Homogenization of tissue samples using a split-pestle.
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Animals↗
Biomedical subjects
M Kusumoto
Publications and source records attributed to M Kusumoto.
Multiphase ECG-triggered 3D contrast-enhanced MR angiography: utility for evaluation of hilar and mediastinal invasion of bronchogenic carcinoma.
The purpose of this study was to evaluate the usefulness of cardiac synchronized magnetic resonance angiography [electrocardiographically (ECG)-triggered MRA] for improving image quality and detection of hilar and mediastinal invasion of bronchogenic carcinoma. Fifty patients, suspected of having hilar or mediastinal invasion of bronchogenic carcinoma, underwent contrast-enhanced computed tomography and MR imaging including conventional and ECG-triggered MRA. Twenty patients subsequently also underwent surgical resection. Vascular enhancement-to-background ratio (VBR), vascular enhancement-to-tumor ratio (VTR), signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR) and image quality scores of thoracic vessels obtained with both MRA techniques were determined and compared. In addition, the diagnostic accuracy of tumor invasion of pulmonary vessels was compared. VBRs and VTRs of both MRA techniques were not significantly different. ECG-triggered MRA significantly improved SNRs and CNRs (P < 0.05). Two readers judged that overall image quality of ECG-triggered MRA was better than that of conventional MRA (kappa > or = 0.41). In conclusion, ECG-triggered MRA improves the image quality and the detection of hilar and mediastinal invasion of bronchogenic carcinoma.
Adult↗
Phase 1 clinical trial of irradiated autologous melanoma cells adenovirally transduced with human GM-CSF gene.
The objective of this study was to determine the safety and antitumor activity of an autologous GM-CSF-secreting melanoma cell vaccine that was engineered ex vivo with recombinant replication-incompetent adenovirus harboring a human GM-CSF gene (Adv/hGM-CSF). Melanoma samples were surgically obtained from 30 patients (15 female and 15 male, ages ranging from 23 to 87) and were processed for vaccine preparation. Due to stringent eligibility criteria, 9 out of 30 patients were enrolled in the phase 1 clinical trial (FDA IND7677). Melanoma cell lines established from surgical specimens of 9 patients were transduced with Adv/hGM-CSF (MOI of 100) and subsequently irradiated at 35 Gy. These cell lines secreted human GM-CSF in vitro at an average rate of 80-424 ng/10(6) cells/24 h. All patients were intradermally and subcutaneously injected at several sites with irradiated autologous melanoma cells (2x10(6)-1x10(7) in 300 microl saline), 2-10 times, at intervals of 4-8 weeks. None of the patients vaccinated showed any serious adverse systemic response. Three patients (nos.1, 6 and 7) demonstrated local reaction (erythema) to the vaccination. Tumor-specific CTL assays performed in the absence of K562 cells showed that the levels of CTLs in peripheral blood of 5 patients increased following vaccination, whereas those in one patient declined. Levels of CTLs assayed in the presence of K562 cells were considerably lower than those assayed in the absence of K562 cells, but were also found to increase following vaccination in the peripheral blood of 6 patients. A patient who had been vaccinated 10 times (patient 1) responded to the vaccination by apparent reduction in size of metastatic tumor in the lung. Immunohistochemical examination of the vaccination sites of patient 1, biopsied after the 3rd and 4th vaccination. showed that the vaccination sites responded with infiltration of inflammatory cells, such as T cells (CD3+, CD8+), macrophages and dendritic cells (CD83+), for a period up to about 8 days. These data suggest that repeated vaccinations with irradiated autologous GM-CSF-producing tumor cells were well tolerated by patients and led to the activation of an antitumor immune response in some patients.
Adenoviridae↗
Effect of fluvoxamine on the pharmacokinetics of mexiletine in healthy Japanese men.
BACKGROUND AND OBJECTIVES: Fluvoxamine, a selective serotonin reuptake inhibitor, is known to inhibit several hepatic cytochrome P450 (CYP) isozymes, in particular CYP1A2. Mexiletine is mainly catalyzed by CYP2D6 and partially catalyzed by CYP1A2. Our objective was to study the potential pharmacokinetic interaction between fluvoxamine and mexiletine. METHODS: A randomized crossover design with two phases was used. A 7-day washout period separated the two treatment conditions. In the one phase, 6 healthy Japanese men received an oral dose of 200 mg of mexiletine alone (study 1); in the other phase, the men received fluvoxamine (50 mg twice a day) for 7 days, and on the eighth day they received oral mexiletine (200 mg) and fluvoxamine concomitantly (study 2). The concentrations of mexiletine were measured with HPLC. RESULTS: The area under the concentration-time curve and serum peak concentration of mexiletine in study 2 were significantly increased compared with those in study 1 (10.4 +/- 4.85 versus 6.70 +/- 3.21 microg x h/mL, P =.006 and 0.623 +/- 0.133 versus 0.536 +/- 0.164 microg/mL, P =.008, respectively). CONCLUSION: The effect of fluvoxamine on the mexiletine disposition is comparatively large, and when mexiletine and fluvoxamine are coadministered careful monitoring of mexiletine is needed.
Administration, Oral↗
Pulmonary amyloidosis diagnosed by CT-guided transbronchial biopsy: a case report.
During a medical check-up, a nodular shadow was detected by chest X-ray in the right lower lung field of a 59-year-old man. On computed tomography (CT), the nodular lesion had a relatively well-defined, irregular margin. A fluoroscopy-guided bronchoscopic biopsy did not uncover any malignancy. Specimens from a subsequent CT-guided bronchoscopic biopsy revealed a pulmonary amyloid deposit. As a rule, it is difficult to exclude malignancy or confirm benign disease in cases of truly benign lesions, particularly if the lesions are difficult to biopsy. Amyloidosis is one of such conditions and requires reliable diagnostic methods to avoid unnecessary surgical resection. From our experience, we consider CT-guided bronchoscopic biopsy to be a safe and accurate procedure, even when applied to truly benign lesions.
Amyloidosis↗
Primary synovial sarcoma of the lung: a case report confirmed by molecular detection of SYT-SSX fusion gene transcripts.
We report a rare case of primary synovial sarcoma of the lung. The patient was a 49-year-old woman who presented with a well-defined oval-shaped mass in the left upper lobe on a chest radiograph. A malignant pulmonary tumor was suspected and consequently a left upper lobectomy was performed. Grossly, the tumor measured 5 x 4 cm, was whitish-yellow in color and soft in consistency. Histologically, the tumor showed a dense proliferation of short spindle cells, partly arranged in interlacing fascicles. In some areas a hemangiopericytoma-like pattern, stromal myxoid change and necrosis of various sizes were noted. Numerous mitotic figures were also seen. Immunohistochemically, the tumor cells were positive for epithelial markers such as cytokeratin and epithelial membrane antigen. As these features suggested a monophasic fibrous type of synovial sarcoma, we examined for the presence of SYT-SSXfusion gene transcripts using RNA samples from the frozen tumor tissue. A reverse transcription polymerase chain reaction amplified a single 583-base pair fragment characteristic of synovial sarcoma. As no other tumorous lesions were found during a follow-up period of 1 year, primary synovial sarcoma of the lung was our final diagnosis. This tumor should be considered in the differential diagnosis of round to short spindle cell tumors arising in the lung.
Female↗
Identification of shiga toxin-producing Escherichia coli possessing insertionally inactivated Shiga toxin gene.
We have investigated the Shiga toxin genes of Shiga toxin-producing Escherichia coli (STEC) strains, using polymerase chain reaction (PCR) amplifying the full lengths of these genes. As a result, we found the Shiga toxin 2 gene which was insertionally inactivated by an insertion sequence (IS). This IS element was identical to IS1203v which has been also found in inactivated Shiga toxin 2 genes, and was inserted at the same site as in the previous paper. On the other hand, both Shiga toxin 2 genes were different (98.3% identity). These suggested that IS1203v independently inserted into each Shiga toxin 2 genes, and STEC strains possessing the insertionally inactivated Shiga toxin genes are most likely to have a wide distribution. Amplification of the full length of the Shiga toxin gene is one of the effective methods to detect the gene no matter where the IS element is included, i.e., the insertion can be reflected in the size of amplicon.
Animals↗
[Adjuvant GM-CSF cytokine gene therapy for breast cancer].
UNLABELLED: The aim of this study was to examine the enhancement of antitumor immunity of irradiated granulocyte macrophage-colony-stimulating factor (GM-CSF) gene-transduced mouse breast cancer cells. METHODS: BALBMC mouse were vaccinated subcutaneously with saline or irradiated mouse breast cancer cells, BALBMC (1 x 10(6)/mouse), infected or not infected with recombinant adenovirus harboring GM-CSF gene on day-7. Mice were injected with parental cells (1 x 10(5)/mouse) on day 0. RESULTS: No mice vaccinated with irradiated GM-CSF producing BALBMC cells developed a tumor during the observation period of up to 16 weeks, whereas 100% of mice injected with saline developed a tumor. CONCLUSION: Our study demonstrates the feasibility of this immunotherapeutic approach as a novel adjuvant cancer therapy after surgery for breast cancer.
Animals↗
[Neoadjuvant chemotherapy for advanced epithelial ovarian cancer].
Primary surgical cytoreduction followed by paclitaxel/carboplatin combination chemotherapy currently is the treatment of choice for advanced epithelial ovarian cancer. Aggressive surgery is widely accepted as a valid approach to initial cytoreduction of stage III disease, but suboptimal residual disease following primary surgical resection is one of the most important adverse prognostic factors in these patients. Neoadjuvant chemotherapy has been proposed as an alternative approach to conventional surgery for initial management of bulky ovarian cancer, with the goal of improving surgical quality. General acceptance of neoadjuvant chemotherapy as an alternative to primary surgery for patients who are not ideal surgical candidates remains limited, because equivalent or superior survival has not yet been demonstrated in a prospective randomized study. A large-scale, prospective, randomized study is being conducted by the European Organization for Research and Treatment of Cancer (EORTC) Gynecologic Cancer Cooperative Group and Gynecologic Oncology Group (GOG) to compare outcomes (overall and progression-free survival, quality of life, treatment complications) of neoadjuvant chemotherapy/interval debulking surgery versus primary cytoreductive surgery/adjuvant chemotherapy in patients with advanced epithelial ovarian carcinoma.
Antineoplastic Combined Chemotherapy Protocols↗
Computed tomography screening for lung carcinoma in Japan.
BACKGROUND: In Japan, lung carcinoma is the leading cause of cancer-related deaths. Adenocarcinoma accounts for roughly half of all lung carcinomas. Earlier detection of lung carcinoma is expected to reduce mortality rates. Computed tomography (CT) provides higher contrast resolution and greater visualization of chest compartments that are difficult to view with chest radiography, such as the mediastinum. CT further permits the detection of minute peripheral nodules. At present, several institutions and research groups are evaluating the utility of low dose spiral CT for lung carcinoma screening. METHODS: From September 1993 to December 1998, 1669 individuals underwent a biannual screening program for lung carcinoma. The program included posteroanterior radiograph, sputum cytology, and low dose spiral CT at a for-profit organization: The Anti-Lung Cancer Association (ALCA). A total of 9993 examinations were carried out. The low dose spiral CT parameters used were 120 kvP, 50 mA, 10-mm collimation, and 2:1 pitch. RESULTS: Peripheral lung carcinoma was detected in 31 of 9993 examinations (0.3%). Of the 31 cases, 24 tumors (77%) were detected by low dose spiral CT but were not visible on standard chest radiography. Twenty-two of the 24 tumors were Stage IA (T1N0M0, according to staging system revised in 1997). CONCLUSIONS: Low dose spiral CT shows promise for lung carcinoma screening. The effectiveness of the technique for the detection of minute lung lesions remains to be established. Routine use of the technique will require resolution of several issues. These issues include the establishment of CT diagnostic criteria, the development of a diagnostic support system, the establishment of methods for definite diagnosis, and assessments of efficacy.
Humans↗
Establishment of a new human pancreatic cancer cell line, NOR-P1, with high angiogenic activity and metastatic potential.
We present here a new cell line, NOR-P1, established from a metastatic subcutaneous tumor of a patient with pancreatic cancer. The cells show rapid growth in culture with a doubling time of 16 h and high migration activity. Genetic and molecular analyses revealed high telomerase activity and a mutation in the K-ras oncogene. Of particular interest, the cells express markedly elevated mRNA levels of angiogenic factors, vascular endothelial growth factor and platelet-derived growth factor, as well as other tumor growth-related factors. Subcutaneous transplantation of the NOR-P1 cells into nude mice formed solid, hemorrhagic tumors which were histologically diagnosed as adenocarcinoma with dense blood vessels and severe extravasation of blood. Furthermore, when NOR-P1 cell suspension was injected directly into the pancreas of nude mice, the cells grew rapidly to form intra-pancreatic tumors associated with liver metastases and peritoneal dissemination that resulted in cachexia and subsequent death. These properties suggest that NOR-P1 is an aggressive pancreatic cancer cell line with a high metastatic potential and may serve as a useful experimental model for studying tumor angiogenesis and metastasis of pancreatic cancer.
Aged↗
Diverse effects of 9-hydroxyellipticine on the chemosensitivity of human pancreatic cancer cells harboring p53 mutations.
Recently, it has been shown that 9-hydroxyellipticine (9-HE), an antitumor alkaloid has a unique property of restoring functional wild-type (wt) p53 activity via inhibition of mutant (mt) p53 protein phosphorylation. In the present study, we investigated the effect of 9-HE on the drug sensitivity of human pancreatic cancer cells. Exposure of cells to 9-HE at a relatively low concentration of 1 microM induced almost no cell death but was sufficient to restore wt p53 activity, as evidenced by an induction of endogenous p21WAF1/CIP1 concomitant with G1 and G2/M arrests in cell-cycle progression. Pretreatment with 1 microM 9-HE markedly enhanced cell killing when combined with cisplatin or mitomycin C. In contrast, 9-HE pretreatment protected cells from killing by 5-fluorouracil, VP-16, or vincristine. These effects of 9-HE were specific for several cell lines containing mt p53 and were not observed in p53-negative or wt p53 expressing cells. Taken together, these findings suggest that 9-HE may exert different effects on the drug sensitivity of pancreatic cancer cells displaying p53 mutations possibly through restoration of wt p53.
Antimetabolites, Antineoplastic↗
Predicting the prognosis of non-small cell lung cancer patient treated with conservative therapy using contrast-enhanced MR imaging.
The aim of this study was to evaluate the therapeutic effect more accurately and predict the prognosis of treated non-small cell lung cancer by using contrast-enhanced magnetic resonance imaging (CE-MRI). Contrast-enhanced computed tomography (CE-CT) and CE-MRI were examined 90 non-small cell lung cancer patients treated with conservative therapies. Enhancement patterns of CE-MRI were classified into three types: peripheral; mottled; and homogeneous. Reduction ratio of tumor size (RRT) based on the World Health Organization response criteria and a new response rate; reduction ratio of viable tumor size (RRVT) which evaluates not only the reduction of tumor size but also changes in necrosis and/or cavity size, were evaluated. Changes of enhancement pattern were compared and correlated with pathological diagnosis. The RRTs, RRVTs, and interobserver agreements evaluated by all modalities were compared. The RRTs and RRVTs in each subgroup were correlated and compared with prognoses. Change of enhancement pattern depended on therapy had no tendency (p = 0.06). Enhancement pattern had significant correlation with pathological diagnosis (p < 0.0001). Partial response (PR) case of RRVT had significant difference between imaging techniques (p = 0.04). The RRVT of other cases and RRT had no significant difference. Interobserver agreements of RRT and RRVT were almost perfect (n > or = 0.93). Prognosis had better correlation with RRVT than with RRT. Differences of relapse-free survival and survival between patients considered as having no change (NC) by RRT and PR by RRVT (NC-PR) and patients considered as having NC by RRT and RRVT were significant (p = 0.03, p = 0.01). There were no significant differences of relapse-free survival and survival between NC-PR patients and patients considered as having PR by RRT and RRVT. The CE-MRI technique could accurately evaluate the therapeutic effect and predict the prognosis of treated non-small cell lung cancer.
Aged↗
GM-CSF gene therapy using adenoviral vector in hamster pancreatic cancer.
The aim of this study was to examine the antitumor effect of irradiated granulocyte macrophage-colony-stimulating factor (GM-CSF)-gene-transduced hamster pancreatic cancer cells and its relationship to the amount of GM-CSF produced by transduced tumor cells. Hamster pancreatic adenocarcinoma cells, HPD1NR, which spontaneously secrete 15.0+/-0.4 pg/106 cells per 24 h of GM-CSF, and HPD2NR cells, which do not secrete GM-CSF, were used. When these cells were infected with recombinant adenovirus harboring the GM-CSF gene, HPD1NR and HPD2NR secreted 624.2+/-9.9 and 157.8 +/-5.7 pg/106 cells per 24 h, respectively. Vaccination with irradiated GM-CSF-secreting HPD2NR completely protected syngeneic hamsters challenged with live parental cells. On the other hand, vaccination with irradiated HPD1NR protected 60% of hamsters from tumor development after challenge with parental cells. None of the tumor-free hamsters initially vaccinated with irradiated GM-CSF-producing HPD2NR cells developed tumor upon repeated challenge with parental cells during the entire observation period. Irradiated GM-CSF-gene-transduced hamster pancreatic cells are promising as a novel adjuvant cancer therapy after surgery for primary and metastatic pancreatic cancer. The results indicate the necessity for a therapeutic strategy for cancer based on the cytokine status of tumors.
Adenoviridae↗
Pure acute subdural haematoma without subarachnoid haemorrhage caused by rupture of internal carotid artery aneurysm.
A 52-year-old female presented with disturbance of consciousness and clinical signs of tentorial herniation. Computed tomography showed a pure acute subdural haematoma (SDH) over the left convexity without subarachnoid haemorrhage. Cerebral angiography showed a saccular aneurysm at the junction of the left internal carotid artery and the posterior communicating artery. Surgery to remove the haematoma and clip the aneurysm showed the rupture point was located in the anterior petroclinoid fold (subdural space). The patient recovered without neurological deficits. Pure SDH caused by ruptured aneurysm is rare. Rupture of an aneurysm adhered to either the dura or falx and located in the subdural space may cause pure SDH. Therefore, ruptured intracranial aneurysm should be considered as a cause of non-traumatic SDH. Immediate removal of the SDH and aneurysmal clipping is recommended in such patients, even those in poor neurological condition.
Aneurysm, Ruptured↗
Up-regulation of telomerase activity in human pancreatic cancer cells after exposure to etoposide.
Telomerase plays a critical role in the development of cellular immortality and oncogenesis. Activation of telomerase occurs in a majority of human malignant tumours, and the relation between telomerase and vulnerability to drug-mediated apoptosis remains unclear. In this study, we demonstrate, for the first time, up-regulation of telomerase activity in human pancreatic cancer cells treated with etoposide, a topoisomerase II inhibitor. Exposure of MIA PaCa-2 cells to etoposide at various concentrations (1-30 microM) resulted in two- to threefold increases in telomerase activity. Up-regulation was detectable 24 h after drug exposure and was accompanied by enhanced expression of mRNA of the human telomerase reverse transcriptase. Telomerase activation was also observed in AsPC-1 and PANC-1 cells but not in KP-3 and KP-1N cells. Furthermore, we found a negative correlation between increased telomerase activity and the percentage of dead cells after etoposide treatment. These findings suggest the existence of an anti-apoptotic pathway through which telomerase is up-regulated in response to DNA damage. This telomerase activation pathway may be one of the mechanisms responsible for the development of etoposide resistance in certain pancreatic cancer cells.
Antineoplastic Agents, Phytogenic↗
Reactivation of insertionally inactivated Shiga toxin 2 genes of Escherichia coli O157:H7 caused by nonreplicative transposition of the insertion sequence.
IS1203v is an insertion sequence which has been found in inactivated Shiga toxin 2 genes of Escherichia coli O157:H7. We analyzed the transpositional mechanism of IS1203v in order to investigate whether the Shiga toxin 2 genes inactivated by IS1203v could revert to the wild type. When the transposase activity of IS1203v was enhanced by artificial frameshifting, IS1203v was obviously excised from the Shiga toxin 2 gene in a circular form. The IS1203v circle consisted of the entire IS1203v, but an extra 3-bp sequence (ATC) intervened between the 5' and 3' ends of IS1203v. The extra 3-bp sequence was identical to a direct repeat which was probably generated upon insertion. Moreover, we detected the Shiga toxin 2 gene with a precise excision of IS1203v. In the wild-type situation, the transposition products of IS1203v could be observed by PCR amplification. These results show that IS1203v can transpose in a nonreplicative manner and that the Shiga toxin gene inactivated by this insertion sequence can revert to the wild type.
Bacterial Toxins↗
Adenoviral GM-CSF Gene Transduction into Breast Cancer Cells Induced Long-Lasting Antitumor Immunity in Mice.
BACKGROUND: Immunogene therapy is regarded as a novel treatment that overcomes the limitation of preexisting adjuvant therapies and demonstrates the potential for the total elimination of cancer cells by affecting concealed tumor cells. The aim of this study was to examine the enhancement of antitumor immunity of irradiated granulocyte-macrophage colony-stimulating factor (GM-CSF) gene-transduced mouse breast cancer cells. METHODS: To study prophylactic vaccine effects, Balb/c mice were vaccinated subcutaneously with saline or irradiated mouse breast cancer cells (BalbMC, 1 x10&sup6; /mouse) infected with or without recombinant adenovirus harboring the GM-CSF gene (Adv/GM-CSF) on day-7. Mice were challenged with parental cells (1x10&sup5;/mouse) on day 0 in the flank opposite the vaccination site. RESULTS: BalbMC cells secreted GM-CSF after infection with Adv/GM-CSF. Vaccination with irradiated GM-CSF-secreting BalbMC completely protected syngeneic mouse challenged with live parental cells. On the other hand, vaccination with irradiated BalbMC protected 60% of mice from tumor development after challenge with parental cells. None of the tumor-free mice initially vaccinated with irradiated GM-CSF-producing BalbMC cells developed tumor upon repeated challenge with parental cells during the entire observation period. CONCLUSION: Our study demonstrated the feasibility of this immunotherapeutic approach as a novel adjuvant therapy after surgery for breast cancer.
Journal Article↗