.

Effects and safety of 131I-metaiodobenzylguanidine (MIBG) radiotherapy in malignant neuroendocrine tumors: Results from a multicenter observational registry

Effective treatments for malignant neuroendocrine tumors are under development. While iodine-131 metaiodobenzylguanidine (¹³¹I-MIBG) radiotherapy has been used in the treatment of malignant neuroendocrine tumors, there are few studies evaluating its therapeutic effects and safety in a multicenter cohort. In the current study, we sought to evaluate the effects and safety of ¹³¹I-MIBG therapy for conditions including malignant pheochromocytoma and paraganglioma within a multicenter cohort. Forty-eight malignant neuroendocrine tumors (37 pheochromocytoma and 11 paraganglioma) from four centers underwent clinical ¹³¹I-MIBG radiotherapy. The tumor responses were observed before and 3 to 6 months after the ¹³¹I-MIBG radiotherapy in accordance with RECIST criteria. We also evaluated the data for any adverse effects. The four centers performed a total of 87 ¹³¹I-MIBG treatments on 48 patients between January 2000 and March 2009. Of the treatments, 65 were evaluable using RECIST criteria. One partial response (PR), 40 stable disease (SD), and 9 progressive disease (PD) in malignant pheochromocytoma were observed after each treatment. Fourteen SD and one PD-were observed in paraganglioma. Patients with normal hypertension (systolic blood pressure (BP) > 130 mmHg) showed significantly reduced systolic BP after the initial follow-up (n=10, 138.1±8.2 to 129.5±13.5 mmHg, P=0.03). In adult neuroendocrine tumors with a treatment-basis analysis, there were side effects following 41 treatments (47.1%) and most of them (90.2%) were minor. In this multicenter registry, PR or SD was achieved in 84.6% of the treatment occasions in adult neuroendocrine tumors through ¹³¹I-MIBG radiotherapy. This indicated that most of the ¹³¹I-MIBG radiotherapy was performed safely without significant side effects.

[18F]fluoromisonidazole and a New PET System With Semiconductor Detectors and a Depth of Interaction System for Intensity Modulated Radiation Therapy for Nasopharyngeal Cancer

PURPOSE The impact of a new type of positron emission tomography (New PET) with semiconductor detectors using 18F-labeled fluoromisonidazole (FMISO)-guided intensity modulated radiation therapy (IMRT) was compared with a state-of-the-art PET/computed tomography (PET/CT) system in nasopharyngeal cancer (NPC) patients. METHODS AND MATERIALS Twenty-four patients with non-NPC malignant tumors (control group) and 16 patients with NPC were subjected to FMISO-PET. The threshold of the tumor-to-muscle (T/M) ratio in each PET scan was calculated. The hypoxic volume within the gross tumor volume (GTVh) was determined using each PET (NewPETGTVh and PET/CTGTVh, respectively). Dose escalation IMRT plans prescribing 84 Gy to each GTVh were carried out. RESULTS The threshold of the T/M ratio was 1.35 for New PET and 1.23 for PET/CT. The mean volume of NewPETGTVh was significantly smaller than that of PET/CTGTVh (1.5±1.6 cc vs 4.7±4.6 cc, respectively; P=.0020). The dose escalation IMRT plans using New PET were superior in dose distribution to those using PET/CT. Dose escalation was possible in all 10 New PET-guided plans but not in 1 PET/CT-guided plan, because the threshold dose to the brainstem was exceeded. CONCLUSIONS New PET was found to be useful for accurate dose escalation in FMISO-guided IMRT for patients with NPC.

Radioiodine therapy for thyroid cancer depicted uterine leiomyoma.

A 55-year-old woman underwent radioiodine therapy for papillary carcinoma of the thyroid. Post-therapeutic I-131 scan revealed radioiodine uptake in the pelvic region and in the thyroid bed. CT revealed a huge mass connected to the uterus. The tumor was operated on and histologically proven to be a leiomyoma of the uterus. Some physiological conditions or nonthyroidal diseases can cause false positives in patients with postoperative thyroid cancer. We suggest that uterine leiomyoma might be added to the pitfall list, although the mechanism of I-131 uptake remains unclear.

68Ga-PSMA-HBED-CC uptake in cervical, coeliac and sacral ganglia as an important pitfall in prostate cancer PET imaging

The study aims to investigate the presence of physiologic prostate-specific membrane antigen (68Ga-PSMA)-ligand uptake on PET in cervical, celiac, and sacral ganglia of the sympathetic trunk as a pitfall for lymph node metastases in prostate cancer imaging. Methods: Four hundred seven patients who underwent Glu-NH-CO-NH-Lys radiolabeled with 68Ga-gallium N,N-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N-diacetic acid (68Ga-PSMA-HBED-CC) PET (combined with a diagnostic CT) were retrospectively analyzed. The number of 68Ga-PSMA PET–positive cervical, celiac, and sacral ganglia was determined, and the configuration and SUVmax of each ganglion were measured. In addition, the configuration and SUVmax of adjacent lymph node metastases in the respective region (cervical, celiac, or sacral) were determined. Results: 68Ga-PSMA-ligand uptake above background was detected in 401 (98.5%) patients in any peripheral ganglia, in 369 (92%) patients in cervical ganglia, in 363 (89%) patients in celiac ganglia, and in 183 (46%) patients in sacral ganglia. The 68Ga-PSMA-ligand uptake was highest in celiac (mean SUVmax, 2.9 ± 0.8 vs. cervical mean SUVmax, 2.4 ± 0.6) and sacral (mean SUVmax 1.7 ± 0.5; both P < 0.0001) ganglia. Intraindividually there was a statistically significant but weak to moderate correlation between the 68Ga-PSMA-ligand uptake in cervical versus celiac ganglia (R = 0.34, P < 0.0001), cervical versus sacral (R = 0.52, P < 0.0001), and celiac versus sacral (R = 0.16, P < 0.05). The 68Ga-PSMA-ligand uptake was significantly more intense in adjacent lymph node metastases than the respective ganglia (cervical: 18.0 ± 16.2 vs. 2.4 ± 0.6, P < 0.0001; celiac: 13.5 ± 12.3 vs. 2.9 ± 0.8, P < 0.0001; sacral: 13.4 ± 11.6 vs. 1.7 ± 0.5, P < 0.0001). Furthermore, ganglia predominantly exhibit a band-shaped configuration (71.2%), followed by a teardrop (26.8%) and only rarely a nodular configuration (2.0%). Conversely, lymph node metastases are only rarely band-shaped (1.1%), but more often show teardrop (40.3%) or nodular appearance (58.6%) (P < 0.00001). Conclusion: 68Ga-PSMA-ligand uptake in ganglia along the sympathetic trunk as assessed by 68Ga-PSMA-HBED-CC PET represents an important pitfall in prostate cancer PET imaging. The 68Ga-PSMA-ligand uptake is higher in celiac ganglia than cervical or sacral ganglia, and the level of 68Ga-PSMA-ligand uptake seems to be patient-related. For the differentiation between lymph node metastases and sympathetic ganglia, both intensity of 68Ga-PSMA-ligand uptake and exact localization and configuration of the respective lesion should be examined carefully.

Histopathologic Characterization of Lung Adenocarcinoma in Relation to Fluorine-18-fluorodeoxyglucose Uptake on Positron Emission Tomography

BACKGROUND Fluorine-18-fluorodeoxyglucose uptake on positron emission tomography is reported to have prognostic significance in patients after resection of lung adenocarcinoma. However, its relationship with histopathologic features remains unknown. METHODS We conducted a retrospective analysis of 205 patients who had undergone surgical resection of primary lung adenocarcinoma (> 1.0 cm) after preoperative fluorine-18-fluorodeoxyglucose-positron emission tomography between January 1999 and December 2008 at Hokkaido University Hospital. Fluorine-18-fluorodeoxyglucose uptake was measured by the maximum standardized uptake value. A histopathologic review was performed according to the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification, and various histopathologic factors were evaluated semi-quantitatively. Correlations between these clinicopathologic factors and the maximum standardized uptake value (high ≥ 2.0 vs low < 2.0) were analyzed. RESULTS Univariate analysis of clinicopathologic factors demonstrated that the following were significantly correlated with a high maximum standardized uptake value: an elevated carcinoembryonic antigen level, larger tumor size, upgraded pT, pN, pStage, non-lepidic histology, abundant fibroblastic/hyalinized stroma, necrosis, presence of pleural involvement, lymphatic and vascular invasion and more intra- and extracellular mucin. Multivariate analysis demonstrated that a tumor size of > 2.0 cm, non-lepidic histology and abundant fibroblastic/hyalinized stroma were significantly correlated with the high maximum standardized uptake value. CONCLUSION More histopathologic factors are known to correlate with poor prognosis in lung adenocarcinomas showing high maximum standardized uptake values than in those showing low maximum standardized uptake values. Therefore, prognostication of patients with a resectable lung adenocarcinoma on the basis of preoperative fluorine-18-fluorodeoxyglucose uptake is histopathologically valid. Such observations may also help us to clarify the pathobiological mechanism responsible for the increased fluorine-18-fluorodeoxyglucose uptake in lung adenocarcinomas with a poor prognosis.

FDG PET performed at thyroid remnant ablation has a higher predictive value for long-term survival of high-risk patients with well-differentiated thyroid cancer than radioiodine uptake.

Purpose The predictive value of FDG PET at thyroid remnant ablation was evaluated in comparison to radioiodine uptake in high-risk patients with differentiated thyroid cancer. Patients and Methods One hundred forty-one patients who underwent radioiodine therapy (RIT) after total thyroidectomy and received at least 1 further RIT due to suspected metastases were retrospectively analyzed. Patients had not received RIT previously. FDG PET was performed before thyroid remnant ablation. Thyroid-stimulating hormone–stimulated serum thyroglobulin (Tg) was measured for biochemical response assessment (change of Tg between the first and second RIT, &Dgr;Tg). Results Biochemical response could be evaluated in 80 patients; survival data could be obtained for 88 patients (maximum, 124 months). Biochemical response was significantly better in patients with radioiodine-positive metastases compared with patients with radioiodine-negative metastases (median &Dgr;Tg I+, 55.8% vs I−, 112.6%; P < 0.01). Regarding survival, deaths occurred later in patients with radioiodine-positive metastases compared with radioiodine-negative patients; however, there was no significant difference regarding overall survival (I+, 61.3% vs I−, 58.2%; P > 0.05). Patients with FDG-positive metastases at thyroid remnant ablation showed a poorer biochemical response compared with patients with FDG-negative metastases (median &Dgr;Tg FDG+, 77.5% vs FDG−, 53.2%; P < 0.05), and these groups also differed significantly regarding survival (overall survival FDG+, 48.5% vs FDG−, 100%, P < 0.05). Conclusions At thyroid remnant ablation, FDG PET is more predictive for long-term survival, whereas radioiodine uptake is more important for short-term response. FDG PET performed at thyroid remnant ablation might represent a useful tool for management of high-risk patients with differentiated thyroid cancer.

Metabolic Activity of Red Nucleus and Its Correlation with Cerebral Cortex and Cerebellum: A Study Using a High-Resolution Semiconductor PET System

The red nucleus (RN) is a pair of small gray matter structures located in the midbrain and involved in muscle movement and cognitive functions. This retrospective study aimed to investigate the metabolism of human RN and its correlation to other brain regions. Methods: We developed a high-resolution semiconductor PET system to image small brain structures. Twenty patients without neurologic disorders underwent whole-brain scanning after injection of 400 MBq of 18F-FDG. The individual brain 18F-FDG PET images were spatially normalized to generate a surface projection map using a 3-dimensional stereotactic surface projection technique. The correlation between the RN and each voxel on the cerebral and cerebellar cortices was estimated with Pearson product-moment correlation analysis. Results: Both right and left RNs were visualized with higher uptake than that in the background midbrain. The maximum standardized uptake values of RN were 7.64 ± 1.92; these were higher than the values for the dentate nucleus but lower than those for the caudate nucleus, putamen, and thalamus. The voxel-by-voxel analysis demonstrated that the right RN was correlated more with ipsilateral association cortices than contralateral cortices, whereas the left RN was equally correlated with ipsilateral and contralateral cortices. The left RN showed a stronger correlation with the motor cortices and cerebellum than the right RN did. Conclusion: Although nonspecific background activity around RNs might have influenced the correlation patterns, these metabolic relationships suggested that RN cooperates with association cortices and limbic areas to conduct higher brain functions.

Use of FDG-PET to detect a chronic odontogenic infection as a possible source of the brain abscess

AbstractThis study describes the use of 18F-fluoro-2-deoxyglucose positron emission tomography (FDG-PET) to detect a chronic odontogenic infection as the possible origin of a brain abscess (BA). A 74-year-old man with esophageal carcinoma was referred to our department to determine the origin of a BA in his oral cavity. He had no acute odontogenic infections. The BA was drained, and bacteria of the Staphylococcus milleri group were detected. Whole body FDG-PET revealed that the only sites of definite uptake of FDG were the esophageal carcinoma and the left upper maxillary region (SUVmax: 4.5). These findings suggested that the BA may have originated from a chronic periodontal infection. Six teeth with progressive chronic periodontal disease were extracted to remove the possible source of BA. These findings excluded the possibility of direct spread of bacteria from the odontogenic infectious lesion to the intracranial cavity. After extraction, there was no relapse of BA.