Kyosan Yoshikawa

Carbon ion radiotherapy for stage I non-small cell lung cancer.

BACKGROUND AND PURPOSE Heavy ion radiotherapy is a promising modality because of its excellent dose localization and high biological effect on tumors. Using carbon beams, a dose escalation study was conducted for the treatment of stage I non-small cell lung cancer (NSCLC) to determine the optimal dose. MATERIALS AND METHODS The first stage phase I/II trial using 18 fractions over 6 weeks for 47 patients and the second one using nine fractions over 3 weeks for 34 patients were conducted by the dose escalation method from 59.4 to 95.4 Gray equivalents (GyE) in incremental steps of 10% and from 68.4 to 79.2 GyE in 5% increments, respectively. The local control and survival rates were obtained using the Kaplan-Meier method. RESULTS Radiation pneumonitis at grade III occurred in three of 81 patients, but they fully recovered. This was not a dose-limiting factor. The local control rates in the first and second trials were 64% and 84%, respectively. The total recurrence rate in both trials was 23.2%. The infield local recurrence in the first trial was significantly dependent on carbon dose. The doses greater than 86.4 GyE at 18 fractions and 72 GyE at nine fractions achieved a local control of 90% and 95%, respectively. The 5 year overall and cause-specific survivals in 81 patients were 42% and 60%, respectively. CONCLUSIONS With our dose escalation study, the optimum safety and efficacy dose of carbon beams was determined. Carbon beam therapy attained almost the same results as surgery for stage I NSCLC although this was a I/II study.

Overview of clinical experiences on carbon ion radiotherapy at NIRS

BACKGROUND AND PURPOSE Carbon ion beams provide physical and biological advantages over photons. This study summarizes the experiences of carbon ion radiotherapy at the Heavy Ion Medical Accelerator in Chiba (HIMAC) at the National Institute of Radiological Sciences. MATERIALS AND METHODS Between June 1994 and August 2003, a total of 1601 patients with various types of malignant tumors were enrolled in phase I/II dose-escalation studies and clinical phase II studies. All but malignant glioma patients received carbon ion radiotherapy alone with a fraction number and overall treatment time being fixed for each tumor site, given to one field per day and 3 or 4 days per week. In dose-escalation studies, the total dose was escalated by 5 or 10% increments to ensure a safe patient treatment and to determine appropriate dose levels. RESULTS In the initial dose-escalation studies, severe late complications of the recto-sigmoid colon and esophagus were observed in those patients who received high dose levels for prostate, uterine cervix and esophageal cancer. Such adverse effects, however, did shortly disappear as a result of determining safe dose levels and because of improvements in the irradiation method. Carbon ion radiotherapy has shown improvement of outcome for tumor entities: (a) locally advanced head and neck tumors, in particular those with non-squamous cell histology including adenocarcinoma, adenoid cystic carcinoma, and malignant melanoma; (b) early stage NSCLC and locally advanced NSCLC; (c) locally advanced bone and soft tissue sarcomas not suited for surgical resection; (d) locally advanced hepatocellular carcinomas; (e) locally advanced prostate carcinomas, in particular for high-risk patients; (f) chordoma and chondrosarcoma of the skull base and cervical spine, and (g) post-operative pelvic recurrence of rectal cancer. Treatment of malignant gliomas, pancreatic, uterine cervix, and esophageal cancer is being investigated within dose-escalation studies. There is a rationale for the use of short-course RT regimen due to the superior dose localization and the unique biological properties of high-LET beams. This has been proven in treatment of NSCLC and hepatoma, where the fraction number has been successfully reduced to 4-12 fractions delivered within 1-3 weeks. Even for other types of tumors including prostate cancer, bone/soft tissue sarcoma and head/neck tumors, it was equally possible to apply the therapy in much shorter treatment times as compared to conventional RT regimen. CONCLUSION Carbon ion radiotherapy, due to its physical and biologic advantages over photons, has provided improved outcome in terms of minimized toxicity and high local control rates for locally advanced tumors and pathologically non-squamous cell type of tumors. Using carbon ion radiotherapy, hypofractionated radiotherapy with application of larger doses per fraction and a reduction of overall treatment times as compared to conventional radiotherapy was enabled.

Age-related reduction of extrastriatal dopamine D2 receptor measured by PET.

Although the aging effect of dopamine D2 receptor in the striatum is well-documented, the effect of age on the extrastriatal dopamine D2 receptor has not been fully examined. Since the density of extrastriatal dopamine D2 receptor is very low, suitable ligands are limited. In this study, we used [11C]FLB 457 to quantify the extrastriatal dopamine D2 receptor in the living human brain. Twenty-seven healthy male subjects aged from 21 to 82 years participated in the positron emission tomography study. Extrastriatal [11C]FLB 457 binding was quantified with a reference tissue model using cerebellum as a reference region. Binding potentials corresponding to Bmax/Kd were used to evaluate age-related change. We found age-related decreases of D2 receptor binding in all measured extrastriatal regions. The decrease of D2 receptor binding was 13.8% per decade in frontal cortex, 12.0% in temporal cortex, 13.4% in parietal cortex, 12.4% in occipital cortex, 12.2% in hippocampus, and 4.8% in thalamus. These findings suggest that the amounts of D2 receptor declines in all brain regions as part of the normal aging process.

Lung as reservoir for antidepressants in pharmacokinetic drug interactions

BACKGROUND Although high-affinity imipramine binding sites have been reported in both rat and human lung, the role of the lungs in the pharmacokinetics of antidepressants has not received much attention. Substantial accumulation of selective serotonin-reuptake inhibitors (SSRIs) in the lungs has been reported. We have investigated the role of the lungs in pharmacokinetic drug interactions between tricyclic antidepressants and SSRIs. METHODS We used a carbon-11-labelled form of the imipramine derivative cyanoimipramine to measure uptake in the lungs and brain of healthy volunteers by positron emission tomography. Clomipramine (50 mg) was administered to measure the effect of antidepressants with high affinity for the serotonin transporter on lung and brain uptake. FINDINGS A large proportion of the injected 11C-cyanoimipramine (68-86% in the four volunteers) was extracted by the lungs. Clomipramine decreased the lung uptake from 68% to 35% and from 81% to 54% in the two volunteers studied. By contrast, whole-brain uptake was low in control studies (1.7-2.0% in three volunteers) and increased after clomipramine administration (to 4.5-4.9%). Plasma radioactivity was also higher after clomipramine than in control studies. INTERPRETATION The lungs may function as a reservoir for antidepressants with high affinity to the serotonin transporter. The accumulated antidepressants may be displaced by other antidepressants, and this displacement would substantially increase plasma concentrations and thus cause toxic effects.

Age-related decline of serotonin transporters in living human brain of healthy males

There is growing interest in serotonin transporter (5-HTT) function in the human brain, since alteration in 5-HTT has been suggested in a variety of neurophychiatric disorders. Age-related decline in postsynaptic 5-HT receptors has been demonstrated in postmortem human studies and in vivo imaging studies, and has been assumed to be related to changes in mental function in the normal aging process. However, few studies have investigated the aging effect on 5-HTT in human brain in vivo, since the availability of suitable ligands has been limited. To investigate the aging effect on 5-HTT in living human brain, we performed positron emission tomography (PET) scans with a selective ligand for 5-HTT, [11C](+)McN5652. We examined 28 healthy male volunteers aged between 20 and 79 years. The uptake was quantified in the thalamus and midbrain by graphical analysis with the cerebellum as a reference tissue, and binding potential (BP) was used for the index of 5-HTT binding. There was a significant age-related decline in BP in the thalamus and midbrain. The decline in [11C](+)McN5652 binding was 9.6% per decade in the thalamus and 10.5% per decade in the midbrain.

FDG-PET for predicting the prognosis of malignant lymphoma

To evaluate the usefulness of FDG-PET as a predictor of prognosis, 34 patients with untreated malignant lymphoma in the head and neck region were studied. After FDG-PET and treatment, they were observed from 15 to 50 months. Tumors which were aggressive and resistant to treatment tended to show high uptake of FDG. The survival rate of patients with high uptake of FDG, DAR > 8, was lower than the rate of the other patients. It is considered to be useful to add FDG uptake of the tumor to other prognostic factors for predicting the prognosis.

Introduction of autopsy imaging redefines the concept of autopsy: 37 cases of clinical experience.

A new autopsy imaging (AI) system was introduced at the Research Center Hospital for Charged Particle Therapy (RCCPT) in January 2000. Autopsy imaging is a postmortem and preautopsy diagnostic procedure using magnetic resonance imaging (MRI). Scanning is performed with a 1.5 Tesla MRI system before autopsy. The AI results are reported to the pathologist and, in light of this information, autopsy is performed with minute precision. Autopsy imaging was performed on 37 cancer cases. In seven cases, AI was less informative than the autopsy, but in 30 cases, more precise reports on the final diagnosis were available with the combined application of autopsy and AI than autopsy alone, particularly in eight limited autopsy cases. Thus, AI provides critical and supplementary information for autopsy; furthermore, AI itself is a unique imaging system of great importance.

First Human Brain Imaging by the jPET-D4 Prototype With a Pre-Computed System Matrix

The jPET-D4 is a novel brain PET scanner which aims to achieve not only high spatial resolution but also high scanner sensitivity by using 4-layer depth-of-interaction (DOI) information. The dimensions of a system matrix for the jPET-D4 are 3.3 billion (lines-of-response) times 5 million (image elements) when a standard field-of-view (FOV) of 25 cm diameter is sampled with a (1.5 mm)3 voxel . The size of the system matrix is estimated as 117 petabytes (PB) with the accuracy of 8 bytes per element. An on-the-fly calculation is usually used to deal with such a huge system matrix. However we cannot avoid extension of the calculation time when we improve the accuracy of system modeling. In this work, we implemented an alternative approach based on pre-calculation of the system matrix. A histogram-based 3D OS-EM algorithm was implemented on a desktop workstation with 32 GB memory installed. The 117 PB system matrix was compressed under the limited amount of computer memory by (1) eliminating zero elements, (2) applying the DOI compression (DOIC) method and (3) applying rotational symmetry and an axial shift property of the crystal arrangement. Spanning, which degrades axial resolution, was not applied. The system modeling and the DOIC method, which had been validated in 2D image reconstruction, were expanded into 3D implementation. In particular, a new system model including the DOIC transformation was introduced to suppress resolution loss caused by the DOIC method. Experimental results showed that the jPET-D4 has almost uniform spatial resolution of better than 3 mm over the FOV. Finally the first human brain images were obtained with the jPET-D4.

Detection of bone metastases using diffusion weighted magnetic resonance imaging: comparison with 11C-methionine PET and bone scintigraphy

PURPOSE We evaluated the ability of diffusion-weighted imaging (DWI) to detect bone metastasis by comparing the results obtained using this modality with those obtained using (11)C-methionine (MET) positron emission tomography (PET) and bone scintigraphy. MATERIALS AND METHODS This retrospective study involved 29 patients with bone metastasis. DWI was obtained using a single-shot echo planar imaging (EPI) sequence with fat suppression using a short inversion time inversion recovery sequence. The detection capabilities of DWI for bone metastases were compared with those of whole body MET PET (in 19 patients) and 99mTc-methylene diphosphonate bone scintigraphy (in 15 patients). RESULTS Among the 19 patients who were diagnosed using DWI and PET, the PET identified 39 bone metastases, while the DWI identified 60 metastases out of 69 metastases revealed with conventional magnetic resonance imaging (MRI). Among the 15 patients who were diagnosed using DWI and bone scintigraphy, the bone scintigraphy identified 18 bone metastases, while the DWI identified 72 metastases out of 78 metastases revealed with conventional MRI. The overall bone metastasis detection rates were 56.5% for PET, 23.1% for bone scintigraphy and 92.3% for DWI. CONCLUSION DWI is a very sensitive method for detecting bone metastasis and is superior to MET PET and bone scintigraphy in terms of its detection capabilities.

Decreased Regional Cerebral Metabolic Rate for Glucose in Systemic Lupus erythematosus Patients with Psychiatric Symptoms

To determine brain functional abnormality in systemic lupus erythematosus (SLE) patients with psychiatric symptoms, we evaluated 12 active SLE patients with or without psychiatric symptoms by means of [18F]2-fluoro-2-deoxy-D-glucose positron emission tomography (PET), magnetic resonance imaging and neuropsychological testing. Patients with psychiatric symptoms showed significantly poorer performance in tests which subserved attentional function. The PET study revealed that the psychiatric patients had significantly decreased regional cerebral metabolic rates for glucose in the prefrontal, inferior parietal and anterior cingulate regions. Prefrontal, inferior parietal and anterior cingulate dysfunction may be related to attentional deficits that are involved in various psychiatric symptoms in SLE. PET is an invaluable tool to reveal such brain functional abnormality seen in SLE patients with psychiatric symptoms.