Biomedical subjects
Publications and source records attributed to M Fukumoto.
Iodine-123-labelled iodoamphetamine single-photon emission computed tomography of patients with reflex sympathetic dystrophy syndrome showed substantial variation in thalamic perfusion of the side contralateral to the painful limb. The variations are related to time from the onset of symptoms, which suggests that the thalamus undergoes adaptive changes in the course of this neurological disorder.
BACKGROUND: Various prognostic markers for lung carcinoma have been proposed, but to the authors' knowledge none is noninvasive and convenient for clinical use. The current study examined the utility of several radiotracers for the prediction of multidrug resistance (MDR) and radioresistance in patients with lung carcinoma. METHODS: Thirty patients with untreated lung carcinoma underwent a dual isotope single photon emission computed tomography (SPECT) scan at 10 minutes and 120 minutes after the injection of technetium-99m ((99m)Tc)-tetrofosmin ((99m)Tc-TF) (370 megabecquerels [MBq]) and thallium-201 ((201)TlCl) (111 MBq). Retention of each tracer was evaluated semiquantitatively. Using radiation and chemotherapy (cisplatin plus etoposide), the patients either were treated sequentially (n = 12) or concurrently (n = 18). The relation between therapeutic response and retention of each tracer was analyzed. The detectability of radioresistance was examined. RESULTS: In patients treated with sequential therapy, the response to radiation was predicted by (99m)Tc-TF retention, whereas (201)Tl retention was found not to be predictive. Regardless of whether the sequential or concurrent protocol was applied, 14 of 18 tumors with high (99m)Tc-TF retention (>/= 15%) exhibited a favorable response to chemoradiotherapy whereas all 12 tumors with low (99m)Tc-TF retention (</= 15%) did not respond to the therapy. In contrast, (201)Tl retention was not found to be a predictive factor. CONCLUSIONS: The employed SPECT method is a useful tool for the in vivo prediction of radioresistance, P-glycoprotein (P-gp), and non-P-gp MDR in lung carcinoma. Low (99m)Tc-TF retention serves as a strong predictor of therapeutic resistance. High (99m)Tc-TF retention implies a favorable response. (201)Tl did not appear to be a predictive factor but is required for localization of the lesion on SPECT imaging.
It is widely accepted that immunoglobulin (Ig)E triggers immediate hypersensitivity responses by activating a cognate high-affinity receptor, FcepsilonRI, leading to mast cell degranulation with release of vasoactive and proinflammatory mediators. This apparent specificity, however, is complicated by the ability of IgE to bind with low affinity to Fc receptors for IgG, FcgammaRII and III. We have addressed the in vivo significance of this interaction by studying IgE-mediated passive systemic anaphylaxis in FcgammaR-deficient mice. Mice deficient in the inhibitory receptor for IgG, FcgammaRIIB, display enhanced IgE-mediated anaphylactic responses, whereas mice deficient in an IgG activation receptor, FcgammaRIII, display a corresponding attenuation of IgE-mediated responses. Thus, in addition to modulating IgG-triggered hypersensitivity responses, FcgammaRII and III on mast cells are potent regulators of IgE-mediated responses and reveal the existence of a regulatory pathway for IgE triggering of effector cells through IgG Fc receptors that could contribute to the etiology of the atopic response.
A fully differentiated spermatozoon of both Ascidia zara and Ascidia gemmata is approximately 35 microM long. It contains a head and a tail lacking a midpiece. The head (approximately 4 microM long for A. zara and 5 microM long for A. gemmata) contains an elongated nucleus and a single mitochondrion that flanks the nucleus. Multiple acrosomal vesicles (three or four in number) are present at the apex of the sperm head in both species. Each vesicle is approximately 50 x 50 x 60 nm, and contains moderately electron-dense material. During spermiogenesis of A. zara, three or four vesicles appear in a blister of an early stage spermatid. These vesicles transform into multiple acrosomal vesicles without fusing with each other. Spermiogenesis and acrosome differentiation are similar in A. gemmata and A. zara. Three types of acrosome differentiation in ascidians are described.
Malignant diffuse mesothelioma is characterized by more difficult diagnosis and worse prognosis than other pleural tumors. In the Department of Thoracic Surgery, Hyogo Medical Center for Adults, 11 patients underwent panpleuropneumonectomy for this disease between January, 1988 and March, 1993. In 7 of these cases, Ga-67 scans were obtained before the operation. To clarify the factors affecting Ga-67 uptake in the pleural tumor, we compared Ga-67 uptake on the involved side of the thorax with CT and the pathological findings of the tumor. Regarding the use of Ga-67 scan imaging for the diagnosis of this disease, a number of related findings must be considered, such as an encircled wide Ga-67 uptake in the thickened pleural involvement and a diffuse slight Ga-67 uptake on the affected side with very slight involvement of the pleura. When the involved pleural thickness was over 6 mm, a definite correlation was found between the degree of Ga-67 uptake and the macroscopic thickness of mesothelioma in resected specimens. Thickness of the pleura on CT images demonstrates the real tumor thickness in the case of thickened involvement but in the case of thin involvement the real thickness of active mesothelioma could not be identified. No definite correlation was found between the degree of Ga-67 uptake and the histological type, or among microscopic findings, such as the extent of tumor parenchyma, interstitial volume and tumor vascularity. Our results suggest that the Ga-67 scan is very useful for revealing the extent of pleural involvement, especially when this involvement is more than 6 mm thick.
Expression of CIRP (cold-inducible RNA-binding protein) is inducible at 32 degrees C in cultured fibroblasts. Because ischemia is known to induce expression of heat shock proteins, its effect on the CIRP expression was examined using the rat transient forebrain ischemia model. The isolated rat CIRP cDNA encoded amino acids 100% identical in its sequence to mouse CIRP. Northern blot analysis revealed that the CIRP transcripts were ubiquitously expressed in various tissues. In situ hybridization histochemistry of normal rat brain revealed the expression of CIRP in neurons in the hippocampus and the cerebral cortex among others. In the hippocampus of postischemic rats, CIRP mRNA level decreased from 3-6 h after the onset of reperfusion, while it did not change in the cerebral cortex. When PC12 pheochromocytoma cells were cultured at 32 degrees C, the CIRP mRNA level was increased. The presence of H2O2 in the culture media inhibited dose dependently this induction as well as constitutive expression, suggesting that the effect of brain ischemia on CIRP expression is related to generation of reactive oxygen species. Further studies are necessary to clarify the roles played by cold shock proteins in the hypothermic therapy of brain damages.
Thymidine phosphorylase (TP) is associated with angiogenesis and the progression of solid tumours. High intracellular levels of this enzyme indicate increased chemosensitivity to pyrimidine antimetabolites. TP gene expression in 56 cases of epithelial ovarian cancer (27 of serous, 10 mucinous, 12 endometrioid, five clear cell and two undifferentiated) were analysed by polymerase chain reaction of RNA after reverse transcription. These included eight of low malignant potential. Twenty were stage I, four stage II, 27 stage III and five stage IV. The level of TP gene expression was presented by the relative yield of the TP gene to the beta2-microglobulin gene. TP gene expression ranged from 0.19 to 5.38 (median 0.93). The value of TP gene expression in stage III-IV was significantly higher than that of TP gene expression in stage I-II (P = 0.0005). Histological grade significantly associated with TP gene expression (P = 0.008), but histological subtype did not (P = 0.166). A follow-up study of 34 cases after complete resection of the primary tumours by surgical operation was performed. TP gene expression of the cases with recurrence showed significantly higher levels compared to cases without recurrence (P = 0.049). Survival data were available for 47 of the 56 patients. The prognosis of the patients with high TP gene expression (equal to, or greater than, median) was to be significantly worse than patients with low TP gene expression (less than median) (P = 0.021). The TP gene expression level may play one of the key roles in the biology of ovarian epithelial cancer and define a more aggressive tumour phenotype. A new therapeutic intervention mediated by TP protein activity is anticipated.
The current prospective randomized study was designed to compare the effects of intracavitary (i.c.) chemotherapy vs immunotherapy vs immunochemotherapy for malignant effusion. Between 1992 and 1995, a total of 42 patients with malignant effusion were registered, and 41 patients were eligible for statistical analysis. The primary diseases of the eligible patients included 27 gastric, four colorectal, four pancreatic, three lung, two liver and one oesophageal cancers. The patients with malignant effusion were randomly assigned into one of three i.c. therapeutic regimens: chemotherapy alone with weekly injection of anticancer agents (ACAs: cisplatin, mitomycin-C, adriamycin, etc.) (Group A, n = 13); immunotherapy alone with weekly injection of streptococcal preparation OK-432 (Group B, n = 14); or immunochemotherapy with ACAs and OK-432 (Group C, n = 14). The response of the effusion, patient survival and the kinetics of cytokines in the effusion were compared. There were no differences in the patients' backgrounds. The side-effects of the regimens included pain, anorexia, fever, leucopenia and anaemia and there were no differences in their incidence among the three groups. One patient died after cisplatin (CDDP) administration in Group A. Cytologic examination revealed that tumour cells in the effusion disappeared in 23% of Group A cases, 36% of Group B cases and 36% of Group C cases. The malignant effusion did not disappear in any of the Group A cases; however, the effusion disappeared in 29% of Group B cases and 43% of Group C cases (P = 0.03, Group A vs Group C). Furthermore, the 50% survival period was 1.6 months for Group A, 2.4 months for Group B and 3.5 months for Group C. The 6-month survival rate was 7% for Group A, 6% for Group B and 34% for Group C, and the 1-year survival rate was 0%, 0% and 17% respectively (P = 0.048, Group A vs Group C by the log-rank test). The analysis of the cytokine kinetics revealed a prominent increase in the level of interleukin-6 in the effusion in Group C. These results suggest that i.c. immunochemotherapy with OK-432 and ACAs may be more beneficial than i.c. chemotherapy alone or immunotherapy alone.
Tyramide signal amplification-avidin-biotin complex (TSA-ABC) method is a powerful technique used to detect antigens that are not detectable by ordinary immunohistochemistry. It is worth trying in cases where localization of antigens by the conventional method has failed and antibodies are precious.
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Owing to recent advances in imaging technology and radiologic intervention, survival rates in patients with hepatocellular carcinoma have improved markedly. However, such prolonged survival has resulted in an increase in extrahepatic metastases. Tc-99m (Sn)-N-pyridoxyl-5-methyltryptophan (Tc-99m PMT), developed for hepatobiliary scintigraphy, has been used to visualize extrahepatic metastases, with most related reports limited to osseous metastases. The authors report two cases of hepatocellular cancer presenting as a hypopharyngeal metastasis and intraperitoneal dissemination along the tract of a fine-needle biopsy. Lesions undetectable on planar imaging could be visualized by Tc-99m PMT SPECT.
A 29-year-old woman with an unusual form of pulmonary metastasis from epithelioid sarcoma of the right forearm is presented. Since she manifested left pneumothorax due to metastatic pulmonary cyst 7 years ago, the only metastatic manifestation has been the presence of bilateral multiple thin-walled pulmonary cysts; no other types of pulmonary lesions, such as nodules, cavitary lesions with thick or irregular walls, or extrapulmonary metastases, have been found. Pathologic studies revealed metastatic proliferation of sarcoma cells in the wall of the pulmonary cysts and infiltration of malignant cells inside the microscopic cavitary metastases surrounded by normal lung parenchyma.
BACKGROUND: Neural invasion is known to be one of the aggressive characteristics of pancreatic adenocarcinoma. However, there have been no systematic studies on intraoperative examination of neural invasion of pancreatic carcinomas after wide dissection of the retroperitoneum, particularly at the surgical margin. METHODS: We performed intraoperative immunostaining on the frozen sections of several excised plexus specimens, using peroxidase-labeled anti-cytokeratin 19 antibody in 17 cases of resectable pancreatic carcinoma. Postoperatively, we also tried to detect occult micrometastasis by direct sequencing of the K-ras gene in the same samples. RESULTS: Intraoperative staining for cytokeratin 19 was positive in 4 of 17 (23.5%) cases. Patients with margin-positive neural invasion had significantly worse prognosis than patients who were margin negative (P < 0.05). One patient had micrometastasis in the nerve plexus, revealed by K-ras mutation, whereas neither cytokeratin 19 staining nor postoperative pathological investigation detected involvement of the analyzed portion. In the four patients margin-positive for cytokeratin 19 staining, the diagnosis of neural invasion by cytokeratin 19 staining was in agreement with the K-ras gene analysis. CONCLUSION: Intraoperative staining for cytokeratin 19 is useful for detecting pancreatic cancer involvement of the neural plexus margin. The results can be also utilized as a prognostic indicator during the follow-up period.
Thorotrast, a colloidal suspension of radioactive (232)ThO(2) that emits alpha particles, was used as a radiographic contrast agent in the 1930s-1950s. Several decades after injection, Thorotrast causes liver cancers, among which intrahepatic cholangiocarcinoma (ICC) is prominent. We investigated mutations of the RAS and the TP53 genes in archival sections of ICC induced by Thorotrast. Compared to ICC that was not associated with Thorotrast, the frequency of mutation of the KRAS gene was lower, while that of the TP53 gene was more than two times higher. The most common mutation of the TP53 gene was A-G transitions. Interestingly, TP53 mutations were also found in noncancerous areas of livers in which Thorotrast had been deposited. Furthermore, mutations tended to accumulate in tissues from more advanced tumors. These results suggest that deposited Thorotrast continuously damages DNA in liver cells in some way, resulting in A-G transitions of the TP53 gene. However, we have not been able to rule out the possibility that genetic insults occur indirectly in the proliferating cells adjacent to the necrosis rather than being a direct effect of alpha particles.
Epidemiological studies have revealed that malignant tumors occur in the liver approximately 20 years after injection of Thorotrast. We investigated genetic changes in the TP53 gene (formerly known as p53) in malignant liver tumors related to Thorotrast to cast light on the mechanisms of alpha-particle carcinogenesis. A total of 19 autopsy cases of liver malignancies [11 hepatocellular carcinomas (HCC), 5 cholangiocellular carcinomas (CCC) and 3 angiosarcomas (AS)] were analyzed. Using archival tissues, loss of heterozygosity (LOH) at the 17p13 locus was analyzed. Then single-strand conformation polymorphism analysis and sequencing were performed to detect mutations in exons 5 to 8 of the TP53 gene. As a result, 15 cases were informative in terms of polymorphism, and 4 cases showed LOH (3 HCC and 1 AS). Eight cases showed 9 mutations in exons and 2 in introns: 7 transitions (6 HCC and 1 CCC), 2 transversions (1 HCC and 1 AS), and 2 deletions (2 HCC). The direct action of alpha particles is thought to result in relatively large deletions such as those detected by LOH. Therefore, the low frequency of such changes (27%) compared to point mutations (47%) suggests that the genetic changes in the TP53 gene in the liver tumors related to Thorotrast were not caused mainly by direct actions of alpha particles but rather by indirect effects that may have been due to cycles of necrosis and regeneration.
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BACKGROUND: Germ-line and sporadic mutations in the tumor suppressor gene PTEN (also known as MMAC or TEP1), which encodes a dual-specificity phosphatase, cause a variety of cancers such as Cowden disease, glioblastoma, endometrial carcinoma and prostatic cancer. PTEN is widely expressed, and Cowden disease consistently affects various organ systems, suggesting that the PTEN protein must have an important, although as yet poorly understood, function in cellular physiology. RESULTS: Homozygous mutant mice lacking exons 3-5 of the PTEN gene (mPTEN3-5) had severely expanded and abnormally patterned cephalic and caudal regions at day 8.5 of gestation. Embryonic death occurred by day 9.5 and was associated with defective chorio-allantoic development. Heterozygous mPTEN3-5 mice had an increased incidence of tumors, especially T-cell lymphomas; gamma-irradiation reduced the time lapse of tumor formation. DNA analysis of these tumors revealed the deletion of the mPTEN gene due to loss of heterozygosity of the wild-type allele. Tumors associated with loss of heterozygosity in mPTEN showed elevated phosphorylation of protein kinase B (PKB, also known as Akt kinase), thus providing a functional connection between mPTEN and a murine proto-oncogene (c-Akt) involved in the development of lymphomas. CONCLUSIONS: The mPTEN gene is fundamental for embryonic development in mice, as mPTEN3-5 mutant embryos died by day 9.5 of gestation, with patterning defects in cephalic and caudal regions and defective placentation. Heterozygous mice developed lymphomas associated with loss of heterozygosity of the wild-type mPTEN allele, and tumor appearance was accelerated by gamma-irradiation. These lymphomas had high levels of activated Akt/PKB, the protein product of a murine proto-oncogene with anti-apoptotic function, associated with thymic lymphomas. This suggests that tumors associated with mPTEN loss of heterozygosity may arise as a consequence of an acquired survival advantage. We provide direct evidence of the role of mPTEN as a tumor suppressor gene in mice, and establish the mPTEN mutant mouse as an experimental model for investigating the role of PTEN in cancer progression.
Apg-1 (Osp94) and apg-2 belong to the heat shock protein (hsp) 110 family. In mouse somatic cells the apg-1 and hsp105/110 transcripts are inducible by a 32 degrees C to 39 degrees C heat shock, while apg-2 is not heat-inducible. Since ischemia is known to induce expression of hsp70, its effect on expression of apg-1 was assessed by using the 20-min forebrain ischemia model of the rat. In the cerebral cortex, Northern blot analysis and in situ hybridization histochemistry demonstrated an increased expression in neuronal cells of apg-1 transcripts 3 h after the onset of reperfusion, with a peak at 12 h, followed by a decline. In the hippocampus, the level was increased at 3 h, remained constant until 24 h, and then declined. Transcript levels of apg-2 as well as hsp 105 were also increased under the present conditions, indicating that the expression of apg-2 was differentially regulated in response to heat and ischemic stresses. The induction kinetics of hsp 105, but neither apg-2 nor hsp 70, were identical to those of apg-1. These results demonstrated that brain ischemia/reperfusion induced expression of each member of the hsp 110 family, although the regulatory mechanisms may not be the same. They also suggest a significant role of apg-1 in both the ischemic- and heat-stress responses and in the normal functioning of the non-stressed neuronal cells.