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

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-[(18)F]fluoro-2-deoxy- D-glucose positron emission tomography ((18)F-FDG PET) for the evaluation of extrahepatic bile duct cancer. Thirty patients with extrahepatic bile duct cancer underwent both (18)F-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 (18)F-FDG PET revealed increased (18)F-FDG uptake in 18 (60%) of them. On the other hand, (18)F-FDG PET showed focal accumulation of (18)F-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 (18)F-FDG PET were 38%, 100% and 73%, respectively. The specificity of (18)F-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, (18)F-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, (18)F-FDG PET offers additional value in relation to CT in evaluating both the primary tumour and regional lymph nodes.     

Linear stapling forms improved anastomoses during esophagojejunostomy after a total gastrectomy

BACKGROUND: Circular stapling devices are commonly used to form esophagojejunal anastomoses after total gastrectomy. However, the technique has potential problems with placement of the purse-string suture and insertion of the anvil of the instrument. METHODS: We describe an improved technique for esophagojejunostomy by functional end-to-end anastomosis with linear stapling devices. RESULTS: Three patients with gastric cancer underwent this procedure after total gastrectomy. No anastomotic leakage or clinical evidence of stenosis was encountered. The maximum diameters of the anastomoses, evaluated by radiography with barium at 6 months after surgery, were 3.5 cm and 4.0 cm in 2 patients. Endoscopic examination revealed clear lines of anastomosis with a straight continuity between the distal esophagus and the jejunum. CONCLUSIONS: Our improved technique for esophagojejunostomy by functional end-to-end anastomosis with two linear staplers is a convenient, safe and reliable procedure that is independent of the width of the esophagus and the depth of the esophageal hiatus.     

Spatial focusing of neuronal responses induced by asynchronous two-tone stimuli in the guinea pig auditory cortex

Spatiotemporal patterns of neuronal responses to asynchronous two-tone stimuli in the anterior field of the auditory cortex of anesthetized guinea pigs were studied using an optical recording method (12 x 12 photodiode array, voltage sensitive dye RH795). Interactions between the onset response to the first tone (masker; 5, 8, 10, 12 and 15 kHz, 200 ms) and to the second tone (probe; 10 kHz, 30 ms) with onset delays relative to the masker onset (0, 5, 10, 15 and 20 ms) were investigated. In general, two-tone interaction was suppressive rather than facilitative. At 0-10 ms probe delays, two-tone responses induced in the probe isofrequency area on the cortex tended to fuse with the masker response. At 15-20 ms probe delays, the probe response was apparently reduced, but was spatially focused and separated from the masker response. This spatial focusing of the probe response may have been due to neuronal inhibition originating after the masker onset response. These results are in agreement with psychoacoustical observations in human subjects, such as auditory segregation, and indicate that the spatial focusing of the cortical response provides a neuronal basis for detecting slightly asynchronous auditory inputs.     

HLA-A2-restricted cytotoxic T lymphocyte activity during interferon beta therapy in patients with chronic hepatitis C

BACKGROUND AND AIMS: Hepatitis C virus (HCV)-specific cytotoxic T lymphocytes (CTL) may contribute to viral clearance and liver cell injury in patients with chronic hepatitis C. In the present study, we attempted to determine the serial HCV-specific CTL activity during interferon-beta (IFN-beta) therapy in patients with chronic hepatitis C and whether there is any relationship between the CTL response and clinical response to IFN-beta therapy. METHODS: Eight HLA-A2-positive patients with chronic hepatitis C were treated initially with 6 million U/ml of IFN-beta every day for 8 weeks and then 3 times weekly for the subsequent 16 weeks. Peripheral blood mononuclear cells (PBMC) were collected before the start, 4 weeks after the start, and after the end of IFN treatment and were stimulated with 2 peptides corresponding to core sequences, which were previously reported to have an HLA-A2 restricted-CTL epitopes. Cytolytic activity was determined by a standard 51Cr-release assay using allogenic HLA-matched EBV-transformed B lymphoblastoid cell lines (B-LCL). RESULTS: HCV-specific CTL responses were detected in 2 of the 8 patients before treatment with IFN-beta. One of 2 patients was not observed HCV-specific CTL responses after 4 weeks of IFN-beta treatment, however these two patients showed CTL responses at the end of IFN-beta treatment, and finally HCV-RNA was negative. In addition, HCV-specific CTL responses were observed in 4 patients after 4 weeks of IFN-beta treatment. Three of these 4 patients showed CTL responses only at 4 weeks after IFN-beta treatment. However, there were no differences between clinical parameters or between IFN efficacy in HCV specific CTL response-positive (n = 4) and -negative (n = 4) patients at 4 weeks after the start of IFN-beta treatment. CONCLUSIONS: These findings suggest that there are few relations between peripheral HCV-specific CTL response and clinical response to IFN therapy in patients with chronic hepatitis C, although IFN enhances the host immune response against HCV synergistically with antiviral activities.     

Alcoholic liver diseases and hepatitis virus C in Japan]

Recently incidence of alcoholic liver disease (ALD) has been increasing in Japan associated with an increase in alcoholic beverage consumption. There have been a large number of reports about the relationship between alcohol and hepatocarcinogenesis, but it remains controversial. In the present study, we addressed the recent trend in incidence of ALD including liver cirrhosis (LC), and hepatocellular carcinoma (HCC) in heavy drinkers in Japan. We carried out nation-wide survey by asking for the hospitals that are approved by the Japanese Society of Gastroenterology for recent aspects of in-patients with ALD. Except for HCC, percentage of ALD without viral hepatitis is more than 70%, which is increased when compared to the national survey carried out in 1992. In alcoholic LC patients, those who did not have viral hepatitis were 81%. However, the percentage of HCC without viral hepatitis was 34% of all of the heavy drinkers with HCC. Regarding the case in our university hospital, 138 cases (32%) of 432 patients with HCC were heavy drinkers. However, regarding in our general hospital, 15 cases of 23 patients with HCC (61%) were heavy drinkers. In conclusion, since the consumption of alcohol is increasing in Japan, the frequency and number of cases of alcoholic liver cirrhosis are increasing. Viral hepatitis infection, however, still plays an important role in hepatocarcinogenesis in heavy drinkers.     

Importance of the CT/MRI fusion method as a learning tool for CT-based postimplant dosimetry in prostate brachytherapy.

BACKGROUND AND PURPOSE: To compare the CT-based and CT/MRI fusion-based postimplant dosimetry after permanent prostate brachytherapy and to evaluate the improvement in CT-based dosimetry by physicians with or without experience in using the CT/MRI fusion method. PATIENTS AND METHODS: Thirty-eight consecutive patients agreed to participate in a prospective study. The prostate contours from CT/MRI fusion are the gold standard for determining the prostate volume and dose volume histogram (DVH). CT-based postimplant dosimetries were performed by two physicians. Observer 1 was a radiologist who had never used CT/MRI fusion method for postimplant dosimetric analysis. Observer 2 was a radiation oncologist experienced in postimplant analysis using the CT/MRI fusion method. The prostate dosimetry was evaluated by prostate D90 and V100. RESULTS: No significant difference was observed in the mean prostate volumes between the two observers and the CT/MRI fusion data. However, the correlation coefficient value for observer 2 (R(2)=0.932) was greater than that for observer 1 (R(2)=0.793). The D90 and V100 values as evaluated by the two observers were significantly underestimated in comparison to those evaluated using the CT/MRI fusion methods. The DVH related parameters were underestimated more frequently by observer 1 than by observer 2: (prostate D90: 99.56% for observer 1, 102.97% for observer 2, 109.37% for CT/MRI fusion. Prostate V100: 88.12% for observer 1, 90.14% for observer 2, 91.91% for CT/MRI fusion). CONCLUSIONS: The difference in the mean value in D90 and V100 by observer 1 was significantly greater than that for observer 2. These findings suggest that the CT/MRI fusion method provides accurate feedback which thereby improves CT-based postimplant dosimetry for prostate brachytherapy.     

Antitumor effects of systemic and local immunization with a CTL-directed peptide in combination with a local injection of OK-432.

PURPOSE: The accumulation of T cells into the tumor site is crucial for the elicitation of in vivo antitumor effects after cancer vaccination. In this study, we investigated the antitumor effects and associated mechanisms of action that were induced by systemic and local immunization with a CTL-directed peptide in combination with a peritumoral injection of a streptococcal preparation, OK-432. EXPERIMENTAL DESIGN AND RESULTS: The human SART3(315-323) peptide, which has the potential to induce human leukocyte antigen-A24-restricted CTLs, not only has the same amino acid sequence as the mouse SART3, but also has the capacity for binding to H-2K(d) molecules. Therefore, the SART3(315-323) peptide could be used as a tumor antigen-derived peptide in H-2(d) mice. Systemic immunization with the SART3(315-323) peptide and the subsequent peritumoral injection of both the SART3(315-323) peptide and OK-432 effectively induced peptide-specific and colon26 carcinoma-reactive CTLs in BALB/c mice. The combination therapy suppressed the growth of s.c. established colon26 carcinoma. The accumulation of both CD8(+) and CD4(+) T cells into the tumor site was more apparent in mice treated with the combination therapy than in those treated with other protocols. In addition, the level of IgG reactive to the administered SART3(315-323) peptide increased in mice that were treated with the combination therapy. CONCLUSION: These results indicate that antitumor effects could be efficiently induced by a combination therapy that included systemic and local immunization with a CTL-directed peptide together with a local injection of OK-432.     

Catechol-O-methyltransferase gene polymorphisms in benign prostatic hyperplasia and sporadic prostate cancer.

Various carcinogenic metabolites, including catechol estrogens, play a role in malignant transformation. An enzyme that is capable of neutralizing the genotoxic effects of these compounds is catechol-O-methyltransferase (COMT). A variant form of this enzyme has been shown to reduce its activity by up to 4-fold; thus, we hypothesize that single nucleotide polymorphisms of the COMT gene can be a risk factor for benign prostatic hyperplasia (BPH) and prostate cancer. To test this hypothesis, the genetic distribution of three different COMT polymorphisms at codon 62 (C-->T), codon 72 (G-->T), and codon 158 (G-->A) were analyzed in 131 normal healthy subjects, 134 BPH, and 178 sporadic prostate cancer samples from a Japanese population. Results of these experiments show that the variant genotype at codon 62 (P = 0.060) and codon 158 (P = 0.047) are risk factors for prostate cancer but not BPH when compared with normal controls. Odds ratio (OR) and 95% confidence interval (95% CI) for cancer were 3.24 and 1.38 to 7.61, respectively, for codon 62 T/T genotype when compared with wild type. At codon 158, the A/A variant for cancer had an OR of 3.00 with a 95% CI of 1.38 to 6.54 compared with wild type. Codons 62 and 158 were in linkage disequilibrium (LD), and when compared with the C-G haplotype, other types (C-A, T-G, T-A) were observed to be associated with prostate cancer (P = 0.040) but not BPH. Codon 72 on the other hand, was not in LD with either codon 62 or 158. The homozygous variant on codon 72 was rare in this Japanese population, and the heterozygous G/T at this codon was not associated with either prostate cancer or BPH. When evaluating the risk of COMT polymorphisms with stage or grade of cancer, no associations were observed for any of the genotypes with the exception of a tendency (P = 0.096) for the variant A allele on codon 158 to be correlated with higher stages (> or = T3) of cancer. This is the first report that shows the polymorphisms of COMT to be associated with sporadic prostatic carcinogenesis. These results are important in understanding the role of COMT polymorphisms in the pathogenesis of prostate cancer.     

Changes in tissue-plasminogen activator mRNA expression following cortical ablation in the rat brain

Tissue plasminogen activator (tPA) has been used to treat acute thrombotic lesions. Roles other than the activation of fibrinolytic pathways have been suggested for tPA in the mature brain. We used the in situ hybridization technique to investigate the changes in tPA mRNA expression within the brain after cortical ablation. We found that expression of tPA mRNA started to increase diffusely in the cortex ipsilateral to the injury 6 h after ablation. This increase had become prominent 24 h after ablation. On d 5, the expression of tPA mRNA had returned to that of the control animals except for the area near the injury. We also found that administration of MK-801 before injury suppressed the increase of tPA mRNA in the ipsilateral cortex. These results suggest that the increase in tPA mRNA is likely to be mediated via activation of NMDA receptors.