Takashi Kato

Image fusion between 18FDG-PET and MRI/CT for radiotherapy planning of oropharyngeal and nasopharyngeal carcinomas

PURPOSEnAccurate diagnosis of tumor extent is important in three-dimensional conformal radiotherapy. This study reports the use of image fusion between (18)F-fluoro-2-deoxy-D-glucose positron emission tomography (18FDG-PET) and magnetic resonance imaging/computed tomography (MRI/CT) for better targets delineation in radiotherapy planning of head-and-neck cancers.nnnMETHODS AND MATERIALSnThe subjects consisted of 12 patients with oropharyngeal carcinoma and 9 patients with nasopharyngeal carcinoma (NPC) who were treated with radical radiotherapy between July 1999 and February 2001. Image fusion between 18FDG-PET and MRI/CT was performed using an automatic multimodality image registration algorithm, which used the brain as an internal reference for registration. Gross tumor volume (GTV) was determined based on clinical examination and 18FDG uptake on the fusion images. Clinical target volume (CTV) was determined following the usual pattern of lymph node spread for each disease entity along with the clinical presentation of each patient.nnnRESULTSnExcept for 3 cases with superficial tumors, all the other primary tumors were detected by 18FDG-PET. The GTV volumes for primary tumors were not changed by image fusion in 19 cases (89%), increased by 49% in one NPC, and decreased by 45% in another NPC. Normal tissue sparing was more easily performed based on clearer GTV and CTV determination on the fusion images. In particular, parotid sparing became possible in 15 patients (71%) whose upper neck areas near the parotid glands were tumor-free by 18FDG-PET. Within a mean follow-up period of 18 months, no recurrence occurred in the areas defined as CTV, which was treated prophylactically, except for 1 patient who experienced nodal recurrence in the CTV and simultaneous primary site recurrence.nnnCONCLUSIONnThis preliminary study showed that image fusion between 18FDG-PET and MRI/CT was useful in GTV and CTV determination in conformal RT, thus sparing normal tissues.

Accumulation of [11C]acetate in normal prostate and benign prostatic hyperplasia : comparison with prostate cancer

Abstract. Carbon-11 acetate positron emission tomography (PET) has been reported to be of clinical value for the diagnosis of prostate cancer. However, no detailed analysis has yet been carried out on the physiological accumulation of [11C]acetate in the prostate. The purpose of this study was to elucidate the physiological accumulation of [11C]acetate in the prostate using dynamic PET. The study included 30 subjects without prostate cancer [21 with normal prostate and nine with benign prostatic hyperplasia (BPH)] and six patients with prostate cancer. A dynamic PET study was performed for 20xa0min after intravenous administration of 555xa0MBq of [11C]acetate. The standardised uptake value (SUV) at 16–20xa0min post tracer administration and the early-to-late-activity ratio of the SUV (E/L ratio), which was determined by dividing the SUV6–10xa0min by the SUV16–20min, were calculated to evaluate the accumulation of [11C]acetate. The prostate was clearly visualised and distinguished from adjacent organs in PET images in most of the cases. The SUV of the prostate (2.6±0.8) was significantly higher than that of the rectum (1.7±0.4) or bone marrow (1.3±0.3) (P<0.0001 in each case). The SUV of the normal prostate of subjects aged <50 years (3.4±0.7) was significantly higher than both the SUV for the normal prostate of subjects aged ≥50 years (2.3±0.7) and that of subjects with BPH (2.1±0.6) (P<0.01 in each case). The primary prostate cancer in six cases was visualised by [11C]acetate PET. However, the difference in the SUV between subjects aged ≥50 with normal prostate or with BPH and the patients with prostate cancer (1.9±0.6) was not statistically significant. There was also no significant difference in the E/L ratio between subjects aged ≥50 with normal prostate (0.98±0.04) or BPH (0.96±0.08) and patients with prostate cancer (1.02±0.12). In conclusion, a normal prostate exhibits age-related physiological accumulation of [11C]acetate. Careful interpretation of [11C]acetate PET images of prostate cancer is necessary because the SUV and the E/L ratio for the normal prostate and for BPH overlap significantly with those for prostate cancer.

Clinical role of 18 F-FDG PET for initial staging of patients with extrahepatic bile duct cancer

Abstract. In extrahepatic bile duct cancer, preoperative evaluation is important because only surgical excision of all detectable tumours is associated with improvement in 5-year survival. However, morphological imaging techniques, including computed tomography (CT), are still insufficient for accurate staging. The purpose of this study was to assess the additional value, in relation to CT, of 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography (18F-FDG PET) for the evaluation of extrahepatic bile duct cancer. Thirty patients with extrahepatic bile duct cancer underwent both 18F-FDG PET and CT for initial staging. The results of the two modalities for evaluation of primary tumours and regional lymph nodes were compared with the final diagnoses based on pathological or clinical findings. The primary tumours were interpreted as malignant on the basis of CT in 24 (80%) of the patients, while 18F-FDG PET revealed increased 18F-FDG uptake in 18 (60%) of them. On the other hand, 18F-FDG PET showed focal accumulation of 18F-FDG in the bile duct in three of the six patients with equivocal findings on CT. The sensitivity, specificity and accuracy of CT for regional lymph node metastases were 54%, 59% and 57%, while those of 18F-FDG PET were 38%, 100% and 73%, respectively. The specificity of 18F-FDG PET for regional lymph node metastases was significantly higher than that of CT (P<0.01). Of 14 patients with N1 or N2 disease diagnosed by CT, only seven (50%) had a final diagnosis of regional lymph node metastasis. In these 14 patients, 18F-FDG PET accurately evaluated the N component of the disease in 12 patients (86%). In conclusion, in the initial staging of patients with extrahepatic bile duct cancer, 18F-FDG PET offers additional value in relation to CT in evaluating both the primary tumour and regional lymph nodes.

Effects of insulin and glucose loading on FDG uptake in experimental malignant tumours and inflammatory lesions

Abstract. Fluorine-18 2-deoxy-2-fluoro-D-glucose (FDG) accumulation in tumours has been well investigated, but much less is known regarding FDG accumulation in inflammatory lesions. In this study, we determined the effects of hypo- and hyperglycaemia on FDG uptake in inflammatory lesions of infectious and non-infectious origin and compared them with those in malignant tumours in rats, to provide a biological basis for differentiating malignant lesions from benign lesions by means of FDG-PET. Rats were inoculated with a suspension of allogenic hepatoma cells (KDH-8) or Staphylococcus aureus, or with turpentine oil into the left calf muscle. Two weeks after KDH-8 inoculation and 1 week after S. aureus and turpentine oil inoculations, the rats were divided into three subgroups: insulin-loaded (2xa0U/kg body weight, i.p.), glucose-loaded (1.2xa0g/kg body weight, p.o.) and control groups. Radioactivity in tissues was determined 1xa0h after i.v. injection of FDG. Intraperitoneal injection of insulin and oral administration of glucose induced hypoglycaemia and hyperglycaemia, respectively. In the control animals, tumours showed a level of FDG uptake which was 2.2 and 3.0 times higher than the levels in the inflammatory lesions induced by S. aureus and turpentine oil, respectively (P<0.0001). There was no significant difference in the level of FDG uptake between the two inflammatory lesions of infectious and non-infectious origin. Insulin loading significantly decreased the level of FDG uptake in tumours and in both types of inflammatory lesion to approximately one-half of the control values (P=0.001 in the tumour group and P<0.0001 in the two inflammatory lesion groups). In the glucose-loaded group, the level of FDG uptake in both types of inflammatory lesion decreased significantly to 50%–61% of the control value (P=0.0002 in the S.aureus group and P<0.0001 in the turpetine group), while the tumour uptake did not decrease significantly (86% of the control value) (P=NS). It is concluded that FDG uptake in both types of inflammatory lesion was significantly impaired in rats with hyperglycaemia induced by glucose loading, while tumour uptake of FDG was not significantly affected. These results indicate that glucose loading has greater effects on FDG uptake in inflammatory lesions than in tumours, providing a biological basis for differentiation of malignant lesions from benign lesions by FDG-PET in a clinical setting.

Fluorodeoxyglucose uptake and glucose transporter expression in experimental inflammatory lesions and malignant tumours: effects of insulin and glucose loading.

The expression of glucose transporters (GLUTs) and its relationship to fluorodeoxyglucose accumulation in malignant tumours have been well investigated, while such a relation has not been studied in inflammatory lesions. The aim of the present study was to investigate the effects of insulin and glucose loading on the expression of GLUTs in inflammatory lesions and compare them with those in malignant tumours in relation to fluorodeoxyglucose accumulation. All tissue specimens used in this study were obtained in our previous study, in which rats were inoculated with allogenic hepatoma cells (KDH-8), Staphylococcus aureus, or turpentine oil into the left calf muscle and divided into three subgroups: insulin loaded, glucose loaded, and control groups. The expression of glucose transporters (GLUT-1 to GLUT-5) was investigated by immunostaining the lesions (n = 5-6, for each group). In all control groups, the expression levels of GLUT-1 and GLUT-3 were significantly higher than those of GLUT-2, GLUT-4 and GLUT-5. Insulin loading did not significantly affect the expression levels of GLUT-1 and GLUT-3 in these lesions except for a significant but slight decrease in the GLUT-1 expression level in the inflammatory lesion of non-infectious origin (89% of the control value). Glucose loading significantly decreased the expression level of GLUT-1 in the inflammatory lesion of non-infectious origin (70% of the control value, P<0.01), and that of GLUT-3 in the inflammatory lesion of infectious origin (70% of the control value, P<0.05), while the expression levels of GLUT-1 and GLUT-3 in the tumour were not significantly affected. These results demonstrate the effects of insulin and glucose loading on the expression level of a molecule (GLUT proteins). The decreased GLUT-1 and GLUT-3 expression levels induced by glucose loading may partly explain the impaired FDG uptake observed in our previous study.

Phase 1/2 clinical study of irinotecan and oral S-1 (IRIS) in patients with advanced gastric cancer

BackgroundIrinotecan and S-1, an oral fluoropyrimidine composed of tegafur, gimeracil, and oteracil potassium, have demonstrated antitumor activity against advanced gastric cancer. We performed a phase 1/2 study to determine the recommended dose, antitumor activity, and safety of a combination of S-1 and irinotecan in patients with advanced gastric cancer.MethodsPatients with previously untreated advanced gastric cancer were enrolled. Patients received irinotecan intravenously on days 1 and 15 plus oral S-1 twice daily on days 1–14 of a 28-day cycle. In the phase 1 part, the dose of irinotecan was escalated from 100 mg/m2 to 125 mg/m2 and then to 150 mg/m2.ResultsA total of 24 patients were enrolled. Overall, the median number of treatment cycles per patient was 5.9, and 92% of the patients completed at least two cycles. The overall response rate was 54.2% (13 of 24). The response rates in differentiated and undifferentiated cancer were 56.3% (nine of 16) and 50.0% (four of eight), respectively. Median survival time was 581 days. The maximum tolerated dose of irinotecan was not reached at the highest level. However, grade 4 neutropenia occurred at 125 mg/m2. We concluded that the recommended dose of irinotecan for the present regimen was 125 mg/m2.ConclusionTreatment with S-1+irinotecan is considered effective in patients with advanced gastric cancer who have not previously received chemotherapy. A combination of irinotecan and S-1 was well tolerated in patients with advanced gastric cancer and could be given on an outpatient basis.

Penetration of linezolid into rabbit intervertebral discs and surrounding tissues

Linezolid belongs to a new class of synthetic antimicrobial agent that is effective for a variety of methicillin-resistant Staphylococcus aureus (MRSA) infections including bone and joint MRSA infections, but the effectiveness of linezolid for the treatment of MRSA spine infection remains controversial. In this study, we investigated the diffusion of linezolid or vancomycin into normal rabbit spinal tissues to determine the adequacy of linezolid for the treatment of spinal infection. The penetration efficacy of linezolid into the annulus fibrosus, nucleus pulposus, and vertebral bone (10, 8, and 10%, respectively) was lower than that of vancomycin (27, 11, and 14%, respectively). The penetration efficacy of linezolid into the bone marrow and iliopsoas muscle (88 and 84%, respectively), however, was higher than that of vancomycin (67 and 9%, respectively). These results suggest that linezolid is inadequate for the treatment of spine infection limited to the intervertebral disc, but may be effective for the treatment of infection extending into the muscle and bone marrow, such as in vertebral osteomyelitis, iliopsoas abscess, and postsurgical infection.

Modified-irinotecan/fluorouracil/levoleucovorin therapy as ambulatory treatment for metastatic colorectal cancer: results of phase I and II studies.

AbstractBackground: Combined therapy with irinotecan/fluorouracil/levoleucovorin (calcium levofolinate) [IFL] has lost its position as the standard regimen for metastatic colorectal cancer because its toxicity and effectiveness have become controversial.n Objective: To (i) identify the optimal regimen for IFL therapy in terms of irinotecan dosage, and (ii) determine the maximum tolerated dose and efficacy of the modified-IFL regimen in patients with histologically confirmed advanced colorectal cancer.n Methods: In a phase I study, nine patients with advanced colorectal cancer received IFL treatment modified such that irinotecan was administered every 2 weeks, as opposed to the more toxic once-weekly administration. The study evaluated three escalating dose levels of irinotecan (100,125 and 150 mg/m2). Each treatment cycle consisted of irinotecan on days 1 and 15; fluorouracil 600 mg/m2 on days 1,8, 15 and 22; and levoleucovorin 250 mg/m2 on days 1, 8, 15 and 22. Data from the phase I study were used to determine the recommended dose of irinotecan for the phase II study. The latter study evaluated the effectiveness (overall response rate, median time to disease progression and median survival time) and tolerability of this modified-IFL therapy as ambulatory treatment in 22 patients with advanced colorectal cancer.n Results: The dose-limiting toxicity of irinotecan was grade 3 neutropenia, which occurred in three patients at dose level 2 (125 mg/m2); furthermore, a fourth patient developed grade 4 neutropenia at this dose level. Therefore, 125 mg/m2 was considered to be the maximum tolerated dose, and the dose of irinotecan for the phase II study was set at 100 mg/m2. Fourteen patients achieved partial response using this modified-IFL regimen, and the overall response rate was 63.6% (95% CI 43.5, 83.7). The median time to progression was 197 days (range 111–283 days) and the median survival time was 414 days (95% CI 116, 712). Toxicities were acceptable and manageable.n Conclusions: Modified-IFL therapy is a practical, effective and tolerable option for ambulatory treatment of advanced colorectal cancer.